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Medial frontal cortex, intentional aspects of language and schizophrenia

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Medial frontal cortex, intentional aspects of language and schizophrenia an fMRI study
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Maron, Leeza
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xiii, 124 leaves : illustrations (some col.) ; 29 cm.

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Schizophrenia ( mesh )
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Cognition -- physiology ( mesh )
Language ( mesh )
Clinical and Health Psychology thesis Ph. D ( mesh )
Dissertations, Academic -- College of Public Health and Health Professions -- Department of Clinical and Health Psychology -- UF ( mesh )
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Thesis (Ph. D.)--University of Florida, 2003.
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Includes bibliographical references (leaves 105-120).
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Typescript.
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Vita.
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Local note: Adviser: Bruce Crosson.
Statement of Responsibility:
by Leeza Maron.

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Full Text
MEDIAL FRONTAL CORTEX, INTENTIONAL ASPECTS OF LANGUAGE AND
SCHIZOPHRENIA: AN fMRI STUDY
By
LEEZA MARON
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2003


Copyright 2003
by
Leeza Marn


To the memory of my father.
In honor of my mother.


ACKNOWLEDGMENTS
This project was the collaborative effort of many individuals. My dissertation
advisor, Bruce Crosson, provided me invaluable exposure to the field of functional
neuroimaging throughout my graduate school career and allowed me the opportunity to
apply this technique to a fascinating, yet poorly understood psychiatric condition. From
him I learned the value of precision and tenacity as it applies to success in research and in
academia in general.
This study could not have been completed without the contribution of Christiana
Leonard, co-chair of my doctoral committee, and John Kuldau, the principal investigator
of the VA Merit Review grant that funded this study. Their laboratory is characterized by
an atmosphere of intellectual curiosity and enthusiasm, in which impromptu discussions
of topics such as the relationship of psychosis to neuroanatomy are common. It is from
these experiences that I developed an interest in the field of schizophrenia, which
continues to guide my future career goals. I am grateful to have worked with them and
appreciate their encouragement and warmth.
I am also fortunate to have learned from Rus Bauer, as a committee member,
clinical supervisor and instructor. The current project benefited considerably from his
extensive knowledge of neuropsychology and research design. Thanks should also be
extended to Bill Perlstein and Richard Briggs for providing critical guidance in the areas
IV


of statistical analysis and technical aspects of functional neuroimaging, respectively.
Their accessibility and willingness to teach did not go unnoticed.
Many individuals provided valuable behind the scenes assistance during this
process, often extending themselves beyond what was simply required. My friend and
colleague, Kaundinya Gopinath (Gopi), devoted many late nights and weekends to
processing raw data, teaching me the technical aspects of functional MRI and discussing
strategies for data analysis. I have come to admire his creativity and innovative approach
to both research and life in general. Thanks should also be extended to Tim Conway for
his assistance in the final stages of data analysis. His camaraderie made the journey much
more bearable.
The multifaceted task of running subjects, presenting and recording data in the
fMRI environment required input from a number of individuals with expertise in various
fields. My gratitude is extended to Yijun Liu and Guojun He (Alex) for sharing their
discoveries on the 3 Tesla magnet in addition to providing scanning assistance. Both
Debbie Moncrieff and Keith White were instrumental in creating an improved system for
the presentation and recording of auditory stimuli, while Andy James, a neuroscience
graduate student, was critically involved in the hands on duties of preparing subjects for
scanning. My thanks also go to Bob Frank and Edward Block for without their
generosity, data collection could not have been completed.
Although data collection was conducted at the University of Florida, my
colleagues at the University of California at San Diego, where the analyses were
completed, are well-deserving of thanks. My current mentor, William Perry, offered
consistent encouragement, reassurance and guidance despite what, at times, felt like a
v


slow and laborious process. Greg Brown, Terry Jernigan and their respective laboratories
generously provided me with didactic opportunities as well as the necessary resources to
complete this project.
Without participants, however, this study could not have taken place. I am
appreciative to those who invested their time and effort as subjects, particularly those
with schizophrenia who were motivated to participate in research in the hope that science
might make the lives of others with this debilitating disease less painful.
The most profound influence throughout my life, however, has been my family.
My father, a university professor, had a passion for learning and gift for teaching.
Although he is not able to share in this milestone with me, he continues to be my source
of inspiration. I am grateful too for my mother who has taught me the importance of
finding balance between work and life. Her dignity and self-reliance even in the most
difficult of circumstances encourage me to continue striving for my goals. It is in their
honor that I dedicate this manuscript.
vi


TABLE OF CONTENTS
page
ACKNOWLEDGMENTS iv
LIST OF TABLES ix
LIST OF FIGURES x
ABSTRACT xii
CHAPTER
1 INTRODUCTION 1
2 DEFINITION AND CLASSIFICATION OF SYMPTOMS OF SCHIZOHPRENIA., .5
3 NEUROPSYCHOLOGICAL FINDINGS IN SCHIZOPHRENIA 9
Methodological Considerations 9
Neuropsychological Deficits in Schizohprenia 13
Correspondence of Schizophrenic Symptoms and Cognitive Performance 17
4 FRITH'S MODEL OF SCHIZOHPRENIA 20
5 FRONTAL LOBES 26
Anatomy and Connectivity 27
Behavior Changes After Medial Frontal Lesions 37
Relationship of Medial to Lateral Frontal Cortex 40
6 STRUCTURAL BRAIN ABNORMALITIES IN SCHIZOPHRENIA 45
7 FUNCTIONAL IMAGING IN SCHIZOPHENIA 49
Methodological Issues 50
The Effect of Medication on Functional Imaging Data 52
Functional Imaging of Cognitive Activation Paradigms 55
Functional Imaging of Verbal Fluency 60
vii


page
8 RATIONALE OF STUDY AND HYPOTHESES 63
9 METHODS 67
Participants 67
Procedure 69
Experimental Tasks 70
Stimulus Delivery and Recording 72
Image Acquisition 73
Image Analysis 74
10 RESULTS 76
Behavioral Results 76
FMRI Results 77
11 DISCUSSION 88
LIST OF REFERENCES 105
APPENDIX
A DSM-IV DIAGNOSIS OF SCHIZOPHRENIA 121
B NATIONAL ADULT READING TEST 123
BIOGRAPHICAL SKETCH 124
viii


LIST OF TABLES
Table page
1. Clinical and Demographic Variables (means and standard deviations) 68
2. Categories and Semantic Descriptors for List 1 72
3. Behavioral Data (means and standard deviations) 76
4. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Schizophrenia and Control Groups on the Free Word
Generation Task 77
5. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Schizophrenia and Control Groups on the Semantic Word
Generation Task 82
6. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Semantic and Free Word Generation in the Schizophrenia
Group 85
7. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(pc.OOl) between Semantic and Free word Generation in the Control Group....86
A-1. DSM-IV Descriptions of Symptoms of Schizophrenia 121
A-2. DSM-IV Features Associated with Schizophrenia but not Central to its
Definition 122
A-3. DSM-IV Subtypes of Schizophrenia 122
B-l. National Adult Reading Test 123
IX


LIST OF FIGURES
Figure page
1. Crosson and colleagues (1999) sketch of the medial frontal cortex demonstrating
the relationship between the cingulate sulcus (CS), the paracingulate sulcus
(PCS), the ventral to dorsal subdivisions of BA 24 (a, b & c) and supracallosal
BA 32 33
2. Sample portion of event related design used in the current experiment 71
3. Sagittal and axial views of medial frontal cortex (BA 8; xyz = -3, 31, 60)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p < .001 78
4. Fractional signal change over time in selected voxels in the medial frontal cortex
region demonstrating between group activity differences for one representative
schizophrenia patient (dotted line) and one representative control subject (straight
line) 79
5. Sagittal and axial views of right lateral prefrontal cortex (BA 10; xyz = 50, 40, 1)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p < .001 80
6. Sagittal and axial views of right lateral prefrontal cortex (BA 46 and 46/9)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p,<.001 80
7. Sagittal view of cortex demonstrating significantly less activation in schizophrenia
patients relative to controls in several right hemisphere regions (BA 47, 19/39 and
46) during semantic word generation, p <.001 82
8. Sagittal, axial and coronal views of prefrontal cortex (BA 45; xyz = 55, 40, 5) in the
right hemisphere demonstrating significantly less activation in schizophrenia
patients relative to controls during semantic word generation, p < .001 83
9. Sagittal and axial views of prefrontal cortex (BA 8; xyz = 29, 34, 53 ) in the right
hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001 83


Figure -page
10. Axial and sagittal views (left and right) of the midbrain and parahippocampal gyri
demonstrating significantly less activation in schizophrenia patients relative to
controls during semantic word generation, g < .001 84
11. Sagittal, axial and coronal views of parietal cortex (BA 7; xyz = 24, -67, 45)
demonstrating significantly more activation during free relative to semantic word
generation in schizophrenia patients g < .001 86
12. Axial, and coronal views of right lateral prefrontal cortex
(BA 8/9; xyz = 19, 44, 26) demonstrating significantly more activation during
semantic relative to free word generation in control subjects, g < .001 87
13. Sagittal, axial and coronal views of right lateral temporal cortex
(BA 21/22; xyz = 65, -39, 8) demonstrating significantly more activation during
free relative to semantic word generation in control subjects, g < .001 87
XI


Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
MEDIAL FRONTAL CORTEX, INTENTIONAL ASPECTS OF LANGUAGE AND
SCHIZOPHRENIA: AN fMRI STUDY
By
Leeza Marn
May 2003
Chair: Bruce Crosson
Cochair: Christiana Leonard
Major Department: Clinical and Health Psychology
Schizophrenia is a disabling mental illness that has been linked to dysfunction in
neural circuitry that includes the frontal lobes. One model of schizophrenia describes a
willed route to action, reliant upon motivation and self-initiation and a stimulus driven
route to action, dependent upon environment cues and contingencies. In schizophrenia,
the former is thought to be impaired, while the latter is considered intact. In relating this
to brain structure, functional imaging and lesion studies in humans as well as
physiological investigations in non-human primates have implicated the medial frontal
cortex in intentional aspects of cognition. The aim of the present study was to map the
hypothesis that schizophrenia patients have a deficit in the internal generation and
monitoring of cognition on to neuroanatomical regions using whole brain functional MRI
(fMRI). Two semantic word generation tasks that varied on the degree to which internal
guidance was required were administered to a sample of 10 clinically stable, medicated
male schizophrenia patients and 10 healthy control subjects matched on age, sex, parental
xii


SES and premorbid intellectual functioning. Monitoring of behavioral task performance
revealed that despite pre-scanning training, schizophrenia patients produced an elevated
number of incorrect responses during the word generation tasks. Analysis of the fMRI
results demonstrated attenuated activity in the schizophrenia group relative to healthy
controls in a number of brain regions including the left medial frontal cortex (BA 8), right
dorsolateral prefrontal cortex (BA 46/9) and parahippocampal gyri bilaterally. The
finding of attenuated medial frontal activity during the most internally guided task
suggests that schizophrenia patients are unable to recruit critical medial frontal structures
to the same extent as controls, reflecting a deficit in intentional aspects of cognition. The
findings also suggest that attentional dysfunction, which increases in severity with greater
semantic processing demands, characterized patients performance during word
generation.
xiii


CHAPTER 1
INTRODUCTION
The notion that schizophrenia involves dysfunction of the frontal lobes dates back
at least to Emile Kraepelin (1971). In his view, the primary behavioral deficit in
schizophrenia was due to volitional difficulties secondary to anatomic pathology of the
frontal cortex. His emphasis on symptoms suggestive of frontal lobe dysfunction has been
echoed throughout this century in the phenomenological and later neuroimaging studies of
the illness. In 1992, Frith published the Cognitive Neuropsychology of Schizophrenia, in
which he integrated neuropsychological investigations of schizophrenia with
neuroanatomical and cognitive models of brain processes, the goal of which was to
describe the information processing abnormalities that underlie the signs and symptoms of
the disease. He described a willed route to action, reliant upon motivation and self-
initiation and a stimulus driven route to action, dependent upon environmental cues, and
hypothesized that in schizophrenia the former is impaired, while the latter is intact. He
posited that both the negative and positive symptoms of schizophrenia are due to deficits
in the internal generation and monitoring of cognition.
For some time, cognitive neuroscientists have known that the medial frontal cortex
plays a role in the internal generation of cognition. Medial frontal lesions cause akinetic
mutism (Nielsen & Jacobs, 1951), a wakeful state of profound apathy in which motor and
cognitive initiative is absent, similar to the negative symptoms of
1


2
schizophrenia. Unilateral medial frontal lesions also cause alien hand syndrome (Frith,
1992) in which actions are released from occurring without a sense of effort or
intendedness, similar to the positive symptoms of schizophrenia. Further, numerous
nonhuman primate investigations have found that the medial frontal cortex supports
intentional aspects of movement (for review see Picard & Stride, 1996).
In terms of the relationship of medial to lateral frontal cortex, Goldberg (1985)
suggested that involvement of medial frontal cortex depends upon whether cognition is
triggered by internal or external contingencies. He maintained that actions driven by
internal models or motivation involve the Supplementary Motor Area (SMA), while
actions driven by external models or contingencies involve lateral premotor cortex.
Passingham (1993) deviated slightly from Goldbergs (1985) hypothesis by concluding
that neither internally nor externally cued movement is the exclusive domain of SMA and
lateral premotor cortex; rather it is the balance between the two that is critical. More
recently, Crosson and colleagues (2001a) published a functional neuroimaging (fMRI)
study with neurologically norma! subjects using word generation tasks that varied in the
degree to which internal guidance was required. The findings demonstrated that as
language output changes from externally to internally guided, greater reliance is placed
upon anterior aspects of the medial frontal cortex (pre-SMA; Brodmanns Area 32)
relative to left lateral frontal regions. Thus, that ratio of medial to lateral frontal activity
appears to be tied to internal guidance, particularly in pre-SMA. Another way of
interpreting these findings; however, is that the medial frontal cortex plays a critical role in
the monitoring of competition between processes that conflict during task performance
(Carter et al., 1998).


3
fMRI has been used to examine brain functioning in both healthy and patient
populations using hemodynamic activity or blood oxygenation level differences as an
indication of neuronal activity. It is a mapping technique ideally suited for the study of
schizophrenia as it provides excellent spatial and temporal resolution, the ability to
monitor behavioral task performance and the associated brain activation and to clarify the
relationship between individuals and diagnostic groups. While some efforts have been
undertaken to map Friths (1992) hypotheses onto brain structure using fMRI in
schizophrenia, none have sought to locate both the stimulus driven and willed routes to
action using tasks that reliably activate these systems in healthy subjects.
In the next chapter the definition and classification of the symptoms of
schizophrenia will be reviewed followed by the neuropsychological findings that
characterize the disorder. While the emphasis will be on measures that assess integrity of
the frontal lobes, such as verbal fluency, more general methodological issues in
neuropsychological studies will be discussed. Friths (1992) theory will be outlined in
greater detail in Chapter 4. Chapter 5 is concerned with the frontal lobes, including
anatomy, connectivity and function, in preparation for a review of the structural brain
abnormalities in schizophrenia in Chapter 6. As functional neuroimaging provides a
unique tool for studying the neural basis of schizophrenia, relevant findings are discussed
in Chapter 7, particularly those that shed light on the functioning of medial and lateral
prefrontal cortex. The challenges that counterbalance the potential of fMRI are included
in that chapter, with an emphasis on the potential implications of mediation on functional
imaging data. Rationale of the current study and hypotheses is presented in Chapter 8.


4
Finally, methods, results and discussion for this study are found in Chapters 9, 10 and 11
respectively.


CHAPTER 2
DEFINITION/CLASSIFICATION OF SYMPTOMS OF SCHIZOHPRENIA
Schizophrenia is a disabling mental illness that involves marked deficits in intellect
and personality, resulting in impairment in social, occupational, and emotional functioning
(Wing, 1978). Its characteristics include disordered cognition and perception, and
various deficits in relating to the environment. Emile Kraepelin (1971) was the first to
unify what had formerly been distinct categories of mental illness under the term
dementia praecox, chosen because of the irreversible intellectual deterioration and the
early age of onset that he observed. According to Kraepelin, dementia praecox involved
apathy and lack of drive, which he related to anatomic pathology of the frontal lobes.
When describing his patients, he searched for a cause of the organic disease that he
thought he had delineated (Gottesman, 1991). Thus, since its early description,
schizophrenia has been considered a disease of brain function that involves not only the
classic symptoms upon which the diagnosis is based but a wide range of cognitive deficits
as well.
In 1908, Eugen Bleuler coined the term schizophrenia, which means splitting of the
mind. By renaming the disease to focus on the splitting of the usually integrated psychic
functions, such as affect and cognition, Bleuler tried to call attention to two phenomena
that Kraepelin had downplayed, namely frequent recovery and affective disturbance
(Gottesman, 1991). He also argued that Kraepelins descriptions were based
5


6
on secondary symptoms rather than the primary symptom of disordered thought
processes. He argued that the primary symptoms of schizophrenia were loosening of
associations, autism (self-centeredness), affective disturbance, and ambivalence.
Delusions, hallucinations and catatonia were therefore thought to be secondary (Wing,
1978).
At present, the DSM-IV classification scheme is amongst the most widely used for
diagnosing schizophrenia in the United States (American Psychiatric Association, 1994).
Descriptions of the DSM-IV characteristic symptoms are provided in Appendix A, Table
A-l. The DSM-IV symptoms that are associated with schizophrenia but not central to its
definition are listed in Appendix A, Table A-2.
The diagnostic criteria of the DSM-IV are based upon symptom presentation and
have little or no relationship to pathophysiology or etiology of the disorder. The five
subtypes, catatonic, disorganized, paranoid, undifferentiated and residual, are described in
more detail in Appendix A, Table A-3. While these subtypes have been differentiated in
terms of age of onset and prognosis (Fenton & McGlashan, 1991), no linkage has been
found with neurological or neuropsychological variables. The lack of significant
relationship between these subtypes and more biological variables is due to a number of
different factors. First, many patients who meet diagnostic criteria for schizophrenia do
not fall within any particular subgroup. Patients may also change from one subtype to
another during the course of their illness (Fenton & McGlashan, 1991).
Symptom overlap between DSM-IV subtypes and the high degree of heterogeneity
of schizophrenic symptoms has provided the impetus for a more feature-oriented approach
to studying neuropathology in schizophrenia (Frith, 1992). Classifying individuals on the


7
basis of symptom clusters has the advantage of grouping schizophrenic patients on
symptoms that have been found to be statistically related to one another. It has therefore
become customary to classify the typical features of schizophrenia into positive and
negative dimensions with reference to behavioral excesses and deficits (Crow, 1980).
Positive features are pathological by their presence and include hallucinations, delusions
and incoherence of speech. Negative features represent the loss of normal functioning and
include affective flattening, poverty of speech, motor retardation, apathy and lack of
sociability. There is some evidence that the clinical correlates of positive and negative
symptoms are not the same and that the two subgroups of symptoms vary independently
within individuals (Johnstone & Frith, 1996). Since they are not mutually exclusive, a high
level of symptoms in one cluster does not predict low levels in the other.
Some evidence from neuroanatomical and neuropsychological studies supports this
classification system. For example, negative symptoms have been associated with
structural brain changes such as enlarged ventricles, poor response to traditional
neuroleptic medication, chronicity and cognitive dysfunction, whereas positive symptoms
have not (Allen et al., 1993; Andreasen & Olsen, 1982). Functional imaging studies;
however have produced mixed results with some finding associations between symptoms
and brain activation (Artiges et al., 2000; Sabri et al., 1997;) while others have not (Frith
et al., 1995).
Since Crow (1980) identified the positive-negative dimension, other symptom
clusters have been found. More recently, Liddle (1987) suggested that disorganization
(inappropriate affect, thought disorder, difficulty in abstract thinking) may exist as a third
factor in addition to negative and positive dimensions. The problem with many of these


8
factor analytic studies; however is that the results are entirely determined by the measures
used to assess behavioral abnormalities (Frith, 1992). For example, Frith (1992) noted
that the Krawiecka scales, which are commonly used to assess the symptomatology of
schizophrenia, include hallucinations and delusions as the only experiential symptoms.
These scales, then, will not reveal different clusters of symptoms within the experiential
domain.
Based upon this brief review, it appears as though slow but consistent progress
has been made in understanding the relationship among the classical symptomatology of
schizophrenia, neurocognitive deficits and brain structure. Many of the behavioral
abnormalities that define the disorder have been eloquently discussed in the past; however,
more recent classification schemes have provided increasing evidence that schizophrenia is
a brain-based disorder. It is essential at this point to examine overall intellectual and
neuropsychological functioning in schizophrenia and its linkage to functional and
structural brain anomalies.


9
CHAPTER 3
NEUROPSYCHOLOGICAL FINDINGS IN SCHIZOHPRENIA
There is broad agreement that schizophrenia produces impairment in
neuropsychological functioning. However, no single test or neurocognitive construct
completely separates schizophrenia and control distributions (Heinrichs & Zakzanis,
1998). The picture is further complicated by a number of methodological issues including
medication effects, education, heterogeneity of symptoms, and the varied psychometric
properties of neuropsychological tests.
Methodological Considerations
The vast majority of schizophrenic patients are treated fairly vigorously with
medication; therefore consideration must be given to the potential effects of antipsychotic
as well as other types of medication on cognitive abilities (Frith, 1992). Anticholinergic
medication, which is often given to treat the extrapyramidal effects of traditional
neuroleptics, has been found to impair performance on neuropsychological tests of
memory (Bartus et al., 1982). Potent dopaminergic antagonists, such as the conventional
antipsychotics, have been hypothesized to affect frontal lobe metabolism as well as
cognitive functioning (Early et al., 1987). For example, evidence from non-human
primates and rats reveals impaired performance on tests of spatial working memory after
administration of haloperidol (Sawaguchi & Goldman-Rakic, 1994). Although it is likely
that typical neuroleptic medication negatively affects cognitive functioning, it is difficult to
maintain that all cognitive deficits in schizophrenia are due to medication effects.
Kraepelin (1971), for example, noted severe cognitive abnormalities amongst his patients,
prior to the invention of traditional neuroleptic medication. Further, some empirical


10
studies have failed to find a relationship between neuroleptics and cognitive function,
while a few have even reported improved cognitive function with antipsychotic medication
(see Rupniak & Iversen, 1993).
There is some evidence that atypical antipsychotics, which are thought to have
different neurochemical properties than the typical neuroleptics (e g., Olanzapine,
Risperidone, Quetiapine, and Ziprasidone) may improve cognitive functioning in
schizophrenia (Keefe et al., 1999). In a meta-analytic study, Keefe and colleagues (1999)
found that atypical antipsychotics, when compared with conventional antipsychotics,
resulted in improved performance on tests of verbal fluency, digit-symbol substitution, fine
motor and general executive functioning. It appears as though measures with a timed
component may be particularly responsive to novel antipsychotics as well as those
involving motor skills. Keefe et al. (1999) hypothesized that the advantage of atypical
antipsychotic medication could partially be a result of the decreased extrapyramidal side
effects of standard antipsychotics. Some researchers have speculated that the cognitive
improvement seen with atypical antipsychotic medication may be the result of effects at
the serotonin receptors. Others have argued that atypical antipsychotics do not actually
improve cognitive functioning but are simply less detrimental to the patients cognition
than typical antipsychotic medication.
The side effects of antipsychotic medication, therefore, complicate the
interpretation of poor performance on neuropsychological tests in that it is often difficult
to decipher whether cognitive deficits are due to medication side effects or are due to the
pathological process that underlies the disorder. In light of this evidence, studying
neuroleptic-naive patients would be an ideal approach to investigate the primary


11
neurocognitive deficits in schizophrenia. However, constraints, including an inability or
refusal on the part of these patients to participate in research as well as the ethical
responsibility on the part of health care workers to offer treatment, make this difficult. A
more practical but slightly less satisfactory approach may be to examine
neuropsychological functioning in patients taking atypical antipsychotic medication.
Other confounds in the research include the failure to control for important
demographic variables. Education is a particularly important factor given that the onset of
schizophrenia is typically in the late teens or twenties, a time when individuals are
beginning post-secondary education. Because reduced educational achievement is one of
the related features of schizophrenia, matching patients and controls on educational
achievement may not be an appropriate comparison (Swanson, et al., 1998). It has been
suggested by some investigators that parental education is a more appropriate matching
variable (Gur et al., 1990).
Another complicating factor in the study of schizophrenia is the role of sex. It has
been found that female schizophrenics typically experience an older age of onset and more
prominent mood symptoms, accompanied by a less chronic disease course (Andreasen et
al., 1990). Males have been found to have more extensive brain abnormalities than their
female counterparts (Andreasen et al., 1990). This evidence suggests that subtle
differences between male and female schizophrenic patients in terms of presentation,
chronicity, and brain structure may significantly affect the results of studies in which both
sexes are grouped together.
The extreme heterogeneity of schizophrenia as previously discussed has significant
implications for studies of neuropsychological functioning. Variance that exists both


12
within and between patient groups may wash out potential differences. Therefore,
examining the neuropsychological deficits associated with specific symptom subtypes or
investigating patterns of strengths and weaknesses in individual subjects may prove
fruitful.
Conflicting findings in the literature may also be due to limitations involving
assessment tools. First, the fact that a number of neuropsychological batteries have been
used in the study of schizophrenia makes comparisons across studies difficult. While some
investigators use a narrow range of neuropsychological tests to assess specific functions,
others use a broadband approach consisting of more extensive batteries to examine
patterns of neuropsychological strengths and weaknesses. This is a significant problem,
because in order to claim that a function is selectively impaired, it must be compared to
overall intellectual functioning. This points to the need for a generally accepted core
procedure for obtaining neuropsychological data that can adequately assess and
characterize patterns of behavioral impairment and preserved abilities in schizophrenia
(Gur et al., 1990). When developing a battery, the lowered threshold of schizophrenic
patients to withstand long testing sessions must be balanced with the desire to obtain
extensive data.
The psychometric properties of various neuropsychological tests may serve as yet
another limitation. Each measure that makes up a test battery is likely to have been
normed on different populations. This increased variability may mask potential subtle
patterns of strengths and deficits amongst schizophrenic patients. It is also likely that when
schizophrenic patients with good premorbid intellectual functioning experience a decline in


13
their neurocognitive functioning, it is not noted because it does not constitute an
impairment as defined by standard cutoffs (Heinrichs & Zakzanis, 1998).
Another concern is that neuropsychological tests that purport to investigate frontal
lobe functioning are relatively poor at pinpointing dysfunction to specific subdivisions of
the prefrontal cortex. The term frontal lobe tests has typically been used to refer to
those measures which are compromised in patients with tumors, vascular insults, traumatic
brain injuries and other diseases that affect the frontal cortex. While these insults affect
the integrity of the frontal lobe, the lesions are rarely circumscribed. Further, areas within
this region are highly interconnected and damage to one region may produce deficits
similar to damage to neighboring sites (Goldman-Rakic, 1987).
The aforementioned issues should be kept in mind when interpreting the results of
neuropsychological studies in schizophrenia. Subject variables such as the influence of
medication on cognition, demographic factors and heterogeneity of symptoms as well as a
number of psychometric issues regarding assessment tools are crucial in understanding the
conflicting findings in this area.
Neuropsychological Deficits in Schizophrenia
It is generally accepted that schizophrenic patients perform more poorly than
normals on a wide range of cognitive tests (Gold & Harvey, 1993). Saykin et al. (1991)
found that a group of unmedicated schizophrenic patients performed at least one standard
deviation below the mean of a normal control group matched for age, parental education,
handedness and race on all measures of a substantial test battery including the Wechsler
Adult Intelligence Scale- Revised. This finding has been corroborated by Kolb and
Wishaw (1983), who found that the mean difference in Full Scale IQ between a group of


14
medicated schizophrenic patients and a normal control group matched on age and
education was approximately 15 points. Upon closer investigation, it was determined that
the significant 19-point difference between Performance IQ scores largely influenced the
difference between groups whereas there was not a significant discrepancy in Verbal IQ.
Intradomain analysis failed to reveal significant differences between subtests within the
verbal domain; however, all subtests within the performance domain were performed more
poorly by the schizophrenic group. The difference in means was largest for the Digit
Symbol subtest and smallest for the Picture Completion subtest.
Considerable evidence exists for intellectual impairment in schizophrenia.
Differential deficits against this background of general cognitive dysfunction; however,
have been found on tests sensitive to frontal lobe damage by a number of investigators
using moderate to extensive test batteries (e.g., Kolb & Wishaw, 1983; Gruzelier et al.,
1988; Mckay et al., 1996). For example, there is substantial evidence that schizophrenics
fall within the impaired range on the Wisconsin Card Sorting Test (WCST; Kolb &
Wishaw, 1983, Sweeney et al., 1992). Their performance is characterized by completion
of fewer categories than normals, as well as increased perseverative errors and responses.
While patients performance may be normalized with explicit card-by-card instructions,
Goldberg et al. (1987) found that when instructions were removed, performance
immediately dropped to deficient levels. These impairments have been described as
deficits in working memory, attention, strategy shifting, abstract concept formation and
problem solving (Saykin et al., 1991).
Schizophrenia patients typically demonstrate deficits on other tests thought to be
reliant upon integrity of the frontal lobes, including the Trail Making Test, Stroop


15
Interference Task, Design Fluency and Continuous Performance Test. For example, Kolb
and Wishaw (1983) found that schizophrenic patients tended to produce a high number of
perseverative responses during the Design Fluency Task, a characteristic that also marks
their performance on the WCST. On the Stroop Interference Task, schizophrenic patients
typically demonstrate difficulty inhibiting inappropriate responses. According to a study
conducted by Beech and colleagues (1991) using a modified Stroop task, schizophrenic
patients also demonstrate premature release from cognitive inhibition. In this study it was
found that when a previously ignored distractor was re-presented, there was an increased
reaction time for normal subjects but not schizophrenics. Another consistent finding is for
schizophrenia patients to perform more poorly than healthy control subjects on nearly all
forms of the Continuous Performance Test (e.g., Heinrichs & Zakzanis, 1998) reflecting
difficulty with sustained attention.
Schizophrenic patients also tend to perform within the impaired range on word
generation or verbal fluency tasks such as Controlled Oral Word Association (COWA)
and letter fluency (Robert et al., 1998; Kolb & Wishaw, 1983; Mckay et al., 1996, Allen et
al., 1993, Gruzelier et al., 1996). These tasks involve the generation of words either to
letter cues (phonemic or letter fluency) or to instances of a category (semantic fluency).
During the fluency task, subjects initiate self-directed searches of the lexicon, in order to
retrieve and produce the appropriate word. Performance is thus dependent upon multiple
cognitive processes including, but not limited to, sensory processing of the cue, retrieval
of words from memory, the selection of an appropriate word, integrity/organization of the
semantic store and articulation of the response. In a meta-analytic review, Heinrichs and
Zakzanis (1998) found that verbal fluency is one of several tests that tend to be the most


16
impaired in schizophrenia. Performance is characterized by the production of fewer words
overall, frequent perseverations and numerous intrusions relative to normal subjects (Allen
et al., 1993; Gruzelier et al., 1988; Kolb & Wishaw, 1983; Liddle & Morris, 1991; Robert
et al., 1998; Sweeney et al., 1992;). These deficits are evident at the early stage of the
illness (Paulsen et al., 1996), appear to remain stable over time (Goldberg et al., 1993) and
cannot be easily explained by a generalized intellectual deficit (Crawford et al., 1993).
The overall number of words generated in verbal fluency tasks; however, does not
adequately capture the processes of initiation, search, retrieval and articulation. Clustering
during verbal fluency allows individuals to search for meaningful semantic fields, allowing
clusters of related words to be made available for recall. The amount of semantic
clustering appears to be positively correlated with the number of words generated by both
schizophrenic patients and normal controls (Robert et al., 1997). Switching, another
component of verbal fluency, has been defined as the ability to shift effectively from one
subcategory to another (Robert et al., 1998). This ability to switch appears to be positively
associated with the number of words generated during phonemic fluency tasks. Robert et
al. (1998) tested 78 medicated and unmedicated schizophrenic patients and found that the
patients differed from the control group on both semantic and phonemic fluency tasks.
The schizophrenic patients demonstrated impaired switching in the phonemic fluency task.
They also demonstrated less clustering and switching in the semantic task, resulting in the
generation of fewer words. Further, patients with schizophrenia have also been found to
benefit from cueing on verbal fluency tasks (Joyce et al., 1996), suggesting that the
presentation of external semantic fields assists patients in initiating and organizing the
preliminary lexical search. Taken together, these findings have been explained in terms of


17
decreased capacity to initiate willed action (Frith, 1992) and reduced access to semantic
memory resulting from difficulties in an organized search process (Allen et al., 1993).
An alternative hypothesis suggests that the temporal lobe mediated semantic store
may be disorganized in schizophrenia. In this regard, some researchers have found
significantly impaired semantic relative to letter fluency amongst schizophrenic patients,
suggesting a selective deficit in semantic information processing (Guorovitch et al., 1996).
Further, atypical associations between words produced on verbal fluency tasks (Rossell et
al., 1999) and the finding that schizophrenia patients verbal fluency performance does not
benefit from cueing (Goldberg et al., 1993) suggest that the breakdown in fluency
performance in schizophrenia may extend beyond that of deficient executive control to
involve disorganization of the semantic store.
Correspondence of Schizophrenic Symptoms and Cognitive Performance
Although it is possible to detect group differences in neurocognitive functioning
between schizophrenic and normal individuals, it is also important to investigate the link
between symptomatology and neuropsychological test performance. The negative
symptoms of schizophrenia have been associated with poor performance on a range of
cognitive tests (Crow, 1980) as well as poor premorbid functioning, chronicity, poor
response to traditional antipsychotic medication and enlarged ventricles (Audreasen et al.,
1982). Positive symptoms, in contrast, have been associated with better prognosis, better
response to traditional neuroleptics and minimal cognitive dysfunction (Andreasen &
Olsen, 1982).
To investigate the relationship between symptomatology and neurocognitive
functioning, Allen et al. (1993) compared 20 stable medicated schizophrenic inpatients


18
with a group of 25 depressed individuals and 10 healthy controls on a semantic verbal
fluency test. The control and schizophrenic groups were matched on sex, age and
premorbid IQ as estimated by the National Adult Reading Test (NART). Results revealed
that schizophrenics with negative symptoms such as poverty of thought, poverty of
movement and flattening of affect produced fewer words than the depressed and control
groups; however they did not differ in terms of the type of words produced. Patients with
incoherence of speech, in contrast, produced more variable words and category
inappropriate responses. These findings support the notion that poor verbal fluency
performance is not associated with the non-specific features of psychiatric illness such as
depressed mood. The findings also suggest that performance on tests of verbal fluency
may be qualitatively different for schizophrenic patients with negative and positive
symptoms. Indeed, other investigators (Liddle & Morris, 1991; Stolar et al., 1994) have
found that patients with negative symptoms demonstrate impaired verbal fluency
performance that can not be attributed solely to slowness in initiating motor responses,
limited switching and reduced clustering (Robert et ah, 1998). Some studies have
associated positive psychotic symptoms with reduced semantic fluency (Rossell et ah,
1999) and atypical associations between words produced (Paulsen et ah, 1996); however
failure to replicate these findings is common (e.g., Howanitz et ah 2000).
Taken together, evidence suggests that schizophrenia patients perform poorly on a
wide range of neuropsychological tests, particularly those that rely heavily upon executive
functions. Verbal fluency is one of several tests that tend to be the most impaired in
schizophrenia. Qualitative analysis of patients linguistic errors demonstrates frequent
perseverations, numerous intrusions, reduced clustering and limited switching. There is


19
also some evidence to suggest that these linguistic errors may be related to
symptomatology.


CHAPTER 4
FRITHS MODEL OF SCHIZOPHRENIA
In The Cognitive Neuropsychology of Schizophrenia (1992), Frith details evidence
from neuropsychological investigations of schizophrenia and integrates it with
neuroanatomical and cognitive models of brain processes. Two routes to action are
described: one that relies on environmental stimuli and contingencies and another that
relies on spontaneous and self-initiated action. In Friths (1992) theory of schizophrenia,
the former is thought to be intact, while the latter is considered impaired. Both the
negative and positive of schizophrenia are posited as resulting from deficits in the internal
generation and monitoring of cognition. Negative symptoms are understood as behavioral
abnormalities that can be observed by others and occur specifically in situations in which
actions must be self-generated. This can manifest in several ways. First, if one is unable
to spontaneously generate a new response, no action may be taken (poverty of action).
Second, an individual faced with the same inability to generate a new response might
repeat a previous response, though inappropriate in the current context (perseverative,
stereotyped responding). Third, one might respond inappropriately to a stimulus in the
environment (stimulus driven behavior). On the basis of this model, it is expected that
patients would not only show a lack of action, but in certain circumstances may evidence
stereotyped behavior or an excess of stimulus driven behavior
20


21
. Friths first prediction that impairment in the willed route to action results in poverty
of action, is supported by the fact that schizophrenia patients show flattening of affect,
poverty of speech and social withdrawal. In this regard, neuropsychological investigations
have demonstrated that schizophrenic patients, like patients with frontal lobe lesions,
demonstrate reduced responding on COWA and design fluency (Kolb & Wishaw, 1983).
Further, a number of studies have associated poor performance on COWA with negative
symptoms (Allen et al., 1993; Liddle et al., 1995). Functional imaging studies
investigating this phenomenon have shown attenuated activation in the medial frontal
cortex during suboptimal verbal fluency performance (Dolan et al., 1986; Fletcher et al.,
1996). Given that schizophrenic patients perform relatively well on vocabulary tests, their
lexicon is thought to be intact; however it is likely that their ability to perform a self-
directed search is impaired (Frith, 1992).
The second prediction is that individuals with a damaged willed route to action
will demonstrate perseverative and stereotyped responses that are manifested not only on
neuropsychological tests but in interactions with others. The tendency for schizophrenia
patients to perseverate on a theme or idea is common. Perseveration can also be observed
during the design fluency task (Kolb & Wishaw, 1983) and during a two choice guessing
task described by Frith (1992). In this task, the subject is required to repeatedly guess
whether the next card in a deck will be red or black. Normal subjects produce a roughly
random sequence of guesses similar to those generated by a computer. Schizophrenic
patients; however, tend to perseverate, giving the same response repeatedly.
The third of Friths (1992) predictions, that difficulties with internal generation will
lead to stimulus driven behavior, relies upon the hypothesis that the stimulus driven route


22
to action remains intact. According to Frith (1992), incoherence and incongruity can be
explained in terms of action excessively determined by irrelevant stimuli. Difficulties on
the Stroop task support this idea and reveal that schizophrenic patients have difficulty
inhibiting dominant response tendencies (Carter et al., 1997). Further, Liddle and Morris
(1991) found that incongruity and incoherence are associated with poor performance on
the Stroop task.
In an attempt to relate the negative features of schizophrenia to brain
abnormalities, Frith (1992) discusses the similarities between patients with frontal lobe
lesions and schizophrenic patients. Both show negative features including decreased
activity, social withdrawal, decreased interpersonal communication, flatness of vocal
inflection and unchanging facial expression. Areas that have been implicated in negative
features include the orbitofrontal cortex, cingulate cortex and supplementary motor area.
Patients with damage to the medial frontal cortex have been found to show akinetic
mutism and lack of spontaneous movement (Barris & Schumann, 1953). In monkeys,
Passingham (1993) has shown that lesions of the anterior cingulate cortex and
supplementary motor area result in impairment of self-initiated action; however, action
that relies upon external cues is spared.
The negative features of schizophrenia, according to Frith (1992) are due to
deficits in the generation of willed actions, while the mechanism underlying the generation
of stimulus driven action remains intact. In this regard, Goldberg (1985) suggested that
there is a medial system consisting of SMA for internally guided actions and a lateral
system for externally guided action. This hypothesis will be discussed more extensively
later; however, evidence supports the idea that damage to the more anterior aspects of the


23
medial frontal cortex can result in behavioral abnormalities similar to those seen in
schizophrenic patients. Given the heterogeneity of schizophrenia; however, the
pathophysiological basis of the disorder, is not likely to be found in one brain region such
as the frontal lobe. Frith (1992) suggests the presence of dysfunction in cortico-striato-
pallido-thalamo-cortical loops first described by Alexander and colleagues (1986). It
should be noted that each of the 5 loops involve frontal regions as targets and are heavily
influenced by dopaminergic input to the striatum.
Frith (1992) also describes a model for the positive or experiential symptoms of
schizophrenia, which he divides into hallucinations and delusions. A defect in the central
monitoring system is hypothesized to underlie both of these phenomena. For example,
patients with hallucinations and delusions fail to monitor their own internally generated
thoughts. As a result, they misperceive their own cognition and identify it as being
initiated by external agents. Some of the best evidence for this hypothesis comes from
passivity experiences, in which patients explicitly attribute their own thoughts to outside
agents in the case of thought insertion and thought broadcasting.
Evidence supporting this hypothesis comes from a study in which schizophrenic
patients were asked to generate category items and then to read category exemplars
presented to them (Bentall et al., 1991). One week later, when asked to identify the source
of the items, schizophrenic patients performed more poorly than normal subjects on the
task. Hallucinating patients were slightly more likely to misattribute items they had
generated themselves to the experimenter. To tease apart the study of self-monitoring
from source memory, Harvey (1985) required schizophrenic patients to first distinguish
between two external sources and then to distinguish between words they had spoken


24
aloud and those they had merely imagined. Results revealed that thought disordered
patients had more difficulty discriminating what they had thought from what they had said
in comparison to other psychotic patients and normal controls. Unfortunately Harvey
(1985) did not examine the relationship between hallucinations and task performance.
Delusions of control refer to experiences in which an individual feels as though his
or her thoughts are being controlled by external forces, rather than by his or her own will.
The neurological phenomenon of alien hand syndrome is similar in a number of ways.
First the alien hand performs actions in situations where such acts do not normally occur.
Second, the patient is not aware of the intended or actual action of the hand unless he or
she receives visual information about what the hand is doing. Alien hand syndrome is
typically associated with unilateral lesions to the medial frontal cortex, most often in and
around the supplementary motor area. Frith (1992) hypothesizes that this region is part of
more extensive neural circuitry that normally monitors (permits or suppresses) stimulus
elicited actions in the hand. As a consequence, the hand is released to perform the actions
that are normally performed without its awareness. Therefore, while delusions of control
are a loss of effort or intendedness that is normally associated with willed actions, the alien
hand syndrome is the release of actions that are not normally accompanied with a feeling
of effort.
The neuroanatomic circuitry that Frith (1992) implicates as underlying the positive
symptoms of schizophrenia is quite similar to that underlying the negative signs. He
suggests that brain structures including the dorsolateral prefrontal cortex, supplementary
motor area and anterior cingulate cortex are involved in the generation and monitoring of
willed action. Medial frontal regions including anterior cingulate cortex are thought to be


25
the source of the corollary discharge that tells whether action is self-generated or elicited
from an external source.
Friths (1992) hypotheses suggest a relationship between positive symptoms and
negative signs in terms of the severity of underlying brain abnormality. Positive
symptoms, as stated previously, are thought to occur because the structures responsible
for willed or internally generated action, no longer send corollary discharges to the
posterior parts of the brain involved in perception. Corollary discharge, according to
Teuber and Mishkin (1954) is the transmission of a signal from anterior to posterior
regions of the brain that informs the perceptual or posterior region about what is occurring
in more anterior regions. For example, in order for preparation for the results of a
voluntary movement to occur, there must be a movement command through the motor
system and a signal (corollary discharge) from anterior or frontal regions to more
posterior areas to anticipate a motor act. This corollary discharge enables the
perceptual areas to recognize that the changing sensory data are due to the commanded
behavior rather than agents in the environment. Thus, self-generated changes in
perception may be misinterpreted as having an external cause when frontal regions are
damaged. Dysfunction in frontal regions may also result in a failure to send messages to
the brain structures associated with response generation. This results in a lack of willed
action and the negative signs of schizophrenia.


CHAPTER 5
THE FRONTAL LOBES
Prior to discussion of anatomy and connectivity of the frontal lobes, several
methodological issues must be addressed. The first is that the majority of our knowledge
of frontal anatomy comes from the study of nonhuman primates. While these studies have
been quite useful in understanding the structure and function of the frontal lobes, it is
likely that the morphological differences between human and primate frontal cortex are
greater than for other cortical areas. This suggests the presence of functional differences
as well. For example, supracallosal Brodmanns Area (BA) 32, a region that is distinct
from BA 24 in terms of its cytoarchitecture, connectivity and function in humans, does not
exist in the monkey. It is important to note; however, that perigenual BA 32 exists in both
humans and monkeys. Although Picard and Strick (1996) have suggested that that
supracallosal BA 32 in humans is analogous to the cingulate motor area in the monkey, its
function, for the most part, remains enigmatic. While certain anatomical similarities are
present between human and monkey frontal cortices, a comprehensive circuit by circuit
comparison has yet to be achieved (Kaufer & Lewis, 1999)
Within the boundaries of the frontal lobe, diverse functions ranging from fine
motor control to working memory to complex social behaviors to attention are subserved
by a number of anatomically distinct but interconnected regions. The frontal lobes have
commonly been referred to as the executor of higher cognitive functions including
26


27
abstraction, problem solving and sequencing. Complex language, a uniquely human
function, is inextricably linked to many of these complex abilities. Given that animals do
not posses the ability to use complex language, it should be recognized that the
generalizability of animal studies is somewhat limited with regard to higher level
processes.
Finally, identification and classification of frontal lobe regions, as with other areas
of the cerebral cortex, are based upon morphological features such as sulcal landmarks
and microscopic analyses of constituent neurons. A number of different cytoarchitectonic
maps of the cerebral cortex have been created based upon laminar distribution and
neuronal density. While a modest amount of agreement exists between different maps,
investigators have varied considerably in defining the boundaries and number of regions in
the frontal lobe. This variation is due to methodological differences, individual subject
variation, and the absence of uniform morphological criteria (Kaufer & Lewis, 1999).
Brodmanns (1909) cytoarchitectural map of the cerebral cortex, which delineates
numerous cortical regions, has become the standard for human brain research and will be
emphasized in the following section (Vogt et al., 1995). It is however, important to
recognize that in the anterior cingulate cortex, for example, Brodmanns map does not
have the same level of detail as do other human and non-human primate classification
systems (see Vogt et al., 1995).
Frontal Anatomy and Connectivity
The frontal lobes comprise the anterior half of the cerebral hemispheres. On the
lateral surface they are demarcated by the central sulcus caudally and by the Sylvian
Fissure inferiorly. Within these borders, three functional regions on the lateral surface


28
have been described; motor, premotor and prefrontal regions. Most caudally, the
precentral gyrus (BA 4) or motor strip is a narrow band of tissue located immediately
anterior to the central sulcus, forming its anterior bank and depth and extending medially
to the depths of the cingulate sulcus. Histologically, it is a homogeneous region of
agranular cortex, characterized by a high density of Betz cells (Damasio & Anderson,
1993). More rostrally, premotor cortex (BA 6) parallels the lateral and medial extent of
the precentral gyrus and is often described as transitional cortex, the function of which is
closely related to motor activity. I will distinguish the lateral premotor cortex from the
medial premotor cortex, often referred to as supplementary motor area (SMA). Anterior
and ventral to lateral BA 6 is the inferior frontal gyrus, the most posterior portion of
which is called BA 44 or pars opercularis (Damasio & Anderson, 1993). BA 44 and an
adjacent region, BA 45 (pars triangularis), comprise Brocas area in the left hemisphere
and are known for their similar anatomic and functional connectivity. According to
Damasio and Anderson (1993) BA 44 and 45, and BA 47 (pars orbitalis), comprise the
frontal operculum. Areas 46 and 9 lie dorsal to BA 44/45, while the frontal eye fields, BA
8, lie dorsal to BA46/9 and are involved in oculomotor control.
There is some debate as to whether BA 8, 44, 45, 47 on the lateral surface should
be classified as part of the prefrontal or premotor cortex. Passingham (1993) defines
prefrontal cortex as the region anterior to BA 8, 44, 45 and 47, which can be divided into
two sectors, dorsal (BA 46 and lateral and medial BA 9) and ventral (BA 11,12, 13, and
14). Others have considered some of these regions, in particular BA 8, to be part of the
prefrontal cortex (Damasio & Anderson, 1993). Many of these schemes have been
created based upon the connectivity of these frontal regions with the thalamus. Prefrontal


29
cortex has commonly been defined as the region that is interconnected with the
dorsomedial nucleus of the thalamus; however evidence suggests that there are also
reciprocal connections between this region and other thalamic nuclei (Leonard, 1969).
The term prefrontal cortex, therefore, lacks specificity in that the constituent regions will
vary depending upon the view of the investigator. This inconsistency has been
demonstrated in our discussion of the lateral frontal regions and is even more marked
when for the premotor and prefrontal divisions of the medial wall. For the remainder of
this paper, the term prefrontal cortex will be used infrequently and regions will be referred
to primarilly by their Brodmanns number, connectivity and function.
On the lateral surface of the frontal lobes, in the most anterior position, lies the
dorsolateral and ventral/orbital regions. The dorsolateral region (BA 46 and 9) is thought
is be involved in spatial working memory and behavioral inhibition as well as a number of
other higher level cognitive processes (Goldman-Rakic, 1987). The more ventral region,
commonly referred to as orbitofrontal cortex (BA 11,12, 13, 14) is largely interconnected
with the limbic system. Although these areas show a fair degree of overlap, they have
different cortical and subcortical connections and are believed to be differentially involved
in behavior and cognition (Goldman-Rakic, 1987). There is a considerable amount of
research investigating the connectivity and function of these regions, as well as their role
in pathological conditions; however, a more detailed description of lateral and
orbitofrontal cortex is beyond the scope of this paper. This cursory overview was
provided in order to address the functional relationship between lateral and medial frontal
cortex.


30
Our understanding of the structure and function of the medial wall of the frontal
lobe has undergone dramatic changes in recent years (see Picard & Stride, 1996). Based
on anatomical work and physiological evidence, Matsuzaka et al. (1992j surmised that
medial BA 6 in the macaque can be divided into a posterior region located caudal to the
level of the genu of the arcuate sulcus and a more anterior region located rostral to the
genu, labeled SMA and pre-SMA respectively. Evidence supporting this division has come
from single cell recordings in which pre-SMA was found to contain a higher proportion of
neurons with cue responses, preparatory activity and time locked activity to a movement
trigger signal, than SMA proper. In other words, activity changes time locked to
movement onset were more frequently seen in SMA while activity changes during a
preparatory period preceding the movement were more common in pre-SMA (Matsuzaka
et al., 1992). Other physiological evidence reveals that intracortical stimulation in the
monkey has failed, for the most part, to evoke movement from pre-SMA (Luppino et al.,
1991). When movement was evoked, it tended to be slow or tonic consisting of multijoint
responses. In contrast, stimulation of SMA produced brisk isolated movements of the
head, forelimbs and hindlimbs in a somatotopic order.
These findings corresponded with histological data that revealed only the rostral
part of BA 6, corresponding to pre-SMA, receives afferent projections from the prefrontal
cortex and non-primary motor cortices (Luppino, et al., 1991). The connectivity of SMA
in contrast, was limited for the most part, to primary motor cortex. These differences
indicate that SMA has more direct access to the motor system than pre-SMA. Pre-SMA
appears to play a greater role in the selection and preparation of movement while SMA
may be more closely related to motor execution (Picard & Strick, 1996). The architectonic


31
distinctions corresponding to SMA and pre-SMA have been debated for some time;
however, the preponderance of evidence supports the distinction of labeling SMA as 6aa
and pre-SMA as 6ap.
In a review of functional imaging studies in humans, Picard and Strick (1996)
found support for two distinct motor areas in human BA 6 similar to those found in the
monkey. SMA was defined as the region caudal to a line extending upward from the
anterior commissure, while pre-SMA was defined as the more rostral region. Several
functional differences were noted between these two areas. The first is that pre-SMA
activation appeared to be associated with complex motor tasks, while SMA activation was
associated with more simple motor tasks. Another factor that influences the relative
amount of activation in SMA and pre-SMA is the level of skill acquisition. Finally,
whether a movement is self-paced or externally cued also appeared to significantly
influence the location of activation on the medial wall. Externally paced or cued tasks
elicited activation of SMA, while tasks that were more self or internally paced did not.
For example, activation of SMA was observed in association with simple repetition of
words (Petersen et al., 1988) while more complex and internally guided verbal tasks, like
silent word generation (Wise et al., 1991; Crosson et al., 1999) and self-ordered number
generation resulted in activation of pre-SMA, in addition to SMA (Petrides et al., 1993).
Another structure on the medial wall of the frontal lobe is the anterior cingulate
cortex, which in non-human primates, is a large and heterogeneous region that lies on the
ventral, rostral and dorsal margins of the corpus callosum and consists of large pyramidal
neurons in layer V that project to the motor system. It is demarcated dorsally by the
cingulate sulcus and ventrally by various portions of the corpus callosum. As studied in


32
primates, it retains diverse thalamic afferents including the anterior, intralaminar and
midline nuclei and the ability to sample inputs from more thalamic nuclei than any other
cortical region (Devinsky et al., 1995). Although non-human primates have a single,
constant and non-segmented cingulate sulcus, it should be noted that the medial surface
features of the human brain are more variable. The anterior cingulate region in humans and
animals consists of limbic cortex in BA 24, 25 and 33; however, supracallosal BA 32,
commonly referred to as paralimbic cortex, is present only in human brains. These regions
have been further subdivided due to their high degree of cytoarchitectonic and functional
differences. One convention involves a superior-inferior as well as an anterior-posterior
dimension (Vogt et al., 1995).
BA 24 forms a belt of tissue that follows the contours of the corpus callosum
extending dorsally into the cingulate sulcus. Within this belt, substantial evidence points to
the existence of a rostral to caudal division based upon cytoarchitectural, connectional and
functional differences in the monkey (Vogt et al., 1995). These regions have been labeled
as 24 and 24 based upon their rostral to caudal location, respectively. Area 24 has also
been referred to as perigenual while area 24 has been labeled as supracallosal. In terms of
their connectivity, area 24 has been found to receive heavy projections from the amygdala,
while area 24 receives projections from parietal cortex.. Differences between these two
regions also include greater neuronal density in area 24 relative to area 24. Functional
differences to be discussed later suggest that while area 24 may be related to some
affective processes, most evidence suggests that its role in affect is secondary to its role in
cognitive processes such as response selection (see Devinsky et al., 1995).


33
Area 24 and 24 have been divided based upon an inferior to superior dimension as
well. From ventral to dorsal, areas 24a and b are on the crest of the cingulate gyrus
whereas area 24c is on the ventral bank of the cingulate sulcus. These a, b and c
differentiations were not reported by Brodmann (1909); however recent evidence has
suggested that there is an inferior to superior transition from limbic cortex on the crest of
the cingulate gyrus to the true neocortex with premotor functions in BA 6 (see Figure 1;
Vogt et al., 1995).
Figure 1: Crosson and colleagues (1999) sketch of the medial frontal cortex
demonstrating the relationship between the cingulate sulcus (CS), the paracingulate sulcus
(PCS), the ventral to dorsal subdivisions of BA 24 (a, b & c) and supracallosal BA 32.
The cingulofrontal transition area 32 also referred to as paralimbic cortex, forms a
dorsal rim around area 24 and occupies the gyrus between the cingulate and paracingulate
sulci, when present. For the purpose of this paper, we are interested primarily in
supracallosal BA 32. The paracingulate sulcus is thought to contain the border between
BA 32 and medial BA 6 as well as separating BA 32 from BA 8 and 9, more anteriorly


34
(Paus et al., 1996). BA 32 is often labeled as transitional cortex because it contains a
mixture of cytoarchitectural features of cingulate cortex and adjacent frontal areas. More
research including functional imaging studies and evaluation of axonal connections in the
human brain is needed to substantiate whether this region has more in common with
cingulate or frontal cortex (Vogt et al., 1995). What is known about area 32 is that is has
a prominent cingulate layer V while also having a thin layer IV and large layer III
pyramidal neurons characteristic of more anterior frontal regions (Vogt et al., 1995).
Another important aspect of the medial frontal region involves the presence of
hemispheric asymmetries. Paus et al., (1996) examined 105 MRIs and found that the
anterior segment of the cingulate sulcus was larger in the right than in the left hemisphere,
whereas the opposite was true for the posterior segment. This is consistent with other
findings of rightward asymmetry of this region (Albanese et al., 1995). Whether or not this
is related to possible dominance of the right over the left anterior cingulate region in
affective processes remains to be determined (Paus et al., 1996). This hypothesis is
supported by a study conducted by Albanese and colleagues (1995) who found an even
more pronounced rightward asymmetry of this region after including the cortex on the
ventral bank of the cingulate sulcus and the medial surface of the cingulate gyrus. Paus et
al., (1996) also investigated the paracingulate sulcus; however the findings were less clear
cut. They noted that of 105 subjects, only 50 had prominent paracingulate sulci in both
hemispheres, thus complicating their findings. Results revealed that the volume of gray
matter buried in the paracingulate sulcus was significantly larger in the left than right
hemisphere. It was hypothesized that the larger paracingulate sulcus in the left hemisphere
may arise in compensation for the smaller anterior segment of the cingulate sulcus in the


35
same hemisphere. The fact that this hypothesized compensation occurs dorsally, not
ventrally to the rostral end of the cingulate sulcus might reflect the relative growth of BA
32 in the left hemisphere (Vogt et al., 1995). These findings have considerable importance
for interpreting functional imaging results that compare activation in terms of its intensity
and spatial extent across hemispheres.
In terms of function, PET studies suggest that perigenual area 24 is distinct from
the more caudal area 24. Caudal area 24, but not the perigenual part has been activated
with the Stroop task, letter and word generation (Petersen et al., 1988), complicated
finger movement sequences, self generated eye movements, and divided attention tasks
(see Vogt et al., 1995). Electrical stimulation studies have implicated area 24 in autonomic
reactivity in terms of changes in respiration, cardiac rates and blood pressure as well as
mydriasis, piloerection and facial flushing (see Devinsky et al,, 1995). Visceral responses
elicited by stimulation of this area have included nausea, vomiting, epigastric sensation,
salivation and bowel/bladder incontinence. Devinsky and colleagues (1995) suggest that
another important functional distinction between area 24 and area 24 is in the processing
of affective material. Electrical stimulation as well as PET studies confirm the
involvement of area 24 in emotional processing, while area 24 apparently has little direct
involvement in such functions. Based upon this evidence, it appears as though area 24
subserves some of the same functions as that of more dorsal regions including BA 32,
which will be discussed shortly and pre-SMA. Thus, connections between this region and
BA 32 in the depths of the cingulate sulcus are particularly important.
There is limited evidence as to the function of BA 32; however several studies
have implicated this region in the processes of generating words, a process that also


36
appears to rely on pre-SMA. Frith et al. (1991) found activation during a phonemic verbal
fluency task in the medial frontal cortex centered in BA 32. Similarly, Raichle et al. (1994)
found elevated blood flow in BA 32 while subjects were generating verbs to a list of
nouns. When the list of nouns was re-presented a number of times, the response
habituated; however the activation returned when a novel list was presented. Crosson et
al. (1999) used fMRI to map functional activity in the medial frontal cortex during the
generation of words to various semantic categories. Results revealed that when the
paracingulate sulcus was present, activity changes were centered within the paracingulate
sulcus including both dorsal and ventral banks The volume of activation seen on the
ventral bank of the paracingulate sulcus was significantly smaller than on the dorsal bank.
Occasionally, activity extended into the cingulate sulcus, but never extended ventrally to
the cingulate gyrus. Thus, the supracallosal medial frontal cortex most heavily connected
to the limbic system did not show any activity increase for word generation. Activation of
medial frontal cortex during word generation has been interpreted as related to the
initiation of cognitive processes. This interpretation is consistent with that of Picard and
Strick (1996) who proposed that simple speech activities like repetition tend to activate
SMA while more complex speech/language activities like word generation tend to activate
pre-SMA and some adjacent regions.
Picard and Strick (1996) also noted that supracallosal area 32 and possibly
supracallosal area 24c is analogous to the cingulate motor area in the monkey. Based
upon their review of the literature (Picard & Strick, 1996) it appears as though activation
in this region is related to the internal selection of movement while activation in more
caudal regions is not. Further, activation of area 24 has been observed in simple tasks


37
similar or identical to those that produce changes in SMA. Thus, the same anterior to
posterior distinction found in medial area 6 (SMA and pre-SMA) may apply to BA32 as
well. Evidence supporting this hypothesis comes from the suggestion that the connectivity
of BA 32 and pre-SMA are similar, an important finding because it explains why studies
investigating the initiation of language have demonstrated activation in both regions
(Picard & Strick, 1996).
In summary, findings suggest that pre-SMA, and adjacent supracallosal area 32 are
functionally related and play a role in initiating cognitive processes necessary for word
generation. This idea is supported by a number of different sources including functional
imaging studies in humans and electrical stimulation in animals, as well as investigations of
cytoarchitecture and connectivity. Lesion studies also contribute to our understanding of
the function of the medial frontal wall.
Behavioral Changes After Medial Frontal Lesions
A factor that complicates the investigation of the contribution of the anterior
cingulate cortex and pre-SMA/SMA to behavior is that although it is not uncommon to
find patients who have lesions involving these regions, isolated cingulate cortex or SMA
lesions are rare and surgical intervention in the inter-hemispheric space is infrequent
(Devinsky et al ., 1995). Spontaneous lesions of the anterior cingulate cortex caused by
tumors and strokes and almost always involve adjacent areas such as SMA, white matter
and the septum. This has caused some debate regarding which structures are necessary for
the initiation of speech and language. The mixed involvement of cingulate and adjacent
cortex in stroke is due to the distribution of the anterior cerebral artery (ACA). The eight
branches of the ACA supply not only the cingulate cortex, but distribute blood to the


38
medial portions of the orbital gyri, the entire medial aspect of the anterior two-thirds of
the cerebral hemispheres including SMA and through the recurrent artery of Huebner, the
head of the caudate nucleus, anterior putamen and the anterior limb of the internal capsule
(Devinsky et al., 1995). The complicated vasculature and anatomical inaccessibility of this
region make functional imaging as well as animal ablation studies particularly useful in
understanding its function.
It is not surprising then that lesions to the anterior cingulate cortex are associated
with a wide range of neuropsychological disorders including akinetic mutism, aberrant
social behavior, diminished self-awareness and depression (Barris & Schumann, 1953;
Devinsky et al., 1995; Nielsen & Jacobs, 1951). Akinetic mutism is a syndrome in which
speech is initiated only with significant external prompting. Barris and Schumann in 1953
reported one of the first cases of this type involving a 40 year old man whose post-mortem
exam revealed a lesion, more extensive on the left than right, in the area of the anterior
cingulate gyrus (BA 24). The lesion was not limited to the anterior cingulated; however,
and was found to encroach upon the inferior-medial portion of BA4 and BA 6 as well as
into BA 32. The patient demonstrated early signs of apathy that progressed to eventual
akinesia and mutism. The clinical course was later characterized by deepening stupor,
coma and death. The global nature of the initiation deficit seen in akinetic mutism,
suggests that the contribution of the medial frontal cortex is not limited to the language
domain (Crosson et al., 1999).
According to Devinsky et al. (1995), the most severe deficits in spontaneity of
speech and other motor functions probably follow bilateral lesions of the anterior cingulate
cortex as well as pre-SMA/SMA. Laplane (1981) reported a case with extensive bilateral


39
anterior cingulate damage accompanied by indifference, amnesia and prominent
inattention; however no akinesia or mutism was noted. It was argued that the
preservation of motor activity was related to sparing of pre-SMA/SMA as well as the
caudal anterior cingulate region, now thought to be analogous to the cingulate motor area
in the monkey. Unilateral neurosurgical resections of medial BA 6 have resulted in only
transient mutism or contralateral hemiplegia (see Devinsky et al., 1995). The behavioral
deficits in these patients have been found to improve so that only a slight hesitation during
rapid alternating movements and speech remains.
Lesion studies of nonhuman primates have provided more information regarding
the functional specificity of the subdivisions of the anterior cingulate as well as pre-
SMA/SMA. In one study non-human primates performed a task in which they raised their
arm to receive a reward (see Passingham, 1993). This is a voluntary task in which they
learned to perform a specific movement, but could work at their own pace. Lesions to
SMA produced far fewer attempts in the first 4 days after surgery. Another group of
animals had the lower bank of the cingulate sulcus (area 24) and the rest of the anterior
cingulate cortex removed. Their performance was similar to that of monkeys with SMA
lesions, consisting of significantly fewer responses compared to their performance prior to
the lesion. Further testing revealed that the monkeys could move with considerable speed.
They were also motivated and evidenced the ability to work on learning tasks for food. Of
interest is the fact that these monkeys performed well on a task in which tones cued them
to move their arm, while performing poorly on the self-initiated version of this task.
There is evidence that non-human primates with medial frontal lesions also
perform poorly on sequencing tasks and on tasks that require alternation between two


40
repetitive movements (see Passingham, 1993). What is common to all of these tasks is
that the animal must learn the correct movement without the aid of external cues.
Passingham (1993) hypothesized that the basic effect of medial premotor cortex lesions is
to impair retrieval of the correct movement in the absence of external cues. A deficit in
internally generated movement resulting from medial frontal lesion in the monkey, is
similar to the intentional deficit seen in humans with medial frontal lesions. These patients
often present as akinetic and mute; however with significant external prompting, they will
produce a response (Devinsky et al., 1995).
Taken together, lesion studies in humans and nonhuman primates reveal a variety
of behavioral disturbances associated with lesions of the medial frontal wall. One of the
most marked findings is a deficit in the generation of internally guided action and
cognition. In monkeys, Passingham (1993) suggested this deficit is accompanied by a
relatively intact system for responding to external cues. This is an important observation
and will be discussed in detail later. In terms of understanding the functional divisions of
the medial frontal cortex; however, human lesion studies are of limited value due to the
vasculature as well as the rarity of neurosurgical intervention in this region.
Relationship of Medial to Lateral Frontal Cortex
In 1985, Goldberg suggested that the involvement of medial frontal cortex depends
upon whether a wide range of behavior, including language, is triggered by internal versus
external contingencies. He focused on the divergent roles of the supplementary motor
area, defined as medial BA 6 and lateral premotor cortex including pars triangularis. The
fact that SMA was defined as the entire medial BA 6 is important since according to
Picard and Strick (1996) there are important functional divisions between the rostral pre-


41
SMA and more caudal SMA. Goldberg (1985) hypothesized that SMA is involved when
internal generation of language or action is required, whereas lateral premotor cortex is
involved in language and action that is externally guided.
After reviewing the literature, Passingham (1993) came to a similar conclusion
regarding the functions of medial and lateral frontal cortex. In applying this principle to
movement, Passingham (1993) noted that lateral premotor cortex is relied upon to a larger
extent when movement is driven by external cues. When movement is driven by internal
cues; however, medial frontal cortex is thought to play a greater role. Passingham (1993)
deviated from Goldbergs (1985) hypothesis; however, when he concluded that neither
internally nor externally cued movement is the exclusive domain of SMA and lateral
premotor cortex, respectively. Rather, it is the balance between the two regions that is
important.
Support for Goldbergs (1985) and later Passinghams (1993) theories has been
mixed. Deiber et al. (1991), using right hand motor tasks, found less activity in BA9 and
46 as well as left SMA during externally versus internally guided movements. In addition,
lateral premotor cortex activation was greater during internally cued movement than
during a fixed-movement control task, whereas this region did not demonstrate significant
activity changes for externally cued movement versus the same control task. Frith (1991)
compared phonemic verbal fluency, an internally guided word production task, to
repetition, a more externally guided task. Phonemic fluency was associated with more
activation in both the medial frontal cortex, centered in BA 32, and lateral frontal cortex,
centered in BA 46. Similar but less extensive changes occurred for an internally as
opposed to an externally guided finger movement task. Neither Deiber et al.(1991) nor


42
Frith et al. (1991); however, compared the degree of change for medial and lateral frontal
cortex (Crosson et al., 2001a). This analysis is of interest because although both regions
show decreases as tasks move from internally to more externally driven, the proportion of
change, as suggested by Passingham (1993) could indicate a shift in the balance of medial
versus lateral frontal activity. Of note is the fact that the studies have been inconsistent in
terms of the areas of medial frontal (BA 32 or medial BA 6) and lateral frontal (BA 9/46
or lateral BA 6) cortex identified.
In an attempt to investigate the relative contribution of medial and lateral frontal
cortex to word generation, Crosson et al. (2001a) used fMRI to examine neural activation
during 3 word generation tasks. Each task varied in the degree to which internal guidance
was required. For example, free word generation required subjects to generate as many
exemplars as possible from a given semantic category. This was the most internally guided
word generation task. Paced word generation required subjects to generate an exemplar
from a given category in response to an auditory cue. This task is somewhat less internally
guided than free word generation. Semantic word generation was the most externally
guided word generation task in that subjects were required to generate exemplars from a
particular category in response to a semantic cue. Subjects also performed a word
repetition task during which they repeated heard words.
Results revealed that for both pre-SMA/BA 32 and the inferior frontal gyrus, there
is a general decrease in activity volume as tasks become more externally guided. The
ratio; however, of medial to lateral frontal activity for pre-SMA/BA 32 and the inferior
frontal gyrus decreased as word generation became more externally driven. This was due
primarily to a more rapid decrease in medial frontal activation. This shift is consistent with


43
Goldbergs (1985) and Passinghams (1993) hypothesis. As predicted by Goldberg
(1985), portions of Brocas area (pars triangularis) were found to be prominent in lateral
frontal activity, although this activity extended into other inferior frontal areas and the
insula as well. The relationship between pre-SMA/BA 32 and the middle frontal gyrus was
somewhat different because there was a large increase in middle frontal gyrus activity
between free and paced generation, which was responsible for the large drop in medial to
lateral frontal ratio. Overall, the ratio of medial to lateral frontal activity decreased as
word generation became more externally driven, representing a shift toward greater
influence of the middle frontal gyrus versus pre-SMA/BAA 32 for externally driven word
generation. With respect to the medial frontal cortex, it appears as though Goldbergs
hypothesis (1985) must be modified in that pre-SMA not SMA is involved in the medial to
lateral shift. Activation also extended into BA 32, a finding that is consistent with
predictions made by Picard and Strick (1996) about the function of BA 32.
In light of this evidence, there are several likely reasons why Frith et al. (1991) did
not observe a shift in medial to lateral frontal cortex during phonemic verbal fluency and
repetition. First, medial and lateral frontal cortex were not divided into the relevant
anatomic subregions. Second, the relative decrease in medial and lateral frontal cortex as
tasks became less internally driven was not compared.
In that regard, Crosson et al. (2001a) found that the ratio of medial to lateral
frontal cortex does not continue to fall as subjects perform a repetition task. Although
repetition is the most externally guided of the tasks, it requires less semantic processing
than the generation tasks. Evidence suggests that repetition can be accomplished primarily
on the basis of lexical information, with no need for semantic information (Crosson et al.,


44
in 2001a). When semantic processing is required, as in the word generation tasks, more
extensive activity has been found in the posterior inferior frontal gyrus in terms of volume
(Crosson et al., 2001a) as well as spatial extent (Petersen et al., 1988). Thus the degree of
internal versus external guidance is not the only difference between the generation and
repetition tasks. The fact that semantic processing is not required by the repetition task
likely accounts for the dramatic drop in inferior and middle frontal gyrus activation. This
may be the reason as to why the medial to lateral frontal ratio does not continue to
decrease during repetition for pre-SMA/BA 32 versus the inferior and middle frontal gyri.
Taken together, evidence supports the role of the medial frontal cortex in
intentional aspects of language production. Unlike Goldbergs hypothesis; however, the
areas on the medial wall involved seem to consist of pre-SMA and BA 32 for word
generation. In contrast, language that is driven by external contingencies relies more
heavily on lateral premotor cortex including pars triangularis. Passinghams (1993)
proposal that it is not a matter of absolute dominance of medial versus lateral frontal
activity for internally versus externally drive actions, it is rather, the shift in balance as the
degree of external guidance changes appears to be consistent with the bulk of the
evidence.


CHAPTER 6
STRUCTURAL BRAIN ABNORMALITIES IN SCHIZOPHRENIA
Post-mortem as well as MRI studies in schizophrenia have revealed reduced brain
size, enlarged ventricles, reduced brain asymmetry, reduced gray matter in association
cortex, basal ganglia and limbic system abnormalities (e.g., Andreasen et al., 1986;
Bogerts et al., 1985; Breier et al., 1992; Gur et al., 1994; Harvey et al., 1993; Jernigan et
al., 1991). The presence of structural abnormalities in the frontal lobes in particular are
commonly found, including overall reduced frontal lobe volume in patients with
schizophrenia (Andreasen et al., 1986; Brier et al., 1992; Harvey et al., 1993; Scheapfer et
al., 1994). Some investigations; however have failed to find differences in frontal lobe
volume between schizophrenics and control subjects (Andreasen, 1990; Young et al.,
1991; Wible et al., 1995). These inconsistencies may be due to inconsistent anatomical
definition. It is possible that in schizophrenia, structural abnormalities in the frontal lobe
are restricted to specific regions and that measuring total prefrontal volume is not specific
enough to reveal more subtle abnormalities within subregions (Baare et al., 1999). It is
also possible that that the neuronal pathology in this disorder is restricted to the cellular,
molecular and physiological domains and could be detected using functional neuroimaging
techniques, but not structural measurement. A competing hypothesis maintains that
quantitative variation in single neural characteristics are associated with specific symptom
dimensions. The vast majority of studies examining structural
45


46
abnormalities in schizophrenia do not investigate the relationship to specific symptoms.
Unlike other neurological disorders such as Alzheimers Disease or Huntingtons Chorea
in which histopathological features are readily identifiable, schizophrenic patients have not
been found to have any obvious changes at either the gross or microscopic level (Benes,
1998; Leonard et al., 1999). This complicates the attempt to establish pathophysiological
correlations and has made studying this disorder particularly difficult.
Several approaches to studying schizophrenic brains offer potential for greater
understanding of the biological basis of the disorder. The first is to focus on variation,
rather than central tendencies. To test the neuroanatomical risk factor hypothesis,
Leonard et al. (1999) selected features such as cerebral and third ventricle volume, and
markers of sulcal interruption or disturbed asymmetry in frontal, cingulate and parietal
association cortex. Results revealed that while individual structure measurement is quite
limited in its ability to distinguish schizophrenics from healthy controls, a combination of
10 measurements can correctly classify individuals approximately 77% of the time. Of
note is the fact that the posterior segment of the cingulate cortex extended less anteriorly
in the schizophrenics, a finding that is consistent with other evidence of disrupted
development and function in the cingulate cortex (Benes, 1998).
Benes (1998) argues that model generation and testing involving key corticolimbic
regions such as the anterior cingulate cortex, has the potential to provide insight into the
underlying pathophysiology of schizophrenia. A series of postmortem studies have shown
loss of interneurons, with changes maximal in layer II, a selective glutamatergic neuron
loss and altered GABA binding in the anterior cingulate of schizophrenic patients (Benes,
1998). Although reduced density of inhibitory interneurons has been found, glial counts in


47
the anterior cingulate are similar amongst schizophrenics and healthy controls. This
suggests that a typical degenerative process does not account for the brain abnormalities
seen in the disorder. Subsequent research examining the role of GABA, the principal
cortical inhibitory neurotransmitter, found evidence of up-regulation of the GABA
receptor at the postsynaptic pyramidal neurons in both the anterior cingulate and
prefrontal cortex. In terms of the role of dopamine, Benes (1998) first hypothesized that
the reduction of nonpyramidal neurons in schizophrenic patients could give rise to a
relative increase of dopaminergic inputs to the remaining GABA cells. However, further
analyses revealed that shift of cortical dopamine afferents from pyramidal to nonpyramidal
neurons in layer II of the anterior cingulate cortex provides a better explanation of
dysfunctional circuitry in schizophrenia. The strength of this model resides in its emphasis
on dysfunctional neural circuitry, emphasizing the role of medial frontal structures.
Further evidence for pathology of medial frontal structures comes from a study
that segmented the cortex of schizophrenic patients into 48 topographically distinct brain
regions on MRI (Goldstein, 1999). The largest volume reductions for the schizophrenics
relative to controls were found in the middle frontal gyrus and paralimbic brain regions
such as the anterior cingulate gyrus and paracingulate gyrus Another investigation
(Albanese et al., 1995) examined the laterality of the anterior cingulate in female
schizophrenic brains post-mortem. Of note is the fact that this investigation was confined
to the anterior (BA 24) and posterior cingulate (BA 23). BA 32 was excluded, as it was
thought to pertain to the frontal cortex and not the anterior cingulate gyrus. Results
indicated that the control subjects anterior cingulate was characterized by greater right
than left gyral weight and surface area. The schizophrenic patients, in contrast, showed a


48
significantly greater incidence of left laterality. At present, this is the first study to find
reversed asymmetry of the anterior cingulate cortex in schizophrenics.
Support for the hypothesis that subtypes or symptom dimensions are correlated
with the integrity of particular brain structures or circuitry is relatively weak (Chua &
McKenna, 1995). Most MRJ studies investigating the relationship between symptoms and
abnormalities in the frontal cortex have failed to find a significant link between the two
variables (Andreasen et al., 1986). Two studies that did find a relationship produced
contradictory results. Uematsu & Kaiya (1989) found that the severity of negative
symptoms was related to reduced frontal volume while Buchanan et al., (1993) found that
the severity of negative symptoms was related to larger prefrontal volumes. It was not
until more recently that Baare et al., (1999) measured volumes of gray and white matter in
the dorsolateral, medial and orbital regions of the prefrontal cortex. The findings included
a significant relationship between orbitofrontal gray matter (including ventral, medial and
lateral areas) and negative symptomatology in schizophrenic patients.
Overall, it is unlikely that an abnormality of only one brain structure can explain
the presence of schizophrenia in every patient with the disorder. Rather it is more likely
that abnormal function within a distributed neuronal circuit produces the characteristic
symptoms of the disease. Research suggests that this circuit likely includes regions of the
medial frontal cortex. Further, different elements of the circuit may be more obviously
affected in one patient than another producing symptoms of varying severity.


CHAPTER 7
FUNCTIONAL IMAGING IN SCHIZOPHRENIA
Functional neuroimaging has considerable potential for identifying the neural
circuitry involved in schizophrenia (Weinberger et al., 1996). Numerous investigations
using a variety of functional imaging techniques, including PET, fMRI, and SPECT, have
been reported in the literature in the past 20 years. While the results are not without
controversy, several general trends can be observed. The first is that groups of
schizophrenic patients tend to have relatively normal global and regional rCBF patterns
during resting conditions. The second is that is that during cognitive activation paradigms,
patients tend to differ from normal controls.
Activation paradigms have been used to examine cerebral blood flow or
metabolism during different behavioral states in order to provide a potential methodology
for studying brain function relevant to schizophrenia (Taylor, 1996). Functional
neuroimaging during the performance of a specific task has been used to control
behavioral state and stabilize brain physiology (Buchsbaum et al., 1984) or to provide a
cortical stress test to uncover diminished capacity (Berman, 1987). When performing
cognitive tasks, patients tend to show different patterns of activation relative to normal
controls. During tests of working memory, for example, they show less activation than
normals in the right dorsolateral prefrontal cortex (Carter et al., 1998). Further,
49


50
hypofrontality has been demonstrated in schizophrenia patients when compared to their
own healthy twin siblings (Berman et al., 1992). During other cognitive tasks such as cued
verbal recall, they show attenuated activation of the cingulate cortex (Dolan et al., 1995)
and deficits in frontal-temporal relationships (Lawrie et al., 2002). In general most of
these findings have been reproduced in acute, unmedicated patients, thus excluding a
primary role for medication artifacts (Weinberger et al., 1996). Results of cognitive
activation paradigms will be discussed at length later.
Methodological Issues
The functional neuroimaging data in patients with schizophrenia have generated a
number of important issues that must be examined. One issue concerns the interpretation
of activation differences in the face of group differences in behavioral performance. It has
been argued that since patients generally perform more poorly on many cognitive tasks,
hypofrontality or other abnormal-task evoked activity reflects a generalized phenomenon
or deficit, such as lack of engagement (Taylor, 1996). In fact, evidence from
neuropsychological investigations reveals that schizophrenia patients have deficits in
sustained attention and vigilance (Carter et al., 2001) that can result in poor task
performance. Activation deficits may therefore be artifacts of performance differences
between groups. One way of addressing this issue is to train subjects prior to scanning in
order to equate behavioral performance in patients and control subjects.
Attenuated activation can appear due to a primary deficit, which is a specific
disturbance in the brain region responsible for a given task that causes poor performance
and reduced activation. It can also occur due to a secondary deficit, which occurs when a
deficit in a brain region outside of the abnormal pattern of activation causes the proximal


51
abnormality (Taylor, 1996). Further, pervasive brain dysfunction, which involves
dysfunction in a system which has wide spread regulatory effects throughout the brain,
such as seen in neurodevelopmental abnormalities, can contribute to activation deficits
(Taylor, 1996). Finally, these deficits can also be viewed in terms of a compensatory
response or a failure to engage as previously discussed.
One method that has been used to address the issue of whether pervasive brain
dysfunction results in abnormal activation and deficits in task performance, is to integrate
a motor response task into the cognitive task (Callicott et al., 1998). Thus, activation of
sensorimotor cortex, a region that has been found to be functionally intact in schizophrenia
(Weinberger et al., 1996; Bogerts, 1993) is used as a reference or control region both
within and across groups.
Most functional imaging studies of schizophrenia have used nuclear medicine
techniques such as single photon emission computed tomography (SPECT) or positron
emission tomography (PET) which tend to have poor spatial resolution and rely upon
group averaging, creating the possibility of overlooking subtle individual differences
thought to be particularly important in studies of schizophrenia. An advantage of
functional magnetic resonance imaging (fMRI) includes improved spatial and temporal
resolution which allows investigation into the possibility that differences in activation
between groups might be due to activation of slightly different brain areas or to differences
in brain anatomy. Other advantages of fMRI include virtually unlimited study repetitions
which facilitate within-subject mapping and provide potential to highlight differences
between individuals and the relationship to symptomatology, straightforward registration
of functional and anatomic scans and the use of available MRI scanners.


52
For these reasons, fMRI can be viewed as an ideal individual mapping technique.
It may offer unique insights into several important questions, including the relationship
between individuals and diagnostic groups, the effects of medication on performance
differences on activation tasks, the distinction between state and trait findings, and the
reliability of findings over time (Callicott et al., 1996).
The unique potential of fMRI is counterbalanced by a unique set of challenges in
data acquisition, analysis and interpretation (Callicott et al., 1996). Any given signal
change detected during an fMRI study may not be related to neuronal activity, it may
instead result from various artifacts, including head movement. Motion has been shown to
account for significant signal changes and can be the source of differences between
populations, particularly with neuropsychiatric patients (Callicott et al., 1996; Weinberger
et al., 1996). Therefore, strategies to diminish patient movement are crucial for the
success of fMRI studies in neuropsychiatric populations. Approaches that have been used
include mechanical devices for limiting motion, image registration programs to correct for
certain types of movement and pre-training in a simulated scanning environment.
The Effects of Medication on Functional Imaging Data
Although all antipsychotic medications share the pharmacological property of
antagonizing D2 dopamine receptors, antipsychotic drugs vary substantially in their
pharmacological profiles, with each affecting a variety of neuroreceptors in the central
nervous system (Keefe et al., 1999). These differences could have important clinical
consequences, including selective effects on cognition and brain activation. It is important
to note that while neuroleptics are thought to have their antipsychotic effect at the D2


53
dopamine receptors (Farde et al., 1992), other neurotransmitter systems are affected by
antipsychotic medications including cholinergic, adrenergic, and serotonergic systems.
The first neuroleptic, chlorpromazine was serendipitously identified as a potent
antipsychotic drug for schizophrenia nearly a half century ago (Holcomb et al., 1996).
Since then, many different neuroleptics including haloperidol have been developed. These
are the classical or typical neuroleptics which have an antipsychotic effect but also induce
extrapyramidal symptoms. The antipsychotic effect is presumably due to binding at the D2
family of dopamine receptors, thereby reducing dopamine-mediated neural transmission. A
cascade of neural changes presumably occurs in the dopamine D2 terminal areas and their
projection sites subsequent to the receptor blockade (Holcomb et al., 1996). D2 receptor
imaging studies have also revealed that standard doses of antipsychotic drugs result in
unnecessarily excessive levels of drug occupancy at D2 receptors and account for the
extrapyramidal side effects (Heinz, et al., 1996).
Holcomb et al., (1996) examined the brain regions functionally altered by
haloperidol using PET. Patients with schizophrenia were scanned during a stable period
of haloperidol treatment and 30 days after cessation of the drug. Results revealed
increased glucose metabolism in the caudate, putamen and thalamus with haloperidol
administration. In contrast, haloperidol was found to decrease glucose utilization in the
medial frontal cortex and inferior frontal gyrus. Holcomb et al., (1996) hypothesized that
this pattern of change is not due to discrete effects of haloperidol at each of these regions,
but is mediated by the brains cortico-striato-pallido-thalamo-cortical networks described
by Alexander et al., (1986).


54
Clozapine, an atypical neuroleptic, is an antipsychotic drug with a clinical and
pharmacological profile that differs from the classical neuroleptics (Lundberg et al.,
1989). It is associated with a low incidence of extrapyramidal side effects and has been
efficacious in treating many patients who do not respond to classical neuroleptics. Farde
et al., (1992) investigated the biochemical properties of clozapine using PET and found
that patients treated with clozapine have significantly lower occupancy of the D2 receptors
in the basal ganglia than patients treated with classical neuroleptics. The patients treated
with clozapine were also found to have similar D1 and D2 receptor occupancies. It was
thus hypothesized that the combination of a relatively low D2 and high D1 occupancy is a
unique property of clozapine. Unfortunately, Farde et al., (1992) examined only the basal
ganglia and did not investigate how the effects of clozapine differ from those of the typical
neuroleptics on the frontal cortex.
In a study using 11-C labeled clozapine visualized by PET, Lundberg et al., (1989)
found a significant amount of binding in the frontal cortex that had not been displaced by
haloperidol. Lundberg et al., (1989) hypothesized that this finding might represent binding
to D1 receptors. It was also suggested that the unique properties of clozapine might be
due to its effect on non-dopaminergic receptors in the frontal cortex. Unlike conventional
antipsychotics, it has been found to have high 5-HT receptor affinity (Pickar et al., 1996).
Clozapine has also been found to have a high affinity for D4 receptors (Van Tol et al.,
1991); however the relationship between the D4 receptors and its antipsychotic effects is
unclear.
Neuropharmacological imaging has revealed some surprising and important results
with respect to the mechanism of action of antipsychotic drugs, demonstrating how these


drugs achieve their antipsychotic effects and the brain regions that are affected. Typical
antipsychotics have been found to decrease glucose metabolism in the medial frontal
cortex. With respect to functional imaging, this is likely to create or contribute to an
attenuated medial frontal response that can be erroneously interpreted as reflecting an
underlying pathological process of schizophrenia. Although less is known about the
regional effects of atypical antipsychotics, clozapine in particular, they appear to have a
lower D2 receptor occupancy than do the typical neuroleptics and may produce less
attenuation of activity in the medial frontal cortex. While further research is clearly
needed in this area, preliminary evidence suggests that when studying the medial frontal
cortex in medicated schizophrenic patients, including only those patients treated with
atypical neuroleptics may prove to be a more stringent method for investigating medial
frontal functioning.
Functional Imaging of Cognitive Activation Paradigms
Some of the first activation studies in schizophrenia were conducted by Franzen
and Ingvar (1975) using Xenon (Xe) 133 methods and suggested that hypoactivation of
the prefrontal cortex characterized the disorder. Support for this finding came from a
number of studies using the Xe probe technique and later SPECT, which found attenuated
prefrontal activation in schizophrenic patients during performance of the WCST
(Weinberger et al., 1986/ The only negative finding occurred in a group of male
schizophrenic patients who did not show performance deficits on the WCST compared to
normal controls (Kawasaki et al., 1993). Prefrontal dysfunction therefore appears to be a
fairly consistent finding in schizophrenics performing the WCST; however it is likely that
differences in performance play a major role in determining the results (Taylor, 1996). To


56
address this issue, Goldberg et al. (1990) matched schizophrenics and patients with
Huntingtons disease on WCST performance and found that the Huntingtons patients
demonstrated greater prefrontal activation than the schizophrenia patients. This finding is
important because it suggests that prefrontal cortical activation is necessary but not
sufficient to perform the WCST (Taylor, 1996).
Since that time, a number of functional imaging studies have been conducted with
schizophrenic patients using a variety of cognitive tasks. One of the most consistent
findings amongst these studies is abnormal activation in the medial frontal cortex. This
should not be a surprising finding given the structural and physiological evidence for
dysfunction in that region. That being said, virtually none of the aforementioned WCST
studies reported abnormal activation of the medial frontal wall; however methodological
constraints of early functional imaging technology made accurate detection of mesial
frontal cortex activation nearly impossible. One of these studies, however using SPECT,
did report attenuated activation in medial frontal structures (Kawasaki et al., 1993).
In this regard, Andreasen et al. (1992) found a failure to activate the mesial frontal
cortex in a group of neuroleptic-naive schizophrenic patients while they performed the
Tower of London task, which requires ordering sequential movements of balls threaded
onto sticks to solve a puzzle. This finding was interpreted as dysfunction specific to the
task at hand, and not general attentional impairment or lack of motivation. Patients with a
high degree of negative symptoms failed to activate medial frontal cortex; however the
same relationship was not found for those without a high degree of negative
symptomatology. This finding can be interpreted in one of two ways. The medial frontal
cortex, including the anterior cingulate cortex, is activated by tasks which involve novelty


57
and is not activated to a great extent by stimuli that are repeatedly presented. It is possible
that the Tower of London task elicited a novelty response in all but the patients with
prominent negative symptoms. A more likely explanation is that decreased activation of
the medial frontal cortex reflects deficiencies in motivating responses to stimuli.
Several studies attempting to relate positive symptoms to patterns of brain
activation have discovered possible medial frontal dysfunction. In 1996, McGuire et al.,
investigated the hypothesis that a predisposition to verbal auditory hallucinations might be
associated with an abnormal pattern of brain activation during tasks which involve the
generation and monitoring of inner speech. Schizophrenics with hallucinations were
compared to those without hallucinations and normal controls on 3 tasks: silent reading,
sentence generation and an auditory verbal imagery task which required subjects to
imagine that sentences they had generated were being spoken to them. When the silent
reading task was subtracted from the auditory verbal imagery task, schizophrenics with
hallucinations displayed reduced activation in the left rostral SMA and left medial BA 8
relative to controls. When compared to non-hallucinators, only left rostral SMA was
significantly less active. McGuire et al., (1998) conducted another study in which thought
disordered schizophrenic patients were instructed to describe viewed pictures while
undergoing PET scans. Results indicated that the severity of thought disorder was
inversely correlated with activity in the left inferior frontal and bilateral cingulate cortex
(BA 24) suggesting that these patients fail to engage areas which normally control the
production of speech. Taken together, these studies reveal that schizophrenic patients with
positive symptoms fail to activate a number medial frontal structures including BA 24,
medial rostral BA 6 and medial BA 8 during two different cognitive tasks. This finding


58
provides support that deficits in the generation and monitoring of cognition (Frith, 1992)
are related to deficits in medial frontal 1 cortex.
In contrast, is a PET study in which patients with passivity experiences, such as
thought insertion and thought broadcasting, performed 3 motor tasks with a joystick: free
movement, stereotyped clockwise movement and rest (Spence et al., 1997). During freely
selected movement, the patients with passivity experiences demonstrated hyperactivation
relative to schizophrenic patients without passivity experiences in the anterior cingulate
gyrus (BA 23/24). When the patients with passivity phenomena were compared to
controls on this task, they demonstrated hyperactivation of the anterior cingulate gyrus
(BA 32) and left medial BA 6. This study appears to contradict findings of attenuated
medial frontal activation during cognitive activation paradigms in schizophrenia. One
explanation is that passivity phenomena are associated with a different pattern of medial
frontal activation than other positive symptoms. Another factor influencing the results may
be the reduced spatial resolution of PET, particularly for medial structures, which makes
ascertaining the laterality of the activation difficult. If differences in hemispheric
asymmetry exist in the medial frontal cortex in schizophrenia (Albanese et al., 1995), it is
possible that one hemisphere may demonstrate hypoactivation while the other may
demonstrate hyperactivation.
Carter et al. (1997) used PET to examine activation while schizophrenics and
healthy controls performed the Stroop task. Attenuated anterior cingulate activation was
found for schizophrenics during the color-incongruent condition relative to controls. The
locus of the reduced response was within the rostral anterior cingulate gyrus (BA 24), and
indicates that this region may play a role in higher level cognitive functioning. This


59
suggests that the rostral/caudal division of the anterior cingulate may be less clear cut than
previously thought. It also suggests the possibility of a pathological processes in
schizophrenia in the pregenual anterior cingulate.
Further, Crespo-Facorro et al. (1999) scanned schizophrenic patients using PET
during recall of novel and practiced word lists. The patients and controls did not differ in
their performance on either task; however the patients demonstrated decreased activation
during the practiced task in left BA 46, bilateral BA 32 and 43, left medial BA 6 and
several other regions relative to controls. Further evidence for dysfunction of BA 32
comes from a study of semantic processing in which schizophrenic patients evidenced a
negative correlation between the left anterior cingulate (BA 32) and superior temporal
gyrus (BA 22) relative to controls (Jennings et al., 1998). Once again, performance
between controls and schizophrenics was not significantly different.
Interpretation of many of these studies is complicated by the fact that little
specificity is provided regarding neuroanatomic regions. For example, during a continuous
performance task, Buchsbaum et al. (1992) reported that schizophrenic patients
demonstrated attenuated activation in medial frontal areas as well as the anterior
cingulate (p.937). Other studies that have revealed attenuated anterior cingulate or
medial BA 6 activation include a finger to thumb opposition task (Schroder et al., 1995)
as well as a serial tone position task (Stevens et al.,1998). In both cases attenuated
activation could not be attributed to a performance deficit. Given the functional
differences of SMA and pre-SMA as well as BA 32 and BA 24, it would be of interest to
decipher if this attenuated activation had a more rostral or caudal extent.


60
Functional Imaging of Verbal Fluency
Functional imaging studies of verbal fluency in schizophrenia for the most part,
reveal attenuated activation in a number of frontal regions. Using fMRJ to examine
activation during a paced phonemic verbal fluency task, Curtis et al., (1998) found that
male schizophrenics receiving stable doses of atypical antipsychotic medication
demonstrated attenuated activation in the left middle and inferior frontal gyri, left insula
and right inferior frontal gyrus relative to controls matched on sex, age, premorbid IQ and
controlled oral word association performance. Schizophrenics also demonstrated
attenuated activation in caudal SMA (medial BA 6) during a repetition task. The finding
of medial frontal dysfunction in schizophrenia has been also been reported in a PET study
in which activation related to a paced verbal repetition task was subtracted from activation
related to a paced verbal generation task (Dolan et al., 1998). While normal controls
revealed a pattern of activation including the left dorsolateral prefrontal cortex, thalamus
and anterior cingulate cortex, a group of unmedicated male schizophrenics failed to show
activation in the anterior cingulate cortex (BA 24/32). After dopaminergic manipulation
with apomorphine, this relative failure of task-induced activity in the anterior cingulate
cortex in schizophrenics was reversed. When the number of subjects was increased,
(Fletcher et al.,1996) the finding of a relative failure to activate the anterior cingulate
gyrus (BA 24/32) amongst schizophrenia patients remained significant. This failure
supports other functional imaging studies that have revealed anterior cingulate
abnormalities in schizophrenia (Andreasen et al., 1992; Liddle et al., 1991; Tamminga et
al., 1992)


61
Verbal fluency without a paced component, was examined using fMRI in both
schizophrenia patients and controls (Yurgelun-Todd et al., 1996). The difference between
the averaged relative change in intensity during the covert verbal fluency task minus
activation related to a covert counting task was calculated and revealed that
schizophrenics fail to activate frontal regions, including dorsolateral prefrontal cortex (BA
46 & 10), during verbal fluency.
In an attempt to relate verbal fluency associated task activation with
symptomatology, Frith (1995) assessed this relationship by dividing 18 stable
schizophrenia patients into 3 groups on the basis of their verbal fluency; (1) poor verbal
fluency (2) odd verbal fluency (3) normal verbal fluency. All patients had marked negative
signs; however those with poor verbal fluency demonstrated a higher severity of negative
features. Disorganized patients tended to be in the second group, while patients with
hallucinations and delusions tended to be in the group with normal verbal fluency. PET
scans during paced phonemic fluency revealed that schizophrenics showed the same
pattern of activity as controls increased activity in left dorsolateral prefrontal cortex,
anterior cingulate and thalamus. Only in the superior temporal gyrus, did schizophrenia
patients show a different pattern of activation relative to controls. Further, no significant
differences were found between the subgroups of schizophrenia patients. This surprising
finding has been interpreted as evidence supporting a disconnection between frontal and
temporal regions in schizophrenia, leading to disinhibition in the latter area. The lack of
significant differences between subgroups may be due to few subjects in each group and/or
the apriori approach of measuring a small number of structures. This hypothesis is
supported by the findings of Lewis et al., (1992) who found a relationship between


62
negative symptoms, written phonemic fluency and reduced left mesial frontal activation
using a larger number of subjects.
Overall, functional imaging studies using cognitive activation paradigms including
verbal fluency consistently reveal prominent differences in the frontal cortex, particularly
in medial frontal regions, in schizophrenic patients relative to healthy comparison subjects.
Task differences, various imaging methodologies and poor definition of structures in the
medial frontal wall; however limit the conclusions that can be made. One tentative
explanation for these findings is that intentional aspects of cognitive activity, which rely
upon the integrity of medial frontal structures, may be disrupted in schizophrenia.


CHAPTER 8
RATIONALE OF STUDY AND HYPOTHESES
Frith (1992) proposed a model of schizophrenia that considers evidence from
neuropsychological investigations and integrates it with neuroanatomical and cognitive
models of brain processes. He posited that schizophrenia patients have a deficit in the
willed route to action. In this model, the negative and positive features of schizophrenia
are due to a deficit in the internal generation and monitoring of cognition. In contrast,
schizophrenia patients are thought to have an intact stimulus route to action, which relies
upon external stimuli and contingencies. In relating these phenomena to brain structure, a
considerable body of evidence from functional imaging and lesion studies in humans as
well as physiological and histological investigations in nonhuman primates, implicates the
medial frontal cortex in the internal generation of action. Goldberg (1985) hypothesized
that actions which are driven by internal models and motivations involve supplementary
motor area (SMA) more than actions that are driven by external models and
contingencies. These actions are thought to involve the lateral premotor cortex, including
Brocas Area when tasks require language production. Passingham (1993) deviated
slightly from Goldbergs (1985) hypothesis, when he concluded that neither internally nor
externally cued movement is the exclusive domain of SMA and lateral premotor cortex,
respectively. Rather, it is the balance between the two regions that is important.
63


64
More recently, an fMRI investigation using word generation tasks that varied on
the degree of external guidance required, found that pre-SMA/BA 32 activity volumes
decreased significantly and inferior frontal sulcus activity volumes increased significantly
as word generation tasks moved from internally to externally guided. These findings reveal
that the medial to lateral shift is less pronounced in SMA than pre-SMA/BA 32.
Passinghams observation was also supported regarding the balance of activation between
the two regions.
There is considerable evidence for frontal lobe dysfunction in schizophrenia, a
portion of which suggests dysfunction of the medial frontal wall. Schizophrenic patients
demonstrate selective deficits against a background of general cognitive impairment on
tests sensitive to frontal lobe damage, including word generation (e.g., Robert et al.,
1998). Although poor performance on frontal lobe tests by no means confirms that the
pathological process in schizophrenia is isolated to the frontal lobes, evidence from
structural and functional imaging studies suggests that frontal as well as other regions are
likely involved in the disease. For example, Benes (1998) conducted a series of
postmortem studies that revealed loss of interneurons, with changes maximal in layer II, a
selective glutamatergic neuron loss and altered GABA binding in the anterior cingulate of
schizophrenic patients. Other structural studies have found volume reductions in the
anterior cingulate gyrus and paracingulate gyrus (Albanese et ah, 1995; Goldstein et ah,
1995)
A number of functional imaging studies have revealed attenuated anterior cingulate
(BA 32/24) and pre-SMA/SMA activation during a variety of cognitive tasks including
word generation. Some have even found a relationship between symptomatology and


65
patterns of medial frontal activation (Andreasen et al., 1992; McGuire et al., 1998;
McGuire et al., 1996; Spence et al., 1996). The majority of these studies; however are
plagued by poor spatial resolution and often do not report with specificity the region of
the medial frontal cortex implicated in the study. This information is crucial given what
has been learned about internally and externally driven tasks and the subdivisions of the
medial frontal cortex (see Picard & Strick, 1996) and recent fMEJ evidence (Crosson et
al., 1999) that activation during internally and externally guided tasks is localized in
different medial frontal regions. Further, most studies do not examine both the willed and
the stimulus driven route to action.
The goal of the present study was to map Friths (1992) hypothesis that
schizophrenia patients have a deficit in the internal generation and monitoring of cognition
onto neuroanatomical regions using fMRI and two word generation tasks that vary in the
degree to which internal versus external guidance was required. These tasks have reliably
activated the medial frontal cortex in normal subjects and have provided evidence
regarding the relative contribution of the medial and lateral frontal cortex to word
generation (Crosson et al., 2001a). The present research therefore employed 2 word
generation tasks, found by Crosson et al. (2001a) to differentially engage medial frontal
regions (pre-SMA/BA 32) and inferior frontal gyrus (BA 44/45/47) and inferior frontal
sulcus (BA 6/8/9), in neurologically and psychiatrically normal subjects. Thus, the present
study compared medial and lateral frontal activity in schizophrenia patients and normal
controls during internally versus externally guided word generation. Experimental
hypotheses were as follows: 1) Patients with schizophrenia should demonstrate attenuated
activity in the left medial frontal cortex relative to controls due to difficulties with


66
internally generated cognitive activity; 2) Between group differences in the medial frontal
should be maximal for the more internally guided word generation task; 3) No discrepancy
between groups in terms of amplitude of response as well as spatial extent of activation in
left lateral frontal regions should be observed as the stimulus driven route to action (Frith,
1992) is thought to be intact.


CHAPTER 9
METHODS
Participants
10 clinically stable, medicated male schizophrenic patients participated in the
study. All met DSM-IV criteria for schizophrenia/schizoaffective disorder as assessed by
the Structural Clinical Interview for DSM-IV (SCID-IV; First et al., 1994) and medical
record review. Ten healthy, right-handed males served as comparison subjects. Exclusion
criteria for the comparison subjects included any lifetime Axis I disorder as confirmed by
the SCID-IV or first-degree family history of psychotic disorder. General exclusion
criteria for all participants included substance abuse within the past 6 months, history of
neurological illness including previous head trauma, mental retardation defined as an IQ
below 70 or being a non-native speaker of English. All participants were paid $10 per
hour for their participation and were informed of the potential risks of the study.
Informed consent was obtained according to institutional guidelines established by the
Health Science Center Institutional Review Board at the University of Florida.
All schizophrenia patients were receiving neuroleptic medication at the time of the
study including a variety of typical and atypical antipsychotic medications in addition to
mood stabilizing agents and antidepressants. Symptomatology was assessed with the Brief
Psychiatric Rating Scale (BPRS, Overall & Gorham., 1988), a 26-item clinician
67


68
rated instrument that measures the severity of a patients psychotic symptomatology on a
scale from 1 to 7. Scores range from 26 (no psychopathology) to 182 (severe psychosis).
An estimate of premorbid verbal intellectual functioning was obtained from the National
Adult Reading Test (NART), a brief screening measure containing 50 irregular words
(Nelson, 1982; Appendix B) that has been used extensively with schizophrenia patients
(e.g., Russell et al., 2000). Raw number of errors was calculated in addition to an estimate
of the premorbid WAIS Verbal Intellectual Quotient (VIQ; Wilson et al., 1978).
Handedness (Briggs & Nebes., 1974), parental socioeconomic status (SES; Hollingshed,
1975) and current general intellectual functioning, as measured by the Broad Cognitive
Ability (BCA) score from the Woodcock-Johnson Test of Cognitive Abilities (Woodcock
et al., 1989), were collected as part of a related study examining the relationship between
brain structure and clinical variables in schizophrenia. Independent sample t-tests were run
to compare clinical and demographic variables between schizophrenia and comparison
groups (Table 1).
Table 1
Clinical and Demograo
lie Variables (means and standard deviations)
Schizophrenia Group (N=10)
Comparison Group (N=10)
Age (years)
42(9.39)
37 (11.48)
Years of Education
13.5(2.37)
15.6(1.78)
Parental SES
43.22(16.32)
44.05(.90)
Handedness3
,42(.65)
,80(.20)
BCAb
103.2(16.66)
116.89(12.87)
NART Errors
17.11(12.33)
14.7(7.12)
NART VIQ
112.44(14.45)
115.2(8.30)
BPRS
61.6(9.13)
27(1.05)
aHandedness quotient ranges from 1 (strongly right hanc
ed) to -1 (strongly left handed)
bBCA scaled scores (mean = 100, sd = 15)


69
The schizophrenia and comparison groups did not differ significantly in terms of
age [t_(18) = -1.06, p = .30], parental SES (t (18) = .14; p = .89], handedness [t_(18) =
1.75; p = .097], NART errors [t (17) -.53, p = .60] or NART estimated premorbid VIQ
[t (17) = .52; p = .61], Although overall handedness scores were not significantly different
between groups, the schizophrenia patients were more variable in their scores as not all
patients were strongly right handed. How this impacts data interpretation will discussed
later, however, it is consistent with the literature demonstrating that the prevalence of
non-right handedness in schizophrenia is significantly higher than in healthy control
subjects (Sommer et al., 2001). Further, a trend was observed for general cognitive ability
to be slightly lower amongst the schizophrenia group [t (17) = 1.99; p = .063], Consistent
with the literature, patients had significantly fewer years of education [t (18) = 2.24; p =
.038] and more severe psychotic symptomatology [t (18) = -11.9; p <000) than
comparison subjects.
Procedure
After signing a statement of informed consent approved by the University of
Florida Health Science Center Institutional Review Board and an MRI screening form,
participants were administered the NART and the BPRS. Standardized instructions
regarding performance on the experimental tasks were presented and then practice trials
administered, during which participants were required to respond out loud. Training
continued until the participants could perform the tasks with at least 78% accuracy. The
goal of this training period was to ensure understanding of the task instructions and the
ability to produce correct responses within a relatively short latency.


70
Experimental Tasks
During 4 functional imaging runs, two experimental word generation tasks
alternated with a baseline word repetition task in an event related design. In one
experimental condition, labeled free word generation (freegen), participants heard the
word generate, followed by a semantic category and then the word go. Participants
were required to overtly generate one category exemplar after the word go. Because
there was no external guidance regarding what exemplar to produce, free generation was
considered an internally guided word generation task. The other experimental condition,
semantic word generation (semgen), involved the presentation of the word generate
followed by a semantic category and then a descriptor. Again, participants were required
to give a single exemplar from the semantic category that matched the descriptor. For
example, subjects would hear the instruction generate, the category birds followed by
the descriptor flightless. For this category the subjects would generate the exemplar
emu or ostrich. Because the descriptors determined what word was produced,
semantic generation was considered an externally guided word generation task. In contrast
to the word generation tasks, baseline word repetition (rep) was performed covertly, and
involved the instruction silent repeat followed by a variable number of words that
participants repeated silently.
Trials of the two experimental conditions, free word generation and semantic word
generation, were 7.5 seconds in length and alternated with variable periods of baseline (10,
12.5 and 15 seconds). The baseline condition involved covert repetition of 3, 5 or 6
words, respectively (see Figure 2). Subjects participated in 4 runs of the experimental
tasks, each lasting 4 minutes and 20 seconds. Each run had 6 trials of free generation and


71
6 trials of semantic generation. Trials of the word generation tasks were presented in a
pseudorandom order, which was different for each of the runs. Baseline repetition was
also distributed within runs in a pseudorandomized order. The order of the 4 runs was
counterbalanced across subjects.
spoken response
spoken response
SILENT
REPEAT
f-
sand
adult box band
+1
dome plants desert
GENERATE
I*1h
crystal station gift beverages go
SILENT
REPEAT GENERATE
Repetition
12.5 sec
5 TR
baseline
Semantic Word
Generation
7.5 sec
3 TR
Repetition
10 sec
4 TR
baseline
Free Word
Generation
7 5sec
3 TR
Figure 2. Sample portion of event related design used in the current experiment.
All semantic categories were emotionally neutral based upon previous research
(Cato, 2002) and were drawn from Affective Norms for Emotional Words (ANEW,
Bradley et al., 1988). The 4 lists of categories were counterbalanced within the two word
generation tasks, in that each list was used both with and without descriptors an equal
number of times within each group. No subject heard a specific category more than once
during the experimental trials. Further, the average frequency of the occurrence of
semantic descriptors in the English language was balanced across lists (Kucera et al.,
1967). Table 2 lists the stimuli used for one experimental trial.


72
Table 2
Categories and Semantic Descriptors for List 1
Categories
Semantic Descriptors
Plants
Dessert
Beverages
From cow
Sources of Light
Made of wax
Reading Materials
Glossy fashion
Musical Instruments
Baby grand
Kitchen Utensils
Cuts
Fabric
Grown in South
Clothing
Short-sleeves
Vegetables
From a pod
Relatives
Mothers sister
Electronic Appliances
Keeps cool
Precious Stones
Marriage
Stimulus Delivery and Recording
All auditory stimuli were delivered binaurally from an IBM 380ED notebook
computer using software written for stimulus presentation. Output from the computer
was amplified using a Kenwood KR-A4070 amplifier and routed through a two-channel
audiometer (Maico model MA52). Auditory stimuli were presented at 80db SPL (.0002
dynes/cm2 through a portable audiometer, Etymotic Research ER-30 transducers, 20 feet
of 4mm medical grade silicone tubing and ER3-14 foam insert earphones.
Participants verbalizations were recorded using a modified Jabba EarSet (TM)
microphone with ambient noise reduction. The microphone was secured to the standard
head coil and positioned proximal (8-10cm) from the mouth of the participant. The
microphone connected to a speaker allowing on-line monitoring of participants responses
during scanning and a Sony Digital Sound Recorder (ICD-R100) allowing verbalizations
to be stored in digital format for later off-line noise reduction using Cool Edit Software
(Syntrillium Software Corporation). Filtering the noise produced by the scanner was


73
necessary to increase intelligibility of spoken responses in order to code subjects
verbalizations according to the following parameters: correct, incorrect, inaudible or no
response. Correct responses were defined as those that were possible exemplars of the
category and/or were consistent with the semantic cue presented. Incorrect responses
were defined as those which were either not exemplars of the category or not did not
match the semantic cue, including bizarre and perseverative responses. Inaudible
responses included those in which a word was produced at the appropriate latency, but
was indecipherable due to ambient noise.
Image Acquisition
Each experimental run had 12 7.5 second periods of word generation (6 semantic
word generation, 6 free word generation). The silent repetition baseline condition
alternated with the word generation conditions and lasted for 10, 12.5 or 15 seconds.
Each length of baseline was used an equal number of times, with the exception of an extra
baseline period that was added to the end of each run.
Whole brain imaging was performed on a 3.0 Tesla GE Signa scanner using a
dome shaped radio frequency head coil. After adjusting sound levels for clear but
comfortable presentation, a series of T-l weighted 3-plane localization scans were
acquired to determine that the head was aligned such that the interhemispheric fissure was
within 1 degree of vertical. Head alignment in the coil was adjusted when necessary. For
fMRI sequences, 24 axial slices (6mm thick) were acquired for whole brain coverage. A 1
shot gradient-echo echo-planar imaging technique was used to acquire images with the
following parameters: TE = 25ms, TR = 2500ms, FA = 90 degrees, FOV (field of view) =
24mm, matrix size = 3.75mm x 3.75mm x 6.5mm. A total of 104 images were collected


74
during each experimental run.. After functional image acquisition, 96 (1.5mm thick)
structural image slices were acquired in the axial plane using a 3d spoiled GRASS
volume acquisition (TE =7ms, TR =23ms, FA = 25 degrees, NEX = 2, FOV = 24, matrix
size = ,7mm x ,7mm x 1,3mm).
Image Analysis
Functional images were analyzed and overlaid onto anatomic images with
Analysis of Functional Neuroimages (AFNI) software (Cox, 1996). To minimize effects
of head motion, time series images were spatially registered in 3-dimensional space. For
each participant, mean slice signal intensities were normalized to the grand mean of slice
intensity across functional runs. Voxels where the standard deviation of the signal
change exceeded 8 percent of the mean signal, were set to zero to attenuate large vessel
effects and residual motion artifact.
Prior to concatenating the time series, orthogonalization for linear trends was
completed. A single estimated hemodynamic response function was deconvolved from
the concatenated time series for each experimental task (freegen, semgen) using the
Deconvolve option in AFNI. The first image after stimulus presentation was excluded
from the analyses to control for motion artifacts. Deconvolution provides a best linear
least squares fit between the acquired time series and the estimated time series that
includes the following parameters: constant baseline and the BOLD (Blood Oxygen Level
Dependent) response to each condition. For purposes of comparison, magnitude of
response to each stimulus type was operationally defined as area under the curve of each
HRF, measured on a voxel-wise basis for the estimated hemodynamic response function
for each task.


After obtaining area under the curve on a voxel-by-voxel basis, anatomic and
3
functional images were interpolated to volumes with 1mm voxels, co-registered and
75
converted to stereotactic coordinate space of Talairach and Toumoux (1988) using AFNI.
Functional image volumes were spatially smoothed using an 8mm Gaussian full-width
half-maximum (FWHM) filter to compensate for variability in structural and functional
anatomy across participants.
Repeated measures t-tests were conducted on a voxel-by-voxel basis comparing
freegen and semgen tasks within each group. These two-tailed t-test procedures yielded t-
test maps. A voxel was considered to have significant activity above baseline levels if its
t-value yielded a probability < .001. To control for the large number of t-tests conducted,
only clusters of contiguously activated voxels equal to or greater than 150 microliters
were interpreted. Between subjects t-test were conducted to compare freegen and semgen
across groups. Between subjects t-tests were also performed comparing responses for
both the freegen and semgen tasks.


CHAPTER 10
RESULTS
Behavioral Data
A between-subjects ANOVA was performed to examine differences in task
performance between groups. Responses were coded as correct, incorrect, inaudible or no
response given.
Table 3
Behavioral Data (means and standard deviations)
Schizophrenia Group (N=10)
Comparison Group (N=10)
Correct responses3
38(4.7)
42.8(3.6)
Incorrect responses
5.6(3.3)
1.3(1.6)
Inaudible responses
l-S(l-S)
2(2.4)
No response
2.7(3.8)
1.8(2.1)
Semgen correctb
18.5(3.5)
21.5(1.3)
Freegen correct
19.5(2.1)
21.3(2.7)
a48 total correct responses possible
b24 total correct responses possible for freegen and semgen
Total number of correct responses across tasks differed between groups, as the
schizophrenia patients generated significantly fewer correct responses than comparison
subjects [F(l, 18) = 6.5, p = .02], This level of performance was due to a greater number
of incorrect responses in schizophrenia patients relative to the control subjects [F(l, 18) =
14.0, p = .001] and not to the number of inaudible responses [F( 1,18) = ,43, p = .52] or
failures to respond [F( 1,18) = .31, p = .58], which did not differ across groups. When
examining semantic and free word generation tasks separately, the schizophrenia patients
76


77
performed significantly more poorly on semgen [F( 1,18) = 6.5, p = .02] than controls.
They did not; however perform more poorly on the freegen task [F( 1,1 8) = 2.8, p = .11],
FMRI Results
The fMRI results from the between group comparisons of each word generation
task, performed with independent samples t-tests on a voxel-by-voxel basis ,will be
considered first given their direct relevance to the a priori hypotheses. Within group
comparisons of each word generation task, performed with repeated measures t-tests, will
follow.
Free Word Generation Across Control and Schizophrenia Groups
At a volume threshold of 150 microliters, a cluster connectivity radius of 1.8mm
and a statistical threshold of p< .001 per voxel, schizophrenia patients demonstrated
attenuated brain activation in the left medial frontal cortex (BA 8) and three lateral
prefrontal regions in the right hemisphere (BA 46, 9 and 10) relative to control subjects
(Table 4).
Table 4
Volumes of tissue (>150 microliters) showing significant activity changes (p< OOP
between schizophrenia and control groups on the free word generation task.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Left Medial Frontal
Cortex
L Medial BA 8
-3, 31, 60
-5.496
850
Right Orbitofrontal
Cortex
R BA 10
50, 40, 1
-6.288
849
Right Dorsolateral
Prefontal Cortex
R BA 46/9
29, 33, 54
-5.167
687
Right Dorsolateral
Prefrontal Cortex
R 46
43, 29, 45
-5.731
207
Note: BA = Brodmanns Area according to Talairach and Tournoux (1988) and Jasper et
al. (1995). Maximum t = maximum t value within a given cluster of activity.


78
Hypothesis 1 stated that schizophrenia patients would demonstrate attenuated
medial frontal activity (pre-SMA, BA 32) related to a deficit in generation and
monitoring of internally driven cognition (Frith, 1992). Consistent with this hypothesis,
schizophrenia patients demonstrated attenuated medial frontal activity relative to control
subjects. Activation in the medial frontal cortex during freegen represented the largest of
all statistically significant clusters for this comparison and was situated in BA 8 and the
anterior most limit of pre-SMA (Figure 3). This finding provides preliminary evidence
that the spatial extent of neural activity in the medial frontal cortex of schizophrenia
patients is diminished during internally guided word generation.
Figure 3. Sagittal and axial views of medial frontal cortex (BA 8; xyz = -3, 31, 60)
demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, p < .001.
The fractional signal change in two representative subjects (one control subject
and one schizophrenia patient) for voxels within the area showing significant between
group activity differences in the medial frontal cortex, is outlined in Figure 4. The
temporal characteristics of the hemodynamic response in these selected voxels, with the
first image excluded, may differ between groups; however there is considerable
variability amongst subjects (Figure 4).


79
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Figure 4. Fractional signal change over time in selected voxels in the medial frontal
cortex region demonstrating between group activity differences for one representative
schizophrenia patient (dotted line) and one representative control subject (straight line).
Hypothesis 3, that left lateral frontal regions, which subserve the stimulus driven
route to action (Frith, 1992) are intact in schizophrenia, was supported in that there were
no significant differences found between patients and controls in this region during free
word generation. Schizophrenia patients did; however show different levels of activity
relative to controls during the free word generation task in the right ventral frontal cortex
(BA 10; Figure 5), and right dorsolateral prefrontal cortex (BA 46 and 9; Figure 6).


80
Figure 5. Sagittal and axial views of right lateral prefrontal cortex (BA 10; xyz = 50, 40,
1) demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, g < .001.
BA 46/9; xyz = 29, 33, 54
BA 46; xyz = 43, 29, 45
Figure 6. Sagittal and axial views of right lateral prefrontal cortex (BA 46 and 46/9)
demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, g < .001,


81
Semantic Word Generation Across Control and Schizophrenia Groups
In contrast to free word generation, no difference in the medial frontal cortex was
observed between the schizophrenia and comparison groups during semantically cued
word generation. When viewed in the context of the free word generation analysis, this
finding is consistent with Hypothesis 2, which stated that between group differences in
the medial frontal cortex should be maximal for free word generation, given the degree to
which internal guidance is required for successful task performance (Crosson et al.,
2001a). Hypothesis 3, that left lateral frontal regions, which subserve the stimulus driven
route to action (Frith, 1992) are intact in schizophrenia, was supported. In that regard,
there were no significant differences between patients and controls in left lateral frontal
regions during semantic word generation
Similar to free word generation, schizophrenia patients demonstrated less activity
in lateral frontal regions in the right hemisphere in addition to several other cortical and
subcortical regions relative to control subjects during this task (Table 5).


82
Table 5
Volumes of tissue i>150microlitersf showing significant activity changes (p<.001)
between schizophrenia and control groups on the semani
tic word generation task
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Posterior
Cingulate Gyrus
BA 30
-7, -34, 1
-5.739
4949
Left
Parahippocampal
Gyrus and midbrain
-16, -27, -12
-5.152
510
Right Inferior
Frontal Gyrus
R BA 45
55, 40, 5
-5.999
432
Right Superior
Frontal Gyrus
RBA 8
29, 34, 53
-4.992
380
Right
Parahippocampal
Gyrus and Midbrain
15,-22, -9
-4.492
235
Right Dorsolateral
Prefrontal Cortex
RBA 46
43,29,45
-5.944
235
Right Angular Gyrus
RBA 19/39
42, -68, 44
-4.680
211
Right Pars Orbitalis
RBA 47
43, 30,-11
-5.074
152
Note: BA = Brodmanns Area according to Talairach and Tournoux (1988) and Jasper et
al., (1995). Maximum t = maximum t value within a given cluster of activity.
Regions in the right lateral frontal cortex demonstrating attenuated activation for
the schizophrenia patients included the frontal operculum (BA 45 and 47; Figure 7 and
8), dorsolateral prefrontal cortex (BA 46; Figure 7) and the superior frontal gyrus (BA 8;
Figure 9).
Figure 7. Sagittal view of cortex demonstrating significantly less activation in
schizophrenia patients relative to controls in several right hemisphere regions (BA 47,
19/39 and 46) during semantic word generation, g < .001.


83
To investigate the possibility of susceptibility artifact affecting activity in BA 47,
the data were examined on an individual subject basis. Results demonstrated that only 4
of 20 subjects showed significant activity in this region, suggesting that artifacts may
have contributed to the between group difference. Further, there appeared to be some
signal dropout in this region. Although it is unclear if this cluster of activity resulted from
artifact alone, caution should be exercised when interpreting this finding.
Figure 8. Sagittal and axial views of prefrontal cortex (BA 45; xyz = 55, 40, 5) in the
right hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001.
Figure 9. Sagittal and axial views of prefrontal cortex (BA 8; xyz = 29, 34, 53 ) in the
right hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001.


84
While both free and semantic word generation tasks resulted in a lesser degree of
activation for nearly identical regions of the dorsolateral prefrontal cortex (BA 46 and 9)
for schizophrenia patients compared to controls, there were several other regions in the
lateral right prefrontal cortex that demonstrated attenuated activation in the patients
during semantic word generation only (BA 45,47 and 8). This task related difference is
likely due to the increased semantic processing demands of the semantic word generation
paradigm (Petersen et al., 1988), a hypothesis that will be addressed more
comprehensively in the following chapter.
Other regions less active in patients relative to controls included the left and right
parahippocampal gyri and midbrain, specifically the substantia nigra on the right side
(Figure 10).
Figure 10. Axial and sagittal views (left and right) of the midbrain and parahippocampal
gyri demonstrating significantly less activation in schizophrenia patients relative to
controls during semantic word generation, g < .001.
Consistent with the pattern of attenuated activation in frontal and subcortical
regions in schizophrenia patients, posterior brain regions such as the angular gyrus (BA
39/19; Figure 7) also demonstrated less activation in the patients relative to controls.


85
Further, a cluster of activity including the posterior cingulate gyrus (BA 30), likely
reflecting venous activity, revealed the same pattern.
Free versus Semantic Word Generation in the Schizophrenia Group
At a volume threshold of 150 microliters, a cluster connectivity radius of 1.8mm
and a statistical threshold of p< .001 per voxel, a repeated measures t-test comparing free
versus semantic word generation in schizophrenia patients demonstrated more activation
in the right superior parietal cortex (BA 7) during free word generation (see Table 6;
Figure 10). This was the only region to demonstrate significant differences between tasks
in the patient group.
Table 6
Volumes of tissue (>15Qmicroliters) showing significant activity changes (pC.OOl)
between semantic and free word generation in the schizon
irenia group.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Parietal
Cortex
R BA 7
24, -67,45
6.736
281
Note: BA = Brodmanns Area according to Talairach and Toumoux (1988). Maximum t
= maximum t value within a given cluster of activity.
Figure 11. Sagittal, axial and coronal views of parietal cortex (BA 7; xyz = 24, -67, 45)
demonstrating significantly more activation during free relative to semantic word
generation in schizophrenia patients, p < .001.


86
Free versus Semantic Word Generation in the Control Group
A repeated measures t-test comparing tasks in control subjects demonstrated that
semantic word generation was associated with increased activation in frontal cortex while
free word generation was associated with greater activation in more posterior, temporal
cortex (Table 7).
Table 7
Volumes of tissue (>150microliters) showing significant activity changes (p<.001)
between semantic and free word generation in the control
grouD.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Superior
Frontal Gyrus
R BA 9
19,44,26
-6.080
315
Right Superior
Temporal Gyrus
R BA 21/22
65, -39, 8
6.157
184
Note: BA = Brodmanns Area according to Talairach and Toumoux (198
8). Maximum t
= maximum t value within a given cluster of activity.
Specifically, semantic word generation was associated with increased activity in more
anterior regions relative to free word generation, including the border between right BA 8
and 9 (Figure 12), while free word generation was associated with increased activity in
the right superior temporal gyrus (BA 21/22; Figure 13).


87
Figure 12. Axial, and coronal views of right lateral prefrontal cortex (BA 8/9; xyz =19,
44,26) demonstrating significantly more activation during semantic relative to free word
generation in control subjects, g < .001.
Figure 13. Sagittal, axial and coronal views of right lateral temporal cortex (BA 21/22;
xyz = 65, -39, 8) demonstrating significantly more activation during free relative to
semantic word generation in control subjects, g < .001


Full Text
MEDIAL FRONTAL CORTEX, INTENTIONAL ASPECTS OF LANGUAGE AND
SCHIZOPHRENIA: AN fMRI STUDY
By
LEEZA MARON
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2003

Copyright 2003
by
Leeza Marn

To the memory of my father.
In honor of my mother.

ACKNOWLEDGMENTS
This project was the collaborative effort of many individuals. My dissertation
advisor, Bruce Crosson, provided me invaluable exposure to the field of functional
neuroimaging throughout my graduate school career and allowed me the opportunity to
apply this technique to a fascinating, yet poorly understood psychiatric condition. From
him I learned the value of precision and tenacity as it applies to success in research and in
academia in general.
This study could not have been completed without the contribution of Christiana
Leonard, co-chair of my doctoral committee, and John Kuldau, the principal investigator
of the VA Merit Review grant that funded this study. Their laboratory is characterized by
an atmosphere of intellectual curiosity and enthusiasm, in which impromptu discussions
of topics such as the relationship of psychosis to neuroanatomy are common. It is from
these experiences that I developed an interest in the field of schizophrenia, which
continues to guide my future career goals. I am grateful to have worked with them and
appreciate their encouragement and warmth.
I am also fortunate to have learned from Rus Bauer, as a committee member,
clinical supervisor and instructor. The current project benefited considerably from his
extensive knowledge of neuropsychology and research design. Thanks should also be
extended to Bill Perlstein and Richard Briggs for providing critical guidance in the areas
IV

of statistical analysis and technical aspects of functional neuroimaging, respectively.
Their accessibility and willingness to teach did not go unnoticed.
Many individuals provided valuable behind the scenes assistance during this
process, often extending themselves beyond what was simply required. My friend and
colleague, Kaundinya Gopinath (Gopi), devoted many late nights and weekends to
processing raw data, teaching me the technical aspects of functional MRI and discussing
strategies for data analysis. I have come to admire his creativity and innovative approach
to both research and life in general. Thanks should also be extended to Tim Conway for
his assistance in the final stages of data analysis. His camaraderie made the journey much
more bearable.
The multifaceted task of running subjects, presenting and recording data in the
fMRI environment required input from a number of individuals with expertise in various
fields. My gratitude is extended to Yijun Liu and Guojun He (Alex) for sharing their
discoveries on the 3 Tesla magnet in addition to providing scanning assistance. Both
Debbie Moncrieff and Keith White were instrumental in creating an improved system for
the presentation and recording of auditory stimuli, while Andy James, a neuroscience
graduate student, was critically involved in the hands on duties of preparing subjects for
scanning. My thanks also go to Bob Frank and Edward Block for without their
generosity, data collection could not have been completed.
Although data collection was conducted at the University of Florida, my
colleagues at the University of California at San Diego, where the analyses were
completed, are well-deserving of thanks. My current mentor, William Perry, offered
consistent encouragement, reassurance and guidance despite what, at times, felt like a
v

slow and laborious process. Greg Brown, Terry Jernigan and their respective laboratories
generously provided me with didactic opportunities as well as the necessary resources to
complete this project.
Without participants, however, this study could not have taken place. I am
appreciative to those who invested their time and effort as subjects, particularly those
with schizophrenia who were motivated to participate in research in the hope that science
might make the lives of others with this debilitating disease less painful.
The most profound influence throughout my life, however, has been my family.
My father, a university professor, had a passion for learning and gift for teaching.
Although he is not able to share in this milestone with me, he continues to be my source
of inspiration. I am grateful too for my mother who has taught me the importance of
finding balance between work and life. Her dignity and self-reliance even in the most
difficult of circumstances encourage me to continue striving for my goals. It is in their
honor that I dedicate this manuscript.
vi

TABLE OF CONTENTS
page
ACKNOWLEDGMENTS iv
LIST OF TABLES ix
LIST OF FIGURES x
ABSTRACT xii
CHAPTER
1 INTRODUCTION 1
2 DEFINITION AND CLASSIFICATION OF SYMPTOMS OF SCHIZOHPRENIA., .5
3 NEUROPSYCHOLOGICAL FINDINGS IN SCHIZOPHRENIA 9
Methodological Considerations 9
Neuropsychological Deficits in Schizohprenia 13
Correspondence of Schizophrenic Symptoms and Cognitive Performance 17
4 FRITH'S MODEL OF SCHIZOHPRENIA 20
5 FRONTAL LOBES 26
Anatomy and Connectivity 27
Behavior Changes After Medial Frontal Lesions 37
Relationship of Medial to Lateral Frontal Cortex 40
6 STRUCTURAL BRAIN ABNORMALITIES IN SCHIZOPHRENIA 45
7 FUNCTIONAL IMAGING IN SCHIZOPHENIA 49
Methodological Issues 50
The Effect of Medication on Functional Imaging Data 52
Functional Imaging of Cognitive Activation Paradigms 55
Functional Imaging of Verbal Fluency 60
vii

page
8 RATIONALE OF STUDY AND HYPOTHESES 63
9 METHODS 67
Participants 67
Procedure 69
Experimental Tasks 70
Stimulus Delivery and Recording 72
Image Acquisition 73
Image Analysis 74
10 RESULTS 76
Behavioral Results 76
FMRI Results 77
11 DISCUSSION 88
LIST OF REFERENCES 105
APPENDIX
A DSM-IV DIAGNOSIS OF SCHIZOPHRENIA 121
B NATIONAL ADULT READING TEST 123
BIOGRAPHICAL SKETCH 124
viii

LIST OF TABLES
Table page
1. Clinical and Demographic Variables (means and standard deviations) 68
2. Categories and Semantic Descriptors for List 1 72
3. Behavioral Data (means and standard deviations) 76
4. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Schizophrenia and Control Groups on the Free Word
Generation Task 77
5. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Schizophrenia and Control Groups on the Semantic Word
Generation Task 82
6. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(p<.001) between Semantic and Free Word Generation in the Schizophrenia
Group 85
7. Volumes of Tissue (>150microliters) Showing Significant Activity Changes
(pc.OOl) between Semantic and Free word Generation in the Control Group....86
A-1. DSM-IV Descriptions of Symptoms of Schizophrenia 121
A-2. DSM-IV Features Associated with Schizophrenia but not Central to its
Definition 122
A-3. DSM-IV Subtypes of Schizophrenia 122
B-l. National Adult Reading Test 123
IX

LIST OF FIGURES
Figure page
1. Crosson and colleagues (1999) sketch of the medial frontal cortex demonstrating
the relationship between the cingulate sulcus (CS), the paracingulate sulcus
(PCS), the ventral to dorsal subdivisions of BA 24 (a, b & c) and supracallosal
BA 32 33
2. Sample portion of event related design used in the current experiment 71
3. Sagittal and axial views of medial frontal cortex (BA 8; xyz = -3, 31, 60)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p < .001 78
4. Fractional signal change over time in selected voxels in the medial frontal cortex
region demonstrating between group activity differences for one representative
schizophrenia patient (dotted line) and one representative control subject (straight
line) 79
5. Sagittal and axial views of right lateral prefrontal cortex (BA 10; xyz = 50, 40, 1)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p < .001 80
6. Sagittal and axial views of right lateral prefrontal cortex (BA 46 and 46/9)
demonstrating significantly less activation in schizophrenia patients relative to
controls during free word generation, p,<.001 80
7. Sagittal view of cortex demonstrating significantly less activation in schizophrenia
patients relative to controls in several right hemisphere regions (BA 47, 19/39 and
46) during semantic word generation, p <.001 82
8. Sagittal, axial and coronal views of prefrontal cortex (BA 45; xyz = 55, 40, 5) in the
right hemisphere demonstrating significantly less activation in schizophrenia
patients relative to controls during semantic word generation, p < .001 83
9. Sagittal and axial views of prefrontal cortex (BA 8; xyz = 29, 34, 53 ) in the right
hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001 83

Figure -page
10. Axial and sagittal views (left and right) of the midbrain and parahippocampal gyri
demonstrating significantly less activation in schizophrenia patients relative to
controls during semantic word generation, g < .001 84
11. Sagittal, axial and coronal views of parietal cortex (BA 7; xyz = 24, -67, 45)
demonstrating significantly more activation during free relative to semantic word
generation in schizophrenia patients g < .001 86
12. Axial, and coronal views of right lateral prefrontal cortex
(BA 8/9; xyz = 19, 44, 26) demonstrating significantly more activation during
semantic relative to free word generation in control subjects, g < .001 87
13. Sagittal, axial and coronal views of right lateral temporal cortex
(BA 21/22; xyz = 65, -39, 8) demonstrating significantly more activation during
free relative to semantic word generation in control subjects, g < .001 87
XI

Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
MEDIAL FRONTAL CORTEX, INTENTIONAL ASPECTS OF LANGUAGE AND
SCHIZOPHRENIA: AN fMRI STUDY
By
Leeza Marn
May 2003
Chair: Bruce Crosson
Cochair: Christiana Leonard
Major Department: Clinical and Health Psychology
Schizophrenia is a disabling mental illness that has been linked to dysfunction in
neural circuitry that includes the frontal lobes. One model of schizophrenia describes a
willed route to action, reliant upon motivation and self-initiation and a stimulus driven
route to action, dependent upon environment cues and contingencies. In schizophrenia,
the former is thought to be impaired, while the latter is considered intact. In relating this
to brain structure, functional imaging and lesion studies in humans as well as
physiological investigations in non-human primates have implicated the medial frontal
cortex in intentional aspects of cognition. The aim of the present study was to map the
hypothesis that schizophrenia patients have a deficit in the internal generation and
monitoring of cognition on to neuroanatomical regions using whole brain functional MRI
(fMRI). Two semantic word generation tasks that varied on the degree to which internal
guidance was required were administered to a sample of 10 clinically stable, medicated
male schizophrenia patients and 10 healthy control subjects matched on age, sex, parental
xii

SES and premorbid intellectual functioning. Monitoring of behavioral task performance
revealed that despite pre-scanning training, schizophrenia patients produced an elevated
number of incorrect responses during the word generation tasks. Analysis of the fMRI
results demonstrated attenuated activity in the schizophrenia group relative to healthy
controls in a number of brain regions including the left medial frontal cortex (BA 8), right
dorsolateral prefrontal cortex (BA 46/9) and parahippocampal gyri bilaterally. The
finding of attenuated medial frontal activity during the most internally guided task
suggests that schizophrenia patients are unable to recruit critical medial frontal structures
to the same extent as controls, reflecting a deficit in intentional aspects of cognition. The
findings also suggest that attentional dysfunction, which increases in severity with greater
semantic processing demands, characterized patients performance during word
generation.
xiii

CHAPTER 1
INTRODUCTION
The notion that schizophrenia involves dysfunction of the frontal lobes dates back
at least to Emile Kraepelin (1971). In his view, the primary behavioral deficit in
schizophrenia was due to volitional difficulties secondary to anatomic pathology of the
frontal cortex. His emphasis on symptoms suggestive of frontal lobe dysfunction has been
echoed throughout this century in the phenomenological and later neuroimaging studies of
the illness. In 1992, Frith published the Cognitive Neuropsychology of Schizophrenia, in
which he integrated neuropsychological investigations of schizophrenia with
neuroanatomical and cognitive models of brain processes, the goal of which was to
describe the information processing abnormalities that underlie the signs and symptoms of
the disease. He described a willed route to action, reliant upon motivation and self-
initiation and a stimulus driven route to action, dependent upon environmental cues, and
hypothesized that in schizophrenia the former is impaired, while the latter is intact. He
posited that both the negative and positive symptoms of schizophrenia are due to deficits
in the internal generation and monitoring of cognition.
For some time, cognitive neuroscientists have known that the medial frontal cortex
plays a role in the internal generation of cognition. Medial frontal lesions cause akinetic
mutism (Nielsen & Jacobs, 1951), a wakeful state of profound apathy in which motor and
cognitive initiative is absent, similar to the negative symptoms of
1

2
schizophrenia. Unilateral medial frontal lesions also cause alien hand syndrome (Frith,
1992) in which actions are released from occurring without a sense of effort or
intendedness, similar to the positive symptoms of schizophrenia. Further, numerous
nonhuman primate investigations have found that the medial frontal cortex supports
intentional aspects of movement (for review see Picard & Stride, 1996).
In terms of the relationship of medial to lateral frontal cortex, Goldberg (1985)
suggested that involvement of medial frontal cortex depends upon whether cognition is
triggered by internal or external contingencies. He maintained that actions driven by
internal models or motivation involve the Supplementary Motor Area (SMA), while
actions driven by external models or contingencies involve lateral premotor cortex.
Passingham (1993) deviated slightly from Goldbergs (1985) hypothesis by concluding
that neither internally nor externally cued movement is the exclusive domain of SMA and
lateral premotor cortex; rather it is the balance between the two that is critical. More
recently, Crosson and colleagues (2001a) published a functional neuroimaging (fMRI)
study with neurologically norma! subjects using word generation tasks that varied in the
degree to which internal guidance was required. The findings demonstrated that as
language output changes from externally to internally guided, greater reliance is placed
upon anterior aspects of the medial frontal cortex (pre-SMA; Brodmanns Area 32)
relative to left lateral frontal regions. Thus, that ratio of medial to lateral frontal activity
appears to be tied to internal guidance, particularly in pre-SMA. Another way of
interpreting these findings; however, is that the medial frontal cortex plays a critical role in
the monitoring of competition between processes that conflict during task performance
(Carter et al., 1998).

3
fMRI has been used to examine brain functioning in both healthy and patient
populations using hemodynamic activity or blood oxygenation level differences as an
indication of neuronal activity. It is a mapping technique ideally suited for the study of
schizophrenia as it provides excellent spatial and temporal resolution, the ability to
monitor behavioral task performance and the associated brain activation and to clarify the
relationship between individuals and diagnostic groups. While some efforts have been
undertaken to map Friths (1992) hypotheses onto brain structure using fMRI in
schizophrenia, none have sought to locate both the stimulus driven and willed routes to
action using tasks that reliably activate these systems in healthy subjects.
In the next chapter the definition and classification of the symptoms of
schizophrenia will be reviewed followed by the neuropsychological findings that
characterize the disorder. While the emphasis will be on measures that assess integrity of
the frontal lobes, such as verbal fluency, more general methodological issues in
neuropsychological studies will be discussed. Friths (1992) theory will be outlined in
greater detail in Chapter 4. Chapter 5 is concerned with the frontal lobes, including
anatomy, connectivity and function, in preparation for a review of the structural brain
abnormalities in schizophrenia in Chapter 6. As functional neuroimaging provides a
unique tool for studying the neural basis of schizophrenia, relevant findings are discussed
in Chapter 7, particularly those that shed light on the functioning of medial and lateral
prefrontal cortex. The challenges that counterbalance the potential of fMRI are included
in that chapter, with an emphasis on the potential implications of mediation on functional
imaging data. Rationale of the current study and hypotheses is presented in Chapter 8.

4
Finally, methods, results and discussion for this study are found in Chapters 9, 10 and 11
respectively.

CHAPTER 2
DEFINITION/CLASSIFICATION OF SYMPTOMS OF SCHIZOHPRENIA
Schizophrenia is a disabling mental illness that involves marked deficits in intellect
and personality, resulting in impairment in social, occupational, and emotional functioning
(Wing, 1978). Its characteristics include disordered cognition and perception, and
various deficits in relating to the environment. Emile Kraepelin (1971) was the first to
unify what had formerly been distinct categories of mental illness under the term
dementia praecox, chosen because of the irreversible intellectual deterioration and the
early age of onset that he observed. According to Kraepelin, dementia praecox involved
apathy and lack of drive, which he related to anatomic pathology of the frontal lobes.
When describing his patients, he searched for a cause of the organic disease that he
thought he had delineated (Gottesman, 1991). Thus, since its early description,
schizophrenia has been considered a disease of brain function that involves not only the
classic symptoms upon which the diagnosis is based but a wide range of cognitive deficits
as well.
In 1908, Eugen Bleuler coined the term schizophrenia, which means splitting of the
mind. By renaming the disease to focus on the splitting of the usually integrated psychic
functions, such as affect and cognition, Bleuler tried to call attention to two phenomena
that Kraepelin had downplayed, namely frequent recovery and affective disturbance
(Gottesman, 1991). He also argued that Kraepelins descriptions were based
5

6
on secondary symptoms rather than the primary symptom of disordered thought
processes. He argued that the primary symptoms of schizophrenia were loosening of
associations, autism (self-centeredness), affective disturbance, and ambivalence.
Delusions, hallucinations and catatonia were therefore thought to be secondary (Wing,
1978).
At present, the DSM-IV classification scheme is amongst the most widely used for
diagnosing schizophrenia in the United States (American Psychiatric Association, 1994).
Descriptions of the DSM-IV characteristic symptoms are provided in Appendix A, Table
A-l. The DSM-IV symptoms that are associated with schizophrenia but not central to its
definition are listed in Appendix A, Table A-2.
The diagnostic criteria of the DSM-IV are based upon symptom presentation and
have little or no relationship to pathophysiology or etiology of the disorder. The five
subtypes, catatonic, disorganized, paranoid, undifferentiated and residual, are described in
more detail in Appendix A, Table A-3. While these subtypes have been differentiated in
terms of age of onset and prognosis (Fenton & McGlashan, 1991), no linkage has been
found with neurological or neuropsychological variables. The lack of significant
relationship between these subtypes and more biological variables is due to a number of
different factors. First, many patients who meet diagnostic criteria for schizophrenia do
not fall within any particular subgroup. Patients may also change from one subtype to
another during the course of their illness (Fenton & McGlashan, 1991).
Symptom overlap between DSM-IV subtypes and the high degree of heterogeneity
of schizophrenic symptoms has provided the impetus for a more feature-oriented approach
to studying neuropathology in schizophrenia (Frith, 1992). Classifying individuals on the

7
basis of symptom clusters has the advantage of grouping schizophrenic patients on
symptoms that have been found to be statistically related to one another. It has therefore
become customary to classify the typical features of schizophrenia into positive and
negative dimensions with reference to behavioral excesses and deficits (Crow, 1980).
Positive features are pathological by their presence and include hallucinations, delusions
and incoherence of speech. Negative features represent the loss of normal functioning and
include affective flattening, poverty of speech, motor retardation, apathy and lack of
sociability. There is some evidence that the clinical correlates of positive and negative
symptoms are not the same and that the two subgroups of symptoms vary independently
within individuals (Johnstone & Frith, 1996). Since they are not mutually exclusive, a high
level of symptoms in one cluster does not predict low levels in the other.
Some evidence from neuroanatomical and neuropsychological studies supports this
classification system. For example, negative symptoms have been associated with
structural brain changes such as enlarged ventricles, poor response to traditional
neuroleptic medication, chronicity and cognitive dysfunction, whereas positive symptoms
have not (Allen et al., 1993; Andreasen & Olsen, 1982). Functional imaging studies;
however have produced mixed results with some finding associations between symptoms
and brain activation (Artiges et al., 2000; Sabri et al., 1997;) while others have not (Frith
et al., 1995).
Since Crow (1980) identified the positive-negative dimension, other symptom
clusters have been found. More recently, Liddle (1987) suggested that disorganization
(inappropriate affect, thought disorder, difficulty in abstract thinking) may exist as a third
factor in addition to negative and positive dimensions. The problem with many of these

8
factor analytic studies; however is that the results are entirely determined by the measures
used to assess behavioral abnormalities (Frith, 1992). For example, Frith (1992) noted
that the Krawiecka scales, which are commonly used to assess the symptomatology of
schizophrenia, include hallucinations and delusions as the only experiential symptoms.
These scales, then, will not reveal different clusters of symptoms within the experiential
domain.
Based upon this brief review, it appears as though slow but consistent progress
has been made in understanding the relationship among the classical symptomatology of
schizophrenia, neurocognitive deficits and brain structure. Many of the behavioral
abnormalities that define the disorder have been eloquently discussed in the past; however,
more recent classification schemes have provided increasing evidence that schizophrenia is
a brain-based disorder. It is essential at this point to examine overall intellectual and
neuropsychological functioning in schizophrenia and its linkage to functional and
structural brain anomalies.

9
CHAPTER 3
NEUROPSYCHOLOGICAL FINDINGS IN SCHIZOHPRENIA
There is broad agreement that schizophrenia produces impairment in
neuropsychological functioning. However, no single test or neurocognitive construct
completely separates schizophrenia and control distributions (Heinrichs & Zakzanis,
1998). The picture is further complicated by a number of methodological issues including
medication effects, education, heterogeneity of symptoms, and the varied psychometric
properties of neuropsychological tests.
Methodological Considerations
The vast majority of schizophrenic patients are treated fairly vigorously with
medication; therefore consideration must be given to the potential effects of antipsychotic
as well as other types of medication on cognitive abilities (Frith, 1992). Anticholinergic
medication, which is often given to treat the extrapyramidal effects of traditional
neuroleptics, has been found to impair performance on neuropsychological tests of
memory (Bartus et al., 1982). Potent dopaminergic antagonists, such as the conventional
antipsychotics, have been hypothesized to affect frontal lobe metabolism as well as
cognitive functioning (Early et al., 1987). For example, evidence from non-human
primates and rats reveals impaired performance on tests of spatial working memory after
administration of haloperidol (Sawaguchi & Goldman-Rakic, 1994). Although it is likely
that typical neuroleptic medication negatively affects cognitive functioning, it is difficult to
maintain that all cognitive deficits in schizophrenia are due to medication effects.
Kraepelin (1971), for example, noted severe cognitive abnormalities amongst his patients,
prior to the invention of traditional neuroleptic medication. Further, some empirical

10
studies have failed to find a relationship between neuroleptics and cognitive function,
while a few have even reported improved cognitive function with antipsychotic medication
(see Rupniak & Iversen, 1993).
There is some evidence that atypical antipsychotics, which are thought to have
different neurochemical properties than the typical neuroleptics (e g., Olanzapine,
Risperidone, Quetiapine, and Ziprasidone) may improve cognitive functioning in
schizophrenia (Keefe et al., 1999). In a meta-analytic study, Keefe and colleagues (1999)
found that atypical antipsychotics, when compared with conventional antipsychotics,
resulted in improved performance on tests of verbal fluency, digit-symbol substitution, fine
motor and general executive functioning. It appears as though measures with a timed
component may be particularly responsive to novel antipsychotics as well as those
involving motor skills. Keefe et al. (1999) hypothesized that the advantage of atypical
antipsychotic medication could partially be a result of the decreased extrapyramidal side
effects of standard antipsychotics. Some researchers have speculated that the cognitive
improvement seen with atypical antipsychotic medication may be the result of effects at
the serotonin receptors. Others have argued that atypical antipsychotics do not actually
improve cognitive functioning but are simply less detrimental to the patients cognition
than typical antipsychotic medication.
The side effects of antipsychotic medication, therefore, complicate the
interpretation of poor performance on neuropsychological tests in that it is often difficult
to decipher whether cognitive deficits are due to medication side effects or are due to the
pathological process that underlies the disorder. In light of this evidence, studying
neuroleptic-naive patients would be an ideal approach to investigate the primary

11
neurocognitive deficits in schizophrenia. However, constraints, including an inability or
refusal on the part of these patients to participate in research as well as the ethical
responsibility on the part of health care workers to offer treatment, make this difficult. A
more practical but slightly less satisfactory approach may be to examine
neuropsychological functioning in patients taking atypical antipsychotic medication.
Other confounds in the research include the failure to control for important
demographic variables. Education is a particularly important factor given that the onset of
schizophrenia is typically in the late teens or twenties, a time when individuals are
beginning post-secondary education. Because reduced educational achievement is one of
the related features of schizophrenia, matching patients and controls on educational
achievement may not be an appropriate comparison (Swanson, et al., 1998). It has been
suggested by some investigators that parental education is a more appropriate matching
variable (Gur et al., 1990).
Another complicating factor in the study of schizophrenia is the role of sex. It has
been found that female schizophrenics typically experience an older age of onset and more
prominent mood symptoms, accompanied by a less chronic disease course (Andreasen et
al., 1990). Males have been found to have more extensive brain abnormalities than their
female counterparts (Andreasen et al., 1990). This evidence suggests that subtle
differences between male and female schizophrenic patients in terms of presentation,
chronicity, and brain structure may significantly affect the results of studies in which both
sexes are grouped together.
The extreme heterogeneity of schizophrenia as previously discussed has significant
implications for studies of neuropsychological functioning. Variance that exists both

12
within and between patient groups may wash out potential differences. Therefore,
examining the neuropsychological deficits associated with specific symptom subtypes or
investigating patterns of strengths and weaknesses in individual subjects may prove
fruitful.
Conflicting findings in the literature may also be due to limitations involving
assessment tools. First, the fact that a number of neuropsychological batteries have been
used in the study of schizophrenia makes comparisons across studies difficult. While some
investigators use a narrow range of neuropsychological tests to assess specific functions,
others use a broadband approach consisting of more extensive batteries to examine
patterns of neuropsychological strengths and weaknesses. This is a significant problem,
because in order to claim that a function is selectively impaired, it must be compared to
overall intellectual functioning. This points to the need for a generally accepted core
procedure for obtaining neuropsychological data that can adequately assess and
characterize patterns of behavioral impairment and preserved abilities in schizophrenia
(Gur et al., 1990). When developing a battery, the lowered threshold of schizophrenic
patients to withstand long testing sessions must be balanced with the desire to obtain
extensive data.
The psychometric properties of various neuropsychological tests may serve as yet
another limitation. Each measure that makes up a test battery is likely to have been
normed on different populations. This increased variability may mask potential subtle
patterns of strengths and deficits amongst schizophrenic patients. It is also likely that when
schizophrenic patients with good premorbid intellectual functioning experience a decline in

13
their neurocognitive functioning, it is not noted because it does not constitute an
impairment as defined by standard cutoffs (Heinrichs & Zakzanis, 1998).
Another concern is that neuropsychological tests that purport to investigate frontal
lobe functioning are relatively poor at pinpointing dysfunction to specific subdivisions of
the prefrontal cortex. The term frontal lobe tests has typically been used to refer to
those measures which are compromised in patients with tumors, vascular insults, traumatic
brain injuries and other diseases that affect the frontal cortex. While these insults affect
the integrity of the frontal lobe, the lesions are rarely circumscribed. Further, areas within
this region are highly interconnected and damage to one region may produce deficits
similar to damage to neighboring sites (Goldman-Rakic, 1987).
The aforementioned issues should be kept in mind when interpreting the results of
neuropsychological studies in schizophrenia. Subject variables such as the influence of
medication on cognition, demographic factors and heterogeneity of symptoms as well as a
number of psychometric issues regarding assessment tools are crucial in understanding the
conflicting findings in this area.
Neuropsychological Deficits in Schizophrenia
It is generally accepted that schizophrenic patients perform more poorly than
normals on a wide range of cognitive tests (Gold & Harvey, 1993). Saykin et al. (1991)
found that a group of unmedicated schizophrenic patients performed at least one standard
deviation below the mean of a normal control group matched for age, parental education,
handedness and race on all measures of a substantial test battery including the Wechsler
Adult Intelligence Scale- Revised. This finding has been corroborated by Kolb and
Wishaw (1983), who found that the mean difference in Full Scale IQ between a group of

14
medicated schizophrenic patients and a normal control group matched on age and
education was approximately 15 points. Upon closer investigation, it was determined that
the significant 19-point difference between Performance IQ scores largely influenced the
difference between groups whereas there was not a significant discrepancy in Verbal IQ.
Intradomain analysis failed to reveal significant differences between subtests within the
verbal domain; however, all subtests within the performance domain were performed more
poorly by the schizophrenic group. The difference in means was largest for the Digit
Symbol subtest and smallest for the Picture Completion subtest.
Considerable evidence exists for intellectual impairment in schizophrenia.
Differential deficits against this background of general cognitive dysfunction; however,
have been found on tests sensitive to frontal lobe damage by a number of investigators
using moderate to extensive test batteries (e.g., Kolb & Wishaw, 1983; Gruzelier et al.,
1988; Mckay et al., 1996). For example, there is substantial evidence that schizophrenics
fall within the impaired range on the Wisconsin Card Sorting Test (WCST; Kolb &
Wishaw, 1983, Sweeney et al., 1992). Their performance is characterized by completion
of fewer categories than normals, as well as increased perseverative errors and responses.
While patients performance may be normalized with explicit card-by-card instructions,
Goldberg et al. (1987) found that when instructions were removed, performance
immediately dropped to deficient levels. These impairments have been described as
deficits in working memory, attention, strategy shifting, abstract concept formation and
problem solving (Saykin et al., 1991).
Schizophrenia patients typically demonstrate deficits on other tests thought to be
reliant upon integrity of the frontal lobes, including the Trail Making Test, Stroop

15
Interference Task, Design Fluency and Continuous Performance Test. For example, Kolb
and Wishaw (1983) found that schizophrenic patients tended to produce a high number of
perseverative responses during the Design Fluency Task, a characteristic that also marks
their performance on the WCST. On the Stroop Interference Task, schizophrenic patients
typically demonstrate difficulty inhibiting inappropriate responses. According to a study
conducted by Beech and colleagues (1991) using a modified Stroop task, schizophrenic
patients also demonstrate premature release from cognitive inhibition. In this study it was
found that when a previously ignored distractor was re-presented, there was an increased
reaction time for normal subjects but not schizophrenics. Another consistent finding is for
schizophrenia patients to perform more poorly than healthy control subjects on nearly all
forms of the Continuous Performance Test (e.g., Heinrichs & Zakzanis, 1998) reflecting
difficulty with sustained attention.
Schizophrenic patients also tend to perform within the impaired range on word
generation or verbal fluency tasks such as Controlled Oral Word Association (COWA)
and letter fluency (Robert et al., 1998; Kolb & Wishaw, 1983; Mckay et al., 1996, Allen et
al., 1993, Gruzelier et al., 1996). These tasks involve the generation of words either to
letter cues (phonemic or letter fluency) or to instances of a category (semantic fluency).
During the fluency task, subjects initiate self-directed searches of the lexicon, in order to
retrieve and produce the appropriate word. Performance is thus dependent upon multiple
cognitive processes including, but not limited to, sensory processing of the cue, retrieval
of words from memory, the selection of an appropriate word, integrity/organization of the
semantic store and articulation of the response. In a meta-analytic review, Heinrichs and
Zakzanis (1998) found that verbal fluency is one of several tests that tend to be the most

16
impaired in schizophrenia. Performance is characterized by the production of fewer words
overall, frequent perseverations and numerous intrusions relative to normal subjects (Allen
et al., 1993; Gruzelier et al., 1988; Kolb & Wishaw, 1983; Liddle & Morris, 1991; Robert
et al., 1998; Sweeney et al., 1992;). These deficits are evident at the early stage of the
illness (Paulsen et al., 1996), appear to remain stable over time (Goldberg et al., 1993) and
cannot be easily explained by a generalized intellectual deficit (Crawford et al., 1993).
The overall number of words generated in verbal fluency tasks; however, does not
adequately capture the processes of initiation, search, retrieval and articulation. Clustering
during verbal fluency allows individuals to search for meaningful semantic fields, allowing
clusters of related words to be made available for recall. The amount of semantic
clustering appears to be positively correlated with the number of words generated by both
schizophrenic patients and normal controls (Robert et al., 1997). Switching, another
component of verbal fluency, has been defined as the ability to shift effectively from one
subcategory to another (Robert et al., 1998). This ability to switch appears to be positively
associated with the number of words generated during phonemic fluency tasks. Robert et
al. (1998) tested 78 medicated and unmedicated schizophrenic patients and found that the
patients differed from the control group on both semantic and phonemic fluency tasks.
The schizophrenic patients demonstrated impaired switching in the phonemic fluency task.
They also demonstrated less clustering and switching in the semantic task, resulting in the
generation of fewer words. Further, patients with schizophrenia have also been found to
benefit from cueing on verbal fluency tasks (Joyce et al., 1996), suggesting that the
presentation of external semantic fields assists patients in initiating and organizing the
preliminary lexical search. Taken together, these findings have been explained in terms of

17
decreased capacity to initiate willed action (Frith, 1992) and reduced access to semantic
memory resulting from difficulties in an organized search process (Allen et al., 1993).
An alternative hypothesis suggests that the temporal lobe mediated semantic store
may be disorganized in schizophrenia. In this regard, some researchers have found
significantly impaired semantic relative to letter fluency amongst schizophrenic patients,
suggesting a selective deficit in semantic information processing (Guorovitch et al., 1996).
Further, atypical associations between words produced on verbal fluency tasks (Rossell et
al., 1999) and the finding that schizophrenia patients verbal fluency performance does not
benefit from cueing (Goldberg et al., 1993) suggest that the breakdown in fluency
performance in schizophrenia may extend beyond that of deficient executive control to
involve disorganization of the semantic store.
Correspondence of Schizophrenic Symptoms and Cognitive Performance
Although it is possible to detect group differences in neurocognitive functioning
between schizophrenic and normal individuals, it is also important to investigate the link
between symptomatology and neuropsychological test performance. The negative
symptoms of schizophrenia have been associated with poor performance on a range of
cognitive tests (Crow, 1980) as well as poor premorbid functioning, chronicity, poor
response to traditional antipsychotic medication and enlarged ventricles (Audreasen et al.,
1982). Positive symptoms, in contrast, have been associated with better prognosis, better
response to traditional neuroleptics and minimal cognitive dysfunction (Andreasen &
Olsen, 1982).
To investigate the relationship between symptomatology and neurocognitive
functioning, Allen et al. (1993) compared 20 stable medicated schizophrenic inpatients

18
with a group of 25 depressed individuals and 10 healthy controls on a semantic verbal
fluency test. The control and schizophrenic groups were matched on sex, age and
premorbid IQ as estimated by the National Adult Reading Test (NART). Results revealed
that schizophrenics with negative symptoms such as poverty of thought, poverty of
movement and flattening of affect produced fewer words than the depressed and control
groups; however they did not differ in terms of the type of words produced. Patients with
incoherence of speech, in contrast, produced more variable words and category
inappropriate responses. These findings support the notion that poor verbal fluency
performance is not associated with the non-specific features of psychiatric illness such as
depressed mood. The findings also suggest that performance on tests of verbal fluency
may be qualitatively different for schizophrenic patients with negative and positive
symptoms. Indeed, other investigators (Liddle & Morris, 1991; Stolar et al., 1994) have
found that patients with negative symptoms demonstrate impaired verbal fluency
performance that can not be attributed solely to slowness in initiating motor responses,
limited switching and reduced clustering (Robert et ah, 1998). Some studies have
associated positive psychotic symptoms with reduced semantic fluency (Rossell et ah,
1999) and atypical associations between words produced (Paulsen et ah, 1996); however
failure to replicate these findings is common (e.g., Howanitz et ah 2000).
Taken together, evidence suggests that schizophrenia patients perform poorly on a
wide range of neuropsychological tests, particularly those that rely heavily upon executive
functions. Verbal fluency is one of several tests that tend to be the most impaired in
schizophrenia. Qualitative analysis of patients linguistic errors demonstrates frequent
perseverations, numerous intrusions, reduced clustering and limited switching. There is

19
also some evidence to suggest that these linguistic errors may be related to
symptomatology.

CHAPTER 4
FRITHS MODEL OF SCHIZOPHRENIA
In The Cognitive Neuropsychology of Schizophrenia (1992), Frith details evidence
from neuropsychological investigations of schizophrenia and integrates it with
neuroanatomical and cognitive models of brain processes. Two routes to action are
described: one that relies on environmental stimuli and contingencies and another that
relies on spontaneous and self-initiated action. In Friths (1992) theory of schizophrenia,
the former is thought to be intact, while the latter is considered impaired. Both the
negative and positive of schizophrenia are posited as resulting from deficits in the internal
generation and monitoring of cognition. Negative symptoms are understood as behavioral
abnormalities that can be observed by others and occur specifically in situations in which
actions must be self-generated. This can manifest in several ways. First, if one is unable
to spontaneously generate a new response, no action may be taken (poverty of action).
Second, an individual faced with the same inability to generate a new response might
repeat a previous response, though inappropriate in the current context (perseverative,
stereotyped responding). Third, one might respond inappropriately to a stimulus in the
environment (stimulus driven behavior). On the basis of this model, it is expected that
patients would not only show a lack of action, but in certain circumstances may evidence
stereotyped behavior or an excess of stimulus driven behavior
20

21
. Friths first prediction that impairment in the willed route to action results in poverty
of action, is supported by the fact that schizophrenia patients show flattening of affect,
poverty of speech and social withdrawal. In this regard, neuropsychological investigations
have demonstrated that schizophrenic patients, like patients with frontal lobe lesions,
demonstrate reduced responding on COWA and design fluency (Kolb & Wishaw, 1983).
Further, a number of studies have associated poor performance on COWA with negative
symptoms (Allen et al., 1993; Liddle et al., 1995). Functional imaging studies
investigating this phenomenon have shown attenuated activation in the medial frontal
cortex during suboptimal verbal fluency performance (Dolan et al., 1986; Fletcher et al.,
1996). Given that schizophrenic patients perform relatively well on vocabulary tests, their
lexicon is thought to be intact; however it is likely that their ability to perform a self-
directed search is impaired (Frith, 1992).
The second prediction is that individuals with a damaged willed route to action
will demonstrate perseverative and stereotyped responses that are manifested not only on
neuropsychological tests but in interactions with others. The tendency for schizophrenia
patients to perseverate on a theme or idea is common. Perseveration can also be observed
during the design fluency task (Kolb & Wishaw, 1983) and during a two choice guessing
task described by Frith (1992). In this task, the subject is required to repeatedly guess
whether the next card in a deck will be red or black. Normal subjects produce a roughly
random sequence of guesses similar to those generated by a computer. Schizophrenic
patients; however, tend to perseverate, giving the same response repeatedly.
The third of Friths (1992) predictions, that difficulties with internal generation will
lead to stimulus driven behavior, relies upon the hypothesis that the stimulus driven route

22
to action remains intact. According to Frith (1992), incoherence and incongruity can be
explained in terms of action excessively determined by irrelevant stimuli. Difficulties on
the Stroop task support this idea and reveal that schizophrenic patients have difficulty
inhibiting dominant response tendencies (Carter et al., 1997). Further, Liddle and Morris
(1991) found that incongruity and incoherence are associated with poor performance on
the Stroop task.
In an attempt to relate the negative features of schizophrenia to brain
abnormalities, Frith (1992) discusses the similarities between patients with frontal lobe
lesions and schizophrenic patients. Both show negative features including decreased
activity, social withdrawal, decreased interpersonal communication, flatness of vocal
inflection and unchanging facial expression. Areas that have been implicated in negative
features include the orbitofrontal cortex, cingulate cortex and supplementary motor area.
Patients with damage to the medial frontal cortex have been found to show akinetic
mutism and lack of spontaneous movement (Barris & Schumann, 1953). In monkeys,
Passingham (1993) has shown that lesions of the anterior cingulate cortex and
supplementary motor area result in impairment of self-initiated action; however, action
that relies upon external cues is spared.
The negative features of schizophrenia, according to Frith (1992) are due to
deficits in the generation of willed actions, while the mechanism underlying the generation
of stimulus driven action remains intact. In this regard, Goldberg (1985) suggested that
there is a medial system consisting of SMA for internally guided actions and a lateral
system for externally guided action. This hypothesis will be discussed more extensively
later; however, evidence supports the idea that damage to the more anterior aspects of the

23
medial frontal cortex can result in behavioral abnormalities similar to those seen in
schizophrenic patients. Given the heterogeneity of schizophrenia; however, the
pathophysiological basis of the disorder, is not likely to be found in one brain region such
as the frontal lobe. Frith (1992) suggests the presence of dysfunction in cortico-striato-
pallido-thalamo-cortical loops first described by Alexander and colleagues (1986). It
should be noted that each of the 5 loops involve frontal regions as targets and are heavily
influenced by dopaminergic input to the striatum.
Frith (1992) also describes a model for the positive or experiential symptoms of
schizophrenia, which he divides into hallucinations and delusions. A defect in the central
monitoring system is hypothesized to underlie both of these phenomena. For example,
patients with hallucinations and delusions fail to monitor their own internally generated
thoughts. As a result, they misperceive their own cognition and identify it as being
initiated by external agents. Some of the best evidence for this hypothesis comes from
passivity experiences, in which patients explicitly attribute their own thoughts to outside
agents in the case of thought insertion and thought broadcasting.
Evidence supporting this hypothesis comes from a study in which schizophrenic
patients were asked to generate category items and then to read category exemplars
presented to them (Bentall et al., 1991). One week later, when asked to identify the source
of the items, schizophrenic patients performed more poorly than normal subjects on the
task. Hallucinating patients were slightly more likely to misattribute items they had
generated themselves to the experimenter. To tease apart the study of self-monitoring
from source memory, Harvey (1985) required schizophrenic patients to first distinguish
between two external sources and then to distinguish between words they had spoken

24
aloud and those they had merely imagined. Results revealed that thought disordered
patients had more difficulty discriminating what they had thought from what they had said
in comparison to other psychotic patients and normal controls. Unfortunately Harvey
(1985) did not examine the relationship between hallucinations and task performance.
Delusions of control refer to experiences in which an individual feels as though his
or her thoughts are being controlled by external forces, rather than by his or her own will.
The neurological phenomenon of alien hand syndrome is similar in a number of ways.
First the alien hand performs actions in situations where such acts do not normally occur.
Second, the patient is not aware of the intended or actual action of the hand unless he or
she receives visual information about what the hand is doing. Alien hand syndrome is
typically associated with unilateral lesions to the medial frontal cortex, most often in and
around the supplementary motor area. Frith (1992) hypothesizes that this region is part of
more extensive neural circuitry that normally monitors (permits or suppresses) stimulus
elicited actions in the hand. As a consequence, the hand is released to perform the actions
that are normally performed without its awareness. Therefore, while delusions of control
are a loss of effort or intendedness that is normally associated with willed actions, the alien
hand syndrome is the release of actions that are not normally accompanied with a feeling
of effort.
The neuroanatomic circuitry that Frith (1992) implicates as underlying the positive
symptoms of schizophrenia is quite similar to that underlying the negative signs. He
suggests that brain structures including the dorsolateral prefrontal cortex, supplementary
motor area and anterior cingulate cortex are involved in the generation and monitoring of
willed action. Medial frontal regions including anterior cingulate cortex are thought to be

25
the source of the corollary discharge that tells whether action is self-generated or elicited
from an external source.
Friths (1992) hypotheses suggest a relationship between positive symptoms and
negative signs in terms of the severity of underlying brain abnormality. Positive
symptoms, as stated previously, are thought to occur because the structures responsible
for willed or internally generated action, no longer send corollary discharges to the
posterior parts of the brain involved in perception. Corollary discharge, according to
Teuber and Mishkin (1954) is the transmission of a signal from anterior to posterior
regions of the brain that informs the perceptual or posterior region about what is occurring
in more anterior regions. For example, in order for preparation for the results of a
voluntary movement to occur, there must be a movement command through the motor
system and a signal (corollary discharge) from anterior or frontal regions to more
posterior areas to anticipate a motor act. This corollary discharge enables the
perceptual areas to recognize that the changing sensory data are due to the commanded
behavior rather than agents in the environment. Thus, self-generated changes in
perception may be misinterpreted as having an external cause when frontal regions are
damaged. Dysfunction in frontal regions may also result in a failure to send messages to
the brain structures associated with response generation. This results in a lack of willed
action and the negative signs of schizophrenia.

CHAPTER 5
THE FRONTAL LOBES
Prior to discussion of anatomy and connectivity of the frontal lobes, several
methodological issues must be addressed. The first is that the majority of our knowledge
of frontal anatomy comes from the study of nonhuman primates. While these studies have
been quite useful in understanding the structure and function of the frontal lobes, it is
likely that the morphological differences between human and primate frontal cortex are
greater than for other cortical areas. This suggests the presence of functional differences
as well. For example, supracallosal Brodmanns Area (BA) 32, a region that is distinct
from BA 24 in terms of its cytoarchitecture, connectivity and function in humans, does not
exist in the monkey. It is important to note; however, that perigenual BA 32 exists in both
humans and monkeys. Although Picard and Strick (1996) have suggested that that
supracallosal BA 32 in humans is analogous to the cingulate motor area in the monkey, its
function, for the most part, remains enigmatic. While certain anatomical similarities are
present between human and monkey frontal cortices, a comprehensive circuit by circuit
comparison has yet to be achieved (Kaufer & Lewis, 1999)
Within the boundaries of the frontal lobe, diverse functions ranging from fine
motor control to working memory to complex social behaviors to attention are subserved
by a number of anatomically distinct but interconnected regions. The frontal lobes have
commonly been referred to as the executor of higher cognitive functions including
26

27
abstraction, problem solving and sequencing. Complex language, a uniquely human
function, is inextricably linked to many of these complex abilities. Given that animals do
not posses the ability to use complex language, it should be recognized that the
generalizability of animal studies is somewhat limited with regard to higher level
processes.
Finally, identification and classification of frontal lobe regions, as with other areas
of the cerebral cortex, are based upon morphological features such as sulcal landmarks
and microscopic analyses of constituent neurons. A number of different cytoarchitectonic
maps of the cerebral cortex have been created based upon laminar distribution and
neuronal density. While a modest amount of agreement exists between different maps,
investigators have varied considerably in defining the boundaries and number of regions in
the frontal lobe. This variation is due to methodological differences, individual subject
variation, and the absence of uniform morphological criteria (Kaufer & Lewis, 1999).
Brodmanns (1909) cytoarchitectural map of the cerebral cortex, which delineates
numerous cortical regions, has become the standard for human brain research and will be
emphasized in the following section (Vogt et al., 1995). It is however, important to
recognize that in the anterior cingulate cortex, for example, Brodmanns map does not
have the same level of detail as do other human and non-human primate classification
systems (see Vogt et al., 1995).
Frontal Anatomy and Connectivity
The frontal lobes comprise the anterior half of the cerebral hemispheres. On the
lateral surface they are demarcated by the central sulcus caudally and by the Sylvian
Fissure inferiorly. Within these borders, three functional regions on the lateral surface

28
have been described; motor, premotor and prefrontal regions. Most caudally, the
precentral gyrus (BA 4) or motor strip is a narrow band of tissue located immediately
anterior to the central sulcus, forming its anterior bank and depth and extending medially
to the depths of the cingulate sulcus. Histologically, it is a homogeneous region of
agranular cortex, characterized by a high density of Betz cells (Damasio & Anderson,
1993). More rostrally, premotor cortex (BA 6) parallels the lateral and medial extent of
the precentral gyrus and is often described as transitional cortex, the function of which is
closely related to motor activity. I will distinguish the lateral premotor cortex from the
medial premotor cortex, often referred to as supplementary motor area (SMA). Anterior
and ventral to lateral BA 6 is the inferior frontal gyrus, the most posterior portion of
which is called BA 44 or pars opercularis (Damasio & Anderson, 1993). BA 44 and an
adjacent region, BA 45 (pars triangularis), comprise Brocas area in the left hemisphere
and are known for their similar anatomic and functional connectivity. According to
Damasio and Anderson (1993) BA 44 and 45, and BA 47 (pars orbitalis), comprise the
frontal operculum. Areas 46 and 9 lie dorsal to BA 44/45, while the frontal eye fields, BA
8, lie dorsal to BA46/9 and are involved in oculomotor control.
There is some debate as to whether BA 8, 44, 45, 47 on the lateral surface should
be classified as part of the prefrontal or premotor cortex. Passingham (1993) defines
prefrontal cortex as the region anterior to BA 8, 44, 45 and 47, which can be divided into
two sectors, dorsal (BA 46 and lateral and medial BA 9) and ventral (BA 11,12, 13, and
14). Others have considered some of these regions, in particular BA 8, to be part of the
prefrontal cortex (Damasio & Anderson, 1993). Many of these schemes have been
created based upon the connectivity of these frontal regions with the thalamus. Prefrontal

29
cortex has commonly been defined as the region that is interconnected with the
dorsomedial nucleus of the thalamus; however evidence suggests that there are also
reciprocal connections between this region and other thalamic nuclei (Leonard, 1969).
The term prefrontal cortex, therefore, lacks specificity in that the constituent regions will
vary depending upon the view of the investigator. This inconsistency has been
demonstrated in our discussion of the lateral frontal regions and is even more marked
when for the premotor and prefrontal divisions of the medial wall. For the remainder of
this paper, the term prefrontal cortex will be used infrequently and regions will be referred
to primarilly by their Brodmanns number, connectivity and function.
On the lateral surface of the frontal lobes, in the most anterior position, lies the
dorsolateral and ventral/orbital regions. The dorsolateral region (BA 46 and 9) is thought
is be involved in spatial working memory and behavioral inhibition as well as a number of
other higher level cognitive processes (Goldman-Rakic, 1987). The more ventral region,
commonly referred to as orbitofrontal cortex (BA 11,12, 13, 14) is largely interconnected
with the limbic system. Although these areas show a fair degree of overlap, they have
different cortical and subcortical connections and are believed to be differentially involved
in behavior and cognition (Goldman-Rakic, 1987). There is a considerable amount of
research investigating the connectivity and function of these regions, as well as their role
in pathological conditions; however, a more detailed description of lateral and
orbitofrontal cortex is beyond the scope of this paper. This cursory overview was
provided in order to address the functional relationship between lateral and medial frontal
cortex.

30
Our understanding of the structure and function of the medial wall of the frontal
lobe has undergone dramatic changes in recent years (see Picard & Stride, 1996). Based
on anatomical work and physiological evidence, Matsuzaka et al. (1992j surmised that
medial BA 6 in the macaque can be divided into a posterior region located caudal to the
level of the genu of the arcuate sulcus and a more anterior region located rostral to the
genu, labeled SMA and pre-SMA respectively. Evidence supporting this division has come
from single cell recordings in which pre-SMA was found to contain a higher proportion of
neurons with cue responses, preparatory activity and time locked activity to a movement
trigger signal, than SMA proper. In other words, activity changes time locked to
movement onset were more frequently seen in SMA while activity changes during a
preparatory period preceding the movement were more common in pre-SMA (Matsuzaka
et al., 1992). Other physiological evidence reveals that intracortical stimulation in the
monkey has failed, for the most part, to evoke movement from pre-SMA (Luppino et al.,
1991). When movement was evoked, it tended to be slow or tonic consisting of multijoint
responses. In contrast, stimulation of SMA produced brisk isolated movements of the
head, forelimbs and hindlimbs in a somatotopic order.
These findings corresponded with histological data that revealed only the rostral
part of BA 6, corresponding to pre-SMA, receives afferent projections from the prefrontal
cortex and non-primary motor cortices (Luppino, et al., 1991). The connectivity of SMA
in contrast, was limited for the most part, to primary motor cortex. These differences
indicate that SMA has more direct access to the motor system than pre-SMA. Pre-SMA
appears to play a greater role in the selection and preparation of movement while SMA
may be more closely related to motor execution (Picard & Strick, 1996). The architectonic

31
distinctions corresponding to SMA and pre-SMA have been debated for some time;
however, the preponderance of evidence supports the distinction of labeling SMA as 6aa
and pre-SMA as 6ap.
In a review of functional imaging studies in humans, Picard and Strick (1996)
found support for two distinct motor areas in human BA 6 similar to those found in the
monkey. SMA was defined as the region caudal to a line extending upward from the
anterior commissure, while pre-SMA was defined as the more rostral region. Several
functional differences were noted between these two areas. The first is that pre-SMA
activation appeared to be associated with complex motor tasks, while SMA activation was
associated with more simple motor tasks. Another factor that influences the relative
amount of activation in SMA and pre-SMA is the level of skill acquisition. Finally,
whether a movement is self-paced or externally cued also appeared to significantly
influence the location of activation on the medial wall. Externally paced or cued tasks
elicited activation of SMA, while tasks that were more self or internally paced did not.
For example, activation of SMA was observed in association with simple repetition of
words (Petersen et al., 1988) while more complex and internally guided verbal tasks, like
silent word generation (Wise et al., 1991; Crosson et al., 1999) and self-ordered number
generation resulted in activation of pre-SMA, in addition to SMA (Petrides et al., 1993).
Another structure on the medial wall of the frontal lobe is the anterior cingulate
cortex, which in non-human primates, is a large and heterogeneous region that lies on the
ventral, rostral and dorsal margins of the corpus callosum and consists of large pyramidal
neurons in layer V that project to the motor system. It is demarcated dorsally by the
cingulate sulcus and ventrally by various portions of the corpus callosum. As studied in

32
primates, it retains diverse thalamic afferents including the anterior, intralaminar and
midline nuclei and the ability to sample inputs from more thalamic nuclei than any other
cortical region (Devinsky et al., 1995). Although non-human primates have a single,
constant and non-segmented cingulate sulcus, it should be noted that the medial surface
features of the human brain are more variable. The anterior cingulate region in humans and
animals consists of limbic cortex in BA 24, 25 and 33; however, supracallosal BA 32,
commonly referred to as paralimbic cortex, is present only in human brains. These regions
have been further subdivided due to their high degree of cytoarchitectonic and functional
differences. One convention involves a superior-inferior as well as an anterior-posterior
dimension (Vogt et al., 1995).
BA 24 forms a belt of tissue that follows the contours of the corpus callosum
extending dorsally into the cingulate sulcus. Within this belt, substantial evidence points to
the existence of a rostral to caudal division based upon cytoarchitectural, connectional and
functional differences in the monkey (Vogt et al., 1995). These regions have been labeled
as 24 and 24 based upon their rostral to caudal location, respectively. Area 24 has also
been referred to as perigenual while area 24 has been labeled as supracallosal. In terms of
their connectivity, area 24 has been found to receive heavy projections from the amygdala,
while area 24 receives projections from parietal cortex.. Differences between these two
regions also include greater neuronal density in area 24 relative to area 24. Functional
differences to be discussed later suggest that while area 24 may be related to some
affective processes, most evidence suggests that its role in affect is secondary to its role in
cognitive processes such as response selection (see Devinsky et al., 1995).

33
Area 24 and 24 have been divided based upon an inferior to superior dimension as
well. From ventral to dorsal, areas 24a and b are on the crest of the cingulate gyrus
whereas area 24c is on the ventral bank of the cingulate sulcus. These a, b and c
differentiations were not reported by Brodmann (1909); however recent evidence has
suggested that there is an inferior to superior transition from limbic cortex on the crest of
the cingulate gyrus to the true neocortex with premotor functions in BA 6 (see Figure 1;
Vogt et al., 1995).
Figure 1: Crosson and colleagues (1999) sketch of the medial frontal cortex
demonstrating the relationship between the cingulate sulcus (CS), the paracingulate sulcus
(PCS), the ventral to dorsal subdivisions of BA 24 (a, b & c) and supracallosal BA 32.
The cingulofrontal transition area 32 also referred to as paralimbic cortex, forms a
dorsal rim around area 24 and occupies the gyrus between the cingulate and paracingulate
sulci, when present. For the purpose of this paper, we are interested primarily in
supracallosal BA 32. The paracingulate sulcus is thought to contain the border between
BA 32 and medial BA 6 as well as separating BA 32 from BA 8 and 9, more anteriorly

34
(Paus et al., 1996). BA 32 is often labeled as transitional cortex because it contains a
mixture of cytoarchitectural features of cingulate cortex and adjacent frontal areas. More
research including functional imaging studies and evaluation of axonal connections in the
human brain is needed to substantiate whether this region has more in common with
cingulate or frontal cortex (Vogt et al., 1995). What is known about area 32 is that is has
a prominent cingulate layer V while also having a thin layer IV and large layer III
pyramidal neurons characteristic of more anterior frontal regions (Vogt et al., 1995).
Another important aspect of the medial frontal region involves the presence of
hemispheric asymmetries. Paus et al., (1996) examined 105 MRIs and found that the
anterior segment of the cingulate sulcus was larger in the right than in the left hemisphere,
whereas the opposite was true for the posterior segment. This is consistent with other
findings of rightward asymmetry of this region (Albanese et al., 1995). Whether or not this
is related to possible dominance of the right over the left anterior cingulate region in
affective processes remains to be determined (Paus et al., 1996). This hypothesis is
supported by a study conducted by Albanese and colleagues (1995) who found an even
more pronounced rightward asymmetry of this region after including the cortex on the
ventral bank of the cingulate sulcus and the medial surface of the cingulate gyrus. Paus et
al., (1996) also investigated the paracingulate sulcus; however the findings were less clear
cut. They noted that of 105 subjects, only 50 had prominent paracingulate sulci in both
hemispheres, thus complicating their findings. Results revealed that the volume of gray
matter buried in the paracingulate sulcus was significantly larger in the left than right
hemisphere. It was hypothesized that the larger paracingulate sulcus in the left hemisphere
may arise in compensation for the smaller anterior segment of the cingulate sulcus in the

35
same hemisphere. The fact that this hypothesized compensation occurs dorsally, not
ventrally to the rostral end of the cingulate sulcus might reflect the relative growth of BA
32 in the left hemisphere (Vogt et al., 1995). These findings have considerable importance
for interpreting functional imaging results that compare activation in terms of its intensity
and spatial extent across hemispheres.
In terms of function, PET studies suggest that perigenual area 24 is distinct from
the more caudal area 24. Caudal area 24, but not the perigenual part has been activated
with the Stroop task, letter and word generation (Petersen et al., 1988), complicated
finger movement sequences, self generated eye movements, and divided attention tasks
(see Vogt et al., 1995). Electrical stimulation studies have implicated area 24 in autonomic
reactivity in terms of changes in respiration, cardiac rates and blood pressure as well as
mydriasis, piloerection and facial flushing (see Devinsky et al,, 1995). Visceral responses
elicited by stimulation of this area have included nausea, vomiting, epigastric sensation,
salivation and bowel/bladder incontinence. Devinsky and colleagues (1995) suggest that
another important functional distinction between area 24 and area 24 is in the processing
of affective material. Electrical stimulation as well as PET studies confirm the
involvement of area 24 in emotional processing, while area 24 apparently has little direct
involvement in such functions. Based upon this evidence, it appears as though area 24
subserves some of the same functions as that of more dorsal regions including BA 32,
which will be discussed shortly and pre-SMA. Thus, connections between this region and
BA 32 in the depths of the cingulate sulcus are particularly important.
There is limited evidence as to the function of BA 32; however several studies
have implicated this region in the processes of generating words, a process that also

36
appears to rely on pre-SMA. Frith et al. (1991) found activation during a phonemic verbal
fluency task in the medial frontal cortex centered in BA 32. Similarly, Raichle et al. (1994)
found elevated blood flow in BA 32 while subjects were generating verbs to a list of
nouns. When the list of nouns was re-presented a number of times, the response
habituated; however the activation returned when a novel list was presented. Crosson et
al. (1999) used fMRI to map functional activity in the medial frontal cortex during the
generation of words to various semantic categories. Results revealed that when the
paracingulate sulcus was present, activity changes were centered within the paracingulate
sulcus including both dorsal and ventral banks The volume of activation seen on the
ventral bank of the paracingulate sulcus was significantly smaller than on the dorsal bank.
Occasionally, activity extended into the cingulate sulcus, but never extended ventrally to
the cingulate gyrus. Thus, the supracallosal medial frontal cortex most heavily connected
to the limbic system did not show any activity increase for word generation. Activation of
medial frontal cortex during word generation has been interpreted as related to the
initiation of cognitive processes. This interpretation is consistent with that of Picard and
Strick (1996) who proposed that simple speech activities like repetition tend to activate
SMA while more complex speech/language activities like word generation tend to activate
pre-SMA and some adjacent regions.
Picard and Strick (1996) also noted that supracallosal area 32 and possibly
supracallosal area 24c is analogous to the cingulate motor area in the monkey. Based
upon their review of the literature (Picard & Strick, 1996) it appears as though activation
in this region is related to the internal selection of movement while activation in more
caudal regions is not. Further, activation of area 24 has been observed in simple tasks

37
similar or identical to those that produce changes in SMA. Thus, the same anterior to
posterior distinction found in medial area 6 (SMA and pre-SMA) may apply to BA32 as
well. Evidence supporting this hypothesis comes from the suggestion that the connectivity
of BA 32 and pre-SMA are similar, an important finding because it explains why studies
investigating the initiation of language have demonstrated activation in both regions
(Picard & Strick, 1996).
In summary, findings suggest that pre-SMA, and adjacent supracallosal area 32 are
functionally related and play a role in initiating cognitive processes necessary for word
generation. This idea is supported by a number of different sources including functional
imaging studies in humans and electrical stimulation in animals, as well as investigations of
cytoarchitecture and connectivity. Lesion studies also contribute to our understanding of
the function of the medial frontal wall.
Behavioral Changes After Medial Frontal Lesions
A factor that complicates the investigation of the contribution of the anterior
cingulate cortex and pre-SMA/SMA to behavior is that although it is not uncommon to
find patients who have lesions involving these regions, isolated cingulate cortex or SMA
lesions are rare and surgical intervention in the inter-hemispheric space is infrequent
(Devinsky et al ., 1995). Spontaneous lesions of the anterior cingulate cortex caused by
tumors and strokes and almost always involve adjacent areas such as SMA, white matter
and the septum. This has caused some debate regarding which structures are necessary for
the initiation of speech and language. The mixed involvement of cingulate and adjacent
cortex in stroke is due to the distribution of the anterior cerebral artery (ACA). The eight
branches of the ACA supply not only the cingulate cortex, but distribute blood to the

38
medial portions of the orbital gyri, the entire medial aspect of the anterior two-thirds of
the cerebral hemispheres including SMA and through the recurrent artery of Huebner, the
head of the caudate nucleus, anterior putamen and the anterior limb of the internal capsule
(Devinsky et al., 1995). The complicated vasculature and anatomical inaccessibility of this
region make functional imaging as well as animal ablation studies particularly useful in
understanding its function.
It is not surprising then that lesions to the anterior cingulate cortex are associated
with a wide range of neuropsychological disorders including akinetic mutism, aberrant
social behavior, diminished self-awareness and depression (Barris & Schumann, 1953;
Devinsky et al., 1995; Nielsen & Jacobs, 1951). Akinetic mutism is a syndrome in which
speech is initiated only with significant external prompting. Barris and Schumann in 1953
reported one of the first cases of this type involving a 40 year old man whose post-mortem
exam revealed a lesion, more extensive on the left than right, in the area of the anterior
cingulate gyrus (BA 24). The lesion was not limited to the anterior cingulated; however,
and was found to encroach upon the inferior-medial portion of BA4 and BA 6 as well as
into BA 32. The patient demonstrated early signs of apathy that progressed to eventual
akinesia and mutism. The clinical course was later characterized by deepening stupor,
coma and death. The global nature of the initiation deficit seen in akinetic mutism,
suggests that the contribution of the medial frontal cortex is not limited to the language
domain (Crosson et al., 1999).
According to Devinsky et al. (1995), the most severe deficits in spontaneity of
speech and other motor functions probably follow bilateral lesions of the anterior cingulate
cortex as well as pre-SMA/SMA. Laplane (1981) reported a case with extensive bilateral

39
anterior cingulate damage accompanied by indifference, amnesia and prominent
inattention; however no akinesia or mutism was noted. It was argued that the
preservation of motor activity was related to sparing of pre-SMA/SMA as well as the
caudal anterior cingulate region, now thought to be analogous to the cingulate motor area
in the monkey. Unilateral neurosurgical resections of medial BA 6 have resulted in only
transient mutism or contralateral hemiplegia (see Devinsky et al., 1995). The behavioral
deficits in these patients have been found to improve so that only a slight hesitation during
rapid alternating movements and speech remains.
Lesion studies of nonhuman primates have provided more information regarding
the functional specificity of the subdivisions of the anterior cingulate as well as pre-
SMA/SMA. In one study non-human primates performed a task in which they raised their
arm to receive a reward (see Passingham, 1993). This is a voluntary task in which they
learned to perform a specific movement, but could work at their own pace. Lesions to
SMA produced far fewer attempts in the first 4 days after surgery. Another group of
animals had the lower bank of the cingulate sulcus (area 24) and the rest of the anterior
cingulate cortex removed. Their performance was similar to that of monkeys with SMA
lesions, consisting of significantly fewer responses compared to their performance prior to
the lesion. Further testing revealed that the monkeys could move with considerable speed.
They were also motivated and evidenced the ability to work on learning tasks for food. Of
interest is the fact that these monkeys performed well on a task in which tones cued them
to move their arm, while performing poorly on the self-initiated version of this task.
There is evidence that non-human primates with medial frontal lesions also
perform poorly on sequencing tasks and on tasks that require alternation between two

40
repetitive movements (see Passingham, 1993). What is common to all of these tasks is
that the animal must learn the correct movement without the aid of external cues.
Passingham (1993) hypothesized that the basic effect of medial premotor cortex lesions is
to impair retrieval of the correct movement in the absence of external cues. A deficit in
internally generated movement resulting from medial frontal lesion in the monkey, is
similar to the intentional deficit seen in humans with medial frontal lesions. These patients
often present as akinetic and mute; however with significant external prompting, they will
produce a response (Devinsky et al., 1995).
Taken together, lesion studies in humans and nonhuman primates reveal a variety
of behavioral disturbances associated with lesions of the medial frontal wall. One of the
most marked findings is a deficit in the generation of internally guided action and
cognition. In monkeys, Passingham (1993) suggested this deficit is accompanied by a
relatively intact system for responding to external cues. This is an important observation
and will be discussed in detail later. In terms of understanding the functional divisions of
the medial frontal cortex; however, human lesion studies are of limited value due to the
vasculature as well as the rarity of neurosurgical intervention in this region.
Relationship of Medial to Lateral Frontal Cortex
In 1985, Goldberg suggested that the involvement of medial frontal cortex depends
upon whether a wide range of behavior, including language, is triggered by internal versus
external contingencies. He focused on the divergent roles of the supplementary motor
area, defined as medial BA 6 and lateral premotor cortex including pars triangularis. The
fact that SMA was defined as the entire medial BA 6 is important since according to
Picard and Strick (1996) there are important functional divisions between the rostral pre-

41
SMA and more caudal SMA. Goldberg (1985) hypothesized that SMA is involved when
internal generation of language or action is required, whereas lateral premotor cortex is
involved in language and action that is externally guided.
After reviewing the literature, Passingham (1993) came to a similar conclusion
regarding the functions of medial and lateral frontal cortex. In applying this principle to
movement, Passingham (1993) noted that lateral premotor cortex is relied upon to a larger
extent when movement is driven by external cues. When movement is driven by internal
cues; however, medial frontal cortex is thought to play a greater role. Passingham (1993)
deviated from Goldbergs (1985) hypothesis; however, when he concluded that neither
internally nor externally cued movement is the exclusive domain of SMA and lateral
premotor cortex, respectively. Rather, it is the balance between the two regions that is
important.
Support for Goldbergs (1985) and later Passinghams (1993) theories has been
mixed. Deiber et al. (1991), using right hand motor tasks, found less activity in BA9 and
46 as well as left SMA during externally versus internally guided movements. In addition,
lateral premotor cortex activation was greater during internally cued movement than
during a fixed-movement control task, whereas this region did not demonstrate significant
activity changes for externally cued movement versus the same control task. Frith (1991)
compared phonemic verbal fluency, an internally guided word production task, to
repetition, a more externally guided task. Phonemic fluency was associated with more
activation in both the medial frontal cortex, centered in BA 32, and lateral frontal cortex,
centered in BA 46. Similar but less extensive changes occurred for an internally as
opposed to an externally guided finger movement task. Neither Deiber et al.(1991) nor

42
Frith et al. (1991); however, compared the degree of change for medial and lateral frontal
cortex (Crosson et al., 2001a). This analysis is of interest because although both regions
show decreases as tasks move from internally to more externally driven, the proportion of
change, as suggested by Passingham (1993) could indicate a shift in the balance of medial
versus lateral frontal activity. Of note is the fact that the studies have been inconsistent in
terms of the areas of medial frontal (BA 32 or medial BA 6) and lateral frontal (BA 9/46
or lateral BA 6) cortex identified.
In an attempt to investigate the relative contribution of medial and lateral frontal
cortex to word generation, Crosson et al. (2001a) used fMRI to examine neural activation
during 3 word generation tasks. Each task varied in the degree to which internal guidance
was required. For example, free word generation required subjects to generate as many
exemplars as possible from a given semantic category. This was the most internally guided
word generation task. Paced word generation required subjects to generate an exemplar
from a given category in response to an auditory cue. This task is somewhat less internally
guided than free word generation. Semantic word generation was the most externally
guided word generation task in that subjects were required to generate exemplars from a
particular category in response to a semantic cue. Subjects also performed a word
repetition task during which they repeated heard words.
Results revealed that for both pre-SMA/BA 32 and the inferior frontal gyrus, there
is a general decrease in activity volume as tasks become more externally guided. The
ratio; however, of medial to lateral frontal activity for pre-SMA/BA 32 and the inferior
frontal gyrus decreased as word generation became more externally driven. This was due
primarily to a more rapid decrease in medial frontal activation. This shift is consistent with

43
Goldbergs (1985) and Passinghams (1993) hypothesis. As predicted by Goldberg
(1985), portions of Brocas area (pars triangularis) were found to be prominent in lateral
frontal activity, although this activity extended into other inferior frontal areas and the
insula as well. The relationship between pre-SMA/BA 32 and the middle frontal gyrus was
somewhat different because there was a large increase in middle frontal gyrus activity
between free and paced generation, which was responsible for the large drop in medial to
lateral frontal ratio. Overall, the ratio of medial to lateral frontal activity decreased as
word generation became more externally driven, representing a shift toward greater
influence of the middle frontal gyrus versus pre-SMA/BAA 32 for externally driven word
generation. With respect to the medial frontal cortex, it appears as though Goldbergs
hypothesis (1985) must be modified in that pre-SMA not SMA is involved in the medial to
lateral shift. Activation also extended into BA 32, a finding that is consistent with
predictions made by Picard and Strick (1996) about the function of BA 32.
In light of this evidence, there are several likely reasons why Frith et al. (1991) did
not observe a shift in medial to lateral frontal cortex during phonemic verbal fluency and
repetition. First, medial and lateral frontal cortex were not divided into the relevant
anatomic subregions. Second, the relative decrease in medial and lateral frontal cortex as
tasks became less internally driven was not compared.
In that regard, Crosson et al. (2001a) found that the ratio of medial to lateral
frontal cortex does not continue to fall as subjects perform a repetition task. Although
repetition is the most externally guided of the tasks, it requires less semantic processing
than the generation tasks. Evidence suggests that repetition can be accomplished primarily
on the basis of lexical information, with no need for semantic information (Crosson et al.,

44
in 2001a). When semantic processing is required, as in the word generation tasks, more
extensive activity has been found in the posterior inferior frontal gyrus in terms of volume
(Crosson et al., 2001a) as well as spatial extent (Petersen et al., 1988). Thus the degree of
internal versus external guidance is not the only difference between the generation and
repetition tasks. The fact that semantic processing is not required by the repetition task
likely accounts for the dramatic drop in inferior and middle frontal gyrus activation. This
may be the reason as to why the medial to lateral frontal ratio does not continue to
decrease during repetition for pre-SMA/BA 32 versus the inferior and middle frontal gyri.
Taken together, evidence supports the role of the medial frontal cortex in
intentional aspects of language production. Unlike Goldbergs hypothesis; however, the
areas on the medial wall involved seem to consist of pre-SMA and BA 32 for word
generation. In contrast, language that is driven by external contingencies relies more
heavily on lateral premotor cortex including pars triangularis. Passinghams (1993)
proposal that it is not a matter of absolute dominance of medial versus lateral frontal
activity for internally versus externally drive actions, it is rather, the shift in balance as the
degree of external guidance changes appears to be consistent with the bulk of the
evidence.

CHAPTER 6
STRUCTURAL BRAIN ABNORMALITIES IN SCHIZOPHRENIA
Post-mortem as well as MRI studies in schizophrenia have revealed reduced brain
size, enlarged ventricles, reduced brain asymmetry, reduced gray matter in association
cortex, basal ganglia and limbic system abnormalities (e.g., Andreasen et al., 1986;
Bogerts et al., 1985; Breier et al., 1992; Gur et al., 1994; Harvey et al., 1993; Jernigan et
al., 1991). The presence of structural abnormalities in the frontal lobes in particular are
commonly found, including overall reduced frontal lobe volume in patients with
schizophrenia (Andreasen et al., 1986; Brier et al., 1992; Harvey et al., 1993; Scheapfer et
al., 1994). Some investigations; however have failed to find differences in frontal lobe
volume between schizophrenics and control subjects (Andreasen, 1990; Young et al.,
1991; Wible et al., 1995). These inconsistencies may be due to inconsistent anatomical
definition. It is possible that in schizophrenia, structural abnormalities in the frontal lobe
are restricted to specific regions and that measuring total prefrontal volume is not specific
enough to reveal more subtle abnormalities within subregions (Baare et al., 1999). It is
also possible that that the neuronal pathology in this disorder is restricted to the cellular,
molecular and physiological domains and could be detected using functional neuroimaging
techniques, but not structural measurement. A competing hypothesis maintains that
quantitative variation in single neural characteristics are associated with specific symptom
dimensions. The vast majority of studies examining structural
45

46
abnormalities in schizophrenia do not investigate the relationship to specific symptoms.
Unlike other neurological disorders such as Alzheimers Disease or Huntingtons Chorea
in which histopathological features are readily identifiable, schizophrenic patients have not
been found to have any obvious changes at either the gross or microscopic level (Benes,
1998; Leonard et al., 1999). This complicates the attempt to establish pathophysiological
correlations and has made studying this disorder particularly difficult.
Several approaches to studying schizophrenic brains offer potential for greater
understanding of the biological basis of the disorder. The first is to focus on variation,
rather than central tendencies. To test the neuroanatomical risk factor hypothesis,
Leonard et al. (1999) selected features such as cerebral and third ventricle volume, and
markers of sulcal interruption or disturbed asymmetry in frontal, cingulate and parietal
association cortex. Results revealed that while individual structure measurement is quite
limited in its ability to distinguish schizophrenics from healthy controls, a combination of
10 measurements can correctly classify individuals approximately 77% of the time. Of
note is the fact that the posterior segment of the cingulate cortex extended less anteriorly
in the schizophrenics, a finding that is consistent with other evidence of disrupted
development and function in the cingulate cortex (Benes, 1998).
Benes (1998) argues that model generation and testing involving key corticolimbic
regions such as the anterior cingulate cortex, has the potential to provide insight into the
underlying pathophysiology of schizophrenia. A series of postmortem studies have shown
loss of interneurons, with changes maximal in layer II, a selective glutamatergic neuron
loss and altered GABA binding in the anterior cingulate of schizophrenic patients (Benes,
1998). Although reduced density of inhibitory interneurons has been found, glial counts in

47
the anterior cingulate are similar amongst schizophrenics and healthy controls. This
suggests that a typical degenerative process does not account for the brain abnormalities
seen in the disorder. Subsequent research examining the role of GABA, the principal
cortical inhibitory neurotransmitter, found evidence of up-regulation of the GABA
receptor at the postsynaptic pyramidal neurons in both the anterior cingulate and
prefrontal cortex. In terms of the role of dopamine, Benes (1998) first hypothesized that
the reduction of nonpyramidal neurons in schizophrenic patients could give rise to a
relative increase of dopaminergic inputs to the remaining GABA cells. However, further
analyses revealed that shift of cortical dopamine afferents from pyramidal to nonpyramidal
neurons in layer II of the anterior cingulate cortex provides a better explanation of
dysfunctional circuitry in schizophrenia. The strength of this model resides in its emphasis
on dysfunctional neural circuitry, emphasizing the role of medial frontal structures.
Further evidence for pathology of medial frontal structures comes from a study
that segmented the cortex of schizophrenic patients into 48 topographically distinct brain
regions on MRI (Goldstein, 1999). The largest volume reductions for the schizophrenics
relative to controls were found in the middle frontal gyrus and paralimbic brain regions
such as the anterior cingulate gyrus and paracingulate gyrus Another investigation
(Albanese et al., 1995) examined the laterality of the anterior cingulate in female
schizophrenic brains post-mortem. Of note is the fact that this investigation was confined
to the anterior (BA 24) and posterior cingulate (BA 23). BA 32 was excluded, as it was
thought to pertain to the frontal cortex and not the anterior cingulate gyrus. Results
indicated that the control subjects anterior cingulate was characterized by greater right
than left gyral weight and surface area. The schizophrenic patients, in contrast, showed a

48
significantly greater incidence of left laterality. At present, this is the first study to find
reversed asymmetry of the anterior cingulate cortex in schizophrenics.
Support for the hypothesis that subtypes or symptom dimensions are correlated
with the integrity of particular brain structures or circuitry is relatively weak (Chua &
McKenna, 1995). Most MRJ studies investigating the relationship between symptoms and
abnormalities in the frontal cortex have failed to find a significant link between the two
variables (Andreasen et al., 1986). Two studies that did find a relationship produced
contradictory results. Uematsu & Kaiya (1989) found that the severity of negative
symptoms was related to reduced frontal volume while Buchanan et al., (1993) found that
the severity of negative symptoms was related to larger prefrontal volumes. It was not
until more recently that Baare et al., (1999) measured volumes of gray and white matter in
the dorsolateral, medial and orbital regions of the prefrontal cortex. The findings included
a significant relationship between orbitofrontal gray matter (including ventral, medial and
lateral areas) and negative symptomatology in schizophrenic patients.
Overall, it is unlikely that an abnormality of only one brain structure can explain
the presence of schizophrenia in every patient with the disorder. Rather it is more likely
that abnormal function within a distributed neuronal circuit produces the characteristic
symptoms of the disease. Research suggests that this circuit likely includes regions of the
medial frontal cortex. Further, different elements of the circuit may be more obviously
affected in one patient than another producing symptoms of varying severity.

CHAPTER 7
FUNCTIONAL IMAGING IN SCHIZOPHRENIA
Functional neuroimaging has considerable potential for identifying the neural
circuitry involved in schizophrenia (Weinberger et al., 1996). Numerous investigations
using a variety of functional imaging techniques, including PET, fMRI, and SPECT, have
been reported in the literature in the past 20 years. While the results are not without
controversy, several general trends can be observed. The first is that groups of
schizophrenic patients tend to have relatively normal global and regional rCBF patterns
during resting conditions. The second is that is that during cognitive activation paradigms,
patients tend to differ from normal controls.
Activation paradigms have been used to examine cerebral blood flow or
metabolism during different behavioral states in order to provide a potential methodology
for studying brain function relevant to schizophrenia (Taylor, 1996). Functional
neuroimaging during the performance of a specific task has been used to control
behavioral state and stabilize brain physiology (Buchsbaum et al., 1984) or to provide a
cortical stress test to uncover diminished capacity (Berman, 1987). When performing
cognitive tasks, patients tend to show different patterns of activation relative to normal
controls. During tests of working memory, for example, they show less activation than
normals in the right dorsolateral prefrontal cortex (Carter et al., 1998). Further,
49

50
hypofrontality has been demonstrated in schizophrenia patients when compared to their
own healthy twin siblings (Berman et al., 1992). During other cognitive tasks such as cued
verbal recall, they show attenuated activation of the cingulate cortex (Dolan et al., 1995)
and deficits in frontal-temporal relationships (Lawrie et al., 2002). In general most of
these findings have been reproduced in acute, unmedicated patients, thus excluding a
primary role for medication artifacts (Weinberger et al., 1996). Results of cognitive
activation paradigms will be discussed at length later.
Methodological Issues
The functional neuroimaging data in patients with schizophrenia have generated a
number of important issues that must be examined. One issue concerns the interpretation
of activation differences in the face of group differences in behavioral performance. It has
been argued that since patients generally perform more poorly on many cognitive tasks,
hypofrontality or other abnormal-task evoked activity reflects a generalized phenomenon
or deficit, such as lack of engagement (Taylor, 1996). In fact, evidence from
neuropsychological investigations reveals that schizophrenia patients have deficits in
sustained attention and vigilance (Carter et al., 2001) that can result in poor task
performance. Activation deficits may therefore be artifacts of performance differences
between groups. One way of addressing this issue is to train subjects prior to scanning in
order to equate behavioral performance in patients and control subjects.
Attenuated activation can appear due to a primary deficit, which is a specific
disturbance in the brain region responsible for a given task that causes poor performance
and reduced activation. It can also occur due to a secondary deficit, which occurs when a
deficit in a brain region outside of the abnormal pattern of activation causes the proximal

51
abnormality (Taylor, 1996). Further, pervasive brain dysfunction, which involves
dysfunction in a system which has wide spread regulatory effects throughout the brain,
such as seen in neurodevelopmental abnormalities, can contribute to activation deficits
(Taylor, 1996). Finally, these deficits can also be viewed in terms of a compensatory
response or a failure to engage as previously discussed.
One method that has been used to address the issue of whether pervasive brain
dysfunction results in abnormal activation and deficits in task performance, is to integrate
a motor response task into the cognitive task (Callicott et al., 1998). Thus, activation of
sensorimotor cortex, a region that has been found to be functionally intact in schizophrenia
(Weinberger et al., 1996; Bogerts, 1993) is used as a reference or control region both
within and across groups.
Most functional imaging studies of schizophrenia have used nuclear medicine
techniques such as single photon emission computed tomography (SPECT) or positron
emission tomography (PET) which tend to have poor spatial resolution and rely upon
group averaging, creating the possibility of overlooking subtle individual differences
thought to be particularly important in studies of schizophrenia. An advantage of
functional magnetic resonance imaging (fMRI) includes improved spatial and temporal
resolution which allows investigation into the possibility that differences in activation
between groups might be due to activation of slightly different brain areas or to differences
in brain anatomy. Other advantages of fMRI include virtually unlimited study repetitions
which facilitate within-subject mapping and provide potential to highlight differences
between individuals and the relationship to symptomatology, straightforward registration
of functional and anatomic scans and the use of available MRI scanners.

52
For these reasons, fMRI can be viewed as an ideal individual mapping technique.
It may offer unique insights into several important questions, including the relationship
between individuals and diagnostic groups, the effects of medication on performance
differences on activation tasks, the distinction between state and trait findings, and the
reliability of findings over time (Callicott et al., 1996).
The unique potential of fMRI is counterbalanced by a unique set of challenges in
data acquisition, analysis and interpretation (Callicott et al., 1996). Any given signal
change detected during an fMRI study may not be related to neuronal activity, it may
instead result from various artifacts, including head movement. Motion has been shown to
account for significant signal changes and can be the source of differences between
populations, particularly with neuropsychiatric patients (Callicott et al., 1996; Weinberger
et al., 1996). Therefore, strategies to diminish patient movement are crucial for the
success of fMRI studies in neuropsychiatric populations. Approaches that have been used
include mechanical devices for limiting motion, image registration programs to correct for
certain types of movement and pre-training in a simulated scanning environment.
The Effects of Medication on Functional Imaging Data
Although all antipsychotic medications share the pharmacological property of
antagonizing D2 dopamine receptors, antipsychotic drugs vary substantially in their
pharmacological profiles, with each affecting a variety of neuroreceptors in the central
nervous system (Keefe et al., 1999). These differences could have important clinical
consequences, including selective effects on cognition and brain activation. It is important
to note that while neuroleptics are thought to have their antipsychotic effect at the D2

53
dopamine receptors (Farde et al., 1992), other neurotransmitter systems are affected by
antipsychotic medications including cholinergic, adrenergic, and serotonergic systems.
The first neuroleptic, chlorpromazine was serendipitously identified as a potent
antipsychotic drug for schizophrenia nearly a half century ago (Holcomb et al., 1996).
Since then, many different neuroleptics including haloperidol have been developed. These
are the classical or typical neuroleptics which have an antipsychotic effect but also induce
extrapyramidal symptoms. The antipsychotic effect is presumably due to binding at the D2
family of dopamine receptors, thereby reducing dopamine-mediated neural transmission. A
cascade of neural changes presumably occurs in the dopamine D2 terminal areas and their
projection sites subsequent to the receptor blockade (Holcomb et al., 1996). D2 receptor
imaging studies have also revealed that standard doses of antipsychotic drugs result in
unnecessarily excessive levels of drug occupancy at D2 receptors and account for the
extrapyramidal side effects (Heinz, et al., 1996).
Holcomb et al., (1996) examined the brain regions functionally altered by
haloperidol using PET. Patients with schizophrenia were scanned during a stable period
of haloperidol treatment and 30 days after cessation of the drug. Results revealed
increased glucose metabolism in the caudate, putamen and thalamus with haloperidol
administration. In contrast, haloperidol was found to decrease glucose utilization in the
medial frontal cortex and inferior frontal gyrus. Holcomb et al., (1996) hypothesized that
this pattern of change is not due to discrete effects of haloperidol at each of these regions,
but is mediated by the brains cortico-striato-pallido-thalamo-cortical networks described
by Alexander et al., (1986).

54
Clozapine, an atypical neuroleptic, is an antipsychotic drug with a clinical and
pharmacological profile that differs from the classical neuroleptics (Lundberg et al.,
1989). It is associated with a low incidence of extrapyramidal side effects and has been
efficacious in treating many patients who do not respond to classical neuroleptics. Farde
et al., (1992) investigated the biochemical properties of clozapine using PET and found
that patients treated with clozapine have significantly lower occupancy of the D2 receptors
in the basal ganglia than patients treated with classical neuroleptics. The patients treated
with clozapine were also found to have similar D1 and D2 receptor occupancies. It was
thus hypothesized that the combination of a relatively low D2 and high D1 occupancy is a
unique property of clozapine. Unfortunately, Farde et al., (1992) examined only the basal
ganglia and did not investigate how the effects of clozapine differ from those of the typical
neuroleptics on the frontal cortex.
In a study using 11-C labeled clozapine visualized by PET, Lundberg et al., (1989)
found a significant amount of binding in the frontal cortex that had not been displaced by
haloperidol. Lundberg et al., (1989) hypothesized that this finding might represent binding
to D1 receptors. It was also suggested that the unique properties of clozapine might be
due to its effect on non-dopaminergic receptors in the frontal cortex. Unlike conventional
antipsychotics, it has been found to have high 5-HT receptor affinity (Pickar et al., 1996).
Clozapine has also been found to have a high affinity for D4 receptors (Van Tol et al.,
1991); however the relationship between the D4 receptors and its antipsychotic effects is
unclear.
Neuropharmacological imaging has revealed some surprising and important results
with respect to the mechanism of action of antipsychotic drugs, demonstrating how these

drugs achieve their antipsychotic effects and the brain regions that are affected. Typical
antipsychotics have been found to decrease glucose metabolism in the medial frontal
cortex. With respect to functional imaging, this is likely to create or contribute to an
attenuated medial frontal response that can be erroneously interpreted as reflecting an
underlying pathological process of schizophrenia. Although less is known about the
regional effects of atypical antipsychotics, clozapine in particular, they appear to have a
lower D2 receptor occupancy than do the typical neuroleptics and may produce less
attenuation of activity in the medial frontal cortex. While further research is clearly
needed in this area, preliminary evidence suggests that when studying the medial frontal
cortex in medicated schizophrenic patients, including only those patients treated with
atypical neuroleptics may prove to be a more stringent method for investigating medial
frontal functioning.
Functional Imaging of Cognitive Activation Paradigms
Some of the first activation studies in schizophrenia were conducted by Franzen
and Ingvar (1975) using Xenon (Xe) 133 methods and suggested that hypoactivation of
the prefrontal cortex characterized the disorder. Support for this finding came from a
number of studies using the Xe probe technique and later SPECT, which found attenuated
prefrontal activation in schizophrenic patients during performance of the WCST
(Weinberger et al., 1986/ The only negative finding occurred in a group of male
schizophrenic patients who did not show performance deficits on the WCST compared to
normal controls (Kawasaki et al., 1993). Prefrontal dysfunction therefore appears to be a
fairly consistent finding in schizophrenics performing the WCST; however it is likely that
differences in performance play a major role in determining the results (Taylor, 1996). To

56
address this issue, Goldberg et al. (1990) matched schizophrenics and patients with
Huntingtons disease on WCST performance and found that the Huntingtons patients
demonstrated greater prefrontal activation than the schizophrenia patients. This finding is
important because it suggests that prefrontal cortical activation is necessary but not
sufficient to perform the WCST (Taylor, 1996).
Since that time, a number of functional imaging studies have been conducted with
schizophrenic patients using a variety of cognitive tasks. One of the most consistent
findings amongst these studies is abnormal activation in the medial frontal cortex. This
should not be a surprising finding given the structural and physiological evidence for
dysfunction in that region. That being said, virtually none of the aforementioned WCST
studies reported abnormal activation of the medial frontal wall; however methodological
constraints of early functional imaging technology made accurate detection of mesial
frontal cortex activation nearly impossible. One of these studies, however using SPECT,
did report attenuated activation in medial frontal structures (Kawasaki et al., 1993).
In this regard, Andreasen et al. (1992) found a failure to activate the mesial frontal
cortex in a group of neuroleptic-naive schizophrenic patients while they performed the
Tower of London task, which requires ordering sequential movements of balls threaded
onto sticks to solve a puzzle. This finding was interpreted as dysfunction specific to the
task at hand, and not general attentional impairment or lack of motivation. Patients with a
high degree of negative symptoms failed to activate medial frontal cortex; however the
same relationship was not found for those without a high degree of negative
symptomatology. This finding can be interpreted in one of two ways. The medial frontal
cortex, including the anterior cingulate cortex, is activated by tasks which involve novelty

57
and is not activated to a great extent by stimuli that are repeatedly presented. It is possible
that the Tower of London task elicited a novelty response in all but the patients with
prominent negative symptoms. A more likely explanation is that decreased activation of
the medial frontal cortex reflects deficiencies in motivating responses to stimuli.
Several studies attempting to relate positive symptoms to patterns of brain
activation have discovered possible medial frontal dysfunction. In 1996, McGuire et al.,
investigated the hypothesis that a predisposition to verbal auditory hallucinations might be
associated with an abnormal pattern of brain activation during tasks which involve the
generation and monitoring of inner speech. Schizophrenics with hallucinations were
compared to those without hallucinations and normal controls on 3 tasks: silent reading,
sentence generation and an auditory verbal imagery task which required subjects to
imagine that sentences they had generated were being spoken to them. When the silent
reading task was subtracted from the auditory verbal imagery task, schizophrenics with
hallucinations displayed reduced activation in the left rostral SMA and left medial BA 8
relative to controls. When compared to non-hallucinators, only left rostral SMA was
significantly less active. McGuire et al., (1998) conducted another study in which thought
disordered schizophrenic patients were instructed to describe viewed pictures while
undergoing PET scans. Results indicated that the severity of thought disorder was
inversely correlated with activity in the left inferior frontal and bilateral cingulate cortex
(BA 24) suggesting that these patients fail to engage areas which normally control the
production of speech. Taken together, these studies reveal that schizophrenic patients with
positive symptoms fail to activate a number medial frontal structures including BA 24,
medial rostral BA 6 and medial BA 8 during two different cognitive tasks. This finding

58
provides support that deficits in the generation and monitoring of cognition (Frith, 1992)
are related to deficits in medial frontal 1 cortex.
In contrast, is a PET study in which patients with passivity experiences, such as
thought insertion and thought broadcasting, performed 3 motor tasks with a joystick: free
movement, stereotyped clockwise movement and rest (Spence et al., 1997). During freely
selected movement, the patients with passivity experiences demonstrated hyperactivation
relative to schizophrenic patients without passivity experiences in the anterior cingulate
gyrus (BA 23/24). When the patients with passivity phenomena were compared to
controls on this task, they demonstrated hyperactivation of the anterior cingulate gyrus
(BA 32) and left medial BA 6. This study appears to contradict findings of attenuated
medial frontal activation during cognitive activation paradigms in schizophrenia. One
explanation is that passivity phenomena are associated with a different pattern of medial
frontal activation than other positive symptoms. Another factor influencing the results may
be the reduced spatial resolution of PET, particularly for medial structures, which makes
ascertaining the laterality of the activation difficult. If differences in hemispheric
asymmetry exist in the medial frontal cortex in schizophrenia (Albanese et al., 1995), it is
possible that one hemisphere may demonstrate hypoactivation while the other may
demonstrate hyperactivation.
Carter et al. (1997) used PET to examine activation while schizophrenics and
healthy controls performed the Stroop task. Attenuated anterior cingulate activation was
found for schizophrenics during the color-incongruent condition relative to controls. The
locus of the reduced response was within the rostral anterior cingulate gyrus (BA 24), and
indicates that this region may play a role in higher level cognitive functioning. This

59
suggests that the rostral/caudal division of the anterior cingulate may be less clear cut than
previously thought. It also suggests the possibility of a pathological processes in
schizophrenia in the pregenual anterior cingulate.
Further, Crespo-Facorro et al. (1999) scanned schizophrenic patients using PET
during recall of novel and practiced word lists. The patients and controls did not differ in
their performance on either task; however the patients demonstrated decreased activation
during the practiced task in left BA 46, bilateral BA 32 and 43, left medial BA 6 and
several other regions relative to controls. Further evidence for dysfunction of BA 32
comes from a study of semantic processing in which schizophrenic patients evidenced a
negative correlation between the left anterior cingulate (BA 32) and superior temporal
gyrus (BA 22) relative to controls (Jennings et al., 1998). Once again, performance
between controls and schizophrenics was not significantly different.
Interpretation of many of these studies is complicated by the fact that little
specificity is provided regarding neuroanatomic regions. For example, during a continuous
performance task, Buchsbaum et al. (1992) reported that schizophrenic patients
demonstrated attenuated activation in medial frontal areas as well as the anterior
cingulate (p.937). Other studies that have revealed attenuated anterior cingulate or
medial BA 6 activation include a finger to thumb opposition task (Schroder et al., 1995)
as well as a serial tone position task (Stevens et al.,1998). In both cases attenuated
activation could not be attributed to a performance deficit. Given the functional
differences of SMA and pre-SMA as well as BA 32 and BA 24, it would be of interest to
decipher if this attenuated activation had a more rostral or caudal extent.

60
Functional Imaging of Verbal Fluency
Functional imaging studies of verbal fluency in schizophrenia for the most part,
reveal attenuated activation in a number of frontal regions. Using fMRJ to examine
activation during a paced phonemic verbal fluency task, Curtis et al., (1998) found that
male schizophrenics receiving stable doses of atypical antipsychotic medication
demonstrated attenuated activation in the left middle and inferior frontal gyri, left insula
and right inferior frontal gyrus relative to controls matched on sex, age, premorbid IQ and
controlled oral word association performance. Schizophrenics also demonstrated
attenuated activation in caudal SMA (medial BA 6) during a repetition task. The finding
of medial frontal dysfunction in schizophrenia has been also been reported in a PET study
in which activation related to a paced verbal repetition task was subtracted from activation
related to a paced verbal generation task (Dolan et al., 1998). While normal controls
revealed a pattern of activation including the left dorsolateral prefrontal cortex, thalamus
and anterior cingulate cortex, a group of unmedicated male schizophrenics failed to show
activation in the anterior cingulate cortex (BA 24/32). After dopaminergic manipulation
with apomorphine, this relative failure of task-induced activity in the anterior cingulate
cortex in schizophrenics was reversed. When the number of subjects was increased,
(Fletcher et al.,1996) the finding of a relative failure to activate the anterior cingulate
gyrus (BA 24/32) amongst schizophrenia patients remained significant. This failure
supports other functional imaging studies that have revealed anterior cingulate
abnormalities in schizophrenia (Andreasen et al., 1992; Liddle et al., 1991; Tamminga et
al., 1992)

61
Verbal fluency without a paced component, was examined using fMRI in both
schizophrenia patients and controls (Yurgelun-Todd et al., 1996). The difference between
the averaged relative change in intensity during the covert verbal fluency task minus
activation related to a covert counting task was calculated and revealed that
schizophrenics fail to activate frontal regions, including dorsolateral prefrontal cortex (BA
46 & 10), during verbal fluency.
In an attempt to relate verbal fluency associated task activation with
symptomatology, Frith (1995) assessed this relationship by dividing 18 stable
schizophrenia patients into 3 groups on the basis of their verbal fluency; (1) poor verbal
fluency (2) odd verbal fluency (3) normal verbal fluency. All patients had marked negative
signs; however those with poor verbal fluency demonstrated a higher severity of negative
features. Disorganized patients tended to be in the second group, while patients with
hallucinations and delusions tended to be in the group with normal verbal fluency. PET
scans during paced phonemic fluency revealed that schizophrenics showed the same
pattern of activity as controls increased activity in left dorsolateral prefrontal cortex,
anterior cingulate and thalamus. Only in the superior temporal gyrus, did schizophrenia
patients show a different pattern of activation relative to controls. Further, no significant
differences were found between the subgroups of schizophrenia patients. This surprising
finding has been interpreted as evidence supporting a disconnection between frontal and
temporal regions in schizophrenia, leading to disinhibition in the latter area. The lack of
significant differences between subgroups may be due to few subjects in each group and/or
the apriori approach of measuring a small number of structures. This hypothesis is
supported by the findings of Lewis et al., (1992) who found a relationship between

62
negative symptoms, written phonemic fluency and reduced left mesial frontal activation
using a larger number of subjects.
Overall, functional imaging studies using cognitive activation paradigms including
verbal fluency consistently reveal prominent differences in the frontal cortex, particularly
in medial frontal regions, in schizophrenic patients relative to healthy comparison subjects.
Task differences, various imaging methodologies and poor definition of structures in the
medial frontal wall; however limit the conclusions that can be made. One tentative
explanation for these findings is that intentional aspects of cognitive activity, which rely
upon the integrity of medial frontal structures, may be disrupted in schizophrenia.

CHAPTER 8
RATIONALE OF STUDY AND HYPOTHESES
Frith (1992) proposed a model of schizophrenia that considers evidence from
neuropsychological investigations and integrates it with neuroanatomical and cognitive
models of brain processes. He posited that schizophrenia patients have a deficit in the
willed route to action. In this model, the negative and positive features of schizophrenia
are due to a deficit in the internal generation and monitoring of cognition. In contrast,
schizophrenia patients are thought to have an intact stimulus route to action, which relies
upon external stimuli and contingencies. In relating these phenomena to brain structure, a
considerable body of evidence from functional imaging and lesion studies in humans as
well as physiological and histological investigations in nonhuman primates, implicates the
medial frontal cortex in the internal generation of action. Goldberg (1985) hypothesized
that actions which are driven by internal models and motivations involve supplementary
motor area (SMA) more than actions that are driven by external models and
contingencies. These actions are thought to involve the lateral premotor cortex, including
Brocas Area when tasks require language production. Passingham (1993) deviated
slightly from Goldbergs (1985) hypothesis, when he concluded that neither internally nor
externally cued movement is the exclusive domain of SMA and lateral premotor cortex,
respectively. Rather, it is the balance between the two regions that is important.
63

64
More recently, an fMRI investigation using word generation tasks that varied on
the degree of external guidance required, found that pre-SMA/BA 32 activity volumes
decreased significantly and inferior frontal sulcus activity volumes increased significantly
as word generation tasks moved from internally to externally guided. These findings reveal
that the medial to lateral shift is less pronounced in SMA than pre-SMA/BA 32.
Passinghams observation was also supported regarding the balance of activation between
the two regions.
There is considerable evidence for frontal lobe dysfunction in schizophrenia, a
portion of which suggests dysfunction of the medial frontal wall. Schizophrenic patients
demonstrate selective deficits against a background of general cognitive impairment on
tests sensitive to frontal lobe damage, including word generation (e.g., Robert et al.,
1998). Although poor performance on frontal lobe tests by no means confirms that the
pathological process in schizophrenia is isolated to the frontal lobes, evidence from
structural and functional imaging studies suggests that frontal as well as other regions are
likely involved in the disease. For example, Benes (1998) conducted a series of
postmortem studies that revealed loss of interneurons, with changes maximal in layer II, a
selective glutamatergic neuron loss and altered GABA binding in the anterior cingulate of
schizophrenic patients. Other structural studies have found volume reductions in the
anterior cingulate gyrus and paracingulate gyrus (Albanese et ah, 1995; Goldstein et ah,
1995)
A number of functional imaging studies have revealed attenuated anterior cingulate
(BA 32/24) and pre-SMA/SMA activation during a variety of cognitive tasks including
word generation. Some have even found a relationship between symptomatology and

65
patterns of medial frontal activation (Andreasen et al., 1992; McGuire et al., 1998;
McGuire et al., 1996; Spence et al., 1996). The majority of these studies; however are
plagued by poor spatial resolution and often do not report with specificity the region of
the medial frontal cortex implicated in the study. This information is crucial given what
has been learned about internally and externally driven tasks and the subdivisions of the
medial frontal cortex (see Picard & Strick, 1996) and recent fMEJ evidence (Crosson et
al., 1999) that activation during internally and externally guided tasks is localized in
different medial frontal regions. Further, most studies do not examine both the willed and
the stimulus driven route to action.
The goal of the present study was to map Friths (1992) hypothesis that
schizophrenia patients have a deficit in the internal generation and monitoring of cognition
onto neuroanatomical regions using fMRI and two word generation tasks that vary in the
degree to which internal versus external guidance was required. These tasks have reliably
activated the medial frontal cortex in normal subjects and have provided evidence
regarding the relative contribution of the medial and lateral frontal cortex to word
generation (Crosson et al., 2001a). The present research therefore employed 2 word
generation tasks, found by Crosson et al. (2001a) to differentially engage medial frontal
regions (pre-SMA/BA 32) and inferior frontal gyrus (BA 44/45/47) and inferior frontal
sulcus (BA 6/8/9), in neurologically and psychiatrically normal subjects. Thus, the present
study compared medial and lateral frontal activity in schizophrenia patients and normal
controls during internally versus externally guided word generation. Experimental
hypotheses were as follows: 1) Patients with schizophrenia should demonstrate attenuated
activity in the left medial frontal cortex relative to controls due to difficulties with

66
internally generated cognitive activity; 2) Between group differences in the medial frontal
should be maximal for the more internally guided word generation task; 3) No discrepancy
between groups in terms of amplitude of response as well as spatial extent of activation in
left lateral frontal regions should be observed as the stimulus driven route to action (Frith,
1992) is thought to be intact.

CHAPTER 9
METHODS
Participants
10 clinically stable, medicated male schizophrenic patients participated in the
study. All met DSM-IV criteria for schizophrenia/schizoaffective disorder as assessed by
the Structural Clinical Interview for DSM-IV (SCID-IV; First et al., 1994) and medical
record review. Ten healthy, right-handed males served as comparison subjects. Exclusion
criteria for the comparison subjects included any lifetime Axis I disorder as confirmed by
the SCID-IV or first-degree family history of psychotic disorder. General exclusion
criteria for all participants included substance abuse within the past 6 months, history of
neurological illness including previous head trauma, mental retardation defined as an IQ
below 70 or being a non-native speaker of English. All participants were paid $10 per
hour for their participation and were informed of the potential risks of the study.
Informed consent was obtained according to institutional guidelines established by the
Health Science Center Institutional Review Board at the University of Florida.
All schizophrenia patients were receiving neuroleptic medication at the time of the
study including a variety of typical and atypical antipsychotic medications in addition to
mood stabilizing agents and antidepressants. Symptomatology was assessed with the Brief
Psychiatric Rating Scale (BPRS, Overall & Gorham., 1988), a 26-item clinician
67

68
rated instrument that measures the severity of a patients psychotic symptomatology on a
scale from 1 to 7. Scores range from 26 (no psychopathology) to 182 (severe psychosis).
An estimate of premorbid verbal intellectual functioning was obtained from the National
Adult Reading Test (NART), a brief screening measure containing 50 irregular words
(Nelson, 1982; Appendix B) that has been used extensively with schizophrenia patients
(e.g., Russell et al., 2000). Raw number of errors was calculated in addition to an estimate
of the premorbid WAIS Verbal Intellectual Quotient (VIQ; Wilson et al., 1978).
Handedness (Briggs & Nebes., 1974), parental socioeconomic status (SES; Hollingshed,
1975) and current general intellectual functioning, as measured by the Broad Cognitive
Ability (BCA) score from the Woodcock-Johnson Test of Cognitive Abilities (Woodcock
et al., 1989), were collected as part of a related study examining the relationship between
brain structure and clinical variables in schizophrenia. Independent sample t-tests were run
to compare clinical and demographic variables between schizophrenia and comparison
groups (Table 1).
Table 1
Clinical and Demograo
lie Variables (means and standard deviations)
Schizophrenia Group (N=10)
Comparison Group (N=10)
Age (years)
42(9.39)
37 (11.48)
Years of Education
13.5(2.37)
15.6(1.78)
Parental SES
43.22(16.32)
44.05(.90)
Handedness3
,42(.65)
,80(.20)
BCAb
103.2(16.66)
116.89(12.87)
NART Errors
17.11(12.33)
14.7(7.12)
NART VIQ
112.44(14.45)
115.2(8.30)
BPRS
61.6(9.13)
27(1.05)
aHandedness quotient ranges from 1 (strongly right hanc
ed) to -1 (strongly left handed)
bBCA scaled scores (mean = 100, sd = 15)

69
The schizophrenia and comparison groups did not differ significantly in terms of
age [t_(18) = -1.06, p = .30], parental SES (t (18) = .14; p = .89], handedness [t_(18) =
1.75; p = .097], NART errors [t (17) -.53, p = .60] or NART estimated premorbid VIQ
[t (17) = .52; p = .61], Although overall handedness scores were not significantly different
between groups, the schizophrenia patients were more variable in their scores as not all
patients were strongly right handed. How this impacts data interpretation will discussed
later, however, it is consistent with the literature demonstrating that the prevalence of
non-right handedness in schizophrenia is significantly higher than in healthy control
subjects (Sommer et al., 2001). Further, a trend was observed for general cognitive ability
to be slightly lower amongst the schizophrenia group [t (17) = 1.99; p = .063], Consistent
with the literature, patients had significantly fewer years of education [t (18) = 2.24; p =
.038] and more severe psychotic symptomatology [t (18) = -11.9; p <000) than
comparison subjects.
Procedure
After signing a statement of informed consent approved by the University of
Florida Health Science Center Institutional Review Board and an MRI screening form,
participants were administered the NART and the BPRS. Standardized instructions
regarding performance on the experimental tasks were presented and then practice trials
administered, during which participants were required to respond out loud. Training
continued until the participants could perform the tasks with at least 78% accuracy. The
goal of this training period was to ensure understanding of the task instructions and the
ability to produce correct responses within a relatively short latency.

70
Experimental Tasks
During 4 functional imaging runs, two experimental word generation tasks
alternated with a baseline word repetition task in an event related design. In one
experimental condition, labeled free word generation (freegen), participants heard the
word generate, followed by a semantic category and then the word go. Participants
were required to overtly generate one category exemplar after the word go. Because
there was no external guidance regarding what exemplar to produce, free generation was
considered an internally guided word generation task. The other experimental condition,
semantic word generation (semgen), involved the presentation of the word generate
followed by a semantic category and then a descriptor. Again, participants were required
to give a single exemplar from the semantic category that matched the descriptor. For
example, subjects would hear the instruction generate, the category birds followed by
the descriptor flightless. For this category the subjects would generate the exemplar
emu or ostrich. Because the descriptors determined what word was produced,
semantic generation was considered an externally guided word generation task. In contrast
to the word generation tasks, baseline word repetition (rep) was performed covertly, and
involved the instruction silent repeat followed by a variable number of words that
participants repeated silently.
Trials of the two experimental conditions, free word generation and semantic word
generation, were 7.5 seconds in length and alternated with variable periods of baseline (10,
12.5 and 15 seconds). The baseline condition involved covert repetition of 3, 5 or 6
words, respectively (see Figure 2). Subjects participated in 4 runs of the experimental
tasks, each lasting 4 minutes and 20 seconds. Each run had 6 trials of free generation and

71
6 trials of semantic generation. Trials of the word generation tasks were presented in a
pseudorandom order, which was different for each of the runs. Baseline repetition was
also distributed within runs in a pseudorandomized order. The order of the 4 runs was
counterbalanced across subjects.
spoken response
spoken response
SILENT
REPEAT
f-
sand
adult box band
+1
dome plants desert
GENERATE
I*1h
crystal station gift beverages go
SILENT
REPEAT GENERATE
Repetition
12.5 sec
5 TR
baseline
Semantic Word
Generation
7.5 sec
3 TR
Repetition
10 sec
4 TR
baseline
Free Word
Generation
7 5sec
3 TR
Figure 2. Sample portion of event related design used in the current experiment.
All semantic categories were emotionally neutral based upon previous research
(Cato, 2002) and were drawn from Affective Norms for Emotional Words (ANEW,
Bradley et al., 1988). The 4 lists of categories were counterbalanced within the two word
generation tasks, in that each list was used both with and without descriptors an equal
number of times within each group. No subject heard a specific category more than once
during the experimental trials. Further, the average frequency of the occurrence of
semantic descriptors in the English language was balanced across lists (Kucera et al.,
1967). Table 2 lists the stimuli used for one experimental trial.

72
Table 2
Categories and Semantic Descriptors for List 1
Categories
Semantic Descriptors
Plants
Dessert
Beverages
From cow
Sources of Light
Made of wax
Reading Materials
Glossy fashion
Musical Instruments
Baby grand
Kitchen Utensils
Cuts
Fabric
Grown in South
Clothing
Short-sleeves
Vegetables
From a pod
Relatives
Mothers sister
Electronic Appliances
Keeps cool
Precious Stones
Marriage
Stimulus Delivery and Recording
All auditory stimuli were delivered binaurally from an IBM 380ED notebook
computer using software written for stimulus presentation. Output from the computer
was amplified using a Kenwood KR-A4070 amplifier and routed through a two-channel
audiometer (Maico model MA52). Auditory stimuli were presented at 80db SPL (.0002
dynes/cm2 through a portable audiometer, Etymotic Research ER-30 transducers, 20 feet
of 4mm medical grade silicone tubing and ER3-14 foam insert earphones.
Participants verbalizations were recorded using a modified Jabba EarSet (TM)
microphone with ambient noise reduction. The microphone was secured to the standard
head coil and positioned proximal (8-10cm) from the mouth of the participant. The
microphone connected to a speaker allowing on-line monitoring of participants responses
during scanning and a Sony Digital Sound Recorder (ICD-R100) allowing verbalizations
to be stored in digital format for later off-line noise reduction using Cool Edit Software
(Syntrillium Software Corporation). Filtering the noise produced by the scanner was

73
necessary to increase intelligibility of spoken responses in order to code subjects
verbalizations according to the following parameters: correct, incorrect, inaudible or no
response. Correct responses were defined as those that were possible exemplars of the
category and/or were consistent with the semantic cue presented. Incorrect responses
were defined as those which were either not exemplars of the category or not did not
match the semantic cue, including bizarre and perseverative responses. Inaudible
responses included those in which a word was produced at the appropriate latency, but
was indecipherable due to ambient noise.
Image Acquisition
Each experimental run had 12 7.5 second periods of word generation (6 semantic
word generation, 6 free word generation). The silent repetition baseline condition
alternated with the word generation conditions and lasted for 10, 12.5 or 15 seconds.
Each length of baseline was used an equal number of times, with the exception of an extra
baseline period that was added to the end of each run.
Whole brain imaging was performed on a 3.0 Tesla GE Signa scanner using a
dome shaped radio frequency head coil. After adjusting sound levels for clear but
comfortable presentation, a series of T-l weighted 3-plane localization scans were
acquired to determine that the head was aligned such that the interhemispheric fissure was
within 1 degree of vertical. Head alignment in the coil was adjusted when necessary. For
fMRI sequences, 24 axial slices (6mm thick) were acquired for whole brain coverage. A 1
shot gradient-echo echo-planar imaging technique was used to acquire images with the
following parameters: TE = 25ms, TR = 2500ms, FA = 90 degrees, FOV (field of view) =
24mm, matrix size = 3.75mm x 3.75mm x 6.5mm. A total of 104 images were collected

74
during each experimental run.. After functional image acquisition, 96 (1.5mm thick)
structural image slices were acquired in the axial plane using a 3d spoiled GRASS
volume acquisition (TE =7ms, TR =23ms, FA = 25 degrees, NEX = 2, FOV = 24, matrix
size = ,7mm x ,7mm x 1,3mm).
Image Analysis
Functional images were analyzed and overlaid onto anatomic images with
Analysis of Functional Neuroimages (AFNI) software (Cox, 1996). To minimize effects
of head motion, time series images were spatially registered in 3-dimensional space. For
each participant, mean slice signal intensities were normalized to the grand mean of slice
intensity across functional runs. Voxels where the standard deviation of the signal
change exceeded 8 percent of the mean signal, were set to zero to attenuate large vessel
effects and residual motion artifact.
Prior to concatenating the time series, orthogonalization for linear trends was
completed. A single estimated hemodynamic response function was deconvolved from
the concatenated time series for each experimental task (freegen, semgen) using the
Deconvolve option in AFNI. The first image after stimulus presentation was excluded
from the analyses to control for motion artifacts. Deconvolution provides a best linear
least squares fit between the acquired time series and the estimated time series that
includes the following parameters: constant baseline and the BOLD (Blood Oxygen Level
Dependent) response to each condition. For purposes of comparison, magnitude of
response to each stimulus type was operationally defined as area under the curve of each
HRF, measured on a voxel-wise basis for the estimated hemodynamic response function
for each task.

After obtaining area under the curve on a voxel-by-voxel basis, anatomic and
3
functional images were interpolated to volumes with 1mm voxels, co-registered and
75
converted to stereotactic coordinate space of Talairach and Toumoux (1988) using AFNI.
Functional image volumes were spatially smoothed using an 8mm Gaussian full-width
half-maximum (FWHM) filter to compensate for variability in structural and functional
anatomy across participants.
Repeated measures t-tests were conducted on a voxel-by-voxel basis comparing
freegen and semgen tasks within each group. These two-tailed t-test procedures yielded t-
test maps. A voxel was considered to have significant activity above baseline levels if its
t-value yielded a probability < .001. To control for the large number of t-tests conducted,
only clusters of contiguously activated voxels equal to or greater than 150 microliters
were interpreted. Between subjects t-test were conducted to compare freegen and semgen
across groups. Between subjects t-tests were also performed comparing responses for
both the freegen and semgen tasks.

CHAPTER 10
RESULTS
Behavioral Data
A between-subjects ANOVA was performed to examine differences in task
performance between groups. Responses were coded as correct, incorrect, inaudible or no
response given.
Table 3
Behavioral Data (means and standard deviations)
Schizophrenia Group (N=10)
Comparison Group (N=10)
Correct responses3
38(4.7)
42.8(3.6)
Incorrect responses
5.6(3.3)
1.3(1.6)
Inaudible responses
l-S(l-S)
2(2.4)
No response
2.7(3.8)
1.8(2.1)
Semgen correctb
18.5(3.5)
21.5(1.3)
Freegen correct
19.5(2.1)
21.3(2.7)
a48 total correct responses possible
b24 total correct responses possible for freegen and semgen
Total number of correct responses across tasks differed between groups, as the
schizophrenia patients generated significantly fewer correct responses than comparison
subjects [F(l, 18) = 6.5, p = .02], This level of performance was due to a greater number
of incorrect responses in schizophrenia patients relative to the control subjects [F(l, 18) =
14.0, p = .001] and not to the number of inaudible responses [F( 1,18) = ,43, p = .52] or
failures to respond [F( 1,18) = .31, p = .58], which did not differ across groups. When
examining semantic and free word generation tasks separately, the schizophrenia patients
76

77
performed significantly more poorly on semgen [F( 1,18) = 6.5, p = .02] than controls.
They did not; however perform more poorly on the freegen task [F( 1,1 8) = 2.8, p = .11],
FMRI Results
The fMRI results from the between group comparisons of each word generation
task, performed with independent samples t-tests on a voxel-by-voxel basis ,will be
considered first given their direct relevance to the a priori hypotheses. Within group
comparisons of each word generation task, performed with repeated measures t-tests, will
follow.
Free Word Generation Across Control and Schizophrenia Groups
At a volume threshold of 150 microliters, a cluster connectivity radius of 1.8mm
and a statistical threshold of p< .001 per voxel, schizophrenia patients demonstrated
attenuated brain activation in the left medial frontal cortex (BA 8) and three lateral
prefrontal regions in the right hemisphere (BA 46, 9 and 10) relative to control subjects
(Table 4).
Table 4
Volumes of tissue (>150 microliters) showing significant activity changes (p< OOP
between schizophrenia and control groups on the free word generation task.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Left Medial Frontal
Cortex
L Medial BA 8
-3, 31, 60
-5.496
850
Right Orbitofrontal
Cortex
R BA 10
50, 40, 1
-6.288
849
Right Dorsolateral
Prefontal Cortex
R BA 46/9
29, 33, 54
-5.167
687
Right Dorsolateral
Prefrontal Cortex
R 46
43, 29, 45
-5.731
207
Note: BA = Brodmanns Area according to Talairach and Tournoux (1988) and Jasper et
al. (1995). Maximum t = maximum t value within a given cluster of activity.

78
Hypothesis 1 stated that schizophrenia patients would demonstrate attenuated
medial frontal activity (pre-SMA, BA 32) related to a deficit in generation and
monitoring of internally driven cognition (Frith, 1992). Consistent with this hypothesis,
schizophrenia patients demonstrated attenuated medial frontal activity relative to control
subjects. Activation in the medial frontal cortex during freegen represented the largest of
all statistically significant clusters for this comparison and was situated in BA 8 and the
anterior most limit of pre-SMA (Figure 3). This finding provides preliminary evidence
that the spatial extent of neural activity in the medial frontal cortex of schizophrenia
patients is diminished during internally guided word generation.
Figure 3. Sagittal and axial views of medial frontal cortex (BA 8; xyz = -3, 31, 60)
demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, p < .001.
The fractional signal change in two representative subjects (one control subject
and one schizophrenia patient) for voxels within the area showing significant between
group activity differences in the medial frontal cortex, is outlined in Figure 4. The
temporal characteristics of the hemodynamic response in these selected voxels, with the
first image excluded, may differ between groups; however there is considerable
variability amongst subjects (Figure 4).

79
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Figure 4. Fractional signal change over time in selected voxels in the medial frontal
cortex region demonstrating between group activity differences for one representative
schizophrenia patient (dotted line) and one representative control subject (straight line).
Hypothesis 3, that left lateral frontal regions, which subserve the stimulus driven
route to action (Frith, 1992) are intact in schizophrenia, was supported in that there were
no significant differences found between patients and controls in this region during free
word generation. Schizophrenia patients did; however show different levels of activity
relative to controls during the free word generation task in the right ventral frontal cortex
(BA 10; Figure 5), and right dorsolateral prefrontal cortex (BA 46 and 9; Figure 6).

80
Figure 5. Sagittal and axial views of right lateral prefrontal cortex (BA 10; xyz = 50, 40,
1) demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, g < .001.
BA 46/9; xyz = 29, 33, 54
BA 46; xyz = 43, 29, 45
Figure 6. Sagittal and axial views of right lateral prefrontal cortex (BA 46 and 46/9)
demonstrating significantly less activation in schizophrenia patients relative to controls
during free word generation, g < .001,

81
Semantic Word Generation Across Control and Schizophrenia Groups
In contrast to free word generation, no difference in the medial frontal cortex was
observed between the schizophrenia and comparison groups during semantically cued
word generation. When viewed in the context of the free word generation analysis, this
finding is consistent with Hypothesis 2, which stated that between group differences in
the medial frontal cortex should be maximal for free word generation, given the degree to
which internal guidance is required for successful task performance (Crosson et al.,
2001a). Hypothesis 3, that left lateral frontal regions, which subserve the stimulus driven
route to action (Frith, 1992) are intact in schizophrenia, was supported. In that regard,
there were no significant differences between patients and controls in left lateral frontal
regions during semantic word generation
Similar to free word generation, schizophrenia patients demonstrated less activity
in lateral frontal regions in the right hemisphere in addition to several other cortical and
subcortical regions relative to control subjects during this task (Table 5).

82
Table 5
Volumes of tissue i>150microlitersf showing significant activity changes (p<.001)
between schizophrenia and control groups on the semani
tic word generation task
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Posterior
Cingulate Gyrus
BA 30
-7, -34, 1
-5.739
4949
Left
Parahippocampal
Gyrus and midbrain
-16, -27, -12
-5.152
510
Right Inferior
Frontal Gyrus
R BA 45
55, 40, 5
-5.999
432
Right Superior
Frontal Gyrus
RBA 8
29, 34, 53
-4.992
380
Right
Parahippocampal
Gyrus and Midbrain
15,-22, -9
-4.492
235
Right Dorsolateral
Prefrontal Cortex
RBA 46
43,29,45
-5.944
235
Right Angular Gyrus
RBA 19/39
42, -68, 44
-4.680
211
Right Pars Orbitalis
RBA 47
43, 30,-11
-5.074
152
Note: BA = Brodmanns Area according to Talairach and Tournoux (1988) and Jasper et
al., (1995). Maximum t = maximum t value within a given cluster of activity.
Regions in the right lateral frontal cortex demonstrating attenuated activation for
the schizophrenia patients included the frontal operculum (BA 45 and 47; Figure 7 and
8), dorsolateral prefrontal cortex (BA 46; Figure 7) and the superior frontal gyrus (BA 8;
Figure 9).
Figure 7. Sagittal view of cortex demonstrating significantly less activation in
schizophrenia patients relative to controls in several right hemisphere regions (BA 47,
19/39 and 46) during semantic word generation, g < .001.

83
To investigate the possibility of susceptibility artifact affecting activity in BA 47,
the data were examined on an individual subject basis. Results demonstrated that only 4
of 20 subjects showed significant activity in this region, suggesting that artifacts may
have contributed to the between group difference. Further, there appeared to be some
signal dropout in this region. Although it is unclear if this cluster of activity resulted from
artifact alone, caution should be exercised when interpreting this finding.
Figure 8. Sagittal and axial views of prefrontal cortex (BA 45; xyz = 55, 40, 5) in the
right hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001.
Figure 9. Sagittal and axial views of prefrontal cortex (BA 8; xyz = 29, 34, 53 ) in the
right hemisphere demonstrating significantly less activation in schizophrenia patients
relative to controls during semantic word generation, p < .001.

84
While both free and semantic word generation tasks resulted in a lesser degree of
activation for nearly identical regions of the dorsolateral prefrontal cortex (BA 46 and 9)
for schizophrenia patients compared to controls, there were several other regions in the
lateral right prefrontal cortex that demonstrated attenuated activation in the patients
during semantic word generation only (BA 45,47 and 8). This task related difference is
likely due to the increased semantic processing demands of the semantic word generation
paradigm (Petersen et al., 1988), a hypothesis that will be addressed more
comprehensively in the following chapter.
Other regions less active in patients relative to controls included the left and right
parahippocampal gyri and midbrain, specifically the substantia nigra on the right side
(Figure 10).
Figure 10. Axial and sagittal views (left and right) of the midbrain and parahippocampal
gyri demonstrating significantly less activation in schizophrenia patients relative to
controls during semantic word generation, g < .001.
Consistent with the pattern of attenuated activation in frontal and subcortical
regions in schizophrenia patients, posterior brain regions such as the angular gyrus (BA
39/19; Figure 7) also demonstrated less activation in the patients relative to controls.

85
Further, a cluster of activity including the posterior cingulate gyrus (BA 30), likely
reflecting venous activity, revealed the same pattern.
Free versus Semantic Word Generation in the Schizophrenia Group
At a volume threshold of 150 microliters, a cluster connectivity radius of 1.8mm
and a statistical threshold of p< .001 per voxel, a repeated measures t-test comparing free
versus semantic word generation in schizophrenia patients demonstrated more activation
in the right superior parietal cortex (BA 7) during free word generation (see Table 6;
Figure 10). This was the only region to demonstrate significant differences between tasks
in the patient group.
Table 6
Volumes of tissue (>15Qmicroliters) showing significant activity changes (pC.OOl)
between semantic and free word generation in the schizon
irenia group.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Parietal
Cortex
R BA 7
24, -67,45
6.736
281
Note: BA = Brodmanns Area according to Talairach and Toumoux (1988). Maximum t
= maximum t value within a given cluster of activity.
Figure 11. Sagittal, axial and coronal views of parietal cortex (BA 7; xyz = 24, -67, 45)
demonstrating significantly more activation during free relative to semantic word
generation in schizophrenia patients, p < .001.

86
Free versus Semantic Word Generation in the Control Group
A repeated measures t-test comparing tasks in control subjects demonstrated that
semantic word generation was associated with increased activation in frontal cortex while
free word generation was associated with greater activation in more posterior, temporal
cortex (Table 7).
Table 7
Volumes of tissue (>150microliters) showing significant activity changes (p<.001)
between semantic and free word generation in the control
grouD.
Location
Anatomic Area
Coordinates
Maximum t
Volume in
microliters
Right Superior
Frontal Gyrus
R BA 9
19,44,26
-6.080
315
Right Superior
Temporal Gyrus
R BA 21/22
65, -39, 8
6.157
184
Note: BA = Brodmanns Area according to Talairach and Toumoux (198
8). Maximum t
= maximum t value within a given cluster of activity.
Specifically, semantic word generation was associated with increased activity in more
anterior regions relative to free word generation, including the border between right BA 8
and 9 (Figure 12), while free word generation was associated with increased activity in
the right superior temporal gyrus (BA 21/22; Figure 13).

87
Figure 12. Axial, and coronal views of right lateral prefrontal cortex (BA 8/9; xyz =19,
44,26) demonstrating significantly more activation during semantic relative to free word
generation in control subjects, g < .001.
Figure 13. Sagittal, axial and coronal views of right lateral temporal cortex (BA 21/22;
xyz = 65, -39, 8) demonstrating significantly more activation during free relative to
semantic word generation in control subjects, g < .001

CHAPTER 11
DISCUSSION
This chapter will begin with a review of the a priori hypotheses regarding the
expected results of the study. The findings will then be reviewed with respect to the
degree each hypothesis was supported and will be compared to the existing literature.
Interpretation of other findings will be discussed followed by limitations of the current
study and future directions.
Hypothesis 1, that schizophrenia patients would demonstrate attenuated medial
frontal activity due to a deficit in the anatomic substrate for the generation and monitoring
of internally driven cognition (Frith, 1992) was partially confirmed. Schizophrenia
patients demonstrated attenuated medial frontal activity relative to control subjects during
free word generation, a task that relies heavily upon internal guidance for successful
performance (Crosson et al., 2001a). No differences were observed in the medial frontal
cortex between patients and controls during a semantically cued, externally guided word
generation task, confirming Hypothesis 2. Therefore, only when a high demand was
placed upon the medial frontal system subserving the willed route to action (Frith, 1992),
did schizophrenia patients evidence possible neural dysfunction.
While schizophrenia patients demonstrated attenuated medial frontal activation as
anticipated, its location differed from the hypothesized pre-SMA/BA 32. Crosson et al
(2001a) observed that the shift from medial to lateral frontal cortex as word generation
88

89
tasks became more externally driven was localized to pre-SMA/BA 32 and the inferior
frontal sulcus, respectively. In contrast, the current study revealed that schizophrenia
patients showed attenuated activation in BA 8 and a small region of cortex in the anterior
most limit of pre-SMA. This finding can be interpreted in several ways. The first is that
the spatial extent of neural activity in the medial frontal cortex of schizophrenia patients is
diminished during internally guided word generation and that between group differences
can be observed only at outskirts of activated cortex. The second is that schizophrenia
patients failed to activate pre-SMA/BA32 as hypothesized, but that the application of an
8mm spatial filter, which serves to reduce variability in both structure and function across
participants, allows less precise localization of function. The third possibility, though
somewhat less likely given the nature of the tasks administered, is that schizophrenia
patients fail to engage BA 8 to the same degree as healthy control subjects during word
generation.
Hypothesis 3, that left lateral frontal regions, which subserve the stimulus driven
route to action (Frith, 1992) are not affected in schizophrenia patients was partially
supported. Unlike the willed route to action, which relies upon internal motivation and
initiation, the stimulus driven route is considered to be dependent upon external events
and contingencies Based upon work by Crosson and colleagues (2001a) as well as
others (Goldberg, 1985; Passingham, 1993), there is compelling evidence that left lateral
frontal cortex is preferentially involved in tasks that require external guidance. Therefore,
a lack of difference between schizophrenia and control subjects in left lateral frontal
activity for either task is consistent with the proposed intactness of the stimulus driven
route to action during word generation. Failure to find between group differences in this

90
region; however may also be due to factors such as insufficient statistical power, anatomic
and functional variability and movement artifacts. In order to conclude intactness of
cortical regions or mechanisms underlying the stimulus driven route to action, replication
of the negative finding is essential.
An alternate way of explaining these findings is that the medial frontal cortex is
involved in the suppression of inappropriate responses. This idea accounts for medial
frontal cortex involvement in the Stroop task, in which prepotent responses must be
inhibited, but also in working memory, in which interference from previous trials must be
controlled. However, if attenuated medial frontal activation in the current study reflects a
deficit in suppressing inappropriate responses, then it would follow that patients would
produce more incorrect exemplars during free relative to semantic word generation. This
was not observed. A more plausible alternate interpretation of the data is based upon a
reconceptualization of the functioning of the medial frontal cortex. Convergence of data
from neuroimaging and ERP investigations implicate the medial frontal cortex not simply
in suppression of incorrect responses or error detection, but in the monitoring of
competition between processes that conflict during task performance (Carter et al., 1998,
Carter et al, 2000; Barch et al., 2000; MacDonald et al., 2000). High conflict situations
such as the incongruent condition of the Stroop task, in which subjects are required to
name the color a word is written in (MacLeod, 1991), engage the medial frontal cortex, in
particular the anterior cingulate, to a greater degree than low conflict situations.
Following conflict detection, regions of the lateral prefrontal cortex associated with
attentional control are hypothesized to be recruited in order to resolve the conflict (Van
Veen & Carter, 2002).

91
The conflict monitoring theory of schizophrenia predicts that if medial frontal
cortex dysfunction contributes to deficits such as behavioral disorganization, decreases in
both error-related and conflict related activity would be observed in the paracingulate
sulcus. An fMRI study, conducted by Carter et al., (2001) demonstrated a reduction of
error-related activity in the anterior cingulate in schizophrenia patients, associated with
decreases in post-error adjustments in performance. Interpreting the current findings
within this framework is somewhat problematic. First, attenuated activation in the
schizophrenia patients was not localized to the anterior cingulate region as previously
discussed. Second, while the free word generation task could be conceptualized as
involving a higher degree of response conflict relative to semantically cued word
generation, the schizophrenia patients did not demonstrate an increased number of errors
on the former, yet evidenced attenuated medial frontal response. In contrast, the patients
committed more errors than controls on the semantic word generation task without the
attenuation in medial frontal cortex activation.
In addition to hypothesized deficits in intentional aspects of word generation,
schizophrenia patients also consistently demonstrated less right lateral frontal activity
during word generation than controls, a phenomenon attributable to possible attentional
dysfunction. According to Posner and Boies, (1971) attention can be subdivided into two
domains, one that represents the intensity aspects of attention (alertness and sustained
attention) and the other, the selection aspects (focused and divided attention). Alertness
can be further broken down into tonic alertness, a general state of wakefulness with a
characteristic circadian variation, and phasic alertness, which involves the ability to
increase response readiness for short periods of time in response to external cues.

92
Notably, response readiness can be modulated in a top-down or self-initiated fashion. This
top-down control of attention accompanied by mental effort is commonly referred to as
sustained attention or vigilance. While not always evident in imaging studies, the
distinction between sustained attention and vigilance lies in the nature of the task
presented to the subject. Sustained attention tasks tend not to focus on speed of response
but rather the number of hits, misses and false alarms during a time course. Vigilance tasks
are characterized by a low frequency of critical stimuli resulting in monotonous situations,
which pose high demands of volitional regulation of a certain attentional level. Results
from both lesion (Posner et al., 1987) and functional imaging studies (Lewin et al., 1996,
Sturm et al., 1999; Pardo et al., 1991) demonstrate; however a common right hemisphere
network for these intensity aspects for attention.
In this regard, Posner et al., (1987) found that patients with right hemisphere
strokes demonstrated attentional impairment as manifested by increased reaction times to
stimuli from various modalities. The mechanism that underlies this phenomenon is
thought to be dysfunction in the noradrenergic system (Sturm & Willmes, 2001). Studies
in rats have revealed a right hemisphere bias in the noradrenergic system which originates
in the locus coeruleus and projects heavily to frontal regions (Robinson et al., 1985). It is
hypothesized that right lateral frontal regions exert top-down control of the noradrenergic
system and that when damaged, result in a decrease in noradrenaline in both hemispheres
and in the locus coeruleus (for review see Sturm & Willmes, 2001). In addition, the
parietal cortex, which has been implicated in the spatial orienting of attention, also appears
to play a critical role in sustained attention.

Functional neuroimaging (fMRI and PET) has contributed significantly to
understanding the neural circuitry underlying sustained attention. Pardo and colleagues
(1991) used both a somatosensory task in which subjects were required to monitor the
interruption of an otherwise continuous tactile stimulus and an analogous visual task in
which subjects were required to monitor the attenuation of a centrally presented light
source, to examine blood flow changes (PET) related to sustained attention or vigilance.
When compared to rest, localized increases in blood flow in the right prefrontal and
superior parietal cortex were found regardless of the modality or laterality of sensory
input. While blood flow increases tended to be localized to BA 7 in the parietal cortex, the
frontal responses were more varied and consisted of a band of activity along the right
dorsolateral convexity corresponding to BA 8, 9, 44, and 46. The authors concluded that
a right hemisphere fronto-parietal network is critically involved in sustained attention and
that the absence of medial frontal activation differences, suggests that this network can
operate independently of midline attentional systems. An attempt to replicate these
findings using fMRI, produced similar results including increased activation in the right
middle frontal gyrus to a visual vigilance task (Lewin et al, 1996). The right middle
frontal gyrus has also been found to be critical for successful performance on the
Continuous Performance Task (CPT), a task which measures sustained attention and other
complex cognitive operations such as working memory (Cohen et al., 1992).
More recent imaging studies have corroborated the involvement of frontal and
parietal cortex in sustained attention and have also suggested a role for subcortical
structures. Using PET, Sturm and colleagues (1999) administered a task in which subjects
were required to make a motor response to a dot centrally presented on a computer

94
monitor. When compared with a sensorimotor control condition, right hemisphere
activation was seen in the anterior cingulate gyrus, dorsolateral prefrontal cortex, inferior
parietal lobule, middle and superior temporal gyrus, right pulvinar and dorsal
pontomesencephalic tegmentum. A similar right hemisphere network was activated in
another study conducted by Weis and colleagues (2000), using an analogous auditory
task. Subtraction of a sensorimotor control task revealed right hemisphere activation in
the dorsolateral and ventrolateral prefrontal cortex, anterior cingulate gyrus, inferior
temporal gyrus and thalamus. When the task was modified to reflect phasic alertness (a
warning stimulus preceded the target), a larger network of activation was revealed
including thalamus and superior and ventrolateral regions in the left frontal lobe. This
extended right hemisphere activation was hypothesized to reflect a response to the
extrinsic warning stimulus, while the additional left hemisphere activation was considered
an indication of elementary attention selectivity, since under phasic alertness, responses to
the warning stimulus have to be actively inhibited.
Taken together, results consistently point to a right hemisphere network, including
dorsolateral frontal regions and parietal cortex, involved in sustained attention to all types
of stimuli. While some studies have implicated regions such the thalamus, mesencephalic
tegmentum, the anterior cingulate and the superior temporal gyrus in sustained attention
(Paus et al., 1997; Strum et al., 1999), others have not (Lewin et al., 1996; Pardo et al.,
1991), suggesting that specific task demands such as degree to which complex selection
processes are necessary and the amount of effort required may determine which brain
regions are recruited.

95
Schizophrenia patients consistently demonstrate attentional dysfunction on a
variety of neuropsychological tests (e.g., Heinrichs & Zakzanis, 1998). Deficient
performance on sustained attention tasks in particular, appears to be a stable, long-lasting
characteristic of the disorder as it can be identified during either acute or chronic states
and is relatively independent of neuroleptic medication (Cohen et al., 1992). One of the
most well studied measures of attentional functioning in schizophrenia is the continuous
performance test (CPT). Although numerous versions of this test have been developed,
such as the degraded stimulus CPT (Neuchterlein et al., 1983), AX-CPT, digit CPT
(Gordon et al., 1986), and identical pairs CPT (Cornblatt et al., 1988) and administered to
schizophrenia patients in various modalities, the findings are remarkably consistent.
Schizophrenia patients demonstrate deficient performance on the CPT regardless of
version (Cohen et al., 1992; Straube et al., 2002). To confirm that poor performance is
due to deficient attentional functioning and not to another cognitive process such as
working memory or perceptual processes, Straube et al., (2002) examined 5 components
of successful CPT performance namely, perceptual organization, selective attention, short
term storage, working memory rehearsal and sustained attention. Results indicated that
while schizophrenia patients performed significantly more poorly than controls on both the
degraded stimulus CPT and the digit CPT, only the perceptual organization and sustained
attention components were impaired.
Several studies have investigated the relationship of impaired CPT performance to
symptom expression. Pandurangi et al., (1994) found that CPT performance was
correlated with positive psychotic symptoms, while others have found a relationship
between poor performance and negative symptoms as well as the deficit syndrome (e g.,

96
Buchanan et al., 1997; Nieuwenstein et al., 2001). Not all studies; however have
documented a relationship between symptoms and sustained attention (Addington et al.,
1998; Comblatt et al., 1985; Kurtz et al., 2001). A possible explanation for these
discrepant findings may lie in the tools selected to assess symptomatology. For example,
studies that have found a significant relationship between sustained attention and
symptomatology used the Thought, Language and Communication Scale (TLC:
Andreasen et al., 1986), a comprehensive measure of thought disorder. It is also possible
that sustained attention in schizophrenia may represent a core information processing
deficit, and is therefore unrelated to symptomatology.
Neuroimaging researchers have used various CPT paradigms to further
understand the nature of attention deficits in schizophrenia. These investigations have
demonstrated attenuated activation in the medial frontal cortex and right middle frontal
gyrus in schizophrenia patients relative to healthy controls (Cohen et al., 1987; Cohen et
al., 1992). In these PET studies, attenuated activation in the right middle frontal gyrus
could not be explained by performance differences as schizophrenia patients
demonstrated lower metabolic rates in this region regardless of their performance
accuracy. Nor could activation differences between groups be attributed to medication
effects, as demonstrated by a group of mediation-withdrawn schizophrenia patients
(Cohen et al., 1998).
Evidence from schizophrenia patients therefore suggests consistent attentional
impairment associated with attenuated activation in the dorsolateral prefrontal cortex, a
critical region in the right hemisphere network subserving sustained attention and
vigilance. The current study demonstrated attenuated activation in the dorsolateral

97
prefrontal cortex (BA 46 and 9), across both word generation tasks in the patient group.
This suggests that schizophrenia patients have difficulty sustaining attention not only
during continuous performance tasks as suggested by the literature (Cohen et ah, 1992),
but during paradigms requiring retrieval of semantic information. One caveat; however is
that the preponderance of word generation tasks have failed to uncover attenuated right
dorsolateral prefrontal activation in schizophrenia patients (Dolan et ah, 1998; Frith et ah,
1991; Yurgelun-Todd et ah, 1996). A possible explanation for this discrepancy is that the
current paradigm which consisted of two types of word generation tasks alternating in a
fairly rapid, pseudo-random fashion, prevented the development of expectancies on the
part of participants and as a result, was more attentionally demanding than other word
generation tasks in which participants are required to generate exemplars to a particular
category over an extended period of time. One way of testing the hypothesis that
schizophrenia patients demonstrate attentional dysfunction during word generation,
would be to alter the stimulus presentation rate. During rapid presentation of stimuli,
attentional demands would presumably be greater, creating a more robust discrepancy
between patients and controls relative to a less attentionally demanding task. The
discrepancy between this investigation and the word generation literature may also relate
to the use of repetition as a baseline condition in the current study. It may be that this
method increases sensitivity to detecting differences in activity.
Attenuated activation in the right dorsolateral prefrontal cortex characterized
schizophrenia patients performance on both word generation tasks. However, attenuated
activation was also observed in additional regions of the right lateral prefrontal cortex
(BA 45, 47 and 8) for the schizophrenia patients during semantic word generation only.

98
This pattern of activity may represent a widespread failure to engage right prefrontal
mechanisms to the same extent as controls due to pervasive attentional dysfunction
during word generation that is semantically cued. This hypothesis is bolstered by 3 other
findings. First, performance decrements were observed in schizophrenia patients on
semantic but not free word generation. Second, in examining task differences within the
patient group, free word generation was associated with activation in the right superior
parietal cortex (BA 7), a region that has been implicated in sustained attention and is
thought to be coactivated by more anterior aspects of the attentional network (Sturm et
al., 2001). Third, attenuated activation in the parahippocampal gyri bilaterally in
schizophrenia patients was found during semantic but not free word generation.
Parahippocampal activation has been found during both episodic encoding
(Gabrieli et ah, 1997; Stem et ah, 1996) and retrieval tasks (Dupont et ah, 2000) in which
participants are required to consciously recollect past events. However, more recent
studies have provided evidence for parahippocampal gyrus involvement in semantic
processing. Crosson and colleagues (2001b) demonstrated activation in the left
parahippocampal gyms during word generation compared to nonsense syllable generation
in neurologically normal subjects, providing evidence that the parahippocampal region
can be engaged in tasks without overt episodic memory demands. Pihlajamaki et ah
(2000) also demonstrated left parahippocampal activity during a category fluency task
relative to the rote listing of numbers. This corroborating finding adds additional support
for the involvement of the parahippocampal gyms in semantic processing, or more
specifically during the retrieval of semantic information. As recent studies have
emphasized the importance of the hippocampus in associative processing (Henke et ah,

99
1999), it likely that associative processes, semantic or episodic, activates the
parahippocampal region.
The question remains as to why attentional dysfunction may have worsened in the
schizophrenia patients during semantically cued word generation and how it is related to
activation of the parahippocampal gyri. One explanation is that schizophrenia patients
have a deficit in attending to and engaging associative retrieval mechanisms most
pronounced during tasks with heavy semantic processing demands. Indirect support for
this hypothesis comes from studies examining retrieval success after depth of processing
modulations in schizophrenia. In this regard, Weiss et al., (2003) discovered attenuated
medial temporal activation during retrieval of semantically encoded words relative to
retrieval of words encoded perceptually, suggesting disruption in the neural circuitry
responsible for semantic associative processing. Of note, the schizophrenia patients in
that study, as was the case in the present investigation, showed no differences in strength
of activation in left lateral prefrontal regions commonly implicated in semantic
processing. Although substantially different tasks were used, Weiss and colleagues
(2003) as well as the current study, suggest that inability to engage associative retrieval
mechanisms on the part of schizophrenia patients, is most striking during tasks with high
semantic processing demands. For example, during free word generation the
schizophrenia patients activated medial temporal regions to the same extent as control
subjects; however as semantic word generation exerted increasing demands upon the
semantic system, a breakdown in the medial temporal lobe memory system was evident.
This pattern of activity in medial temporal regions was just opposite to the pattern of
activation observed in the medial frontal cortex; as task performance became more

100
heavily reliant on internal guidance, the medial frontal lobe system responsible for
intentional aspects of cognition began to breakdown, whereas medial temporal activity
was attenuated in schizophrenia subjects when the demands for semantic specificity
increased.
An alternative and seemingly less cumbersome explanation of the data involves
the HERA hypothesis (hemispheric encoding retrieval asymmetry; Tulving et ah, 1994),
which, based solely upon functional imaging studies, states that the left and the right
prefrontal cortical regions are differentially involved in episodic and semantic memory
processes. Left prefrontal regions are hypothesized to be preferentially involved in
retrieval of information from semantic memory as well as encoding of information into
episodic memory. Right prefrontal regions are posited to be preferentially involved in
retrieval of episodic information. Appling this model to the current data might suggest
that schizophrenia patients fail to engage right hemisphere retrieval mechanisms during
word generation. This hypothesis does not; however account for why the addition of a
semantic cue would result in more widespread right hemisphere and medial temporal lobe
dysfunction. Further, it associates right prefrontal functioning with retrieval of
information from episodic memory, yet the current word generation task clearly requires
retrieval of information from semantic memory.
Taken together, results of the current study suggest that as semantic processing
demands increase, patients with schizophrenia are unable to adequately attend to semantic
information, resulting in associative retrieval deficits and poor task performance. As tasks
require more internal guidance, schizophrenia patients are similarly unable to recruit the
critical medial frontal stmctures, suggesting a deficit in intentional aspects of cognition.

101
Attenuated activity in particular brain regions accompanied by adequate task
performance, as in the case of free word generation in the schizophrenia group, may also
be interpreted as reflecting increased efficiency, not dysfunction of that region. The
functional imaging literature in Alzheimers disease; however argues against this
explanation. Bookheimer et al. (2000) compared neurologically normal older subjects at
risk for Alzheimers disease (positive for the APOE G4 allele) to those not at risk for
Alzheimers disease (homozygous for the APOE £3 allele). The at-risk subjects
demonstrated greater magnitude and extent of activity during verbal memory tasks
relative to those not at-risk in left hippocampal, parietal and prefrontal regions. This
increased activity predicted memory deterioration 2 years later, which was interpreted as
reflecting a compensatory mechanism for presymptomatic deterioration. In a related
study, Backman and colleagues (1999) showed that patients already diagnosed with
Alzheimers disease failed to activate the left hippocampal formation and parietal lobe to
the same extent as control subjects during verbal memory tasks. Taken together, these
findings suggest increased activity in the structures critically involved in verbal memory
prior to the onset of the symptoms of Alzheimers disease; however, once individuals
become symptomatic, activity becomes attenuated in these regions during verbal memory
tasks. As the schizophrenia patients in the current study demonstrated significant levels of
symptomatology, it is likely that attenuated activation reflects neural dysfunction not
increased efficiency.
A comment is required regarding the finding of attenuated activation in the
substantia nigra in schizophrenia patients. Typical neuroleptic drugs are thought to
achieve their antipsychotic potency through influences on the mesolimbic dopamine

102
system; however clinical doses of these medications also result in a depolarization block
of cells in the substantia nigra (Lidsky, 1995). Given that approximately one third of
patients in this relatively small sample were taking conventional antipsychotic
medication, there is a strong possibility that attenuated activity in the substantia nigra is
likely a reflection of medication effects and should therefore be interpreted with caution.
Other clinical variables that may play a role in the current study and limit its
generalizability include the patients symptom state as well as the chronicity of their
illness. Future directions should include replication of the current findings with a large
same of medication-withdrawn patients.
Another complicating factor when interpreting imaging results in schizophrenia is
that increased motion artifact in patients relative to comparison subjects (Weinberger et
al., 1996) is likely to create artifacts that lead to voxel instabilities. Increased variance in
signal intensity over time, whether due to movement or other factors such as the
heterogeneity of schizophrenia, can lead to spurious findings such as lack of activity.
Caution is therefore necessary when attributing less fMRI signal to dysfunction in that
brain region. Novel ways of analyzing data on a single subject basis may begin to address
this complicated issue. Replication of these findings then becomes even more critical in
order to more definitively ascertain why schizophrenia patients demonstrated less activity
in the medial frontal cortex, right lateral prefrontal cortex and parahippocampal gyri
bilaterally.
If schizophrenia is a neurodevelopmental disorder, it is likely that dysfunction of
large scale neuronal interactions underlies the behavioral and neurocognitive deficits
manifested in the disorder. While the current study focused on dysfunction in particular

103
brain regions, future directions should include approaching functional imaging data with
analyses that emphasize neural integration and functional connectivity.
Lastly, the issue of handedness is also important when interpreting functional
imaging results. While the schizophrenia group in this study did not differ significantly
in overall handedness they did demonstrate more variability, consistent with the
literature indicating increased variability resulting from more mixed or ambiguous
handedness in this population relative to healthy control subjects (Sommer et al., 2000).
Handedness, a manifestation of cerebral dominance, is closely correlated with anatomic
asymmetry and language lateralization (Crow, 1997). It is therefore possible that
differences in brain activity between schizophrenia patients and controls in the current
study may have been influenced by the different handedness characteristics of each group.
The major findings of the current study are twofold. First, schizophrenia patients
failed to engage the medial frontal cortex to the same extent as healthy controls during
internally guided word generation. This finding likely reflects a deficit in the neural
substrates of intention, dysfunction in the willed route to action (Frith, 1992). Lateral
frontal regions in the left hemisphere thought to underlie the stimulus driven route to
action (Frith, 1992) were not similarly affected. The results of the current study are,
therefore consistent with Friths (1992) model of schizophrenia in which a compromised
willed route to action and an intact stimulus driven route to action underlie both the signs
and symptoms of schizophrenia. Second, schizophrenia patients demonstrated
consistently lower activity in mechanisms thought to subserve sustained attention and
vigilance (e.g., right dorsolateral prefrontal cortex). This attentional deficit became more
pervasive as semantic processing demands increased, suggesting difficulties attending to

104
and engaging associative retrieval mechanisms. In summary, the current findings suggest
that both intentional and attentional deficits characterize the performance of
schizophrenia patients during word generation.

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APPENDIX A
DSM-IV DIAGNOSIS OF SCHIZOPHRENIA
Table A-l
DSM-IV Descriptions of Symptoms of Schizophrenia
1..Delusions are erroneous beliefs that involve a misinterpretation of perceptions or
experiences. Content may include a variety of themes; however, persecutory and referential
delusions are amongst the most common. Bizarre delusions are those that would be regarded
as wholly implausible, and are thought to be especially characteristic of schizophrenia. For
example, due to the unusual nature of delusions of control or passivity, only this single
symptom is needed to meet one of the diagnostic criteria for schizophrenia.
2. Hallucinations are disorders of perception. They may occur in any sensory modality, but
most commonly occur in the auditory modality. Auditory hallucinations are usually
experienced as voices, perceived as distinct from the persons own thoughts. The
hallucinations may be pejorative or threatening. Tactile and/or visual hallucinations are
occasionally present. Olfactory or gustatory hallucinations are rather rare.
3. Disorganized thinking or formal thought disorder involves a disturbance in how thoughts
are communicated to others. Disorganization may manifest as derailment in speech, or as
tangentiality. In its most severe form, disorganization may involve incomprehensible speech.
Another disturbance of thought is poverty of content of speech, which refers to speech that is
adequate in amount, but conveys little information.
4. Grossly disorganized behavior refers to a variety of behaviors including silliness and
unpredictable agitation. Marked difficulties may be noted in goal-directed behavior that
involve activities of daily living such as maintaining hygiene. Sexually inappropriate
behavior may also be observed.
5. Catatonic behaviors include a decrease in reactivity to the environment and may involve
rigid posturing, resistance or excitation of motor responses. The DSM-IV describes 5 types
of catatonia: catatonic stupor, catatonic rigidity, catatonic negativism, catatonic posturing,
catatonic excitement.
Negative Symptoms refer to a diminution or loss of normal functioning. Affective flattening
includes a diminished range of emotional expression, poor eye contact, and reduced body
language. Alogia is poverty of speech and refers to minimal verbal responding, decreased
spontaneous speech and diminished fluency. Avolition manifests in terms of diminished
interest and drive, as well as the inability to initiate and follow through with goal directed
activity.
121

122
Table A-2
DSM-IV Features Associated with Schizophrenia but Not Central to its Definition
1. Inappropriate Affect is the expression of affect that is not congruent with the situation
or the content of speech. It may include inappropriate smiling or laughing.
2. Anhedonia is defined as a loss of interest or pleasure in the environment.
3. Dysphoric mood may take the form of depression, anxiety or anger.
4. Psvchomotor abnormalities are frequently observed and may include pacing, rocking
or apathetic immobility.
5. Concentration Difficulties are frequently evident and reflect problems focusing
attention or lack of freedom from distractibility due to preoccupation with
delusions/hallucinations.
6. Depersonalization and Derealization involve a disturbance in the sense of self
evidenced by extreme confusion about ones identity and loss of self-directedness.
Table A-3
DSM-IV Subtypes of Schizophrenia
1. Paranoid Type involves preoccupation with one or more delusions or frequent
auditory hallucinations related to a particular theme.
2. Disorganized Type is marked by disorganized speech, disorganized behavior, and flat
or inappropriate affect.
3. Catatonic Type is characterized by motor abnormalities in the form of catatonic
rigidity, posturing, stupor, negativism, or excessive motor activity. Echolalia and
echopraxia may also be observed.
4. Undifferentiated Type refers to a patient who demonstrates prominent psychotic
symptoms, but either can not be classified or meet criteria for more than one subtype.
5. Residual Type involves the absence of prominent delusions, hallucinations,
disorganized speech and grossly disorganized or catatonic behavior; however, they
may still show some negative features.

APPENDIX B
NATIONAL ADULT READING TEST
Table B-l
National Adult Reading Test (NART) Word Card
CHORD
ACHE
DEPOT
AISLE
BOUQUET
PSALM
CAPON
DENY
NAUSEA
DEBT
COURTEOUS
RAREFY
EQUIVOCAL
NAIVE
CATACOMB
GAOLED
THYME
HEIR
RADIX
ASSIGNATE
HIATUS
SUBTLE
PROCREATE
GIST
GOUGE
SUPERFLUOUS
SIMILE
BANAL
QUADRUPED
CELLIST
FACADE
ZEALOT
DRACHM
AEON
PLACEBO
ABSTEMIOUS
DETENTE
IDYLL
PUERPERAL
AVER
GAUCHE
TOPIARY
LEVIATHAN
BEATIFY
PRELATE
SIDEREAL
DEMENSE
SYNCOPE
LABILE
CAMPANILE
Nelson, H.E. (1982). National Adult Reading Test. Test Manual. Windsor: NFER-
NELSON
123

BIOGRAPHICAL SKETCH
Leeza Marn received her bachelors degree in 1995 from Tufts University where
she majored in psychology. In 1996, she entered the doctoral program in Clinical and
Health Psychology at the University of Florida, specializing in neuropsychology. As part
of her doctoral degree requirements, she completed a clinical internship at the University
of California at San Diego, focused largely on neuropsychological evaluation of
psychiatric, geriatric and general medical populations. Primary areas of interest include
adult neuropsychology and functional neuroimaging in clinical populations. Ms. Marons
plans include pursuing her research and clinical interests in the neuropsychology of
schizophrenia as part of an NIMH funded postdoctoral fellowship in the Department of
Psychiatry at the University of California at San Diego.
124

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate,jn^scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
/ Bruce Crosson, Chair
Professor of Clinical and Health
Psychology
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Christiana M. Leonard, Cochair
Professor of Neuroscience
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Professor of Clinical and Health
Psychology
I certify that I have read this tudy and that in my opinion it conforms to acceptable
standards of scholarly presentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.
'1,
Ly/A/. sf\ .<,ds£ y
John Kuldau
Professor of Psychiatry
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Associate Professor of Biochemistry
And Molecular Biology

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Assistant Professor of Clinical and
Health Psychology
This dissertation was submitted to the Graduate Faculty of the College of Health
Professions and to the Graduate School and was accepted as partial fulfillment of the
requirements for the degree of Doctor of Philosophy.
May 2003
Dean, College of Health Professions
Dean, Graduate School