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Cognitive Changes after Deep Brain Stimulation Surgery for Parkinson's Disease

Permanent Link: http://ufdc.ufl.edu/UFE0022024/00001

Material Information

Title: Cognitive Changes after Deep Brain Stimulation Surgery for Parkinson's Disease
Physical Description: 1 online resource (65 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Our purpose was to investigate the effects of unilateral deep brain stimulation surgery on cognition in patients with Parkinson?s disease. We also sought to examine the significance of effects in individual patients as well as the predictors of cognitive changes after surgery. Deep brain stimulation surgery to the globus pallidus internus (GPi) or subthalamic nucleus (STN) is regarded as an effective treatment for medication-refractory Parkinson?s disease. However, research has shown that it may lead to specific cognitive declines in some patients. We compared neuropsychological data from a group of DBS patients before and 1 year after unilateral surgery to data collected from a group of PD patients tested over a 1-year interval who did not undergo surgery. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (i.e., letter fluency, semantic fluency, and Digit Span Backward) but not on tasks with less involvement of dorsolateral prefrontal cortex (i.e., Vocabulary, Boston Naming Test). We also predicted that a greater proportion of DBS patients would be classified as having declined significantly using Reliable Change Indexes (RCIs). Finally, we hypothesized that age, baseline cognitive status, preoperative depression severity, and left-sided surgery would be associated with cognitive changes in the DBS group. We used the University of Florida Movement Disorders Center research database to compile data from 20 DBS patients and 19 PD controls of similar age, education and disability level. Cognitive testing was conducted at the University of Florida Psychology Clinic, and motor testing was conducted at the Movement Disorders Center Clinic. Compared to PD controls, DBS patients declined on both tasks of verbal fluency, but not on Digit Span Backward or the non-dorsolateral prefrontal cortex tasks. RCI analyses revealed that 45% of DBS patients experienced significant declines on at least one verbal fluency measure, as compared to 11% of controls, and this difference was significant. There was a trend for DBS patients who declined significantly on verbal fluency to experience less motor improvement than DBS patients who did not decline. None of the hypothesized predictors were significantly associated with changes on the test of letter fluency. Only side of surgery was significantly associated with changes on the measure of semantic fluency, such that patients who underwent left-sided surgery were more likely to decline. Our results suggest that unilateral DBS surgery is associated with verbal fluency declines. Further, left-sided surgery appears to be more associated with declines in semantic fluency than right-sided surgery, and fluency changes do not seem to be significantly related to the patient characteristics of age, baseline cognitive status or pre-operative depressive symptomatology. Finally, classification based on Reliable Change highlights the impact of individual variability in outcome and indicates that fluency declines likely reflect significant changes in a subset of DBS patients who may demonstrate a relatively poor surgical outcome in general.
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.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Bowers, Dawn.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022024:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022024/00001

Material Information

Title: Cognitive Changes after Deep Brain Stimulation Surgery for Parkinson's Disease
Physical Description: 1 online resource (65 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Our purpose was to investigate the effects of unilateral deep brain stimulation surgery on cognition in patients with Parkinson?s disease. We also sought to examine the significance of effects in individual patients as well as the predictors of cognitive changes after surgery. Deep brain stimulation surgery to the globus pallidus internus (GPi) or subthalamic nucleus (STN) is regarded as an effective treatment for medication-refractory Parkinson?s disease. However, research has shown that it may lead to specific cognitive declines in some patients. We compared neuropsychological data from a group of DBS patients before and 1 year after unilateral surgery to data collected from a group of PD patients tested over a 1-year interval who did not undergo surgery. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (i.e., letter fluency, semantic fluency, and Digit Span Backward) but not on tasks with less involvement of dorsolateral prefrontal cortex (i.e., Vocabulary, Boston Naming Test). We also predicted that a greater proportion of DBS patients would be classified as having declined significantly using Reliable Change Indexes (RCIs). Finally, we hypothesized that age, baseline cognitive status, preoperative depression severity, and left-sided surgery would be associated with cognitive changes in the DBS group. We used the University of Florida Movement Disorders Center research database to compile data from 20 DBS patients and 19 PD controls of similar age, education and disability level. Cognitive testing was conducted at the University of Florida Psychology Clinic, and motor testing was conducted at the Movement Disorders Center Clinic. Compared to PD controls, DBS patients declined on both tasks of verbal fluency, but not on Digit Span Backward or the non-dorsolateral prefrontal cortex tasks. RCI analyses revealed that 45% of DBS patients experienced significant declines on at least one verbal fluency measure, as compared to 11% of controls, and this difference was significant. There was a trend for DBS patients who declined significantly on verbal fluency to experience less motor improvement than DBS patients who did not decline. None of the hypothesized predictors were significantly associated with changes on the test of letter fluency. Only side of surgery was significantly associated with changes on the measure of semantic fluency, such that patients who underwent left-sided surgery were more likely to decline. Our results suggest that unilateral DBS surgery is associated with verbal fluency declines. Further, left-sided surgery appears to be more associated with declines in semantic fluency than right-sided surgery, and fluency changes do not seem to be significantly related to the patient characteristics of age, baseline cognitive status or pre-operative depressive symptomatology. Finally, classification based on Reliable Change highlights the impact of individual variability in outcome and indicates that fluency declines likely reflect significant changes in a subset of DBS patients who may demonstrate a relatively poor surgical outcome in general.
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.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Bowers, Dawn.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022024:00001


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COGNITIVE CHANGES AFTER DEEP BRAIN STIMULATION SURGERY FOR PARKINSONS DISEASE By LAURA BETH ZAHODNE A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2008 1

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2 2008 Laura Beth Zahodne

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ACKNOWLEDGMENTS I would like to thank my mentor, Dawn Bowers for her guidance, sincerity, and generous provision of time. I am grateful for her cen tral role in my academic and professional development. I would also like to extend my gratitude to Hubert Fernandez for his encouragement and the many opportunities he has afforded me. I would like to thank Michael Okun, Kelly Foote, and their colle agues for their certain dedication to the Movement Disorder Center and the care of its patients Finally, I would like to thank the patients represented in this study for their selfless and enthusiastic contributions to research. 3

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TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................3 LIST OF TABLES................................................................................................................. ..........6 LIST OF FIGURES.........................................................................................................................7 ABSTRACT.....................................................................................................................................8 CHAPTER 1 INTRODUCTION................................................................................................................. .10 Parkinsons Disease............................................................................................................ ....10 Pathophysiology and Treatment......................................................................................10 Cognitive Sequelae..........................................................................................................11 Deep Brain Stimulation Surgery.............................................................................................12 Description......................................................................................................................12 Efficacy............................................................................................................................13 Cognitive Outcome..........................................................................................................14 2 STATEMENT OF THE PROBLEM......................................................................................17 Specific Aim I.........................................................................................................................19 Specific Aim II.......................................................................................................................20 Specific Aim III......................................................................................................................20 3 METHODS...................................................................................................................... .......22 Participants and Procedures.................................................................................................... 22 Recruitment.................................................................................................................... .22 Parkinsons Disease Diagnosis........................................................................................22 Inclusion and Exclusion Criteria.....................................................................................23 Motor Testing Instruments.....................................................................................................2 3 Unified Parkinsons Disease Rating Scale-Motor Examination (UPDRS-III)................23 Hoehn and Yahr Stage Scale...........................................................................................23 Neuropsychological/Mood Testing Instruments.....................................................................24 Dementia Screening.........................................................................................................24 Mini-Mental State Examination (MMSE)................................................................24 Dementia Rating Scale 2 (DRS-2)...........................................................................24 Dorsolateral Prefront al Cognitive Tests..........................................................................24 Controlled Oral Word Association Test (COWAT)................................................24 The Animal Fluency Test.........................................................................................25 Digit Span Backward...............................................................................................25 4

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Other Cognitive Tests......................................................................................................26 Boston Naming Test (BNT).....................................................................................26 Vocabulary...............................................................................................................26 Mood Measure: Beck Depression Inventory 2nd Edition (BDI-II)..................................26 Statistical Analyses........................................................................................................... ......26 4 RESULTS...................................................................................................................... .........29 Demographic and Disease Vari ables: DBS vs. Controls........................................................29 Aim 1: Group Differences in Cognitive Performance over Time..........................................30 Aim 2: Reliable Change Results.............................................................................................31 Aim 3: Predictors of Cognitive Change..................................................................................32 Regression Results...........................................................................................................32 Exploratory Group Comparisons.....................................................................................33 5 DISCUSSION................................................................................................................... ......40 Summary and Interpretation of Findings................................................................................41 Interpretation and Relati onship to the Literature....................................................................43 Study Limitations.............................................................................................................. ......48 Directions for Future Research...............................................................................................51 LIST OF REFERENCES...............................................................................................................54 BIOGRAPHICAL SKETCH.........................................................................................................65 5

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LIST OF TABLES Table page 4-1. Comparisons between DBS a nd PD controls at baseline......................................................35 4-2. Performance (T-scores) on specif ic cognitive tests at Times 1 & 2......................................35 4-3. Repeated-measures analyses of variance...............................................................................36 4-4. Proportion of DBS patients vs controls evidencing decline.................................................37 4-5. Predictor variables regressed on semantic fluency change scores........................................37 4-6. Baseline and change score compar isons in decliners vs. non-decliners................................37 6

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LIST OF FIGURES Figure page 4-1. Letter fluency interaction.............................................................................................. ........38 4-2. Semantic fluency interaction............................................................................................ ....39 7

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Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science COGNITIVE CHANGES AFTER DEEP BRAIN STIMULATION SURGERY FOR PARKINSONS DISEASE By Laura Beth Zahodne May 2008 Chair: Dawn Bowers Major: Psychology Our purpose was to investigate the effects of unilateral deep brain stimulation surgery on cognition in patients with Parkinsons disease. We also sought to examine the significance of effects in individual patients as well as the predictors of cognitive changes after surgery. Deep brain stimulation surgery to the globus pallidus internus (GPi) or subthalamic nucleus (STN) is regarded as an effective treatment for medication-refractory Parkinsons disease. However, research has shown that it ma y lead to specific cognitive declines in some patients. We compared neuropsychological data fr om a group of DBS patients before and 1 year after unilateral surgery to data collected from a group of PD pa tients tested over a 1-year interval who did not undergo surgery. We hypothesized th at compared to PD controls, DBS patients would decline on tasks involving do rsolateral prefrontal cortex circuitry (i.e., letter fluency, semantic fluency, and Digit Span Backward) but not on tasks with less involvement of dorsolateral prefrontal cortex (i.e., Vocabulary, Boston Naming Test). We also predicted that a greater proportion of DBS patients would be classified as having declined significantly using Reliable Change Indexes (RCIs). Finally, we hy pothesized that age, baseline cognitive status, preoperative depression severity, and left-sided surgery would be associated with cognitive changes in the DBS group. 8

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9 We used the University of Florida Movement Disorders Center research database to compile data from 20 DBS patients and 19 PD contro ls of similar age, e ducation and disability level. Cognitive testing was conduc ted at the University of Flor ida Psychology Clinic, and motor testing was conducted at the Move ment Disorders Center Clinic. Compared to PD controls, DBS patients declin ed on both tasks of verbal fluency, but not on Digit Span Backward or the non-dorsolateral pr efrontal cortex tasks. RCI analyses revealed that 45% of DBS patients expe rienced significant declines on at least one verbal fluency measure, as compared to 11% of controls, and this difference was signifi cant. There was a trend for DBS patients who declined significantly on verbal fluency to experience less motor improvement than DBS patients who did not declin e. None of the hypothesized predictors were significantly associated with changes on the test of letter fluency. Only side of surgery was significantly associated with changes on the measur e of semantic fluency, such that patients who underwent left-sided surgery were more likely to decline. Our results suggest that unilate ral DBS surgery is associated with verbal fluency declines. Further, left-sided surgery appears to be more a ssociated with declines in semantic fluency than right-sided surgery, and fluency changes do not seem to be signi ficantly related to the patient characteristics of age, baseline cognitive stat us or pre-operative de pressive symptomatology. Finally, classification based on Reliable Change highlights the impact of individual variability in outcome and indicates that fluency declines likely reflect signifi cant changes in a subset of DBS patients who may demonstrate a relatively poor surgical outcome in general.

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CHAPTER 1 INTRODUCTION Parkinsons Disease Parkinsons disease (PD) is the second most common neurodegenerative disease. Its prevalence in the elderly population is estimated to be about 160 per 100,000, and it is estimated that 16 to 19 new cases of PD are diagnosed pe r 100,000 each year (Hirtz et al., 2007; Twelves et al., 2003). Moreover, due to the aging of our populat ion, general incidence is expected to triple over the next 50 years (Tanner, Goldman & Ro ss, 2002). Most PD patients develop symptoms gradually in the 6th or 7th decade of life, and the mean age at diagnosis is 70.5 (Van Den Eeden et al., 2003). The incidence of PD is significantly gr eater in men, with a male to female ratio estimated to be between 1.5 and 2, and the averag e age of onset in men is, on average, 2.2 years younger than in women (Twelves et al., 2003; Haaxma et al., 2006). In addition to the prominent motor symptoms, namely, resting tremor, bradykinesia, rigidity and postural inst ability, patients experience a variety of non-motor complications such as autonomic dysfunction, disturbances of mood and cognitive deficits Increasing attention paid to these non-motor signs has improved the treatment of the whole Parkinsons patient by expanding our understanding of past, pres ent and possible treatments. Pathophysiology and Treatment PD is defined by the death of dopamine-contai ning neurons in the substantia nigra pars compacta, which results in a reduc tion of dopamine in the nigrostria tal pathway as well as in the mesolimbic and mesocortical pathways. The defici ency in striatal dopamine disrupts activity in the cortico-basal ganglia-thalamocortical circu its, which leads to pronounced motor impairments (Albin, Young, & Penney, 1989). Specifically, reduced striatal input reduces positive feedback via the direct pathway and increases negative feedback via the indirect pathway, resulting in 10

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the hallmark overall reduction in movement s een in patients with PD (Alexander, DeLong, & Strick, 1986). Dopamine depletion in other pa thways may contribute to mood and autonomic dysfunctions. Historically, treatment of PD has largel y sought to enhance dopaminergic activity pharmacologically; however, drug treatments are often associated with adverse side effects such as unpredictable on/off motor fluctu ations and dyskinesias, or exces sive movement in particular areas of musculature (Marsden, Parkes, & Quinn, 1982). Motor fluctuations and/or dyskinesias occur in approximately 40% of PD patients r eceiving levodopa therapy for 4-6 years (Ahlskog & Muenter, 2001). The risk of developing these pot entially disabling side effects increases with disease duration, and they repres ent a distinct challenge in th e long-term management of PD (Papapetropoulos & Mash, 2007). Ad junct surgical intervention re presents an alternative to exclusive pharmacological management of PD and has been shown to redu ce the burden of these drug-related side effects. For example, researcher s estimate that bilateral Deep Brain Stimulation (DBS) of the globus pallidus internus (GPi) redu ces dyskinesia severity 41 to 87%, and DBS of the subthalamic nucleus (STN) reduces dyskinesias by an average of 70% (Fabbrini et al., 2007). Cognitive Sequelae Parkinsons disease is associated with specific cognitive deficits due to fronto-striatal neuropathology. Incidence of cognitive impairment in PD increases with age from 2.7% per year at ages 55-64 to 13.7% per year at ages 70-79 (Galvin, 2006). Approxi mately 25-30% of PD patients will develop a full-blown dementia syndrome (Aarsland, Zaccai, & Brayne, 2005). However, estimates of dementia prevalence in PD is complicated by the fact that most studies have used diagnostic criteria defined by the Diagnostic and Statisti cal Manual of Mental Disorders IV (American Ps ychiatric Association [ DSM-IV-TR ], 2000), which includes memory deficits in the definition of dementia, and a memory dysfunction may not be prominent in many 11

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patients with Parkinsons Disease Dementia (C aballol, Mart, & Tolosa, 2007). Even those patients who do not go on to manifest dementia per s will commonly evidence a pattern of cognitive impairments that resembles that seen in frontal lobe patients. Indeed, there is an increasing recognition that cognitive impairments in PD are not unique to Parkinsons Disease Dementia (PDD) and may occur in the earliest stages of the disease (Cooper et al., 1991; Muslimovic et al., 2005). The pattern of cognitive deficits commonl y seen in PD involves impairments in attentional set shifting, memory re trieval, visuospatial abilities, and directed verbal fluency. The latter ability is tested with tasks requiring pa tients to rapidly produce words from pre-defined phonemic or semantic categories within a given period of time. The pathophysiology of PD-type deficits may involve extrastriatal dopamine systems or non-dopaminergic pathology (WilliamsGray et al., 2006). Of note, the impairment in verb al fluency is thought to relate to dysfunction of self-generated search strategies due to execu tive dysfunction rather than a true language dysfunction (Pillon et al., 2001). Given that PD is associated with a variety of cognitive abnormalities that manifest throughout the disease course, studies looking at cognitive deficits associated with DBS surgery must control for defi cits related to the underlying disease process. Deep Brain Stimulation Surgery Description Deep Brain Stimulation is currently consider ed the gold standard surgical treatment for PD and has surpassed ablative surgeries largely becau se of its reversibility and flexibility, in that one can modify stimulation parameters to achieve optimal clinical benefit (Kopell et al., 2006; Okun et al., 2007). DBS involves impl anting a lead with electrodes at the tip into specific brain regions via stereotactic neurosurgery. The most commonly targeted brai n regions are GPi and STN, although surgeries involving th e ventral intermediate nucleus of the thalamus are also 12

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regularly conducted. An electrical pulse that is generated by a neurostimulator implanted below the clavicle travels through a subcutaneous wi re and delivers high frequency stimulation (HFS) to subcortical target areas. Since traditional DB S electrodes have multiple contact points and can be programmed to produce varying frequencies of stimulation, unique stimulator settings can be determined and adjusted for individu al patients and changed over time. The mechanism of action of HFS is not fully understood, although it is generally conceptualized as a reversible functional lesion in that stimulation disrupts the abnormal electrical activity in ba sal ganglia circuits. Current theories suggest a modulati on of patterns of both excitation and inhibition of neural tissue. W ithin the localized electrical field, stimulation appears to inhibit neurons of th e STN and excite other fibers th at are exiting, passing through or passing near the structure (Fila li et al., 2004; McIntyre et al., 2004; Vitek, 2002; Windels et al., 2003). The underlying physiology of these effects lik ely involves some combination of events such as jamming of feedback loops, activation of inhibitory structures included in a more complex network, induction of early genes, chan ges in local blood flow, desynchronization of network oscillations, depression of intrinsic voltage-gated current s, synaptic inhibition and/or synaptic failure (Benabid, Benazzous, & Pollak, 2002; Meissner et al., 20 05; Beurrier et al., 2001; Dostrovsky et al., 2000; Urbano & Llinas, 2002). Efficacy Motor functioning following optimal DB S programming is markedly improved, on average, as commonly assessed with the Unifie d Parkinsons Disease Rating Scale (UPDRS). Recent meta-analyses have reported 40-52% reduc tions in scores on subscale III of the UPDRS, which assesses the cardinal motor symptoms of PD, in patients evaluated in the off medication state before and after bilateral GPi or STN surg ery (Kleiner-Fisman et al., 2006; Weaver et al., 13

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2005). PD symptoms most noticeably and consis tently responsive to DBS include: tremor, rigidity and limb akinesia (Kumar et al., 1998; Limousin et al., 1998; Vesper et al., 2002). Cognitive Outcome Compared to the body of literature devoted to motor outcomes, studies of cognitive effects following DBS surgery are limited. Recentl y, researchers have increasingly attended to non-motor effects of surgery, which can include both mood and cognitive changes. A recent meta-analysis reported that c ognitive problems occurred in approximately 41% of patients who underwent bilateral STN DBS (Temel et al., 2006 ). There is some data to suggest that stimulation of the STN is more likely to produce non-motor side effects than stimulation of the GPi, perhaps due to a greater risk of electrode mi splacement or current spr ead attributable to the relatively small size of the STN (Walter & Vite k, 2004). Alternatively, this finding may be an artifact of the fact that fewer reports of GPi DBS are availabl e, and limited data suggests that fluency impairments, which represent the most commonly reported cognitive deficit in the STN literature, also occur after GPi DBS (Kern & Kumar, 2007). Despite the heterogeneity of results, the most robust and consistent finding across studies is a decline in verbal fluency in patien ts who have undergone DBS (Voon et al. 2006; Funkiewiez et al., 2004; Rothlind et al., 2007; De Gaspari et al., 2006; Smeding et al., 2006; Castelli et al., 2006; Gironell et al., 2003) One meta-analysis calculated Cohens d effect sizes of .51 for letter fluency and .73 for semantic fluency (Parsons et al., 2006). Further parsing verbal fluency tasks into their subcomponents of clustering (generation of contiguous words within a semantic sub-category) and switching (disenga ging from a prior sub-category and shifting to another), several groups have reported that on ly the latter subcomponent declined following STN DBS (Saint-Cyr et al., 2000; De Gaspari et al., 2006). Convergent findings from neuropsychological and neuroima ging studies indicate that clustering relies primarily on 14

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temporal structures, while switch ing relies on frontal-subcortical circuit integrity (Troyer et al., 1998; Trster et al., 1998; Frith et al., 1991; Parks et al., 1988 ; Schlsser et al., 1998). Using ECD-SPECT, researchers have recently associ ated post-STN DBS fluency declines with perfusion decrements in left dor solateral prefrontal cortex (Ci lia et al., 2007). Thus, it is reasonable to hypothesize that fluency deficits following high frequency stimulation of DBS target structures result from a disrupt ion of frontal-subcortical circuitry. Aside from verbal fluency, there is little agreement on the other cognitive tasks affected by DBS. A qualitative review of the literature di scovered a multitude of disparate findings across studies (Voon et al., 2006). Task s reported to decline after DB S included: verbal memory, visuospatial memory, Stroop, wo rking memory, conditional asso ciative learning, Trails B, construction and episodic memory. Many studies did not document declines on Digit Span Backward, a specific working memory task; however, most studies either di d not administer this test or had small sample sizes. Numerous studies in the literature have reported declines in the working memory domain (Hershey et al., 2004; Saint-Cyr et al., 2000; Morrison et al., 2004). One meta-analysis attempted to identify specific neurocognitive domains represented by the various tasks used in studies of cognitive outcome following DBS. Aside from large effects for both letter and semantic fluency, the authors reported significant declines on measures of executive and verbal functions; however effect sizes were small: Cohens d = .08 & .21, respectively (Parsons et al., 2006). Thus, there is a need to reso lve the discrepancies currently existing in the literature in order to de termine the true effects of DBS on cognition. One proposed hypothesis for these cognitive changes following DBS implicates a disruption in the associative basa l ganglia-thalamocortical loop due to the spread of electrical current beyond the targeted brain tissue. Althoug h neurosurgeons attempt to target the more 15

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16 lateral sensorimotor subregions of GPi or STN in order to correct the path ological activity in the motor loop, it is conceivable that el ectrical current may affect neur al activity in the associative subregions, which are directly adjacent to the sensorimotor subregions in both GPi and STN. Indeed, high frequency stimulation has been found to differentially affect the associative and limbic basal ganglia-thalamocortical loops (Haegelen et al., 2005; Schroeder et al., 2003; Sestini et al., 2002; Hilker et al., 2004). Imaging studies have revealed that high frequency stimulation modifies cerebral blood flow in the cortical areas of these non-motor loops during cognitive tasks (Limousin et al., 1997; Schroeder et al., 2003). Additionally, non-motor subregions of GPi and STN may possess different physiological properties such that different stimulation frequencies may exert different eff ects on motor behaviors and cognition (Temel et al., 2005). Evidence from human studies supports th is idea in that high frequency stimulation leads to motor improvement and concomitant cognitive deterioration, while low frequency stimulation enhances cognitive performance in a context of motor worsening (Wojtecki et al., 2006). Additionally, modifying stimulation parame ters may change the extent to which nonmotor features are expresse d (Francel et al., 2004).

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CHAPTER 2 STATEMENT OF THE PROBLEM In both efficacy and frequency, Deep Brai n Stimulation surgery for the treatment of Parkinsons disease has surpassed traditional surgi cal approaches such as ablative procedures (e.g. pallidotomy), which aim to destroy circum scribed regions of subcortical tissue. FDA approval of and subsequent media attention directed toward DBS procedures have led to their being more regularly offered at a variety of medi cal facilities, not just tertiary-care specialty centers. This increased accessibility and commo nness of DBS surgery in the U.S. is largely attributable to the numerous published reports of the treatments effectiveness in controlling cardinal motor symptoms and reducing both unpr edictable on-off fl uctuations and druginduced side effects such as dyskinesias. Howe ver, the number of articles aimed at examining cognitive side effects of DBS is relatively meager Additionally, significant conflict persists, and recently, criticism has been directed toward the imperfect statistical methodologies used in the majority of cognitive studies. Given the unresolved state of the extant literature and the rising incidence of DBS throughout the world, it is im portant for researchers to work toward identifying the nature, frequency, predictors and causes of cognitive side effects in order to ensure that Parkinsons patients are well-in formed and receive the best possible care. It is difficult to synthesize findings from the literature on cognitive changes after DBS due to differences in neuropsyc hological testing batteries, vari ation in time to follow-up, nonroutine reporting of st imulation parameters and lack of post-operative target confirmation. Additionally, most previouslypublished studies suffer from major methodological limitations, including small sample sizes, an exclusive fo cus on group mean differences and a failure to include a non-surgical control group. Unlike most previous research on cognitive outcome 17

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following DBS surgery that analyzed large neur opsychological datasets using an exploratory approach, the present stu dy reflects a theory-driven method of task selection. A recent article that reviewed 30 studies ex amining cognitive effects of DBS to the STN in PD patients revealed that due to insufficient sample sizes, the majority of these studies possessed adequate power to detect only those effect sizes that are very large according to Cohens conventions (Woods et al., 2006). These studies suffered from Type II error risk in that they possessed surprisingly low estimated power to detect changes associated with small, medium and large effect sizes. The authors of the re view concluded that future efforts be directed toward examining the significance of effects at the individual le vel, not just group differences. One recommended method for characterizing indivi dual changes in performance over time uses a Reliable Change Index (RCI), which takes in to account the imprecision of a measurement instrument and places a confidence interval around post-test scores that c ould be obtained due to chance. Unlike traditional statis tical approaches that examine mean scores to determine the statistical rarity of post-test scores, the RCI method determines the stat istical significance of individual changes in performance, thereby allowing for the differentiation of group differences resulting from small changes in the majority of a sample versus those due to relatively large changes in a subset of a sample. We chose to include a cont rol group of PD patients who di d not undergo surgery because we believe it to be essential in this type of research for two primary reasons. First, the neurodegenerative process of Parkinsons disease itself leads to cognitive changes that may not be attributable to the surgical intervention. Second, virtually all se rial neuropsychological research can be influenced by practice effects, or the tendency for patients to perform better on a measure simply as a result of their taking it twice. Comparisons with a control group reduce the 18

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influence of these confounds on the interpretatio n of results. The overall aim of the present study is to advance our understanding of the cognitive effects of Deep Brain Stimulation surgery for the treatment of Parkinsons disease. The sp ecific aims and hypotheses are outlined below. Specific Aim I To test the hypothesis that cognitive declines associated with Deep Brain Stimulation surgery manifest in diminished performance on neuropsychological tasks shown to involve the dorsolateral prefrontal cortex (DLPFC). To inve stigate this hypothesis, we chose to examine performance changes on three task s, two involving directed flue ncy and one involving working memory. Tasks included: the Controlled Oral Word Association Test (COWAT), the Animal Fluency Test and Digit Span Backward from th e Wechsler Adult Intelligence Scale (WAIS-III). Each of these tasks has been s hown, in lesion and/or functional neuroimaging studies, to involve participation of dorsolateral prefrontal regi ons of the brain. In addition, we analyzed performance on tasks that do not predominately involve the dorsolateral prefrontal cortex, namely, the Boston Naming Test (BNT) and the Vo cabulary subtest of the Wechsler Abbreviated Scale of Intelligence (WASI). We included these ta sks in order to rule out the possibility that cognitive declines seen after DBS represent arb itrary or more wide-sprea d cognitive dysfunction. Unlike previous studies of cognitive outcome following DBS that have analyzed large and disparate cognitive batteries in an explor atory manner, the presen t study involved tasks selected in a hypothesis-driven manner, based on evidence for their activation of dorsolateral prefrontal cortex circuitry. Furthermore, we compared da ta from pre-operative and postoperative (1-year) neuropsychological assessments to data from patients with PD who did not undergo surgery in order to control for possibl e practice effects or disease-related cognitive decline. We predicted that performance on the three cogniti ve tasks shown to involve dorsolateral prefrontal cortex would decline in the DBS group as compared to controls, while 19

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performance on tasks requiring less involvement of dorsolateral prefrontal cortex would be similar in DBS and control subjects at both time points. Specific Aim II To determine the significance of changes in performance on tasks shown to decline in the DBS group using Reliable Change Indexes (RCIs). The heterogeneity of results in the extant literature on cognitive decline subs equent to DBS surgery may be at least partially explainable by the extensive variability of outcome amongst patients. That is, while many patients do not shown cognitive dysfunction after surgery, a subset of patients seems to experience pronounced impairments. The traditional inferential statistica l procedures employed by the vast majority of studies published to date examine mean scores in order to determine the statistical rarity of posttest scores. These methods provide limited informa tion about the individual variability within a sample and no information about the significance of individual changes in performance. In order to address these potentially useful clinical questions, we used the method of Reliable Change, first described by Jacobson & Truax (1991) and later modified by Chelune et al. (1993) to additionally control for practice effects. We hypothesized that co mpared to the control group, a greater proportion of patients undergoing DBS su rgery would fall below th e confidence intervals defined by Reliable Change. Specific Aim III To identify risk factors for the developm ent of post-operative cognitive dysfunction. The discovery of factors that predic t which patients are more likely to experience adverse cognitive side effects as a result of DBS surgery is im perative, and current re search has failed to demonstrate consistent findings (Temel et al., 2006). Studies ha ve implicated a handful of disparate factors that may predict post-surgical declines in cognitive performance, including age, side of surgery, and a variety of pre-operative pa tient attributes such as poor cognitive status, 20

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21 depressive symptomatology, apathy, neuropsychiatric conditi ons, disease duration and/or severity, and dopaminergic psychosis (Smeding et al., 2006; Funkiewiez et al., 2004; De Gaspari et al., 2006; Perriol et al ., 2006). However, predictors vary ac ross studies, and many studies have not identified any factors, pre-ope rative, surgery-related or post-operative, that significantly predict cognitive outcome. We hypothesized that age, baseline cognitive status, side of surgery (i.e., left) and pre-operative de pressive symptomatology would be associated with adverse cognitive outcome.

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CHAPTER 3 METHODS Participants and Procedures Recruitment Participants included thirty-nine patients with idiopathic Parkinsons disease who are being followed by the Movement Disorders Center (MDC) at the University of Florida (UF) and who signed informed consent for their data to be included in the UF MDC research database. Motor, neuropsychological and demographic data were obtained from this IRB-approved database. All patients underwent neuropsychol ogical evaluation through the University of Florida Psychology Clinic and were taking thei r normal dopa medications at the time of assessment. The PD DBS group comprised 20 individuals who underw ent unilateral DBS surgery to either the right (N=7 ) or left (N=13) brain. Surgical targets included GPi (N=11) or STN (N=9). The PD control group comprised 19 individuals who were followed over time without undergoing DBS surgery. Parkinsons Disease Diagnosis All patients included in this study underwent extensive neurological screening in order to establish a definitive diagnosis of idiopathic Pa rkinsons disease. Consistent with the UK Brain Bank criteria (Hughes et al., 1992), the presence of bradykinesia as well as at least one other motor sign (i.e., rigidity, resting tremor or postu ral instability) were required for diagnosis. The diagnosis was ruled out if patients met any of th e UK Brain Bank exclusion criteria (e.g., history of repeated head injury, history of definite encephalitis, supranuc lear gaze palsy, cerebellar signs, etc). Also consistent with the UK Brain Ba nk criteria, Dr. Okun and his team required a demonstrated good response to levodopa therapy in or der to exclude patients with Parkinson plus syndromes (e.g., progressive supranuclear palsy, multiple systems atrophy, corticobasal 22

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degeneration, Lewy body disease, etc.). Other s upportive prospective positive criteria from the UK Brain Bank list, including unilateral onset, persistent asymmetry and levodopa-induced chorea, were taken into account as well. Inclusion and Exclusion Criteria All patients included in this study were requ ired to be between the ages of 50 to 75. Of the 23 patients identified as meeting inclusion criteria for the DBS group, 3 were excluded from the present analyses in order to render the DBS and control groups more comparable on age. On average, these excluded patients were 51.67 y ears old (range 51 to 52), and they did not significantly differ from the rema ining 20 DBS patients with regard to their level of education, severity of motor symptoms or disease stage. Pa tients were excluded from either group if they: evidenced dementia (MMSE < 25; DRS-2 < 130), had undergone previous DBS or ablative procedures, or received bilateral DBS surgery. Motor Testing Instruments Unified Parkinsons Disease Rating Scale-Motor Examination (UPDRS-III) The UPDRS-III (Fahn, Elton, & Committee, 19 87) quantifies the type, number and severity of motor symptoms common to Parkinsons disease. It takes approximately 15 minutes to administer and was conducted by a MDC neurologist or physicians assistant. The UPDRS is routinely administered in the UF MDC both in PD clinical trials and as part of patients normal clinical care. This assessment was carried out wh en patients were on and off medications. Hoehn and Yahr Stage Scale The Hoehn & Yahr Scale (Hoehn & Yahr, 1967) is a clinician-rated scale of diseaserelated disability that allocates a stage (0-5) and is a ubiquitous measure of disease severity. 23

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Neuropsychological/Mood Testing Instruments Dementia Screening Mini-Mental State Examination (MMSE) The MMSE (Folstein, Folstein, & McHugh, 1975) is routinely administered as a rapid screen for dementia in a variety of clinical and research settings. The maximum score on the MMSE is 30 points, and it assesses several domains of functioning: memory, attention, formation, orientation, figure copying, reading and writing. Consiste nt with previous research, we included only patients obtaini ng a score of 25 or above in order to minimize the possibility that patients evidenced probable dementia. Dementia Rating Scale 2 (DRS-2) The DRS-2 (Mattis, 2001) is a widely-used screening measure for dementia. It takes about 20-30 minutes to administer and assesse s domains of memory, attention, initiation, language and visuoconstruction. The maximum score on the DRS-2 is 144, and we employed a cut-off score of 130, considering scores below 130 as indicative of probable dementia. Total, raw DRS-2 scores were used in analyses for Aim 3. Dorsolateral Prefrontal Cognitive Tests Controlled Oral Word Association Test (COWAT) The COWAT (Benton, Hamsher, & Sivan, 1994) is the most commonly-used measure of letter fluency in a variety of patient populations. The te st allows patients 60 seconds to generate words beginning with a particular letter. The fo rm employed in the present study used the letters F, A and S, and the instructions given to pati ents were those describe d by Spreen and Benton (1977). Patients were told not to provide prope r nouns or multiple words containing the same stem. Convergent evidence from lesion and functiona l imaging studies suggest s that this type of intrinsic word generation to letters involves seve ral prefrontal subregi ons, including Brodmanns 24

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areas (BA) 4, 6, 44 and 45 (Baldo et al., 2006; Costafreda et al., 2006; Amunts et al., 2004; Friston et al., 1991). The total number of word s generated for each of the three letters was converted to T-scores based on age, educat ion, and gender norms (Heaton et al, 2004). The Animal Fluency Test The Animal Fluency Test, a measure of seman tic fluency, asks patien ts to generate names of animals for 60 seconds. The instructions gi ven to patients were those described by Rosen (1980). In addition to engaging left dorsolateral pr efrontal cortex, semantic fluency may also rely on its right homologue (Szatkowska, Grabowska, & Szymanska, 2000). The total number of words generated was converted to T-scores ba sed on age, education, and gender norms (Heaton et al, 2004). Digit Span Backward The Digit Span task is one subtest from the Wechsler Adult Intelligence Scale-3rd edition (WAIS-III; Wechsler, 1997) and is widely rega rded as a conventional measure of auditory working memory. The backward portion is thought to measure brief storage, mental tracking and mental manipulation (Lezak, 1995). It takes about 5 minutes to administer and requires patients to first listen to a string of numbers verbally pres ented by an experimenter and to then repeat the string aloud with the numbers in the reverse order. The first tw o trials contain 2 digits, and subsequent trials include increasi ng numbers of digits, with two tr ials of each difficulty level. Testing is discontinued when patients fail to correct ly complete two trials of the same difficulty level. Imaging studies using this working memo ry task have reported activations in several prefrontal areas, including BA 6, 9, 44 and 46 (Owen, 2000; Tsukiura et al., 2001). Compared with the forward portion, Digit Span Backward se lectively activates dors olateral prefrontal cortex in younger adults (Hoshi et al., 2000). The total number of co rrect trials was converted to scaled scores based on age-based norms (Wechsler, 1997) and then to T-Scores. 25

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Other Cognitive Tests Boston Naming Test (BNT) The BNT is a 60-item test of visual confrontation naming (Kaplan, Goodglass, & Weintraub, 1983). In this test, pa tients are asked to name visu ally-presented images. Scores representing the total number of correct namings were converted to T-scores based on age, education, and gender norms (Heaton et al, 2004). Vocabulary Vocabulary is one subtest from the Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler, 1999) and requires patients to provide verbal definitions of a series of words that increase in difficulty. Patients can obtain 0, 1 or 2 points on each trial, depending on the depth and accuracy of the response. Administration is di scontinued when the patient obtains a score of on five consecutive trials. Sc ores representing total points obt ained were converted to scaled scores based on age-based norms (Wech sler, 1999) and then to T-Scores. Mood Measure: Beck Depression Inventory 2nd Edition (BDI-II) The BDI-II (Beck, Steer, & Brown, 1996) is a self-report measure of depressive symptomatology that is routinel y given to patients at the UF MDC and UF Psychology Clinic. For each of the 21 items representing differe nt depressive symptoms, patients choose one statement that best describes how they have fe lt over the past week. For each item, statements correspond to 0, 1, 2 or 3 points, and total scores can range from 0 to 63. Raw scores were used in analyses for Aim 3. Statistical Analyses The first prediction was that compared to a control group, DBS patients would decline only on those neuropsychological task s with greater dorsolateral pref rontal cortex involvement. To test this prediction, repeated-measures anal yses of variance (ANOVAs) were conducted on 26

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the dependent variables (T-scores) in each of the five cognitive tests (COWAT, Animal Fluency, Digit Span Backward, Vocabulary and BNT). For each ANOVA, the between-subjects variable was group membership (DBS vs. PD control) and the within-subjects variable was time. Bonferroni-corrected follow-up t-tests were c onducted in order to explicate specific group differences when a significant Group X Time in teraction was detected. To ensure that the assumptions required for General Linear Model analyses were met, data were screened for homogeneity of variance and normality through examination of descriptive statistics and graphical distributions. For all group comparis ons, Levenes tests for the homogeneity of variance were conducted before analyses were performed, and appropriate statistics were used when this test indicated non-homogeneity of variance. The second aim was to examine the significan ce of individual cha nges in performance on tasks shown to decline in the DBS group. To test this aim, Reliable Change Indexes (RCIs) corrected for practice effects were calculated using formulas described by Jacobson & Truax (1991) and modified by Chelune, et al. (1993). Consistent with the majority of previous literature using RCIs, 90% confidence intervals were c hosen. Patients were then classified as decliners if the difference between their obtain ed post-test score and their i ndividualized expected score fell outside of the RCI for the specific cognitive test. Pearson chi square tests were then conducted in order to assess the significance of proportional differences between the numbers of decliners in the two groups. In addition, phi values were obtai ned to index effect sizes, and odds ratios were calculated to facili tate interpretation. The third prediction was that age, side of surgery, cognitive impairment and depressive symptomatology would correlate with cognitive decline in the DBS group. To test this prediction, independent linear regr essions were conducted in whic h the dependent variable in 27

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each analysis was performance change (post-test T-scores minus pre-test T-scores) on each of the cognitive tests identified by significant Group X Time inte ractions in Aim 1 repeatedmeasures ANOVAs. Independent variables (i.e., predictors) in each regression were: baseline age, total baseline DRS-2 scores, total baselin e BDI-II scores and side of surgery. Overall significance of the model and, when appropriate, th e relative contribution of each predictor were reported. To further explicate the role of the above-mentioned predictors, follow-up t-tests were conducted comparing DBS patients classified as decliners and non-decliners. Additionally, a selection of decliners and non-decliners baseline dis ease variables (i.e., UPDRS on and off and disease duration) as well as change (post minus pre) variables (i.e., Hoehn & Yahr stage, UPDRS on and off levodopa equivalent dose and BDI-II) we re statistically compared using independent samples t-tests. 28

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CHAPTER 4 RESULTS Demographic and Disease Variables: DBS vs. Controls Table 4-1 compares demographic and dis ease-related data on the two groups. DBS patients included 16 men and 4 women who ranged in age from 53 to 70 years ( M = 61.3, SD = 5.2). These patients had obtained an average of 14 years of education ( SD = 2.3, range 7 to 16 years). On average, the DBS patients motor symp toms were moderately severe when they were assessed on medications with the motor portion of the Unified Parkinsons Disease Rating Scale (UPDRS-III = 23.0, SD = 8.5, range 8 to 41), and they were in the middle stage of PD as defined by the Hoehn & Yahr staging system ( M = 2.2, SD = 0.4, range 2 to 3). PD control patients included 12 men and 7 women who ranged in age from 54 to 74 years ( M = 64.7, SD = 6.6). These patients had obtained an average of 15.4 years of education (SD = 3.0, range = 12 to 20 years). Like those of DBS patients, the motor symptoms of the PD controls were moderately severe when patients were assessed on medications (UPDRS-III = 25.3, SD = 8.5, range 14 to 43), and they were in the middle stage of PD, as defined by the Hoehn & Yahr staging system ( M = 2.4, SD = 0.4, range 2 to 3). As shown in Table 4-1, there were no significant differences between groups on any of these variables. More over, there were no significant differences at baseline between the DBS and PD controls on th e two cognitive screening measures (i.e., DRS-2 and MMSE) or on a self-report measure of de pressive severity (i.e., BDI-2). Duration of parkinsonian symptoms, per patient self-report, was approximately 147.3 months for the DBS group ( SD = 64.6, range 52 to 319 months) and approximately 76.5 months for the PD controls ( SD = 69.1, range 21 to 310 months). This difference in symptom duration (i.e., 70.7 months) was significant ( t (37) = -3.30, p = .002, r = .48). In addition, DBS patients motor symptoms were more severe than those of PD controls when patients were assessed off 29

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medications with the UPDRS-III (DBS group M = 45.2 vs. PD control M = 30.8; t (37) = -4.38, p < .001, r = .58). Aim 1: Group Differences in Cognitive Performance over Time Mean scores of the DBS and PD control patients tested at baseline (Time 1) and again at Time 2 across each of the five cognitive tests are shown in Table 4.2. Two of these tasks were predicted not to be affected by DBS (i.e., WA SI Vocabulary, Boston Naming Test), whereas three tasks were predicted to decline followi ng DBS (i.e., Digit Span Backward, COWAT and Animal Fluency Test). Results from five sepa rate repeated-measures ANOVAs are presented in Table 4.3. As shown, there were no significant main effects of Group or Time for any of the cognitive tests. However, significant Group X Time interactions were detected for the two fluency tasks: COWAT ( F [1, 37] = 10.83; p = .002; p 2 = .23) and Animal Fluency Test ( F [1, 37] = 4.45; p = .04; p 2 = .11). These interactions are displayed graphically in Figures 4-1 and 4-2. Decomposition of these interactions using Bonferroni-corrected t-tests revealed the following. For letter fluency (COWAT) DBS and PD control patients did not differ at baseline testing (Control M = 48.4 vs. DBS M = 47.7; t (37) = 0.2; p = .84; r = .03); however, the DBS patients produced significantly fewer words than PD controls at follow-up testing (Control M = 50.5 vs. DBS M = 41.4; t (37) = 2.23; p = .03; r = .34). Furthermore, DBS patients post-surgery scores were significantly lower th an their baseline scores (Pre M = 47.7 vs. Post M = 41.4; t (19) = 3.55; p = .001; r = .63), while control patients preand post-test scor es did not differ significantly (Pre M = 48.4 vs. Post M = 50.5; t (18) = 1.14; p = .26; r = .24). For semantic fluency (Animal Fluency Test) DBS and PD control patients did not differ at baseline (Control M = 47.7 vs. DBS M = 51.5; t (37) = 0.99; p = .33; r = .16) or at follow-up testing (Control M = 48.4 vs. DBS M = 44.5; t (37) = 0.90; p = .37; r = .15). However, DBS patients produced significantly fewer animal names at pos t testing than at baseline (Pre M = 51.5 vs. Post M = 41.4; 30

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t (19) = 2.74; p = .009; r = .53), while control patients preand post-test scores did not differ significantly (Pre M = 47.8 vs. Post M = 48.4; t (18) = 0.28; p = .63; r = .07). Because DBS patients and PD controls differed significantly on two key disease variables (i.e., disease duration and UPDRS-III off ), analyses of variance were re-run using these variables as covariates (ANCOV As). Results revealed a trend for the Group X Time interaction to persist for letter fluency (F (1, 32) = 4.05, p = .053, p 2 = .11); however, the interaction was no longer significant for semantic fluency ( F (1, 32) = 0.4, p = .53, p 2 = .01). No other main effects or interactions approached signi ficance in either of the ANCOVAs. Aim 2: Reliable Change Results Reliable Change Indexes (RCIs) corrected for practice effects were ca lculated in order to determine the statistical significance of individual changes on the two cognitive tests for which Group X Time interactions were identified, name ly, letter and semantic fluency. Test-retest correlations and standard deviati ons used to calculate standard errors of the measures using Equation 4-1 were obtained by examining data from the PD control group. RCIs for each measure were calculated separately using the stan dard error of the differe nce in the PD control group (Equation 4-2). The sizes of the 90% confid ence intervals were defined using Equation 4-3 (Jacobson & Truax, 1991). Practice e ffects were calculated separate ly for each cognitive test by subtracting mean pre-test scores from mean post-test scores obtained by the PD controls. For each test, each individual patients predicted scor e was estimated by adding the expected practice effect to the patients baseline score on the test (C helune et al., 1993). Patien ts were classified as decliners on a measure if they obtaine d a lower post-test score than could be expected due to chance, that is, if the difference between thei r obtained and predicted scores exceeded the RCI for the particular cognitive test. SEM = SD (1rxx) (4-1) 31

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SEDIFF = (SEM(Time 1)2 + SEM(Time 2)2) (4-2) RCI = .645 SEDIFF (4-3) As shown in Table 4-4, two (11%) of the PD control patients show ed significant decline on one fluency measure, and none showed declin e on both measures. In contrast, 9 (45%) DBS patients evidenced significant decline on one or both fluency measures. Specifically, 5 DBS patients declined on only one measure (3 on Lett er Fluency and 2 on Semantic Fluency) and 4 DBS patients declined on both. There was a signif icant and moderate asso ciation between having surgery and declining on at least one verbal fluency measure ( 2(1) = 5.72, p = .02, Phi = .38). Using Equation 4-4, the odds of d eclining were calculated separa tely for DBS patients and PD controls. Next, odds ratios were calculated using Equation 4-5. Compared to patients who did not undergo surgery, DBS patients had 7 times greater odds of experiencing si gnificant decline on at least one measure of verbal fluency. Looking at letter and semantic fluency individually, DBS patients had 10 times greater odds of declining on letter fluency and 7.7 times greater odds of declining on semantic fluency, as compared to PD controls. oddsdeclining = (# of decliners) / (# of non-decliners) (4-4) odds ratio = oddsdeclining after DBS / oddsdeclining as PD control (4-5) Aim 3: Predictors of Cognitive Change Regression Results To determine which factors (i.e., age, baseline cognitive status, baseline depression status, side of DBS surgery) we re significantly related to changes in performance on the verbal fluency tasks, two linear regres sions were conducted. For both regr essions, these four variables were regressed on change (T-score) in letter fluency or semantic fluency, respectively. The model was not significant in predicting change in performance on letter fluency ( R2 = .14; p = 32

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.74); however, the model was significant in predicting change in performance on semantic fluency ( R2 = .69; p = .005). Table 4-5 displays the unstandardized and sta ndardized beta weights for the predictors in the semantic fluency model. Importantly, only the predictor side was significantly related to change in semantic fluency performance ( = -.80; p < .001). On average, patients who underwent surgery to their right brain experienced an in crease in performance of 5.1 points, while patients who underwent surgery to their left brain experienced a decrease in performance of 13.5 points; this difference was large and significant ( t [18] = 4.88; p < .001; r = .75). Of the 7 patients who underwent surgery to their right brain, none experienced a significant decline on the measure of semantic fluency, according to the RCI analyses. In contrast, 6 out of the 13 patients who underwent left-sided surgery experienced significant decline on this measure. There was a significan t association between side of surgery and semantic fluency decline ( 2(1) = 4.62; p = .03; Phi = .48). Exploratory Group Comparisons In order to investigate other possible diffe rences between DBS patients who experienced significant declines in verbal fluency and those who did not, a seri es of exploratory t-tests were conducted. These tests compared decliners and nondecliners on a variety of baseline factors as well as on variables reflecting ch anges after surgery. As shown in Table 4-6, none of the baseline characteristics examined (i.e., age, BDI-II, DRS-2, months with symptoms, UPDRS-III on or off ) were significantly di fferent between the groups. However, the groups did significantly differ on side of surgery. Namely, 8 out of the 9 decliners had undergone surgery to their left brain ( t (17.13) = -2.25; p = .038; r = .48). With regard to patients motor changes, th ere were trends for d ecliners and non-decliners to evidence moderately-sized differences on cha nges in their UPDRS scores when they were 33

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assessed both on ( t (17) = -2.08; p = .054; r = .45) and off medications (t (17) = -1.89; p = .079; r = .42). Note that lower scores indicate better motor performance. On average, nondecliners experienced a reduction of 4.8 points when assessed on medications and a reduction of 14.2 points when assessed off medications. In contrast, decliners experienced an increase of 3.8 points when assessed on medications and a reduction of only 5.4 points when assessed off medications. 34

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Table 4-1. Comparisons between DB S and PD controls at baseline Controls DBS t df p Age (years) 64.6 (6.6) 61.3 (5.2) 1.80 37 .08 Education (years) 15.4 (3.0) 14.1 (2.3) 1.56 37 .13 Male/Female 12/7 16/4 1.15 35.01 .26 Months with symptoms 76.5 (69.1) 147.3 (64.6) -3.30 37 .002 Hoehn & Yahr stage 2.4 (0.4) 2.2 (0.4) 1.12 35 .27 UPDRS on 25.3 (8.5) 23.0 (8.5) 0.83 34 .41 UPDRS off 30.8 (8.3) 45.2 (11.2) -4.38 34 <.001 BDI-II 9.2 (8.6) 9.9 (8.4) -0.22 32 .83 MMSE (raw) 28.3 (1.9) 28.7 (1.5) -0.71 37 .48 DRS-2 (raw) 138.6 (3.5) 138.0 (4.4) 0.46 37 .65 Table 4-2. Performance (T-scores) on specific cognitive tests at Times 1 & 2 Controls DBS t df p Vocabulary Time 1 58.0 (7.9) 55.0 (6.8) 1.24 37 .22 Time 2 57.1 (13.1) 54.3 (8.3) 0.80 35 .43 BNT Time 1 55.5 (10.8) 55.1 (11.5) 0.15 37 .88 Time 2 55.8 (11.9) 53.9 (12.9) 0.49 37 .63 Digit Span Backward Time 1 51.9 (13.5) 52.8 (6.8) -0.25 37 .80 Time 2 50.1 (8.6) 50.0 (6.2) 0.05 36 .96 COWAT Time 1 48.4 (10.4) 47.7 (13.5) 0.20 37 .84 Time 2 50.5 (11.7) 41.4 (13.6) 2.23 37 .03 Animal Fluency Time 1 47.7 (11.0) 51.5 (12.7) -0.99 37 .33 Time 2 48.4 (12.7) 44.5 (14.6) 0.90 37 .37 35

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Table 4-3. Repeated-measures analyses of variance SS MS F p Effect Size ( p 2) Power Vocabulary Group 184.95 184.94 1.36 .25 .04 .21 Error (between) 4744.99 135.57 Time 23.58 23.58 0.64 .43 .02 .12 Group x Time 1.53 1.53 0.04 .84 .00 .06 Error (within) 1281.33 36.61 BNT Group 29.56 29.56 0.11 .74 .00 .06 Error (between) 9613.44 259.82 Time 2.996 2.996 0.15 .69 .00 .07 Group x Time 9.77 9.77 0.52 .48 .01 .11 Error (within) 693.95 18.76 Digit Span Backward Group 5.26 5.26 0.04 .84 .00 .06 Error (between) 4579.72 127.22 Time 113.80 113.80 2.63 .11 .07 .35 Group x Time 8.22 8.22 0.19 .67 .01 .07 Error (within) 1558.22 43.28 COWAT Group 472.17 472.17 1.70 .20 .04 .25 Error (between) 10261.37 277.33 Time 85.83 85.83 2.77 .11 .07 .37 Group x Time 335.83 335.83 10.83 .002 .23 .89 Error (within) 1147.35 31.01 Animal Fluency Group 0.21 0.21 0.001 .98 .00 .05 Error (between) 9803.8 264.97 Time 191.11 191.11 2.91 .10 .07 .38 Group x Time 291.62 291.62 4.45 .04 .11 .54 Error (within) 2426.84 65.59 36

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Table 4-4. Proportion of DBS patient s vs. controls evidencing decline Controls DBS patients Odds ratio Pearson chisquare p Phi Letter fluency 1 7 10 5.28 .022 .37 Semantic fluency 1 6 7.7 4.05 .044 .32 Either measure 2 (11%) 9 (45%) 7 5.72 .017 .38 Note, 2 cells had expected count le ss than 5 in chi-square tests fo r individual fluency measures Table 4-5. Predictor vari ables regressed on semantic fluency change scores B (std error) Beta t p Age 0.08 (0.44) .03 0.18 .86 DRS-2 -0.45 (0.46) -.17 -0.97 .35 BDI 0.20 (0.28) .13 0.72 .49 Side of surgery -20.39 (4.23) -.80 -4.83 <.001 R square = .69; p = .005 Table 4-6. Baseline and change score comparisons in decliners vs. non-decliners Decliners Non-decliners t df p r Age 61.8 (5.6) 60.8 (5.1) -0.40 18 .69 .01 BDI-II 11.1 (10) 8.5 (6.6) -0.63 15 .54 .16 DRS-2 137.8 (5) 138.2 (4) 0.20 18 .84 .05 UPDRS on 23.8 (7.1) 22.3 (9.8) -0.39 18 .71 .09 UPDRS off 42.4 (10.7) 47.4 (11.6) 0.95 16 .36 .23 Disease duration (months) 150.9 (72.3) 144.3 (61) -0.22 18 .83 .05 Left/Right 8/1 5/6 -2.25 17.13 .038 .48 Hoehn & Yahr change 0.4 (0.7) -0.1 (0.5) -1.71 14 .11 .42 UPDRS on change 3.8 (6.7) -4.8 (10.2) -2.08 17 .05 .45 UPDRS off change -5.4 (12.3) -14.2 (6.9) -1.89 15 .08 .42 BDI-II change 4.9 (8.7) 0.1 (6.2) -1.29 15 .22 .32 DRS-2 change -5.6 (5.9) -3.7 (6.8) 0.64 18 .53 .15 37

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Figure 4-1. Letter fl uency interaction 38

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Figure 4-2. Semantic fluency interaction 39

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CHAPTER 5 DISCUSSION The present study investigated three major aims. First, we hy pothesized that compared to PD patients who did not undergo surgery, DBS patients would experience worsened performance on cognitive tests thought to involv e the dorsolateral prefrontal co rtex. This prediction was based on the supposition that cognitive effects of DBS su rgery result from the spread of electrical current from the sensorimotor subregions of s ubcortical target struct ures into subregions identified as being involved in the associative basa l ganglia-thalamocorti cal loop, the cortical target of which is the dorsolateral prefrontal cortex. Indeed, previous research has documented declines within cognitive domains commonly associated with dorsolateral prefrontal cortex circuitry. The second aim sought to assess the signifi cance of individual changes in cognitive performance. The first aim employed inferential statistical procedures in order to infer the statistical rarity of group differences; however, these strategies offer little to no information regarding individual vari ability in outcome or the significan ce of individual changes. For this second aim, Reliable Change Indexes (RCIs) correct ed for practice effects were calculated based on data from the PD control group in order to identify the magnit ude of change that could be expected to occur by chance in an individual patient. Patients whose obtained post-test scores exceeded these 90% confidence interval s were classified as decliners and we hypothesized that compared to patients who did not under go surgery, a greater proportion of DBS patients would evidence significant decline, as assessed by chi square tests. A final, more exploratory aim of this study at tempted to identify fact ors that differentiate patients who experience cognitive declines after DBS from those who do not Linear regressions were conducted in order to assess the relative ab ilities of pre-selected variables identified as 40

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being possibly related to cognitive declines in previous studies (i.e., age, baseline cognitive status, pre-operative depressive symptomatology a nd side of surgery) to explain variance in cognitive changes. Also, independent samples ttests were conducted to compare DBS decliners and non-decliners (defined via RCI classification) on a variety of baseline and change variables. Summary and Interpretation of Findings The first hypothesis was partially supported by the data. That is, patients who underwent DBS surgery experienced greater declines than c ontrols on the two verbal fluency measures, as predicted, but not on the working memory task (Digit Span Backward) as predicted. The prediction that no signif icant differences between DBS and control patients would be found on the control tasks of Vocabulary and the Boston Naming Test was supported. Thus, it seems that PD patients were more likely to experience selectiv e cognitive decline after undergoing DBS surgery, and these declines were not general acro ss cognitive domains. The declines observed in the present study related to tasks of speeded ve rbal fluency, which have long been associated with frontal lobe dysfunction. Howe ver, evidence for the extent to which declines are observable on all tasks engaging dorsolateral prefrontal cortex circuitry is limited in the present study. An important contribution of the present st udy to the literature on DBS-related cognitive changes lies in its use of Reliable Change, a we ll-established method for defining true, functional change within an individual. Since group comp arisons rely on mean performance, it is not possible to fully interp ret the meaning of significant gr oup differences without examining individual variability. Significant differences may result from eith er the majority of a sample performing slightly worse or a subset of a samp le performing extremely worse at post-testing. As such, one cannot draw definitive conclusions about th e ubiquity of an effect using an exclusively inferential approach. To date, only one publishe d study using RCIs to analyze cognitive effects of DBS surgery for PD exists, and this report f eatured a shorter (six months) follow-up period, 41

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and the authors only studied patients undergoi ng bilateral implantati on in the subthalamic nucleus (York et al., 2007). The second hypothesis was supported by th e data. The present study documented significant cognitive declines in 45% of the DBS patient group, as compared to only 11% in the control group. This finding supports the view that groupspecific cognitive decl ines likely reflect large and meaningful declines in a subset of patients rather than ne gligible effects in most or all patients. Individual variability in outcome a nd the meaningfulness of individual changes may represent the most important information for th e clinician, and communica ting the incidence of cognitive side effects following DBS surgery to prospective surgical candidates may be more effective with this type of terminology. The third hypothesis was not fully suppor ted by the data. None of the hypothesized variables (i.e., age, baseline c ognitive status, baseline depressi on score, surgery side) was found to be significantly associated with performance changes on the measure of letter fluency. Moreover, only side of surgery predicted a si gnificant amount of the variance in performance changes on the measure of semantic fluency. It should be noted that the regression analyses used to address this aim were underpowered. The hypothesis that patients undergoing left-sided surgery would experience greater cognitive declines was supported in that significantly more patients who declined had undergone surgery to their left brain. Furthe r comparisons between decliners and non-decliners on a variety of other va riables revealed that while these patients did not differ on any baseline measures, there was a tre nd for decliners to fail to show the degree of motor improvement experienced by non-decliner s. Specifically, scores on the UPDRS motor examination, which quantifies the severity of PD-specific motor symptoms, improved moreso in those DBS patients who did not show cognitive d ecline. This finding could be interpreted as 42

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suggesting that patients who d ecline cognitively after DBS surg ery are those who show a poorer response to surgery in general, perhaps due to variables such as electrode misplacement (Smeding et al., 2007) or the extent of intra-operative complications. Interpretation and Relationship to the Literature The majority of studies examining cognitive changes after Deep Brain Stimulation surgery for the treatment of Parkinsons diseas e document verbal fluency declines; however, reports of working memory changes after surgery, which were not identified in the present study, have been conflicting. The absence of a working memory deficit in this and some previous studies may be at least partially explainable by th e fact that verbal fluency tasks and Digit Span Backward engage different neural networks. While research strongly sugges ts that both verbal fluency and working memory engage the dorsola teral prefrontal corte x, these two types of cognitive tasks involve their ow n unique and complex neural circ uits. Word generation activates a network of frontal, thalamic and basal ganglia structures (Crosson et al., 2003; Friston et al., 1991), while manipulation of auditory material stored in worki ng memory depends on connected areas of various frontal and pari etal structures (Jon ides et al., 1998). Furthermore, both Digit Span Backward and verbal fluency are composite tasks, comprising multiple subcomponents that seem to differentially employ different areas within these networks (Champod & Petrides, 2007; Trster et al., 1998). Aside from differences in the neural circuitry engaged, these two types of neuropsychological tasks differ in the nature of the cognitive abilities they assess. For example, the fluency measures are timed tasks. In contra st, patients are allowed to respond at their own pace in the Digit Span task. Thus, the former tasks are more sensitive to parkinsonian bradyphrenia, or an overall slowing of informati on processing, which affects patients response output. Furthermore, the fluency measures require patients to generate endogenous words. In 43

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contrast, patients hear and manipulate exogenous stimuli duri ng the Digit Span task. Some authors have suggested that flue ncy deficits in PD may be rela ted to a disease-related reduction in self-directed, goal-oriented behavior related to post-surgical apathy (Funkiewiez et al., 2004). Apathy may result from dysfunction in prefront al cortex-basal ganglia circuits, which are believed to be involved in the generation and control of self-g enerated purposeful behavior (Levy & Dubois, 2005). Indeed, several reports have suggested that apathy increases after DBS surgery in PD; however, many of these studies suffer from methodological limitations such as inadequate screening measures, and results ar e conflicting (Van Horn, Schiess, & Soukup, 2001; Saint-Cyr et al., 2000; Drapier et al., 2006). Furthermore, one review concluded that the incidence of apathy following bilateral STN DB S was lower than 0.5% (Temel et al., 2006). A recent study aimed at characterizing the relatio nship between post-DBS fluency declines and apathy failed to document an association (Castelli et al., 2007). It is difficult to determine the role of task difficulty in the finding that DBS patients performed more poorly on fluency measures, but not on Digit Span Backward, after undergoing surgery. Baseline T scores were slightly higher on the working memory measure than on either fluency measure. It is unclear whether group-sp ecific declines would have emerged on a more challenging and sensitive task i nvolving working memory or if pa tients had undergone bilateral, rather than unilateral surgery. Research imp licates greater, and possi bly more bilateral, involvement of prefrontal cortex with increa sing working memory load (Jonides et al., 1997; Klingberg, OSullivan, & Roland, 1997). Future st udies should employ more working memory tasks with varying difficulty levels to address this question. Alternatively, the finding that DBS patients declined on verbal fluency but not on a working memory task may reflect a different mechanism underlying cognitive decline after DBS. 44

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Group-specific declines on fluency measures ma y result not from current spread within subcortical target structures, but rather from direct damage to frontal areas along the electrode trajectory during the DBS surgical procedure. Several studies have documented similarly impaired cognitive performance both with stimulators turned on and off Such findings have been interpreted as providing evidence that cognitiv e declines after surgery may not be related to high frequency stimulation per s, but rather from damage caused during implantation (Morrison et al., 2004; Daniele et al., 2003). However, th ere are several methodol ogical problems with many of the on-off DBS stimulation studies. Most have employed a relatively short wash-out period separating the on and off conditions, and the effects of stimulation may have persisted well beyond the point at which stimulators were turned off. Additionally, other studies comparing performance with stimulators turned on and off have reported opposite findings, namely, that impairments were most prevalent in the on stimulation condition (Jahanshahi et al., 2000; Hershey et al., 2004; Pillon et al ., 2000). In addition, other researchers have documented an association between impaired task performance on a resp onse conflict task and decreased activation in anteri or cingulate cortex when stimulators were turned on (Schroeder et al., 2002). Future research is needed to clarify these conflicting findings. The second aim employed Reliabl e Change Indexes (RCIs), to supplement the inferential statistical approach of Aim 1. The finding that 45% of the DBS patients evidenced a significant cognitive decline on at least one measure of ve rbal fluency, as compared to only 11% in the control group, supports the notion th at group-specific cognitive decl ines likely reflect large and meaningful declines in a subset of patients rather than negligible effects in most or all patients. Researchers have posited that even when results suggest stable cognitive functioning overall in group studies, individu al changes can vary greatly (D ujardin et al., 2001). This idea 45

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was recently highlighted by the only published study using RCI analyses to investigate cognitive outcome six months after bilateral DBS surgery to the STN (York et al., 2007). The authors reported verbal fluency declines only at the tren d level when using group comparisons, but they found that 40% of patients eviden ced significant declines on their measure of semantic fluency and 26% on their measure of letter fluency. Thes e findings are consistent with those of the present study. Also, this group documented a significant difference between the proportions of DBS and PD control patients experiencing decl ines, which was found in the present study. Previous research attempting to identify baseline characteristics that predict which patients are more likely to experience cognitive decline after DBS surg ery has been largely unsuccessful. Clinically, it is now generally recognized that very old age, frailty and compromised baseline cognitive functioning put patie nts at greater risk for cognitive side effects and other complications. For this reason, most centers routinely screen out ol der, frail individuals and those who are demented when assessing surg ical candidacy (Okun et al., 2007). However, most studies have failed to docum ent a significant linear relations hip between these variables and cognitive outcome (Ory-Magne et al., 2007; Pa rsons et al., 2006; Voon et al., 2006). Indeed, rather than employing specific cu t-off scores or looking at only one or two variables, most centers exclude patients evidencing frank de mentia or very old patients with major comorbidities. In the present study, no patients in the DBS group were over the age of 70, and only patients in whom dementia was vigilantly ru led out were included as per the protocol for candidate selection used by the Movement Disorder s Center at the University of Florida. The resultant limited range most likel y accounts for the lack of associ ation between age or baseline cognitive functioning and post-surgical cognitive changes in the present study. 46

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The only variable that predicted a significan t amount of the variance in cognitive change was side of surgery such that le ft-sided surgery was associated with greater declines in semantic fluency. The vast majority of the literature on DBS outcomes has not addr essed this question, as most patients now undergo simultaneous or closel y staged bilateral procedures. Nevertheless, many researchers have documented greater declin es in a variety of cognitive tests, including fluency, following left-sided ab lative procedures (i.e., pallidot omy or subthalamic nucleotomy) for PD (Trster, Woods, & Fields, 2003; Cahn et al., 1998; Obwegeser et al., 2000; McCarter et al., 2000). In one of the only studies of this kind in DBS patients, Rothlind et al. (2007) recently reported that in a group of patients undergoing st aged bilateral DBS to either GPi or STN, performance on the Animal Fluency Test declined more in patients whose initial surgery was to their left, as opposed to their right brain. Given that letter fluency seems to be more le ft lateralized than semantic fluency, which seems to activate both left and right cortical areas (Billingsley et al., 2004; Szatkowska, Grabowska, & Szymanska, 2000), it is somewhat su rprising that left-sided surgery was strongly related only to semantic fluency declines. While both fluency tasks require some of the same processing abilities (i.e., retrieval strategies, generating words, monitoring and inhibiting the tendency to perseverate), semantic fluency requ ires the additional ability to produce category exemplars. Respondents must possess adequate knowledge of the attributes that define a semantic category. For this reason, semantic fluenc y tasks are considered more sensitive to the breakdown in the structure of semantic knowledge than are letter fluency tasks, which can be completed with phonemic or lexical cues (Newco mbe, 1969; Butters et al., 1987). Thus, while both letter and semantic fluency engage frontally-mediated processe s and are sensitive to frontal damage, semantic fluency is thought to rely on th e overall integrity of the whole left hemisphere 47

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(Jurado et al., 2000). Thus, our finding of greater semantic fluency, but not letter fluency, declines following left-sided DB S may reflect dysfunction in regions of the left hemisphere other than the frontal lobes. Interestingly, our data suggests that patie nts who showed a poorer response to surgery (i.e., showed smaller reductions in motor sy mptom severity after surgery) more often experienced significant declines in verbal fluency. It is possible that electrode misplacement in a subset of patients led to thei r obtaining less motor benefit due to inadequate stimulation in sensorimotor subregions and concomitant incr eased stimulation in a ssociative subregions. Stimulation in these latter regions may lead to cognitive dysfunction via disruption of the associative basal ganglia-thalamocortical circuit. The implication that cognitive deficits are related to a lack of motor improvement is not pr evalent in the literature; however, most studies have merely dismissed this explanation in light of overall cognitive declines that appear in the context of motor improvements in the same group of patients. However, the logic in using group comparisons to address this question is flaw ed in that averaging outcomes might mask associations that exist in individual patients. While this approach tests for a systematic relationship between motor and cognitive changes, it does not examine motor changes in a particular patient experiencing si gnificant decline. One group that attempted to characterize the relationship between motor and non-motor outcome by comparing patients who were stratified based on relatively arbitrary cut-offs failed to identify an association between cognitive decline and poor motor response (Perriol et al., 2006). Ho wever, these authors only assessed patients using a global measure of cognition (DRS-2). Study Limitations The sample used in the present study compri sed a relatively small number of both DBS and control patients. A recent meta-analysis highl ighted how widespread and problematic this 48

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limitation is in the extant literature on postDBS cognitive morbidity (Woods et al., 2006). These authors recommended that future studies s hould aim to include at l east 48 surgical patients in order to demonstrate adequate power and reduce the risk of Type II error, which could lead to an overestimation of the cognitive safety of DBS procedures. The present study attempted to address this limitation by its not relying solely on inferential statistical procedures. Reliable Change Indexes were used in order to capture individual changes that may have been masked by group averaging. Indeed, the findi ng that 45% of DBS patients ev idenced a decline in verbal fluency despite small effect sizes in repeated -measures analyses of variance underscores the importance of increased cons ideration of these issues. Another limitation of the present study is its lack of sample diversity. The generalizability of findings is limited due to the fact that the va st majority of patients (i.e., 37 of 39) were Caucasian. Furthermore, as mentioned above, the l ack of diversity with regard to patients age and baseline cognitive functioning reduces both the generalizability as well as the interpretability of results. Findings would also have been enha nced by the inclusion of more neuropsychological tests. Only five measures were selected in accordance with the specific hypotheses set forth; however, recent studies have iden tified other tests that may be sensitive to post-DBS changes (York et al., 2007). An important limitation of the present study lies in its failure to more fully match DBS and PD control groups. As compared to cont rol patients, DBS patients reported having parkinsonian symptoms for a longer period of ti me and were experiencing more severe motor dysfunction when assessed off medication. These important differences make it impossible to completely rule out the contri bution of the disease process to our findi ng of DBS-specific 49

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cognitive declines. As highlighted in Chapter 1, PD itself is associated wi th particular cognitive impairments, including verbal fluency deficits. A strength of the present study was its inclus ion of a PD control group. While the ideal PD control group would be one that is waitlisted to have DBS surgery, methodological and ethical issues related to the av ailability and recognized efficacy of DBS make such a group difficult to obtain. To date, no cont rolled studies in the extant liter ature have adequately resolved this problem. In many studies, groups were not matched on at least one important disease variable (York et al., 2007; Smed ing et al., 2006) or had very sma ll sample sizes (Moretti et al., 2003; Morrison et al., 2004; Gironell et al., 2003). In the present study, including the variables UPDRS off and disease duration as covariates in the analyses of variance conducted as part of Aim 1 rendered all effects nonsignificant. While no main effects were found for ei ther of these variable s, the power of these analyses was so low as to make it impossibl e to draw conclusions. Correlational analyses identified no significant associations between verbal fluency change and either UPDRS off or disease duration. Finally, there were no significant differenc es between decliners and nondecliners on either of these vari ables. Thus, while the data does not seem to suggest that the identified DBS-specific cognitive ch anges are more related to diseas e duration or severity than to surgery, it is not possible to completely elucidate the relative contributions of these variables. Finally, the present study made no attempt to characterize the real-world significance of the identified deterioration in verb al fluency. It is possi ble that these declines do not significantly impact on patients everyday functio ning or quality of life or that they are considered negligible by patients in the face of motor symptom impr ovement and the resultant enhancement of functional abilities. Current research on the ecological validity of neuropsychological tests 50

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suggests that commonly-used measures possess only a moderate ability to predict everyday functioning (Burgess et al., 1998; Chaytor & Sc hmitter-Edgecomb, 2003). Unfortunately, other researchers interested in non-motor outcomes following DBS surgery for PD have similarly made little effort to address this important issue. However, these declines may point to bona fi de problems that enter some patients lives after undergoing DBS. One study that documented significant worsening on neuropsychological tests qualitatively reported that declines were of concern to patients and that many of these patients stated that they would not have d ecided positively for the surgery had they known beforehand that they would experience them (Smeding et al., 2006). A nother group interpreted worsening patient scores on the Cognition subscale of the Parkinsons Di sease Quality of Life Scale (PDQ-39), a ubiquitous, multifactorial measure of quality of life in PD, combined with non-significant changes on formal neuropsychological tests as sugge sting that these instruments do not fully capture the subjective experience of patients with regard to their cognitive functioning (Ory-Magne et al., 2007 ). Drapier et al. (2005) docu mented a dissociation between changes in physical and other aspects of quality of life scales. In this study of only 27 patients, cognitive items on the PDQ-39 did not show improvement, and the Communication subscale showed a trend to worsen. These findings could reflect the role of verbal fluency impairments in patients real-world functioning. Directions for Future Research Our study provides evidence that DBS surgery is associated with verbal fluency declines in a subset of PD patients. As highlighted above, future research is needed in order to explicate the effects of Deep Brain Stimulation surger y on other cognitive domains, namely, working memory, verbal information processing, and specif ic tasks of executive function. These studies would also be informed by a more systematic inve stigation of the outcome differences in left vs. 51

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right DBS that are revealed by the present st udy. Neuropsychological tasks that may be more sensitive to right-brain dysfunction (e.g. Tower of London) may be appropriate in this regard. The present study was unable to address differe nces in outcome related to surgery site (i.e., GPi vs. STN). This question is important for determining the ideal site for individual patients and should be investigated with larg er samples and randomization protocols. An ongoing NIH-funded study at the University of Flor ida is currently addre ssing the topic of DBS surgery site in relation to outco me and laterality. Also, the pres ent study looked only at unilateral DBS, and additional research is needed to compar e unilateral and bilateral procedures in order to establish whether neuropsychologi cal deficits associated with DBS are incremental. Future studies should also aspire to longer follow-up in order to determ ine the persistence and stability of these deficits. Another important area for future study i nvolves differentiating th e effects of the DBS neurosurgical procedure and high frequency stimulation per s. The former could be partly captured by examining variables such as duratio n of the operation, the number of electrode passes, intra-operative complicatio ns and post-surgical recovery time, while the latter may be characterized by systematically an alyzing the effects of stimulat ion parameters (e.g. pulse width, electrode location, frequency) as well as through well-designe d studies in which the same patients are tested on and off stimulation. Finally, future efforts should be directed towa rd investigating the real-world significance of DBS-related cognitive changes. Since the relationship between neuropsychological tests and everyday functioning is likely moderated by other f actors such as depression levels and social support (Chaytor et al., 2007; O kun et al., 2008), researchers should be cognizant of these 52

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53 variables when drawing conclu sions. Tests of everyday functi oning and patient and caregiver self-report measures could be de veloped to address this question. To conclude, the present study adds to the literature by providing additional support for the existence of verbal fluency declines after DBS surgery. Further, the findings lend support to the view that declines in semantic fluency appe ar more often after surg ery to left subcortical target structures. Also, results suggested that fluency changes ar e not systematically related to the patient characteristics of age, baseline cognitive status or pre-operative depressive symptomatology. Finally, classi fication based on Reliable Change highlights the impact of individual variability in outcome, as results indicated that fluenc y declines reflected significant changes in a subset of DBS patient s that was proportionally larger than that of controls and who may have demonstrated a relatively poor surgical outcome in general.

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65 BIOGRAPHICAL SKETCH Laura Beth Zahodne was born in Royal Oak, Michigan. She received a Bachelor of Science with high distinction in biopsychology and cognitive scie nce from the University of Michigan in Ann Arbor, where she first enga ged in neuropsychological research under the mentorship of Patricia Reuter-Lorenz. She is currently pursuing a doc torate in clinical psychology, with a specialization in neuropsychology, at the Universi ty of Florida. Her research interests include the cognitive and affective concomitants of aging and its related neurological disorders, with a present focus on the non-motor sy mptoms of Parkinsons disease. She currently coordinates two investigat or-initiated clinical trials at the University of Florida Movement Disorders Center that are aimed at treating ap athy and depression in Parkinsons disease and psychosis in cognitively-imp aired Parkinsons patients.