Neuromodulation: Technology at the Neural Interface Received: February 25, 2014
Revised: May 31, 2014
Accepted: July 2, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12233
Five-Months-Postoperative Neuropsychological Outcome From a Pilot Prospective Randomized Clinical Trial of Thalamic Deep Brain Stimulation for Tourette Syndrome Mike R. Schoenberg, PhD*; Brian N. Maddux, MD, PhD†; David E. Riley, MD†; Christina M. Whitney, RNCS, PhD†; Paula K. Ogrocki, PhD†; Deborah Gould, MD†; Robert J. Maciunas, MD, MPH† Objective: Tourette syndrome (TS) is a neuropsychiatric disorder presenting with motor and/or sonic tics associated with frontostriatal dysfunction. This study provided pilot data of the neuropsychological safety of bilateral thalamic deep brain stimulation (DBS) to treat medication-refractory TS in adults. Method: This study used a repeated-measures design with pretest and 3-month follow-up from start of continuous bilateral DBS. Five male patients underwent DBS surgery for medically refractory TS. Repeated-measures ANOVA was used to evaluate for any change in neuropsychological test scores, employing a false discovery rate. Outcome measures included 14 neuropsychological tests assessing psychomotor speed, attention, memory, language, visuoconstructional, and executive functions, as well as subjective mood ratings of depression and anxiety. Results: Average age was 28.2 years (SD = 7.5) with 12–17 years of education. Participants were disabled by tics, with a tic frequency of 50–80 per minute before surgery. At baseline, subjects’ cognitive function was generally average, although mild deficits in sequencing and verbal fluency were present, as were clinically mild obsessive–compulsive symptoms. At 3 months of continuous DBS (5 months after implantation), 3 of 5 participants had clinical reductions in motor and sonic tics. Cognitive scores generally remained stable, but declines of moderate to large effect size (Cohen’s d > 0.6) in verbal fluency, visual immediate memory, and reaction time were observed. Fewer symptoms of depression and anxiety, as well as fewer obsessions and compulsions, were reported after 3 months of continuous high-frequency DBS. Conclusions: Bilateral centromedian–parafascicular thalamic DBS for medically refractory TS shows promise for treatment of medically refractory TS without marked neuropsychological morbidity. Symptoms of depression and anxiety improved. Keywords: cognitive, complications, deep brain stimulation, neuropsychology, outcome, psychological, Tourette syndrome Conflict of Interest: Dr. Schoenberg is on the Board of Directors for the American Board of Clinical Neuropsychology. He also receives royalty payments for book sales from Springer and receives a stipend from Taylor & Francis Publishing for his services as an associate editor for a neuropsychological scientific journal.
INTRODUCTION
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Address correspondence to: Mike R. Schoenberg, PhD, Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, 3515 E. Fletcher Ave., Tampa, FL 33613, USA. Email: mschoenb@ health.usf.edu * Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA † Neurological Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1
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Tourette syndrome (TS) is a neurological disorder characterized by motor and sonic tics beginning in childhood (1,2). The severity of motor and sonic tics varies intra-individually; type and severity of tics change over time (2). While the onset of tics predominantly occurs in childhood, TS remains a chronic condition into adulthood (2,3). A longitudinal study found that 90% of children with TS continued to have tics into adulthood, and one-quarter of this adult cohort were rated as disabled by tics (3). Despite medication, up to a quarter of adults with TS continue to have moderate to severe tics, which can often result in limitations of social activities such as attending school and/or work activities (4,5). TS has classically been associated with behavioral disinhibition (4,5) and dysfunction of frontostriatal pathways (6–9). However, investigations have not found consistent evidence of neuropsychological dysfunction in TS (10–15). While early studies in TS reported
impairment in visuoconstructional, fine motor, and executive functions (10,11), they did not control for comorbid obsessive– compulsive disorder (OCD) or attention-deficit/hyperactivity disorder (ADHD) on executive dysfunction (12–15). While some
SCHOENBERG ET AL. studies have not identified neuropsychological impairment among subjects with only TS (13), recent data suggest mild impairment in behavioral inhibition in subjects with uncomplicated TS (14,15). Deep brain stimulation (DBS) surgery has revolutionized the treatment of movement disorders (16) and has become a mainstay in ameliorating medication-refractory symptoms of Parkinson’s disease, essential tremor, and generalized dystonia (16,17). Successful stimulation targets have been identified in areas of the basal ganglia and thalamus, including the globus pallidus interna (GPi), subthalamic nucleus (STN), and ventral intermediate nucleus of the thalamus (VIM). Application of DBS has been attempted for treatment of epilepsy (18), OCD (19), and TS (20–23). The application of DBS to refractory TS is a recent development (20–23). Case reports have documented 70–90% reductions in motor and sonic tics with DBS; however, neuropsychological outcome data are limited (20,23). A case report of two patients (20) reported a decline in psychomotor speed, visual reaction time, and verbal fluency for one patient, but no decline was observed for the other patient. In a prospective study, 15 patients with severe tics receiving thalamic DBS to the centromedian and parafascicular nuclei (Cm-Pf ) and ventralis oralis anterior exhibited no meaningful change in selected neuropsychological measures at 24-month follow-up (23). However, the neuropsychological outcomes reported by Porta et al. (23) were limited to five measures and did not include assessment of verbal memory. The use of DBS for the treatment of TS is potentially unique compared with other applications of DBS, as patients undergoing DBS are on average in young to middle adulthood (i.e., 18–40 years-old), and the effects of even subtle neuropsychological deficits could potentially impact educational/career development. While data to date are promising with respect to neurological outcome, there remain concerns regarding neuropsychological comorbidity with DBS (20). Thus, adults with refractory TS treated with DBS may present with neuropsychological deficits due to TS itself or secondarily due to complications of thalamic DBS placement and/or chronic high-frequency electrical stimulation (20–22,24–26). This study reports the baseline and 5-months-postoperative neuropsychological outcome from a prospective trial of thalamic DBS in five adults with refractory TS. We previously reported (21) that DBS of the Cm-Pf thalamic nuclei resulted in a significant reduction in motor tics, and three of the five participants exhibited a pronounced reduction in tics at 5 months post-operation (21). The primary objective of this study was to report the neuropsychological outcome for these patients undergoing bilateral thalamic DBS treatment of TS symptoms.
METHODS Study methods and experimental procedures were summarized in Maciunas et al. (21) and are elaborated below along with additional details of the neuropsychological methods. This trial is registered with www.clinicaltrials.gov (NCT00311909).
high-resolution MRI, comprehensive neuropsychological evaluations (MRS or PJO), two quality-of-life instruments, two tic severity rating scales, and a video recording session. Inclusion criteria included the following: 1) diagnosis of TS by DSM-IV criteria (1); 2) tic frequency at least one per minute at screening; 3) age of 18 or older; 4) prior failure of at least two dopamine antagonists; and 5) tics negatively impacting quality of life. Exclusion criteria included the following: 1) significant structural brain lesion; 2) dementia; 3) history of head trauma preceding tic onset; 4) use of dopamine receptor blockers prior to onset of tics; 5) prior implanted electrical device; 6) electroconvulsive therapy in the past two years; 7) suicide attempt in last year; 8) significantly sociopathic personality; and 9) current or planned pregnancy. Participants with comorbid OCD and/or ADHD were not excluded unless these conditions were considered by the evaluating physicians to produce a greater impact than the tics themselves. Participants’ medication regimen had to remain stable from 21 days prior to DBS surgery through the 3-month follow-up visit. Finally, subjects had to be willing and able to travel to Cleveland, Ohio, USA, for required visits. A total of 10 subjects were screened, and five subjects entered the study. The remaining five completed the initial screening, but three choose not to undergo the surgical procedure or could not return to Cleveland for the trial visits, and two were excluded due to psychiatric comorbidity. There were no significant neuropsychological or demographic differences between the five subjects completing the study and the five subjects who did not complete the study.
Experimental Design Participants underwent bilateral implantation of DBS electrodes in one session, placement of pulse generators 4–7 days later, and initial programming 17 to 21 days after DBS surgery. At that point, subjects entered a 4-week phase in which stimulators were assigned in random order for 1 week in each of the four possible combinations of states: bilaterally active, unilaterally active (left or right), or bilaterally off. Upon completion of the randomized double-blind phase, an open-label phase (bilateral stimulators active) ensued. During the randomized phase, stimulation parameters were fixed. However, during the open-label phase, DBS parameters could be adjusted as necessary to achieve optimum benefit (decrease in tics). Participants’ medication regimen had to remain stable from 21 days prior to DBS surgery through the follow-up visit 3 months after the start of the open-label phase. Neuropsychological, behavioral/mood, and quality-of-life measures were obtained during screening and 3 months after start of continuous bilateral DBS (5 months after surgical implantation). University Hospitals Case Medical Center Institutional Review Board approved all procedures. The Food and Drug Administration (FDA) approved an investigational device exemption for a pilot study limited to five participants. A control group was not part of the study design due to budgetary and practical limitations.
Procedures
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Patient Selection Participants were selected from among patients being treated at the University Hospitals Case Medical Center Movement Disorder Center or from new referrals. All participants provided informed consent and permission to review medical records. All screening candidates were evaluated by a neurosurgeon (RJM), a neurologist (BNM or DER), and a psychiatrist (DG). Additional screening included www.neuromodulationjournal.com
Implantation and Programming The surgical target used to anchor the electrode trajectory was the Cm-Pf of the thalamus, whose coordinates were reported by Visser-Vandewalle et al. (20). Our group previously reported trajectory angles in anteroposterior and lateral planes (21). Conventional stereotactic targeting and procedures were performed using the Medtronic Model 3387 stimulating electrode (Medtronic, Minneapolis, MN, USA). All patients underwent postoperative MRI
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COGNITION AFTER DBS FOR TOURETTE SYNDROME scanning to confirm proper electrode placement. All surgical procedures were completed by the same surgeon (RJM) between June 3 and July 1, 2005, and all microelectrode recording was accomplished by the same neurologist (BNM). All neurostimulators were the Soletra model (Medtronic). Following surgery, a 1.5-T MRI study of the head was obtained for confirmation of surgical location for implanted electrodes, and study personnel ensured proper electrode conduction and function of the programmable neurostimulators. Details regarding the initial programming and selection of stimulator parameters have been provided (21). All stimulator programming was performed by the same investigator (CMW). Statistical Procedures To evaluate for differences between presurgical and 5-monthspostsurgical assessments, standardized test scores were compared using paired-samples t-tests. To control for multiple comparisons and limited sample size, a false discovery rate (FDR) (23) method was employed and adjusted for dependent groups (27). The FDR is a method to calculate the anticipated proportion of falsely rejected null hypotheses from among all rejected hypotheses and has been shown to increase power for research in which many comparisons must be made and sample size is limited (23,27).
Measures Neuropsychological Assessment Neuropsychological evaluations were completed prior to DBS surgery and 5 months after DBS surgical implantation, which included 3 months of continuous bilateral Cm-Pf DBS. Cognitive and psychological tests were administered in a fixed order, and alternative test forms were used when available. The measures and procedure of this trial were established prior to the recommendations of Mink et al. (22) and were derived from research on neuropsychological deficits in TS (10–15) as well as tests shown to be sensitive to DBS in Parkinson’s disease (24,25) and essential tremor (26). Tests were scored according to their respective manuals. To maintain a common metric, cognitive test scores are provided as standardized T-scores (mean of 50 and SD of 10, such that scores between 40 and 60 fall in the normal range) from healthy age-matched normative data (also education-matched when available) for each test.
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Subjective Psychological/Behavioral and Quality-of-Life Measures Psychological and mood measures included patient-reportand examiner-based assessments including the Beck Depression Inventory—Second Edition (BDI-2; a self-report measure of depression symptoms) (39), Hamilton Rating Scale for Depression (HAM-D; examiner-completed checklist of depression symptoms) (40), Hamilton Rating Scale for Anxiety (HAM-A; examiner-completed checklist of anxiety symptoms) (41), Yale–Brown Obsessive Compulsive Scale (Y-BOCS; examiner-completed checklist of obsessive and compulsive behaviors) (42), and the Minnesota Multiphasic Personality Inventory—Second Edition (MMPI-2; a detailed self-report test assessing mood, personality, and affective variables) (43). Qualityof-life measures were administered at each visit and included the 36-Item Short Form Health Survey (SF-36) (44) and a visual analog scale (VAS) (45). Scores on the BDI-2, HAM-A, HAM-D, and Y-BOCS are given as raw scores. Scores on the SF-36 were transformed into normalized scores with a mean score of 50 and standard deviation of 10 based on US population norms. The VAS was a 100-mm bar, with the distance in millimeters from the left edge of the line marked by the participant being the recorded score.
RESULTS Average age of the sample was 28.2 years (minimum 18, maximum 34). Participants were all native English speakers with a mean WRAT-3 reading score in the average range (mean 105.4, minimum 99, maximum 114, SD 5). Participants had completed an average of 13.8 years of education (minimum 12, maximum 17). Of the five subjects, all were right-handed, and one was employed at screening. The following comorbidities were identified at screening: ADHD (3), OCD (4), and depression (5). Target Verification and Assessment of Neurological Outcome and Quality of Life In all five subjects, postoperative MRI demonstrated placement in the thalamic Cm-Pf. During the randomized phase, motor and sonic tics were significantly reduced when both stimulators were on, compared with the other tested states (21). After three months of open-label continuous bilateral stimulation, video records of three of five subjects demonstrated meaningful decline in motor tics, and the average raw numbers of motor and sonic tics were reduced by 40% and 21%, respectively (21). Assessment with tic rating scales revealed reduction in tic burden along with improvement in scores for quality of life (see Table 1). Similarly, quality-of-life measures improved after 3 months of continuous DBS compared with preoperative. Presurgical Neuropsychological Functioning Table 2 provides the mean group performances in standardized T-scores. As a group, subjects performed below normal (T-scores < 40) on Part B of the Trail Making Test, the written version of the Symbol Digit Modalities Test, CPT-2 hit rate, and the Stroop Color and Word Test. Depression and anxiety symptoms and obsessions and compulsions were mild.
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Quantitative Neuropsychological Tests The Reading subtest of the Wide Range Achievement Test—Third Edition (WRAT-3) (28) was administered at the presurgical visit as a measure of general cognitive ability. The neuropsychological battery consisted of 14 tests with 29 variables spanning five neuropsychological domains: 1) attention/vigilance, 2) memory, 3) language, 4) cognitive and motor speed, and 5) executive/other cognitive functions. Tests of attention/vigilance included Conners’ Continuous Performance Test—Second Edition (CPT-2; a computerized task requiring the subject to detect the occurrence of specific letter) (29) and the written and oral tasks of the Symbol Digit Modalities Test (a timed graphomotor coding task) (30). Tests of memory included the Rey Auditory Verbal Learning Test (a word list verbal memory task; parallel forms used for different test days) (31) and the Medical College of Georgia Complex Figure Test (a visual memory test with immediate and delayed recall; parallel forms were used for different test days) (32). Tests of language ability included the Controlled Oral Word Association Test (a timed test of phonemic verbal fluency; parallel forms were used for different test days) (33), the Semantic Fluency Test (a timed semantic verbal fluency task) (34), and the Boston Naming Test (a visual confrontation naming test) (35). Tests of cognitive and motor speed included the Halstead–Reitan Finger
Oscillation Test (a test of motor speed) (36). Tests of executive function and other cognitive tests included the Halstead–Reitan Trail Making Test (timed tests of graphomotor and sequencing) (36), the Stroop Color and Word Test (timed tests on reading words, naming colors, and an interference task) (37), and the Wisconsin Card Sorting Test (a problem solving and set-shifting task) (38).
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Table 1. Presurgical and Postsurgical Neurological Outcomes of Deep Brain Stimulation for Tic Counts, Tic Severity Scores, and Quality of Life. Measure
Presurgical, mean (SD)
Postsurgical, mean (SD)*
Pre–post score difference, mean
Raw p†
FDR-q
Pre–post effect size (Cohen’s d)
mRVRS YGTSS Tic SF-36 Physical Mental
17.0 (2.65) 37.2 (9.0)
14.4 (4.04) 28.2 (14.3)
2.6 9.0
0.36 0.26
0.79 0.79
0.76 0.75
40.7 (14.1) 41.2 (8.9)
48.5 (7.7) 49.0 (7.6)
7.8 7.8
0.31 0.09
0.79 0.70
0.69 0.94
*Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. FDR-q, false discovery rate-adjusted p value; mRVRS, modified Rush Video-Based Rating Scale; SF-36, 36-Item Short Form Health Survey; YGTSS, Yale Global Tic Severity Scale.
Table 2. Presurgical and Postsurgical Standardized T-Scores for Neuropsychological Tests in Deep Brain Stimulation. Measure Motor Finger tapping (dominant hand) Finger tapping (nondominant hand) General cognitive WRAT-3 Attention/executive measures Trails A Trails B SDMT written SDMT oral CPT-2 omissionsठCPT-2 commissionsठCPT-2 hit rateठStroop word Stroop color Stroop interference task WCST total errors Learning/memory measures RAVLT total RAVLT immediate delay RAVLT 30-min delay Visuoconstructional MCG copy MCG immediate delay MCG 30-min delay Language Boston Naming Test Letter fluency Semantic fluency
Raw p†
FDR-q
1.2 3.0
0.83 0.53
0.92 0.79
0.1 0.38
55.0 (2.6)
−1.6
0.41
0.79
−0.49
41.0 (7.6) 38.8 (7.9) 36.6 (7.8) 43.0 (9.3) 54.8 (17.0) 41.8 (7.4) 66.0 (10.7) 37.6 (10.0) 36.0 (11.6) 39.2 (11.6) 50.8 (5.0)
41.4 (10.5) 35.8 (6.8) 34.0 (11.0) 40.2 (16.7) 51.3 (8.7) 42.0 (9.9) 73.3 (11.5) 34.4 (7.3) 33.8 (9.1) 38.4 (8.6) 50.6 (5.5)
−0.4 3.0 2.6 2.8 3.5 −0.3 −7.3 3.2 2.2 0.8 0.2
0.94 0.61 0.47 0.59 0.79 0.97 0.05 0.25 0.39 0.81 0.92
0.97 0.79 0.79 0.79 0.92 0.97 0.70 0.79 0.79 0.92 0.97
−0.04 0.41 0.27 0.21 0.26 −0.02 −0.66 0.37 0.21 0.08 0.04
40.6 (6.8) 47.2 (11.3) 43.8 (9.4)
37.6 (15.0) 41.2 (19.0) 38.8 (18.4)
3.0 6.0 5.0
0.73 0.58 0.58
0.91 0.79 0.79
0.26 0.38 0.34
47.0 (13.0) 53.6 (9.6) 51.6 (9.1)
52.0 (4.8) 46.0 (9.7) 48.2 (9.0)
−5.0 7.6 3.4
0.49 0.13 0.51
0.79 0.79 0.79
−0.51 0.79 0.38
42.6 (8.6) 41.0 (7.0) 46.8 (2.2)
43.6 (9.0) 35.4 (6.4) 38.4 (9.1)
−1.0 5.6 8.4
0.54 0.26 0.08
0.79 0.79 0.70
−0.11 0.83 1.27
Presurgical, mean (SD)
Postsurgical, mean (SD)*
49.4 (11.1) 51.0 (6.6)
48.2 (13.1) 48.0 (9.1)
53.4 (3.8)
Pre–post score difference, mean
Pre–post effect size (Cohen’s d)
*Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. ‡ One subject was unable to complete the CPT-2 at presurgical visit, so means are based on N = 4. § Scores deviating more from a score of 50 represent worse (abnormal) performance. FDR-q, false discovery rate-adjusted p value; WRAT-3, Wide Range Achievement Test—Third Edition; Trails, Trail Making Test; SDMT, Symbol Digit Modalities Test; CPT-2, Conners’ Continuous Performance Test—Second Edition; WCST TE, Wisconsin Card Sorting Test; RAVLT, Rey Auditory Verbal Learning Test; MCG, Medical College of Georgia Complex Figure Test.
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Due to motor tics, one subject was unable to complete the CPT-2 at the presurgical visit. Analyses of the CPT-2 are limited to the four subjects completing both presurgical and 5-months-postsurgical visits. All other analyses are based on the entire sample of five participants. www.neuromodulationjournal.com
Postsurgical Neuropsychological Functioning Review of Table 2 indicates subjects scored impaired (T-scores < 40) on the Trail Making Test Part B, the written task of the Symbol Digit Modalities Test, CPT-2 hit rate, and the Stroop Color and Word test. In addition, the average score on the Rey Auditory Verbal
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Table 3. Presurgical and Postsurgical Raw Scores on Subjective Psychological Measures. Measure Mood BDI-2 HAM-A HAM-D Y-BOCS
Presurgical, mean (SD)
Postsurgical, mean (SD)*
Pre–post score difference, mean
Raw p†
FDR-q
Pre–post effect size (Cohen’s d)
10.6 (7.6) 16.4 (4.2) 13.6 (1.5) 12.6 (10.7)
4.2 (5.4) 8.0 (7.0) 9.6 (6.5) 7.0 (4.2)
6.4 8.4 4.0 5.6
0.28 0.07 0.27 0.24
0.79 0.70 0.79 0.79
0.97 1.46 0.85 0.69
Higher scores reflect more symptoms. *Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. FDR-q, false discovery rate-adjusted p value; BDI-2, Beck Depression Inventory—Second Edition; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; Y-BOCS, Yale–Brown Obsessive Compulsive Scale..
Learning Test (total number of words recalled after five learning trials, words recalled after 30 min) indicated impairment. Letter (phonemic) and semantic verbal fluency test scores also indicated impairment. Depression and anxiety symptoms and obsessions and compulsions were generally in the nonclinical range (see Table 2).
Evaluation of Postsurgical Change in Neuropsychological Functioning Neuropsychological Measures Using repeated-measures ANOVA, there were no significant changes in scores across measures of attention/executive function, learning/memory, and language ability (see Table 2). No comparison met the FDR method constraint (critical value) for rejection, and the adjusted FDR-q values from statistical calculations (46) are provided in Table 2 (27,47). There were trend declines 5 months postsurgery in measures of psychomotor speed (CPT-2 hit rate; raw p = 0.05, adjusted FDR-q = 0.70) and semantic verbal fluency (raw p = 0.08, adjusted FDR-q = 0.70). Further evaluation of change using effect size calculations (Cohen’s d) (48) generally found the differences between presurgical and postsurgical neuropsychological test scores to be small (Cohen’s d ≤ 0.3)—less than a third of one standard deviation. However, the average declines in semantic verbal fluency and phonemic verbal fluency scores were large (Cohen’s d > 0.8). Declines of moderate effect size (i.e., d > 0.5) were observed for CPT-2 hit rate (d = 0.7) and immediate memory score for the visual memory task (d = 0.8). A medium-sized effect (d = 0.51) of improved performance was found for a visuoconstructional skill task (Table 3). Psychological Measures The average raw scores on the psychological tests before and 5 months following DBS surgery are displayed in Table 2. Decreasing trends were observed in symptoms of anxiety (HAM-A) and depression (BDI-2, HAM-D) at 5 months postoperative. Additionally, most participants reported a decrease in obsessions and compulsions 5 months after DBS surgery, with the average postoperative score falling into the nonclinical range.
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Individual Change Analyses Participants 1, 2, and 4 exhibited significant reductions in motor and sonic tics 3 months after DBS surgery, and participant 3 had a nonsignificant reduction in tics (21). Participant 5 had no change in motor or sonic tics following DBS surgery. Supporting Information Figures S1–S11 provide changes in selected outcome measures from preoperative baseline to 5-months-postoperative evaluation for each participant. Those with baseline scores in the impaired range and those with large effect size changes (d > 0.80) are indicated. Evaluation of correlation between response to DBS and neuropsychological outcome found limited relationships. Regardless of DBS outcome, participants tended to exhibit a decline in verbal fluency, with the exception of participant 4, who exhibited improved performance on neuropsychological tests and had a good response to DBS. In contrast, participant 2 exhibited a decline in scores on multiple neuropsychological tests, including Trail Making Test Part B, Symbol Digit Modalities Test, verbal fluency tests, and both memory tests. Most participants reported fewer symptoms of depression and anxiety 3 months after continuous DBS thalamic stimulation (5 months after surgical implantation), with the exception of participant 5, who reported more depression and anxiety symptoms. There was no consistent relationship between response to DBS and reductions in depression, anxiety, or obsessions/compulsions.
DISCUSSION This study provides cautious support for the cognitive safety of bilateral thalamic DBS in young adults with refractory TS. While several individuals exhibited a decline in measures of verbal fluency, verbal memory, and hit rate reaction time, these declines were generally less than what might be expected due to error and chance variables. These data extend Maciunas et al.’s (21) report that
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Stimulation Parameters and Outcome Maciunas et al. (21) reported stimulator settings for all five participants individually. For the group, the mean pulse amplitude for left side stimulation was 3.6 (minimum = 3.5, maximum = 3.6), pulse width of 132 μs (minimum = 90, maximum = 210) and pulse rate of 155 Hz (minimum = 130, maximum = 185). Average right-side stimulation settings were a pulse amplitude of 3.6 V (minimum = 3.5,
maximum = 3.6), pulse width of 126 μs (minimum = 90, maximum = 210), and pulse rate of 152 Hz (minimum = 130, maximum = 185). While research has suggested a potential relationship between DBS stimulation parameters and neuropsychological function in Parkinson’s disease (49), the limited sample size prevented quantitative analysis. Qualitatively, no consistent association was observed. While participant 2 had the highest DBS stimulator parameters (pulse amplitude of 3.6 V, pulse width of 210 μs, and pulse rate of 185 Hz; bilateral) and exhibited decline on most measures of neuropsychological function, the participant with the next highest stimulation parameters, participant 4, exhibited improved cognitive function at follow-up.
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bilateral DBS of the Cm-Pf resulted in significant reduction of motor and sonic tics for three of five participants with refractory TS. Neuropsychological outcome measures following 3 months of chronic bilateral thalamic DBS (5 months after surgical implantation) to treat refractory TS did not reveal marked neuropsychological morbidity; however, the average performance of participants declined on measures of sustained attention, verbal fluency, and memory. At an individual level, change in neuropsychological test scores was minimal for four of the five subjects. While participant 2 exhibited a decline in neuropsychological test scores (and had reduced tics with DBS), he did not show appreciable cognitive morbidity and reported fewer symptoms of depression and anxiety. In contrast, on average, participants’ anxiety and depression symptoms, as well as obsessions and compulsions, improved after 3 months of continuous DBS stimulation. The psychiatric finding that most participants experienced reductions in symptoms of anxiety and depression and in obsessive and compulsive behaviors mirrors observations of reduced anxiety following DBS for treatment of Parkinson’s disease (24). While it may be tempting to suggest that reductions in anxiety and depressive symptoms and in obsessions and compulsions are due to TS symptom relief, participant 3 had fewer symptoms of depression at follow-up despite not having a reduction in motor or sonic tics. Furthermore, there was no consistent association between decline in neuropsychological function after DBS and symptoms of anxiety or obsessions and compulsions. One possible interpretation of the improvements in anxiety and depressive symptoms after Cm-Pf bilateral DBS is a positive effect on the theorized disruption of the corticostriatothalamocortical circuit underlying TS (12–15,20,50). Our neuropsychological outcome data add substantively to the extant neuropsychological outcome data for adults with refractory TS undergoing Cm-Pf thalamic DBS. In particular, these data are consistent with one of two case reports of bilateral thalamic DBS for refractory TS, in which a decline in processing speed occurred (20). While there was no change in neuropsychological outcomes reported for 12 subjects by Porta et al. (23), the neuropsychological measures used by Porta et al. were limited and did not include measures of sustained attention or verbal memory. Our findings extend those of Porta et al. (23) that young adults can exhibit neuropsychological decline 5 months after undergoing Cm-Pf thalamic DBS. This conclusion is consistent with studies suggesting that DBS of VIM (26), STN, and GPi (24,25) for treatment of Parkinson’s disease and essential tremor do not result in pronounced cognitive morbidity but performance on measures of verbal fluency and memory significantly declines after DBS (24–26). Indeed, the effect size changes observed in this study are similar to those reported in a metaanalysis of STN-DBS in Parkinson’s disease for verbal fluency and memory (24). These data contribute significantly to the extant literature documenting neuropsychological outcome from Cm-Pf thalamic DBS for treatment of TS, in which we are aware of fewer than 30 individual cases published worldwide (20–23), and support and extend recommendations by Mink et al. (22). Generalizability of these results to adults with TS is increased, given that the preoperative neuropsychological results were similar to previous studies of subjects with TS and comorbid ADHD and/or OCD that found mild deficits in selected executive functions (Trails B, Stroop, and CPT-2) (12,13). While impaired scores on the Trail Making Test, CPT-2, and the written task of SDMT could be explained by severe motor tics, the lower scores for Trails B compared with Trails A (which also requires graphomotor skills) argue for abnormality (35). In contrast, there was no significant interference deficit assessed by the Stroop Color and Word Test, which is considered www.neuromodulationjournal.com
sensitive to deficits in behavioral inhibition and associated with anterior cingulate and ventrolateral prefrontal cortex activity (34). This may reflect recent observations that neuropsychological deficits in behavioral inhibition associated with TS are minimal (14,15). Several limitations of this study are noteworthy. First, study generalizability is limited due to small sample size. The sample size was limited by regulatory agencies. To mitigate experimental false negative errors, this study used a FDR procedure (27,47). The study also employed evaluation of effect size. A second limitation was that one subject (participant 3) suffered a head injury in a motor vehicle accident about 2 months after he underwent DBS surgery, confounding the ability to draw conclusions regarding the effect of DBS surgery and/or chronic high-frequency stimulation on his neuropsychological function. The participant reported a brief loss of consciousness in the motor vehicle accident. Brain imaging following the accident did not reveal any structural lesion or change in DBS electrode placement. Nevertheless, it is possible this participant’s neuropsychological function was adversely affected by the motor vehicle accident. Financial constraints limited follow-up data collection beyond the initial study design. While these data add substantively to documented neuropsychological outcomes from DBS for TS, the declines observed at 5 months in some subjects may not remain longer-term per the report of Porta et al. (23), in which no decline in neuropsychological function was observed 2 years after DBS implantation. While cognitive outcomes were generally good, evaluation of effect size suggested risks of neuropsychological comorbidity with possible declines in verbal fluency, reaction time, and verbal and visual memory. With the possibility of presurgical neuropsychological dysfunction and variable changes in neuropsychological function following DBS surgery, we recommend future studies incorporate a comprehensive neuropsychological assessment. Clearly, these data argue against only a brief neuropsychological assessment as suggested by Mink et al. (22). We also advise against using the grooved pegboard test (34), as several of our participants were unable to complete this task due to severe motor tics. Finally, with the variability in performances on executive function tests observed for patients with TS (14,15), we advise future trials incorporate more comprehensive testing of executive function than Mink et al. (22) and Porta et al. (23).
Acknowledgements This research was conducted with an investigational device exemption from the U.S. Food and Drug Administration (FDA) and with the approval of the University Hospitals Case Medical Center Institutional Review Board. We also thank Medtronic, Inc., for their financial support of this project through a physician-sponsored research agreement with Dr. Maciunas; without it, this study would not have been possible. Medtronic also provided deep brain surgical materials as part of investigator-initiated study support.
Authorship Statements Drs. Schoenberg, Maddux, Riley, Maciunas, Ogrocki, Gould, and Whitney designed and conducted the study, including participant recruitment, data collection, participant safety, surgical implantation, and data analyses. Dr. Schoenberg prepared the manuscript draft with important intellectual contributions from Drs. Maddux, Riley, and Maciunas. All authors except Dr. Maciunas approved the
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COGNITION AFTER DBS FOR TOURETTE SYNDROME final manuscript. Unfortunately, Dr. Maciunas died prior to the final manuscript being accepted for publication, but all substantive analyses, results, and conclusions had been completed, reviewed, and approved by him prior to his death. Statistical analyses were completed by Drs. Schoenberg and Maddux with input from Drs. Riley and Maciunas. Drs. Maddux, Maciunas, and Schoenberg had complete access to the study data.We would like to dedicate this article to the memory of Robert J. Maciunas, MD, a wonderful friend and a truly phenomenal clinician, teacher, researcher, and colleague.
How to Cite this Article: Schoenberg M.R., Maddux B.N., Riley D.E., Whitney C.M., Ogrocki P.K., Gould D., Maciunas R.J. 2015. Five-MonthsPostoperative Neuropsychological Outcome From a Pilot Prospective Randomized Clinical Trial of Thalamic Deep Brain Stimulation for Tourette Syndrome. Neuromodulation 2015; 18: 97–104
REFERENCES
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1. Individual changes in Conners’ Continuous Performance Test hit rate T-score. Figure S2. Individual changes in time to complete Trails B T-score. Figure S3. Individual changes in Rey Auditory Verbal Learning Test words recalled after short-delay T-score. Figure S4. Individual changes in Rey Auditory Verbal Learning Test words recalled after 30-min-delay T-score. Figure S5. Individual changes in semantic verbal fluency T-score.
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SCHOENBERG ET AL. Figure S6. Individual changes in total letter (phonemic) fluency T-score.
Figure S11. Individual changes in total obsessive and compulsive symptoms (raw scores).
Figure S7. Individual changes in T-score for Medical College of Georgia Complex Figure Test after an immediate-delay.
COMMENT
Figure S8. Changes in Beck Depression Inventory symptoms reported (raw scores).
This paper provides important safety data on the neuropsychological profiles in patients undergoing Tourette Syndrome DBS.
Figure S9. Individual changes in Hamilton Anxiety symptoms (raw scores).
Michael Okun, M.D. Gainesville, FL, USA
Figure S10. Individual changes in Hamilton Depression symptoms (raw scores).
Comments not included in the Early View version of this paper.
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Revised: May 31, 2014
Accepted: July 2, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12233
Five-Months-Postoperative Neuropsychological Outcome From a Pilot Prospective Randomized Clinical Trial of Thalamic Deep Brain Stimulation for Tourette Syndrome Mike R. Schoenberg, PhD*; Brian N. Maddux, MD, PhD†; David E. Riley, MD†; Christina M. Whitney, RNCS, PhD†; Paula K. Ogrocki, PhD†; Deborah Gould, MD†; Robert J. Maciunas, MD, MPH† Objective: Tourette syndrome (TS) is a neuropsychiatric disorder presenting with motor and/or sonic tics associated with frontostriatal dysfunction. This study provided pilot data of the neuropsychological safety of bilateral thalamic deep brain stimulation (DBS) to treat medication-refractory TS in adults. Method: This study used a repeated-measures design with pretest and 3-month follow-up from start of continuous bilateral DBS. Five male patients underwent DBS surgery for medically refractory TS. Repeated-measures ANOVA was used to evaluate for any change in neuropsychological test scores, employing a false discovery rate. Outcome measures included 14 neuropsychological tests assessing psychomotor speed, attention, memory, language, visuoconstructional, and executive functions, as well as subjective mood ratings of depression and anxiety. Results: Average age was 28.2 years (SD = 7.5) with 12–17 years of education. Participants were disabled by tics, with a tic frequency of 50–80 per minute before surgery. At baseline, subjects’ cognitive function was generally average, although mild deficits in sequencing and verbal fluency were present, as were clinically mild obsessive–compulsive symptoms. At 3 months of continuous DBS (5 months after implantation), 3 of 5 participants had clinical reductions in motor and sonic tics. Cognitive scores generally remained stable, but declines of moderate to large effect size (Cohen’s d > 0.6) in verbal fluency, visual immediate memory, and reaction time were observed. Fewer symptoms of depression and anxiety, as well as fewer obsessions and compulsions, were reported after 3 months of continuous high-frequency DBS. Conclusions: Bilateral centromedian–parafascicular thalamic DBS for medically refractory TS shows promise for treatment of medically refractory TS without marked neuropsychological morbidity. Symptoms of depression and anxiety improved. Keywords: cognitive, complications, deep brain stimulation, neuropsychology, outcome, psychological, Tourette syndrome Conflict of Interest: Dr. Schoenberg is on the Board of Directors for the American Board of Clinical Neuropsychology. He also receives royalty payments for book sales from Springer and receives a stipend from Taylor & Francis Publishing for his services as an associate editor for a neuropsychological scientific journal.
INTRODUCTION
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Address correspondence to: Mike R. Schoenberg, PhD, Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, 3515 E. Fletcher Ave., Tampa, FL 33613, USA. Email: mschoenb@ health.usf.edu * Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA † Neurological Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1
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Tourette syndrome (TS) is a neurological disorder characterized by motor and sonic tics beginning in childhood (1,2). The severity of motor and sonic tics varies intra-individually; type and severity of tics change over time (2). While the onset of tics predominantly occurs in childhood, TS remains a chronic condition into adulthood (2,3). A longitudinal study found that 90% of children with TS continued to have tics into adulthood, and one-quarter of this adult cohort were rated as disabled by tics (3). Despite medication, up to a quarter of adults with TS continue to have moderate to severe tics, which can often result in limitations of social activities such as attending school and/or work activities (4,5). TS has classically been associated with behavioral disinhibition (4,5) and dysfunction of frontostriatal pathways (6–9). However, investigations have not found consistent evidence of neuropsychological dysfunction in TS (10–15). While early studies in TS reported
impairment in visuoconstructional, fine motor, and executive functions (10,11), they did not control for comorbid obsessive– compulsive disorder (OCD) or attention-deficit/hyperactivity disorder (ADHD) on executive dysfunction (12–15). While some
SCHOENBERG ET AL. studies have not identified neuropsychological impairment among subjects with only TS (13), recent data suggest mild impairment in behavioral inhibition in subjects with uncomplicated TS (14,15). Deep brain stimulation (DBS) surgery has revolutionized the treatment of movement disorders (16) and has become a mainstay in ameliorating medication-refractory symptoms of Parkinson’s disease, essential tremor, and generalized dystonia (16,17). Successful stimulation targets have been identified in areas of the basal ganglia and thalamus, including the globus pallidus interna (GPi), subthalamic nucleus (STN), and ventral intermediate nucleus of the thalamus (VIM). Application of DBS has been attempted for treatment of epilepsy (18), OCD (19), and TS (20–23). The application of DBS to refractory TS is a recent development (20–23). Case reports have documented 70–90% reductions in motor and sonic tics with DBS; however, neuropsychological outcome data are limited (20,23). A case report of two patients (20) reported a decline in psychomotor speed, visual reaction time, and verbal fluency for one patient, but no decline was observed for the other patient. In a prospective study, 15 patients with severe tics receiving thalamic DBS to the centromedian and parafascicular nuclei (Cm-Pf ) and ventralis oralis anterior exhibited no meaningful change in selected neuropsychological measures at 24-month follow-up (23). However, the neuropsychological outcomes reported by Porta et al. (23) were limited to five measures and did not include assessment of verbal memory. The use of DBS for the treatment of TS is potentially unique compared with other applications of DBS, as patients undergoing DBS are on average in young to middle adulthood (i.e., 18–40 years-old), and the effects of even subtle neuropsychological deficits could potentially impact educational/career development. While data to date are promising with respect to neurological outcome, there remain concerns regarding neuropsychological comorbidity with DBS (20). Thus, adults with refractory TS treated with DBS may present with neuropsychological deficits due to TS itself or secondarily due to complications of thalamic DBS placement and/or chronic high-frequency electrical stimulation (20–22,24–26). This study reports the baseline and 5-months-postoperative neuropsychological outcome from a prospective trial of thalamic DBS in five adults with refractory TS. We previously reported (21) that DBS of the Cm-Pf thalamic nuclei resulted in a significant reduction in motor tics, and three of the five participants exhibited a pronounced reduction in tics at 5 months post-operation (21). The primary objective of this study was to report the neuropsychological outcome for these patients undergoing bilateral thalamic DBS treatment of TS symptoms.
METHODS Study methods and experimental procedures were summarized in Maciunas et al. (21) and are elaborated below along with additional details of the neuropsychological methods. This trial is registered with www.clinicaltrials.gov (NCT00311909).
high-resolution MRI, comprehensive neuropsychological evaluations (MRS or PJO), two quality-of-life instruments, two tic severity rating scales, and a video recording session. Inclusion criteria included the following: 1) diagnosis of TS by DSM-IV criteria (1); 2) tic frequency at least one per minute at screening; 3) age of 18 or older; 4) prior failure of at least two dopamine antagonists; and 5) tics negatively impacting quality of life. Exclusion criteria included the following: 1) significant structural brain lesion; 2) dementia; 3) history of head trauma preceding tic onset; 4) use of dopamine receptor blockers prior to onset of tics; 5) prior implanted electrical device; 6) electroconvulsive therapy in the past two years; 7) suicide attempt in last year; 8) significantly sociopathic personality; and 9) current or planned pregnancy. Participants with comorbid OCD and/or ADHD were not excluded unless these conditions were considered by the evaluating physicians to produce a greater impact than the tics themselves. Participants’ medication regimen had to remain stable from 21 days prior to DBS surgery through the 3-month follow-up visit. Finally, subjects had to be willing and able to travel to Cleveland, Ohio, USA, for required visits. A total of 10 subjects were screened, and five subjects entered the study. The remaining five completed the initial screening, but three choose not to undergo the surgical procedure or could not return to Cleveland for the trial visits, and two were excluded due to psychiatric comorbidity. There were no significant neuropsychological or demographic differences between the five subjects completing the study and the five subjects who did not complete the study.
Experimental Design Participants underwent bilateral implantation of DBS electrodes in one session, placement of pulse generators 4–7 days later, and initial programming 17 to 21 days after DBS surgery. At that point, subjects entered a 4-week phase in which stimulators were assigned in random order for 1 week in each of the four possible combinations of states: bilaterally active, unilaterally active (left or right), or bilaterally off. Upon completion of the randomized double-blind phase, an open-label phase (bilateral stimulators active) ensued. During the randomized phase, stimulation parameters were fixed. However, during the open-label phase, DBS parameters could be adjusted as necessary to achieve optimum benefit (decrease in tics). Participants’ medication regimen had to remain stable from 21 days prior to DBS surgery through the follow-up visit 3 months after the start of the open-label phase. Neuropsychological, behavioral/mood, and quality-of-life measures were obtained during screening and 3 months after start of continuous bilateral DBS (5 months after surgical implantation). University Hospitals Case Medical Center Institutional Review Board approved all procedures. The Food and Drug Administration (FDA) approved an investigational device exemption for a pilot study limited to five participants. A control group was not part of the study design due to budgetary and practical limitations.
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Patient Selection Participants were selected from among patients being treated at the University Hospitals Case Medical Center Movement Disorder Center or from new referrals. All participants provided informed consent and permission to review medical records. All screening candidates were evaluated by a neurosurgeon (RJM), a neurologist (BNM or DER), and a psychiatrist (DG). Additional screening included www.neuromodulationjournal.com
Implantation and Programming The surgical target used to anchor the electrode trajectory was the Cm-Pf of the thalamus, whose coordinates were reported by Visser-Vandewalle et al. (20). Our group previously reported trajectory angles in anteroposterior and lateral planes (21). Conventional stereotactic targeting and procedures were performed using the Medtronic Model 3387 stimulating electrode (Medtronic, Minneapolis, MN, USA). All patients underwent postoperative MRI
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COGNITION AFTER DBS FOR TOURETTE SYNDROME scanning to confirm proper electrode placement. All surgical procedures were completed by the same surgeon (RJM) between June 3 and July 1, 2005, and all microelectrode recording was accomplished by the same neurologist (BNM). All neurostimulators were the Soletra model (Medtronic). Following surgery, a 1.5-T MRI study of the head was obtained for confirmation of surgical location for implanted electrodes, and study personnel ensured proper electrode conduction and function of the programmable neurostimulators. Details regarding the initial programming and selection of stimulator parameters have been provided (21). All stimulator programming was performed by the same investigator (CMW). Statistical Procedures To evaluate for differences between presurgical and 5-monthspostsurgical assessments, standardized test scores were compared using paired-samples t-tests. To control for multiple comparisons and limited sample size, a false discovery rate (FDR) (23) method was employed and adjusted for dependent groups (27). The FDR is a method to calculate the anticipated proportion of falsely rejected null hypotheses from among all rejected hypotheses and has been shown to increase power for research in which many comparisons must be made and sample size is limited (23,27).
Measures Neuropsychological Assessment Neuropsychological evaluations were completed prior to DBS surgery and 5 months after DBS surgical implantation, which included 3 months of continuous bilateral Cm-Pf DBS. Cognitive and psychological tests were administered in a fixed order, and alternative test forms were used when available. The measures and procedure of this trial were established prior to the recommendations of Mink et al. (22) and were derived from research on neuropsychological deficits in TS (10–15) as well as tests shown to be sensitive to DBS in Parkinson’s disease (24,25) and essential tremor (26). Tests were scored according to their respective manuals. To maintain a common metric, cognitive test scores are provided as standardized T-scores (mean of 50 and SD of 10, such that scores between 40 and 60 fall in the normal range) from healthy age-matched normative data (also education-matched when available) for each test.
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Subjective Psychological/Behavioral and Quality-of-Life Measures Psychological and mood measures included patient-reportand examiner-based assessments including the Beck Depression Inventory—Second Edition (BDI-2; a self-report measure of depression symptoms) (39), Hamilton Rating Scale for Depression (HAM-D; examiner-completed checklist of depression symptoms) (40), Hamilton Rating Scale for Anxiety (HAM-A; examiner-completed checklist of anxiety symptoms) (41), Yale–Brown Obsessive Compulsive Scale (Y-BOCS; examiner-completed checklist of obsessive and compulsive behaviors) (42), and the Minnesota Multiphasic Personality Inventory—Second Edition (MMPI-2; a detailed self-report test assessing mood, personality, and affective variables) (43). Qualityof-life measures were administered at each visit and included the 36-Item Short Form Health Survey (SF-36) (44) and a visual analog scale (VAS) (45). Scores on the BDI-2, HAM-A, HAM-D, and Y-BOCS are given as raw scores. Scores on the SF-36 were transformed into normalized scores with a mean score of 50 and standard deviation of 10 based on US population norms. The VAS was a 100-mm bar, with the distance in millimeters from the left edge of the line marked by the participant being the recorded score.
RESULTS Average age of the sample was 28.2 years (minimum 18, maximum 34). Participants were all native English speakers with a mean WRAT-3 reading score in the average range (mean 105.4, minimum 99, maximum 114, SD 5). Participants had completed an average of 13.8 years of education (minimum 12, maximum 17). Of the five subjects, all were right-handed, and one was employed at screening. The following comorbidities were identified at screening: ADHD (3), OCD (4), and depression (5). Target Verification and Assessment of Neurological Outcome and Quality of Life In all five subjects, postoperative MRI demonstrated placement in the thalamic Cm-Pf. During the randomized phase, motor and sonic tics were significantly reduced when both stimulators were on, compared with the other tested states (21). After three months of open-label continuous bilateral stimulation, video records of three of five subjects demonstrated meaningful decline in motor tics, and the average raw numbers of motor and sonic tics were reduced by 40% and 21%, respectively (21). Assessment with tic rating scales revealed reduction in tic burden along with improvement in scores for quality of life (see Table 1). Similarly, quality-of-life measures improved after 3 months of continuous DBS compared with preoperative. Presurgical Neuropsychological Functioning Table 2 provides the mean group performances in standardized T-scores. As a group, subjects performed below normal (T-scores < 40) on Part B of the Trail Making Test, the written version of the Symbol Digit Modalities Test, CPT-2 hit rate, and the Stroop Color and Word Test. Depression and anxiety symptoms and obsessions and compulsions were mild.
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Quantitative Neuropsychological Tests The Reading subtest of the Wide Range Achievement Test—Third Edition (WRAT-3) (28) was administered at the presurgical visit as a measure of general cognitive ability. The neuropsychological battery consisted of 14 tests with 29 variables spanning five neuropsychological domains: 1) attention/vigilance, 2) memory, 3) language, 4) cognitive and motor speed, and 5) executive/other cognitive functions. Tests of attention/vigilance included Conners’ Continuous Performance Test—Second Edition (CPT-2; a computerized task requiring the subject to detect the occurrence of specific letter) (29) and the written and oral tasks of the Symbol Digit Modalities Test (a timed graphomotor coding task) (30). Tests of memory included the Rey Auditory Verbal Learning Test (a word list verbal memory task; parallel forms used for different test days) (31) and the Medical College of Georgia Complex Figure Test (a visual memory test with immediate and delayed recall; parallel forms were used for different test days) (32). Tests of language ability included the Controlled Oral Word Association Test (a timed test of phonemic verbal fluency; parallel forms were used for different test days) (33), the Semantic Fluency Test (a timed semantic verbal fluency task) (34), and the Boston Naming Test (a visual confrontation naming test) (35). Tests of cognitive and motor speed included the Halstead–Reitan Finger
Oscillation Test (a test of motor speed) (36). Tests of executive function and other cognitive tests included the Halstead–Reitan Trail Making Test (timed tests of graphomotor and sequencing) (36), the Stroop Color and Word Test (timed tests on reading words, naming colors, and an interference task) (37), and the Wisconsin Card Sorting Test (a problem solving and set-shifting task) (38).
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Table 1. Presurgical and Postsurgical Neurological Outcomes of Deep Brain Stimulation for Tic Counts, Tic Severity Scores, and Quality of Life. Measure
Presurgical, mean (SD)
Postsurgical, mean (SD)*
Pre–post score difference, mean
Raw p†
FDR-q
Pre–post effect size (Cohen’s d)
mRVRS YGTSS Tic SF-36 Physical Mental
17.0 (2.65) 37.2 (9.0)
14.4 (4.04) 28.2 (14.3)
2.6 9.0
0.36 0.26
0.79 0.79
0.76 0.75
40.7 (14.1) 41.2 (8.9)
48.5 (7.7) 49.0 (7.6)
7.8 7.8
0.31 0.09
0.79 0.70
0.69 0.94
*Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. FDR-q, false discovery rate-adjusted p value; mRVRS, modified Rush Video-Based Rating Scale; SF-36, 36-Item Short Form Health Survey; YGTSS, Yale Global Tic Severity Scale.
Table 2. Presurgical and Postsurgical Standardized T-Scores for Neuropsychological Tests in Deep Brain Stimulation. Measure Motor Finger tapping (dominant hand) Finger tapping (nondominant hand) General cognitive WRAT-3 Attention/executive measures Trails A Trails B SDMT written SDMT oral CPT-2 omissionsठCPT-2 commissionsठCPT-2 hit rateठStroop word Stroop color Stroop interference task WCST total errors Learning/memory measures RAVLT total RAVLT immediate delay RAVLT 30-min delay Visuoconstructional MCG copy MCG immediate delay MCG 30-min delay Language Boston Naming Test Letter fluency Semantic fluency
Raw p†
FDR-q
1.2 3.0
0.83 0.53
0.92 0.79
0.1 0.38
55.0 (2.6)
−1.6
0.41
0.79
−0.49
41.0 (7.6) 38.8 (7.9) 36.6 (7.8) 43.0 (9.3) 54.8 (17.0) 41.8 (7.4) 66.0 (10.7) 37.6 (10.0) 36.0 (11.6) 39.2 (11.6) 50.8 (5.0)
41.4 (10.5) 35.8 (6.8) 34.0 (11.0) 40.2 (16.7) 51.3 (8.7) 42.0 (9.9) 73.3 (11.5) 34.4 (7.3) 33.8 (9.1) 38.4 (8.6) 50.6 (5.5)
−0.4 3.0 2.6 2.8 3.5 −0.3 −7.3 3.2 2.2 0.8 0.2
0.94 0.61 0.47 0.59 0.79 0.97 0.05 0.25 0.39 0.81 0.92
0.97 0.79 0.79 0.79 0.92 0.97 0.70 0.79 0.79 0.92 0.97
−0.04 0.41 0.27 0.21 0.26 −0.02 −0.66 0.37 0.21 0.08 0.04
40.6 (6.8) 47.2 (11.3) 43.8 (9.4)
37.6 (15.0) 41.2 (19.0) 38.8 (18.4)
3.0 6.0 5.0
0.73 0.58 0.58
0.91 0.79 0.79
0.26 0.38 0.34
47.0 (13.0) 53.6 (9.6) 51.6 (9.1)
52.0 (4.8) 46.0 (9.7) 48.2 (9.0)
−5.0 7.6 3.4
0.49 0.13 0.51
0.79 0.79 0.79
−0.51 0.79 0.38
42.6 (8.6) 41.0 (7.0) 46.8 (2.2)
43.6 (9.0) 35.4 (6.4) 38.4 (9.1)
−1.0 5.6 8.4
0.54 0.26 0.08
0.79 0.79 0.70
−0.11 0.83 1.27
Presurgical, mean (SD)
Postsurgical, mean (SD)*
49.4 (11.1) 51.0 (6.6)
48.2 (13.1) 48.0 (9.1)
53.4 (3.8)
Pre–post score difference, mean
Pre–post effect size (Cohen’s d)
*Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. ‡ One subject was unable to complete the CPT-2 at presurgical visit, so means are based on N = 4. § Scores deviating more from a score of 50 represent worse (abnormal) performance. FDR-q, false discovery rate-adjusted p value; WRAT-3, Wide Range Achievement Test—Third Edition; Trails, Trail Making Test; SDMT, Symbol Digit Modalities Test; CPT-2, Conners’ Continuous Performance Test—Second Edition; WCST TE, Wisconsin Card Sorting Test; RAVLT, Rey Auditory Verbal Learning Test; MCG, Medical College of Georgia Complex Figure Test.
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Due to motor tics, one subject was unable to complete the CPT-2 at the presurgical visit. Analyses of the CPT-2 are limited to the four subjects completing both presurgical and 5-months-postsurgical visits. All other analyses are based on the entire sample of five participants. www.neuromodulationjournal.com
Postsurgical Neuropsychological Functioning Review of Table 2 indicates subjects scored impaired (T-scores < 40) on the Trail Making Test Part B, the written task of the Symbol Digit Modalities Test, CPT-2 hit rate, and the Stroop Color and Word test. In addition, the average score on the Rey Auditory Verbal
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Table 3. Presurgical and Postsurgical Raw Scores on Subjective Psychological Measures. Measure Mood BDI-2 HAM-A HAM-D Y-BOCS
Presurgical, mean (SD)
Postsurgical, mean (SD)*
Pre–post score difference, mean
Raw p†
FDR-q
Pre–post effect size (Cohen’s d)
10.6 (7.6) 16.4 (4.2) 13.6 (1.5) 12.6 (10.7)
4.2 (5.4) 8.0 (7.0) 9.6 (6.5) 7.0 (4.2)
6.4 8.4 4.0 5.6
0.28 0.07 0.27 0.24
0.79 0.70 0.79 0.79
0.97 1.46 0.85 0.69
Higher scores reflect more symptoms. *Five months after baseline; after 3 months of continuous deep brain stimulation. † Original p value of paired samples t-test. FDR-q, false discovery rate-adjusted p value; BDI-2, Beck Depression Inventory—Second Edition; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; Y-BOCS, Yale–Brown Obsessive Compulsive Scale..
Learning Test (total number of words recalled after five learning trials, words recalled after 30 min) indicated impairment. Letter (phonemic) and semantic verbal fluency test scores also indicated impairment. Depression and anxiety symptoms and obsessions and compulsions were generally in the nonclinical range (see Table 2).
Evaluation of Postsurgical Change in Neuropsychological Functioning Neuropsychological Measures Using repeated-measures ANOVA, there were no significant changes in scores across measures of attention/executive function, learning/memory, and language ability (see Table 2). No comparison met the FDR method constraint (critical value) for rejection, and the adjusted FDR-q values from statistical calculations (46) are provided in Table 2 (27,47). There were trend declines 5 months postsurgery in measures of psychomotor speed (CPT-2 hit rate; raw p = 0.05, adjusted FDR-q = 0.70) and semantic verbal fluency (raw p = 0.08, adjusted FDR-q = 0.70). Further evaluation of change using effect size calculations (Cohen’s d) (48) generally found the differences between presurgical and postsurgical neuropsychological test scores to be small (Cohen’s d ≤ 0.3)—less than a third of one standard deviation. However, the average declines in semantic verbal fluency and phonemic verbal fluency scores were large (Cohen’s d > 0.8). Declines of moderate effect size (i.e., d > 0.5) were observed for CPT-2 hit rate (d = 0.7) and immediate memory score for the visual memory task (d = 0.8). A medium-sized effect (d = 0.51) of improved performance was found for a visuoconstructional skill task (Table 3). Psychological Measures The average raw scores on the psychological tests before and 5 months following DBS surgery are displayed in Table 2. Decreasing trends were observed in symptoms of anxiety (HAM-A) and depression (BDI-2, HAM-D) at 5 months postoperative. Additionally, most participants reported a decrease in obsessions and compulsions 5 months after DBS surgery, with the average postoperative score falling into the nonclinical range.
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Individual Change Analyses Participants 1, 2, and 4 exhibited significant reductions in motor and sonic tics 3 months after DBS surgery, and participant 3 had a nonsignificant reduction in tics (21). Participant 5 had no change in motor or sonic tics following DBS surgery. Supporting Information Figures S1–S11 provide changes in selected outcome measures from preoperative baseline to 5-months-postoperative evaluation for each participant. Those with baseline scores in the impaired range and those with large effect size changes (d > 0.80) are indicated. Evaluation of correlation between response to DBS and neuropsychological outcome found limited relationships. Regardless of DBS outcome, participants tended to exhibit a decline in verbal fluency, with the exception of participant 4, who exhibited improved performance on neuropsychological tests and had a good response to DBS. In contrast, participant 2 exhibited a decline in scores on multiple neuropsychological tests, including Trail Making Test Part B, Symbol Digit Modalities Test, verbal fluency tests, and both memory tests. Most participants reported fewer symptoms of depression and anxiety 3 months after continuous DBS thalamic stimulation (5 months after surgical implantation), with the exception of participant 5, who reported more depression and anxiety symptoms. There was no consistent relationship between response to DBS and reductions in depression, anxiety, or obsessions/compulsions.
DISCUSSION This study provides cautious support for the cognitive safety of bilateral thalamic DBS in young adults with refractory TS. While several individuals exhibited a decline in measures of verbal fluency, verbal memory, and hit rate reaction time, these declines were generally less than what might be expected due to error and chance variables. These data extend Maciunas et al.’s (21) report that
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Stimulation Parameters and Outcome Maciunas et al. (21) reported stimulator settings for all five participants individually. For the group, the mean pulse amplitude for left side stimulation was 3.6 (minimum = 3.5, maximum = 3.6), pulse width of 132 μs (minimum = 90, maximum = 210) and pulse rate of 155 Hz (minimum = 130, maximum = 185). Average right-side stimulation settings were a pulse amplitude of 3.6 V (minimum = 3.5,
maximum = 3.6), pulse width of 126 μs (minimum = 90, maximum = 210), and pulse rate of 152 Hz (minimum = 130, maximum = 185). While research has suggested a potential relationship between DBS stimulation parameters and neuropsychological function in Parkinson’s disease (49), the limited sample size prevented quantitative analysis. Qualitatively, no consistent association was observed. While participant 2 had the highest DBS stimulator parameters (pulse amplitude of 3.6 V, pulse width of 210 μs, and pulse rate of 185 Hz; bilateral) and exhibited decline on most measures of neuropsychological function, the participant with the next highest stimulation parameters, participant 4, exhibited improved cognitive function at follow-up.
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bilateral DBS of the Cm-Pf resulted in significant reduction of motor and sonic tics for three of five participants with refractory TS. Neuropsychological outcome measures following 3 months of chronic bilateral thalamic DBS (5 months after surgical implantation) to treat refractory TS did not reveal marked neuropsychological morbidity; however, the average performance of participants declined on measures of sustained attention, verbal fluency, and memory. At an individual level, change in neuropsychological test scores was minimal for four of the five subjects. While participant 2 exhibited a decline in neuropsychological test scores (and had reduced tics with DBS), he did not show appreciable cognitive morbidity and reported fewer symptoms of depression and anxiety. In contrast, on average, participants’ anxiety and depression symptoms, as well as obsessions and compulsions, improved after 3 months of continuous DBS stimulation. The psychiatric finding that most participants experienced reductions in symptoms of anxiety and depression and in obsessive and compulsive behaviors mirrors observations of reduced anxiety following DBS for treatment of Parkinson’s disease (24). While it may be tempting to suggest that reductions in anxiety and depressive symptoms and in obsessions and compulsions are due to TS symptom relief, participant 3 had fewer symptoms of depression at follow-up despite not having a reduction in motor or sonic tics. Furthermore, there was no consistent association between decline in neuropsychological function after DBS and symptoms of anxiety or obsessions and compulsions. One possible interpretation of the improvements in anxiety and depressive symptoms after Cm-Pf bilateral DBS is a positive effect on the theorized disruption of the corticostriatothalamocortical circuit underlying TS (12–15,20,50). Our neuropsychological outcome data add substantively to the extant neuropsychological outcome data for adults with refractory TS undergoing Cm-Pf thalamic DBS. In particular, these data are consistent with one of two case reports of bilateral thalamic DBS for refractory TS, in which a decline in processing speed occurred (20). While there was no change in neuropsychological outcomes reported for 12 subjects by Porta et al. (23), the neuropsychological measures used by Porta et al. were limited and did not include measures of sustained attention or verbal memory. Our findings extend those of Porta et al. (23) that young adults can exhibit neuropsychological decline 5 months after undergoing Cm-Pf thalamic DBS. This conclusion is consistent with studies suggesting that DBS of VIM (26), STN, and GPi (24,25) for treatment of Parkinson’s disease and essential tremor do not result in pronounced cognitive morbidity but performance on measures of verbal fluency and memory significantly declines after DBS (24–26). Indeed, the effect size changes observed in this study are similar to those reported in a metaanalysis of STN-DBS in Parkinson’s disease for verbal fluency and memory (24). These data contribute significantly to the extant literature documenting neuropsychological outcome from Cm-Pf thalamic DBS for treatment of TS, in which we are aware of fewer than 30 individual cases published worldwide (20–23), and support and extend recommendations by Mink et al. (22). Generalizability of these results to adults with TS is increased, given that the preoperative neuropsychological results were similar to previous studies of subjects with TS and comorbid ADHD and/or OCD that found mild deficits in selected executive functions (Trails B, Stroop, and CPT-2) (12,13). While impaired scores on the Trail Making Test, CPT-2, and the written task of SDMT could be explained by severe motor tics, the lower scores for Trails B compared with Trails A (which also requires graphomotor skills) argue for abnormality (35). In contrast, there was no significant interference deficit assessed by the Stroop Color and Word Test, which is considered www.neuromodulationjournal.com
sensitive to deficits in behavioral inhibition and associated with anterior cingulate and ventrolateral prefrontal cortex activity (34). This may reflect recent observations that neuropsychological deficits in behavioral inhibition associated with TS are minimal (14,15). Several limitations of this study are noteworthy. First, study generalizability is limited due to small sample size. The sample size was limited by regulatory agencies. To mitigate experimental false negative errors, this study used a FDR procedure (27,47). The study also employed evaluation of effect size. A second limitation was that one subject (participant 3) suffered a head injury in a motor vehicle accident about 2 months after he underwent DBS surgery, confounding the ability to draw conclusions regarding the effect of DBS surgery and/or chronic high-frequency stimulation on his neuropsychological function. The participant reported a brief loss of consciousness in the motor vehicle accident. Brain imaging following the accident did not reveal any structural lesion or change in DBS electrode placement. Nevertheless, it is possible this participant’s neuropsychological function was adversely affected by the motor vehicle accident. Financial constraints limited follow-up data collection beyond the initial study design. While these data add substantively to documented neuropsychological outcomes from DBS for TS, the declines observed at 5 months in some subjects may not remain longer-term per the report of Porta et al. (23), in which no decline in neuropsychological function was observed 2 years after DBS implantation. While cognitive outcomes were generally good, evaluation of effect size suggested risks of neuropsychological comorbidity with possible declines in verbal fluency, reaction time, and verbal and visual memory. With the possibility of presurgical neuropsychological dysfunction and variable changes in neuropsychological function following DBS surgery, we recommend future studies incorporate a comprehensive neuropsychological assessment. Clearly, these data argue against only a brief neuropsychological assessment as suggested by Mink et al. (22). We also advise against using the grooved pegboard test (34), as several of our participants were unable to complete this task due to severe motor tics. Finally, with the variability in performances on executive function tests observed for patients with TS (14,15), we advise future trials incorporate more comprehensive testing of executive function than Mink et al. (22) and Porta et al. (23).
Acknowledgements This research was conducted with an investigational device exemption from the U.S. Food and Drug Administration (FDA) and with the approval of the University Hospitals Case Medical Center Institutional Review Board. We also thank Medtronic, Inc., for their financial support of this project through a physician-sponsored research agreement with Dr. Maciunas; without it, this study would not have been possible. Medtronic also provided deep brain surgical materials as part of investigator-initiated study support.
Authorship Statements Drs. Schoenberg, Maddux, Riley, Maciunas, Ogrocki, Gould, and Whitney designed and conducted the study, including participant recruitment, data collection, participant safety, surgical implantation, and data analyses. Dr. Schoenberg prepared the manuscript draft with important intellectual contributions from Drs. Maddux, Riley, and Maciunas. All authors except Dr. Maciunas approved the
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COGNITION AFTER DBS FOR TOURETTE SYNDROME final manuscript. Unfortunately, Dr. Maciunas died prior to the final manuscript being accepted for publication, but all substantive analyses, results, and conclusions had been completed, reviewed, and approved by him prior to his death. Statistical analyses were completed by Drs. Schoenberg and Maddux with input from Drs. Riley and Maciunas. Drs. Maddux, Maciunas, and Schoenberg had complete access to the study data.We would like to dedicate this article to the memory of Robert J. Maciunas, MD, a wonderful friend and a truly phenomenal clinician, teacher, researcher, and colleague.
How to Cite this Article: Schoenberg M.R., Maddux B.N., Riley D.E., Whitney C.M., Ogrocki P.K., Gould D., Maciunas R.J. 2015. Five-MonthsPostoperative Neuropsychological Outcome From a Pilot Prospective Randomized Clinical Trial of Thalamic Deep Brain Stimulation for Tourette Syndrome. Neuromodulation 2015; 18: 97–104
REFERENCES
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1. Individual changes in Conners’ Continuous Performance Test hit rate T-score. Figure S2. Individual changes in time to complete Trails B T-score. Figure S3. Individual changes in Rey Auditory Verbal Learning Test words recalled after short-delay T-score. Figure S4. Individual changes in Rey Auditory Verbal Learning Test words recalled after 30-min-delay T-score. Figure S5. Individual changes in semantic verbal fluency T-score.
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SCHOENBERG ET AL. Figure S6. Individual changes in total letter (phonemic) fluency T-score.
Figure S11. Individual changes in total obsessive and compulsive symptoms (raw scores).
Figure S7. Individual changes in T-score for Medical College of Georgia Complex Figure Test after an immediate-delay.
COMMENT
Figure S8. Changes in Beck Depression Inventory symptoms reported (raw scores).
This paper provides important safety data on the neuropsychological profiles in patients undergoing Tourette Syndrome DBS.
Figure S9. Individual changes in Hamilton Anxiety symptoms (raw scores).
Michael Okun, M.D. Gainesville, FL, USA
Figure S10. Individual changes in Hamilton Depression symptoms (raw scores).
Comments not included in the Early View version of this paper.
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