Publications by authors named "Joohi Jimenez-Shahed"

72 Publications

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

JAMA Netw Open 2021 Oct 1;4(10):e2129397. Epub 2021 Oct 1.

Teva Pharmaceuticals, Netanya, Israel.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia.

Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome.

Design, Setting, And Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020.

Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period.

Main Outcomes And Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires.

Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate.

Conclusions And Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified.

Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.29397DOI Listing
October 2021

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation.

Stereotact Funct Neurosurg 2021 Oct 14:1-4. Epub 2021 Oct 14.

Department of Neurosurgery, Center for Neuromodulation, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.
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http://dx.doi.org/10.1159/000519578DOI Listing
October 2021

Safety and Efficacy of Flexible-Dose Deutetrabenazine in Children and Adolescents With Tourette Syndrome: A Randomized Clinical Trial.

JAMA Netw Open 2021 Oct 1;4(10):e2128204. Epub 2021 Oct 1.

Teva Pharmaceuticals, Netanya, Israel.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults.

Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents.

Design, Setting, And Participants: This phase 2/3, randomized, double-masked, placebo-controlled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] ≥20). The trial was conducted over 12 weeks, with 1 week of follow-up from February 2018 to November 2019 at 36 centers in the United States, Canada, Denmark, Russia, Serbia, and Spain. Data analysis was conducted from January 31 to April 22, 2020.

Intervention: Patients were randomized (1:1) to receive deutetrabenazine or placebo, titrated during 7 weeks to an optimal level, followed by a 5-week maintenance period. The maximum total daily deutetrabenazine dose was 48 mg/d.

Main Outcomes And Measures: The primary efficacy end point was change from baseline to week 12 in YGTSS-TTS. Key secondary end points included changes in Tourette Syndrome-Clinical Global Impression, Tourette Syndrome-Patient Global Impression of Impact, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety was assessed based on treatment-emergent adverse events, vital signs, questionnaires, and laboratory parameters.

Results: A total of 119 participants were randomized to deutetrabenazine (59 participants; mean [SD] age, 11.5 [2.5] years; 53 [90%] boys; 49 [83%] White; 3 [5%] Black) and placebo (60 participants; mean [SD] age, 11.5 [2.6] years; 51 [85%] boys; 53 [88%] White; 3 [5%] Black). At week 12, the difference in YGTSS-TTS score was not significant between deutetrabenazine and placebo (least squares mean difference, -0.7; 95% CI, -4.1 to 2.8; P = .69; Cohen d, -0.07). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 38 patients (66%) and 33 patients (56%) receiving deutetrabenazine and placebo, respectively, and were generally mild or moderate.

Conclusions And Relevance: In this study of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. These results may be informative for future studies of treatments for tics in Tourette syndrome.

Trial Registration: ClinicalTrials.gov Identifier: NCT03452943.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493441PMC
October 2021

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

JAMA 2021 09;326(10):926-939

University of Cincinnati, Cincinnati, Ohio.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.

Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.

Design, Participants, And Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.

Main Outcomes And Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions And Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.
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http://dx.doi.org/10.1001/jama.2021.10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441591PMC
September 2021

Long-Term Deutetrabenazine Treatment Is Associated With Continued Improvement in Tardive Dyskinesia in the Completed 3-Year Open-Label Extension Study.

CNS Spectr 2021 04;26(2):162

Georgetown University, Washington, DC, USA.

Background: The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C-20) evaluated long-term efficacy and safety of deutetrabenazine in TD.

Methods: Patients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being "much improved" or "very much improved" on Clinical Global Impression of Change (CGIC).

Results: 343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was -4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was -5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was -6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.

Conclusions: Patients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002606DOI Listing
April 2021

Effect of Deutetrabenazine on Metabolic Parameters in the Treatment of Tardive Dyskinesia.

CNS Spectr 2021 04;26(2):159-160

Teva Pharmaceuticals, Basel, Switzerland.

Background: Deutetrabenazine, a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. Dopamine-receptor antagonists (DRAs) are associated with worsening of metabolic parameters, including weight gain, hyperlipidemia, and elevated blood glucose. This post hoc analysis assessed the short- and long-term effects of deutetrabenazine treatment on weight and metabolic parameters in individuals treated for TD.

Methods: Two 12-week, randomized placebo-controlled trials (RCTs) of deutetrabenazine for patients with TD evaluated either fixed dosing (AIM-TD; 12, 24, or 36 mg) or dose titration (ARM-TD; max dose, 48 mg/day). Patients completing ARM-TD or AIM-TD were included in an open-label extension (OLE) study, in which all patients underwent response-driven titration of deutetrabenazine from 12 mg/day up to a maximum total dose of 48 mg/day. Weight, body mass index (BMI), serum glucose, serum total cholesterol, and serum triglycerides were evaluated at baseline and during treatment in the RCTs and in the OLE.

Results: In the RCTs, 282 and 133 patients received deutetrabenazine or placebo. At baseline, 77% of patients used DRAs. At Week 12, no meaningful changes in weight were observed, with mean (standard error) weight changes of 0.9-1.2 (0.3-0.5) and 0.2 (0.3) kg in the deutetrabenazine and placebo groups, respectively, and mean BMI changes of 0.3-0.5 (0.1-0.2) and 0.1 (0.1) kg/m2. 337 patients were included in the analysis of the OLE study. No meaningful changes were observed in weight (mean change: 0.4 [0.4] kg at Week 54, -0.5 [0.6] kg at Week 106, and -1.1 [0.6] kg at Week 145) or BMI (mean change: 0.1 [0.2] kg/m2 at Week 54, -0.2 [0.2] kg/m2 at Week 106, and -0.3 [0.2] kg/m2 at Week 145). Across the studies, no meaningful changes were observed in triglyceride, cholesterol, or glucose levels.

Conclusion: Deutetrabenazine does not affect common metabolic parameters in patients with TD, even during long-term exposure.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002564DOI Listing
April 2021

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

Neuromodulation 2021 May 27. Epub 2021 May 27.

Department of Neurosurgery, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

Objective: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.

Materials And Methods: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs. omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.

Results: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs. 21.2% (41/193) who preferred the omnidirectional period.

Conclusion: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.
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http://dx.doi.org/10.1111/ner.13407DOI Listing
May 2021

Response to "Comment on: "Point of view: Wearable systems for at-home monitoring of motor complications in Parkinson's disease should deliver clinically actionable information".

Parkinsonism Relat Disord 2021 05 17;86:134. Epub 2021 Apr 17.

Icahn School of Medicine at Mount Sinai, New York City, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2021.04.015DOI Listing
May 2021

Dyskinesia estimation during activities of daily living using wearable motion sensors and deep recurrent networks.

Sci Rep 2021 04 12;11(1):7865. Epub 2021 Apr 12.

Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA.

Levodopa-induced dyskinesias are abnormal involuntary movements experienced by the majority of persons with Parkinson's disease (PwP) at some point over the course of the disease. Choreiform as the most common phenomenology of levodopa-induced dyskinesias can be managed by adjusting the dose/frequency of PD medication(s) based on a PwP's motor fluctuations over a typical day. We developed a sensor-based assessment system to provide such information. We used movement data collected from the upper and lower extremities of 15 PwPs along with a deep recurrent model to estimate dyskinesia severity as they perform different activities of daily living (ADL). Subjects performed a variety of ADLs during a 4-h period while their dyskinesia severity was rated by the movement disorder experts. The estimated dyskinesia severity scores from our model correlated highly with the expert-rated scores (r = 0.87 (p < 0.001)), which was higher than the performance of linear regression that is commonly used for dyskinesia estimation (r = 0.81 (p < 0.001)). Our model provided consistent performance at different ADLs with minimum r = 0.70 (during walking) to maximum r = 0.84 (drinking) in comparison to linear regression with r = 0.00 (walking) to r = 0.76 (cutting food). These findings suggest that when our model is applied to at-home sensor data, it can provide an accurate picture of changes of dyskinesia severity facilitating effective medication adjustments.
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http://dx.doi.org/10.1038/s41598-021-86705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041801PMC
April 2021

Ensemble deep model for continuous estimation of Unified Parkinson's Disease Rating Scale III.

Biomed Eng Online 2021 Mar 31;20(1):32. Epub 2021 Mar 31.

Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA.

Background: Unified Parkinson Disease Rating Scale-part III (UPDRS III) is part of the standard clinical examination performed to track the severity of Parkinson's disease (PD) motor complications. Wearable technologies could be used to reduce the need for on-site clinical examinations of people with Parkinson's disease (PwP) and provide a reliable and continuous estimation of the severity of PD at home. The reported estimation can be used to successfully adjust the dose and interval of PD medications.

Methods: We developed a novel algorithm for unobtrusive and continuous UPDRS-III estimation at home using two wearable inertial sensors mounted on the wrist and ankle. We used the ensemble of three deep-learning models to detect UPDRS-III-related patterns from a combination of hand-crafted features, raw temporal signals, and their time-frequency representation. Specifically, we used a dual-channel, Long Short-Term Memory (LSTM) for hand-crafted features, 1D Convolutional Neural Network (CNN)-LSTM for raw signals, and 2D CNN-LSTM for time-frequency data. We utilized transfer learning from activity recognition data and proposed a two-stage training for the CNN-LSTM networks to cope with the limited amount of data.

Results: The algorithm was evaluated on gyroscope data from 24 PwP as they performed different daily living activities. The estimated UPDRS-III scores had a correlation of [Formula: see text] and a mean absolute error of 5.95 with the clinical examination scores without requiring the patients to perform any specific tasks.

Conclusion: Our analysis demonstrates the potential of our algorithm for estimating PD severity scores unobtrusively at home. Such an algorithm could provide the required motor-complication measurements without unnecessary clinical visits and help the treating physician provide effective management of the disease.
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http://dx.doi.org/10.1186/s12938-021-00872-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010504PMC
March 2021

Device profile of the percept PC deep brain stimulation system for the treatment of Parkinson's disease and related disorders.

Expert Rev Med Devices 2021 Apr 5;18(4):319-332. Epub 2021 Apr 5.

Movement Disorders Neuromodulation & Brain Circuit Therapeutics, Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, USA.

Introduction: Several software and hardware advances in the field of deep brain stimulation (DBS) have been realized in recent years and devices from three manufacturers are available. The Percept™ PC platform (Medtronic, Inc.) enables brain sensing, the latest innovation. Clinicians should be familiar with the differences in devices, and with the latest technologies to deliver optimized patient care.: In this device profile, the sensing capabilities of the Percept™ PC platform are described, and the system capabilities are differentiated from other available platforms. The development of the preceding Activa™ PC+S research platform, an investigational device to simultaneously sense brain signals and provide therapeutic stimulation, is provided to place Percept™ PC in the appropriate context.: Percept™ PC offers unique sensing and diary functions as a means to refine therapeutic stimulation, track symptoms and correlate them to neurophysiologic characteristics. Additional features enhance the patient experience with DBS, including 3 T magnetic resonance imaging compatibility, wireless telemetry, a smaller and thinner battery profile, and increased battery longevity. Future work will be needed to illustrate the clinical utility and added value of using sensing to optimize DBS therapy. Patients implanted with Percept™ PC will have ready access to future technology developments.
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http://dx.doi.org/10.1080/17434440.2021.1909471DOI Listing
April 2021

The 5 Pillars in Tourette Syndrome Deep Brain Stimulation Patient Selection: Present and Future.

Neurology 2021 04 16;96(14):664-676. Epub 2021 Feb 16.

From the Department of Clinical Neurosciences (D.M., T.M.P.), Cumming School of Medicine, University of Calgary, Calgary AB, Canada; Hotchkiss Brain Institute (D.M., T.M.P.), University of Calgary, Calgary AB, Canada; Alberta Children's Hospital Research Institute (D.M.), University of Calgary, Calgary AB, Canada; Mathison Centre for Mental Health Research and Education (D.M., T.M.P.), Calgary, AB, Canada; UMass Memorial Medical Center and UMass Medical School (W.D.), Worcester, MA, United States; Department of Neurology (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Neurology (I.M., M.S.O.), Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, United States; Department of Psychiatry (T.M.P.), Pediatrics and Community Health Sciences, University of Calgary, AB, Canada; Edmond J. Safra Program in Parkinson's Disease (A.F.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute (A.F.), Toronto, Ontario, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA) (A.F.), Toronto, ON, Canada; Movement Disorders and Neuromodulation Unit (C.G.), Charité, University Medicine Berlin, Department of Neurology, Berlin, Germany; and Strategic Regulatory Partners (W.W.), LLC.

The selection of patients with Tourette syndrome (TS) for deep brain stimulation (DBS) surgery rests on 5 fundamental pillars. However, the operationalization of the multidisciplinary screening process to evaluate these pillars remains highly diverse, especially across sites. High tic severity and tic-related impact on quality of life (first 2 pillars) require confirmation from objective, validated measures, but malignant features of TS should per se suffice to fulfill this pillar. Failure of behavioral and pharmacologic therapies (third pillar) should be assessed taking into account refractoriness through objective and subjective measures supporting lack of efficacy of all interventions of proven efficacy, as well as true lack of tolerability, adherence, or access. Educational interventions and use of remote delivery formats (for behavioral therapies) play a role in preventing misjudgment of treatment failure. Stability of comorbid psychiatric disorders for 6 months (fourth pillar) is needed to confirm the predominant impact of tics on quality of life, to prevent pseudo-refractoriness, and to maximize the future DBS response. The 18-year age limit (fifth pillar) is currently under reappraisal, considering the potential impact of severe tics in adolescence and the predictive effect of tic severity in childhood on tic severity when transitioning into adulthood. Future advances should aim at a consensus-based definition of failure of specific, noninvasive treatment strategies for tics and of the minimum clinical observation period before considering DBS treatment, the stability of behavioral comorbidities, and the use of a prospective international registry data to identify predictors of positive response to DBS, especially in younger patients.
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http://dx.doi.org/10.1212/WNL.0000000000011704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105965PMC
April 2021

Parkinson's disease mortality and socioeconomic status: New information from a Korean study.

Parkinsonism Relat Disord 2020 11 18;80:212-213. Epub 2020 Nov 18.

Bonnie and Tom Strauss Movement Disorders Center, Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.11.005DOI Listing
November 2020

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia.

Expert Rev Neurother 2021 Jan 23;21(1):9-20. Epub 2020 Nov 23.

Movement Disorders Neuromodulation & Brain Circuit Therapeutics, Departments of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai , New York, NY, USA.

: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that arises as a complication of exposure to dopamine receptor blocking agents. Vesicular monoamine transporter type 2 (VMAT2) inhibitors reduce dyskinesia by decreasing transport of monoamines, including dopamine, into presynaptic vesicles, leaving unpackaged dopamine to be metabolized by monoamine oxidase. Deutetrabenazine was adapted from an earlier VMAT2 inhibitor, tetrabenazine, by substituting three deuterium isotopes in place of three hydrogen isotopes at the site of metabolic degradation to improve upon the pharmacokinetics of the parent compound. : The authors reviewed the pivotal trials examining the safety and efficacy of deutetrabenazine, as well as long-term data from an open-label extension. Also reviewed were posters and oral presentations, as well as information from the product label and the United States Food and Drug Administration. : Deutetrabenazine is effective at decreasing dyskinesia in TD, but drug selection and cost-effectiveness between existing VMAT2 inhibitors are evolving areas of study. Other areas of investigation include novel anti-dyskinetic agents and use of deep brain stimulation.
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http://dx.doi.org/10.1080/14737175.2021.1848548DOI Listing
January 2021

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

Neurology 2021 01 12;96(4):e563-e574. Epub 2020 Oct 12.

From the Departments of Biomedical Engineering (A.G.S., S.B.B.) and Neurology (A.G.S.), Case Western University School of Medicine; Neurological Institute (A.G.S.), University Hospitals Cleveland; Neurology Service (A.G.S.), Louis Stokes Cleveland VA Medical Center, OH; Department of Neurology (L.S., G.K.-B., A.F., S. Factor, H.A.J.), Human Genetics (H.A.J.), and Pediatrics (H.A.J.), Emory University School of Medicine, Atlanta, GA; Institute of Neurogenetics (C.K., J.J., S.L., N.B., A.M., T.B.), University of Lübeck, Germany; Department of Neurology (M.V., E.R., C.B.), Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (J.J.), Baylor College of Medicine, Houston, TX; Neurology and Neurosurgery (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurology (N.P.), Henry Ford Health System, West Bloomfield, MI; Department of Psychiatry and Neurology (L.M.), Baylor College of Medicine, Houston, TX; Department of Neurological Sciences (C.C.), Rush University Medical Center, Chicago, IL; Department of Neurology (R.L.B.), University of Rochester, NY; Department of Neurology (B.D.B.), University of Colorado School of Medicine, Aurora; Department of Neurology (I.M., A.W.S.), Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville; Department of Neurology (S.G.R.), University of Maryland School of Medicine, Baltimore; University of Tennessee Health Science Center (M.S.L.), Memphis; Department of Neurosciences (A.B.), Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome; IRCCS Neuromed (G.F.), Pozzilli, Italy; The University of Alabama at Birmingham (N.S.); Methodist Neurological Institute (W.O.), Houston, TX; Department of Neurology (S.P.R.), University of New Mexico Health Sciences Center, Albuquerque; Department of Neurology (R.S.-P.), Mount Sinai Beth Israel, New York, NY; Lou Ruvo Center for Brain Health (Z.M.), Cleveland Clinic, Las Vegas, NV; Booth Gardner Parkinson's Care Center (P.A.), Kirkland, WA; Mayo Clinic (C.A.), Scottsdale, AZ; Andre Barbeau Movement Disorders Unit (S.C.), Montreal University Hospital Center (CHUM); Movement Disorder Clinic (S.H.F.), Toronto Western Hospital, Division of Neurology University of Toronto, Canada; UC Davis School of Medicine (A.B.), Sacramento; The Parkinson's and Movement Disorder Institute (D.T.), Orange Coast Memorial Medical Center, Fountain Valley, CA; Department of Medicine (O.S.), Medical Genetics, and Pediatrics, University of Alberta, Canada; Department of Neurology (S. Frank), Beth Israel Deaconess Medical Center, Boston, MA; and Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy (J.P.), Washington University School of Medicine, St Louis, MO.

Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.

Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.

Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.

Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.
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http://dx.doi.org/10.1212/WNL.0000000000011049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905789PMC
January 2021

Dyskinesia Severity Estimation in Patients with Parkinson's Disease Using Wearable Sensors and A Deep LSTM Network.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:6001-6004

Dyskinesias are abnormal involuntary movements that patients with mid-stage and advanced Parkinson's disease (PD) may suffer from. These troublesome motor impairments are reduced by adjusting the dose or frequency of medication levodopa. However, to make a successful adjustment, the treating physician needs information about the severity rating of dyskinesia as patients experience in their natural living environment. In this work, we used movement data collected from the upper and lower extremities of PD patients along with a deep model based on Long Short-Term Memory to estimate the severity of dyskinesia. We trained and validated our model on a dataset of 14 PD subjects with dyskinesia. The subjects performed a variety of daily living activities while their dyskinesia severity was rated by a neurologist. The estimated dyskinesia severity ratings from our developed model highly correlated with the neurologist-rated dyskinesia scores (r=0.86 (p<0.001) and 1.77 MAE (6%)) indicating the potential of the developed the approach in providing the information required for effective medication adjustments for dyskinesia management.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176847DOI Listing
July 2020

Randomized, Double-Blind Assessment of LFP Versus SUA Guidance in STN-DBS Lead Implantation: A Pilot Study.

Front Neurosci 2020 12;14:611. Epub 2020 Jun 12.

Department of Biomedical Engineering, University of Houston, Houston, TX, United States.

The efficacy of deep brain stimulation (DBS) therapy in Parkinson's disease (PD) patients is highly dependent on the precise localization of the target structures such as subthalamic nucleus (STN). Most commonly, microelectrode single unit activity (SUA) recordings are performed to refine the target. This process is heavily experience based and can be technically challenging. Local field potentials (LFPs), representing the activity of a population of neurons, can be obtained from the same microelectrodes used for SUA recordings and allow flexible online processing with less computational complexity due to lower sampling rate requirements. Although LFPs have been shown to contain biomarkers capable of predicting patients' symptoms and differentiating various structures, their use in the localization of the STN in the clinical practice is not prevalent. Here we present, for the first time, a randomized and double-blinded pilot study with intraoperative online LFP processing in which we compare the clinical benefit from SUA- versus LFP-based implantation. Ten PD patients referred for bilateral STN-DBS were randomly implanted using either SUA or LFP guided targeting in each hemisphere. Although both SUA and LFP were recorded for each STN, the electrophysiologist was blinded to one at a time. Three months postoperatively, the patients were evaluated by a neurologist blinded to the intraoperative recordings to assess the performance of each modality. While SUA-based decisions relied on the visual and auditory inspection of the raw traces, LFP-based decisions were given through an online signal processing and machine learning pipeline. We found a dramatic agreement between LFP- and SUA-based localization (16/20 STNs) providing adequate clinical improvement (51.8% decrease in 3-month contralateral motor assessment scores), with LFP-guided implantation resulting in greater average improvement in the discordant cases (74.9%, = 3 STNs). The selected tracks were characterized by higher activity in beta (11-32 Hz) and high-frequency (200-400 Hz) bands ( < 0.01) of LFPs and stronger non-linear coupling between these bands ( < 0.05). Our pilot study shows equal or better clinical benefit with LFP-based targeting. Given the robustness of the electrode interface and lower computational cost, more centers can utilize LFP as a strategic feedback modality intraoperatively, in conjunction to the SUA-guided targeting.
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http://dx.doi.org/10.3389/fnins.2020.00611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325925PMC
June 2020

Impulsivity and Compulsivity After Subthalamic Deep Brain Stimulation for Parkinson's Disease.

Front Behav Neurosci 2020 23;14:47. Epub 2020 Apr 23.

Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Impulsivity and compulsivity are prominent non-motor problems in Parkinson's disease (PD). Despite 20 years of research, there is still an ongoing debate as to whether subthalamic deep brain stimulation (STN DBS) for PD exacerbates or improves these symptoms. Here, we review how STN DBS affects clinical symptoms and neurocognitive aspects of impulsivity and compulsivity. When comparing patients post- to pre-surgery, in the majority of studies STN DBS for PD is associated with a decrease in clinically diagnosed impulse-control disorders and disorders of compulsivity. To avoid confounds, such as post-surgical decreases in dopaminergic medication doses, comparisons can also be made between DBS "On" versus "Off" conditions. These experimentally assayed effects of STN DBS with respect to neurocognitive aspects of impulsivity and compulsivity are more mixed. STN DBS improves behavioral flexibility without impairing negative feedback learning, delay discounting, or inhibitory control, as long as stimulation is restricted to the dorsal STN. However, STN DBS may drive impulsive actions when a subject is faced with competing choices. We discuss how motivated responses may be either enhanced or impaired by STN DBS depending on engagement of dorsal or ventral STN-mediated circuits. Future studies should combine structural and functional circuit measures with behavioral testing in PD patients on and off medication and stimulation. A more sophisticated understanding of how to modulate cortico-striatal-thalamo-cortical loops will increase the likelihood that these circuit manipulation techniques can successfully be applied to a wider range of neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fnbeh.2020.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191054PMC
April 2020

Subthalamic Single Cell and Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient With Parkinson's Disease.

Front Neurosci 2020 24;14:391. Epub 2020 Apr 24.

Department of Biomedical Engineering, University of Houston, Houston, TX, United States.

Single cell neuronal activity (SUA) and local field potentials (LFP) in the subthalamic nucleus (STN) of unmedicated Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery have been well-characterized during microelectrode recordings (MER). However, there is limited knowledge about the changes in the firing patterns and oscillations above and within the territories of STN after the intake of dopaminergic medication. Here, for the first time, we report the STN single cell and oscillatory neural dynamics in a medicated patient with idiopathic PD using intraoperative MER. We recorded LFP and SUA with microelectrodes at various depths during bilateral STN-DBS electrode implantation. We isolated 26 neurons in total and observed that tonic and irregular firing patterns of individual neurons predominated throughout the territories of STN. While burst-type firings have been well-characterized in the dorsal territories of STN in unmedicated patients, interestingly, this activity was not observed in our medicated subject. LFP recordings lacked the excessive beta (8-30 Hz) activity, characteristic of the unmedicated state and signal energy was mainly dominated by slow oscillations below 8 Hz. We observed sharp gamma oscillations between 70 and 90 Hz within and above the STN. Despite the presence of a broadband high frequency activity in 200-400 Hz range, no cross-frequency interaction in the form of phase-amplitude coupling was noted between low and high frequency oscillations of LFPs. While our results are in agreement with the previously reported LFP recordings from the DBS lead in medicated PD patients, the sharp gamma peak present throughout the depth recordings and the lack of bursting firings after levodopa intake have not been reported before. The lack of bursting in SUA, the lack of excessive beta activity and cross frequency coupling between HFOs and lower rhythms further validate the link between bursting firing regime of neurons and pathological oscillatory neural activity in PD-STN. Overall, these observations not only validate the existing literature on the PD electrophysiology in healthy/medicated animal models but also provide insights regarding the underlying electro-pathophysiology of levodopa-induced dyskinesias in PD patients through demonstration of multiscale relationships between single cell firings and field potentials.
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http://dx.doi.org/10.3389/fnins.2020.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193777PMC
April 2020

Medical and Surgical Treatments of Tourette Syndrome.

Neurol Clin 2020 05 9;38(2):349-366. Epub 2020 Mar 9.

Movement Disorders Neuromodulation & Brain Circuit Therapeutics, Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai West, 1000 10th Avenue, Suite 10C, New York, NY 10019, USA. Electronic address:

Tourette syndrome is a complex neuropsychiatric disorder with a wide phenotypic spectrum, including tics and psychiatric comorbidities, such as obsessive-compulsive disorder and attention-deficit disorder. Often considered a neurodevelopmental disorder, it is most prevalent during childhood and treatment strategies can vary according to degree of severity and patient-specific symptom manifestations. This review focuses on established and emerging management options for tics, including behavioral interventions and nonpharmacologic therapies, medication management, and promising surgical approaches.
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http://dx.doi.org/10.1016/j.ncl.2020.01.006DOI Listing
May 2020

Grouping Neuronal Spiking Patterns in the Subthalamic Nucleus of Parkinsonian Patients.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:4221-4224

The subthalamic nucleus (STN) is a commonly used target in deep brain stimulation (DBS) to control the motor symptoms of Parkinson's Disease (PD). Identification of the spiking patterns in the STN is important in order to understand the neuropathophysiology of PD and can also assist in electrophysiological mapping of the structure. This study aims to provide a tool for grouping these firing patterns based on several extracted features from the spiking data. Single neuronal activity from the STN of PD subjects was detected and sorted to compute the binary spike trains. Several features including loca variation, bursting index and the prominence of the peak frequency of the power spectrum were extracted. Clustering of spike train segments was performed based on combination of features in 3D space to scrutinize how well they describe different firing regimes. The results show that this approach could be used to automate the grouping of stereotypic firing patterns in STN.
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http://dx.doi.org/10.1109/EMBC.2019.8857418DOI Listing
July 2019

Acute readmission following deep brain stimulation surgery for Parkinson's disease: A nationwide analysis.

Parkinsonism Relat Disord 2020 01 19;70:96-102. Epub 2019 Dec 19.

Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Introduction: Deep brain stimulation (DBS) surgery is an efficacious, underutilized treatment for Parkinson's disease (PD). Studies of DBS post-operative outcomes are often restricted to data from a single center and consider DBS in isolation. National estimates of DBS readmission and post-operative outcomes are needed, as are comparisons to commonly performed surgeries.

Methods: This study used datasets from the 2013 and 2014 Nationwide Readmissions Database (NRD). Our sample was restricted to PD patients discharged alive after hospitalization for DBS surgery. Descriptive analyses examined patient, clinical, hospital and index hospitalization characteristics. The all-cause, non-elective 30-day readmission rate after DBS was calculated, and logistic regression models were built to examine factors associated with readmission. Readmission rates for the most common surgical procedures were calculated and compared to DBS.

Results: There were 6058 DBS surgeries for PD in our sample, most often involving a male aged 65 and older, who lived in a high socioeconomic status zip code. DBS patients had an average of four comorbidities. With respect to outcomes, the majority of patients were discharged home (95.3%). Non-elective readmission was rare (4.9%), and was associated with socioeconomic status, comorbidity burden, and teaching hospital status. Much higher acute, non-elective readmission rates were observed for common procedures such as upper gastrointestinal endoscopy (16.2%), colonoscopy (14.0%), and cardiac defibrillator and pacemaker procedures (11.1%).

Conclusion: Short-term hospitalization outcomes after DBS are generally favorable. Socioeconomic disparities in DBS use persist. Additional efforts may be needed to improve provider referrals for and patient access to DBS.
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http://dx.doi.org/10.1016/j.parkreldis.2019.11.023DOI Listing
January 2020

Wearable Sensors for Estimation of Parkinsonian Tremor Severity during Free Body Movements.

Sensors (Basel) 2019 Sep 28;19(19). Epub 2019 Sep 28.

Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA.

Tremor is one of the main symptoms of Parkinson's Disease (PD) that reduces the quality of life. Tremor is measured as part of the Unified Parkinson Disease Rating Scale (UPDRS) part III. However, the assessment is based on onsite physical examinations and does not fully represent the patients' tremor experience in their day-to-day life. Our objective in this paper was to develop algorithms that, combined with wearable sensors, can estimate total Parkinsonian tremor as the patients performed a variety of free body movements. We developed two methods: an ensemble model based on gradient tree boosting and a deep learning model based on long short-term memory (LSTM) networks. The developed methods were assessed on gyroscope sensor data from 24 PD subjects. Our analysis demonstrated that the method based on gradient tree boosting provided a high correlation ( = 0.96 using held-out testing and = 0.93 using subject-based, leave-one-out cross-validation) between the estimated and clinically assessed tremor subscores in comparison to the LSTM-based method with a moderate correlation ( = 0.84 using held-out testing and = 0.77 using subject-based, leave-one-out cross-validation). These results indicate that our approach holds great promise in providing a full spectrum of the patients' tremor from continuous monitoring of the subjects' movement in their natural environment.
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http://dx.doi.org/10.3390/s19194215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806340PMC
September 2019

Multilevel Features for Sensor-Based Assessment of Motor Fluctuation in Parkinson's Disease Subjects.

IEEE J Biomed Health Inform 2020 05 26;24(5):1284-1295. Epub 2019 Sep 26.

Motor fluctuations are a frequent complication in patients with Parkinson's disease (PD) where the response to medication fluctuates between ON states (medication working) and OFF states (medication has worn off). This paper describes a new data analysis approach that can be used along with two wearable IMU (inertial measurement units) sensors to continuously assess motor fluctuations in PD patients while moving in their natural environment. We hypothesized that joint analysis of the sensor data in its spectral, temporal and sensor domain could generate multilevel features that can be used to detect PD-related patterns successfully as the subject's motor state fluctuates between medication ON and OFF states. For this purpose, we utilized time-frequency (TF) representation and multiway data analysis tools (i.e., tensor decomposition) to decompose the TF representation of the two sensors' data into its multilevel structures, which were next used to extract multilevel features representing the PD symptoms in different medication states. The extracted multilevel features were used in a classification model based on support vector machine to detect medication ON and OFF states. For comparison purposes, we implemented a traditional feature extraction method. We also developed a hierarchical feature extraction method based on the combination of those two methods. The performances of the three methods were evaluated using a dataset of 19 PD subjects with a total duration of 17.54 hours. The multilevel features achieved 8.25% improvement in the accuracy over the traditional features, and the hierarchical features resulted in 10.73% improvement indicating that our approach holds great promise to continuously detect medication states from continuous monitoring of the subjects' movement. Such information can be used by the treating physician to tailor the adjustments to each subject's unique impairment(s), thereby improving therapeutic decision-making and patient outcomes.
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http://dx.doi.org/10.1109/JBHI.2019.2943866DOI Listing
May 2020

Distinct subthalamic coupling in the ON state describes motor performance in Parkinson's disease.

Mov Disord 2020 01 26;35(1):91-100. Epub 2019 Jul 26.

Department of Biomedical Engineering, University of Houston, Houston, Texas, USA.

Objective: Cross-frequency coupling has been reported in the STN of patients with PD, but its significance and functional role are still not well understood. This study investigates pharmacological modulations of subthalamic oscillations and their nonlinear cross-frequency interactions across three consecutive cycles over unique 24-hour-long recordings.

Background: Identifying neurobiomarkers for PD can drive the development of novel personalized treatments by providing objective assessment of impairment. In particular, distinct frequency bands in LFP recordings and their interaction with one another have been shown to modulate with dopaminergic medication and thus, proposed as such biomarkers.

Methods: We recorded local field potentials 3 weeks postoperatively from externalized leads in 9 patients and correlated the neural patterns with improvements in motor signs over three medication intake cycles. We used two modalities to assess symptoms in the unmedicated OFF and the l-dopa-induced motor ON state: a subsection of the UPDRS and a keyboard tapping score measuring bradykinesia.

Results: In the OFF state, the amplitude of high-frequency oscillations in the 200- to 300-Hz range was coupled with the phase of low-beta (13-22 Hz) in all patients. After transition to the ON state, three distinct coupling patterns were observed among subjects. Among these, patients showing ON coupling between high-beta (22-30 Hz) and high-frequency oscillations in the 300- to 400-Hz range had significantly greater improvement in bradykinesia, according to the keyboard scores.

Conclusion: Observing diminished coupling in the ON state, previous studies have hypothesized that the sole existence of coupling in STN has an "impeding" effect on normal processes, and thus it was considered to be pathological. In contrast, our observation of ON state coupling at distinct frequencies associated with the improvements in motor features suggest that the underlying mechanism of coupling might have impeding or enhancing effects depending on the coupled frequencies. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27800DOI Listing
January 2020

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

J Neurol Neurosurg Psychiatry 2019 12 10;90(12):1317-1323. Epub 2019 Jul 10.

Georgetown University, Washington, District of Columbia, USA.

Objective: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).

Method: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change.

Results: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8).

Conclusions: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD.

Trial Registration Number: NCT02198794.
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http://dx.doi.org/10.1136/jnnp-2018-319918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902058PMC
December 2019

Assessment of response to medication in individuals with Parkinson's disease.

Med Eng Phys 2019 05 12;67:33-43. Epub 2019 Mar 12.

Department of Computer and Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA. Electronic address:

Background And Objective: Motor fluctuations between akinetic (medication OFF) and mobile phases (medication ON) states are one of the most prevalent complications of patients with Parkinson's disease (PD). There is a need for a technology-based system to provide reliable information about the duration in different medication phases that can be used by the treating physician to successfully adjust therapy.

Methods: Two KinetiSense motion sensors were mounted on the most affected wrist and ankle of 19 PD subjects (age: 42-77, 14 males) and collected movement signals as the participants performed seven daily living activities in their medication OFF and ON phases. A feature selection and a classification algorithm based on support vector machine with fuzzy labeling was developed to detect medication ON/OFF states using gyroscope signals. The algorithm was trained using approximately 15% of the data from four activities and tested on the remaining data.

Results: The algorithm was able to detect medication ON and OFF states with 90.5% accuracy, 94.2% sensitivity, and 85.4% specificity. It performed equally well for all the activities with an average accuracy of 91.3% for the activities that were used in the training phase and 88.4% for the new activities.

Conclusions: The developed sensor-based algorithm could provide objective and accurate assessment of medication states that can lead to successful adjustment of the therapy resulting in considerably improved care delivery and quality of life of PD patients.
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http://dx.doi.org/10.1016/j.medengphy.2019.03.002DOI Listing
May 2019

Deep brain stimulation for Parkinson's disease - Does measuring quality matter?

Parkinsonism Relat Disord 2019 03 15;60:1-2. Epub 2019 Feb 15.

Baylor College of Medicine, 7200 Cambridge St., 9th floor, Houston, TX, 77030, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2019.02.018DOI Listing
March 2019
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