Publications by authors named "Michael S Okun"

567 Publications

TNFα increases tyrosine hydroxylase expression in human monocytes.

NPJ Parkinsons Dis 2021 Jul 20;7(1):62. Epub 2021 Jul 20.

Department of Neuroscience, University of Florida, Center for Translational Research in Neurodegenerative Disease, Norman Fixel Institute for Neurological Diseases, Gainesville, FL, USA.

Most, if not all, peripheral immune cells in humans and animals express tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Since TH is typically studied in the context of brain catecholamine signaling, little is known about changes in TH production and function in peripheral immune cells. This knowledge gap is due, in part, to the lack of an adequately sensitive assay to measure TH in immune cells expressing lower TH levels compared to other TH expressing cells. Here, we report the development of a highly sensitive and reproducible Bio-ELISA to quantify picogram levels of TH in multiple model systems. We have applied this assay to monocytes isolated from blood of persons with Parkinson's disease (PD) and to age-matched, healthy controls. Our study unexpectedly revealed that PD patients' monocytes express significantly higher levels of TH protein in peripheral monocytes relative to healthy controls. Tumor necrosis factor (TNFα), a pro-inflammatory cytokine, has also been shown to be increased in the brains and peripheral circulation in human PD, as well as in animal models of PD. Therefore, we investigated a possible connection between higher levels of TH protein and the known increase in circulating TNFα in PD. Monocytes isolated from healthy donors were treated with TNFα or with TNFα in the presence of an inhibitor. Tissue plasminogen activator (TPA) was used as a positive control. We observed that TNFα stimulation increased both the number of TH+ monocytes and the quantity of TH per monocyte, without increasing the total numbers of monocytes. These results revealed that TNFα could potentially modify monocytic TH production and serve a regulatory role in peripheral immune function. The development and application of a highly sensitive assay to quantify TH in both human and animal cells will provide a novel tool for further investigating possible PD immune regulatory pathways between brain and periphery.
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http://dx.doi.org/10.1038/s41531-021-00201-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292430PMC
July 2021

Laterality of motor symptom onset and facial expressivity in Parkinson disease using face digitization.

Laterality 2021 Jul 5:1-14. Epub 2021 Jul 5.

Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA.

The onset of motor symptoms in Parkinson disease (PD) is typically unilateral. Previous work has suggested that laterality of motor symptoms may also influence non-motor symptoms including cognition and emotion perception. In line with hemispheric differences in emotion processing, we tested whether left side/right brain motor onset was associated with worse expression of facial affect when compared to right side/left brain motor onset. We evaluated movement changes associated with facial affect in 30 patients with idiopathic PD (15 left-sided motor onset, 15 right-sided motor onset) and 20 healthy controls. Participants were videotaped while posing three facial expressions: fear, anger, and happiness. Expressions were digitized and analyzed using software that extracted three variables: two measures of dynamic movement change (total entropy and entropy percent change) and a measure of time to initiate facial expression (latency). The groups did not differ in overall amount of movement change or percentchange. However, left-sided onset PD patients were significantly slower in initiating anger and happiness facial expressions than were right-sided onset PD patients and controls. Our results indicated PD patients with left-sided symptom onset had greater latency in initiating two of three facial expressions, which may reflect laterality effects in intentional behaviour.
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http://dx.doi.org/10.1080/1357650X.2021.1946077DOI Listing
July 2021

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Contemp Clin Trials Commun 2021 Jun 5;22:100785. Epub 2021 Jun 5.

Butler Hospital, 345 Blackstone Blvd, Providence, RI, 02906, USA.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.
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http://dx.doi.org/10.1016/j.conctc.2021.100785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219641PMC
June 2021

Home Health Management of Parkinson Disease Deep Brain Stimulation: A Randomized Clinical Trial.

JAMA Neurol 2021 Jun 28. Epub 2021 Jun 28.

Scientific Computing and Imaging Institute, University of Utah, Salt Lake City.

Importance: The travel required to receive deep brain stimulation (DBS) programming causes substantial burden on patients and limits who can access DBS therapy.

Objective: To evaluate the efficacy of home health DBS postoperative management in an effort to reduce travel burden and improve access.

Design, Settings, And Participants: This open-label randomized clinical trial was conducted at University of Florida Health from November 2017 to April 2020. Eligible participants had a diagnosis of Parkinson disease (PD) and were scheduled to receive DBS independently of the study. Consenting participants were randomized 1:1 to receive either standard of care or home health postoperative DBS management for 6 months after surgery. Primary caregivers, usually spouses, were also enrolled to assess caregiver strain.

Interventions: The home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the iPad-based Mobile Application for PD DBS system. Prior to the study, the home health nurse had no experience providing DBS care.

Main Outcomes And Measures: The primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. Secondary outcomes included changes from baseline on the Unified Parkinson's Disease Rating Scale part III.

Results: Approximately 75 patients per year were scheduled for DBS. Of the patients who met inclusion criteria over the entire study duration, 45 either declined or were excluded for various reasons. Of the 44 patients enrolled, 19 of 21 randomized patients receiving the standard of care (mean [SD] age, 64.1 [10.0] years; 11 men) and 23 of 23 randomized patients receiving home health who underwent a minimum of 1 postoperative management visit (mean [SD] age, 65.0 [10.9] years; 13 men) were included in analysis. The primary outcome revealed that patients randomized to home health had significantly fewer clinic visits than the patients in the standard of care arm (mean [SD], 0.4 [0.8] visits vs 4.8 [0.4] visits; P < .001). We found no significant differences between the groups in the secondary outcomes measuring the efficacy of DBS. No adverse events occurred in association with the study procedure or devices.

Conclusions And Relevance: This study provides evidence supporting the safety and feasibility of postoperative home health DBS management.

Trial Registration: ClinicalTrials.gov Identifier: NCT02474459.
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http://dx.doi.org/10.1001/jamaneurol.2021.1910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240011PMC
June 2021

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis.

J Manag Care Spec Pharm 2021 Jun;27(6):785-790

Norman Fixel Institute for Neurological Diseases, Department of Neurology, University of Florida, Gainesville.

Pimavanserin is approved for treatment of Parkinson disease (PD)-related psychosis, but its use has been associated with an increased risk of death during clinical trials, as well as during postmarketing surveillance. Previous reports on the association between pimavanserin and mortality have not taken into account limitations of data sources nor included comparable populations or comparisons to relevant treatment alternatives. To conduct a comparative pharmacovigilance assessment of pimavanserin vs treatment alternatives and by restricting surveillance data to more representative populations. This was a retrospective analysis of adverse event case reports submitted to the FDA's Adverse Event Reporting System (FAERS) from 2016 through 2019 quarter 3 (Q3). FAERS data are collected from the full population, were further restricted to only those with PD, and were based on PD medication use. Reports were assessed for exposure to pimavanserin, clozapine, quetiapine, haloperidol, and other atypical antipsychotics. The outcome of interest was all-cause death. A proportional reporting ratio (PRR) and 95% confidence limits were calculated for each 2 by 2 contingency of outcome (death) and exposure (pimavanserin and others). For each outcome/exposure pair, the baseline population was altered to include the full FAERS sample, only reports with PD, reports with PD treated with levodopa, and reports with PD treated with multiple PD medications. The sample was also stratified by time period before April 2018 and after September 2018 to capture periods of public knowledge and federal response. A lower 95% CI (Lower95CI) ≥ 2 for the PRR was considered as the accepted threshold for a drug safety signal. As of 2019 Q3, there were 2,287 reports of death associated with pimavanserin. Compared within the full FAERS base population, pimavanserin yielded a PRR Lower95CI = 2.08 but was smaller when restricted to comparison among only a base population with PD (Lower95CI = 1.09), PD treated with levodopa (Lower95CI = 1.15), or PD treated with multiple PD medications (Lower95CI = 1.63). Metrics for quetiapine, clozapine, and other atypical antipsychotics were similar in magnitude. Stratification by time showed a possible reporting bias associated with pimavanserin, since no safety signal was detected before April 2018; however, a signal was present thereafter. Compared in context with treatment alternatives for patients with PD, pimavanserin was not associated with excess reports of death in the FAERS data. This information should be used in shared decision making between physicians and PD patients to balance the risks and benefits of pimavanserin and other treatments for PD psychosis. No outside funding supported this study. The authors report no disclosures or conflicts of interest relevant to this study. Armstrong receives research support from the NIA (P30AG047266, R01AG068128) and the Florida Department of Health (grant 20A08). She is the local principal investigator of a Lewy Body Dementia Association Research Center of Excellence. She also receives compensation from the American Academy of Neurology for work as an evidence-based medicine methodology consultant. She is on the level of evidence editorial board for and related publications (uncompensated), receives publishing royalties for (Oxford University Press, 2014), and has received an honorarium for presenting for Medscape CME in 2018. Okun serves as a consultant for the Parkinson's Foundation and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. Okun has participated as a site principal investigator and/or co-investigator for several NIH-, foundation-, and industry-sponsored trials over the years but has not received honoraria. Malaty has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, Abbvie, Boston Scientific, Eli Lilly, Neuroderm, Pfizer, Revance, and Teva. She has received travel compensation and/or honoraria from the Tourette Association of America, NeuroChallenge Foundation and NIH/Neurobiology of Disease in Children, Parkinson Foundation, Medscape, International Association of Parkinsonism and Related Disorders, and Cleveland Clinic, and royalties from Robert Rose publishers. The other authors have no disclosures.
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http://dx.doi.org/10.18553/jmcp.2021.27.6.785DOI Listing
June 2021

Bad Air and Parkinson Disease-The Fog May Be Lifting.

JAMA Neurol 2021 Jul;78(7):793-795

Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamaneurol.2021.0863DOI Listing
July 2021

Distinct Roles of the Human Subthalamic Nucleus and Dorsal Pallidum in Parkinson's Disease Impulsivity.

Biol Psychiatry 2021 Mar 6. Epub 2021 Mar 6.

Department of Neuroscience, University of Florida, Gainesville, Florida; J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida.

Background: Impulsivity and impulse control disorders are common in Parkinson's disease and lead to increased morbidity and reduced quality of life. Impulsivity is thought to arise from aberrant reward processing and inhibitory control, but it is unclear why deep brain stimulation of either the subthalamic nucleus (STN) or globus pallidus internus (GPi) affects levels of impulsivity. Our aim was to assess the role of the STN and GPi in impulsivity using invasive local field potential (LFP) recordings from deep brain stimulation electrodes.

Methods: We measured LFPs during a simple rewarding Go/NoGo paradigm in 39 female and male human patients with Parkinson's disease manifesting variable amounts of impulsivity who were undergoing unilateral deep brain stimulation of either the STN (18 nuclei) or GPi (28 nuclei). We identified reward-specific LFP event-related potentials and correlated them to impulsivity severity.

Results: LFPs in both structures modulated during reward-specific Go and NoGo stimulus evaluation, reward feedback, and loss feedback. Motor and limbic functions were anatomically separable in the GPi but not in the STN. Across participants, LFP reward processing responses in the STN and GPi uniquely depended on the severity of impulsivity.

Conclusions: This study establishes LFP correlates of impulsivity within the STN and GPi regions. We propose a model for basal ganglia reward processing that includes the bottom-up role of the GPi in reward salience and the top-down role of the STN in cognitive control.
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http://dx.doi.org/10.1016/j.biopsych.2021.03.002DOI Listing
March 2021

Safety and Tolerability of Burst-Cycling Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease.

Front Hum Neurosci 2021 26;15:651168. Epub 2021 Apr 26.

Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States.

: Freezing of gait (FOG) is a common symptom in Parkinson's disease (PD) and can be difficult to treat with dopaminergic medications or with deep brain stimulation (DBS). Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation (BCDBS) delivers current in various frequencies of bursts (e.g., 4, 10, or 15 Hz), while maintaining an intra-burst frequency identical to conventional DBS. : To evaluate the safety and tolerability of BCDBS in PD patients with FOG. : Ten PD subjects with STN or GPi DBS and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state. : There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS. : BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy.
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http://dx.doi.org/10.3389/fnhum.2021.651168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109241PMC
April 2021

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

Front Hum Neurosci 2021 19;15:644593. Epub 2021 Apr 19.

Neurologischen Klinik Universitätsklinikum Würzburg, Würzburg, Germany.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.
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http://dx.doi.org/10.3389/fnhum.2021.644593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092047PMC
April 2021

Mapping autonomic, mood, and cognitive effects of hypothalamic region deep brain stimulation.

Brain 2021 Apr 26. Epub 2021 Apr 26.

Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Due to its involvement in a wide variety of cardiovascular, metabolic, and behavioral functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequalae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied at multiple international centers 58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation - including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear - were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic gray- and white-matter structures. K-nearest neighbor classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves (AUROC) between 0.67 - 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.
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http://dx.doi.org/10.1093/brain/awab170DOI Listing
April 2021

Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation.

Brain 2021 Apr 23. Epub 2021 Apr 23.

Department of Radiology, Mayo Clinic, Jacksonville, FL, USA.

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.
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http://dx.doi.org/10.1093/brain/awab074DOI Listing
April 2021

Global Variability in Deep Brain Stimulation Practices for Parkinson's Disease.

Front Hum Neurosci 2021 31;15:667035. Epub 2021 Mar 31.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Introduction: Deep brain stimulation (DBS) has become a standard treatment option for select patients with Parkinson's disease (PD). The selection process and surgical procedures employed have, to date, not been standardized.

Methods: A comprehensive 58-question web-based survey was developed with a focus on DBS referral practices and peri-operative management. The survey was distributed to the Parkinson's Foundation Centers of Excellence, members of the International Parkinson's Disease and Movement Disorders Society, and the Parkinson Study Group (Functional Neurosurgery Working Group) between December 2015 and May 2016.

Results: There were 207 individual respondents (20% response rate) drawn from 59 countries and 6 continents, of whom 64% received formal training in DBS. Thirteen percent of centers reported that DBS could proceed despite a confidence level of < 50% for PD diagnosis. A case-based approach to DBS candidacy was applied in 51.3% of centers without a cut-off for levodopa-responsiveness. Surprisingly, 33% of centers regularly used imaging for diagnostic confirmation of idiopathic PD. Thirty-one percent of centers reported that neuropsychological evaluation did not affect DBS target selection. Approximately half of the respondents reported determination of DBS candidacy based on a multidisciplinary committee evaluation and 1/3 reported that a committee was used for target selection. Eight percent of respondents felt that psychosocial factors should not impact DBS candidacy nor site selection. Involvement of allied health professionals in the preoperative process was sparse. There was high variability in preoperative education about DBS outcome expectations. Approximately half of the respondents did not utilize a "default brain target," though STN was used more commonly than GPi. Specific DBS procedure techniques applied, as well as follow-up timelines, were highly variable.

Conclusion: Results revealed high variability on the best approaches for DBS candidate selection, brain target selection, procedure type, and postoperative practices. Cognitive and mood assessments were underutilized. There was low reliance on multidisciplinary teams or psychosocial factors to impact the decision-making process. There were small but significant differences in practice across global regions, especially regarding multidisciplinary teams. The wide variability of responses across multiple facets of DBS care highlights the need for prospective studies to inform evidence-based guidelines.
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http://dx.doi.org/10.3389/fnhum.2021.667035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044366PMC
March 2021

Parkinson's disease.

Lancet 2021 Jun 10;397(10291):2284-2303. Epub 2021 Apr 10.

Institute of Neurogenetics and Department of Neurology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.

Parkinson's disease is a recognisable clinical syndrome with a range of causes and clinical presentations. Parkinson's disease represents a fast-growing neurodegenerative condition; the rising prevalence worldwide resembles the many characteristics typically observed during a pandemic, except for an infectious cause. In most populations, 3-5% of Parkinson's disease is explained by genetic causes linked to known Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 genetic risk variants collectively explain 16-36% of the heritable risk of non-monogenic Parkinson's disease. Additional causal associations include having a relative with Parkinson's disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson's disease. The diagnosis is clinically based; ancillary testing is reserved for people with an atypical presentation. Current criteria define Parkinson's disease as the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, the clinical presentation is multifaceted and includes many non-motor symptoms. Prognostic counselling is guided by awareness of disease subtypes. Clinically manifest Parkinson's disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. There is no reason to postpone symptomatic treatment in people developing disability due to Parkinson's disease. Levodopa is the most common medication used as first-line therapy. Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson's disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential. With the perspective of people with Parkinson's disease as a so-called red thread throughout this Seminar, we will show how personalised management of Parkinson's disease can be optimised.
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http://dx.doi.org/10.1016/S0140-6736(21)00218-XDOI Listing
June 2021

A novel local field potential-based functional approach for targeting the centromedian-parafascicular complex for deep brain stimulation.

Neuroimage Clin 2021 26;30:102644. Epub 2021 Mar 26.

J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville FL, United States.

Background: The centromedian-parafascicular (Cm-Pf) complex of the thalamus is a common deep brain stimulation (DBS) target for treatment of Tourette syndrome (TS). Currently, there are no standardized functional intraoperative neurosurgical targeting approaches. Collectively, these issues have led to variability in DBS lead placement. Therefore, more defined methods are needed to improve targeting accuracy.

Objective: The objective of this observational study was to develop and to verify a functional mapping task capable of differentiating the Cm-Pf region from the nearby ventral intermediate (Vim) nucleus region of the thalamus. The overarching goal was to improve the reproducibility of DBS targeting in the Cm-Pf region.

Methods: Seven TS patients completed a modified Go/NoGo task (five in the post-operative setting and two in the intra-operative setting). Post-operative neural signals from Cm-Pf region were collected using sensing-enabled implanted neural stimulators, and intraoperative neural signals from the Cm-Pf region were collected using an external amplifier. Event-related potential (ERP) features were identified by using the grand-average of stimulus onset signals derived from the postoperative participants. These features were correlated with anatomical locations for the specific electrode recordings. The same features were extracted from the intraoperative patients in order to verify electrode positions in the operating room environment.

Results: Two features - a positive and a negative deflection - were identified in the average ERP from the post-operative participants. The peak amplitudes of both features were significantly correlated with the electrode depth position (p = 0.025 for positive deflection and p = 0.039 for negative deflection). The same result was reproduced intra-operatively in the two most recent patients, where more ventral electrode contacts revealed stronger peak amplitudes in comparison to the dorsal electrode contacts.

Conclusion: This process was used to physiologically confirm accurate lead placement in the operating room setting. The modified Go/NoGo task elicited robust neural responses in the Cm-Pf region however the signal was not present in the Vim nucleus region of thalamus along the DBS electrode trajectory. We conclude that the differences in ERP responses may be a potentially novel LFP based functional approach for future targeting of the Cm-Pf complex for TS DBS.
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http://dx.doi.org/10.1016/j.nicl.2021.102644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064020PMC
March 2021

Palliative Care and Parkinson's Disease: Time to Move Beyond Cancer.

Mov Disord 2021 06 30;36(6):1325-1329. Epub 2021 Mar 30.

Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.

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http://dx.doi.org/10.1002/mds.28556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217287PMC
June 2021

Closed-Loop Deep Brain Stimulation to Treat Medication-Refractory Freezing of Gait in Parkinson's Disease.

Front Hum Neurosci 2021 1;15:633655. Epub 2021 Mar 1.

Norman Fixel Institute for Neurological Diseases and The Program for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, United States.

: Treating medication-refractory freezing of gait (FoG) in Parkinson's disease (PD) remains challenging despite several trials reporting improvements in motor symptoms using subthalamic nucleus or globus pallidus internus (GPi) deep brain stimulation (DBS). Pedunculopontine nucleus (PPN) region DBS has been used for medication-refractory FoG, with mixed findings. FoG, as a paroxysmal phenomenon, provides an ideal framework for the possibility of closed-loop DBS (CL-DBS). : In this clinical trial (NCT02318927), five subjects with medication-refractory FoG underwent bilateral GPi DBS implantation to address levodopa-responsive PD symptoms with open-loop stimulation. Additionally, PPN DBS leads were implanted for CL-DBS to treat FoG. The primary outcome of the study was a 40% improvement in medication-refractory FoG in 60% of subjects at 6 months when "on" PPN CL-DBS. Secondary outcomes included device feasibility to gauge the recruitment potential of this four-lead DBS approach for a potentially larger clinical trial. Safety was judged based on adverse events and explantation rate. : The feasibility of this approach was demonstrated as we recruited five subjects with both "on" and "off" medication freezing. The safety for this population of patients receiving four DBS leads was suboptimal and associated with a high explantation rate of 40%. The primary clinical outcome in three of the five subjects was achieved at 6 months. However, the group analysis of the primary clinical outcome did not reveal any benefit. : This study of a human PPN CL-DBS trial in medication-refractory FoG showed feasibility in recruitment, suboptimal safety, and a heterogeneous clinical effect in FoG outcomes.
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http://dx.doi.org/10.3389/fnhum.2021.633655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959768PMC
March 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

Cognitive subtypes in individuals with essential tremor seeking deep brain stimulation.

Clin Neuropsychol 2021 Feb 10:1-23. Epub 2021 Feb 10.

Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA.

Essential tremor (ET) is a common neurological disorder that has been associated with 60% increased risk of developing dementia. The goals of the present study were to: (a) learn whether individuals with advanced ET symptoms seeking deep brain stimulation (DBS) surgery would fall into distinct cognitive subgroups, and (b) learn how empirically derived subgroups map onto criteria for mild cognitive impairment (MCI). Patients with ET ( = 201; mean age = 68.9 ± 8.9 years) undergoing pre-surgical evaluation for DBS completed a multi-domain neurocognitive assessment consisting of memory, executive function, visuospatial skill, language, and processing speed. Two cluster analytic approaches (-means, hierarchical) were independently conducted to classify cognitive patterns using domain composites. Demographics, clinical characteristics, and proportion of cases meeting neuropsychologically defined criteria for MCI were examined among clusters. A three-cluster solution reflected a Low Executive group ( = 64), Low Memory Multi-Domain group ( = 41), and Cognitively Normal group ( = 96). The Cognitively Normal group was older and more educated, with a higher Dementia Rating Scale-2 score. In total, 27.4% of participants met criteria for MCI. Of the MCI cases, most were in the Low Executive (41.8%) or Low Memory Multi-Domain groups (49.1%). In the latter, 65.9% of its members were classified as MCI versus 35.9% in the Low Executive group. Our study identified three cognitive subtypes of ET patients presenting for DBS. Future work should examine the subgroups for progression to dementia, particularly the Low Memory Multi-Domain subgroup which may be at highest risk.
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http://dx.doi.org/10.1080/13854046.2021.1882578DOI Listing
February 2021

Basal Ganglia Pathways Associated With Therapeutic Pallidal Deep Brain Stimulation for Tourette Syndrome.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Nov 24. Epub 2020 Nov 24.

Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah; Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah; Department of Neurology, University of Utah, Salt Lake City, Utah; Department of Neurosurgery, University of Utah, Salt Lake City, Utah; Department of Psychiatry, University of Utah, Salt Lake City, Utah. Electronic address:

Background: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients' symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes.

Methods: Retrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement.

Results: The best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation.

Conclusions: Differences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.005DOI Listing
November 2020

Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease.

Alzheimers Dement 2021 05 21;17(5):777-787. Epub 2021 Jan 21.

Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada.

Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation.

Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients' implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning-based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks.

Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites.

Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.
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http://dx.doi.org/10.1002/alz.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247976PMC
May 2021

Reply to: "Toward a Personalized Approach to Parkinson's Cell Therapy".

Mov Disord 2020 11;35(11):2120-2121

Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1002/mds.28329DOI Listing
November 2020

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Transl Psychiatry 2021 01 18;11(1):56. Epub 2021 Jan 18.

Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.
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http://dx.doi.org/10.1038/s41398-020-01082-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814139PMC
January 2021

Detection of postural control in early Parkinson's disease: Clinical testing vs. modulation of center of pressure.

PLoS One 2021 12;16(1):e0245353. Epub 2021 Jan 12.

Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States of America.

Introduction: Little is known about the early stage balance changes in PD. Many clinicians assume that there are no postural issues in early PD because of failure to identify them on bedside and clinical testing. Here, we quantify balance changes in early and moderate stage PD and compared these values to healthy controls (HC) using clinical assessments of balance and posturography.

Methods: We compared 15 HC with 15 early PD (PD-II; Hoehn and Yahr stage II) and 15 moderate PD (PD-III; H&Y stage III). Participants performed various clinical tests of balance and a standing postural task on a force platform. We quantified the spatiotemporal parameters of the center of pressure (COP), the sample entropy and power spectral density (PSD) of the COP.

Results: The PSD of the COP differentiated PD-II from HC from 0-0.5 Hz and PD-II from PD-III from 0.5-1 Hz. Specifically, PD-II and PD-III manifested greater power than HC from 0-0.5 Hz, whereas PD-III exhibited greater power than PD-II and HC from 0.5-1.0 Hz (p<0.05). However, there were no significant differences between PD-II and HC in all clinical tests and in spatiotemporal parameters of the COP (p>0.05). Although the sample entropy was significantly lower in the PD groups (p<0.05), entropy failed to differentiate PD-II from PD-III.

Conclusion: The low-frequency modulation of the COP in this small cohort differentiated early PD from HC and from moderate PD. Clinicians should be aware that there are early balance deficits in PD. A larger sample size is needed to confirm these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245353PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802937PMC
June 2021

Cognitive Outcomes for Essential Tremor Patients Selected for Thalamic Deep Brain Stimulation Surgery Through Interdisciplinary Evaluations.

Front Hum Neurosci 2020 11;14:578348. Epub 2020 Dec 11.

Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States.

: Deep brain stimulation (DBS) targeted to the ventral intermediate (VIM) nucleus of the thalamus is effective for motor symptoms in essential tremor (ET), but there is limited data on cognitive outcomes. We examined cognitive outcomes in a large cohort of ET DBS patients (pre-DBS and 1+ year after DBS). : In a retrospective analysis, we used repeated-measures ANOVA testing to examine whether the age of tremor onset, age at DBS surgery, hemisphere side implanted with lead, unilateral vs. bilateral implantations, and presence of surgical complications influenced the cognitive outcomes. Neuropsychological outcomes of interest were verbal memory, executive functioning, working memory, language functioning, visuospatial functioning, and general cognitive function. : We identified 50 ET DBS patients; 29 (58%) males; the mean age of tremor onset was 35.84 (±21.50) years with a median age of 38 years. The mean age at DBS was 68.18 (±10.07) years. There were 37 unilateral 30 left, seven right, and 13 bilateral brain implantations. In the subgroup analysis, there was a significant interaction between assessment (pre vs. post) and age of tremor onset (<38 vs. >38 years); = 4.47; = 0.043 for working memory. The testing found improvements for younger onset ET. Similarly, there was a significant interaction between assessment (pre vs. post) and complications vs. no complications subgroups; = 4.34; = 0.043 for verbal memory with worsening scores seen for ET patients with complications. The remaining tests were not significant. : In this large cohort of ET patients with (>30% improvements), DBS was not accompanied by a significant decline in many cognitive domains. These outcomes were possibly related to the selection of patients with normal cognitive functioning before surgery, unilateral DBS implantations for the majority, and selection of patients with optimal response to DBS.
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http://dx.doi.org/10.3389/fnhum.2020.578348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759538PMC
December 2020

Chronic embedded cortico-thalamic closed-loop deep brain stimulation for the treatment of essential tremor.

Sci Transl Med 2020 12;12(572)

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.

Deep brain stimulation (DBS) is an approved therapy for the treatment of medically refractory and severe movement disorders. However, most existing neurostimulators can only apply continuous stimulation [open-loop DBS (OL-DBS)], ignoring patient behavior and environmental factors, which consequently leads to an inefficient therapy, thus limiting the therapeutic window. Here, we established the feasibility of a self-adjusting therapeutic DBS [closed-loop DBS (CL-DBS)], fully embedded in a chronic investigational neurostimulator (Activa PC + S), for three patients affected by essential tremor (ET) enrolled in a longitudinal (6 months) within-subject crossover protocol (DBS OFF, OL-DBS, and CL-DBS). Most patients with ET experience involuntary limb tremor during goal-directed movements, but not during rest. Hence, the proposed CL-DBS paradigm explored the efficacy of modulating the stimulation amplitude based on patient-specific motor behavior, suppressing the pathological tremor on-demand based on a cortical electrode detecting upper limb motor activity. Here, we demonstrated how the proposed stimulation paradigm was able to achieve clinical efficacy and tremor suppression comparable with OL-DBS in a range of movements (cup reaching, proximal and distal posture, water pouring, and writing) while having a consistent reduction in energy delivery. The proposed paradigm is an important step toward a behaviorally modulated fully embedded DBS system, capable of delivering stimulation only when needed, and potentially mitigating pitfalls of OL-DBS, such as DBS-induced side effects and premature device replacement.
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http://dx.doi.org/10.1126/scitranslmed.aay7680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182660PMC
December 2020

Case Report: Globus Pallidus Internus (GPi) Deep Brain Stimulation Induced Keyboard Typing Dysfunction.

Front Hum Neurosci 2020 9;14:583441. Epub 2020 Nov 9.

Department of Neurology, McKnight Brain Institute, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States.

Typing on a keyboard requires complex collaboration between visuospatial/procedural memory, language, and motor function. The impaired ability to type, independent of motor deficits, apraxia, or aphasia has been coined "dystypia." : A 68-year-old woman with a history of blepharospasm, oromandibular, and segmental dystonia underwent bilateral pallidal deep brain stimulation (DBS) because of a waning response to botulinum toxin therapy. Following DBS, she discovered she no longer "remembered" how to type fluidly and had to "hunt and peck" for letters on the keyboard. This issue persisted at a 2-year follow-up. The patient underwent serial typing tests with the DBS ON vs. OFF. Post-operative lead reconstruction was performed using Lead-DBS. The volume of tissue activation (VTA) modeling was combined with whole-brain tractography. : Typing improved when the device was switched to the DBS OFF state. Cortical mapping revealed strong modulation of the right angular gyrus, left calcarine fissure, and left cuneus. There was also activation of bilateral supplemental motor areas and superior parietal gyri. : Shared lesion topography analysis of dystypia cases in the literature has suggested the involvement of the superior longitudinal fasciculus (SLF). The SLF involves the superior parietal lobe, angular gyrus, supramarginal gyrus, and arcuate fasciculus. Our patient's connectivity pattern suggested SLF involvement. The improvement in OFF state typing and her imaging together suggested that the dystypia in her case was a stimulation-induced side effect. : Dystypia is a rare side effect of Globus Pallidus Internus (GPi) DBS therapy and may be associated with SLF involvement.
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http://dx.doi.org/10.3389/fnhum.2020.583441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680927PMC
November 2020

STN Versus GPi Deep Brain Stimulation for Action and Rest Tremor in Parkinson's Disease.

Front Hum Neurosci 2020 23;14:578615. Epub 2020 Oct 23.

Department of Neurology, Normal Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States.

Objective: To investigate the effects of subthalamic nucleus (STN) and globus pallidus internus (GPi), deep brain stimulation (DBS) on individual action tremor/postural tremor (AT) and rest tremor (RT) in Parkinson's disease (PD). Randomized DBS studies have reported marked benefit in tremor with both GPi and STN and DBS, however, there is a paucity of information available on AT vs RT when separated by the surgical target.

Methods: We retrospectively reviewed the 1-year clinical outcome of PD patients treated with STN and GPi DBS at the University of Florida. We specifically selected patients with moderate to severe AT. Eighty-eight patients (57 STN and 31 GPi) were evaluated at 6 and 12 months for changes in AT and RT in the OFF-medication/ON stimulation state. A comparison of "response" was performed and defined as greater than or equal to a 2-point decrease in tremor score.

Results: STN and GPi DBS both improved AT at 6- and 12-months post-implantation ( < 0.001 and < 0.001). The STN DBS group experienced a greater improvement in AT at 6 months compared to the GPi group ( = 0.005) but not at the 12 months follow-up ( = 0.301). Both STN and GPi DBS also improved RT at 6- and 12-months post-implantation ( < 0.001 and < 0.001). There was no difference in RT scores between the two groups at 6 months ( = 0.23) or 12 months ( = 0.74). The STN group had a larger proportion of patients who achieved a "response" in AT at 6 months ( < 0.01), however, this finding was not present at 12 months ( = 0.23). A sub-analysis revealed that in RT, the STN group had a larger percentage of "responders" when followed through 12 months ( < 0.01).

Conclusion: Both STN and GPi DBS reduced PD associated AT and RT at 12 months follow-up. There was no advantage of either brain target in the management of RT or AT. One nuance of the study was that STN DBS was more effective in suppressing AT in the early postoperative period, however, this effect diminished over time. Clinicians should be aware that it may take longer to achieve a similar tremor outcome when utilizing the GPi target.
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http://dx.doi.org/10.3389/fnhum.2020.578615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651783PMC
October 2020

Reforming the Process for Deep Brain Stimulation and Neurologic Device Approval in Rare Diseases.

JAMA Neurol 2021 01;78(1):5-6

Neuroethics Studies Program, Pellegrino Center for Clinical Bioethics, Department of Neurology, Georgetown University Medical Center, Washington, DC.

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http://dx.doi.org/10.1001/jamaneurol.2020.4232DOI Listing
January 2021

Globus Pallidus Internus (GPi) Deep Brain Stimulation for Parkinson's Disease: Expert Review and Commentary.

Neurol Ther 2021 Jun 2;10(1):7-30. Epub 2020 Nov 2.

Departments of Neurology and Neurosurgery, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.

Introduction: The globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients.

Methods: The literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping.

Results: There are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD.

Conclusion: GPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.
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http://dx.doi.org/10.1007/s40120-020-00220-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140010PMC
June 2021
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