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1.  Stimulation region within the globus pallidus does not affect verbal fluency performance 
Brain stimulation  2012;6(3):248-253.
Background
Subthalamic (STN) and globus pallidus (GP) deep brain stimulation (DBS) have been previously shown to be efficacious in the treatment of selected Parkinson patients with medication resistant motor fluctuations and/or tremor. Deep brain stimulation of the STN has been implicated with more cognitive and mood side effects as compared to GP DBS; however, more studies are needed to better understand possible target differences. Previously, Mikos et al. (1) reported worsening of verbal fluency depending on the stimulation location within the STN region.
Objective/Hypothesis
The current study applied the methods used by Mikos et al. (2011) to a different sample of Parkinson patients who underwent GP DBS. Based on differences in the size and functional somatotopy between structures (GP 412mm3 vs. STN 167mm3), we hypothesized that there would be a less robust relationship between volume of tissue activated, fluency performance, and stimulation contact within the GP compared to what was reported in the STN.
Methods
Patient-specific DBS models were created and the volume of tissue activated within the GP was calculated. These data were correlated with patients’ verbal fluency performance at dorsal, optimal, and ventral stimulation contacts.
Results
In contrast to STN findings, there was no significant relationship between stimulation location and fluency performance in patients who received GP DBS.
Conclusion(s)
These results suggest that fluency may be less sensitive to stimulation location in the globus pallidus and thus there may be more flexibility in terms of DBS programming with GP DBS patients.
doi:10.1016/j.brs.2012.05.011
PMCID: PMC3491090  PMID: 22766102
DBS; Parkinson’s; globus pallidus; verbal fluency; cognition
2.  Influence of Hypertension on Neurocognitive Domains in Nondemented Parkinson's Disease Patients 
Parkinson's Disease  2014;2014:507529.
Objective. Health comorbidities, particularly cardiovascular risk factors, are well known to pose risks for cognitive decline in older adults. To date, little attention has focused on the impact of these comorbidities on Parkinson's disease (PD). This study examined the prevalence and contribution of comorbidities on cognitive status in PD patients, above and beyond the effects of disease severity. Methods. A cross sectional design was used, including neuropsychological data on 341 PD patients without severe cognitive decline. Comorbidity data were collected via medical chart review. Data were analyzed using a series of multiple hierarchical regressions, controlling for PD-related disease variables. Results. Overall sample characteristics are 69% male, disease duration 9.7 years, Unified Parkinson's Disease Rating Scale 26.4, and age 64.7 years. Hypercholesterolemia (41.6%), hypertension (38.1%), and hypotension (30.2%) were the most reported comorbidities. The presence of hypertension significantly contributed to domains of executive function and verbal memory. The cooccurrence of orthostatic hypotension moderated the relationship between hypertension and executive function. Conclusions. This study on a large cohort of PD patients provides evidence for a detrimental influence of health comorbidities, particularly hypertension, on cognitive domains that have traditionally been conceptualized as being frontally and/or temporally mediated.
doi:10.1155/2014/507529
PMCID: PMC3920751  PMID: 24587937
3.  DBS Candidates That Fall Short on a Levodopa Challenge Test 
The neurologist  2011;17(5):263-268.
Introduction
Candidacy for deep brain stimulation (DBS) in Parkinson disease (PD) is typically assessed by the preoperative motor response to levodopa along with an interdisciplinary evaluation. However, recent cases treated at our institution have achieved good outcomes with DBS despite a sub-30% improvement in motor scores. The aim of this study was to examine the outcomes of DBS in a subset of patients who failed to reach the 30% motor improvement threshold.
Methods
A review of all DBS patients treated at the University of Florida Movement Disorders Center between 2002 and 2009 was performed utilizing a DBS database. All patients with sub-30% improvement in Unified Parkinson Disease Rating Scale Part III after dopaminergic medication administration were included.
Results
Nine patients were identified; DBS was performed for severe dyskinesia (n = 5), “on/off motor” fluctuations (n = 1) and medication-refractory tremor (n = 3). The target symptoms were improved in all patients. Postoperatively, scores on the Unified Parkinson Disease Rating Scale Part II and III and subscores on Parkinson disease questionnaire-39 improved (P < 0.05).
Conclusions
Although motor response to levodopa remains the primary selection criteria for DBS candidacy in Parkinson disease, patients who do not meet the 30% threshold and have disabling symptoms may still benefit from DBS. Select patients with severe dyskinesia, “on/off” motor fluctuations, and/or medication-refractory tremor may experience significant benefits from DBS and should be considered on a case by case basis through an interdisciplinary team evaluation.
doi:10.1097/NRL.0b013e31822d1069
PMCID: PMC3789884  PMID: 21881468
deep brain stimulation; Parkinson disease; levodopa challenge test; dyskinesia; on-off motor fluctuations; tremor; quality of life
4.  Are Selective Serotonin Reuptake Inhibitors Associated With Greater Apathy in Parkinson’s Disease? 
Apathy is a common neuropsychiatric feature of Parkinson’s disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinson’s patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD.
doi:10.1176/appi.neuropsych.11090210
PMCID: PMC3759813  PMID: 23037646
5.  Components of Depression in Parkinson Disease 
Depression is a clinically heterogeneous disorder common in Parkinson disease (PD). The goal of this study was to characterize PD depression in terms of components, including negative affect, apathy, and anhedonia. Ninety-five, nondemented individuals with idiopathic PD underwent a diagnostic interview and psychological battery. Twenty-seven patients (28%) met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition [DSM-IV]) criteria for a current depressive episode. The best-fitting confirmatory factor analysis model had 3 factors (negative affect, apathy, and anhedonia). Apathy loaded most strongly onto a second-order factor representing global psychological disturbance. All factors are uniquely associated with depression status. Negative affect exhibited the strongest relationship. Psychological disturbance in PD is heterogeneous and can produce symptoms of apathy, anhedonia, and negative affect. Apathy appears to be the core neuropsychiatric feature of PD, whereas negative affect (eg, dysphoria) seems to be most pathognomonic of depression. Future studies should examine the specific neural correlates and treatment response patterns unique to these 3 components.
doi:10.1177/0891988712455236
PMCID: PMC3490054  PMID: 22859701
apathy; anhedonia; negative affect; dysphoria; anxiety; confirmatory factor analysis
6.  Emotional state affects gait initiation in individuals with Parkinson’s disease 
The purpose of the present study was to determine the impact of manipulating emotional state on gait initiation in persons with Parkinson’s disease (PD) and healthy older adults. Following the presentation of pictures that are known to elicit specific emotional responses, participants initiated gait and continued to walk for several steps at their normal pace. Reaction time, the displacement and velocity of the center of pressure (COP) trajectory during the preparatory postural adjustments, and length and velocity of the first two steps were measured. Analysis of the gait initiation measures revealed that exposure to (1) threatening pictures, relative to all other pictures, speeded the initiation of gait for PD patients and healthy older adults; (2) approach-oriented emotional pictures (erotic and happy people), relative to withdrawal-oriented pictures, facilitated the anticipatory postural adjustments of gait initiation for PD patients and healthy older adults, as evidenced by greater displacement and velocity of the COP movement; and (3) emotional pictures modulated gait initiation parameters in PD patients to the same degree as in healthy older adults. Collectively, these findings hold significant implications for understanding the circuitry underlying the manner by which emotions modulate movement and for the development of emotion-based interventions designed to maximize improvements in gait initiation for individuals with PD.
doi:10.3758/s13415-011-0071-9
PMCID: PMC3618281  PMID: 22194236
Emotion; Motor; Basal ganglia
7.  Do Stable Patients With a Premorbid Depression History Have a Worse Outcome After Deep Brain Stimulation for Parkinson Disease? 
Neurosurgery  2011;69(2):357-361.
BACKGROUND
Deep brain stimulation (DBS) has been associated with mood sequelae in a subset of patients operated on in either the subthalamic nucleus or the globus pallidus internus for the treatment of Parkinson disease.
OBJECTIVE
To compare mood and motor outcomes in those with and without a presurgical history of depression.
METHODS
Unilateral subthalamic nucleus or unilateral globus pallidus internus DBS patients followed up for a minimum of 6 months were included. All patients underwent a comprehensive outpatient psychiatric evaluation by a board-certified psychiatrist. Psychiatric diagnoses were based on Diagnostic and Statistical Manual, fourth edition, text revision, nomenclature (American Psychiatric Association, 2000). Motor and mood outcomes were compared.
RESULTS
A total of 110 patients were included. There were no significant differences in baseline variables between the 2 groups. Those with a preoperative history of depression had significantly higher Beck Depression Inventory scores than the nondepression group after DBS (8.97 ± 7.55 vs 5.92 ± 5.71; P = .04). Patients with a depression history had less improvement (11.6%) in pre/post-DBS change when Unified Parkinson Disease Rating Scale motor scores were compared (P = .03) after adjustment for stimulation site and baseline demographic and clinical variables. Patients with a higher levodopa equivalent dose had a worse clinical motor outcome.
CONCLUSION
Patients with a preoperative depression history had higher Beck Depression Inventory scores after DBS and significantly less (albeit small) improvement in pre/post-DBS change in Unified Parkinson Disease Rating Scale motor scores than patients without a history of depression.
doi:10.1227/NEU.0b013e3182160456
PMCID: PMC3593636  PMID: 21415789
DBS; Deep brain stimulation; Depression; DSM; Outcomes; Psychiatry; Psychology
8.  Mood and Motor Trajectories in Parkinson's Disease: Multivariate Latent Growth Curve Modeling 
Neuropsychology  2011;26(1):71-80.
Objective
Apathy is a common feature of Parkinson's disease (PD) that can manifest independently of depression, but little is known about its natural progression in medically-managed patients. The present study sought to characterize and compare trajectories of apathy, depression, and motor symptoms in PD over 18 months.
Method
Data from a sample of 186 PD patients (mean disease duration of 8.2 years) followed by the University of Florida Movement Disorders Center were obtained from a clinical research database. Scores on the Unified Parkinson's Disease Rating Scale (motor portion), Apathy Scale, and Beck Depression Inventory at three time-points (baseline, 6 months, 18 months) were analyzed in a structural equation modeling framework.
Results
A multivariate growth model controlling for age, sex, education, and disease duration identified linear worsening of both apathy (slope estimate = 0.73; p <.001) and motor symptoms (slope estimate = 1.51; p <.001), and quadratic changes in depression (slope estimate = 1.18; p = .07). All symptoms were positively correlated. Higher education was associated with lower apathy, depression, and motor severity. Advanced age was associated with greater motor and apathy severity. Female sex and longer disease duration were associated with attenuated motor worsening. Antidepressant use was associated only with depression scores.
Conclusions
These longitudinal results support the differentiation of apathy and depression in PD. Like motor progression, apathy progression may be linked at least partially to dopaminergic neurodegeneration. Empirically-supported treatments for apathy in PD are needed.
doi:10.1037/a0025119
PMCID: PMC3296901  PMID: 22142359
Apathy; depression; antidepressants; structural equation modeling; neurodegeneration
9.  The Prevalence of Fatigue Following Deep Brain Stimulation Surgery in Parkinson's Disease and Association with Quality of Life 
Parkinson's Disease  2012;2012:769506.
Fatigue is a common and disabling nonmotor symptom seen in Parkinson's disease (PD). While deep brain stimulation surgery (DBS) improves motor symptoms, it has also been associated with non-motor side effects. To date no study has utilized standardized instruments to evaluate fatigue following DBS surgery. Our objective was to determine the prevalence of fatigue following DBS surgery in PD its impact on quality of life and explore predictive factors. We recruited 44 PD subjects. At least one year following DBS placement, we administered the Fatigue Severity Scale (FSS), the Parkinson's Disease Questionnaire (PDQ-39), the Beck Depression Inventory, the Beck Anxiety Inventory, the UPDRS, and a neuropsychological battery. Fifty-eight percent of subjects had moderate to severe fatigue. Fatigue was significantly associated with quality of life, depression, and anxiety. Depression preoperatively was the only predictive factor of fatigue. Fatigue is common following DBS surgery and significantly impacts quality of life.
doi:10.1155/2012/769506
PMCID: PMC3359731  PMID: 22666631
10.  Clock Drawing in the Montreal Cognitive Assessment: Recommendations for Dementia Assessment 
Background
Clock drawing is part of the Montreal Cognitive Assessment (MoCA) test but may have administration and scoring limitations. We assessed (1) the reliability of the MoCA clock criteria relative to a published error scoring approach, (2) whether command-only administration could distinguish dementia from cognitively intact individuals and (3) the value of adding a clock copy condition to the MoCA.
Methods
Three novice raters and clocks from dementia and control participants were used to assess the 3 aims.
Results
MoCA interrater and intrarater reliability were low (i.e. intraclass correlation coefficient = 0.12–0.31) and required repeat training. Clocks drawn to command classified dementia at chance. Inclusion of a copy condition demonstrated expected dementia subgroup patterns.
Conclusion
Reliable clock scoring with MoCA criteria requires practice. Supplementing a clock copy to the standard MoCA test (takes <1 min) will improve dementia assessment.
doi:10.1159/000324639
PMCID: PMC3065510  PMID: 21389719
Montreal Cognitive Assessment scoring, rater reliability; Parkinson disease with dementia; Alzheimer disease; Vascular dementia; Cognition
11.  Apathy and Depression: Separate Factors in Parkinson’s Disease 
The objective of this study was to test the hypothesis that apathy and depression are dissociable in Parkinson disease (PD) by conducting a confirmatory factor analysis (CFA) of items from two commonly used mood scales. A total of 161 non-demented PD patients (age = 64.1; ± 8.4 years) were administered the Apathy Scale and the Beck Depression Inventory-II. Items were hypothesized to load onto four factors: (1) an apathy factor representing loss of motivation, (2) dysphoric mood factor representing sadness and negativity, (3) loss of interest/pleasure factor representing the features common to both apathy and depression, and (4) a somatic factor representing bodily complaints. Results indicated a good fit for the overall CFA model, χ2 (128, N = 146) = 194.9; p<.01. RMSEA was .060 (p = .16). The four-factor model was significantly better than all alternative nested models at p < .001, including an overarching single factor model, representing “depression.” Results support the concept that apathy and depression are discrete constructs. We suggest a “factor based” scoring of the Apathy Scale and Beck Depression Inventory-II that disentangles symptoms related to apathy, depression, overlapping symptoms, and somatic complaints. Such scoring may be important in providing useful information regarding differential treatment options.
doi:10.1017/S1355617711001068
PMCID: PMC3302577  PMID: 22040900
Parkinson’s disease; Apathy; Depression; Confirmatory factor analysis; Apathy Scale
12.  MEASUREMENT OF PATIENT CENTERED OUTCOMES IN PARKINSON’S DISEASE: WHAT DO PATIENTS REALLY WANT FROM THEIR TREATMENT? 
Background
Parkinson’s disease (PD) impacts several domains of functioning, some of which may be neglected when designing treatment or evaluating outcome using current clinical standards. We therefore argue that taking the patients’ perspectives of their condition may allow for a more in-depth assessment of patient goals and subsequent tailoring of care.
Methods
One hundred and forty-eight patients with idiopathic PD completed a modified version of the Patient Centered Outcomes Questionnaire (PCOQ-PD), to evaluate treatment success and expectations from the patient’s perspective across 10 motor and non-motor functional domains. We also examined patient subgroups based on importance of improvement in various domains.
Results
Patients’ ratings suggested there was substantial variation in functional interference that was generally unrelated to demographic variables. On average, across all domains, patients indicated a 50.32% reduction in symptoms would be successful (range= 40.63% to 58.23%), regardless of treatment experience. Change scores between patients’ usual levels of symptom interference and their treatment success levels suggested a greater degree of change was desired in motor versus non-motor domains (p<.05). Finally, cluster analyses revealed two patient subgroups based on overall importance of improvement (High vs. Low Importance Endorsement). Notably, the two groups differed in self-reported usual symptom levels despite having similar clinical severity.
Conclusions
We empirically examined treatment success from the PD patient’s view as opposed to clinician judgment alone, thereby broadening the set of criteria by which to evaluate outcome. Findings from this exploratory study may guide future treatment emphases and guide patient-provider communication via clarification of patient-defined success.
doi:10.1016/j.parkreldis.2010.09.005
PMCID: PMC3034811  PMID: 20952243
Parkinson’s disease; patient-centered; treatment outcome; success criteria; improvement importance
13.  Smile and Laughter Induction and Intraoperative Predictors of Response to Deep Brain Stimulation for Obsessive Compulsive Disorder 
NeuroImage  2010;54S1:S247-S255.
We recently treated six patients for OCD utilizing deep brain stimulation (DBS) of the anterior limb of the internal capsule and the nucleus accumbens region (ALIC-NA). We individually tested leads via a scripted intraoperative protocol designed to determine DBS-induced side effects and mood changes. We previously published qualitative data regarding our observations of induced emotional behaviors in our first five subjects. We have now studied these same behaviors in the full cohort of six patients over two years of follow-up and have examined the relationship of these behaviors to intraoperative mood changes and postoperative clinical outcomes.
Five patients experienced at least one smile response during testing. At higher voltages of stimulation some of these smiles progressed to natural laughter. Smiles and laughter were associated with mood elevation. At stimulation locations at which smiles were observed, voltage and mood were significantly correlated (p=0.0004 for right brain and p<0.0001 for left brain). In contrast, at contacts where smiles were not observed, mood was negatively correlated with voltage (p=0.0591 for right brain and p=0.0086 for left). Smile and laughter-inducing sites were located relatively medial, posterior, and deep in the ALIC-NA.
The presence of stimulation induced laughter predicted improvement in OCD symptoms at two years. The higher the percentage of laugh conditions experienced in an individual patient, the greater the reduction in YBOCS (24 months, p=0.034). Other correlations between clinical outcomes and percent of smile/laugh conditions were not significant. These stimulation-induced behaviors were less frequently observed with one and two-month postoperative test stimulation and were not observed at subsequent test stimulation sessions.
Intraoperative stimulation-induced laughter may predict long-term OCD response to DBS. Identifying other potential response predictors for OCD will become increasingly important as more patients are implanted with DBS devices. A larger study is needed to better delineate the relationship between induced intraoperative and postoperative emotional behavior and clinical outcome in patients treated with DBS therapy.
doi:10.1016/j.neuroimage.2010.03.009
PMCID: PMC2907450  PMID: 20226259
14.  Do Patient's Get Angrier Following STN, GPi, and Thalamic Deep Brain Stimulation 
NeuroImage  2010;54S1:S227-S232.
Objective
The objective of the study was to examine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), the globus pallidus internus (GPi), and/or the ventralis intermedius thalamic nucleus (Vim) was associated with making patients angrier pre to post-surgical intervention.
Background
Secondary outcome analysis of the NIH COMPARE Parkinson's Disease DBS trial revealed that participants were angrier and had more mood and cognitive side effects following DBS. Additionally blinded on/off analysis did not change anger scores. The sample size was small but suggested that STN DBS may have been worse than GPi in provoking anger. We endeavored to examine this question utilizing a larger dataset (the UF INFORM database), and also we included a third surgical target (Vim) which has been utilized for a different disease, essential tremor.
Methods
Consecutive patients from the University of Florida Movement Disorders Center who were implanted with unilateral DBS for Parkinson's Disease (STN or GPi) or Essential Tremor (Vim) were included. Patients originally implanted at outside institutions were excluded. Pre- and 4-6 month postoperative Visual Analog Mood Scales (VAMS) scores for all three groups were compared; additionally, pre- and 1-3 month scores were compared for STN and GPi patients. A linear regression model was utilized to analyze the relationship between the VAMS anger score and the independent variables of age, years with symptoms, Mini-mental status examination (MMSE) score, handedness, ethnicity, gender, side of surgery, target of surgery, baseline Dementia Rating Scale (DRS) total score, baseline Beck Depression Index (BDI) score, micro and macro electrode passes, and years of education. Levodopa equivalent dosages and dopamine agonist use was analyzed for a potential impact on anger scores.
Results
A total of 322 unilateral DBS procedures were analyzed, with STN (n= 195), Vim (n=71), and GPi (n=56) making up the cohort. An ANOVA analysis was used to detect significant differences among the three targets in the changes pre- to post-operatively. Similar to the COMPARE dataset, at four months the only subscore of VAMS to reveal a significant difference between the three targets was the angry subscore, with GPi revealing a mean (standard) change of 2.38 (9.53), STN 4.82 (14.52), and Vim -1.17 (11.51) (p-value = 0.012). At 1-3 months postop, both STN and GPi groups were significantly angrier (p= 0.004), but there was no significant difference between the two groups. However, GPi patients were significantly more confused as compared to STN patients (p= 0.016). The linear regression model which sought independent explanatory variables revealed a relationship between the VAMS anger score and the surgical target and the disease duration. The mean changes for STN and GPi DBS pre- to post were 11.67 (p= 0.001) and 8.21 (p= 0.022) units more than those with Vim, respectively. For every year added of disease duration, the VAMS anger score increased by 0.24 (p= 0.022). For the GPi and STN groups, number of microelectrode passes was significantly associated with angry score changes (p= 0.014), with the anger score increasing 2.29 units per microelectrode pass. Independent variables not associated with the VAMS anger score included the surgery side, handedness, gender, ethnicity, education, age at surgery, MMSE, DRS, and BDI scores. Although the STN group significantly decreased in LED when compared to GPi, there was no relationship to anger scores. Similarly dopamine agonist use was not different between STN and GPi groups, and did not correlate with the VAMS anger score changes.
Conclusions
STN and GPi DBS for Parkinson's disease were associated with significantly higher anger scores pre- to post-DBS as compared to Vim for essential tremor. Anger score changes in STN and GPi patients seem to be associated with microelectrode passes, suggesting it may be a lesional effect. PD patients with longer disease durations may be particularly susceptible, and this should be kept in mind when discussing the potential of DBS surgery for an individual patient. Essential tremor patients who on average have much longer disease durations did not get angrier. The changes in anger scores were not related to LED change or dopamine agonist use. Whether the induction of anger is disease specific or target specific is not currently known, however our data would suggest that PD patients implanted in STN or GPi are at a potential risk. Finally, on closer inspection of the COMPARE DBS data VAMS anger scores did not change on or off DBS, suggesting that anger changes may be more a lesional effect rather than a stimulation induced one(Okun et al., 2009).
doi:10.1016/j.neuroimage.2010.09.077
PMCID: PMC3014411  PMID: 20932923
Subthalamic nucleus; globus pallidus; ventralis intermedius nucleus; deep brain stimulation; anger; Parkinson's disease; tremor
15.  Challenges and opportunities for characterizing cognitive aging across species 
The gradual decline of cognitive ability with age, even in the absence of overt brain disease, is a growing problem. Although cognitive aging is a common and feared accompaniment of the aging process, its underlying mechanisms are not well understood and there are no highly effective means to prevent it. Additional research on cognitive aging is sorely needed, and methods that enable ready translation between human subjects and animal models stand to provide the most benefit. Here and in the six companion pieces in this special issue, we discuss a variety of challenges and opportunities for studying cognitive aging across species. We identify tests of associative memory, recognition memory, spatial and contextual memory, and working memory and executive function as cognitive domains that are age-sensitive and amenable to testing with parallel means in both humans and animal models. We summarize some of the important challenges in using animal models to test cognition. We describe unique opportunities to study cognitive aging in human subjects, such as those provided by recent large-scale initiatives to characterize cognition in large groups of subjects across the lifespan. Finally, we highlight some of the challenges of studying cognitive aging in human subjects.
doi:10.3389/fnagi.2012.00006
PMCID: PMC3439634  PMID: 22988434
cognition; aging; memory; human; animal models
16.  Characterizing cognitive aging in humans with links to animal models 
With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline.
doi:10.3389/fnagi.2012.00021
PMCID: PMC3439638  PMID: 22988439
aging; cognition; memory; executive function; processing speed; visuospatial function; language
17.  Binge Eating in Parkinson Disease: Prevalence, Correlates, and the Contribution of Deep Brain Stimulation 
Of 96 Parkinson’s disease (PD) patients at the University of Florida Movement Disorders Center, one (1%) met diagnostic criteria for binge eating disorder (BED). Eight (8.3%) exhibited subthreshold BED. Psychometric criteria classified problem gambling in 17.8%, hoarding in 8.3%, buying in 11.5%, hypersexuality in 1.0%, and mania in 1.0% of patients. More overeaters met psychometric criteria for at least one additional impulse control disorder (67% vs. 29%). No more overeaters than non-overeaters were taking a dopamine agonist (44% vs. 41%). More overeaters had a history of subthalamic DBS (44% vs. 14%). History of DBS was the only independent predictor of overeating.
doi:10.1176/appi.neuropsych.23.1.56
PMCID: PMC3075093  PMID: 21304139
Parkinson’s disease; binge eating; impulse control disorders
18.  The Case for Testing Memory with Both Stories and Word Lists Prior to DBS Surgery for Parkinson’s Disease 
The Clinical neuropsychologist  2011;25(3):348-358.
Patients seeking deep brain stimulation (DBS) surgery for Parkinson’s disease (PD) typically undergo neuropsychological assessment to determine candidacy for surgery, with poor memory performance interpreted as a contraindication. Patients with PD may exhibit worse memory for word lists than for stories due to the lack of inherent organization in a list of unrelated words. Unfortunately, word list and story tasks are typically developed from different normative datasets, and the existence of a memory performance discrepancy in PD has been challenged. We compared recall of stories and word lists in 35 non-demented PD candidates for DBS. We administered commonly-used neuropsychological measures of word list and story memory (Hopkins Verbal Learning Test, Logical Memory), along with a second word list task that was co-normed with the story task. Age-corrected scores were higher for the story task than for both word list tasks. Compared to story recall, word list recall correlated more consistently with motor severity and composite measures of processing speed, working memory, and executive functioning. These results support the classic view of fronto-subcortical contributions to memory in PD and suggest that executive deficits may influence word list recall more than story recall. We recommend a multi-componential memory battery in the neuropsychological assessment of DBS candidates to characterize both mesial temporal and frontal-executive memory processes. One should not rely solely on a word list task because patients exhibiting poor memory for word lists may perform better with stories and therefore deserve an interdisciplinary discussion for DBS surgery.
doi:10.1080/13854046.2011.562869
PMCID: PMC3077807  PMID: 21491347
19.  Pre- and Post- GPi DBS Neuropsychological Profiles in a Case of X-Linked Dystonia-Parkinsonism 
The Clinical neuropsychologist  2011;25(1):141-159.
We present the pre to post bilateral globus pallidus interna (GPi) deep brain stimulation neuropsychological profiles of a 69-year-old patient with a 12-year history of X-linked dystonia-Parkinsonism (XDP). Pre-operative cognitive function was impaired in almost all domains and this impaired performance was not dependent on his medications. Following DBS, changes in neuropsychological functioning were examined using Reliable Change Indices and standardized z-score comparisons. Results showed reductions in processing speed in the context of stable performance in language and visuospatial domains. Postoperative improvements occurred on a cognitive screening measure, verbal memory, and a test of problem-solving skills. This is the first report on an individual with XDP who was cognitively impaired, but had good outcome following GPi bilateral stimulation to treat debilitating motor symptoms. The possible mechanisms for his stable cognitive performance include the target of his DBS, reduced medication dosage, and improvement in dystonia that may in turn have reduced patient’s pain.
doi:10.1080/13854046.2010.532812
PMCID: PMC3070298  PMID: 21253963
XDP; Lubag; X-linked dystonia-Parkinsonism; Neuropsychological assessment; Dystonia; Parkinson disease
20.  COGNITIVE DECLINES AFTER UNILATERAL DEEP BRAIN STIMULATION SURGERY IN PARKINSON’S DISEASE: A CONTROLLED STUDY USING RELIABLE CHANGE, PART II 
The Clinical neuropsychologist  2009;24(2):235-245.
Deep brain stimulation (DBS) surgery, an effective treatment for medication-refractory Parkinson’s disease (PD), may also lead to selective cognitive declines. In this continuation of a report by Zahodne et al. (2009), we compare cognitive performance of 24 PD patients who underwent unilateral implantation of the globus pallidus internal segment (GPi) or subthalamic nucleus (STN) to that of 19 PD controls. We used group statistical comparisons as well as Reliable Change Indexes (RCIs) to examine performance on measures of memory, processing speed, executive function, and visuospatial perception at baseline and 16 months after surgery. Significant between-group differences were noted on a psychomotor processing speed task. However, a significantly higher proportion of DBS patients than controls demonstrated reliable individual decline on a word list recall task (HVLT-R) and on several processing speed tests. Reliable improvements were noted on tests of visuospatial functioning. There was variability in individual outcome on executive functioning tests, with a small proportion of DBS patients demonstrating reliable decline and some demonstrating reliable improvement. Use of Reliable Change highlights the occurrence of individual variability, revealing declines and improvements in a small proportion of unilateral DBS patients that were not evident upon group comparison. These findings must be interpreted in light of group-level differences between the PD control and DBS patients on demographic and disease-related factors.
doi:10.1080/13854040903277297
PMCID: PMC3045858  PMID: 19953428
Parkinson’s disease; Deep brain stimulation; Reliable Change
21.  Examination of the Lille Apathy Rating Scale in Parkinson Disease 
Apathy is a unique, multidimensional syndrome commonly encountered in patients with Parkinson disease (PD). Recently, the Lille Apathy Rating Scale (LARS), a semistructured interview yielding a global score, and composite subscores for different domains of apathy (i.e., cognitive, behavioral, affective, self awareness), was developed and given to a sample of patients with PD in France. This study is the first outside of its original developers to examine the English language version of the LARS in PD. We found the LARS to be a coherent instrument demonstrating both convergent and divergent validity, as compared to the Apathy Scale (AS) and Beck Depression Inventory (BDI-II). Using a receiver operating characteristic (ROC) analysis comparing the LARS to the AS, a validated and widely-used measure, we identified a cut-off score (sensitivity = 64%, specificity = 92%, PPV = 88%, NPV = 75%) that was higher than that proposed by the original authors, who derived their cutoff by comparing LARS global scores to clinical judgments of apathy. Although the present study does not compare the LARS to a diagnostic gold standard or promote its utility for diagnosing apathy, it provides further support for the LARS as a promising instrument to examine apathy in PD.
doi:10.1002/mds.22441
PMCID: PMC3045860  PMID: 19133658
Parkinson’s disease; apathy; rating scales
22.  Greater improvement in quality of life following unilateral deep brain stimulation surgery in the globus pallidus as compared to the subthalamic nucleus 
Journal of neurology  2009;256(8):1321-1329.
While deep brain stimulation (DBS) surgery is a well-accepted treatment for Parkinson disease (PD) that improves overall quality of life (QoL), its effects across different domains of QoL are unclear. The study reported here directly compared the effects of unilateral DBS in subthalamic nucleus (STN) or globus pallidus (GPi) on QoL in 42 non-demented patients with medication-refractory PD. Patients were enrolled in the COMPARE trial, a randomized clinical trial of cognitive and mood effects of STN versus GPi DBS conducted at the University of Florida Movement Disorders Center. Patients underwent motor, mood, verbal fluency and QoL (Parkinson disease questionnaire: PDQ-39) measures before and 6 months following surgery. Groups experienced motor and mood improvements that did not differ by target. Patients with STN DBS evidenced a slight decrement on letter fluency. On average, all patients endorsed better overall QoL after surgery. However, despite similar motor and mood improvements, GPi patients improved more than STN patients (38 vs. 14%, respectively; P = 0.03). Patients reported better QoL on subscales of mobility, activities of daily living (ADLs), emotional well-being, stigma, cognition and discomfort, but not on those of social support and communication. Improvements on the mobility, ADLs, stigma and social support subscales were greater amongst GPi patients. In regression analyses, only depression changes independently predicted changes in overall QoL as well as emotional well-being and social support changes. Within the STN group only, declining category fluency scores correlated with poorer QoL on the communication subscale. Unilateral DBS in both STN and GPi improved QoL overall and in disparate domains 6 months after surgery. Patients receiving GPi DBS reported greater improvements that cannot be explained by differential mood or motor effects; however, verbal fluency changes may have partially contributed to lesser QoL improvements amongst STN patients.
doi:10.1007/s00415-009-5121-7
PMCID: PMC3045861  PMID: 19363633
Cognition; Deep brain stimulation; Depression; Parkinson disease; Quality of life
23.  COGNITIVE DECLINES ONE YEAR AFTER UNILATERAL DEEP BRAIN STIMULATION SURGERY IN PARKINSON’S DISEASE: A CONTROLLED STUDY USING RELIABLE CHANGE 
The Clinical neuropsychologist  2008;23(3):385-405.
Conflicting research suggests that deep brain stimulation surgery, an effective treatment for medication-refractory Parkinson’s disease (PD), may lead to selective cognitive declines. We compared cognitive performance of 22 PD patients who underwent unilateral DBS to the GPi or STN to that of 19 PD controls at baseline and 12 months. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (letter fluency, semantic fluency, and Digit Span Backward) but not on other tasks (Vocabulary, Boston Naming Test), and that a greater proportion of DBS patients would fall below Reliable Change Indexes (RCIs). Compared to controls, DBS patients declined only on the fluency tasks. Analyses classified 50% of DBS patients as decliners, compared to 11% of controls. Decliners experienced less motor improvement than non-decliners. The present study adds to the literature through its hypothesis-driven method of task selection, inclusion of a disease control group, longer-term follow-up and use of Reliable Change. Our findings provide evidence that unilateral DBS surgery is associated with verbal fluency declines and indicate that while these changes may not be systematically related to age, cognitive or depression status at baseline, semantic fluency declines may be more common after left-sided surgery. Finally, use of Reliable Change highlights the impact of individual variability and indicates that fluency declines likely reflect significant changes in a subset of patients who demonstrate a poorer surgical outcome overall.
doi:10.1080/13854040802360582
PMCID: PMC3045862  PMID: 18821180
Parkinson’s disease; Deep brain stimulation; Reliable Change
24.  How Cautious Should We Be When Assessing Apathy with the Unified Parkinson’s Disease Rating Scale? 
Current practice often assesses apathy with a single item from the Unified Parkinson’s Disease Rating Scale (UPDRS, item 4). Yet, the relationship between the UPDRS item 4 and the validated Apathy Scale (AS) is unknown. The purpose of this study was to evaluate the operating characteristics of UPDRS item 4 in relation to the AS. Three hundred and one patients with PD were administered the AS and the UPDRS. We compared the UPDRS item 4 to the standard AS classification of ≥14 as apathetic. A receiver operating characteristics (ROC) curve was obtained, and sensitivity, specificity, positive, and negative predictive power were calculated. The ROC curve showed area under the curve as 0.75. A cut-off of 1 had good sensitivity (81%) but poor specificity (53%; high false positive rate). A cut-off point of 2 had acceptable specificity (87%) but poor sensitivity (52%, high false negative rate). Continuing to increasing the cut-off point (e.g., 3, 4) continues to increase specificity at the expense of dramatically reducing sensitivity. These findings suggest the use of caution when screening for apathy with item 4 due to its poor sensitivity in relation to the AS.
doi:10.1002/mds.22437
PMCID: PMC3045863  PMID: 19185011
Parkinson’s disease; apathy; mood disorders; UPDRS; assessment
25.  Cognition and Mood in Parkinson Disease in STN versus GPi DBS: The COMPARE Trial 
Annals of neurology  2009;65(5):586-595.
Objective
There is a paucity of level-one evidence comparing STN and GPi DBS. Our aim in this prospective blinded randomized trial was to compare the cognitive and mood effects of unilateral subthalamic nucleus (STN) vs. unilateral globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with Parkinson disease (PD).
Methods
Fifty-two subjects with moderate-to-advanced PD were randomized to either unilateral STN or GPi DBS. Right or alternatively left sided stimulation was chosen to address the side of the body with the most bothersome symptoms. The co-primary outcome measures were the change in the 8 subscales of the Visual Analog Mood Scale (VAMS), and the change in the 2 versions of verbal fluency (i.e. semantic and letter), at 7 months post-DBS in the optimal setting compared to the pre-DBS state. In addition, at 7 months post-DBS, after subjects underwent initial evaluation off medications and on optimized DBS therapy, they were tested in four randomized and counterbalanced conditions (optimal DBS, ventral DBS, dorsal DBS, and off DBS) while remaining off medication. Secondary outcome measures then compared the differences in the VAMS items and verbal fluency subscales within the 4 DBS conditions at 7 months, and the change in the VAMS items and verbal fluency subscales from the pre-DBS state to the other 3 DBS conditions (ventral, dorsal and off ) at 7 months.
Results
Forty-five subjects (23 GPi and 22 STN) completed the protocol. The study revealed no significant difference between STN and GPi DBS in the change of co-primary mood and cognitive outcomes from pre- to post-DBS in the optimal setting (Hotelling's T2 test: p=0.16 and 0.08 respectively). When comparing the 4 DBS conditions at 7 months, subjects in both targets were less “happy”, less “energetic” and more “confused” when stimulated ventrally to the optimal stimulation site. When comparing the other 3 DBS conditions (ventral, dorsal and off DBS) to the pre-DBS state, the STN group showed a larger deterioration of letter verbal fluency scores than the GPi group, especially in the off DBS state. A 12-point mean improvement in the UPDRS motor subscale was seen post DBS, but there was no significant difference between targets.
Interpretations
There were no significant differences in in the co-primary outcome measures of mood and cognition between STN and GPi in the optimal DBS state.. However, adverse mood effects were noted when stimulating ventrally to the optimal site in both targets. Furthermore, a worsening for letter verbal fluency was noted in the 3 non-optimal post-DBS states in the STN target only. The persistence of deterioration in verbal fluency in the off DBS state at 7 months is, suggestive of a surgical rather than a stimulation-induced effect at the STN target. STN and GPi DBS resulted in similar motor improvement.
doi:10.1002/ana.21596
PMCID: PMC2692580  PMID: 19288469
GPi; STN; DBS; Mood; Cognition; Side Effects; verbal fluency; motor; UPDRS

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