Journal of Parkinson’s Disease xx (20xx) x–xx 1

DOI 10.3233/JPD-140448
IOS Press

1 Neuropsychological Effects of Deep Brain

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2 Stimulation in Subjects with Early Stage
3 Parkinson’s Disease in a Randomized

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4 Clinical Trial
5

6
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Michael G. Tramontanaa , Anna L. Molinarib , Peter E. Konradc , Thomas L. Davisb , Scott A. Wylieb ,
Joseph S. Neimatc , Alexandra T. Mayd , Fenna T. Phibbsb , Peter Hederab , Chandler E. Gille ,
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7 Ronald M. Salomona , Lily Wangf , Yanna Songf and David Charlesb,∗
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a Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
9
b Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
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c Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, USA

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d School of Medicine, Vanderbilt University, Nashville, TN, USA
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e Department of Neurology, Loyola University Chicago, Chicago, IL, USA

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f Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
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14 Abstract.
15 Background: Deep brain stimulation (DBS) is an effective treatment for patients with advanced Parkinson’s disease (PD) and
16 motor symptom complications. Recently, attention has been focused on whether offering DBS earlier in the course of PD is
beneficial.
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17

18 Objective: The purpose of this study was to determine the effects of DBS on neuropsychological functioning in subjects with
19 early stage PD.
20 Methods: Thirty subjects with early PD (Hoehn & Yahr Stage II off medication) were randomized to optimal drug therapy (ODT)
21 (n = 15) or bilateral subthalamic nucleus (STN) DBS+ODT (n = 15) after completing an expanded informed consent process
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22 specially designed for the study and administered by a medical ethicist and the study team. Comprehensive neuropsychological
23 testing was completed in the treatment-withdrawn state at baseline and at 12 month and 24 month follow-ups.
24 Results: Two serious adverse events occurred in the DBS+ODT group. One subject experienced a stroke and another developed
25 infected hardware that contributed to specific declines in cognitive functioning. However, compared to the ODT group, the
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26 remaining subjects in the DBS+ODT group exhibited modest reductions on a few measures of attention, executive function, and
27 word fluency at 12 months. These differences were largely diminished at 24 months, especially when those with the adverse
28 events were excluded.
Conclusions: The results of this trial provide novel data regarding the effects of DBS on cognitive function in early PD. We
29
believe that the findings and insights from this trial can help guide the safety analysis and risk-benefit evaluations in future
30
discussions of DBS in early stage PD.
31

32 Keywords: Parkinson’s disease, deep brain stimulation, subthalamic nucleus, neuropsychological tests

∗ Correspondence
INTRODUCTION 33
to: P. David Charles, MD, VUMC Depart-
ment of Neurology, 1161 21st Avenue South, Suite A-1106 MCN,
Nashville, TN 37232, Tel.: 615 936 0060; Fax: 615 936 2675; Subthalamic nucleus (STN) deep brain stimula- 34

E-mail: david.charles@vanderbilt.edu. tion (DBS) is an important and effective treatment 35

ISSN 1877-7171/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
 2 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

36 option for patients with advanced Parkinson’s dis- The risks associated with the DBS surgical proce- 88

37 ease (PD) accompanied by motor complications. STN dure in advanced PD are well defined, with stroke 89

38 DBS improves motor symptoms and quality of life and (0–2%), intracranial hemorrhage (0–10%), infection 90

39 reduces medication requirements and financial burden (0–15%), and death (0–4.4%) being the most com- 91

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40 [1–3]. Additionally, STN DBS produces only mild and mon [9]. In addition to the surgical risks, it was 92

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41 selective effects on non-motor functioning, including important to determine whether the combined effects 93

42 cognition, in subjects with advanced PD. A meta- of surgery and chronic stimulation, compared to 94

43 analysis by Parsons et al. (2006) and a comprehensive ODT alone, produce adverse outcomes that persist 95

44 review by Massano and Garrett (2012) concluded sim- in the treatment-withdrawn state and result in lasting 96

45 ilarly that STN DBS has minimal effects on most underlying changes in functioning. Neuropsychologi- 97

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46 cognitive functions [4, 5]. An exception noted was a cal testing was therefore completed off all therapy to 98

47 moderate reduction in the speed of controlled word eliminate the potentially confounding effects of active 99

48 generation (i.e., verbal fluency) [4, 5]. Other cognitive treatment, including stimulation. 100

49

50

51
processes, such as attention, executive functions and
memory, were inconsistently affected [4, 5]. Given the
benefits of DBS in advanced PD, recent research has
or
This report focuses on the cognitive and neurobe-
havioral outcomes in the study. A neuropsychological
battery designed to capture major dimensions of cogni-
101

102

103
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52 focused on implanting the therapy in earlier stages of tive and neurobehavioral functioning, minimize motor 104

53 the disease [6, 7]. demands, and emphasize executive functions often 105

54 We conducted a prospective, randomized, single- impacted by PD was administered to subjects at 106

55 blind, parallel-group, controlled clinical trial of STN baseline and at 12 month and 24 month follow-up eval- 107

56 DBS in the earliest stage of PD studied to date (United uations in the treatment-withdrawn state. We report 108
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57 States Food and Drug Administration, Investiga- the data on these outcome measures over the two-year 109

58 tional Device Exemption (IDE) G050016, Vanderbilt follow-up in a sample of subjects with early PD treated 110

59 University Institutional Review Board # 040797, clini- with DBS+ODT versus those treated with ODT alone. 111

60 caltrials.gov NCT00282152). Research was conducted A full description of the remaining results of the trial 112

61 in accordance with ethical standards. There has been is provided in Charles et al., 2014 [10]. 113
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62 thoughtful discussion and some debate over the poten-

63 tial merits of applying STN DBS in earlier stages of
64 PD, especially for patients who may still be responsive METHODS 114

65 to standard medications. In this study, special atten-

66 tion was given to various ethical considerations that The FDA limited enrollment to 30 subjects under the 115
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67 should be incorporated into subject recruitment and IDE. Enrollment was conducted from August, 2006 116

68 the informed consent process in a pilot trial like this. to April, 2009. The study design (Fig. 1), inclusion 117

69 An expanded informed consent process was utilized and exclusion criteria (Table 1), and methods related 118

70 to ensure that potential subjects fully understood the to the recruitment of subjects, informed consent pro- 119
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71 study and had appropriate expectations (see Finder et cess, surgical and targeting procedures, and follow-up 120

72 al. for a full discussion of the ethical principles and visits have been previously reported [11–14]. Subjects 121

73 consent procedures followed) [8]. with a clinical diagnosis of probable idiopathic PD 122

74 The purpose of this trial was to examine the safety who also met the following requirements fulfilled the 123
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75 and tolerability of STN DBS in early stage PD. This criteria for early stage PD: Hoehn & Yahr Stage II 124

76 study was not designed to address the efficacy of the off medication, on antiparkinsonian medications for 125

77 therapy in early stage PD or the ethics of changing at least 6 months but not more than 4 years, with no 126

78 the standard of care to include DBS as an alternative current or past history of motor fluctuations or dyskine- 127

79 treatment option earlier in the course of the disease. A sias, and demonstrating a stable response to levodopa, 128

80 key question of the study was whether DBS negatively defined as demonstrating at least 30% improvement 129

81 impacted subjects compared to standard medical treat- in the UPDRS-III following the administration of 130

82 ment. Because this trial involved exposing subjects their dopaminergic drug(s). Please see Table 1 for a 131

83 with early stage PD to substantial risks, and because complete list of enrollment criteria. Consented sub- 132

84 DBS had not been previously studied in this stage of jects who were enrolled in the trial first completed a 133

85 PD, it was necessary that this trial focus on testing screening neuropsychological assessment (Table 2), a 134

86 the safety rather than the efficacy of both the surgical psychiatric evaluation, and motor examinations on and 135

87 procedure and stimulation. off antiparkinsonian medications. Signs of dementia, 136

 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS 3

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Fig. 1. Study Design – Study design indicating study visit duration and frequency. The baseline visit and all visits thereafter included 7-day
medication washouts. Adapted from Charles et al., 2012 [11] and reprinted from Charles et al., 2014 [10].

137 depression or other major psychiatric disorder led to visit, a neuropsychological test battery consisting of 142

138 exclusion. 12 tests, yielding a total of 22 specific neuropsycho- 143

139 Subjects meeting all enrollment criteria underwent logical variables and 10 personality test variables, was 144

140 a detailed 8-day inpatient baseline evaluation that administered in the off medication state. Table 2 lists 145

141 included a 7-day medication washout. During this the neuropsychological tests and putative functions 146
4 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

Table 1
Inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
Clinical diagnosis of probable idiopathic PD Evidence of an alternative diagnosis or secondary parkinsonism.

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Demonstrated response to dopaminergic therapy. Uncontrolled medical condition or clinically significant medical

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disease that would increase the risk of developing pre- or
postoperative complications.
Treatment with antiparkinsonian medications ≥ 6 months < 4 years Evidence of dementia
Hoehn and Yahr (H&Y) stage II when OFF medication Major psychiatric disorder
Age between 50 and 75 years old. Previous brain operation or injury.
No contraindications to surgery. Active participation in another clinical trial for the treatment of PD.
Available for follow-up for the entire duration of the study. Patients with demand cardiac pacemakers or medical conditions

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that require repeat MRI scans.
Provide informed consent. Evidence of existing dyskinesias or motor fluctuations.
MRI within normal range for age.

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Strict enrollment criteria were used for this trial to limit enrollment to subjects with early stage Parkinson’s disease. All subjects underwent
detailed testing during a screening assessment to determine their eligibility for the trial. Subjects not meeting all criteria did not proceed in the
trial. Adapted from Charles et al., 2012 and reprinted from Charles et al. 2014 [10, 11].
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Table 2
Battery of neuropsychological tests and descriptions.
SCREENING
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Test Description
Mattis Dementia Rating Scale (DRS-2) General cognitive screening
Attention Estimate of verbal intelligence
Initiation/Perseveration Depression index
Construction Anxiety index
Conceptualization
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Memory
Total Score
WAIS-IIIa Vocabulary
Beck Depression Inventory (BDI-II)
Beck Anxiety Inventory (BAI)
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BASELINE, 12 MONTHS, 24 MONTHS

Test Description
Purdue Pegboard Manual dexterity
(Dominant, Non-Dominant, Both Hands) Visual-spatial orientation (non-motor)
Benton Judgment of Line Orientation Test Confrontation naming
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Boston Naming Test Rapid word production

Verbal Fluency Attention/working memory
Phonemic (FAS Words) Attention/working memory/processing speed
Semantic (Animal Words) Immediate and delayed verbal memory
WAIS-IIIa Digit Span Immediate and delayed verbal memory (non-motor)
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Paced Auditory Serial Addition Test Executive functioning/flexible problem-solving

(rates at 2.4, 2.0, 1.6, and 1.2 sec) Processing speed/control of competing responses
WMS-IIIb Word List Learning I & II Emotional status and personality
WMS-IIIb Memory for Faces I & II
Wisconsin Card Sorting Test
Categories Achieved
Total Errors
Perseverative Errors
Stroop Color and Word Test
Word Reading
Color Reading
Color/Word Reading
Minnesota Multiphasic Personality Inventory-2
Complete list of all neuropsychological assessments and the neuropsychological domains assessed by each test.
All tests completed at baseline, 12 months, and 24 months were conducted in the treatment-withdrawn state.;
a Wechsler Adult Intelligence Scale – Third Edition; b Wechsler Memory Scale – Third Edition.
 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS 5

147 assessed by these measures (see Strauss, Sherman RESULTS 197

148 and Spreen, 2006, for detailed descriptions of these

149 tests) [15]. All subjects were tested individually Subject characteristics at screening and baseline 198

150 by a single certified Master’s Degree-level testing

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151 technician. On the final day of the washout, sub- Thirty-seven subjects with idiopathic PD were 199

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152 jects were randomized to ODT (n = 15) or bilateral enrolled in the trial and underwent a screening evalu- 200

153 STN DBS + ODT (n = 15). ODT was defined as the ation. Seven subjects failed screening (Fig. 1), leaving 201

154 antiparkinsonian oral medication regimen that pro- 30 subjects (27 men, 3 women) to proceed to the 202

155 vided maximum therapeutic benefit and minimal side baseline visit and subsequent randomization. Table 3 203

156 effects. describes the general screening and baseline charac- 204

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157 Follow-up neuropsychological testing was adminis- teristics of enrolled subjects and the results obtained 205

158 tered by the same testing technician and was completed on the neuropsychological screening measures. There 206

159 annually at the 12 and 24 month visits in the treatment- were no differences on any of these measures. 207

160

161

162
withdrawn state (which included both medication
as well as stimulation, if applicable). An identical
neuropsychological test battery, with a set order of
or
Table 4 compares the neuropsychological test results
for the DBS+ODT and ODT groups. At baseline, there
were no significant differences on any of the tests.
208

209

210
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163 individual tests, was maintained throughout the study. Thus, the randomization procedure was successful in 211

producing two groups with similar baseline cognitive 212

164 Statistical analysis and emotional functioning. 213

165 Detailed descriptions of the power calculations and 12 Month follow-up 214
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166 randomization process have been previously described

167 [11]. We compared the outcomes of the DBS + ODT There were few differences between the groups 215
168 and ODT groups using mixed effects models, which at 12 months (Table 4). The ODT group performed 216
169 included fixed effects (treatment, time, and treatment better than the DBS+ODT group at 12 months on 217
170 x time interaction), and an autoregressive covariance the Phonemic Fluency and Stroop Color-Word tests 218
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171 structure to account for repeated measures at baseline, (p = 0.047 and p = 0.035, respectively). Additionally, 219
172 12 months, and 24 months. Parameters were estimated the DBS+ODT group had significantly greater decre- 220
173 from this model and were used to compare: (1) group ments in the change scores from baseline to 12 221
174 differences at each time point, and (2) group differ- months on the Phonemic Fluency and Stroop Color- 222
175 ences in terms of average change scores from baseline Word tasks (p = 0.036 and p = 0.002, respectively). The 223
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176 to 12 months, and from baseline to 24 months. Because DBS+ODT group performed approximately 1 scaled 224
177 adjusting for multiplicity can be counterproductive for score point lower on Phonemic Fluency at 12 months 225
178 safety considerations, formal correction for multiple compared to baseline, whereas the ODT group per- 226
179 comparisons was not pursued. A p value less than or formed approximately 1 scaled score point higher at 227
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180 equal to 0.05 was considered statistically significant. 12 months compared to baseline. On the Stroop Color- 228
181 All tests were two-tailed. All analyses were performed Word test, the DBS+ODT group performed an average 229
182 using the statistical software SAS (version 9.3; SAS of 2.58 scaled-score points lower at 12 months com- 230
183 Institute, Cary, NC) and R (http://www.r-project.org/). pared to baseline whereas the ODT group performed 231
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184 Separate analyses were performed to account for about the same at both time points. The two groups also 232
185 serious surgical or device-related adverse events (AEs) differed significantly in the mean change from baseline 233
186 that occurred in two subjects in the DBS+ODT group to 12 months on the WAIS-III Digit Span (p = 0.004), 234
187 (see Results section for a complete description). Fol- WCST Perseverative Errors (p = 0.053), and on the 235
188 lowing the intention-to-treat principle, the primary slowest and fastest paced rates of the Paced Auditory 236
189 analysis included data for all enrolled subjects who Serial Addition Test (PASAT; p = 0.009 and p = 0.005, 237
190 completed at least one follow-up visit (n = 15 for respectively). On all of these measures, the ODT group 238
191 DBS+ODT and n = 14 for ODT). A secondary analy- showed a greater average improvement from base- 239
192 sis, excluding all data for the subject who experienced a line to 12 months, although the mean scores for the 240
193 perioperative stroke and data for the 24 month visit for DBS+ODT group remained within an average range. 241
194 the subject who suffered post-operative infection, was There were no significant differences between the two 242
195 conducted to determine the safety and tolerability of groups from baseline to 12 months on the remaining 243
196 chronic stimulation, not confounded by surgical AEs. measures. 244
 6 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

Table 3
Characteristics of subjects at screening and baseline
Characteristic ODT (n = 15) DBS+ODT (n = 15)
Gender

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Male 13 14

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Female 2 1
Age (yrs) at Enrollment
Mean 60 ± 7.0 60 ± 6.8
Range 51–69 52–74
Baseline Medicine Use
Mean Duration (yrs) 2.1 ± 1.1 2.2 ± 1.4
Mean L-dopa equivalents (mg/day)a 494.0 ± 208.7 417.2 ± 306.6

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Baseline UPDRS Scores
Mean Totalb 36 ± 15 39 ± 14
Mean UPDRS-III offc 25.6 ± 5.8 25.3 ± 9.0
Mean UPDRS-III ond 12.3 ± 6.4 11.1 ± 6.9
Neuropsychological Screening
DRS-2e
Attention
Initiation/Perseveration
or
12.5 ± 0.9
10.3 ± 1.8
12.7 ± 0.7
11.1 ± 0.4
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Construction 10.0 ± 0.0 10.0 ± 0.0
Conceptualization 11.5 ± 1.0 11.2 ± 1.3
Memory 11.9 ± 1.7 12.3 ± 1.4
Total 142.1 ± 2.3 142.7 ± 1.5
WAIS-IIIf Vocabulary 12.7 ± 2.4 12.7 ± 2.7
BDI-IIg 7.0 ± 5.6 7.1 ± 4.5
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BAIh 4.5 ± 5.2 3.9 ± 3.9

Average characteristics of enrolled subjects at screening and baseline and the mean scores on the screen-
ing neuropsychological measures. There were no significant between-group differences on any of the
measures. Adapted from Charles et al., 2014 and Charles et al., 2012 [10, 12].; a 100 mg of levodopa
with a dopa-decarboxylase inhibitor = 133 mg of controlled-release levodopa preparations = total levodopa
dose+(total levodopa dose x 0.33) mg of levodopa with dopa-decarboxylase and entacapone = 1 mg of
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pergolide, pramipexole, rasagiline, or lisuride = 3 mg of ropinirole = 10 mg bromocriptine or oral selegi-

line = 100 mg amantadine [19].; b Total UPDRS on score, including rigidity, assessed by the principal
investigator at baseline.; c UPDRS-III off score, including rigidity, after a 36 hour medication washout
at the screening visit.; d UPDRS-III on score, including rigidity, assessed by the principal investigator at
baseline.; e Dementia Rating Scale – Second Edition. A total score on the DRS-II of less than 121, repre-
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senting two or more standard deviations (SDs) below the mean for the subject’s age, designated probable
dementia and precluded a subject’s eligibility in the trial.; f Wechsler Adult Intelligence Scale – Third
Edition. The WAIS-III Vocabulary test was used to provide an estimate of premorbid intelligence.; g Beck
Depression Inventory – Second Edition; h Beck Anxiety Inventory
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245 24 Month follow-up Secondary analysis 261

246 Differences between the two groups at 24 months As noted above, there were two serious AEs related 262

247 were even fewer. The ODT group performed better to the surgery or device. One subject experienced a 263
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248 than the DBS+ODT group on the Phonemic Fluency perioperative infarction in the left basal ganglia that 264

249 task (p = 0.029), although the comparative change from resulted in right-sided weakness of the face and hand, 265

250 baseline to 24 months between the two groups was changes in speech and new onset cognitive problems, 266

251 no longer significantly different (p = 0.069). On the including difficulty with comprehension and orienta- 267

252 Stroop Color-Word task, the two groups did not dif- tion to novel tasks. The motor weaknesses resolved 268

253 fer significantly in the mean scores at 24 months or after several weeks, but the other deficits persisted. 269

254 in the change scores from baseline to 24 months. The The other subject developed a right superior frontal 270

255 only measures on which the two groups differed in infection along the lead extension 12 months post- 271

256 comparative changes from baseline to 24 months were operatively that required removal of the right lead and 272

257 the Categories Achieved and Perseverative Errors por- internal pulse generator 17 months post-operatively 273

258 tions of the WCST (p = 0.051 and 0.053, respectively), (20 months after baseline). Therefore, this subject 274

259 with the ODT group performing slightly better on both received stimulation only to the left brain for the 275

260 measures. remainder of the study. At his 24-month visit, he 276

 Table 4
Neuropsychological Outcomes at Baseline, 12 months, and 24 months
Mean test scoresa,b Mean difference scores from baselinea
Baseline 12 months 24 months 12 months 24 months
Outcome ODT DBS P Value ODT DBS P Value ODT DBS P Value ODT DBS P Value ODT DBS P Value

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Purdue Pegboard
Dominant Hand 7.9 (3.8) 6.4 (2.8) 0.29 6.0 (3.8) 5.3 (4.0) 0.59 6.5 (3.9) 4.5 (3.7) 0.15 –1.9 (5.3) –1.1 (3.2) 0.59 –1.4 (5.6) –1.9 (3.4) 0.76

M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

Non-Dominant Hand 7.0 (3.4) 7.2 (3.6) 0.89 6.6 (4.4) 5.3 (3.7) 0.40 6.5 (4.7) 4.7 (3.8) 0.22 –0.4 (3.2) –1.9 (3.2) 0.24 –0.5 (3.5) –2.5 (2.9) 0.21
Both Hands 7.8 (3.5) 6.2 (3.4) 0.23 5.1 (4.4) 4.4 (3.2) 0.58 3.4 (3.1) 3.8 (3.7) 0.89 –2.6 (3.1) –1.8 (3.0) 0.46 –4.3 (2.0) –2.4 (3.4) 0.23

Boston Naming Test

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Judgment of Line Orientation 12.9 (2.1) 12.7 (2.2)
12.5 (4.0) 13.5 (2.7)
0.84 12.3 (2.3) 11.9 (2.6)
0.47 12.7 (2.9) 13.3 (3.1)
0.66 12.1 (2.3) 11.1 (3.4)
0.59 13.3 (2.4) 13.5 (2.9)
0.29
0.83
–0.6 (2.3)
0.2 (2.7)
–0.8 (3.1)
0.1 (1.9)
0.83
0.81
–0.7 (2.6) –1.53 (3.3)
0.8 (3.3) 0.3 (1.4)
0.51
0.60
Verbal Fluency
Phonemic
Semantic
10.3 (3.3) 9.6 (3.5)
10.6 (3.6) 10.1 (3.1) rre
0.61 11.2 (4.0) 8.5 (3.6)
0.68 9.7 (3.1) 7.9 (3.9)
0.05* 11.5 (3.2) 8.5 (4.3)
0.15 10.1 (2.9) 9.3 (3.0)
0.03* 0.9 (2.9) –1.1 (2.7)
0.51 –0.9 (3.2) –2.1 (4.3)
0.04* 1.2 (3.0)
0.36 –0.4 (2.8)
–1.1 (3.5)
–0.7 (3.8)
0.07
0.85
WAIS-III Digit Span
PASAT
2.4
10.9 (2.8) 12.8 (3.7)

8.6 (2.8) 8.7 (2.6) 0.93 9.8 (2.4) 8.4 (2.9) cte
0.10 11.4 (3.1) 11.5 (2.8) 0.97 11.3 (3.0) 11.9 (3.1)

0.17 9.4 (2.7) 8.9 (2.7)

0.62

0.62
0.6 (1.0) –1.3 (2.5)

1.1 (1.6) –0.3 (1.3)

0.00* 0.4 (1.4)

0.01* 0.8 (1.0)

–0.9 (2.8)

0.2 (1.6)
0.12

0.43
2.0
1.6
1.2
9.5 (1.6) 9.9 (2.3)
9.8 (2.0) 9.9 (1.8)
9.9 (1.3) 10.3 (2.4)
0.64 10.4 (2.1) 9.5 (3.5)
0.85 10.3 (2.0) 10.4 (1.9)
0.48 11.0 (1.4) 10.5 (1.5) dA
0.37 10.7 (2.2) 9.6 (3.0)
0.98 10.6 (2.1) 10.0 (2.3)
0.25 11.1 (1.4) 10.5 (1.9)
0.23
0.45
0.42
0.9 (1.2)
0.5 (1.4)
1.1 (0.9)
–0.4 (2.7)
0.4 (1.8)
–0.1 (1.7)
0.11
0.78
0.01*
1.2 (1.4)
0.8 (1.4)
1.2 (1.2)
–0.3 (1.8)
0.1 (1.8)
0.2 (2.0)
0.12
0.36
0.08

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WMS-III
Word List I 10.7 (2.9) 9.2 (2.9) 0.22 10.9 (3.0) 9.1 (3.5) 0.14 11.9 (3.4) 10.5 (3.8) 0.26 0.2 (3.0) –0.1 (2.9) 0.77 1.1 (3.7) 1.3 (4.0) 0.92
Word List II 11.9 (1.6) 11.1 (1.2) 0.32 12.2 (1.7) 11.2 (1.7) 0.14 12.6 (1.7) 11.8 (2.7) 0.27 0.3 (1.3) –0.1 (1.4) 0.57 0.6 (1.9) 0.4 (2.3) 0.94
Faces I 10.6 (2.5) 10.5 (3.8) 0.93 11.4 (2.9) 11.9 (3.3) 0.67 12.6 (3.1) 12.2 (3.4) 0.76 0.7 (2.6) 1.3 (2.7) 0.55 1.9 (2.9) 1.7 (2.5) 0.84
Faces II
WCST
12.0 (3.4) 12.1 (2.7) 0.95 12.7 (3.1) 11.9 (3.0) 0.47 13.1 (3.3) 13.5 (3.4) 0.74

or
0.7 (3.2) –0.2 (1.9) 0.35 1.1 (3.2) 1.5 (3.3) 0.80

Pr
Categories Achieveda 5.6 (1.1) 5.9 (0.3) 0.23 6.0 (0.0) 5.9 (0.5) 0.40 6.0 (0.0) 5.7 (0.9) 0.17 0.4 (1.1) –0.1 (0.6) 0.07 0.4 (1.1) –0.3 (1.0) 0.05*
Total Errors 9.9 (2.3) 10.4 (2.0) 0.47 10.9 (1.0) 10.2 (1.5) 0.21 11.6 (1.4) 10.5 (1.8) 0.09 1.0 (2.4) –0.2 (1.6) 0.07 1.7 (2.4) 0.1 (2.2) 0.06
Perseverative Errors 9.8 (2.1) 10.5 (1.8) 0.28 11.3 (1.3) 10.7 (1.8) 0.31 11.5 (1.1) 10.6 (1.8) 0.16 1.5 (2.1) 0.3 (1.8) 0.05* 1.7 (2.0) 0.1 (2.3) 0.05*
Stroop
Word 9.0 (2.8) 9.0 (3.6) 1.00 8.6 (2.6) 8.4 (3.9) 0.85 8.5 (2.9) 8.7 (4.1) 0.88 –0.4 (2.5) –0.6 (3.0)
oo
0.81 –0.5 (1.8) –0.6 (2.0) 0.88
Color
Color/Word
10.7 (3.0) 8.9 (2.0)
11.1 (2.4) 11.3 (2.4)
0.13 10.3 (3.2)
0.84 11.5 (3.2)
8.6 (3.2)
8.8 (2.8)
0.14 10.3 (3.2)
0.04* 11.4 (3.8)
7.4 (2.6)
9.4 (3.7)
0.01* –0.4 (1.7)
0.12 0.4 (2.1)
–0.3 (3.0)
–2.6 (2.1)
0.95 –0.4 (2.3)
0.00* 0.3 (2.6)
f
–1.5 (3.2)
–1.9 (2.4)
0.35
0.07
(continued next page)

7
 8
Un
co Table 4

M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

(continued)

Outcome ODT
Baseline
DBS P Value ODT rre
Mean test scoresa,b
12 months
DBS P Value ODT
24 months
DBS P Value ODT
Mean difference scores from baselinea
12 months
DBS P Value ODT
24 months
DBS P Value
MMPIb
Hs
D
67.4 (11.4)
58.0 (9.4)
66.8 (13.9)
58.7 (13.4)
0.93
0.81
68.3 (12.5)
60.2 (12.5)
71.9 (12.0)
64.1 (12.4) cte
0.58
0.49
72.1 (12.5)
63.8 (12.7)
74.9 (13.4)
65.6 (16.7)
0.49
0.62
1.8 (9.6)
2.4 (7.5)
5.1 (9.0)
5.3 (5.6)
0.39
0.43
5.9 (11.2)
6.2 (8.8)
8.1 (9.8)
6.9 (6.0)
0.43
0.73
Hy
Pd
Mf
66.4 (12.2)
53.9 (5.9)
43.5 (6.7)
71.3 (15.3)
52.1 (8.8)
47.0 (7.1)
0.32
0.55
0.23
71.2 (11.6)
56.2 (10.6)
42.7 (8.1)
72.7 (13.3)
52.1 (10.8)
46.1 (5.0)
0.77
0.25
0.25
71.3 (7.8)
53.7 (6.6)
47.6 (13.1) dA
79.4 (14.1)
56.9 (11.5)
45.7 (6.3)
0.09
0.44
0.54
3.9 (10.3) 1.5 (9.5)
1.3 (8.7) 0.1 (9.5)
–0.6 (5.2) –0.9 (8.1)
0.38
0.57
0.97
5.9 (11.6)
–0.1 (6.8)
5.4 (11.6)
8.1 (11.8)
4.9 (9.7)
–1.3 (8.3)
0.47
0.26
0.18

uth
Pa 50.2 (8.2) 48.8 (10.4) 0.60 49.8 (6.5) 53.2 (11.2) 0.28 51.6 (9.1) 54.6 (7.2) 0.38 –2.3 (8.4) 4.4 (9.4) 0.13 1.1 (10.3) 5.8 (11.4) 0.26
Pt 56.0 (8.2) 53.7 (12.7) 0.61 56.3 (5.9) 57.5 (13.6) 0.78 55.4 (8.6) 60.7 (15.6) 0.25 –0.4 (5.1) 3.8 (10.3) 0.34 –0.4 (8.6) 7.0 (10.8) 0.12
Sc 58.9 (8.0) 58.6 (9.4) 0.93 59.3 (5.1) 62.7 (10.1) 0.35 61.2 (8.2) 67.7 (14.9) 0.10 –0.4 (6.7) 4.1 (9.2) 0.30 2.6 (9.0) 9.1 (10.6) 0.15
Ma 53.2 (8.0) 48.0 (10.2) 0.15 52.2 (5.5) 49.9 (7.5) 0.38 49.8 (7.5) 51.9 (11.0) 0.60 0.3 (6.0) 1.9 (6.8) 0.48 –2.0 (4.9) 3.9 (8.8) 0.07
Si 48.2 (11.5) 48.6 (8.6) 0.90 48.1 (10.8) 51.5 (10.0) 0.47 51.3 (11.1) 51.6 (11.0) 0.60 1.2 (4.9)

or
2.9 (5.1) 0.21 2.7 (6.8) 3.0 (6.0) 0.53
Table 4 lists the results of the trial. Raw scores are listed as mean (SD). A p value equal to or less than 0.05 was considered statistically significant. Except where noted otherwise, all scores were
scaled scores (mean = 10, standard deviation = 3). Table format adapted from Weaver et al., 2009 [20].; a WCST – Categories Achieved was a raw score based on the actual number of category

Pr
solutions on the task (0–6); b Minnesota Multiphasic Personality Inventory. The scores for the MMPI were T scores (mean = 50, standard deviation = 10). The scale abbreviations were as follows: Hs
(Hypochondriasis), D (Depression), Hy (Conversion Hysteria), Pd (Psychopathic Deviate), Mf (Masculinity-Femininity), Pa (Paranoia), Pt, (Psychasthenia), Sc (Schizophrenia), Ma (Hypomania),

oo
Si (Social Introversion); Other abbreviations: PASAT (Paced Auditory Serial Addition Test); WAIS-III (Wechsler Adult Intelligence Scale-Third Edition); WMS-III (Wechsler Memory Scale-Third
Edition); WCST (Wisconsin Card Sorting Test).

f
 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS 9

277 showed increased depression and declines in several PASAT 2.4 (p = 0.020), and PASAT 1.2 (p = 0.005) in 308

278 areas, including manual dexterity and both phonemic change scores from baseline to 12 months. However, 309

279 and semantic word fluency. no between-group differences were observed on any 310

280 With a few exceptions, the results of the secondary measure at 24 months in the secondary analysis, either 311

f
281 analysis were similar to those in the primary analysis. in terms of mean scores or changes from baseline to 312

roo
282 One exception was that the differences on compo- 24 months. 313

283 nents of the WCST found in the primary analysis were

284 not significant in the secondary analysis. In addition, General trends 314

285 whereas Phonemic Fluency was significantly differ-

286 ent between the two groups at 12 months and 24 There were some similar changes in both groups. 315

P
287 months in the primary analysis, the groups were not Both groups scored significantly better over time on the 316

288 different at either time point in the secondary analysis Perseverative Errors index of the WCST in both the pri- 317

289 (p = 0.066 at 12 months and p = 0.096 at 24 months). mary and secondary analyses (p = 0.033 and p = 0.015, 318

290

291

292
Also, unlike the primary analysis, the secondary anal-
ysis found no difference between the two groups in
changes in Phonemic Fluency from baseline to 12
or
respectively). Significant improvements from baseline
through 24 months were also exhibited on the mem-
ory measures, including Faces I (p = 0.038), Faces II
319

320

321
uth
293 months (p = 0.079). There again was no difference (p = 0.017), and Word List I (p = 0.042). These find- 322

294 between the groups in changes in Phonemic Fluency ings likely reflected practice effects that benefitted both 323

295 from baseline to 24 months. The two groups’ perfor- groups similarly 324

296 mance on the Phonemic Fluency task, excluding data Both groups performed progressively worse over 325

297 for the two subjects with serious AEs, is presented in time on the Purdue Pegboard when executed with 326
dA

298 Fig. 2. both hands. This reflected deterioration in higher-level 327

299 Figure illustrates the mean scores on the Stroop manual speed and coordination over the two year 328

300 Color-Word task based on the secondary analysis. follow-up period and was evident in both the primary 329

301 The results on this task were consistent with the pri- and secondary analyses (p = 0.0001 in both cases). Fig- 330

302 mary analysis, with the ODT group again performing ure illustrates the changes in this task found in the 331
cte

303 better than the DBS+ODT group at 12 months in secondary analysis. Declines were not significant for 332

304 mean performance and change from baseline to 12 performance with either the dominant or non-dominant 333

305 months (p = 0.037 and p = 0.003, respectively). Also, hand alone. 334

306 compared to the DBS+ODT group, the ODT group Subjects in both groups also exhibited changes 335

307 performed better on WAIS-III Digit Span (p = 0.013), in emotional status over time. Subjects expressed 336
rre
co
Un

Fig. 2. Phonemic Word Fluency. Mean scores on the Phonemic Fig. 3. Stroop Color-Word. Mean scores on the Stroop Color-Word
Word Fluency task at each time point by treatment group (mean = 10, task at each time point by treatment group (mean = 10, SD = 3). Data
SD = 3). Data from the two cases with the major surgical AEs were from the two cases with the major surgical AEs were excluded.
excluded. Higher scores indicate better performance. Higher scores indicate better performance.
 10 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

f
P roo
or
uth
Fig. 4. Purdue Pegboard, Both Hands and MMPI-Depression. (A) Purdue Pegboard, Both Hands. Mean scores on the Purdue Pegboard,
Both Hands task at each time point by treatment group (mean = 10, SD = 3). Data from the two cases with the major surgical AEs were excluded.
Higher scores indicate better performance. (B) MMPI Depression. Mean scores on the MMPI Depression Scale at each time point by treatment
group (mean = 50, SD = 10). Data from the two cases with the major surgical AEs were excluded. Higher scores indicate higher levels of
self-reported depression.
dA

337 increasing, but essentially equivalent, concerns about study and most evident at the 12 month assessment. 365

338 their physical and emotional well being with the In fact, differences in phonemic fluency between the 366

339 progression of their illness. Increased elevations (indi- DBS+ODT and ODT groups at 12 months as well as 367

340 cating more self-reported problems) on both the at 24 months were non-significant when the two sub- 368
cte

341 Hypochondriasis and Depression scales of the MMPI- jects who suffered serious AEs were excluded. Various 369

342 2 were observed and were essentially the same in interpretations have been offered to explain the decline 370

343 the primary and secondary analyses (p = 0.035 and in verbal fluency experienced by many patients with 371

344 p = 0.005, respectively). Figure 4 also illustrates the advanced PD after undergoing DBS surgery, includ- 372

345 changes on the Depression scale based on the sec- ing the potential for stimulation-induced reduction 373
rre

346 ondary analysis. of a verbal fluency-related frontotemporal network 374

[4, 5, 16]. However, that interpretation is not applicable 375

347 DISCUSSION to this study, as subjects in the DBS+ODT group were 376

tested off stimulation and medication at each follow-up 377

co

348 This study yielded initial safety and tolerability data assessment. In addition, the possibility of cumula- 378

349 of DBS in early stage PD with a focus on cogni- tive adverse effects from stimulation-induced changes 379

350 tive and neurobehavioral outcomes. AE rates in this over time would not be consistent with our finding 380

351 trial were similar to what was reported in a large trial that phonemic verbal fluency changes seen in the 381
Un

352 of DBS in subjects with advanced PD [9]. Of the DBS+ODT group were not worse at 24 months com- 382

353 15 subjects in our DBS+ODT group, two of them pared to 12 months. Rather, the changes in phonemic 383

354 experienced serious AEs that resulted in some per- verbal fluency experienced by the DBS+ODT group, 384

355 sistent cognitive changes. There were few differences and mainly with the two surgical AE cases included, 385

356 between the two groups at 12 months and they were may have reflected surgical microlesioning or inser- 386

357 further diminished at 24 months when data from these tion effects that were still present at 12 months, but did 387

358 two subjects were removed. Nevertheless, the AEs not worsen beyond that. This explanation is supported 388

359 reported in this trial must be factored into future dis- by a study by Okun et al. (2009), in which a decline in 389

360 cussions regarding the risk-benefit of offering DBS to phonemic verbal fluency was found 7 months after uni- 390

361 subjects with early stage PD. lateral STN DBS, irrespective of which contacts were 391

362 Declines in phonemic word fluency, the most com- stimulated and whether the device was turned on [17]. 392

363 monly reported negative cognitive effect associated Verbal fluency may be particularly vulnerable to dis- 393

364 with STN DBS in advanced patients, were small in our ruption, as deficits are often seen in PD and become 394
 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS 11

395 increasingly common in later stages of the illness [16]. or experiences over a recent time period may have been 447

396 More research is needed to determine the safety of negatively affected by untreated motor symptoms and 448

397 DBS in early PD and to elucidate the precise factors resulting functional limitations during the medication 449

398 contributing to declines in verbal fluency and other washout period. Finally, the use of repeated measures 450

f
399 cognitive areas. However, the fact that areas of function introduced the possibility of practice effects, which 451

roo
400 like verbal fluency tend to worsen with disease pro- may have confounded the results of several assess- 452

401 gression, coupled with our findings showing relatively ments. 453

402 minimal impact in patients with early PD, suggests Despite these limitations, the results can help guide 454

403 that earlier application of STN DBS may be advan- larger-scale and more definitive evaluations provided 455

404 tageous because patients with early PD have not yet by potential future trials testing the safety and effi- 456

P
405 experienced substantial declines in verbal fluency or cacy of DBS in early stage PD. Future trials should 457

406 other cognitive functions imparted by their underlying conduct neuropsychological testing in both the treated 458

407 disease. Thus, compared to their more advanced coun- and untreated states to discern potential benefits or 459

408

409

410
terparts, patients with early PD may be less vulnerable
cognitively and better able to tolerate, or recover
from, potential negative cognitive effects associated
or
adverse effects of DBS. The test battery should uti-
lize some of the same neuropsychological measures
used in studies of DBS in advanced PD to allow
460

461

462
uth
411 with STN DBS. However, any definitive conclusions for comparability in the areas examined. It should 463

412 involving such differences would require a controlled include measures that assess cognitive domains that 464

413 comparison of treatment outcomes and relative cogni- have been found to be adversely affected by STN DBS 465

414 tive risks in patients with early versus later PD. in advanced patients, such as verbal fluency, while 466

415 The results indicated some similar changes in both also incorporating measures sensitive to cognitive pro- 467
dA

416 groups irrespective of treatment modality. Specifically, cesses associated with basal ganglia (including STN) 468

417 both groups showed nearly equivalent progressive function, such as measures of inhibitory action con- 469

418 declines in bilaterally executed fine motor dexterity in trol, reward learning, and risk decision-making [18]. 470

419 the treatment-withdrawn state at 12 and 24 months. Additional measures of emotional symptoms common 471

420 Both groups also showed similar increases in self- to PD, such as apathy and impulse control disorder, 472
cte

421 reported depression and health concerns across the should also be included in future designs. In order to 473

422 study period, possibly reflecting increasing difficulty mitigate the confounding effects of practice over serial 474

423 coping with disease progression and its impact on assessments, repeatable measures (including alternate 475

424 activities of daily life. forms, where available) will be important components 476

425 This study had certain limitations. Most importantly, of future trials. These combined features will enhance 477
rre

426 all neuropsychological assessments and measures were the sensitivity and balance necessary for effective neu- 478

427 conducted in an open label manner. Additionally, being ropsychological assessment in future trials. 479

428 an initial, small cohort study investigating DBS in early Important questions remain regarding the relative 480

429 stage PD, it was not designed to provide definitive merits of applying STN DBS in early stage PD. The 481
co

430 evidence regarding the safety of DBS in early PD or potential benefits of STN DBS in early PD are dis- 482

431 to permit a comparison of DBS in early versus more cussed in the primary report on this trial, which reports 483

432 advanced subjects. Furthermore, the data from the lim- motor and quality-of-life outcomes [10]. Future stud- 484

433 ited two year duration of follow-up in this initial study ies are necessary to determine whether any advantages 485
Un

434 cannot inform physicians and their patients about the derived from the early use of STN DBS, especially 486

435 long-term effects of STN DBS applied in early stage with patients still responsive to standard medical treat- 487

436 PD, as PD is a chronic neurodegenerative process ment, outweigh any added risks that may be involved. 488

437 causing disability that develops over many years. In We believe that these initial insights can help guide 489

438 addition, because subjects were tested off therapy to and inform discussions regarding future trials inves- 490

439 assess the safety of the therapy on the untreated state tigating the safety and efficacy of DBS in early 491

440 of PD, the results provided little information about the stage PD. 492

441 differential effects of active DBS stimulation and medi-

442 cation on cognitive and emotional functioning. It is also
443 possible that testing in the treatment-withdrawn state ACKNOWLEDGMENTS 493

444 may have impacted the validity of the personality and

445 mood measures used in this study. For example, ques- We would like to thank the trial’s coordinator, 494

446 tionnaires asking subjects to rate their emotional states Ms. Odessa Lankford, for her dedication to the 495
 12 M. G. Tramontana et al. / Neuropsychological Effects of STN DBS

496 trial. Research reported in this publication was sup- of data; drafting of the manuscript; critical revision 543

497 ported by Medtronic, Inc., by Vanderbilt CTSA grant of the manuscript; administrative or technical sup- 544

498 UL1TR000445 from the National Center for Advanc- port. Peter Konrad made substantial contributions to 545

499 ing Translational Sciences (NCATS), by NCATS/NIH the conception and design; acquisition of data; inter- 546

f
500 award UL1TR000011, by NIH R01 EB006136, and by pretation of data; critical revision of the manuscript; 547

roo
501 private donations. Medtronic representatives did not administrative, technical or material support; super- 548

502 take part in data collection, management, analysis, or vision. Thomas Davis made substantial contributions 549

503 interpretation of the data or in preparation, review, or to the conception and design; critical revision of 550

504 approval of the manuscript. the manuscript; administrative, technical or material 551

support. Scott Wylie made substantial contributions 552

P
to the interpretation of data; critical revision of the 553
505 CONFLICT OF INTEREST
manuscript; administrative, technical or material sup- 554

port. Joseph Neimat made substantial contributions 555

Vanderbilt University has received income from a
506

507

508
grant from Shire for research, nonrelated to this study,
led by Michael Tramontana. Michael Tramontana also
receives book royalties from Springer, Plenum, and
or
to the interpretation of data; critical revision of the
manuscript; administrative, technical or material sup-
port; supervision. Alexandra May made substantial
556

557

558
uth
509
contributions to the interpretation of data; critical revi- 559
510 McGraw Hill. Peter E. Konrad receives research fund-
sion of the manuscript; administrative, technical or 560
511 ing by Medtronic and the NIH, is on the speaker’s
material support. Fenna Phibbs made substantial con- 561
512 bureau for Medtronic and FHC, and also holds a
tributions to the interpretation of data; critical revision 562
513 fiduciary position (Board of Directors) with Neuro-
of the manuscript; administrative, technical or material 563
targeting, the American Society for Stereotactic and
dA

514
support. Peter Hedera made substantial contributions 564
515 Functional Neurosurgery, and the North American
to the interpretation of data; critical revision of the 565
516 Neuromodulation Society. Fenna T. Phibbs has done
manuscript; administrative, technical or material sup- 566
517 consulting work for Medtronic and has received speak-
port. Chandler Gill made substantial contributions to 567
518 ing honoraria from Teva. Peter Hedera has received
the acquisition of data; interpretation of data; critical 568
519 speaking honoraria from Teva. Joseph S. Neimat has
cte

revision of the manuscript; administrative or technical 569

520 done consulting work for Medtronic and has received
support. Ronald Salomon made substantial contribu- 570
521 research funding from Medtronic and the NIH. Van-
tions to the conception and design; acquisition of 571
522 derbilt University has received income from an NIH
data; interpretation of data; critical revision of the 572
523 grant for research, nonrelated to this study, led by Scott
manuscript; administrative, technical or material sup- 573
rre

524 Wylie. Vanderbilt University has received income from

port. Lily Wang made substantial contributions to the 574
525 a St. Jude’s grant for research, nonrelated to this study,
conception and design; interpretation of data; statisti- 575
526 led by Ronald Salomon. Vanderbilt University has
cal analysis; critical revision of the manuscript. Yanna 576
527 received income in excess of $10,000 from grants or
Song made substantial contributions to the interpreta- 577
contracts with Medtronic, Allergan, Ipsen, Merz, UCB,
co

528
tion of data; statistical analysis; critical revision of the 578
529 and Teva for educational or research programs led
manuscript. David Charles made substantial contribu- 579
530 by David Charles. David Charles receives income in
tions to the conception and design; acquisition of data; 580
531 excess of $10,000 from Medtronic, Allergan, Ipsen,
interpretation of data; drafting and critical revision of 581
Un

532 and the Alliance for Patient Access for education and
the manuscript; obtaining funding;. David Charles has 582
533 consulting services. Anna L. Molinari, Thomas L.
full access to the study data and takes full responsibility 583
534 Davis, Chandler E. Gill, Alexandra T. May, Yanna
for the integrity and accuracy of data analysis. 584
535 Song, and Lily Wang, do not have conflicts of interest.

536 AUTHORS’ ROLES REFERENCES 585

[1] Benabid AL, Chabardes S, Mitrofanis J, & Pollak P (2009) 586

537 Michael Tramontana made substantial contribu- Deep brain stimulation of the subthalamic nucleus for the 587
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