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Disruption of Attentional Processing in Closed Head Injury

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Title:
Disruption of Attentional Processing in Closed Head Injury an Event-Related Potential Investigation
Physical Description:
1 online resource (101 p.)
Language:
english
Creator:
Sozda, Christopher N
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Psychology, Clinical and Health Psychology
Committee Chair:
Perlstein, William Michael
Committee Members:
Robinson, Mike E
Kerkhoff, Thomas R
Price, Catherine Elizabeth
Levy, Charles Edward

Subjects

Subjects / Keywords:
ant -- attention -- chi -- eeg -- erps -- tbi
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre:
Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Emerging from acceleration or deceleration forces, closed head injuries (CHI) continue to remain a significant public health-care issue in the United States. Whereas the nature and pattern of neurocognitive difficulties following injury often varies widely from patient-to patient, cognitive impairments in attentional processes are commonly observed across injury severity level. However, it is unknown how CHI affects interactive component processes of attention. To examine the effects of CHI on the neurobehavioral indices of three attentional networks (alerting, orienting, and executive control), electroencephalogram (EEG) and behavioral data (RT and error rates) were acquired while 12 moderate-to severe CHI participants and 12 demographically matched neurologically-healthy controls performed an attention network test (ANT; Fan et al., 2002).  Significant alerting and executive control RT differences were observed between groups; however, after controlling for generalized slowing, only the alerting network remained significantly reduced in CHI patients. No group differences were observed in orienting, as both groups showed RT improvement on target conditions preceded by spatially informative cues. Both groups committed significantly more errors on incongruent vs. congruent trials, though this effect was not different between groups.  Cue-related event-related potential (ERP) data revealed that bilateral posterior-parietal N1 amplitude reflecting alerting was greater in controls than CHI participants; however, both groups demonstrated similar-magnitude enhancement of N1 amplitude to more than less spatially informative cues, reflective of similarity in orienting network functioning. Regarding executive control, target-related P3 amplitude was attenuated to incongruent “conflict” conditions at central-posterior scalp sites, an effect that did not significantly differ between groups.  Taken together, CHI participants demonstrated behavioral and neural alterations in only the alerting network. Such difficulties in alerting likely reflect difficulty in processing ambiguous stimuli, rather than in-maintaining an alert state, and may be the result of disruptions in norepinephrine neurotransmitter systems. Difficulties in executive control were manifested as cognitive slowing, rather than core impairment in executive functioning, and suggest that given enough time, CHI may perform at levels equal of controls. Lastly, CHI patients significantly benefited from spatially informative cues to aid their task performance, similar to that observed in controls.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Christopher N Sozda.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Perlstein, William Michael.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045682:00001

MISSING IMAGE

Material Information

Title:
Disruption of Attentional Processing in Closed Head Injury an Event-Related Potential Investigation
Physical Description:
1 online resource (101 p.)
Language:
english
Creator:
Sozda, Christopher N
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Psychology, Clinical and Health Psychology
Committee Chair:
Perlstein, William Michael
Committee Members:
Robinson, Mike E
Kerkhoff, Thomas R
Price, Catherine Elizabeth
Levy, Charles Edward

Subjects

Subjects / Keywords:
ant -- attention -- chi -- eeg -- erps -- tbi
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre:
Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Emerging from acceleration or deceleration forces, closed head injuries (CHI) continue to remain a significant public health-care issue in the United States. Whereas the nature and pattern of neurocognitive difficulties following injury often varies widely from patient-to patient, cognitive impairments in attentional processes are commonly observed across injury severity level. However, it is unknown how CHI affects interactive component processes of attention. To examine the effects of CHI on the neurobehavioral indices of three attentional networks (alerting, orienting, and executive control), electroencephalogram (EEG) and behavioral data (RT and error rates) were acquired while 12 moderate-to severe CHI participants and 12 demographically matched neurologically-healthy controls performed an attention network test (ANT; Fan et al., 2002).  Significant alerting and executive control RT differences were observed between groups; however, after controlling for generalized slowing, only the alerting network remained significantly reduced in CHI patients. No group differences were observed in orienting, as both groups showed RT improvement on target conditions preceded by spatially informative cues. Both groups committed significantly more errors on incongruent vs. congruent trials, though this effect was not different between groups.  Cue-related event-related potential (ERP) data revealed that bilateral posterior-parietal N1 amplitude reflecting alerting was greater in controls than CHI participants; however, both groups demonstrated similar-magnitude enhancement of N1 amplitude to more than less spatially informative cues, reflective of similarity in orienting network functioning. Regarding executive control, target-related P3 amplitude was attenuated to incongruent “conflict” conditions at central-posterior scalp sites, an effect that did not significantly differ between groups.  Taken together, CHI participants demonstrated behavioral and neural alterations in only the alerting network. Such difficulties in alerting likely reflect difficulty in processing ambiguous stimuli, rather than in-maintaining an alert state, and may be the result of disruptions in norepinephrine neurotransmitter systems. Difficulties in executive control were manifested as cognitive slowing, rather than core impairment in executive functioning, and suggest that given enough time, CHI may perform at levels equal of controls. Lastly, CHI patients significantly benefited from spatially informative cues to aid their task performance, similar to that observed in controls.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Christopher N Sozda.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Perlstein, William Michael.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045682:00001


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1 DISRUPTION OF ATTENTIONAL PROCESSING IN CLOSED HEAD INJURY: AN EVENT RELATED POTENTIAL INVESTIGATION By CHRISTOPHER NICHOLAS SOZDA 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 2013

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2 2013 Christopher Nicholas Sozda

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3 To my parents wife family, friends and God forever indebted for your love, blessings, patience, inspiration, encouragement, and unwavering support

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4 ACKNOWLEDGMENTS Foremost, I thank my ad visor, Dr. William M. Perlstein. I am grateful for his patience, guidance, motivation, and enthusiasm that, taken tog ether, make him a great mentor. I also tha nk Dr. David A.S. Kaufmann for his assistance in task development and technical trouble shoot ing. I extend my gratitude to Dr. Anthony Eloy Kline and Dr. Vonetta Dotson for their continued encouragement mentorship, and support in my professional developme nt Additionally I extend my thanks and gratitude to the members of the Clinical Cognitive Neuroscience Lab and Geriatric Neuropsychology and Mood Disorders Lab for their willingness to give assistance whenever needed. Taken together, this project could not have been done without you! Lastly, I wish to thank Dr. Thomas Kerkhoff, Dr. Charles Levy, Dr. Catherine Price, and Dr. Michael Robinson for serving on my doctoral candidacy qualifying examination and dissertation committee s This work was partially supported by a 2011 American Psychological Association Dissertation Research Award

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 12 Closed Head Injury ................................ ................................ ................................ 12 Epidemiology ................................ ................................ ................................ .... 12 Neurobehavioral S equ elae ................................ ................................ ............... 13 Closed Head Injury and Attentional Impairment: A Closer Look ............................. 15 Attention in the 21 st Century: The Attention Network Test (ANT) ............................ 17 Attention Components (Alerting, Orienting, and Executive C ontrol) ................. 17 Neurochemical M echanisms ................................ ................................ ............ 19 Anatomical/Functional Indices of A ttention ................................ ....................... 19 A Brief Overview of Scalp Recorded Event Related Potentials (ERPS) ................. 20 Neural Correlates of the ANT ................................ ................................ .................. 22 Clos ed Head Injury and the ANT ................................ ................................ ............ 23 ERP Investigations of Closed Head Injury ................................ .............................. 25 Rationale for the Current Study ................................ ................................ .............. 27 Study Predictions ................................ ................................ ................................ .... 28 Behavioral Dat a ................................ ................................ ................................ 28 ERP Data ................................ ................................ ................................ ......... 29 2 M ETHODS ................................ ................................ ................................ .............. 30 Participants ................................ ................................ ................................ ............. 30 Assessment of Cognitive Functioning ................................ ................................ ..... 32 Assessment of Behavioral and Emotional Functioning ................................ ........... 36 Cognitive Tasks and Stimuli ................................ ................................ .................... 38 Electrophysiological Data Acquisition and Reduction ................................ ............. 40 Data Analyses ................................ ................................ ................................ ......... 41 Demographic and Neuropsychological Data Analyses ................................ ..... 42 Behavioral Data Analyses ................................ ................................ ................ 42 ERP Data Analyses ................................ ................................ .......................... 43 3 RE SULTS ................................ ................................ ................................ ............... 49 ANT Behavioral Performance ................................ ................................ ................. 49 Brief Summary of Behavioral Data Findings ................................ ..................... 49 Reaction Time and Attention Network Effects ................................ .................. 49 Relationships Between Behavioral and Neuropsychological Data ................... 51 Performance Accuracy ................................ ................................ ..................... 52

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6 Cue locked E RP Data ................................ ................................ ............................. 52 N1 Latency ................................ ................................ ................................ ....... 53 N1 Amplitude ................................ ................................ ................................ .... 53 P3 Latency ................................ ................................ ................................ ....... 53 P3 Mean Amplitude ................................ ................................ .......................... 54 Extended Cue locked ERP Data ................................ ................................ ............. 54 N1 Latency (Alerting Network: Double cue vs. No cue) ................................ ... 54 N1 Amplitude (Alerting Network: Double cue vs. No cue) ................................ 55 N1 Latency (Orienting Network: Spatial cue vs. Center cue) ........................... 55 N1 Amplitude (Orienting Network: Spatial cue vs. Center cue) ........................ 55 Target locked ERP Data ................................ ................................ ......................... 56 N1 Latency ................................ ................................ ................................ ....... 56 N1 Amplitude ................................ ................................ ................................ .... 56 P3 Latency (Conflict Network: Congruent vs. Incongruent) .............................. 56 P3 Amplitude (Conflict Network: Congruent vs. Incongruent) ........................... 57 4 DISCUSSION ................................ ................................ ................................ ......... 75 Study Limitations and Future Directions ................................ ................................ 81 Summary ................................ ................................ ................................ ................ 85 LIST OF REFERENCES ................................ ................................ ............................... 86 BIOGRAPHICAL S KETCH ................................ ................................ .......................... 101

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7 LIST OF TABLES Table page 2 1 Demographic, injury, and questionnaire data for control and moderate to severe CHI participant groups ................................ ................................ ............ 44 2 2 Injury characteristics and neuroradiological information for CHI patie nts ( n =12). ................................ ................................ ................................ ................ 45 2 3 Neuropsychological data for control and moderate to severe CHI participant groups ................................ ................................ ................................ ................ 46 3 1 Mean ( SD) attention network effects (RT), Z score transformations for attention network effects, and mean error rates as a function of flanker type and group ................................ ................................ ................................ ........... 58 3 2 locked activity as a function of group ................................ ................................ ................................ .............. 59 3 3 locked related activity as a function of group and electrode site ................................ ................ 59 3 4 related activity as a function of group and channel ................................ ................................ ............ 60

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8 LIST OF FIGURES Figure page 2 1 Diagram of the attention network test ................................ ................................ 47 2 2 Electrical geodesics sensor layout for the 64 channel geodesic sensor net (EGI; Eugene, Oregon). ................................ ................................ ...................... 48 3 1 Mean ( SE) median correct trial RTs as a function of group, flanker type, and cue type. ................................ ................................ ................................ ...... 61 3 2 Mean ( SE) error rates as a function of group, flanker type, and cue type. CHI patients did not commit any errors on any congruent trials. ........................ 62 3 3 Grand average event related potential waveforms showing the cue locked N1 (150 250 ms) component for double and spatial cue conditions. ................. 63 3 4 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity. ................................ ................................ ............. 64 3 5 Grand average event related potential waveforms showing the cue locked P3 (275 500 ms) components for double and spatial cue conditions. ..................... 65 3 6 Top view of the spline interpolated voltage distribution maps showing mean voltages for P3 activity. ................................ ................................ ....................... 66 3 7 Grand average event related potential waveforms showing the extended cue 800 ms post cue onset) for spatial and center cue conditions. ................................ ................................ ........................ 67 3 8 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity. ................................ ................................ ............. 68 3 9 Grand average event related potential waveforms showing the extended cue 800 ms post cue onset) for double and no cue conditions. ................................ ................................ .............................. 69 3 10 Posterior view of the spline interpolated voltage distribution maps showing mea n voltages for N1 activity. ................................ ................................ ............. 70 3 11 Grand average event related potential waveforms showing the target locked N1 component (betwe en 150 250 ms post target onset) for incongruent and congruent target conditions. ................................ ................................ .............. 71 3 12 Posterior view of the spline interpolat ed voltage distribution maps showing mean voltages for N1 activity. ................................ ................................ ............. 72

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9 3 13 Grand average event related potential waveforms showing the target locked 550 ms post target onset) for incongruent and congru ent target conditions. ................................ ................................ .............. 73 3 14 Top view of the spline interpolated voltage distribution maps showing mean voltages for P3 activi ty. ................................ ................................ ....................... 74

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10 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 DISRUPTION OF ATTENTIONAL PROCESSING IN CLOSED HEAD INJURY: AN EVENT RELATED POTENTIAL INVESTIGATION By Christopher Nicholas Sozda August 2013 Chair: William M. Perlstein Major: Psychology Emerging from acce leration or deceleration forces, closed head injuries (CHI) continue to remain a significant public health care issue in the United States. Whereas t he nature and pattern of neuro cognitive difficulties following injury often varies widely from patient to patient cognitive impairments in attentional processes are commonly observed across injury severity level However, it is unknown how CHI affects interactive co mponent processes of attention. To examine the effects of CHI on the neurobehavioral indices of three attentional networks (alerting, orienting, and executive control) electroencephalogram (EEG) and behavioral data ( RT and error rates) were acquired while 12 moderate to severe CHI participants and 1 2 demographically matched neurologically healthy controls performe d an attention n etwo rk test (ANT; Fan et al., 2002) Significant alerting and executive control RT differences were observed between groups ; however, after controlling for generalized slowing, only the alerting network remained significa ntly reduced in CHI patients. No group differences were observed in orienting as both groups showed RT improvement on target conditions preceded by

PAGE 11

11 spatially informative cues. Both groups committed significant ly more errors on incongruent vs. congruent tria ls, though this effect was not different between groups. Cue related event related potential (ERP) data revealed that bilateral posterior parietal N1 amplitude reflecting alerting was greater in controls than CHI participants ; however, b oth groups dem onstrated similar magnitude enhancement of N1 amplitude to more than less spatially informative cues, reflective of similarity in orienting network functioning. Regarding executive control, target related P3 amplitude was attenuated to at central posterior scalp sites, an effect that did not significantly differ between groups. Taken together, CHI participants demonstrated behavioral and neural alterations in only the alerting network Such difficulties in alerting like ly reflect difficulty in processing ambiguous stimuli rather than in maintaining an alert state and may be the result of disruptions in norepinephrine neurotransmitter systems Difficulties in executive control were manifested as cognitive slowing, rath er than core impairment in executive functioning, and suggest that given enough time, CHI may perform at levels equal of controls. Lastly, CHI patients significantly benefited from spatially informative cues to aid their task performance similar to that observed in controls

PAGE 12

12 CHAPTER 1 INTRODUCTION Closed Head Injury Epidemiology Closed head injury (CHI), a non penetrating insult to the brain that emerges from inertia (acceleration or deceleration forces) or external contact, remains a significant public health care issue in the United States, and is among the leading causes of morbidity and disability among individuals under 45 years of age (C oronado, Thomas, Sattin, & Johnson, 2005; NIH, 1998; Thurman, Alverson, Dun n, Guerrero, & Sniezek, 1999). Specifically, CHI and penetrating head injuries (e.g., gunshot wounds) affect approximately 1.7 million individuals in the United States annually (Fa ul, Xu, Wald, & Coronado, 2010), and are two times more likely to occur in males than females (Langlois, Rutland Brown, & Thomas, 2004). Historically, the major cause of CHI related injuries have been attributable to motor ve hicle accidents (MVA), but rec ent data suggest that injuries due to falls (28%) now exceed those caused by MVAs (20%; Langlois, Rutland Brown, & Wald, 2006). This is likely attributable to increasing r ates of CHI in young children (less than 4 years of age ) and older adults ( over 75 years of age ) where falls account for most injuries in these populations (Langlois et al., 2004). Lastly, since 2000, approximately 230,000 servi ce members serving in operations enduring freedom (OEF), Iraqi freedom (OIF) and new dawn (OND) have been di agnosed with a brain injury (DVBIC, 2012). Although nearly 75% of all injuries are classified as mil d (e.g., concussion; CDC, 2003), approximately 275,000 injuries are severe enough to warrant hospitalization, where an estimated 52,000 individuals will die (CDC, 2010). M ild CHI patients often do

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13 not require long term medical care or extensive treatment for functional recovery; however, long term rehabilitation is often required to maximize recovery of function for i ndividuals who sustain moderate to severe injuries (Levin et al., 1990). Specifically, more than 80,000 survivors will endure life long p hysical, cognitive and/or functional occupational to pre morbid levels of physi cal and cognitive functioning (Thurman, Coronado, & Selassie, 2007). Whereas the emotional cost of injury is immeasurable, the economic consequences to society attributable to CHI have been estimated to exceed $60 billion per year (Finkelstein, Corso, & Miller, 2006). As staggering as these numbers read, they do not account for individuals who fail to seek medical treatment, or seek out medical care in various outpatient clinics, family medical practices, or military facilities (Finkelstein et al, 2006) Neurobehavioral S equelae Often viewed as a multi f aceted process, the neurobehavioral sequelae of CHI often include cognitive, behavioral, affective, physical, and/or somatic changes (Riggio, 2011). Notably, brain injuries are often heterogeneous in nat ure and typically acquired via coup contrecoup or diffuse axonal injury (DAI) mechanisms. In coup contrecoup injuries, brain damage often occurs at both the impact site (coup bruising), as well as tissue opposite to the initial impact location (contrecoup injury; Drew & Dr ew, 2004; Levin & Kraus, 1994). In contrast, DAI is characterized by shearing and /or stretching of axonal white matter nerve fibers and blood vessels due to rapid changes in acceleration deceleration forces and rotational movement of the skull (Adams, Graham, Murray, & Scott, 1982; Strich, 1961). Additionally, damage from CHI occurs not only at the time of injury, but also in the hours and days following injury due to secondary

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14 mechanisms such as intracranial hemorrhag ing diffuse brain s welling, edema, and hypoxia ( Marion, Darby, & Yonas 1991). Taken together, primary and secondary injury mechanisms often result in a heterogeneous patient population, which poses a major challenge to developing effective interventions to maximize functional outcome after CHI for as many patients as possible in the most cost effective manner Whereas mild CHI patients (e.g., an athlete who sustains a concussion) often only experience transient symptoms that typi cally resolve within days to weeks following injury (Bigler, 2008), moderate to severe CHI patients will often face persistent neurobehavioral dysfunction (e.g., Dikmen et al., 2009). Affective changes may manifest as depression, anxiety, apathy, agitatio n, impulsivity, anger, and/or aggression (e.g. Kim et al., 2007, Schwarzbold et al., 2008 ). P hysical or somatic symptoms can include headaches, fatigue, dizziness, seizures, and gait and balance difficulties (Parikh, Koch, & Narayan, 2007). However, even in patients with good neurological recovery, the most common complaint of CHI survivors are persistent cognitive difficulties (Cicerone et al., 2005; Lovell & Franzen, 1994) which cut across cognitive domains including attention (e.g., Willmott, Ponsfor d, Hocking, & Schnberger, 2009 ), working memory (e.g., Anderson & Knight, 2010), learning and memory (Ruttan, Martin, Liu, Colella, & Green, 2008), information processing speed (e.g., Kinsella, 2008), verbal fluency (e.g., Capitani, Rosci, Saetti, & Laiacon a, 2009), and executive function s including but not limited to task switching, response inhibition, context processing, and error monitoring (e.g., Larson, Kaufman, & Perlstein, 2009 ; Larson, Perlstein, Demery, & Stigge Kaufman, 2006; Larson, Stigge Kaufma n Schmulfass, & Perlstein, 2007; Sozda, Larson, Kaufman, Schmalfuss, & Perlstein, 2011 ). Taken together post morbid

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15 cognitive difficulties often inhibit functional outcomes of patients in areas including independent li ving, vocational re attainment, a nd psychosocial adaptation (Ben Yishay & Diller, 1993; Cicerone et al., 2000; Sherer, Madison, & Hannay, 2000). Closed Head Injury and Attentional Impairment: A Closer Look Of the aforementioned cognitive changes, impairments of attention can be particula rly frustrating for patients and caregivers to manage as they often affect an handle many everyday activities that were once secondhand such as maintaining focus when reading a book or listening to their spouse discuss their day (Robertson, Manly, Andrade, Baddeley, & Yiend, 1997). More s f or processing relevant environmental stimuli necessary for learning, memory, and multi tasking (Van Zomeren & Brouwer, 1994; McCullagh & Feinstein, 2005), as well as assisting with adaptation to constantly changing environmental demands (Daffner et al., 20 06), attentional processes are often viewed as forming the backbone of the cognitive information related phenomena including visuospatial orienting, attention span, focused/selectiv e attention, divided attention, and sustained attention (e.g., Ashcraft, 2006). Arising from focal damage (e.g., coup contrecoup injuries) and/or diffuse axonal injury (DAI) that cause s disruptions of fronto temporal cortical neural networks involving sero tonergic and catecholaminergic tracts and subcortical white matter pathways (Graham, 1999; Povlishock & Katz, 2005), impairments of concentration and attentional processes are nearly universally observed at all levels of injury severity (e.g., Gronwall, 19 87; Whyte, Hart, Laborde, & Rosenthal, 2004). Attentional difficulties may manifest in

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16 trouble with maintaining focus on a task or thought at hand (e.g., reading a story), switching between tasks, and multitasking (e.g., Lux, 2007), or in even more basic tasks (e.g., listening to another person talk). Tasks that require astute observation and processing of ever become disrupted. Moreover, attentional impairments may underlie difficulties in other cognitive domains (e.g., memory problems may ar ise from difficulty attending and focusing on stimuli to be encoded rather than in core learning or retrieval abilities; Hertzog, Dixon, & Hultsch, 1990). Although a plethora of studies have exam ined CHI related attentional impairments (e.g., Catena, van Don kelaar, Halterman, & Chou, 2009; Whyte et al., 2008), differing methodological designs, aspects of attention measured, tests employed, and patient samples studied have produced inconsistencies regarding the nature and extent of reported difficul ties (Mathias & Wheaton, 2007). For example, CHI related attention deficits reported in clude visuospatial orienting (Bate, Mathias, & Crawford, 2001; Catena et al., 2009), sustained attention (Dockree et al., 2006), dual task performance and divided attention (Azouvi et al., 2004; Couillet et al., 2010), executive attention (Whyte et al., 2008), focused/selective attention (Ziino & Ponsford, 2006) and supervisory attentional control (Rios et al., 2004). Additionally, multiple studies from our laboratory have observed CHI related impairments in cognitive processes dependent upon intact anterior attentional networks (Larson et al., 2007; 2009). Notably an ongoing debate remains about whether deficits in attention are the result of pervasive slowing of information processing speed (e.g., generalized slowing) or are reflective of a specific cognitive deficit (Brouwer, Withaar, Tant, & van Zomeren,

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17 2002; Perianez & Munoz Cespedes, 2004). This generalized versus specific deficit issue is an important one as processing s peed impairment may mask impairments in more specific areas of cognitive functioning. For example, the magnitude of a discrepancy between Stroop interference scores may be small between g roups due to poor performance on word reading and color naming trial conditions, suggesting non impaired conflict resolution Alternatively, reported impairment in specific cognitive processes may be attributable to cognitive slowing, which is often overl ooked in many research studies. For example, discrepancies on interference trials of cognitive tasks patient groups also typically manifest slower RTs overall (e.g., generalized slowing) compared to neurologically health control participants As such, if RTs are normalized, the discrepancy score investigated may not be disproportionate to what would be expected given the slower overall processing speed of each group. Taken together, ruling out the confounding nature of generalized slowing is i mportant in identifying true patient deficits which has important implications for cognitive rehabilitation. Attention in the 21 st Century: The Attention Network Test (ANT) Attention Components (Alerting, Orienting, and Executive C ontrol) Due to the different methodological designs, post injury interval windows, tests of attention, and different constructs of attention Mathias and Wheaton (2007) have suggested that the lack of standardization hinders our ability to determine whether one measure is p articularly sensitive to impairments in attention, as well as whether more severe impairments of attention are observed in specific aspects of attention than others (e.g., attentional components). In an attempt to reconcile these discrepancies, recent stu dies of attentional impairments have been based on evolving theories which suggest

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18 is dissociable yet interrelated anatomical and functional attentional neural networks supporting phasic alerting, spatial orienting, and executive control (Fan, McCandliss, Sommers, Raz, & Posner, 2002; Posner & Fan, 2004; Posner & Peterson, 1990). Briefly, the alerting system functions to achieve and sustain an alert state via external st imulus cueing (Fan et al., 2002) The orienting network functions serve to filter and manipulate information from sensory input, and through spatial cuing, covertly directs attention (Posner, 1980; Fan et al., 2002). Lastly, the executive control network reflects higher order cognitive processes necessary for successful response conflict resolution involving inhibition of prepotent, but contextually inappropriate responses (Fan et al., 2002). Executive control is especially important when environmental s ituations are novel or difficult (Fan & Posner, 2004). A three construct for dissociating specific rather than broad attentional impairments, and experimental use of the Attention Net work Test (ANT), an experimental paradigm designed by Fan and colleagues (2002) which combines features of the Posner spatial cuing task (Posner & Petersen, 1990) and Eriksen Flanker task (Eriksen & Eriksen, 1974), has been found to reliably assay the func tion of the three networks in a plethora of studies of healthy adults (i.e. Fan, Wu, Fossella, & Posner 2001 a ; Fossella et al. 2002, Redick & Engle, 2006). While it has previously been thought that these networks have revealed significant inter network correlations, suggesting the three atte ntional networks are not truly independent (Macleod et al., 2010). Despite this, the widespread utility of the ANT to detect specific

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19 attentional impairments is evidenced by i ts use in studies of schizophrenia (Neuhaus et al., 2007), post traumatic stress disorder (Leskin & White, 2007), and attention deficit/ hyperactivity disorder (Adolfsdottir Sorensen, & Lundervold, 2008), among others. Neurochemical M echanisms P harmacological manipulations of the neurochemical mechanisms of attention suggest that a specific chemical neuromodulator is principal to each attentional network (Marocco & Davidson, 1998). Specifically, norepinephrine has been suggested as a primary n euromodulator involved in alerting, acetylcholine as an important neuromodulator involved in orienting (Davidson & Marrocco, 2000), and dopamine as an underlying neuromodulator involved in executive control (Marrocco & Davidson, 1998). As previously menti oned secondary injury mechanisms often cause disruption in neurotransmitter systems in CHI patients including dopaminergic and cholinergic systems Consequently examination of ANT performance may one day inform which neurotransmitter systems may be most responsive to pharmacological treatment (e.g., poor alerting may suggest disruption of norepinephrine transmission) A breadth of studies are examining such pharmacological treatments of cognition in non human animal models of CHI (e.g., Kline, Olsen, So zda Hoffman, & Cheng, in press; Olsen, Sozda, Cheng, Hoffman, & Kline, in press), and will eventually be the subject of translational research. Anatomical/Functional Indices of A ttention N euroimaging techniques have also provided insight into how specifi c attentional components are affected following head injury thro ugh examination of spatial and temporal neural indices Recent studies (e.g., Fan, Hof, Guise, Fossella, & Posner, 2007; Fan, McCandliss, Fossella, Flombaum, & Posner, 2005) have successfully

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20 employed event related functional magnetic resonance imaging (fMRI) to demonstrate differential anatomical localization of the three attentional networks. Specifically, the thalamus and right frontal parietal hemisphere has been shown to be associated wi th the alerting network (Fan et al., 2005), superior parietal lobe activation with the orienting network (Corbetta et al., 2000; Fan, et al., 2005), and the anterior cingulate cortex (ACC) and lateral prefrontal cortex (PFC) with the executive control netw ork (Bush, Luu, & Posner, 2000; Fan, McCandliss, Flombaum, Thomas, & Posner, 2001b). However, the utility of using fMRI to examine temporally locked neural correlates associated with dynamic attentional processes is significantly restricted due to the relatively poor temporal resolution inherent to hemodynamic neuroimaging methodologies. For example, attentional processes typically occur on the order milliseconds (e.g., Hillyard, Hink, Schwent, & Picton, 1973); however, the hemodynamic response measure d using fMRI is usually delayed in onset by approximately 4 6 s after initial stimulus presentation (Buckner, 1998; Rosen, Buckner, & Dale, 1998). As such, recent neuroimaging studies of attention, and of the ANT specifically (e.g., Fan et al., 2007 a; 200 7b ; Neuhaus et al., 2007; 2010), have attempted to resolve this issue by obtaining scalp recorded brain event related potentials (ERPs) during task performance, which provide unparalleled sensitivity needed for examining the temporal dynamics of neuronal correlates. A Brief Overview of Scalp Recorded Event Related Potentials (ERPS) Over the past four decades, technological advances, most noticeable with increased use of the electroencephalogram (EEG) which provides a detailed temporal record of electrical activity conducted from brain to scalp (Davi dson, Jackson, & Larson, 2000), have aided researchers investigating the complex processes and neural

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21 mechanisms that underlie different cognitive functions. Measured by scalp electrodes, EEG electrical activity is subject ed to various artifact correction procedures (e.g., eye blink correction and noise filtering ), before being averaged to coincide with time locked events of interest (e.g., stimuli presentation). Although an event related response is not visible by simply examining the ongoing EEG activity, an event related potential (ERP) waveform time locked to specific stimulus presentations can be extracted by averaging repeated multiple samples of a particular class of stimulus and/or response events within the EEG (Fabiani, Gratton, & Coles, 2000). Averaging EEG signal is based on the assumption that brain activity for the same conditions should remain constant during the duration of the experiment (Otten & Rugg, 2005). As such, when averaged, the ERP signa l if relatively consistent from trial to trial will strengthen, while noise and random activity inherent within the ongoing background EEG is averaged out of the resulting waveforms (Otten & Rugg, 2005) leaving in theory, task relevant information ERPs provide unmatched sensitiv ity to examine the dynamic temporal changes in neural activity on the leve l of milliseconds (ms; Fabiani et al., 2000). Specific ERP waveforms often consist of averaged voltage deflections (peaks and troughs) as measured by ampl itude (microvolts). Voltage deflec tions will have either positive or nega tive going polarity depending on where and when on the scalp the data are measured. Each component may also contain a time point at which the voltage deflection (e.g., amplitude) is highest or lowest over the course of a selected time frame, referred to as peak latency, and measured in ms. Taken together, researchers often combine polarity and peak latency information to refer to discrete ERP components

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22 peak with latency onset occurring approximately 100 ms after stimulus presentation. Additionally, since the N100 is usually the first negative peak post stimulus onset, this component is also reflective of being the first negative peak following the time locked stimuli. Likewise, the P300 component descr ibes a peak positive voltage deflection occurring approximately 300 ms post stimulus onset. If the P300 also was the third pos itive component, it can also be referred to as the P3. Neural Correlates of the ANT Of the three attentional components, the aler ting network has received the least investigation in the literature. Neuhaus and colleagues (2010) reported observing increases in cue locked target amplitude occurring approximately 100 200 ms following stimulus onset (e.g., N1). This finding was recent ly replicated in our laboratory, and although not yet well understood, likely reflect s processing of stimuli which facilitates response preparation via external stimulus cueing which is likely mediated by activation within the thalamus and posterior cor tic al sites (Fan et al., 2005). Visual orienting of attention, as assessed with measures other than the ANT, have consistently reported increased posterior negativity amplitude also occurring approximately 100 ms (e.g., N1) following validly cued target stim uli (Harter, Miller, Price, LaLonde, & Keyes 1989; Hopf & Mangun, 2000; Nobre, Sebestyen, & Miniussi, 2000; Talsma, Slagter, Nieuwenhuis, Hage, & Kok, 2005). Again, these results have been replicated using the ANT both in and outside of our laboratory (Ne uhaus et al., 2010), and are thought to reflect successful shifts of visual attention from one stimuli to another mediated by activation within a dorsal fronto parietal network (e.g., Fan et al., 2005; Mangun, 1995; Hillyard, Vogel, & Luck, 1998).

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23 With r espect to executive control, several electrophysiological investigations employing the ANT have demonstrated attenuat ed P3 amplitudes that is, a posterior positivity occurring approximately 300 ms following incongruent compared to congruent target stimul i (Neuhaus et al., 2007, 2010). Briefly, the P3 ERP component was first discussed in the literature nearly five decades ago (Sutton, Braren, Zubin, & John, 1965), and is one of the most frequently investigated ERP components in electrophysiological resear ch today. P3 is thought to reflect the allocation of attentional resources necessary to support and continuously update active memory processes (Polich, 1996), reflecting stimulus evaluation and categorization, and is a reliable electrophysiological probe of the diversion of attention resources in both healthy participants and individuals with cognitive dysfunction (Polich, 1991, 2004). In addition, P3 latency may reflect the upper boundary on stimulus evaluation time (Coles, Smid, Scheffers, & Otten, 199 5). Although the P3 component is frequently observed in numerous cognitive paradigms (e.g., Polich, 2007), in the context of the ANT, the P3 component likely reflects activity in the anterior cingulate cortex (ACC) which mediat es conflict resolution assoc iated with response inhibition involved in over riding a strong pre potent response tendency (Fan et al., 2005, 2007; Neuhaus et al., 2007, 2010). Closed Head Injury and the ANT Despite the sensitivity of the ANT to identify anatomically and functionally d issociable neural networks of attention in a plethora of neurological and non neurological conditions, only three studies, all with mild CHI patient samples, have used the ANT to examine attentional disruptions following brain injury Results have been co nsistent and suggest that while the alerting network is relatively unaffected after injury, the ANT is sensitive to disruptions of orienting and executive control (Catena et

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24 al., 2009; Halterman et al., 2006; van Donkelaar et al., 2005). However, the inte rpretation of behavioral fin dings in two of the three above mentioned studies (Halterman et al., 2006; van Donkelaar et al., 2005) is incorrect with regard to the orienting network. For example, both papers (Halterman et al., 2006; van Donkelaar et al., 2005) reported that CHI rienting, as evidenced by a significantly greater difference score between spatial and center cue conditions in mild CHI than control participants. However, the reported results would actually suggest that CHI patients obtained greater benefit from spatia l cuing than controls (e.g., generalized slowing, rather than of orienting. orienting we re attenuated within a week of injury, this likely reflects improvements in overall speediness as evidenced by quicker reaction times collapsed across conditions. Regardless of the incorrect interpretation of the effects of CHI on orienting of attention, deficits of executive control were noted to remain at one month post injury (Halterman et al., 2006). Taken together, these results point to the sensitivity of the ANT to track short term recovery of m CHI patients across different attentional components. However, to date, the ANT has not yet been used to examine behavioral attentional networks and underlying neural correlates in moderate to severe CHI survivors. Variants of alerting, orienting, and executive control functions have been examined in measu res other than ANT with the use of moderate to severe patients. Results contrast those observed on the ANT with respect to alerting, where numerous studies have reported observing reduced initial and sustained level of performance v ersus controls

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25 ( e.g., Whyte, Polansky, Fleming, Coslett, & Cavallucci, 1995; Zinno & Ponsford, 2006), but coincide with studies reporting benefits of spatial cuing (e.g., Bate et al., 2001) and difficulties in executive control (e.g., Larson et al., 2007) However, use of the ANT has the potential to examine performanc e on all components in a single efficient task, rather than across measures, and is amenable to ERP investigation which has the ability to provide markers that correspond with behavioral impairment. This is espe cially important given the calls for the development of rehabilitative techniques targeting specific attention networks (Sohlberg, McLaughlin, Pavese, Heidrich, & Posner, 2000). ERP Investigations of Closed Head Injury Despite the lack of CHI related ANT s tudies, several researchers employing measures other than the ANT have examined the effects of CHI on ERP components that are of interest to the present study, specifically, N1 (reflective of attention allocation) and P3 (reflective of stimulus processing a nd categorization) While the effects of CHI on the N1 component has received the least research attention, most studies conducted have revealed that neither visual or auditory N1 properties sensitively differentiate between survivors of head injury and h ealthy controls (e.g., Potter & Barrett, 1999; Potter, Jory, Bassett, Barrett, & Mychalkiw, 2002). More recent findings revealed that N1 amplitude was significantly different between CHI patients and controls following auditory stimuli presentation, but n ot visual stimuli presentation (Duncan, Kosmidis, & Mirsky, 2005). Lastly, a recent study of reward processing also failed to demonstrate that N1 amplitude significantly differed between severe CHI patients and healthy controls (Larson et al., 2007); howe ver, it should be noted that the N1 was not the main component of interest in this study.

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26 The effects of CHI on P3 are more pronounced and numerous researchers have reported amplitude reductions and peak latency differences in CHI patients versus healthy controls using various cognitive paradigms (for review see Dockree & Robertson, 2011 ). Briefly, in an oddball discrimination task, the P3 component was reduced in amplitude and delayed in onset compared t o controls, which was thought to reflect both psychomotor and perceptual difficulties (Lew, Gray, & Poole, 2009). In a separate study, P3 peak amplitudes were not observable in 9 of 40 CHI patients during completion of an auditory oddball task, which the authors characterized as a marker of central nervous system damage (Keren, Ben Dror, Stern, Goldberg, & Groswasser, 1998; Naito, Ando, Yamaguchi, 2005). Notably, the P3 appears to be a particularly sensitive index of disrupted neural processing, as P3 amp litude significantly differentiate s between healthy controls and patients sustaining mild head injuries (e.g., concussions) 8 years earlier (Bernstein, 2002). Although not examined through evaluation of the P3 several studies have directly investigated t he effects of CHI on the neural correlates of conflict resolution (e.g., executive control network; Perlstein, Larson, Dotson, & Kelly, 2006). Specifically, during completion of a cued Stroop task, CHI patients demonstrated impairments when required to ac tively switch between different sets of tasks instructions, and inhibit a strong prepotent response tendency under incongruent target conditions (Perlstein et al., 2006). Moreover, these patients did not produce an ACC mediated fronto central N450 compone nt that is consis tently present in controls and is thought to be an electrophysiological marker of conflict d etection and response resolution (Perlstein et al., 2006; van Veen & Carter, 2002). In sum, the above results suggest alteration of

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27 neural corre lates necessary for allocation of attentional resources and efficient conflict detection and resolution following CHI. Rationale for the Current Study CHI patients often experience difficulties with multitasking, sustaining and switching their attentional focus, and executive functioning, which is likely attributable at least in part to damage of frontal lobe structures and white matter pathways involving subcortical structures. Although much information has been gathered about the widespread attentional deficits associated with CHI many important gaps remain in our understanding of CHI related attentional behavioral impairment and the neural bases underlying deficits of attention. Attempting to fill these gaps will aid researchers in the ongoing debate about differentiating whether 1) CHI related deficits in attention are the result of pervasive slowing of information processing, or are truly reflective of a specific cognitive deficit (Brouwer et al., 2002; Rios et al., 2004) ; 2) whether CHI patients ar e impaired in one or more component processes of attention; and 3) how neural correlates of attentional processing may manifest and impact behavioral performance These are particularly important questions to address, as disruption of attentional processe s have ramifications for successful adaptation in an ever changing environment with constantly changing demands as well as responsiveness to cognitive rehabilitation efforts For example, individuals must be able to successfully process incoming sensory information such that unnecessary details are disregarded or de prioritized Additionally, these processes facilitate other cognitive functions, such as transferring meaningful information into memory, and interpreting environmental dangers. Not surprisi ngly, failure to detect and process such information from the environment correctly may contribute to underlie other cognitive or emotional problems.

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28 As previously discussed, scalp recorded ERPs are a sensitive method of dissociating the dynamic temporal correlates of neural processes involved in attention. Despite the wealth of research studies in the field of CHI and attention, no systematic neurobehavioral examinations of attentional alerting, orienting, and executive functioning have been conducted using the three component model of attention to examine the neural underpinnings of disrupted attentional components in moderate to severe CHI patients. Given the fact that attentional impairments are nearly universally observed at all levels of injury severity (e.g., Gronwall, 1987; Whyte et al., 2004), the present study has the potential to identify behavioral an d neural correlates sensitive to brain injury that may be indicative of real world fun ctioning. Study Predictions Behavioral D ata It is predicted that m oderate to severe CHI (m/sCHI) patients will show generalized slowing across all task conditions, as evidenced by slower reaction times (RTs) compared to healthy controls as well as great er error rates on incongruent target conditions Both healthy controls and m/sCHI patients are expected to demonstrate an interference as evidenced by greater error rates and slower RTs to incongruent compared to congruent and neutral s timuli. Regarding attention network effects, as compared to healthy controls m/sCH I patients are expected to show less efficient alerting (e.g., smaller difference RT scores between no cue and double cue conditions), as well as greater conflict interfere nce (e.g., larger difference RT scores between congruent and incongruent target stimuli) However, CHI participants are not expected to show significant differences compared to controls in the extent to which they benefit from spatial cuing (orienting n etwork)

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29 ERP D ata Corresponding with behavioral findings, c ompared to controls, m/sCH I patients will demonstrate attenuation in N1 amplitude during examination of alerting (double vs. no cue conditions) but not orienting (center vs. spatial cue conditions) networks Regarding executive control, both groups are expected to demons trate reduced P3 amplitude to incongruent vs. congruent target stimuli Additionally, it is expected tha t CH I patients will demonstrate a disproportionately greater reduc tion in P3 amplitude, compared to healthy controls.

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30 CHAPTER 2 METHODS Participants Participants included 12 patients with moderate to severe CHI (m/sCHI ; 5 females, 7 males; mean age 28.7 9.5 years ) and 12 demographically matched healthy adults (6 females, 6 mal es; mean age 24.8 9.9 years). All participants were between the ages of 18 and 55 years and healthy control participants did not have any history of sustained traumatic bone fracture or impact involving the head. As displayed in Table 2 1, c ontrols were demographically selected and matched, on average, to CHI patients for age t (22) = .97, p = .35, educational attainment, t (22) = 1.03, p = .31, gender, 2(1) = .17, p = .69 and ethnicity, 2(3) = 6.4, p = .096 Regard ing the la tter, all CHI patients were Caucasian while four control part icipants self identified as Asian/Indian or African American. CHI participants we re tested between six months to eight years post injury (mean time since injury 59.7 24.5 months ), a nd sustained a m/s CHI as defined by Lezak, Howieson, and Loring (2004). Injury characteristics for participants are presented in Table 2 2. CHI severity was determined by assessing the following acute neurological indices: duration of loss of consciousne ss (LOC), duration of post traumatic amnesia, and Glasgow Coma Scale score (GCS; Teasdale & Jennett, 1974). Specifically, moderate CHI was defined as either LOC lasting 30 minutes to 6 hour s, PTA between 1 and 7 days, and/or GCS score between 9 and 12. Severe CHI was defined as either LOC > 6 hours, PTA > 7 days, and/or GCS score between 3 and 8 (Bigler, 1990; Bond, 1986; Lezak, et al., 2004). If severity criteria for any individual overlap ped (e.g., PTA in the moderate rang e and GCS in th e severe range), the more severe injury indicator was

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31 used. Additionally, in cases where initial GCS was unobtainable from patient significant other or medical records, his or her duration of PTA was used for injury classification. PTA has been suggested to be more sensitive to the severity of injury than GCS (van der Naalt, 2001), as the latter can be affected by intubation, as well as an inability to record a GCS score immediately after injury. GCS scores for participants ranged from 3 13 Importantly, the patient who reported a GCS score of 13 also reported experiencing PTA for at least three days following injury which is more suggestive of a moderate than mild injury. Additionally, GCS scores were unavailable for two patients; however, both patients reported PTA duration of at least one week following injury, suggestive of moderate to severe injuries. Overall, t wo CHI participants were classified as having sustained moderate injuries, while the remaining 10 patients fell within the sev ere range. Neither time since injury or duration of PTA was correlated with attention network scores ( rs < .40, ps > .20), and as such, all CHI participants were averaged together for subsequent data analyses. All participants provided written informed c onsent in accordance with procedures established by the University of Florida Health Science Center Institutional Review Board. CHI participants and s everal control participants received compensation of $10 per hour up to $50 for their participation. Seve ral control participants elected to receive psychological research participation credit in lieu of financial compensation for their participation. Participants were recruited through collaborations with Brooks Rehabilitation Hospital in Jacksonville, IRB approved flyers located throughout the University of Florida and local community, public service radio announcements and the University of Florida Psychology Research Participant Pool

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32 With the exception of one ambidextrous CHI patient, a ll participants were right handed, as determined by hand used to write, native English speakers CH I participants provided written release to allow available medical records from hospitalization to be examined to obtain information pertaining to reported CHI Any participant that 1) c ould not provide writt e n informed consent, 2) exhibit evidence that she or he does not fully understand the nature of the study and requirements of participation, 3) c ould not understand task instructions and perform the e xperimental t asks, or 4) reported involvement in current litigation, w ere excluded from participation in the research. Individuals with history of any type of penetrating head injury, prior CHI, neurological disorder (e.g. stroke, epilepsy, seizure disorder) not dire ctly related to the CHI or uncorrected visual impairment were also excluded. However, CHI patients with non recurring post traumatic seizures were recruited provided they have not taken antiepileptic medication. Any individual with a psychological histo ry that could confound test results such as substance abuse disorder, psychotic disorder (e.g., schizophrenia) bipolar disorder, a prior history of ADHD, reported history of learning disability, and/or substance ab use within two weeks of testing were also excluded from participation. Approximately 120 potential participants were excluded from study participation. The most common exclusion reasons were history of multiple head injuries, injury greater than 10 years old, and participant age greater than 55 years old. Assessment of Cognitive Functioning During recruitment, participants completed a brief telephone screening to assess inclusion and exclusion criteria, and all eligible individuals were invited to participate in the research. Following informed consent procedures, a brief interview with patient, and if available, significant other was conducted to review medical history and records pre

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33 and post morbid psychological functioning, and durat ion of PTA, LOC, and GCS score. Neurocognitive functioning of CHI patients was characterized through administration of a brief neuropsychological test battery designed to provide an overview of performance across broad cognitive domains The Rey 15 Item Test (FIT; Rey, 1964) was used a s a brief screening measure of participant effort. Briefly, participants were presented a sheet of 15 items to memori ze for 10 s. The test was described to participants as items consist ed of five patterns which make th e test much easier than was portrayed. In accord ance with previous studies of CHI patients, scores of 8 or lower were presumed to reflect poor effort (T aylor, Kreutzer, & West, 2003). However, n o participants in either group achieved a score lower than 1 2 As such, effort was deemed to be appropriate for all study participants. Pre morbid intellectual functioning was estimated using the North American Adult Reading Test (NAART; (Spreen & Strauss, 1991). Although the NAART may underestimate high IQ scores and overestimate low IQ scores (Johnstone, Callahan, Kapila, & Bouman, 1996), it has been found to provide a good estimate of average WAIS R and WAIS III overall intelligence composite scores (Johnstone e t al., 1996). As shown in Table 2 1, controls and participants with CHI committed nearly identical numbers of NAART errors, resulting in similar mean estimates of premorbid WAIS R FSIQ scores (Controls = 110.2, CHI = 109. 4; Spreen & Strauss, 1991) that fe ll within the average to high average range s of intellectual functioning (Wechsler, 1981). Simple attention span and working memory was assessed using traditional Digit Span Forward/Backward and Letter Number Sequencing subtests, respectively, from

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34 the Wechsler Adult Intelligence Scale Third Edition (WAIS III). In each task, participants were presented with a series of numbers, or numbers and letter, and had to repeat t he numbers either in the same, reverse order, or correctly order the numbers and letters in numerical and alphabetical order, respectively. Reliability estimates of the Digit Span subtest in normative samples range from 0.84 to 0.93 (WAIS III and WMS III Technical Manual, 1997). The Stroop test (Golden, 1978) consisting of word read ing, color naming, and color word trials, was used to assess selective attention, processing speed and response inhibition. Executive control of planning, sequencing, perseveration, and problem solving was measured using the Wisconsin Card Sorting Test (W CST; Heaton, Chelune, Talley, Kay, & Curtis 1993). Specifically, participants were required to sort 128 cards according to shifting matching rules based on card properties. The WCST w as also used to assess supervisory attentional control, and has been foun d to elucidate difficulties in esta blishing and switching set in CH I patients that likely reflect focal lesions and diffuse axonal injury (Fork et al., 2005; Gansler, Covall, McGrath, & Oscar Berman, 1996). The Trail Making Test (TMT; Reitan, 1992) was ad ministered to assess processing speed, visual tracking, set shifting, and focused/selective attention. Specifically, on part A of the TMT participants were instructed to correctly sequence a series of ascending numbers in correct numerical sequence as qui ckly as possible. On part B of the TMT, participants were instructe d to correctly alternate sequencing between numbers and letters as fast as possible Psychometric studies indicate reliability coefficients above .80 (Spreen & Strauss, 1991), and Trails B has been observed to be specifically sensitive to prefrontal dysfunction due to set switching requirements (Butters, Kaszniak,

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35 Glisky, Eslinger, & Schachter, 1994). Confrontational word naming was assessed using the Boston Naming Test (BNT; Kaplan, Goo dglass, & Weintraub, 2001 ) Specifically, participants were shown pictures of various items and asked to name each object within 20 s. If participants did not know the name of an object, they were provided with a phonemic cue intended to aid word retriev al. Additionally, Contr olled Oral Word Association (COWAT; letters FAS) and Category Fluency (Benton & Hamsher, 1976) tests were administered to measure self initiation, response inhibition, cognitive efficiency, and organization of verbal retrieval and recall (Henry & Crawford, 2004). In each task, participants had to name as many words that began with the letters F, A, and S, as well as nam e as many animals as possible within 60 s. Regarding memory functions, the Wechsler Memory Scale Revised (WMS R) Logical Memory I and II subtests (Wechsler, 1987) were used to examine encoding, retrieval, and recognition of verbally prese nted information in paragraph form. Specifically, two different short stories are read requiring both immediate and delayed recall following a 25 35 m inute delay. The first story was read aloud once, whereas the second story was presented twice to allow f or examination of how repetition may have improve d performance. Estimates of reliability for Logical Memory I and Logical Memory II are .74 and .75, respectively (Wechsler, 1987). Lastly, visuoperception was assessed using the Facial Recognition Test (BF RT, Benton, Hamsher, Varney, & Spreen, 1983). Par ticipants w ere shown various faces at 45 o in black and white color, which they were required to match with identical or variations of faces that were rotated or shaded differently on another sheet of paper.

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36 The first six trials only required 1 match, whereas on later trials participants had to make three matches. As presented in Table 2 3 and characteristic of impairments usually observed after moderate to severe brain injury participants with CHI perform ed significantly worse than controls on tests broadly assessing processing speed ( Stroop Word reading/Color naming; TMT Part A), executive functioning ( TMT Part B ), delayed verbal memory (WMS R Logical Memory II) and confrontational naming (BNT) Although CHI participants performed significantly worse than controls on the Facial Recognition Test, the scores for both groups fell within the normal range of functioning. Additionally CH I patients did not differ from controls on verbal fluency measure s (COWAT and category fluency), the initial encoding/immediate recall of verbal memory information (WMS R Logical Memory I) or on tests broadly assessing attention (Stroop Color word; WCST; Digit Span and Letter number Sequencing subtests from the WAIS II I) Correlations between measures of attention/executive function and attention network scores were examined for experimental purposes to determine the potential overlap between research and clinical measures of attention and are presented in the results section. Assessment of Behavioral and Emotional Functioning Pre existing Axis I disorders and general psychopathology (e.g., post traumatic stress disorder, bipolar, schizophrenia, psychotic, and substance abuse disorders), among CHI patients and healthy c ontrols were assessed using a brief psychopathology screening measure adapted from the Mental Health Screening Form III (MHSF III; Carroll & McGinley, 2000). The MHSF III consists of 18 questions, and has been found to possess high inter rater reliability >

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37 .83; Carroll & McGinley, 2001). The MHSF III was also chosen due to short a dministration time of less than 15 minutes. Additionally, participants completed the B eck Depression Inventory 2 nd edition (BDI II; Beck, Steer, & Brown, 1996) and the State Trait Anxiety Inventory (STAI; Speilberger et al., 1983) to assess and quantify current depressive and anxiety symptomatology, respectively. Self reported symptoms of apathy were assessed using a modified version of the Apathy Evaluation Scale (AES; Starkstein et al., 1992). Finally, the Pittsburgh Sleep Quality Index (PSQI, Buysse, Reynolds, Mark, Berman, & Kupfer, 1989) was administered to examine the potential adverse effect of sleep disruptio n on cognitive performance which is not uncommon after CHI (Castriotta & Lai, 2001). As shown in Table 2 1, groups did not differ in the extent to which they endorsed symptoms of depression, state anxiety or apathy H owever, participants with CHI report ed a significantly greater level of trait anxiety t (22) = 2.5, p < .022. Though the mean scores for both groups were within the normal range (controls = 28.1, CHI = 37.6), t wo CHI participants had elevated trait anxiety scores Lastly, CHI patients also endorsed a significantly greater number of sleep complaints on the PSIQ than controls, (Mean PSIQ scores: controls = 3.3, CHI = 5.6), t (22) = 2.4, p < .024. Three controls and seven CHI participants had PSIQ scores of 5 or greater, suggesting possible c linically significant sleep disturbances among these participants. PSIQ and trait anxiety scores were not significantly correlated with attention network scores ( rs <.29, ps > .36), and ANCOVAs were deemed un necessary. Self a nd significant other reported CH I related symptomatology were obtained using a modified version of the Neurobehavioral Rating Scale (NRS; Levin et al., 1987;

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38 Mathias and Coats, 1999), as well as the Frontal Systems Behavior Scale (FrSBe). Briefly, the NRS is a 27 item instrument th at was originally based on clinician ratings to estimate cognitive, emotional, and behavioral changes following brain injury (Levin et al., 1987). The present study utilize d a modified version of the NRS developed by Mathias and Coats (1999), which enable d collection of self report observations from patients and their significant other. Participants and their significant others independently rate d each item using a 5 point scale (responses range Factor analysis studies (e.g ., Levin e t al., 1987) suggest answers can be clustered to form three stable factors: mood/affect, activity/beha vior, and cognition/attention. Lastly, internal consistency for self and significant the NRS were found to range from 0.92 to 0.96 (Mathias & Coats, 1999). The FrSBe consists of 46 items designed to measure behavioral changes that are associated with frontal brain injuries, such as disinhibition, executive function, and apathy. U nlik e the NRS, the FrSBE also allowed for pati ents and others to make ratings of pre morbid behavioral functioning. Lastly, adequate reliability (internal consistency 0.96) and validity (Grace & Malloy, 2001) have been reported with use of the FrSBE. Correlations between self report measures of CHI r elated symptomatology and attention network scores were examined for experimental purposes to determine the potential overlay between the experimental task and real world functioning, and are presented in the results section. Additionally, significant oth er ratings were only available for three participants, and data were not included in statistical analyses. Cognitive Tasks and Stimuli Participants completed the Attention Network Test (ANT), an experimental computerized task, while hi gh density scalp recorded event related potentials (ERPs)

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39 were recorded. The ANT was programmed and presented using E Prime software (v.1.0, Psychology Software Tools, Inc. Sharpsburg, PA ) experimental control software Stimuli were viewed from an approximate di stance of 60 70 cm, and responses were collected via two adjacent input keys on a standard keyboard that rested on the All participant s responded using their right hand, using their index and middle fingers to respond to left and right pointe d target stimuli respectively Briefly, the ANT, as depicted in Figure 2 1 is a computerized experimental task that was identical to the procedure used by Fan et al. (2002) and in previous studies in our laboratory Task stimuli consisted of fixation or without left or right ward pointing arrowheads -Individuals were instructed to focu s on a centrally located fixation cross throughout the procedure, and to determine as rapidly and accurately as possible whether the target probe, a central arrow, located above or below central fixation pointed left or right. In addition to varying targe t locations, on 75% of trials the target probe was preceded by different types of cues (center, double, spatial, no cue), and on 67% of trials the target probe was accompanied by cong ruent or incongruent flankers. The task utilize d two target locations (a bo ve or below central fixation), two targ et directions (left or right), four cue conditions (no cue, center cue, do uble cue and spatial cue), and three flanker conditions (congruent, incongruent, or neutral), yielding 48 different ty pes of trials. Each tr ial lasted ~4000 ms and consisted of five events: 1) random variable pre cue fixation (400 1600 ms), 2) warning cue presentation (100 ms), 3) post cue fixation (400 ms), 4) target and flanker presentation (self terminating up to 1700 ms), and 5) post targe t

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40 fixation (3500 ms minus duration of pre cue fixation mi nus RT). All participants complete d a 24 trial practice block, followed by 3 experimental blocks of 96 pseudo random trials (2 target locations x 2 target directions x 2 repetitions x 3 flanker c onditions x 4 cue conditions). Accuracy and RT feedback were provided to participants during only the practice block. Completion of the ANT including set up and participant breaks lasted approximately 40 minutes. Electrophysiological Data Acquisition an d Reduction Electroencephalogram (EEG) was recorded from 64 scalp sites using a geodesic sensor net and Electrical Geodesics, Inc., (EGI; Eugene, Oregon) amplifier system (20K gain, nominal bandpass = .10 100 Hz). Following data acquisition, but prior to analyses, e lectrode sites were interpolated from a 64 channel geodesic sensor net (Figure 2 2) to conform to th e international 10 10 positions. Electrode placements enabled recording of vertical and horizontal eye movements reflecting electro oculographic (EOG) activity. A right posterior electrode served as common ground, and electrode impedances were maintained below 5 at 250 Hz with a 16 bit analog to digital converter and referenced to Cz. Following recording, EEG data were re referenced offline to an average reference, and were adjusted for movement, electromyographic artifact, electro ocular eye movement, and blink artifacts using computer algorithms implemented using Brain Electrical Source Analysis software (BES A version 5.1; Scherg, 1990). EEG activity was excluded from the remaining data using threshold criteria that maximized the number of trials accepted from each individual. The average voltage threshold used for excluding trials was SD : 10.73 r ange: 100 t (22) = 0, p = 1.0. Point to point transitions did not

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41 Individual subject event related potentials (ERPs) were separately extracted and averaged together from the continuous EEG re cording in discrete temporal windows coinciding with e ach stimulus onset for cue locked ( center, double, spatial, and no cue) extended cue locked (center, double, spatial, and no cue) and target locked (congruent, incongruent) conditions. Epoch duration of cue locked and extended cue locked epochs was set to 1600 ms (300 ms pre cue to 800 ms post probe including 400 ms cue offset probe onset interval); target locked epochs were extrac ted with duration of 200 ms pre and 1200 ms post target probe presentation. All averaged ERP epochs were digitally filtered at 30 Hz low pass and baseline corrected using respective pre stimulus windows. Cue locked N1 and P3 mean amplitudes and peak late ncies were measured over central posterior medial electrode sites (e.g., 10 10 equivalents = CPz, P2, P3, PZ, PO3, PO4, and P O z), between 168 236 ms and 344 432 ms, respectively. Mean amplitude and peak latency values for extended cue locked N1 amplitude was measured bilaterally over posteri or parietal scalp sites (1 0 10 system equivalents = P9, P07, P08, P10 ) between 160 224 ms post target onset corresponding to 660 724 ms post cue onset Target locked N1 and P3 mean amplitudes and peak latency were mea sured over central posterior medial elec trode sites ( 10 10 equivalents = CPz, P2, P3, PZ, PO3, PO4, and P O z ), between 160 224 ms and 3 16 464 ms post target onset, respectively. Data Analyses Statistical analyses were carried out with JMP v. 9.0. 2 (SAS Institute Inc., Cary, NC, USA). All statistical tests will have an alpha level of .05 Interaction effects were decomposed using least square means contrasts, and Cohen s d effect sizes (Cohen, 1988) were calculated using pooled standard deviations for group and/or condition

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42 related effects and are presented where appropriate Dem ographic and Neuropsychological D ata A nalyses Chi square analyses were used to compare categorical demographic variables (e.g., sex ethnicity ) across groups. Neuropsych ological variables and continuous demographic variables (e.g., age, education) were analyzed using one way analyses of variance (ANOVAs). Pearson product correlations were used to examine relationships between behavioral task performance, neuropsychologic al test data, ERP amplitudes, and measures of real world functioning. Behavioral D ata A nalyses As suggested by Fan et al. (2002), attention network effects were calculated using the following cognitive subtractions: alerting effect = no cue RT minus double cu e RT; orienting effect = center cue RT minus spatial cue RT; executive control (conflict) effect = incongruent RT minus congruent RT. Attention network difference scores were analyzed using one way anal yses of variance (ANOVAs). Median correct trial R T (Ratcliff, 1993) and mean error rates excluding non responses (e.g., errors of omission) were analyzed separately using 2 Group ( controls, CHI ) x 3 Flanker type (incongruent, neutral, congruent) x 4 Cue type (no, spatial, double, and center) REML ANOVAs. Additionally, to examine whether condition related RT effects are artificially created due to generalized slowing experienced by CHI patients, z score transformations of participant RTs were calculated by taking the mean over all conditions for a given individual, subtracting his/her condition mean from the overall mean, and dividing by the overall standard deviation across the overall mean. Th is method has shown to be effective in identifying cognitive deficits independent of generalized slowing using the ANT (Jennings, Dagenbach, Engle, & Funke 2007).

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43 ERP Data A nalyses In accordance with Neuhaus and colleagues (2010), as well as recent studies from our laboratory (e.g., Sozda, Kaufman, Dotson, & Perlstein, 2011), attention network ERPs were examined using the following cognitive comparisons: alerting effect = no cue mean amplitude vs. double cue mean ampl itude; orienting effect = center cue mean incongruent mean amplitude vs. congruent mean amplitude. For analysis of attention network ERP activity, ANOVAs included the factors group and condition (either double c ue and no cue, spatial cue and center cue, or congruent probe and incongruent probe, depending on the attention network being analyzed). For analysis of cue locked ERP activity, ANOVAs included the factors group and condition (double cue, no cue, spatial cue, and center cue). For analysis of target related N1 ERP activity, ANOVAs included the factors group and condition (congruent and incongruent probe). Selection of electrode sites for analyses of electrophysiological data was based on prior findings ind icating modulations of interest over parieto occipital sites for extended cue locked data (e.g., N1, Neuhaus et al., 2010) and posterior parietal sites for target locked effects (e.g ., P300, Neuhaus et al., 2007). ERP figures for display here were created using DeltaGraph v. 4.0 .5 (SPSS Inc., Richmond, CA).

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44 Table 2 1 Demographic injury, and questionnaire data for control and moderate to severe CHI participant groups Controls m/sCHI Analysis Mean SD Mean SD t p d Age (yrs) 24.83 9.9 28.67 9.5 .97 .34 .40 Educational Level (yrs) 15.42 2.1 14.58 1.9 1.03 .31 .42 PTA (days) --54.75 63.1 ---Time since injury (months) --59.67 24.5 ---BDI II Score 3.17 2.4 8.67 9.0 2.05 .053 .84 Apathy Scale Score 8.33 4.0 11.42 5.1 1.65 .11 .67 STAI State Score 28.25 5.8 34.25 11.3 1.64 .12 .67 STAI Trait Score 28.08 3.6 37.58 12.8 2.48 .021 1.01 PSQI Score 3.33 1.6 5.58 2.8 2.43 .023 .99 NRS Total Score --66.50 17.4 ---FrSBE Total Score (pre morbid) --86.08 17.9 ---FrSBE Total Score (post) --92.92 20.0 ---BDI II = Beck depression i nvento ry s econd e dition; FrSBE = Frontal systems behavior scale; NRS = Neurobehavioral rating scale; PTA = Duration of post traumatic amnesia; STAI = state trait anxiety i nventory; PSQI = Pittsburgh sleep quality i ndex

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45 Table 2 2 Injury c hara cteristics and neuroradiological i nformation for CH I patients ( n =12 ). Age (yrs) Sex Etiology GCS LOC (days) PTA (days) Time Post Injury (months) Radiological Findings 22 M Bicycle Accident 12 Unknown 10 23 Small hemorrhage areas consistent with diffuse axonal injury 22 M Fall 13 Unknown 3 81 Left temporal fracture 20 F MVA Unknown Unknown 5 6 Subdural hematoma; Intraparenchymal hemorrhage 27 F MVA 3 14 14 89 Subarachnoid hemorrhage 23 F MVA 4 49 49 71 Diffuse axonal injury 42 M Motorcycle Accident 3 28 36 72 Small bilateral intraventricular hemorrhages 46 F MVA 6 1 15 79 Left temporal occipital subarachnoid hemorrhage 26 M MVA 3 21 168 57 Intraventricular hemorrhage 26 M MVA 3 28 168 71 Left frontal subdural hematoma 18 M Bicycle Accident 6 42 126 44 Unavailable 42 F MVA 5T 42 7 58 Right frontal hemorrhage; subdural hematoma 30 M Animal Accident 3 84 56 65 Unavailable GCS = Glasgow coma scale score ; LOC = loss of consciousness; PTA = post traumatic amnesia

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46 Table 2 3 N europsychological data for control and moderate to severe CHI participant groups Controls m/sCHI Analysis Mean SD Mean SD t p d NAART FSIQ Estimate 110.17 6.24 109.42 6.5 .29 .78 .12 FIT Score 14.83 .58 14.67 .89 .55 .59 .21 BNT Score (T) 46.75 11.7 38.58 5.2 2.20 .038 .90 Fluency FAS (T) 50.17 10.4 43.17 12.3 1.50 .15 .61 Fluency Animals (T) 48.50 8.7 42.83 12.8 1.27 .22 .52 Digit Span (SS) 11.00 3.1 10.67 1.6 .33 .75 .13 Letter number Sequencing (SS) 12.12 2.7 10.42 3.2 1.46 .16 .57 Facial Recognition Test 48.33 3.1 44.25 3.6 2.99 .007 1.21 Logical Memory I (SS) 12.33 2.7 10.67 3.2 1.37 .18 .56 Logical Memory II (SS) 13.08 1.9 10.50 3.6 2.21 .038 .90 Logical Memory Recognition 27.08 2.0 26.17 3.4 .81 .43 .33 Stroop Test Word reading (T) 49.25 6.3 39.83 8.1 3.18 .004 1.30 Stroop Test Color naming (T) 49.33 8.5 41.25 7.5 2.48 .022 1.01 Stroop Test Color word (T) 54.58 10.2 51.33 10.8 .76 .46 .31 Stroop Test Interference (T) 53.33 8.3 58.33 6.7 1.63 .12 .66 TMT Part A (T) 57.75 10.4 42.08 17.6 2.65 .015 1.08 TMT Part B (T) 52.83 11.8 42.58 11.1 2.20 .039 .89 TMT B minus A (sec) 27.42 12.9 40.58 18.6 2.01 .057 .82 WCST Categories Completed 5.75 .87 5.66 1.2 .20 .84 .09 WCST Preservative Errors (T) 60.42 15.0 59.50 4.9 .14 .89 .08 BNT = Boston naming test; FIT = Rey fi fteen item test; NAART = North A merican adult reading test; TMT = trail making test; WCST = Wisconsin card sorting t est; T = T score (Mean = 50, SD = 10) ; SS = Scaled Score (Mean = 10, SD = 3).

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47 Figure 2 1 Diagram of the attention network test ( a) the four cue conditions; (b) the six stimuli used in the present experiment; and (c) an example sample spatial cue incongruent trial (pre cue fixation, cue presentation, pre target fixation, target presentation, post target fixation.

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48 Figure 2 2 Electrical geodesics sensor layout for the 64 channel geodesic sensor net (EGI; Eugene, Oregon).

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49 CHAPTER 3 RESULTS ANT Behavioral P erformanc e Brief Summary of Behavioral Data F indings Significant alerting and executive control RT differences were observed between groups ; however, after controlli ng for generalized slowing, only the alerting network remained significantly reduced in CHI patients. No group differences were observed in orienting, as both groups showed RT improvement on target conditions preceded by spatially informative cues. Regar ding performance accuracy, b oth groups committed significantly more errors on incongruent vs. congruent trials, though this effect was not different between groups. Reaction Time and Attention Network E ffects Mean attention network effects z score transf o rmed attention network effects, and correct trial median RT data for both groups as a function of flanker type and cue type are summarized in Table 3 1 and Figure 3 1 A Group Flanker type x Cue type REML ANOVA conducted on correct trial median RTs reve aled a significant main effect of group, F (1, 22 ) = 8.38 p < .0 09 reflecting the expected generalized slowing in CHI participants. As expected, a significant main effect of flanker type, F (2, 242 ) = 315.47 p < .0001, was observed, reflecting increased slowing when faced with incongruent flankers. Participants responded more quickly as cue types became more spatially informative (no cue RT< center cue RT < double cue RT < spatial cue RT), as evidence d by a sign ificant main effect of cue type, F (3, 242 ) = 38.64 p < .0001. In addition a significant Group x Flanker type interaction, F (2, 242 ) = 11.61 p < .0 001 indicated that although both groups responded significantly more slowly to incongruent

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50 compared to neut ral and congruent stimuli. Additionally, CHI patients responded disproportionately more slowly to incongruent versus congruent stimuli than controls. Group x Cue type F (3, 242 ) = .94 p = 42 F lanker type x Cue type, F (6, 242 ) = .89 p = 50 and Group x Flanker type x Cue type, F (6, 242 ) = .85 p = 53 interactions were not significant. Regarding attention network functioning and measured using difference scores, significant differences were observed between groups for alerting ( no cue R T minus double cue RT: Controls = 46 .8 21 ms; CHI = 21.4 33 ms), F (1,22 ) = 5.04 p < .0 36 d = .92, and executive control ( incongruent flanker RT minus congruent flanker RT: Controls = 88.1 25 ms; CHI = 13 6.3 65 ms), F (1,22 ) = 5.72 p < .0 26 d = 98. No differences were observed in the orienting network ( center cue RT minus spatial cue RT: Controls = 43.5 30 ms; CHI = 42.5 31 ms), F (1,22 ) = .0059 p = .94 d = .03 To examine the potential effect of generalized slowing on network performance data were normalized for both groups using z score calculations. After normalization of RT data, significant group differences for attention network difference scores were observed for the alerting network F (1,22) = 8.98, p < .007 d =1.20 but not orienti ng F (1,22) = 0.61, p >.44, d = .33, or executive control F (1,22) = .73, p > .40, d = .36. In addition to using z scores to control for the potential influence of generalized slowing on difference scores we also followed the suggestion of Chapman, C hapman, Curran and Miller (1994 ) to perform residualized scores as individual and group differences in performance difference scores are heavily influenced by overall response time Specifically, to determine whether observed group differences in a difference score reflect ed a dispr oportionate difference of the CH I group relative to that predicted

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5 1 by general performance level in controls difference scores for controls were examined to see if they significantly correlate d with the derived measure of overa ll res ponse speed in controls (e.g ., the sum of the two scores). Thus, d ifference scores (e.g., c enter c ue RT minus s patial c ue RT ) were also correlated with the sum of both conditions (e.g., cente r c ue RT plus s patial c ue RT) for each network for controls to d etermine if network effects were associated with overall RT No significant associations between difference and sum mated RT scores were observed for any network ( r (11) s < 26 ps > .42 ), and as such, subsequent residual ized regression was not deemed appropriate, as significant correlations are a prerequisite for this approach. RT correlations were also conducted between attentional networks for each group to determine the interrelation among attentional components A lerting and orienting networks, r (11) = .32, p = .31, and orienting and executive control networks, r (11) = .32, p = .30, were not significant related for control participants. In contrast, controls demonstrated moderate negative RT correlation between the alerting and executive control networks that trended towards statistical significance, r (11) = .54, p = .07. CHI participants did not show any patterns of RT correlation between any pairs of attentional networks ( r (11) s <.39, ps > .21). Relationships Between Behavioral and N europsycho logical D ata Additional correlations were conducted between network scores and neuropsychological measures of attention/executive function, collapsed across groups. A lerting network scores were significantly correlated with Stroop (word reading) performance, r (22) = .51, < = .002, but not any other neuropsychological measures of attention/executive function ( rs < .35, ps >.10). Orienting network scores were not corre lated with any attention/executive functioning neuropsychological test measures ( rs < .38, ps > .07). Executive control network score s were significantly correlated with

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52 Letter number sequencing, r (22) = .48 p < .02, Trails A, r (22) = .49 p < .02, Tra ils B, r (22) = 53 p < .009, Stroop (word reading), r (22) = .60, < = .002, Stroop (color naming), r (22) = .49 p < .02, Stroop (color word), r (22) = .49, p < .02, COWA T (FAS; T score), r (22) = .42, p < .05, and COWA T (Animals; T score) performance r (22) = .42, p < .05 Increased self reports of CHI related symptomatology as obtained from the N eurobehavioral Rating Scale (NRS) were also significantly associated with executive control network scores r (11) = .62, p < .03, but not alerting, r (11) = .2 1, p = .46, or orienting, r (11) = .14, p = .67. In contras t, neither total nor subscale FrS BE scores were correlated with any attentional network ( rs < .46, ps > .14). Performance A ccuracy Regarding task performance accuracy (Table 3 1 and Figure 3 2 ), a Group Flanker type x Cue type REML ANOVA on mean error rates excluding non responses revealed a significant main effect of flanker type, F (2, 242 ) = 44.57 p < .0001, reflecting increased error s. Notably, t he group main effect, F (1, 22 ) = 26 p = .62 and Group x Flanker interaction, F (2, 242 ) = .06 p = 95 were not significant, suggesting equal task performance across groups regardless of task difficulty The main effect of cue type F (3, 242 ) = 1.03 p = .38 Group x Cue, F (2, 242 ) = .59 p = 62 and Group x Flanker type x Cue type, F (6, 242 ) = .25 p = 96 effects were not significant, and suggest that spatial cuing did not aid performance accuracy on any flanker conditions Lastly, RT was not significantly associated with error rates, ( rs < .38, ps > .22), indicating that there was not a speed/performance accuracy tradeoff. Cue l ocked ERP D ata Mean cue locked target N1 and P3 amplitudes for each cueing condition are

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53 presented in Table 3 2 Calculation of grand averages was based on a mean number of 53. 45 7.7 segmented sweeps for controls and 54.08 10.7 segmented sweeps for CHI patients. Average number of segmented sweeps was not significantly different between groups, t (22) = .16 p = .87 N1 L atency Grand average cue locked ERP waveforms are shown in Figure 3 3 ; spline interpolated distribution maps are shown in Figure 3 4 The Group x Condition REML ANOVA did not reveal significant g roup, F (1,22) = 1.49 p = 24 c ondition F (3, 66 ) = .30 p = 8 3, or Group x Condition interaction effects F (3,66 ) = 1.42 p = 24 indicating that N1 peak latency onset was not different between cuing conditions or between groups. N1 A mplitude The Group x Condition REML ANOVA yielded a significant main effect of condition, F ( 3, 66 ) = 38.55 p < .000 1. Follow up contrasts revealed that amplitude of double cue, t (22) = 10.06 p < .0001, and spatial cue, t (22) = 3.08, p < .002, conditions, but not center cue, t (22) = 1.78, p = .08, was significantly enhanced relative to the no cue condition. Additionally, a Group x Condition interaction, F ( 3,66 ) = 4.26 p < .00 9 revealed that N1 amplitude was significantly larger in the controls relative to CHI participants for the double cue condition t ( 22 ) = 2.54 p < .0 2. Importantly, t his interaction occurred in the absence of a significant main effect of group F (1, 22 ) = .51 p = 48 suggesting that the effect is not because of an overall attenuation of N1 component amplitude in CHI participants. P3 L atency Grand average cue locked ERP waveforms are shown in Figure 3 5; spline

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54 interpolated distribution maps are shown in Figure 3 6 The Group x Condition REML ANOVA did not reveal significant g roup, F (1,22) = .08 p = 78 c ondition, F (3,66) = 1.85 p = 15 or Group x Condition interaction effects F (3,66) = 1. 61 p = .2 0 indicating that P3 peak latency onset was not different between cuing conditions or between groups. P3 Mean A mplitude The Group x Condition REML ANOVA yielded a significant main effect of condition, F (3, 66) = 14.7 p < .0001. Follow up contrasts revealed that P3 amplitude for double cue, t (22) = 5.07 p < .0001, and spatial cue, t (22) = 5.78 p < .00 01 conditions, but not center cue, t (22) = 1. 91 p = .0 6 was significantly enhanced relative to the no cue condition. Additionally, P3 amplitude of the most informative cue (spatial) was significantly greater in controls than CHI participants, t (22) = 2.48 p < .0 2. The main effect of group, F (1, 22 ) = 1.79 p = 1 9, and Group x Condition interaction, F (3,66) = 1.81 p = .16 were not significant As was the case for N1, the absence of a significant group main effect on P3 amplitude suggests that observed group related effects are not due to an overall attenuation of P3 amplitude in CHI participants Extended C ue locked ERP D ata Mean extended cue locked target N1 and P3 amplitudes for each cueing condition are presented in Table 3 3 N1 L atency (A lerting N etwork : Double cue vs. N o cue) C alculation of grand averages were based on a mean of 53.88 7.5 segmented sweeps for controls and 53.88 10.7 segmented sweeps for CHI patients Average number of segmented sweeps was identical between groups, t ( 22 ) = 0 p = 1.0 Grand average extended cue l ocked ERP waveforms are shown in Figure 3 7; spline interpolated distribution maps are shown in Figure 3 8 The Group x Condition REML

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55 ANOVA did not reveal significant main effects of group F (1,22) = .22 p = .65, condition, F (1,22) = 2.92 p = .11, or a Group x Condition interaction F ( 1,22) = .88 p = .36. N1 A mplitude (A lerting N etwork : Double cue vs. N o cue) The Group x Condition REML ANOVA yielded a significant main effect of condition, F ( 1, 22 ) = 9.16 p < .00 7, indicating increased amplitude for double vs no cue conditions Moreover, a Group x Condition interaction, F ( 1,22 ) = 8.51 p = .00 8 revea led that N1 amplitude was significantly larger in the controls relative to CHI participants for the double cue condition This interaction occurred in the absence of a significant main effect of group F (1, 22 ) = 2.36 p = 14 suggesting that the effect i s not because of an overall attenuation of N1 component amplitude in CHI participants N1 L atency (O rienting N etwork : Spatial cue vs. C enter cue) Calculation of grand averages w ere based on a mean of 53.04 8.2 segmented sweeps for controls and 54.29 10.9 segmented sweeps for participants with CHI Average number of segmented sweeps was not significantly different between groups, t ( 22 ) = .32 p = 75 Grand average extended cue locked ERP waveforms are shown in Figure 3 9; spline interpolated distri bution maps are shown in Figure 3 10 The Group x Condition REML ANOVA revealed a significant main effect of group F (1,22) = 8.26 p < .009, indicating that onset of the N1 was about 5 ms earlier for the spatial vs. center cue condition. The main effect of group F ( 1,22 ) = 08 p = .78 and Group x Condition interaction F ( 1,22) = .04 p = .85 were not significant. N1 A mplitude (O rienting N etwork : Spatial cue vs. C enter cue) The Group x Condition REML ANOVA yielded significant main effects of group, F (1,22 ) = 4.52 p = .0 45 and condition, F (1,22 ) = 8. 45 p < .009. The main effect of

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56 group reflected significantly smaller N1 amplitude in CHI compared to controls while increased amp litude to spatial vs. center cueing was revealed in the condition main effect The Group x Condition interaction was not significant, F (1,22) = 2.22, p < .15. Target locked ERP D ata Mean N1 and P3 amplitudes for each target condition are presented in Table 3 4 Calculation of grand averages w ere based on a mean of 72.13 8.8 segmented sweeps for controls and 70.46 11. 4 segmented sweeps for CHI patients The average number of segmented sweeps was not significantly different between groups, t ( 22) = .40 p = 69 N1 L atency Grand average target related E RP are illustrated in Figure 3 11; spline interpolated distribution maps are shown in Figure 3 12 The Group x Condition REML ANOVA did not reveal significant main effects of group F (1,22) = .20 p = .66, condition, F (1,22) = .003 p = .96, or a Group x Condition interact ion F ( 1,22) = .38 p = .54. N1 A mplitude The Group x Condition REML ANOVA revealed a trend towards a main effect of group F (1,22) = 4.18 p = .053, suggesting reduced amplitude in CHI participants. The main effect of condition, F (1,22) = .10 p = .75, and Group x Condition interaction F ( 1,22) = .031 p = .86, were not significant. P3 L atency (C onflict Ne twork : Congruent vs. I ncongruent) Grand average target related E RP are illustrated in Figure 3 13; spline interpolated distribution maps are shown in F igure 3 14 The Group x Condition REML ANOVA did not reveal significant main effects of group F (1,22) = 3.62 p = .07, condition, F (1,22) = .25 p = .62, or a Group x Condition interaction F ( 1,22) = 1.01 p =

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57 .33, indicating that P3 peak latency onset was not different between cuing conditions or between groups. P3 A mplitude (Co nflict N etwork : Congruent vs. I ncongruent) The Group Condition REML ANOVA yielded a significant main effect of condition, F (1,22 ) = 5.27 p < .0 26 which reflected significantl y reduced amplitude t o incongruent v s. congruent target conditions. The main effect of group F ( 1,22) = 1.94 p = .18 and Group x Condition interaction F ( 1,22) = .46 p = .41 were not significantly different between groups.

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58 Table 3 1 Mean ( SD) attention network effects (RT) Z score transformations for attention network effects, and mean error rates as a function of flanker type and group Controls m/sCHI Analysis Mean SD Mean SD t p d Mean RT (ms) 536.31 75.9 667.39 167.4 8.56 .0001 1.01 Alerting effect (ms) 46. 83 21.2 21.42 32. 9 2. 24 .0 3 6 .92 Orienting effect (ms) 43. 50 30.0 42.54 31. 3 .077 .94 .03 Conflict effect (ms) 88.08 25.1 136.25 65.1 2 .39 .0 2 6 .98 Z score RT transformations Alerting effect .74 .29 .32 .40 3.00 .007 1.20 Orienting effect .82 .42 .68 .43 .78 .44 .33 Conflict effect 1.42 .45 1.56 .32 85 .40 .36 Mean Error Rates (%) 2.1 4.0 1.7 4.4 .7 7 .44 .10 Congruent .52 1.6 0 0 2.21 0 3 .46 Incongruent 4 .7 5 .6 4.5 6.7 .16 .88 .03 Neutral 1 .0 2.2 .61 1.7 1.07 .29 .20 Alerting = no cue (RT) minus double cue (RT); Orienting = center cue (RT) minus spatial cue (RT); Conflict = incongruent (RT) minus congruent (RT)

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59 Table 3 2 Mean N1 and P3 cue locked activity as a function of group Controls m/sCHI Analysis Mean SD Mean SD t p d N1 voltage, Mean (no cue) .20 .43 .10 .70 .18 .86 .17 N1 voltage, Mean (double cue) 3.39 2.23 1.97 1.47 2.54 .0148 .75 N1 voltage, Mean (center cue) .53 1.37 .66 .86 .22 .83 .11 N1 voltage, Mean (spatial cue) 1.07 1.77 .93 1.22 .25 .81 .09 P3 voltage, Mean (no cue) .06 .62 .07 .39 .26 .80 .25 P3 voltage, Mean (double cue) 1.67 1.99 1.19 1.51 .92 .36 .27 P3 voltage, Mean (center cue) .63 1.06 .45 .93 .35 .73 .18 P3 voltage, Mean (spatial cue) 2.29 1.85 .98 1.02 2.48 .016 .88 Table 3 3 Mean N1 and P3 extended cue locked related activity as a function of group and electrode site Controls m/sCHI Analysis Mean SD Mean SD t p d N1 voltage, Mean (no cue) 1.83 2.10 1.47 1.69 .43 .67 .19 N1 voltage, Mean (double cue) 3.60 2.55 1.50 1.94 2.45 .021 .93 N1 voltage, Mean (center cue) 2.35 2.21 1.24 1.61 1.30 .20 .57 N1 voltage, Mean (spatial cue) 3.94 2.56 1.76 1.87 2.56 .0156 .97 P3 voltage, Mean (no cue) 3.59 2.62 1.57 2.20 2.12 .042 .84 P3 voltage, Mean (double cue) 2.62 2.67 1.44 1.74 1.24 .22 .52 P3 voltage, Mean (center cue) 3.63 2.13 1.90 2.65 1.83 .08 .72 P3 voltage, Mean (spatial cue) 2.18 2.78 .81 1.51 1.44 .16 .61

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60 Table 3 4 Mean N1 and P3 related activity as a function of group and channel Controls m/sCHI Analysis Mean SD Mean SD t p d N1 voltage, Mean (neutral) 1.71 1.49 .34 1.72 2.11 .045 .85 N1 voltage, Mean (congruent) 1.49 1.68 .22 1.39 1.06 .062 .82 N1 voltage, Mean (incongruent) 1.55 1.64 .24 1.59 2.03 .054 .81 P3 voltage, Mean (neutral) 2.19 2.10 1.00 1.62 1.63 .12 .63 P3 voltage, Mean (congruent) 2.11 2.25 1.02 1.35 1.48 .15 .59 P3 voltage, Mean (incongruent) 1.57 1.97 .72 1.25 1.16 .26 .52

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61 Figure 3 1 Mean ( SE) median correct trial RTs as a function of group, flanker type, and cue type.

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62 Figure 3 2 Mean ( SE) error rates as a function of group, flanker type, and cue type. CHI patients did not commit any errors on any congruent trials.

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63 Figure 3 3 Grand average event related potential waveforms showing the cue locked N1 (150 250 ms) component for double and spatial cue conditions. Waveforms were average d over central posterior medial electrode sites (10 10 equivalents = C Pz, P2, P3, PZ, PO3, PO4, and PO z ).

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64 Figure 3 4 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity at 204 ms for A) controls double cue; B) CH I double cue; C) controls spatial cue; D) CH I spatial cue. A) B) C) D)

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65 Figure 3 5 Grand average event related potential waveforms showing the cue locked P3 (275 500 ms) components for double and spatial cue conditions. Waveforms were averaged over central posteri or medial electrode sites (10 10 equivalents = CPz, P2, P3, PZ, PO3, PO4, and Poz ).

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66 Figure 3 6 Top view of the spline interpolated voltage distribution maps showing mean voltages for P3 activity at 844 ms f or A) controls double cue; B) CH I double cue; C) controls spatial cue; D) CH I spatial cue. A) B) C) D)

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67 Figure 3 7 Grand average event related potential waveforms showing the extended cue locked 600 800 ms post cue onset) for spatial and center cue conditions. Waveforms were averaged over posterior parietal scalp sites (10 10 system equivalents = P9, P07, P08, P10)

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68 Figure 3 8 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity at 696 ms for A) controls no cue; B) CH I no cue; C) controls double cue; D) CH I double cue. A) B) C) D)

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69 Figure 3 9 Grand average event related potential wavefor ms showing the extended cue locked 600 800 ms post cue onset) for double and no cue conditions. Waveforms were averaged over posterior parietal scalp sites (10 10 system equivalents = P9, P07, P08, P10)

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70 Figure 3 10 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity at 696 ms for A) controls center cue; B) CHI center cue; C) controls spatial cue; D) CH I spatial cue. A) B) C) D)

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71 Figure 3 1 1 Grand average event related potential waveforms showing the target locked N1 component (between 150 250 ms post target onset) for incongruent and congruent target conditions. Waveforms were averaged over central posterior medial electrode sites (10 10 equivalents = C Pz, P2, P3, PZ, PO3, PO4, and PO z ).

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72 Figure 3 12 Posterior view of the spline interpolated voltage distribution maps showing mean voltages for N1 activity at 196 ms for A) controls congruent; B) CH I congruent; C) controls incongruent flanker; D) CH I incongruent flanker. A) B) C) D)

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73 Figure 3 13 Grand average event related potential waveforms showing the target locked P3 (between 250 550 ms post target onset) for incongruent and congruent target conditions. Waveforms were averaged over central posterior medial electrode sites (10 10 equivalents = C Pz, P2, P3, PZ, PO3, PO4, and PO z ).

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74 Figure 3 14 Top view of the spline interpolated voltage distribution maps showing mean voltages for P3 activity at 392 ms for A) controls congruent; B) CHI congruent; C) controls incongruent flanker; D) CHI incongruent flanker. A) B) C) D)

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75 CHAPTER 4 DISCUSSI ON The present study investigated the effects of CHI on the behavioral and neural correlates associated with three interactive attentional networks (alerting, orienting, and executive control) in the context of the Attention Network Test by measuring behavioral performance (RTs and error rates) and high density ERPs, respectively. Behaviorally, results from the current study revealed significant CHI related RT differences in alerting and executive control, as evidenced as reduced RT benefit in response preparation and increased slowing in resolving conflict, respectively. H owever, after controlling for gener alized slowing, only the alerting network remained significantly impaired in CHI patients compared with healthy controls. These results suggest that CHI demonstrated difficulty in phasic alerting and response preparation however, they were not impaired i n their ability to use peripheral spatial information to aid performance (e.g., orienting), or in their ability to successfully resolve response conflict and inhibit contextually inappropriate pre potent response tendencies (e.g., executive control). The alerting and orienting behavioral results were c onsistent with initial hypothese s, as well as a larger body of attentional research in CHI patients demonstrating reduced response preparation/sustained vigilance (e.g., Whyte et al., 1995; Zinno & Ponsford, 2006), yet beneficial improvements in performance through spatial cuing (e.g., Bate et al., 2001). Regarding executive control, it was predicted that CHI patients would be significantly slower resolving conflict than controls. Whereas CHI participants wer e initially observed to demonstrate increased conflict effects, this effect was attributable to generalized slowing, as no difference in conflict resolution were observed after normalizing RT data. Although the initial hypothese s were only partially suppo rted, taken together they

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76 suggest that difficulties in alerting, but not executive control, are reflective of impairment in a core component of attention processing rather than solely attributable to post injury generalized cognitive slowing. With regard t o performance accuracy, consistent with study predictions, examination of error rates revealed that both controls and CHI participants experienced difficult incongruent However, error rates and interference effects did not significantly differ between groups which was contrary to initial predictions. It is highly likely that the ANT is more sensitive to processing speed rather than error commission given low error rates on the task among patient groups such as disease (Fernandez Duque & Black, 2006). Despite a lack of sensitivity to differences in p erformance accuracy, t hese results further demonstrate how gener alized slowing can affect tasks, and that m/s CHI patients can perform at equal levels of accuracy as their healthy peers Whereas it is common to view task accuracy as a common outcome measur e after head injury speed of task completion is crucial for successful decision making in a constantly changing environment and during highly demanding tasks (e.g., driving). As such, the ANT provided relatively high sensitivity to detec t specific processing speed difficulties. Event related potentials were also examined to characterize the resources and rapid neural changes and correlates that could underlie behavioral task performance. With respect to alerting, examination of extended cue locked ERP data revealed that double cue conditions significantly enhanced N1 amplitude relative to the no cue

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77 condition, a result consistent with a recent study of the ANT which reported significant inc reases in cue locked target N1 amplitude (Neuhaus et al., 2 010). Additionally, in the absence of a main effect of reduced group amplitude, a significant Group x C ondition interaction revealed that this effect was more pronounced for CHI patients. These results corroborate initial predictions as well as behaviora l findings which suggested that CHI patients demonstrated difficulty in alerting. In contrast to previous studies examining ANT performance in mild CHI patients which have not found significant differences in alerting (Halterman et al., 2006; van Donkelaa r et al., 2005) patients with more severe injuries and likely more diffuse brain damage demonstrated both behavioral and neural alterations compared to their healthy peers. Alerting has been conceptualized as a system that functions to achieve and sustain an alert state (Fan et al., 2002), which can be obtained via external stimulus cueing. Although such conceptualization would suggest a possible impairment in vigilance, CHI patients were able to benefit from spatial cues and maintain vigilance under more informative task conditions. Consequently, it is more likely that rather than an impairment in vigilance, CHI patients struggled with the ambiguous nature of the double cue condition. In contrast to the spatial cue which would always validly predict the location of target presentation, the location of targets following double cue presentation was indeterminable based on cue presentation, as a cue appeared both above and below central fixation Whereas the double cue benefit controls by allowing them to prepare for response, the ambiguous target location likely caused brief confusion in CHI patients. Moreover, after RT data were corrected for generalized slowing, the difference in benefits of alerting became more discrepant between groups.

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78 That is, the proportion of improvement was even less had scores not been corrected for overall task speed. Notably, the alerting network has received the least focus of the three attentional networks in the literature, and to date has been scarcely exa mined using ER Ps. Nonetheless, recent neuroimaging findings suggest that common activation sites such as the ACC and fronto parietal regions are recruited by both the alerting and executive attention networks (Fan et al., 2007b 2009). P harmacological evaluations of the neuroc hemical mechanisms of attention have demonstrated norepinephrine as a primary neuromodulator involved in alerting (Marocco & Davidson, 1998). Consequently, such difficulties in alerting may be partially attributable to disruption in neurotransmi tter systems, such as norepinephrine, which is not uncommon after CHI (e.g., Mautes et al., 2001) Additionally, the frontal lobes are one of the most susceptible areas involved in CHI, and diffuse damage to frontal regions likely partially contribute s to changes in alerting network functioning observed in CHI patients Regarding visual orienting of attention spatial cues significantly enhance d N1 amplitude compared to center cues in both controls and CHI participants. No interaction effects were observe d, suggesting that both groups equally engaged neur al processes underlying attentional orienting and subsequent processing of target information. A significant main effect of group N1 amplitude revealed generalized amplitude reduction in CHI participants, however, this is not uncommon following CHI (for review see Dockree & Robertson, 2011) and did not confound evaluation of potential interaction effects. These results imply that valid cueing was beneficial and had a lasting effect on subsequent processing of target stimuli, a result consistent with

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79 recent ERP examinations of the ANT demonstrating enhanced N1 activity during attentional orienting (Neuhaus et a l., 2010), as well as studies of orienting of visual attention as assessed with measures other than the ANT, which have found similar enhancements in N1 like posterior negativities following validly cued target stimuli (Harter et al., 1989; Hopf & Mangun, 2000; Nobre et al. 2000; Talsma et al., 2005). Such results also suggest that although CHI may demonstrate less efficient response preparation as evidenced by reduced alerting, reduced attentional resources may be diverted to attend to more meaningful st imuli, such as task informative spatial cues, rather than less relevant (e.g., no cue, center, double cue) conditions. These results are also consistent with examination of orienting function following mild CHI (Halterman et al., 2006; van Donkelaar et al ., 2005) Surprisingly, mild CHI obtained greater benefit from spatial cuing than controls (e.g., RTs significant ly increase d with spatial cuing). Whereas in the present study CHI obtained benefits at similar levels to controls rather than greater benefi t, the mild CHI patients in the studies by Halterman et al. and Donkelarr et al. were tested within days of initial injury, and likely had greater room for improvement as they had overall reduced RTs compared to controls. Nonetheless lack of differences in orienting functioning between CHI and controls may be masked by ceiling limitations for controls, rather than normal orienting functioning in CHI participants. Lastly, examination of target probe ERP data revealed that both controls and CHI patients showed significant posterior P3 amplitude reductions to versus congruent target stimuli Notably, both groups did not significantly differ to the extent that they demonstrated this effect, suggesting that CHI patients engaged simil ar

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80 mechanisms of conflict processing and that cortical systems underlying inhibitory processes were relatively intact. Whereas this study is the first to employ ERPs to examine the ANT in moderate to severe CHI patients o ur health control data support recent ERP studies employing the ANT which have also demonstrated P3 reductions to incongruent versus congruent target stimuli (e.g., Neuhaus et al., 2007, 2010). Similar congruency effects have been observed in Stroop paradigms (Zurron Pousoa, Lindna, Galdoa, & Daza 2009), which have been interpreted in the context of well replicated reductions in posterior P3 amplitude as task difficulty increases ( Katayama & Polich, 1998 ; Polich, 1987). Given these consistent findings across different paradigms, i t appears that reductions in P3 amplitudes reflect greater difficulty associated with processing incongruent stimuli relative to congruent stimuli. Importantly, our findings suggest that congruency effects on P3 amplitudes are present in both healthy cont rol and CHI participants These findings are in contrast to initial study hypotheses which predicted that CHI patients would demonstrate significantly reduced P3 relative to controls, which would be exacerbated for the incongruent condition, as well as p revious research which has found reduced P3 amplitude in numerous cognitive tasks (e.g., Dockree & Robertson, 2011). One explanation for these inconsistent findings is that task performance was not significantly different between groups. Consequently, d ifferences in behavioral performance would be expected to be associated with P3 amplitude reductions, however, both groups displayed similar levels of task accuracy. As such, the presence of group related P3 amplitude differences in the absence of signifi cant executive control behavioral performance difficulties would be more unusual than what

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81 was observed in the present study. It should also be noted that a body of literature employing tasks with high levels of response conflict have commonly observed fr onto central negativity peaking approximately 450 ms after stimulus presentation ( e.g., Liotti, Woldorff, Perez, & Mayberg, 2000; Perlstein et al. 2006). This is in contrast to the present study and previous ERP studies employing the ANT which have observed P3 related conflict effects (e.g., Neuhaus 2007, 2010). Whereas both components overlap temporally, and negativity to ANT flankers is observe d, component scalp distributions differ such that N450 is observed over more anterior sites, whereas P3 has a greater posterior distribution. Although greater examination and discussion of this finding is beyond the scope of this dissertation it may part ially reflect the influence of processing preceding cue stimuli with target information Study Limitations and Future Directions Regarding limitations of the present study, the near ceiling accuracy level with which participants in both groups completed t he ANT makes this study relatively uninform ative with respect to cognitive process es such as performance monitoring (e.g., van Veen & Carter, 2002) Specifically, examination of electrophysiological reflections of error processing such as error related n egativity (ERN ), a fronto medial ERP response locked component peaking within 100 ms following error commission ( Falkenstein, Hohnsbein, Hoormann, & Banke, 1991), is restricted due to the insufficient number of trials needed for averaging. Similarly, insu fficient power also hindered the ability to separately examine the neural reflections of each congruency condition as a function of cue condition. Instead, target congruency had to be collapsed across conditions in order to maintain adequate signal to noi se ratio for ERP averages, which

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82 may have masked more meaningful insights into the differential effects of cueing on conflict processing. Future studies could increase power to examine effects more efficiently by removing the neutral trial condition, whic h showed similar RT and amplitude data as congruent trials. Additionally, it should be noted that the current study only employed the use of valid cu e ing conditions which likely contributed to the exceedingly high accuracy rates for both groups Recentl y, several investigators have included invalid cues in their ANT paradigms, and have noted both beneficial and detrimental effects on the ability to overcome response conflict following valid and invalid cues, respectively (e.g., Fan et al., 2009). Specif ically, whereas valid cues likely enhance prepotent stimulus processing and effecting shifting of attention, invalid cueing conditions likely require the re direction of attentional processes and the use of additional resources for conflict resolution (e.g ., Posner, Nissen, & Ogden, 1977; Posner, 1980) Consequently, future studies should investigate the differential effects of cue validity on components such as P1 (a positive going component which often peaks within 100 ms of stimuli presentation and refl ective of early visual stream processing) and N1, which have been found in other paradigms to be differentially sensitive to the effects of valid and invalid cueing conditions (e.g., Talsma et al., 2005; Wright, Geffen, & Geffen, 1995). Additionally, inva lid cueing may exacerbate conflict effects in CHI patients, and lead to more clinically meaningful results regarding patient impairment s. Given that impairments in attentional processe s are a frequent complaint of CH I survivors and have been shown to be an indicator of post morbid vocational outcome and community functioning (Brooks, Fos, Greve, & Hammond; 1999; Cicerone, 1996),

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83 the development of effective treatment strategies for impairments of attention are critical for long term functional recovery fo llowing head injury However, real world insurance and healthcare system financial limitations often hinder the extent of patient contact and treatment. Additionally, heterogeneity within the CHI population often precludes use of a cost effective treatme nt that can be effective for the majority of injured patients. Specifically most studies o f neuro cognitive sequelae of CH I have relied on group averaging of data including this study, to arrive at general conclusions regarding CH I related cogni tive im pairments. Not surprisingly, group averaging can mask more clinically meaningful effects. For example, in the present study, several patients had alerting scores of under 10 ms, whereas another subset had scores of over 50 ms. When averaged together, th e interpretation is that CHI patients as a group were impaired relative to controls, however, in actuality not all patients showed the reported effect. Such heterogeneity is especially prominent in CHI patients, and should be used to identify potential ne uro cognitive subtypes of patients that are more impaired on one domain than another (e.g., alerting vs. orienting). Neurocognitive subtyping has the potential to aid in tailoring treatment strategies as patients may be more responsive to treatments that tailor specific deficit areas, and lead to a better understanding of the underlying etiology and treatment of a particular disorder (Morris & Fletcher, 1988). Notably, cluster analysis approaches are not feasible with the current sample size of 12 patient s, however, should be utilized in the future if appropriate. Based on the widespread use and sensitivity of the ANT to successfully assay the three attentional components across various disorders, researchers have recently modified the original ANT in an a ttempt to assess differential hemispheric attentional

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84 abilities by simply rotating stimuli by 90 0 (Greene et al., 2008). Researchers have termed this paradigm the lateralized attention network test (LANT), and the rationale for this task was based on behavioral, neuroimaging, and clinical evidence suggesting hemispheric asymmetries across attentional networks (e.g., Fan, Flombaum, McCandliss, Thomas, & Posner, 2003). For example, alerting (e.g., vigilance) and orienting of attention have been observed to reflect greater right hemisphere function (e.g., Posner & Peterson, 1990; Corbetta et al. 2000), whereas conflict resolution (e.g., executive control) has been observed to engage midline anterior cingulate and left frontal cortices (e.g., Fan et al., 2003). Recent behavioral findings in healthy adults using the LANT suggest that each hemisphere is capable of supporting all three networks, with a trend toward greater orienting in the right hemisphere (e.g., predominately left visual field; Greene et a l., 2008). However, a follow reported attent ion difficulties revealed that higher self reported scores of attention difficulties were correla ted with reduced efficiency of left visual field orienting but not rig ht visual field orienting (Poynter, Ingram, & Minor, 2010). Although these results have not yet been replicated, they suggest that the LANT may be sensitive to examine visual field/hemispheric orienting differences clinically. This is especially relevant to the present study, as patients suffering right hemisphere parietal lesions often display greater contralateral neglect than individuals sustaining left hemisphere lesions (e.g., n, 2006). Explanations for these findings can be traced back to classic theories of orienting asymmetry which suggest that the right hemisphere is largely responsible for

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85 shifts of attention in both visual fields, whereas the left hemisphere is only respo nsible for attentional shifts to the right visual field (e.g., Heilman, 1995). Regardless of etiology, use of the LANT may provide greater insight into the behavioral and neural correlates of attentional disruptions following brain injury, specifically, v isual field orienting, than the ANT alone, however, this has yet to be reported in the literature. Summary In summary, t he current study examine d the effect s of moderate to severe CHI on the behavioral and neural correlates of three interactive attentional networks (alerting, orienting, and executive control) Specifically, the major aims of the study sought to determine 1) whether CHI related impairments in attention were due to a core cognitive impairment or due to generalized slowing; 2) whet her CHI patients demonstrate impairments in one or more components of attention; and 3) how injury has affected the underlying neural characteristics of attentional processing. Results revealed both significant behavioral and neural group differences in t he alerting network even after controlling for generalized slowing and ERP component amplitude reductions. Such difficulties in alerting likely reflect difficulty in processing ambiguous stimuli, and may reflect diffuse frontal lobe damage and disruption of neurotransmitter systems. In contrast, d ifficulties in executive control were largely the result of generalized slowing, and suggest that given enough time, CHI can perform at levels equal of controls. Lastly, CHI patients significantly benefited from spatially informative cues to aid their task performance.

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101 BIOGRAPHICAL SKETCH Christopher Nicholas Sozda received his Bachelor of Science degree in psychology in 2006 from the University of Pittsburgh, where he studied under the mentorship of Dr. Anthony E. Kline. Christopher began his doctoral training at the University of Florida in 2007 under the guidance and mentorship of Dr William M. Perlstein In 2009, he earned his Master of Science degree in psychology. In 2013, h e completed a one year clinical internship at the VA Northern California Health Care System and will continue training in neuropsychology at the VA Northern California Heath Care System through completion of a two year post doctoral residency program.