Publications by authors named "Brian D Berman"

61 Publications

Hold that pose: capturing cervical dystonia's head deviation severity from video.

Authors:
Zheng Zhang Elizabeth Cisneros Ha Yeon Lee Jeanne P Vu Qiyu Chen Casey N Benadof Jacob Whitehill Ryin Rouzbehani Dominique T Sy Jeannie S Huang Terrence J Sejnowski Joseph Jankovic Stewart Factor Christopher G Goetz Richard L Barbano Joel S Perlmutter Hyder A Jinnah Brian D Berman Sarah Pirio Richardson Glenn T Stebbins Cynthia L Comella David A Peterson

Ann Clin Transl Neurol 2022 May 25;9(5):684-694. Epub 2022 Mar 25.

Institute for Neural Computation, University of California, San Diego, La Jolla, California, USA.

Objective: Deviated head posture is a defining characteristic of cervical dystonia (CD). Head posture severity is typically quantified with clinical rating scales such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Because clinical rating scales are inherently subjective, they are susceptible to variability that reduces their sensitivity as outcome measures. The variability could be circumvented with methods to measure CD head posture objectively. However, previously used objective methods require specialized equipment and have been limited to studies with a small number of cases. The objective of this study was to evaluate a novel software system-the Computational Motor Objective Rater (CMOR)-to quantify multi-axis directionality and severity of head posture in CD using only conventional video camera recordings.

Methods: CMOR is based on computer vision and machine learning technology that captures 3D head angle from video. We used CMOR to quantify the axial patterns and severity of predominant head posture in a retrospective, cross-sectional study of 185 patients with isolated CD recruited from 10 sites in the Dystonia Coalition.

Results: The predominant head posture involved more than one axis in 80.5% of patients and all three axes in 44.4%. CMOR's metrics for head posture severity correlated with severity ratings from movement disorders neurologists using both the TWSTRS-2 and an adapted version of the Global Dystonia Rating Scale (rho = 0.59-0.68, all p <0.001).

Conclusions: CMOR's convergent validity with clinical rating scales and reliance upon only conventional video recordings supports its future potential for large scale multisite clinical trials.
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http://dx.doi.org/10.1002/acn3.51549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082391PMC
May 2022

Current Guidelines for Classifying and Diagnosing Cervical Dystonia: Empirical Evidence and Recommendations.

Authors:
Gamze Kilic-Berkmen Sarah Pirio Richardson Joel S Perlmutter Mark Hallett Christine Klein Aparna Wagle-Shukla Irene A Malaty Stephen G Reich Brian D Berman Jeanne Feuerstein Marie Vidailhet Emmanuel Roze Joseph Jankovic Abhimanyu Mahajan Alberto J Espay Richard L Barbano Mark S LeDoux Alexander Pantelyat Samuel Frank Natividad Stover Alfredo Berardelli Julie Leegwater-Kim Giovanni Defazio Scott A Norris Hyder A Jinnah

Mov Disord Clin Pract 2022 Feb 1;9(2):183-190. Epub 2021 Dec 1.

Department of Neurology Emory University School of Medicine Atlanta Georgia USA.

Background: The dystonias are phenotypically and etiologically heterogenous disorders. Many proposals and a consensus recommendation have been provided for the diagnosis and classification of the dystonias, but these recommendations serve only as general guidelines. Current diagnosis and classification may still depend on clinical judgment causing different opinions.

Objective: To delineate clinical features used by movement disorder specialists in the diagnosis and classification of isolated focal cervical dystonia, and to develop recommendations for a more consistent approach to classification according to anatomical regions involved.

Methods: Cross-sectional data for subjects diagnosed with isolated dystonia were acquired from the Dystonia Coalition, an international, multicenter collaborative research network. Data from many movement disorder specialists were evaluated to determine how diagnoses of cervical dystonia related to their recorded examinations. Cases were included if they were given a diagnosis of focal cervical dystonia. Cases were also included if they had dystonia of the neck on exam, but were given an alternative diagnosis such as segmental dystonia.

Results: Among 2916 subjects with isolated dystonia, 1258 were diagnosed with focal cervical dystonia. Among these 1258 cases, 28.3% had dystonia outside of the neck region. Regions involved outside of the neck included the shoulder, larynx, and sometimes other regions. Analysis of the results pointed to several factors that may influence specialists' use of current diagnostic guidelines for making a diagnosis of isolated focal cervical dystonia including varied interpretations of involvement of nearby regions (shoulder, larynx, platysma), severity of dystonia across different regions, and occurrence of tremor in different regions.

Conclusions: Although focal cervical dystonia is the most common type of dystonia, a high percentage of subjects given this diagnosis had dystonia outside of the neck region. This observation points to the need for more specific guidelines for defining this common disorder. Such guidelines are proposed here.
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http://dx.doi.org/10.1002/mdc3.13376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810420PMC
February 2022

Gender disparity and abuse in functional movement disorders: a multi-center case-control study.

Authors:
Isaiah Kletenik Samantha K Holden Stefan H Sillau Nicola O'Connell Lindsey MacGillivray Joel Mack Beatrix Haddock M Ashworth Dirac Anthony S David Timothy R Nicholson Sanaz N Attaripour Isfahani Carine W Maurer Sarah C Lidstone Mark Hallett Kathrin LaFaver Brian D Berman Jon Stone

J Neurol 2022 Jun 31;269(6):3258-3263. Epub 2022 Jan 31.

Centre for Clinical Brain Sciences, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: To determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history.

Methods: We performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence.

Results: Higher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval 2.31-9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval 1.53-5.12; p = 0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05-0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites.

Conclusions: Our study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider.
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http://dx.doi.org/10.1007/s00415-021-10943-6DOI Listing
June 2022

GABAergic Modulation in Movement Related Oscillatory Activity: A Review of the Effect Pharmacologically and with Aging.

Authors:
Christopher L Groth Arun Singh Qiang Zhang Brian D Berman Nandakumar S Narayanan

Tremor Other Hyperkinet Mov (N Y) 2021 10;11:48. Epub 2021 Nov 10.

Department of Neurology, University of Iowa, Iowa City, IA 52242, US.

Gamma-aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter critical to the control of movement both cortically and subcortically. Modulation of GABA can alter the characteristic rest as well as movement-related oscillatory activity in the alpha (8-12 Hz), beta (13-30 Hz, and gamma (60-90 Hz) frequencies, but the specific mechanisms by which GABAergic modulation can modify these well-described changes remains unclear. Through pharmacologic GABAergic modulation and evaluation across the age spectrum, the contributions of GABA to these characteristic oscillatory activities are beginning to be understood. Here, we review how baseline GABA signaling plays a key role in motor networks and in cortical oscillations detected by scalp electroencephalography and magnetoencephalography. We also discuss the data showing specific alterations to baseline movement related oscillatory changes from pharmacologic intervention on GABAergic tone as well as with healthy aging. These data provide greater insight into the physiology of movement and may help improve future development of novel therapeutics for patients who suffer from movement disorders.
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http://dx.doi.org/10.5334/tohm.655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588888PMC
January 2022

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

Authors:
Huma Nawaz Lana Sargent Helengrace Quilon Leslie J Cloud Claudia M Testa Jon D Snider Sarah K Lageman Mark S Baron Brian D Berman Kristin Zimmerman Elvin T Price Nitai D Mukhopadhyay Matthew J Barrett

J Parkinsons Dis 2022 ;12(2):599-606

Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.

Background: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications.

Objective: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients.

Methods: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients.

Results: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55).

Conclusion: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.
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http://dx.doi.org/10.3233/JPD-212769DOI Listing
April 2022

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases.

Authors:
Laura M Scorr Stewart A Factor Sahyli Perez Parra Rachel Kaye Randal C Paniello Scott A Norris Joel S Perlmutter Tobias Bäumer Tatiana Usnich Brian D Berman Marie Mailly Emmanuel Roze Marie Vidailhet Joseph Jankovic Mark S LeDoux Richard Barbano Florence C F Chang Victor S C Fung Sarah Pirio Richardson Andrew Blitzer H A Jinnah

Front Neurol 2021 16;12:700714. Epub 2021 Sep 16.

Department of Neurology, Emory University, Atlanta, GA, United States.

The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.
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http://dx.doi.org/10.3389/fneur.2021.700714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481678PMC
September 2021

Diagnostic criteria for blepharospasm: A multicenter international study.

Authors:
Giovanni Defazio Hyder A Jinnah Alfredo Berardelli Joel S Perlmutter Gamze Kilic Berkmen Brian D Berman Joseph Jankovic Tobias Bäumer Cynthia Comella Adam C Cotton Tommaso Ercoli Gina Ferrazzano Susan Fox Han-Joon Kim Emile Sami Moukheiber Sarah Pirio Richardson Anne Weissbach Laura J Wrigth Mark Hallett

Parkinsonism Relat Disord 2021 10 8;91:109-114. Epub 2021 Sep 8.

Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA.

Background: There are no widely accepted criteria to aid the physician in diagnosing BSP.

Objective: To validate recently proposed diagnostic criteria for blepharospasm in a larger and geographically diverse population and to develop a screening system for blepharospasm.

Methods: Video-recordings from 211 blepharospasm patients and 166 healthy/disease controls were examined by 8 raters. Agreement for presence of orbicularis oculi spasms, sensory trick, and increased blinking was measured by k statistics. Inability to voluntarily suppress the spasms was asked by the examiner but not captured in the video. Patients/controls were also requested to fill a self-administered questionnaire addressing relevant blepharospasm clinical aspects. The diagnosis at each site was the gold standard for sensitivity/specificity.

Results: All the study items yielded satisfactory inter/intra-observer agreement. Combination of items rather than each item alone reached satisfactory sensitivity/specificity. The combined algorithm started with recognition of spasms followed by sensory trick. In the absence of a sensory trick, including "increased blinking" or "inability to voluntarily suppress the spasms" or both items yielded 88-92% sensitivity and 79-83% specificity. No single question of the questionnaire yielded high sensitivity/specificity. Serial application of the questionnaire to our blepharospasm and control subjects and subsequent clinical examination of subjects screening positive by the validated diagnostic algorithms yielded 78-81% sensitivity and 83-91% specificity.

Conclusion: These results support the use of proposed diagnostic criteria in multi-ethnic, multi-center cohorts. We also propose a case-finding procedure to screen blepharospasm in a given population with less effort than would be required by examination of all subjects.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048224PMC
October 2021

A Multi-center Genome-wide Association Study of Cervical Dystonia.

Authors:
Yan V Sun Chengchen Li Qin Hui Yunfeng Huang Richard Barbano Ramon Rodriguez Irene A Malaty Stephen Reich Kimberly Bambarger Katie Holmes Joseph Jankovic Neepa J Patel Emmanuel Roze Marie Vidailhet Brian D Berman Mark S LeDoux Alberto J Espay Pinky Agarwal Sarah Pirio-Richardson Samuel A Frank William G Ondo Rachel Saunders-Pullman Sylvain Chouinard Stover Natividad Alfredo Berardelli Alexander Y Pantelyat Allison Brashear Susan H Fox Meike Kasten Ulrike M Krämer

Mov Disord 2021 12 28;36(12):2795-2801. Epub 2021 Jul 28.

Department of Neurology, University of Lübeck, Lübeck, Germany.

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility.

Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.

Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal.

Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).

Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688173PMC
December 2021

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

Authors:
Meng Wang Tolulope Sajobi Francesca Morgante Charles Adler Pinky Agarwal Tobias Bäumer Alfredo Berardelli Brian D Berman Joel Blumin Max Borsche Allison Brashear Andres Deik Kevin Duque Alberto J Espay Gina Ferrazzano Jeanne Feuerstein Susan Fox Samuel Frank Mark Hallett Joseph Jankovic Mark S LeDoux Julie Leegwater-Kim Abhimanyu Mahajan Irene A Malaty William Ondo Alexander Pantelyat Sarah Pirio-Richardson Emmanuel Roze Rachel Saunders-Pullman Oksana Suchowersky

Eur J Neurol 2021 12 4;28(12):3999-4009. Epub 2021 Aug 4.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background And Purpose: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.

Methods: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.

Results: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.

Conclusions: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.
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http://dx.doi.org/10.1111/ene.15031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100858PMC
December 2021

Does Raising the Arms Modify Head Tremor Severity in Cervical Dystonia?

Authors:
Elizabeth Cisneros Jeanne P Vu Ha Yeon Lee Qiyu Chen Casey N Benadof Zheng Zhang Emily A Pettitt Subhagya K Joshi Richard L Barbano Joseph Jankovic Hyder A Jinnah Joel S Perlmutter Brian D Berman Abhimanyu Mahajan Christopher G Goetz Glenn T Stebbins Cynthia L Comella David A Peterson

Tremor Other Hyperkinet Mov (N Y) 2021 06 23;11:21. Epub 2021 Jun 23.

Institute for Neural Computation, University of California, San Diego, La Jolla, CA, USA.

Background: A defining characteristic of dystonia is its position-dependence. In cervical dystonia (CD), sensory tricks ameliorate head tremor (HT). But it remains unknown whether raising the arms alone has the same impact.

Methods: We analyzed data collected from patients enrolled by the Dystonia Coalition. For 120 patients with HT, we assessed how raising their arms without touching their head changed their HT severity.

Results: Forty-eight out of 120 patients exhibited changes in HT severity when raising their arms. These patients were more likely to exhibit decreases in HT severity (N = 35) than increases (N = 13, χ (1, N = 48) = 10.1, p = 0.002). Demographic factors and sensory trick efficacy were not significant predictors of whether HT severity changed when raising their arms.

Discussion: Raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our results extend the concept of position-dependent motor symptoms in CD to include the position of the arms.

Highlights: Head tremor (HT) is a prevalent symptom of cervical dystonia (CD) that can often be disabling. This study demonstrates that raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our findings also identify a novel form of position-dependence in CD.
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http://dx.doi.org/10.5334/tohm.623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231450PMC
June 2021

The aging slow wave: a shifting amalgam of distinct slow wave and spindle coupling subtypes define slow wave sleep across the human lifespan.

Authors:
Brice V McConnell Eugene Kronberg Peter D Teale Stefan H Sillau Grace M Fishback Rini I Kaplan Angela J Fought A Ranjitha Dhanasekaran Brian D Berman Alberto R Ramos Rachel L McClure Brianne M Bettcher

Sleep 2021 10;44(10)

Neurology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

Study Objectives: Slow wave and spindle coupling supports memory consolidation, and loss of coupling is linked with cognitive decline and neurodegeneration. Coupling is proposed to be a possible biomarker of neurological disease, yet little is known about the different subtypes of coupling that normally occur throughout human development and aging. Here we identify distinct subtypes of spindles within slow wave upstates and describe their relationships with sleep stage across the human lifespan.

Methods: Coupling within a cross-sectional cohort of 582 subjects was quantified from stages N2 and N3 sleep across ages 6-88 years old. Results were analyzed across the study population via mixed model regression. Within a subset of subjects, we further utilized coupling to identify discrete subtypes of slow waves by their coupled spindles.

Results: Two different subtypes of spindles were identified during the upstates of (distinct) slow waves: an "early-fast" spindle, more common in stage N2 sleep, and a "late-fast" spindle, more common in stage N3. We further found stages N2 and N3 sleep contain a mixture of discrete subtypes of slow waves, each identified by their unique coupled-spindle timing and frequency. The relative contribution of coupling subtypes shifts across the human lifespan, and a deeper sleep phenotype prevails with increasing age.

Conclusions: Distinct subtypes of slow waves and coupled spindles form the composite of slow wave sleep. Our findings support a model of sleep-dependent synaptic regulation via discrete slow wave/spindle coupling subtypes and advance a conceptual framework for the development of coupling-based biomarkers in age-associated neurological disease.
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http://dx.doi.org/10.1093/sleep/zsab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503831PMC
October 2021

Parkinsonism and Positive Dopamine Transporter Imaging in a Patient with a Novel KMT2B Variant.

Authors:
Jeanne S Feuerstein Matthew Taylor Jennifer J Kwak Brian D Berman

Mov Disord Clin Pract 2021 Feb 2;8(2):279-281. Epub 2021 Feb 2.

Department of Neurology University of Colorado School of Medicine Aurora Colorado USA.

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http://dx.doi.org/10.1002/mdc3.13140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008275PMC
February 2021

Cervical Dystonia Is Associated With Aberrant Inhibitory Signaling Within the Thalamus.

Authors:
Christopher L Groth Mark Brown Justin M Honce Erika Shelton Stefan H Sillau Brian D Berman

Front Neurol 2020 9;11:575879. Epub 2021 Feb 9.

Department of Neurology, University of Colorado Anschutz Medical, Aurora, CO, United States.

The objective of this study is to investigate whether alterations in the neurotransmission of gamma-aminobutyric acid (GABA) in the thalamus are present in patients with cervical dystonia compared to healthy controls. GABA magnetic resonance spectroscopy was used to investigate concentration levels of GABA in the thalamus of cervical dystonia patients ( = 17) compared to healthy controls ( = 18). Additionally, a focused analysis of thalamic GABA receptor availability data in a similar cohort ( = 15 for both groups) using data from a previously collected C-flumazenil positron emission tomography study was performed. Group comparisons for all evaluations were performed using two-sided -tests with adjustments for age and sex, and Bonferroni correction for multiple comparisons was applied. Spearman's coefficient was used to test correlations. We found significantly reduced GABA+/Cre levels in the thalamus of cervical dystonia patients compared to controls, and these levels positively correlated with disease duration. Although mean thalamic GABA receptor availability did not differ between patients and controls, GABA availability negatively correlated with both disease duration and dystonia severity. These findings support that aberrant inhibitory signaling within the thalamus contributes to the pathophysiology of cervical dystonia. Additionally, these results suggest that an inadequate ability to compensate for the loss of GABA through upregulation of GABA receptors may underlie more severe symptoms.
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http://dx.doi.org/10.3389/fneur.2020.575879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900407PMC
February 2021

Quality of life in isolated dystonia: non-motor manifestations matter.

Authors:
Johanna Junker Brian D Berman James Hall Deena W Wahba Valerie Brandt Joel S Perlmutter Joseph Jankovic Irene A Malaty Aparna Wagle Shukla Stephen G Reich Alberto J Espay Kevin R Duque Neepa Patel Emmanuel Roze Marie Vidailhet H A Jinnah Norbert Brüggemann

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurology, University of Luebeck, Luebeck, Germany

Objective: To evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition.

Methods: Natural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis.

Results: Reduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes.

Conclusion: HR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health.
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http://dx.doi.org/10.1136/jnnp-2020-325193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356023PMC
February 2021

Head tremor and pain in cervical dystonia.

Authors:
Jeanne P Vu Ha Yeon Lee Qiyu Chen Elizabeth Cisneros Richard L Barbano Christopher G Goetz Joseph Jankovic Hyder A Jinnah Joel S Perlmutter Brian D Berman Mark I Appelbaum Glenn T Stebbins Cynthia L Comella David A Peterson

J Neurol 2021 May 8;268(5):1945-1950. Epub 2021 Jan 8.

Institute for Neural Computation, University of California, La Jolla, San Diego, CA, USA.

Background: Although head tremor (HT) and pain are prevalent in cervical dystonia (CD), their joint relationship to phenotypic features of focal dystonia remains unclear.

Objectives: We examined how severity of HT and pain are associated with age of CD onset and duration, and whether HT subtypes ("jerky" or "regular") exhibit distinct relationships between severity of HT and pain.

Methods: The severity of HT and pain were assessed with the Toronto Western Spasmodic Torticollis Rating Scale in retrospective review of 188 CD patients recruited through the Dystonia Coalition.

Results: HT severity was associated with longer CD duration (p < 0.0005), whereas pain severity was associated with younger age at onset (p = 0.043). HT severity and pain severity were not correlated for jerky HT (p = 0.996), but positively correlated for regular HT (p = 0.01).

Conclusions: The distinct associations of HT and pain with age at onset, disease duration, and HT subtype further characterize the heterogeneity of CD's clinical presentation and suggest similarly heterogeneous underlying mechanisms.
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http://dx.doi.org/10.1007/s00415-020-10378-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076053PMC
May 2021

It's tricky: Rating alleviating maneuvers in cervical dystonia.

Authors:
Elizabeth Cisneros Glenn T Stebbins Qiyu Chen Jeanne P Vu Casey N Benadof Zheng Zhang Richard L Barbano Susan H Fox Christopher G Goetz Joseph Jankovic Hyder A Jinnah Joel S Perlmutter Charles H Adler Stewart A Factor Stephen G Reich Ramon Rodriguez Lawrence L Severt Natividad P Stover Brian D Berman Cynthia L Comella David A Peterson

J Neurol Sci 2020 Dec 1;419:117205. Epub 2020 Nov 1.

Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America; CNL-S, Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, United States of America. Electronic address:

Objectives: To investigate hypothesized sources of error when quantifying the effect of the sensory trick in cervical dystonia (CD) with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-2), test strategies to mitigate them, and provide guidance for future research on the sensory trick.

Methods: Previous analyses suggested the sensory trick (or "alleviating maneuver", AM) item be removed from the TWSTRS-2 because of its poor clinimetric properties. We hypothesized three sources of clinimetric weakness for rating the AM: 1) whether patients were given sufficient time to demonstrate their AM; 2) whether patients' CD was sufficiently severe for detecting AM efficacy; and 3) whether raters were inadvertently rating the item in reverse of scale instructions. We tested these hypotheses with video recordings and TWSTRS-2 ratings by one "site rater" and a panel of five "video raters" for each of 185 Dystonia Coalition patients with isolated CD.

Results: Of 185 patients, 23 (12%) were not permitted sufficient testing time to exhibit an AM, 23 (12%) had baseline CD too mild to allow confident rating of AM effect, and 1 site- and 1 video-rater each rated the AM item with a reverse scoring convention. When these confounds were eliminated in step-wise fashion, the item's clinimetric properties improved.

Conclusions: The AM's efficacy can contribute to measuring CD motor severity by addressing identified sources of error during its assessment and rating. Given the AM's sensitive diagnostic and potential pathophysiologic significance, we also provide guidance on modifications to how AMs can be assessed in future CD research.
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http://dx.doi.org/10.1016/j.jns.2020.117205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728456PMC
December 2020

Altered between-network connectivity in individuals prone to obesity.

Authors:
Kristina T Legget Korey P Wylie Marc-Andre Cornier Brian D Berman Jason R Tregellas

Physiol Behav 2021 02 3;229:113242. Epub 2020 Nov 3.

Department of Psychiatry, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, United States; Research Service, Rocky Mountain Regional VA Medical Center, Aurora, CO, United States.

Objective: Investigating intrinsic brain functional connectivity may help identify the neurobiology underlying cognitive patterns and biases contributing to obesity propensity. To address this, the current study used a novel whole-brain, data-driven approach to examine functional connectivity differences in large-scale network interactions between obesity-prone (OP) and obesity-resistant (OR) individuals.

Methods: OR (N = 24) and OP (N = 25) adults completed functional magnetic resonance imaging (fMRI) during rest. Large-scale brain networks were identified using independent component analysis (ICA). Voxel-specific between-network connectivity analysis assessed correlations between ICA component time series' and individual voxel time series, identifying regions strongly connected to many networks, i.e., "hubs".

Results: Significant group differences in between-network connectivity (OP vs. OR; FDR-corrected) were observed in bilateral basal ganglia (left: q = 0.009; right: q = 0.010) and right dorsolateral prefrontal cortex (dlPFC; q = 0.026), with OP>OR. Basal ganglia differences were largely driven by a more strongly negative correlation with a lateral sensorimotor network in OP, with dlPFC differences driven by a more strongly negative correlation with an inferior visual network in OP.

Conclusions: Greater between-network connectivity was observed in the basal ganglia and dlPFC in OP, driven by stronger associations with lateral sensorimotor and inferior visual networks, respectively. This may reflect a disrupted balance between goal-directed and habitual control systems and between internal/external monitoring processes.
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http://dx.doi.org/10.1016/j.physbeh.2020.113242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775284PMC
February 2021

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

Authors:
Aasef G Shaikh Sinem Balta Beylergil Laura Scorr Gamze Kilic-Berkmen Alan Freeman Christine Klein Johanna Junker Sebastian Loens Norbert Brüggemann Alexander Münchau Tobias Bäumer Marie Vidailhet Emmanuel Roze Cecilia Bonnet Joseph Jankovic Joohi Jimenez-Shahed Neepa Patel Laura Marsh Cynthia Comella Richard L Barbano Brian D Berman Irene Malaty Aparna Wagle Shukla Stephen G Reich Mark S Ledoux Alfredo Berardelli Gina Ferrazzano Natividad Stover William Ondo Sarah Pirio Richardson

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

Basal ganglia and cerebellar circuits have distinct roles in blepharospasm.

Authors:
Amanda Glickman Phuong Nguyen Erika Shelton David A Peterson Brian D Berman

Parkinsonism Relat Disord 2020 09 28;78:158-164. Epub 2020 Jul 28.

Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA. Electronic address:

Introduction: To identify areas of brain activity associated with involuntary muscle contractions in patients with blepharospasm using functional MRI.

Methods: 15 patients with blepharospasm underwent 8-min resting state scans with spontaneous orbicularis oculi muscle contractions simultaneously recorded using MRI-compatible surface electromyography. Spasm severity and spasm onset/offset were modeled using the amplitude of the electromyography signal (EMG-Amp) and its first temporal derivative (EMG-Onset), respectively, and included in a multiple regression functional MRI analysis using SPM12. Primary outcome was within-group blood-oxygen-level dependent activations that co-varied with EMG-Amp and EMG-Onset following correction for multiple comparisons for an overall cluster corrected p < 0.05. Secondary analyses included testing for correlations between imaging findings and symptom severity, as measured by clinical dystonia rating scales, using an uncorrected voxel-level threshold of p < 0.001.

Results: Imaging data from one subject were excluded due to excessive movement. EMG-Amp co-activated within the left sensorimotor cortex and cerebellum, as well as right lingual gyrus and superior temporal gyrus. EMG-Onset co-activated within the left posterior putamen/pallidum and a frontal eye field region in the left superior frontal gyrus. Symptom severity and EMG-Amp significantly co-varied in a small cluster within the left cerebellum.

Conclusion: Our preliminary findings here suggest that cerebello-cortical circuits in blepharospasm could drive the intensity of eyelid spasms while basal ganglia circuits are associated with the triggering of spasms. This supports the network model for dystonia and identifies specific areas of involvement consistent with known brain regions responsible for control of movement.
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http://dx.doi.org/10.1016/j.parkreldis.2020.06.034DOI Listing
September 2020

Clinical and Demographic Characteristics of Upper Limb Dystonia.

Authors:
Scott A Norris Hyder A Jinnah Christine Klein Joseph Jankovic Brian D Berman Emmanuel Roze Abhimanyu Mahajan Alberto J Espay Avinash V Murthy Victor S C Fung Mark S LeDoux Florence C F Chang Marie Vidailhet Claudia Testa Richard Barbano Irene A Malaty Tobias Bäumer Sebastian Loens Laura J Wright Joel S Perlmutter

Mov Disord 2020 11 26;35(11):2086-2090. Epub 2020 Aug 26.

Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies.

Objective: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource.

Methods: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset.

Results: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately.

Conclusions: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350751PMC
November 2020

Spike-associated networks and intracranial electrographic findings.

Authors:
Joshua J Bear Heidi E Kirsch Brian D Berman Kevin E Chapman Jason R Tregellas

Epileptic Disord 2020 Jun;22(3):291-299

Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora,, Research Service, Rocky Mountain Regional VA Medical Center, Aurora, USA.

Functional connectivity is providing new insights into the network nature of epilepsy with growing clinical applications. Our objective was to validate a novel magnetoencephalography-based method to non-invasively measure the epileptic network. We retrospectively identified pediatric and adult patients with refractory focal epilepsy who underwent pre-surgical magnetoencephalography with subsequent intracranial electrographic monitoring. Magnetoencephalography tracings were visually reviewed, and interictal epileptiform discharges ("spikes") were individually marked. We then evaluated differences in whole-brain connectivity during brief epochs preceding the spikes and during the spikes using the Network-Based Statistic to test differences at the network level. In six patients with statistically-significant network differences, we observed substantial overlap between the spike-associated networks and electrographically active areas identified during intracranial monitoring (the spike-associated network was 78% and 83% sensitive for intracranial electroencephalography-defined regions in the irritative and seizure onset zones, respectively). These findings support the neurobiological validity of the spike-associated network method. Assessment of spike-associated networks has the potential to improve surgical planning in epilepsy surgery patients by identifying components of the epileptic network prior to implantation.
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http://dx.doi.org/10.1684/epd.2020.1163DOI Listing
June 2020

Abnormal Neural Responses During Reflexive Blinking in Blepharospasm: An Event-Related Functional MRI Study.

Authors:
Phuong Nguyen Diane Kelly Amanda Glickman Salem Argaw Erika Shelton David A Peterson Brian D Berman

Mov Disord 2020 07 6;35(7):1173-1180. Epub 2020 Apr 6.

Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Background: The neurophysiological disruptions underlying blepharospasm, a disabling movement disorder characterized by increased blinking and involuntary muscle spasms of the eyelid, remain poorly understood.

Objective: To investigate the neural substrates underlying reflexive blinking in blepharospasm patients compared to healthy controls using simultaneous functional MRI and surface electromyography.

Methods: Fifteen blepharospasm patients and 15 healthy controls were recruited. Randomly timed air puffs to the left eye were used to induce reflexive eye blinks during two 8-minute functional MRI scans. Continuous surface electromyography and video recordings were used to monitor blink responses. Imaging data were analyzed using an event-related design.

Results: Fourteen blepharospasm patients (10 female; 61.6 ± 8.0 years) and 15 controls (11 female; 60.9 ± 5.5 years) were included in the final analysis. Reflexive eye blinks in controls were associated with activation of the right hippocampus and in patients with activation of the left caudate nucleus. Reflexive blinks in blepharospasm patients showed increased activation in the right postcentral gyrus and precuneus, left precentral gyrus, and left occipital cortex compared to controls. Dystonia severity negatively correlated with activity in the left occipital cortex, and disease duration negatively correlated with reflexive-blink activity in the cerebellum.

Conclusions: Reflexive blinking in blepharospasm is associated with increased activation in the caudate nucleus and sensorimotor cortices, suggesting a loss of inhibition within the sensorimotor corticobasal ganglia network. The association between decreasing neural response during reflexive blinking in the cerebellum with disease duration suggests an adaptive role. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28042DOI Listing
July 2020

Defining research priorities in dystonia.

Authors:
Codrin Lungu Laurie Ozelius David Standaert Mark Hallett Beth-Anne Sieber Christine Swanson-Fisher Brian D Berman Nicole Calakos Jennifer C Moore Joel S Perlmutter Sarah E Pirio Richardson Rachel Saunders-Pullman Laura Scheinfeldt Nutan Sharma Roy Sillitoe Kristina Simonyan Philip A Starr Anna Taylor Jerrold Vitek

Neurology 2020 03 25;94(12):526-537. Epub 2020 Feb 25.

From the Division of Clinical Research (C.L.), National Institute of Neurological Disorders and Stroke, National Institutes of Health; Harvard Medical School (L.O., N.S.), Massachusetts General Hospital, Boston, MA; University of Alabama, Birmingham (D.S.), Birmingham, AL; Medical Neurology Branch (M.H.), NINDS, NIH, Bethesda, MD; Division of Neuroscience (B.-A.S., C.S.-F.), NINDS, NIH, Bethesda, MD; Department of Neurology (B.D.B.), University of Colorado Denver, Aurora, CO; Duke University School of Medicine, Durham, NC; RUCDR/Infinite Biologics (J.C.M.), Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ; Washington University School of Medicine (J.S.P.), St Louis, MO; Department of Neurology (S.E.P.R.), University of New Mexico Health Sciences Center, Albuquerque, NM; Department of Neurology (R.S.-P.), Icahn School of Medicine at Mount Sinai, New York, NY; Coriell Institute for Medical Research (L.S.), Camden, NJ; Department of Neuroscience (R.S.), Baylor College of Medicine, Houston, TX; Harvard Medical School (K.S.), Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear Institute, Boston, MA; Department of Neurological Surgery (P.A.S.), University of California San Francisco, San Francisco, CA; Division of Extramural Activities (A.T.), NINDS, NIH, Rockville, MD; and Department of Neurology (J.V.), University of Minnesota, Minneapolis, MN.

Objective: Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities.

Methods: The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations.

Results: The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia.

Conclusion: Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.
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http://dx.doi.org/10.1212/WNL.0000000000009140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274927PMC
March 2020

Gender as a Risk Factor for Functional Movement Disorders: The Role of Sexual Abuse.

Authors:
Isaiah Kletenik Stefan H Sillau Sanaz Attaripour Isfahani Kathrin LaFaver Mark Hallett Brian D Berman

Mov Disord Clin Pract 2020 Feb 13;7(2):177-181. Epub 2019 Dec 13.

Department of Neurology University of Colorado School of Medicine Aurora Colorado USA.

Background: The prevalence of functional movement disorders is 2 to 3 times higher in women than in men. Trauma and adverse life events are important risk factors for developing functional movement disorders. On a population level, rates of sexual abuse against women are higher when compared with the rates against men.

Objectives: To determine gender differences in rates of sexual abuse in functional movement disorders compared with other neurologic disorders and evaluate if the gender prevalence is influenced by higher rates of sexual abuse against women.

Methods: We performed a case-control series including 199 patients with functional movement disorders (149 women) and 95 controls (60 women). We employed chi-squared test to assess gender and sexual abuse associations and Bayes formula to condition on sexual abuse.

Results: Our analysis showed an association between sexual abuse and functional movement disorders in women (odds ratio, 4.821; 95% confidence interval, 2.089-12.070;  < 0.0001), but not men. Bayesian analysis found the functional movement disorder prevalence ratio between women and men conditional on sexual abuse to be 4.87 times the unconditioned ratio.

Conclusions: There is a statistically significant association between sexual abuse and functional movement disorders in women and a greater likelihood that women who are sexually abused will develop functional movement disorders than men who are sexually abused. Our findings suggest that the increased prevalence of functional movement disorders in women is associated, at least in part, with sexual abuse and its sequelae; however, further research is needed to explore the role of other traumatic and nontraumatic factors.
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http://dx.doi.org/10.1002/mdc3.12863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011626PMC
February 2020

Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study.

Authors:
Brian D Berman Christopher L Groth Stefan H Sillau Sarah Pirio Richardson Scott A Norris Johanna Junker Norbert Brüggemann Pinky Agarwal Richard L Barbano Alberto J Espay Joaquin A Vizcarra Christine Klein Tobias Bäumer Sebastian Loens Stephen G Reich Marie Vidailhet Cecilia Bonnet Emmanuel Roze Hyder A Jinnah Joel S Perlmutter

J Neurol Neurosurg Psychiatry 2020 03 17;91(3):314-320. Epub 2019 Dec 17.

Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.

Objective: Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients.

Methods: Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread.

Results: 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009).

Conclusions: Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.
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http://dx.doi.org/10.1136/jnnp-2019-321794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024047PMC
March 2020

Hemodynamic responses are abnormal in isolated cervical dystonia.

Authors:
Brian D Berman Christopher L Groth Erica Shelton Stefan H Sillau Brianne Sutton Kristina T Legget Jason R Tregellas

J Neurosci Res 2020 04 6;98(4):692-703. Epub 2019 Nov 6.

Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA.

Neuroimaging studies using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting the changes in blood oxygenation levels, are advancing our understanding of the pathophysiology of dystonia. Neurobiological disturbances in dystonia, however, may affect neurovascular coupling and impact the interpretability of fMRI studies. We evaluated here whether the hemodynamic response patterns during a behaviorally matched motor task are altered in isolated cervical dystonia (CD). Twenty-five CD patients and 25 healthy controls (HCs) underwent fMRI scanning during a paced finger tapping task (nondystonic task in patients). Imaging data were analyzed using a constrained principal component analysis-a statistical method that combines regression analysis and principal component analysis and enables the extraction of task-related functional networks and determination of the spatial and temporal hemodynamic response patterns associated with the task performance. Data from three patients and two controls were removed due to excessive movement. No significant differences in demographics or motor performance were observed. Three task-associated functional brain networks were identified. During task performance, reduced hemodynamic responses were seen in a sensorimotor network and in a network that included key nodes of the default mode, executive control and visual networks. During rest, reductions in hemodynamic responses were seen in the cognitive/visual network. Lower hemodynamic responses within the primary sensorimotor network in patients were correlated with the increased dystonia severity. Pathophysiological disturbances in isolated CD, such as alterations in inhibitory signaling and dopaminergic neurotransmission, may impact neurovascular coupling. Not accounting for hemodynamic response differences in fMRI studies of dystonia could lead to inaccurate results and interpretations.
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http://dx.doi.org/10.1002/jnr.24547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015799PMC
April 2020

Head tremor at disease onset: an ataxic phenotype of cervical dystonia.

Authors:
Aristide Merola Alok K Dwivedi Aasef G Shaikh Tamour Khan Tareen Gustavo A Da Prat Marcelo A Kauffman Jennie Hampf Abhimanyu Mahajan Luca Marsili Joseph Jankovic Cynthia L Comella Brian D Berman Joel S Perlmutter Hyder A Jinnah Alberto J Espay

J Neurol 2019 Aug 26;266(8):1844-1851. Epub 2019 Apr 26.

Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA.

Background: Cervical dystonia (CD) can present with head tremor. It is unclear whether ataxic features are differentially associated with this phenotype at onset of CD.

Objectives: We sought to evaluate: (1) the demographic features of CD patients with (Tr-CD) and without head tremor (nTr-CD) at onset, and (2) the differential ataxic features between these CD subtypes.

Methods: For the first objective, we compared demographic data in Tr-CD versus nTr-CD subtypes in the entire cohort of CD subjects enrolled in the Dystonia Coalition Natural History and Biorepository studies (n = 1608). For the second objective, we rated the standardized videos from consecutively enrolled Tr-CD subjects (n = 50) and age-, gender-, and disease duration-matched nTr-CD subjects (n = 50) for ataxia severity scoring using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS); and for dystonia severity using the Toronto Western Spasmodic Torticollis Rating Scale section-I (TWSTRS) and the Global Dystonia Rating Scale (GDRS).

Results: Of 1,608 subjects, 18.1% (n = 291) were classified as Tr-CD and 81.9% (n = 1317) as nTr-CD. The Tr-CD cohort was older, predominantly female, and had longer disease duration than the nTr-CD cohort (p = 0.01). Compared to nTr-CD, Tr-CD subjects had worse generalized ataxia, speech, and gait and posture scores. High ataxia severity with low dystonia severity distinguished Tr-CD from nTr-CD with high accuracy (area under the curve, 0.91 (95% CI 0.85-0.97).

Conclusions: Head tremor at disease onset represents a clinically distinguishable subtype of cervical dystonia affecting predominantly older women, with worse ataxia and milder dystonia than the non-tremulous dystonic phenotype.
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http://dx.doi.org/10.1007/s00415-019-09341-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642013PMC
August 2019

Feasibility of home-based automated transcranial electrical stimulation during slow wave sleep.

Authors:
Brice V McConnell Rini I Kaplan Peter D Teale Eugene Kronberg Josiane L Broussard Jacob R Guzetti Stefan H Sillau A Ranjitha Dhanasekaran Benzi M Kluger Brian D Berman

Brain Stimul 2019 May - Jun;12(3):813-815. Epub 2019 Feb 20.

University of Colorado, Anschutz Medical Campus, USA.

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http://dx.doi.org/10.1016/j.brs.2019.02.014DOI Listing
February 2019

Predictors of alcohol responsiveness in dystonia.

Authors:
Johanna Junker Valerie Brandt Brian D Berman Marie Vidailhet Emmanuel Roze Anne Weissbach Cynthia Comella Irene A Malaty Joseph Jankovic Mark S LeDoux Alfredo Berardelli Richard Barbano Stephen G Reich Joel S Perlmutter H A Jinnah Norbert Brüggemann

Neurology 2018 11 19;91(21):e2020-e2026. Epub 2018 Oct 19.

From the Institute of Neurogenetics (J. Junker, V.B., A.W., N.B.) and Department of Neurology (J. Junker, N.B.), University of Luebeck, Germany; Department of Psychology (V.B.), Centre for Innovation in Mental Health, University of Southampton, UK; Department of Neurology (B.D.B.), University of Colorado Anschutz Medical Campus, Aurora; Neurology Section (B.D.B.), Denver VA Medical Center, CO; Département de Neurologie (M.V., E.R.), Hôpital Pitié-Salpêtrière, Assistance Publique-Hopitaux de Paris; Sorbonne Universités (M.V.), Pierre Marie Curie Paris-6, Institute of Brain and Spine (ICM), Inserm U 1127, Paris, France; Department of Neurology (C.C.), Rush University Medical Center, Chicago, IL; Department of Neurology (I.A.M.), Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville; Department of Neurology (J. Jankovic), Baylor College of Medicine, Houston, TX; Department of Neurology (M.S.L.), University of Tennessee Health Science Center, Memphis; Neuromed Institute (IRCCS) (A.B.), Pozzilli (IS), and Department of Neurology and Psychiatry, Sapienza University di Roma, Italy; Department of Neurology (R.B.), University of Rochester Medical Center, NY; Department of Neurology (S.G.R.), University of Maryland Medical Center, Baltimore; Department of Neurology (J.S.P.), Washington University in St. Louis, MO; and Department of Neurology and Human Genetics (H.A.J.), Emory University, Atlanta, GA.

Objective: To determine predictors of alcohol responsiveness in a large cohort of patients with dystonia.

Methods: A total of 2,159 participants with dystonia were prospectively enrolled in the cross-sectional Dystonia Coalition multicenter study. Patients with secondary, combined, or confirmed genetic dystonia (total n = 164) or unknown alcohol responsiveness (n = 737) were excluded. Patients answered a standardized questionnaire and were clinically examined using a standardized video protocol and the Burke-Fahn-Marsden Dystonia Rating Scale. Alcohol responsiveness was determined by patients' self-report.

Results: A total of 1,258 patients with isolated dystonia (mean age: 59.5 ± 12.2 years; 898 women) met the inclusion criteria; 369 patients (29.3%) reported improvement of dystonia after alcohol consumption. Alcohol responsiveness was not related to sex ( = 0.742), age ( = 0.715), or severity of dystonia ( = 0.623). Age at onset was lower in patients who responded to alcohol ( < 0.001). Alcohol responsiveness differed across dystonia subgroups (multifocal/generalized > segmental [ = 0.014]; cervical and laryngeal > cranial and limb [ < 0.001]) and was related to a positive family history of movement disorders ( = 0.001), and presence of tremor ( < 0.001).

Conclusion: The association of alcohol responsiveness with a positive family history for movement disorders, generalized dystonia, and an earlier age at onset suggests that patients with dystonia who have an underlying genetic contribution may be more likely to respond beneficially to alcohol. The fact that dystonic tremor may respond to alcohol is in keeping with the observation that the intake of GABAergic drugs may have a beneficial effect in a proportion of patients.
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http://dx.doi.org/10.1212/WNL.0000000000006551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260199PMC
November 2018

Validation of a performance-based assessment of cognitive functional ability in Parkinson's disease.

Authors:
Samantha K Holden Luis D Medina Brian Hoyt Stefan H Sillau Brian D Berman Jennifer G Goldman Daniel Weintraub Benzi M Kluger

Mov Disord 2018 11 10;33(11):1760-1768. Epub 2018 Oct 10.

Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Background: Outcome measures that capture functional abilities related to cognition offer the potential to demonstrate real-world effectiveness of cognitive-enhancing treatments. However, distinguishing functional disability related to cognition from that attributed to motor symptoms can be difficult in PD. A performance-based functional assessment allows for direct observation of activity of daily living skills and separation of cognitive from motoric disabilities.

Objectives: Validate the University of California San Diego Performance-Based Skills Assessment in PD.

Methods: One hundred PD participants, ranging from normal cognition to dementia, completed the University of California San Diego Performance-Based Skills Assessment, a performance-based measure of cognitively demanding activities of daily living, as well as a neuropsychological battery and motor examination. Cognitive classification was determined by consensus conference, blinded to University of California San Diego Performance-Based Skills Assessment scores. Psychometric properties of the University of California San Diego Performance-Based Skills Assessment, including internal consistency, test-retest and inter-rater reliability, and discriminant validity for dementia, were examined.

Results: The University of California San Diego Performance-Based Skills Assessment demonstrated strong internal consistency (Cronbach's α = 0.82) and test-retest reliability (r = 0.89) and correlated strongly with global cognition (Mattis Dementia Rating Scale: r = 0.80; P < 0.001). University of California San Diego Performance-Based Skills Assessment regression models indicated greater contribution from cognitive explanatory variables (marginal partial: R  = 0.33) than motor variables (marginal partial: R  = 0.05), controlling for age, education, disease duration, and l-dopa equivalent dose. Additionally, the University of California San Diego Performance-Based Skills Assessment exhibited strong discriminant validity for dementia (area under the curve = 0.91).

Conclusions: The University of California San Diego Performance-Based Skills Assessment is a valid measure of functional abilities related to cognition rather than motor symptoms in PD. Furthermore, it reliably distinguishes demented from nondemented participants. The University of California San Diego Performance-Based Skills Assessment may be considered as an outcome measure that combines cognitive and functional abilities in treatment trials for cognitive impairment in PD. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261681PMC
November 2018
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