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A validated measure of rigidity in Parkinson's disease using alternating finger tapping on an engineered keyboard. Parkinsonism & related disorders Trager, M. H., Wilkins, K. B., Koop, M. M., Bronte-Stewart, H. 2020; 81: 161?64
Abstract

INTRODUCTION: Reliable and accurate measures of rigidity have remained elusive in remote assessments of Parkinson's disease (PD). This has severely limited the utility of telemedicine in the care and treatment of people with PD. It has also had a large negative impact on the scope of available outcomes, and on the costs, of multicenter clinical trials in PD. The goal of this study was to determine if quantitative measures from an engineered keyboard were sensitive and related to clinical measures of rigidity.METHODS: Sixteen participants with idiopathic PD, off antiparkinsonian medications, and eleven age-matched control participants performed a 30second repetitive alternating finger tapping task on an engineered keyboard and were assessed with the Unified Parkinson's Disease Rating Scale - motor (UPDRS-III).RESULTS: The speed of the key release was significantly slower in the PD compared to control cohorts (p<0.0001). In the PD cohort key release speed correlated with the lateralized upper extremity UPDRS III rigidity score (r=- 0.58, p<0.0001), but not with the lateralized upper extremity tremor score (r=- 0.14, p=0.43).CONCLUSIONS: This validated measure of rigidity complements our previous validation of temporal metrics of the repetitive alternating finger tapping task with the UPDRS III, bradykinesia and with the ability to quantify tremor, arrhythmicity and freezing episodes, and suggests that 30seconds of alternating finger tapping on a portable engineered keyboard could transform the treatment of PD with telemedicine and the precision of multicenter clinical trials.

View details for DOI 10.1016/j.parkreldis.2020.10.047

View details for PubMedID 33157435
Perspective: Evolution of Control Variables and Policies for Closed-Loop Deep Brain Stimulation for Parkinson's Disease Using Bidirectional Deep-Brain-Computer Interfaces FRONTIERS IN HUMAN NEUROSCIENCE Bronte-Stewart, H. M., Petrucci, M. N., O'Day, J. J., Afzal, M., Parker, J. E., Kehnemouyi, Y. M., Wilkins, K. B., Orthlieb, G. C., Hoffman, S. L. 2020; 14
View details for DOI 10.3389/fnhum.2020.00353

View details for Web of Science ID 000570514300001
A Closed-loop Deep Brain Stimulation Approach for Mitigating Burst Durations in People with Parkinson's Disease. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Petrucci, M. N., Anderson, R. W., O'Day, J. J., Kehnemouyi, Y. M., Herron, J. A., Bronte-Stewart, H. M. 2020; 2020: 3617?20
Abstract

Increased beta band synchrony has been demonstrated to be a biomarker of Parkinson's disease (PD). This abnormal synchrony can often be prolonged in long bursts of beta activity, which may interfere with normal sensorimotor processing. Previous closed loop deep brain stimulation (DBS) algorithms used averaged beta power to drive neurostimulation, which were indiscriminate to physiological (short) versus pathological (long) beta burst durations. We present a closed-loop DBS algorithm using beta burst duration as the control signal. Benchtop validation results demonstrate the feasibility of the algorithm in real-time by responding to pre-recorded STN data from a PD participant. These results provide the basis for future improved closed-loop algorithms focused on burst durations for in mitigating symptoms of PD.

View details for DOI 10.1109/EMBC44109.2020.9176196

View details for PubMedID 33018785
Demonstration of Kinematic-Based Closed-loop Deep Brain Stimulation for Mitigating Freezing of Gait in People with Parkinson's Disease. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference O'Day, J. J., Kehnemouyi, Y. M., Petrucci, M. N., Anderson, R. W., Herron, J. A., Bronte-Stewart, H. M. 2020; 2020: 3612?16
Abstract

Impaired gait in Parkinson's disease is marked by slow, arrhythmic stepping, and often includes freezing of gait episodes where alternating stepping halts completely. Wearable inertial sensors offer a way to detect these gait changes and novel deep brain stimulation (DBS) systems can respond with clinical therapy in a real-time, closed-loop fashion. In this paper, we present two novel closed-loop DBS algorithms, one using gait arrhythmicity and one using a logistic-regression model of freezing of gait detection as control signals. Benchtop validation results demonstrate the feasibility of running these algorithms in conjunction with a closed-loop DBS system by responding to real-time human subject kinematic data and pre-recorded data from leg-worn inertial sensors from a participant with Parkinson's disease. We also present a novel control policy algorithm that changes neurostimulator frequency in response to the kinematic inputs. These results provide a foundation for further development, iteration, and testing in a clinical trial for the first closed-loop DBS algorithms using kinematic signals to therapeutically improve and understand the pathophysiological mechanisms of gait impairment in Parkinson's disease.

View details for DOI 10.1109/EMBC44109.2020.9176638

View details for PubMedID 33018784
Alterations of Brain Signal Oscillations in Older Individuals with HIV Infection and Parkinson's Disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology Muller-Oehring, E. M., Hong, J., Hughes, R. L., Kwon, D., Bronte-Stewart, H. M., Poston, K. L., Schulte, T. 2020
Abstract

More than 30years after the human immunodeficiency virus (HIV) epidemic, HIV patients are now aging due to the advances of antiretroviral therapy. With immunosenescence and the susceptibility of dopamine-rich basal ganglia regions to HIV-related injury, older HIV patients may show neurofunctional deficits similar to patients with Parkinson's disease (PD). We examined the amplitudes of low frequency fluctuations (ALFF) across different frequency bands of the BOLD signal in 30 older HIV-infected individuals, 33 older healthy controls, and 36 PD patients. Participants underwent resting-state fMRI, neuropsychological testing, and a clinical motor exam. HIV patients mainly showed abnormalities in cortical ALFF with reduced prefrontal amplitudes and enhanced sensorimotor and inferior temporal amplitudes. Frontal hypoactivation was overlapping for HIV and PD groups and different from controls. PD patients further exhibited reduced pallidum amplitudes compared to the other groups. In the HIV group, lower pallidum amplitudes were associated with lower CD4+ nadir and CD4+ T cell counts. Abnormalities in ALFF dynamics were largely associated with cognitive and motor functioning in HIV and PD groups. The disruption of neurofunctional frequency dynamics in subcortical-cortical circuits could contribute to the development of cognitive and motor dysfunction and serve as a biomarker for monitoring disease progression with immunosenescence. Graphical Abstract.

View details for DOI 10.1007/s11481-020-09914-x

View details for PubMedID 32291601
Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease. Journal of neuropsychology M�ller-Oehring, E. M., Fama, R., Levine, T. F., Hardcastle, C., Goodcase, R., Martin, T., Prabhakar, V., Bront�-Stewart, H. M., Poston, K. L., Sullivan, E. V., Schulte, T. 2020
Abstract

Despite the life-extending success of antiretroviral pharmacotherapy in HIV infection (HIV), the prevalence of mild cognitive impairment in HIV remains high. Near-normal life expectancy invokes an emerging role for age-infection interaction and a potential synergy between immunosenescence and HIV-related health factors, increasing risk of cognitive and motor impairment associated with degradation in corticostriatal circuits. These neural systems are also compromised in Parkinson's disease (PD), which could help model the cognitive deficit pattern in HIV.�This cross-sectional study examined three groups, age 45-79�years: 42 HIV, 41 PD, and 37 control (CTRL) participants, tested at Stanford University Medical School and SRI International. Neuropsychological tests assessed executive function (EF), information processing speed (IPS), episodic memory (MEM), visuospatial processing (VSP), and upper motor (MOT) speed and dexterity. The HIV and PD deficit profiles were similar for EF, MEM, and VSP. Although only the PD group was impaired on MOT compared with CTRL, MOT scores were related to cognitive scores in HIV but not PD. Performance was not related to depressive symptoms, socioeconomic status, or CD4+ T-cell counts. The overlap of HIV-PD cognitive deficits implicates frontostriatal disruption in both conditions. The motor-cognitive score relation in HIV provides further support for the hypothesis that these processes share similar underlying mechanisms in HIV infection possibly expressed with or exacerbated by ageing.

View details for DOI 10.1111/jnp.12227

View details for PubMedID 33029951
The turning and barrier course reveals gait parameters for detecting freezing of gait and measuring the efficacy of deep brain stimulation. PloS one O'Day, J., Syrkin-Nikolau, J., Anidi, C., Kidzinski, L., Delp, S., Bronte-Stewart, H. 2020; 15 (4): e0231984
Abstract

Freezing of gait (FOG) is a devastating motor symptom of Parkinson's disease that leads to falls, reduced mobility, and decreased quality of life. Reliably eliciting FOG has been difficult in the clinical setting, which has limited discovery of pathophysiology and/or documentation of the efficacy of treatments, such as different frequencies of subthalamic deep brain stimulation (STN DBS). In this study we validated an instrumented gait task, the turning and barrier course (TBC), with the international standard FOG questionnaire question 3 (FOG-Q3, r = 0.74, p < 0.001). The TBC is easily assembled and mimics real-life environments that elicit FOG. People with Parkinson's disease who experience FOG (freezers) spent more time freezing during the TBC compared to during forward walking (p = 0.007). Freezers also exhibited greater arrhythmicity during non-freezing gait when performing the TBC compared to forward walking (p = 0.006); this difference in gait arrhythmicity between tasks was not detected in non-freezers or controls. Freezers' non-freezing gait was more arrhythmic than that of non-freezers or controls during all walking tasks (p < 0.05). A logistic regression model determined that a combination of gait arrhythmicity, stride time, shank angular range, and asymmetry had the greatest probability of classifying a step as FOG (area under receiver operating characteristic curve = 0.754). Freezers' percent time freezing and non-freezing gait arrhythmicity decreased, and their shank angular velocity increased in the TBC during both 60 Hz and 140 Hz STN DBS (p < 0.05) to non-freezer values. The TBC is a standardized tool for eliciting FOG and demonstrating the efficacy of 60 Hz and 140 Hz STN DBS for gait impairment and FOG. The TBC revealed gait parameters that differentiated freezers from non-freezers and best predicted FOG; these may serve as relevant control variables for closed loop neurostimulation for FOG in Parkinson's disease.

View details for DOI 10.1371/journal.pone.0231984

View details for PubMedID 32348346
Perspective: Evolution of Control Variables and Policies for Closed-Loop Deep Brain Stimulation for Parkinson's Disease Using Bidirectional Deep-Brain-Computer Interfaces. Frontiers in human neuroscience Bronte-Stewart, H. M., Petrucci, M. N., O'Day, J. J., Afzal, M. F., Parker, J. E., Kehnemouyi, Y. M., Wilkins, K. B., Orthlieb, G. C., Hoffman, S. L. 2020; 14: 353
Abstract

A deep brain stimulation system capable of closed-loop neuromodulation is a type of bidirectional deep brain-computer interface (dBCI), in which neural signals are recorded, decoded, and then used as the input commands for neuromodulation at the same site in the brain. The challenge in assuring successful implementation of bidirectional dBCIs in Parkinson's disease (PD) is to discover and decode stable, robust and reliable neural inputs that can be tracked during stimulation, and to optimize neurostimulation patterns and parameters (control policies) for motor behaviors at the brain interface, which are customized to the individual. In this perspective, we will outline the work done in our lab regarding the evolution of the discovery of neural and behavioral control variables relevant to PD, the development of a novel personalized dual-threshold control policy relevant to the individual's therapeutic window and the application of these to investigations of closed-loop STN DBS driven by neural or kinematic inputs, using the first generation of bidirectional dBCIs.

View details for DOI 10.3389/fnhum.2020.00353

View details for PubMedID 33061899

View details for PubMedCentralID PMC7489234
Gait variability is linked to the atrophy of the Nucleus Basalis of Meynert and is resistant to STN DBS in Parkinson's disease. Neurobiology of disease Wilkins, K. B., Parker, J. E., Bronte-Stewart, H. M. 2020: 105134
Abstract

Parkinson's disease (PD) is a systemic brain disorder where the cortical cholinergic network begins to degenerate early in the disease process. Readily accessible, quantitative, and specific behavioral markers of the cortical cholinergic network are lacking. Although degeneration of the dopaminergic network may be responsible for deficits in cardinal motor signs, the control of gait is a complex process and control of higher-order aspects of gait, such as gait variability, may be influenced by cognitive processes attributed to cholinergic networks. We investigated whether swing time variability, a metric of gait variability that is independent from gait speed, was a quantitative behavioral marker of cortical cholinergic network integrity in PD. Twenty-two individuals with PD and subthalamic nucleus (STN) deep brain stimulation (PD-DBS cohort) and twenty-nine age-matched controls performed a validated stepping-in-place (SIP) task to assess swing time variability off all therapy. The PD-DBS cohort underwent structural MRI scans to measure gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. In order to determine the role of the dopaminergic system on swing time variability, it was measured ON and OFF STN DBS in the PD-DBS cohort, and on and off dopaminergic medication in a second PD cohort of thirty-two individuals (PD-med). A subset of eleven individuals in the PD-DBS cohort completed the SIP task again off all therapy after three years of continuous DBS to assess progression of gait impairment. Swing time variability was significantly greater (i.e., worse) in PD compared to controls and greater swing time variability was related to greater atrophy of the NBM, as was gait speed. STN DBS significantly improved cardinal motor signs and gait speed but did not improve swing time variability, which was replicated in the second cohort using dopaminergic medication. Swing time variability continued to worsen in PD, off therapy, after three years of continuous STN DBS, and NBM atrophy showed a trend for predicting the degree of increase. In contrast, cardinal motor signs did not progress. These results demonstrate that swing time variability is a reliable marker of cortical cholinergic health, and support a framework in which higher-order aspects of gait control in PD are reliant on the cortical cholinergic system, in contrast to other motor aspects of PD that rely on the dopaminergic network.

View details for DOI 10.1016/j.nbd.2020.105134

View details for PubMedID 33045357
Neural Closed loop deep brain stimulation for freezing of Gait. Brain stimulation Petrucci, M. N., Neuville, R. S., Afzal, M. F., Velisar, A., Anidi, C. M., Anderson, R. W., Parker, J. E., O'Day, J. J., Wilkins, K. B., Bronte-Stewart, H. M. 2020
View details for DOI 10.1016/j.brs.2020.06.018

View details for PubMedID 32634599
Safety of Plasma Infusions in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Parker, J. E., Martinez, A., Deutsch, G. K., Prabhakar, V., Lising, M., Kapphahn, K. I., Anidi, C. M., Neuville, R., Coburn, M., Shah, N., Bronte-Stewart, H. M. 2020
Abstract

Young plasma infusions have emerged as a potential treatment for neurodegenerative disease, and convalescent plasma therapy has been used safely in the management of viral pandemics. However, the effect of plasma therapy in Parkinson's disease (PD) is unknown.The objective of this study was to determine the safety, tolerability, and feasibility of plasma infusions in people with PD.A total of 15 people with clinically established PD, at least 1 cognitive complaint, and on stable therapy received 1 unit of young fresh frozen plasma twice a week for 4?weeks. Assessments and adverse effects were performed/reported on and off therapy at baseline, immediately after, and 4?weeks after the infusions ended. Adverse effects were also assessed during infusions. The primary outcomes were safety, tolerability, and feasibility. Exploratory outcomes included Unified Parkinson's Disease Rating Scale Part III off medication, neuropsychological battery, Parkinson's Disease Questionnaire-39, inflammatory markers (tumor necrosis factor-?, interleukin-6), uric acid, and quantitative kinematics.Adherence rate was 100% with no serious adverse effects. There was evidence of improvement in phonemic fluency (P = 0.002) and in the Parkinson's Disease Questionnaire-39 stigma subscore (P = 0.013) that were maintained at the delayed evaluation. Elevated baseline tumor necrosis factor-? levels decreased 4?weeks after the infusions ended.Young fresh frozen plasma was safe, feasible, and well tolerated in people with PD, without serious adverse effects and with preliminary evidence for improvements in phonemic fluency and stigma. The results of this study warrant further therapeutic investigations in PD and provide safety and feasibility data for plasma therapy in people with PD who may be at higher risk for severe complications of COVID-19. � 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

View details for DOI 10.1002/mds.28198

View details for PubMedID 32633860
Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson?s Disease Frontier in Aging Neuroscience Prabhakar, V., Martin, T., M�ller-Oehring, E. M., Goodcase, R., Schulte, T., Poston, K. L., Bront�-Stewart, H. M. 2020: 539598
Abstract

Introduction: Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson's disease (PD), and healthy controls. Methods: Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests. Results: HIV demonstrated RAFT deficits similar to PD such as reduced amplitude (P = 0.023) and greater amplitude variability (P = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV's immune health, measured by their CD4+ T cell count (P < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV (P = 0.006, P = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD (P < 0.05) although motor deficits predominated in PD. Conclusions: Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.

View details for DOI 10.3389/fnagi.2020.539598

View details for PubMedCentralID PMC7575770
Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics FRONTIERS IN NEUROSCIENCE Ramirez-Zamora, A., Giordano, J., Boyden, E. S., Gradinaru, V., Gunduz, A., Starr, P. A., Sheth, S. A., McIntyre, C. C., Fox, M. D., Vitek, J., Vedam-Mai, V., Akbar, U., Almeida, L., Bronte-Stewart, H. M., Mayberg, H. S., Pouratian, N., Gittis, A. H., Singer, A. C., Creed, M. C., Lazaro-Munoz, G., Richardson, M., Rossi, M. A., Cendejas-Zaragoza, L., D'Haese, P., Chiong, W., Gilron, R., Chizeck, H., Ko, A., Baker, K. B., Wagenaar, J., Harel, N., Deeb, W., Foote, K. D., Okun, M. S. 2019; 13
View details for DOI 10.3389/fnins.2019.00936

View details for Web of Science ID 000485218000001
Reply to letter to the editor "Adaptive DBS in Parkinson's disease: Headlines, perspectives and challenges". Brain stimulation Velisar, A., Bronte-Stewart, H. 2019
View details for DOI 10.1016/j.brs.2019.06.014

View details for PubMedID 31235368
Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson's disease. Neuroscience and biobehavioral reviews Sundaram, S., Hughes, R. L., Peterson, E., Muller-Oehring, E. M., Bronte-Stewart, H. M., Poston, K. L., Faerman, A., Bhowmick, C., Schulte, T. 2019
Abstract

Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson's disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.

View details for DOI 10.1016/j.neubiorev.2019.05.016

View details for PubMedID 31132378
Information Processing Deficit in Older Adults With HIV Infection: A Comparison With Parkinson's Disease NEUROPSYCHOLOGY Sundaram, S., Mueller-Oehring, E. M., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Goodcase, R., Martin, T., Prabhakar, V., Karpf, J., Schulte, T. 2019; 33 (2): 157?68
View details for DOI 10.1037/neu0000500

View details for Web of Science ID 000457254300002
Dual threshold neural closed loop deep brain stimulation in Parkinson disease patients. Brain stimulation Velisar, A., Syrkin-Nikolau, J., Blumenfeld, Z., Trager, M. H., Afzal, M. F., Prabhakar, V., Bronte-Stewart, H. 2019
Abstract

Closed loop deep brain stimulation (clDBS) in Parkinson's disease (PD) using subthalamic (STN) neural feedback has been shown to be efficacious only in the acute post-operative setting, using externalized leads and stimulators.To determine feasibility of neural (N)clDBS using the clinical implanted neurostimulator (Activa? PC�+�S, FDA IDE approved) and a novel beta dual threshold algorithm in tremor and bradykinesia dominant PD patients on chronic DBS.13 PD subjects (20 STNs), on open loop (ol)DBS for 22?�?7.8 months, consented to NclDBS driven by beta (13-30?Hz) power using a dual threshold algorithm, based on patient specific therapeutic voltage windows. Tremor was assessed continuously, and bradykinesia was evaluated after 20?min of NclDBS using a repetitive wrist flexion-extension task (rWFE). Total electrical energy delivered (TEED) on NclDBS was compared to olDBS using the same active electrode.NclDBS was tolerated for 21.67 [21.10-26.15] minutes; no subject stopped early. Resting beta band power was measurable and similar between tremor and bradykinesia dominant patients. NclDBS improved bradykinesia and tremor while delivering only 56.86% of the TEED of olDBS; rWFE velocity (p?=?0.003) and frequency (p?
View details for DOI 10.1016/j.brs.2019.02.020

View details for PubMedID 30833216
Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics. Frontiers in neuroscience Ramirez-Zamora, A., Giordano, J., Boyden, E. S., Gradinaru, V., Gunduz, A., Starr, P. A., Sheth, S. A., McIntyre, C. C., Fox, M. D., Vitek, J., Vedam-Mai, V., Akbar, U., Almeida, L., Bronte-Stewart, H. M., Mayberg, H. S., Pouratian, N., Gittis, A. H., Singer, A. C., Creed, M. C., Lazaro-Munoz, G., Richardson, M., Rossi, M. A., Cendejas-Zaragoza, L., D'Haese, P. F., Chiong, W., Gilron, R., Chizeck, H., Ko, A., Baker, K. B., Wagenaar, J., Harel, N., Deeb, W., Foote, K. D., Okun, M. S. 2019; 13: 936
Abstract

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.

View details for DOI 10.3389/fnins.2019.00936

View details for PubMedID 31572109

View details for PubMedCentralID PMC6751331
Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease NEUROBIOLOGY OF DISEASE Anidi, C., O'Day, J. J., Anderson, R. W., Afzal, M., Syrkin-Nikolau, J., Velisar, A., Bronte-Stewart, H. M. 2018; 120: 107?17
View details for DOI 10.1016/j.nbd.2018.09.004

View details for Web of Science ID 000448232100010
Information processing deficit in older adults with HIV infection: A comparison with Parkinson's disease. Neuropsychology Sundaram, S., Muller-Oehring, E. M., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Goodcase, R., Martin, T., Prabhakar, V., Karpf, J., Schulte, T. 2018
Abstract

OBJECTIVE: Individuals with HIV treated with antiretroviral therapy can expect to reach average life span, making them susceptible to combined disease and aging effects on cognitive and motor functions. Slowed processing speed in HIV is a concern for cognitive and everyday functioning and is sensitive to declines in aging. We hypothesized that information processing (IP) deficits, over and above that expected with normal aging, would occur in older HIV patients similar to those observed in Parkinson's disease (PD) patients, with both conditions affecting frontostriatal pathways.METHOD: Groups comprised 26 individuals with HIV infection, 29 with mild-to-moderate PD, and 21 healthy controls (C). Speed of IP was assessed with the oral version of the Symbol Digit Modalities Test and the color naming condition of the Golden Stroop Task.RESULTS: The HIV group was impaired on speed of IP tasks compared with both the C and PD groups. Even after controlling for normal aging effects, older age in the HIV group correlated with IP slowing. Slower IP speed was associated with poorer general cognitive ability and more extrapyramidal motor signs in older HIV-infected individuals.CONCLUSIONS: The notable effects of impaired IP speed, over and above neurotypical age-related declines, indicate that older HIV-infected individuals may have an enhanced vulnerability for developing nonmotor and motor symptoms despite antiretroviral therapy. Assessing for oral IP speed may provide the unique opportunity to identify early signs of progressive clinical declines in HIV. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

View details for PubMedID 30475047
Biophysical basis of subthalamic local field potentials recorded from deep brain stimulation electrodes JOURNAL OF NEUROPHYSIOLOGY Maling, N., Lempka, S. F., Blumenfeld, Z., Bronte-Stewart, H., McIntyre, C. C. 2018; 120 (4): 1932?44
Abstract

Clinical deep brain stimulation (DBS) technology is evolving to enable chronic recording of local field potentials (LFPs) that represent electrophysiological biomarkers of the underlying disease state. However, little is known about the biophysical basis of LFPs, or how the patient's unique brain anatomy and electrode placement impact the recordings. Therefore, we developed a patient-specific computational framework to analyze LFP recordings within a clinical DBS context. We selected a subject with Parkinson's disease implanted with a Medtronic Activa PC+S DBS system and reconstructed their subthalamic nucleus (STN) and DBS electrode location using medical imaging data. The patient-specific STN volume was populated with 235,280 multicompartment STN neuron models, providing a neuron density consistent with histological measurements. Each neuron received time-varying synaptic inputs and generated transmembrane currents that gave rise to the LFP signal recorded at DBS electrode contacts residing in a finite element volume conductor model. We then used the model to study the role of synchronous beta-band inputs to the STN neurons on the recorded power spectrum. Three bipolar pairs of simultaneous clinical LFP recordings were used in combination with an optimization algorithm to customize the neural activity parameters in the model to the patient. The optimized model predicted a 2.4-mm radius of beta-synchronous neurons located in the dorsolateral STN. These theoretical results enable biophysical dissection of the LFP signal at the cellular level with direct comparison to the clinical recordings, and the model system provides a scientific platform to help guide the design of DBS technology focused on the use of subthalamic beta activity in closed-loop algorithms. NEW & NOTEWORTHY The analysis of deep brain stimulation of local field potential (LFP) data is rapidly expanding from scientific curiosity to the basis for clinical biomarkers capable of improving the therapeutic efficacy of stimulation. With this growing clinical importance comes a growing need to understand the underlying electrophysiological fundamentals of the signals and the factors contributing to their modulation. Our model reconstructs the clinical LFP from first principles and highlights the importance of patient-specific factors in dictating the signals recorded.

View details for PubMedID 30020838

View details for PubMedCentralID PMC6230781
Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease. Neurobiology of disease Anidi, C. M., O'Day, J. J., Anderson, R. W., Afzal, M. F., Syrkin-Nikolau, J., Velisar, A., Bronte-Stewart, H. M. 2018
Abstract

Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects. Additionally, there is a lack of gait tasks that reliably elicit FOG. Since FOG is episodic, we hypothesized that dynamic features of subthalamic (STN) beta oscillations, or beta bursts, may contribute to the Freezer phenotype in PD during gait tasks that elicit FOG. We also investigated whether STN DBS at 60?Hz or 140?Hz affected beta burst dynamics and gait impairment differently in Freezers and Non-Freezers. Synchronized STN local field potentials, from an implanted, sensing neurostimulator (Activa PC?+?S, Medtronic, Inc.), and gait kinematics were recorded in 12 PD subjects, off-medication during forward walking and stepping-in-place tasks under the following randomly presented conditions: NO, 60?Hz, and 140?Hz DBS. Prolonged movement band beta burst durations differentiated Freezers from Non-Freezers, were a pathological neural feature of FOG and were shortened during DBS which improved gait. Normal gait parameters, accompanied by shorter bursts in Non-Freezers, were unchanged during DBS. The difference between the mean burst duration between hemispheres (STNs) of all individuals strongly correlated with the difference in stride time between their legs but there was no correlation between mean burst duration of each STN and stride time of the contralateral leg, suggesting an interaction between hemispheres influences gait. These results suggest that prolonged STN beta burst durations measured during gait is an important biomarker for FOG and that STN DBS modulated long not short burst durations, thereby acting to restore physiological sensorimotor information processing, while improving gait.

View details for PubMedID 30196050
Motor function impairment in chronic HIV is similar but less severe to that seen in Parkinson's disease Bronte-Stewart, H., Prabhakar, V., Martin, T., Trager, M., Velisar, A., Koop, M., Muller-Oehring, E., Poston, K., Schulte, T. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000453090804356
Sixty hertz subthalamic deep brain stimulation improves freezing of gait with less attenuation of beta band power than 140Hz stimulation Anidi, C., O'Day, J., Afzal, M., Syrkin-Nikolau, J., Velisar, A., Bronte-Stewart, H. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000453090802452
Efficacy of Subthalamic Neural Closed-loop Deep Brain Stimulation for Bradykinesia in Parkinson's Disease Bronte-Stewart, H., Afzal, M., Velisar, A., Anidi, C. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000453090802439
Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank FRONTIERS IN NEUROSCIENCE Ramirez-Zamora, A., Giordano, J. J., Gunduz, A., Brown, P., Sanchez, J. C., Foote, K. D., Almeida, L., Starr, P. A., Bronte-Stewart, H. M., Hu, W., McIntyre, C., Goodman, W., Kumsa, D., Grill, W. M., Walker, H. C., Johnson, M. D., Vitek, J. L., Greene, D., Rizzuto, D. S., Song, D., Berger, T. W., Hampson, R. E., Deadwyler, S. A., Hochberg, L. R., Schiff, N. D., Stypulkowski, P., Worrell, G., Tiruvadi, V., Mayberg, H. S., Jimenez-Shahed, J., Nanda, P., Sheth, S. A., Gross, R. E., Lempka, S. F., Li, L., Deeb, W., Okun, M. S. 2018; 11: 734
Abstract

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.

View details for PubMedID 29416498
Coordinated Reset Vibrotactile Stimulation Shows Prolonged Improvement in Parkinson's Disease MOVEMENT DISORDERS Syrkin-Nikolau, J., Neuville, R., O'Day, J., Anidi, C., Koop, M., Martin, T., Tass, P. A., Bronte-Stewart, H. 2018; 33 (1): 179?80
View details for PubMedID 29150859

View details for PubMedCentralID PMC5836884
Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proceedings of the National Academy of Sciences of the United States of America Wu, H., Miller, K. J., Blumenfeld, Z., Williams, N. R., Ravikumar, V. K., Lee, K. E., Kakusa, B., Sacchet, M. D., Wintermark, M., Christoffel, D. J., Rutt, B. K., Bronte-Stewart, H., Knutson, B., Malenka, R. C., Halpern, C. H. 2018; 115 (1): 192?97
Abstract

Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

View details for PubMedID 29255043
Subthalamic neural entropy is a feature of freezing of gait in freely moving people with Parkinson's disease NEUROBIOLOGY OF DISEASE Syrkin-Nikolau, J., Koop, M., Prieto, T., Anidi, C., Afzal, M., Velisar, A., Blumenfeld, Z., Martin, T., Trager, M., Bronte-Stewart, H. 2017; 108: 288?97
Abstract

The goal of this study was to investigate subthalamic (STN) neural features of Freezers and Non-Freezers with Parkinson's disease (PD), while freely walking without freezing of gait (FOG) and during periods of FOG, which were better elicited during a novel turning and barrier gait task than during forward walking.Synchronous STN local field potentials (LFPs), shank angular velocities, and ground reaction forces were measured in fourteen PD subjects (eight Freezers) off medication, OFF deep brain stimulation (DBS), using an investigative, implanted, sensing neurostimulator (Activa� PC+S, Medtronic, Inc.). Tasks included standing still, instrumented forward walking, stepping in place on dual forceplates, and instrumented walking through a turning and barrier course.During locomotion without FOG, Freezers showed lower beta (13-30Hz) power (P=0.036) and greater beta Sample Entropy (P=0.032), than Non-Freezers, as well as greater gait asymmetry and arrhythmicity (P<0.05 for both). No differences in alpha/beta power and/or entropy were evident at rest. During periods of FOG, Freezers showed greater alpha (8-12Hz) Sample Entropy (P<0.001) than during walking without FOG.A novel turning and barrier course was superior to FW in eliciting FOG. Greater unpredictability in subthalamic beta rhythms was evident during stepping without freezing episodes in Freezers compared to Non-Freezers, whereas greater unpredictability in alpha rhythms was evident in Freezers during FOG. Non-linear analysis of dynamic neural signals during gait in freely moving people with PD may yield greater insight into the pathophysiology of FOG; whether the increases in STN entropy are causative or compensatory remains to be determined. Some beta LFP power may be useful for rhythmic, symmetric gait and DBS parameters, which completely attenuate STN beta power may worsen rather than improve FOG.

View details for PubMedID 28890315
Sixty-hertz stimulation improves bradykinesia and amplifies subthalamic low-frequency oscillations. Movement disorders Blumenfeld, Z., Koop, M. M., Prieto, T. E., Shreve, L. A., Velisar, A., Quinn, E. J., Trager, M. H., Bront�-Stewart, H. 2017; 32 (1): 80-88
Abstract

The objective of this study was to investigate the hypothesis that attenuation of subthalamic nucleus (STN) alpha-/beta-band oscillations is causal to improvement in bradykinesia.STN local field potentials from a sensing neurostimulator (Activa(�) PC+S; Medtronic, Inc.) and kinematics from wearable sensors were recorded simultaneously during 60- and 140-Hz deep brain stimulation (DBS) in 9 freely moving PD subjects (15 STNs) performing repetitive wrist flexion-extension. Kinematics were recorded during 20-Hz DBS in a subgroup.Both 60- and 140-Hz DBS improved the angular velocity and frequency of movement (P�=�0.002 and P�=�0.029, respectively, for 60 Hz; P�<�0.001 and P�<�0.001, respectively, for 140 Hz), but 60-Hz DBS did not attenuate beta-band power (13-30 Hz). In fact, 60-Hz DBS amplified alpha/low-beta (11-15 Hz, P�=�0.007) and attenuated high-beta power (19-27 Hz, P�<�0.001), whereas 140-Hz DBS broadly attenuated beta power (15-30 Hz, P�<�0.001). Only 60-Hz DBS improved the regularity of angular range (P�=�0.046) and 20-Hz DBS did not worsen bradykinesia. There was no correlation between beta-power modulation and bradykinesia.These novel results obtained from freely moving PD subjects demonstrated that both 140- and 60-Hz DBS improved bradykinesia and attenuated high beta oscillations; however, 60-Hz DBS amplified a subband of alpha/low-beta oscillations, and DBS at a beta-band frequency did not worsen bradykinesia. Based on recent literature, we suggest that both 140- and 60-Hz DBS decouple the cortico-STN hyperdirect pathway, whereas 60-Hz DBS increases coupling within striato-STN circuitry. These results inform future algorithms for closed-loop DBS in PD. � 2016 International Parkinson and Movement Disorder Society.

View details for DOI 10.1002/mds.26837

View details for PubMedID 27859579
Model Predictive Control of Deep Brain Stimulation for Parkinsonian Tremor Haddock, A., Velisar, A., Herron, J., Bronte-Stewart, H., Chizeck, H. J., IEEE IEEE. 2017: 358?62
View details for Web of Science ID 000428143200086
Subthalamic oscillations and phase amplitude coupling are greater in the more affected hemisphere in Parkinson's disease. Clinical neurophysiology Shreve, L. A., Velisar, A., Malekmohammadi, M., Koop, M. M., Trager, M., Quinn, E. J., Hill, B. C., Blumenfeld, Z., Kilbane, C., Mantovani, A., Henderson, J. M., Bront�-Stewart, H. 2017; 128 (1): 128-137
Abstract

Determine the incidence of resting state oscillations in alpha/beta, high frequency (HFO) bands, and their phase amplitude coupling (PAC) in a large cohort in Parkinson's disease (PD).Intra-operative local field potentials (LFPs) from subthalamic nucleus (STN) were recorded from 100 PD subjects, data from 74 subjects were included in the analysis.Alpha/beta oscillations were evident in >99%, HFO in 87% and PAC in 98% of cases. Alpha/beta oscillations (P<0.01) and PAC were stronger in the more affected (MA) hemisphere (P=0.03). Alpha/beta oscillations were primarily found in 13-20Hz (low beta). Beta and HFO frequencies with the greatest coupling, were positively correlated (P=0.001). Tremor attenuated alpha (P=0.002) and beta band oscillations (P<0.001).STN alpha/beta band oscillations and PAC were evident in ?98% cases and were greater in MA hemisphere. Resting tremor attenuated underlying alpha/beta band oscillations.Beta band LFP power may be used to drive adaptive deep brain stimulation (aDBS), augmented by a kinematic classifier in tremor dominant PD.

View details for DOI 10.1016/j.clinph.2016.10.095

View details for PubMedID 27889627
Subthalamic beta oscillations are attenuated after withdrawal of chronic high frequency neurostimulation in Parkinson's disease. Neurobiology of disease Trager, M. H., Koop, M. M., Velisar, A., Blumenfeld, Z., Nikolau, J. S., Quinn, E. J., Martin, T., Bronte-Stewart, H. 2016; 96: 22-30
Abstract

Subthalamic nucleus (STN) local field potential (LFP) recordings demonstrate beta (13-30Hz) band oscillations in Parkinson's disease (PD) defined as elevations of spectral power. The amount of attenuation of beta band power on therapeutic levels of high frequency (HF) deep brain stimulation (DBS) and/or dopaminergic medication has been correlated with the degree of improvement in bradykinesia and rigidity from the therapy, which has led to the suggestion that elevated beta band power is a marker of PD motor disability. A fundamental question has not been answered: whether there is a prolonged attenuation of beta band power after withdrawal of chronic HF DBS and whether this is related to a lack of progression or even improvement in the underlying motor disability. Until now, in human PD subjects, STN LFP recordings were only attainable in the peri-operative period and after short periods of stimulation. For the first time, using an investigational, implanted sensing neurostimulator (Activa� PC+S, Medtronic, Inc.), STN LFPs and motor disability were recorded/assessed after withdrawal of chronic (6 and 12month) HF DBS in freely moving PD subjects. Beta band power was similar within 14s and 60min after stimulation was withdrawn, suggesting that "off therapy" experiments can be conducted almost immediately after stimulation is turned off. After withdrawal of 6 and 12months of STN DBS, beta band power was significantly lower (P<0.05 at 6 and 12months) and off therapy UPDRS scores were better (P<0.05 at 12months) compared to before DBS was started. The attenuation in beta band power was correlated with improvement in motor disability scores (P<0.05). These findings were supported by evidence of a gradual increase in beta band power in two unstimulated STNs after 24months and could not be explained by changes in lead impedance. This suggests that chronic HF DBS exerts long-term plasticity in the sensorimotor network, which may contribute to a lack of progression in underlying motor disability in PD.

View details for DOI 10.1016/j.nbd.2016.08.003

View details for PubMedID 27553876
Auditory cueing in Parkinson's patients with freezing of gait. What matters most: Action-relevance or cue-continuity? NEUROPSYCHOLOGIA Young, W. R., Shreve, L., Quinn, E. J., Craig, C., Bronte-Stewart, H. 2016; 87: 54-62
Abstract

Gait disturbances are a common feature of Parkinson's disease, one of the most severe being freezing of gait. Sensory cueing is a common method used to facilitate stepping in people with Parkinson's. Recent work has shown that, compared to walking to a metronome, Parkinson's patients without freezing of gait (nFOG) showed reduced gait variability when imitating recorded sounds of footsteps made on gravel. However, it is not known if these benefits are realised through the continuity of the acoustic information or the action-relevance. Furthermore, no study has examined if these benefits extend to PD with freezing of gait. We prepared four different auditory cues (varying in action-relevance and acoustic continuity) and asked 19 Parkinson's patients (10 nFOG, 9 with freezing of gait (FOG)) to step in place to each cue. Results showed a superiority of action-relevant cues (regardless of cue-continuity) for inducing reductions in Step coefficient of variation (CV). Acoustic continuity was associated with a significant reduction in Swing CV. Neither cue-continuity nor action-relevance was independently sufficient to increase the time spent stepping before freezing. However, combining both attributes in the same cue did yield significant improvements. This study demonstrates the potential of using action-sounds as sensory cues for Parkinson's patients with freezing of gait. We suggest that the improvements shown might be considered audio-motor 'priming' (i.e., listening to the sounds of footsteps will engage sensorimotor circuitry relevant to the production of that same action, thus effectively bypassing the defective basal ganglia).

View details for DOI 10.1016/j.neuropsychologia.2016.04.034

View details for Web of Science ID 000379373500006

View details for PubMedID 27163397
Kinematic Adaptive Deep Brain Stimulation for Resting Tremor in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Malekmohammadi, M., Herron, J., Velisar, A., Blumenfeld, Z., Trager, M. H., Chizeck, H. J., Bront�-Stewart, H. 2016
View details for PubMedID 26813875
Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies. Frontiers in integrative neuroscience Deeb, W., Giordano, J. J., Rossi, P. J., Mogilner, A. Y., Gunduz, A., Judy, J. W., Klassen, B. T., Butson, C. R., van Horne, C., Deny, D., Dougherty, D. D., Rowell, D., Gerhardt, G. A., Smith, G. S., Ponce, F. A., Walker, H. C., Bronte-Stewart, H. M., Mayberg, H. S., Chizeck, H. J., Langevin, J., Volkmann, J., Ostrem, J. L., Shute, J. B., Jimenez-Shahed, J., Foote, K. D., Wagle Shukla, A., Rossi, M. A., Oh, M., Pourfar, M., Rosenberg, P. B., Silburn, P. A., de Hemptine, C., Starr, P. A., Denison, T., Akbar, U., Grill, W. M., Okun, M. S. 2016; 10: 38-?
Abstract

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

View details for PubMedID 27920671
Aging with HIV-1 Infection: Motor Functions, Cognition, and Attention--A Comparison with Parkinson's Disease. Neuropsychology review DeVaughn, S., M�ller-Oehring, E. M., Markey, B., Bront�-Stewart, H. M., Schulte, T. 2015; 25 (4): 424-438
Abstract

Recent advances in highly active anti-retroviral therapy (HAART) in their various combinations have dramatically increased the life expectancies of HIV-infected persons. People diagnosed with HIV are living beyond the age of 50 but are experiencing the cumulative effects of HIV infection and aging on brain function. In HIV-infected aging individuals, the potential synergy between immunosenescence and HIV viral loads increases susceptibility to HIV-related brain injury and functional brain network degradation similar to that seen in Parkinson's disease (PD), the second most common neurodegenerative disorder in the aging population. Although there are clear diagnostic differences in the primary pathology of both diseases, i.e., death of dopamine-generating cells in the substantia nigra in PD and neuroinflammation in HIV, neurotoxicity to dopaminergic terminals in the basal ganglia (BG) has been implied in the pathogenesis of HIV and neuroinflammation in the pathogenesis of PD. Similar to PD, HIV infection affects structures of the BG, which are part of interconnected circuits including mesocorticolimbic pathways linking brainstem nuclei to BG and cortices subserving attention, cognitive control, and motor functions. The present review discusses the combined effects of aging and neuroinflammation in HIV individuals on cognition and motor function in comparison with age-related neurodegenerative processes in PD. Despite the many challenges, some HIV patients manage to age successfully, most likely by redistribution of neural network resources to enhance function, as occurs in healthy elderly; such compensation could be curtailed by emerging PD.

View details for DOI 10.1007/s11065-015-9305-x

View details for PubMedID 26577508
Editorial Comments to the Special Issue of Neuropsychology Review on the Basic Neuroscience and Neuropsychology of Selective Movement Disorders NEUROPSYCHOLOGY REVIEW Schulte, T., Bronte-Stewart, H. 2015; 25 (4): 369?70
View details for PubMedID 26590835

View details for PubMedCentralID PMC4670790
High Frequency Deep Brain Stimulation and Neural Rhythms in Parkinson's Disease NEUROPSYCHOLOGY REVIEW Blumenfeld, Z., Bronte-Stewart, H. 2015; 25 (4): 384-397
Abstract

High frequency (HF) deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD). It effectively treats the cardinal motor signs of PD, including tremor, bradykinesia, and rigidity. The most common neural target is the subthalamic nucleus, located within the basal ganglia, the region most acutely affected by PD pathology. Using chronically-implanted DBS electrodes, researchers have been able to record underlying neural rhythms from several nodes in the PD network as well as perturb it using DBS to measure the ensuing neural and behavioral effects, both acutely and over time. In this review, we provide an overview of the PD neural network, focusing on the pathophysiological signals that have been recorded from PD patients as well as the mechanisms underlying the therapeutic benefits of HF DBS. We then discuss evidence for the relationship between specific neural oscillations and symptoms of PD, including the aberrant relationships potentially underlying functional connectivity in PD as well as the use of different frequencies of stimulation to more specifically target certain symptoms. Finally, we briefly describe several current areas of investigation and how the ability to record neural data in ecologically-valid settings may allow researchers to explore the relationship between brain and behavior in an unprecedented manner, culminating in the future automation of neurostimulation therapy for the treatment of a variety of neuropsychiatric diseases.

View details for DOI 10.1007/s11065-015-9308-7

View details for Web of Science ID 000365807600003

View details for PubMedID 26608605
Aging with HIV-1 Infection: Motor Functions, Cognition, and Attention - A Comparison with Parkinson's Disease NEUROPSYCHOLOGY REVIEW DeVaughn, S., Mueller-Oehring, E. M., Markey, B., Bronte-Stewart, H. M., Schulte, T. 2015; 25 (4): 424-438
View details for DOI 10.1007/s11065-015-9305-x

View details for Web of Science ID 000365807600006
Beta Oscillations in Freely Moving Parkinson's Subjects Are Attenuated During Deep Brain Stimulation MOVEMENT DISORDERS Quinn, E. J., Blumenfeld, Z., Velisar, A., Koop, M. M., Shreve, L. A., Trager, M. H., Hill, B. C., Kilbane, C., Henderson, J. M., Bronte-Stewart, H. 2015; 30 (13): 1750-1758
Abstract

Investigations into the effect of deep brain stimulation (DBS) on subthalamic (STN) beta (13-30 Hz) oscillations have been performed in the perioperative period with the subject tethered to equipment. Using an embedded sensing neurostimulator, this study investigated whether beta power was similar in different resting postures and during forward walking in freely moving subjects with Parkinson's disease (PD) and whether STN DBS attenuated beta power in a voltage-dependent manner.Subthalamic local field potentials were recorded from the DBS lead, using a sensing neurostimulator (Activa(�) PC+S, Medtronic, Inc., Food and Drug Administration- Investigational Device Exemption (IDE)-, institutional review board-approved) from 15 PD subjects (30 STNs) off medication during lying, sitting, and standing, during forward walking, and during randomized periods of 140 Hz DBS at 0 V, 1 V, and 2.5/3 V. Continuous video, limb angular velocity, and forearm electromyography recordings were synchronized with neural recordings. Data were parsed to avoid any movement or electrical artifact during resting states.Beta power was similar during lying, sitting, and standing (P = 0.077, n = 28) and during forward walking compared with the averaged resting state (P = 0.466, n = 24), although akinetic rigid PD subjects tended to exhibit decreased beta power when walking. Deep brain stimulation at 3 V and at 1 V attenuated beta power compared with 0 V (P < 0.003, n = 14), and this was voltage dependent (P < 0.001).Beta power was conserved during resting and forward walking states and was attenuated in a voltage-dependent manner during 140-Hz DBS. Phenotype may be an important consideration if this is used for closed-loop DBS.

View details for DOI 10.1002/mds.26376

View details for Web of Science ID 000368327900008
Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease. Brain imaging and behavior M�ller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638
Abstract

Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

View details for DOI 10.1007/s11682-014-9317-9

View details for PubMedID 25280970

View details for PubMedCentralID PMC4385510
Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease BRAIN IMAGING AND BEHAVIOR Mueller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638
Abstract

Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

View details for DOI 10.1007/s11682-014-9317-9

View details for Web of Science ID 000361604300021

View details for PubMedCentralID PMC4385510
Long-term detection of Parkinsonian tremor activity from subthalamic nucleus local field potentials. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Houston, B., Blumenfeld, Z., Quinn, E., Bronte-Stewart, H., Chizeck, H. 2015; 2015: 3427-3431
Abstract

Current deep brain stimulation paradigms deliver continuous stimulation to deep brain structures to ameliorate the symptoms of Parkinson's disease. This continuous stimulation has undesirable side effects and decreases the lifespan of the unit's battery, necessitating earlier replacement. A closed-loop deep brain stimulator that uses brain signals to determine when to deliver stimulation based on the occurrence of symptoms could potentially address these drawbacks of current technology. Attempts to detect Parkinsonian tremor using brain signals recorded during the implantation procedure have been successful. However, the ability of these methods to accurately detect tremor over extended periods of time is unknown. Here we use local field potentials recorded during a deep brain stimulation clinical follow-up visit 1 month after initial programming to build a tremor detection algorithm and use this algorithm to detect tremor in subsequent visits up to 8 months later. Using this method, we detected the occurrence of tremor with accuracies between 68-93%. These results demonstrate the potential of tremor detection methods for efficacious closed-loop deep brain stimulation over extended periods of time.

View details for DOI 10.1109/EMBC.2015.7319129

View details for PubMedID 26737029
Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What's in the Pipeline INTERNATIONAL JOURNAL OF NEUROSCIENCE Gunduz, A., Morita, H., Rossi, P. J., Allen, W. L., Alterman, R. L., Bronte-Stewart, H., Butson, C. R., Charles, D., Deckers, S., de Hemptinne, C., DeLong, M., Dougherty, D., Ellrich, J., Foote, K. D., Giordano, J., Goodman, W., Greenberg, B. D., Greene, D., Gross, R., Judy, J. W., Karst, E., Kent, A., Kopell, B., Lang, A., Lozano, A., Lungu, C., Lyon, K. E., Machado, A., Martens, H., McIntyre, C., Min, H., Neimat, J., Ostrem, J., Pannu, S., Ponce, F., Pouratian, N., Reymers, D., Schrock, L., Sheth, S., Shih, L., Stanslaski, S., Steinke, G. K., Stypulkowski, P., Troester, A. I., Verhagen, L., Walker, H., Okun, M. S. 2015; 125 (7): 475-485
Abstract

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

View details for DOI 10.3109/00207454.2014.999268

View details for Web of Science ID 000359884200001

View details for PubMedID 25526555

View details for PubMedCentralID PMC4743588
Sixty Hertz Neurostimulation Amplifies Subthalamic Neural Synchrony in Parkinson's Disease PLOS ONE Blumenfeld, Z., Velisar, A., Koop, M. M., Hill, B. C., Shreve, L. A., Quinn, E. J., Kilbane, C., Yu, H., Henderson, J. M., Bronte-Stewart, H. 2015; 10 (3)
Abstract

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson's disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony. Here we demonstrate for the first time that during intra-operative 60 Hz STN DBS, one or more bands of resting state neural synchrony were amplified in the STN in PD. We recorded intra-operative STN resting state local field potentials (LFPs) from twenty-eight STNs in seventeen PD subjects after placement of the DBS lead (model 3389, Medtronic, Inc.) before and during three randomized neurostimulation sets (130 Hz/1.35V, 130 Hz/2V, 60 Hz/2V). During 130 Hz/2V DBS, baseline (no DBS) STN alpha (8 - 12 Hz) and beta (13 - 35 Hz) band power decreased (N=14, P < 0.001 for both), whereas during 60 Hz/2V DBS, alpha band and peak frequency power increased (P = 0.012, P = 0.007, respectively). The effect of 60 Hz/2V DBS opposed that of power-equivalent (130 Hz/1.35V) DBS (alpha: P < 0.001, beta: P = 0.006). These results show that intra-operative 60 Hz STN DBS amplified whereas 130 Hz STN DBS attenuated resting state neural synchrony in PD; the effects were frequency-specific. We demonstrate that neurostimulation may be useful as a tool to selectively modulate resting state resonant bands of neural synchrony and to investigate its influence on motor and non-motor behaviors in PD and other neuropsychiatric diseases.

View details for DOI 10.1371/journal.pone.0121067

View details for PubMedID 25807463
Arrhythmokinesis is evident during unimanual not bimanual finger tapping in Parkinson's disease. Journal of clinical movement disorders Trager, M. H., Velisar, A., Koop, M. M., Shreve, L., Quinn, E., Bronte-Stewart, H. 2015; 2: 8-?
Abstract

Arrhythmokinesis, the variability in repetitive movements, is a fundamental feature of Parkinson's disease (PD). We hypothesized that unimanual repetitive alternating finger tapping (AFT) would reveal more arrhythmokinesis compared to bimanual single finger alternating hand tapping (SFT), in PD.The variability of inter-strike interval (CVISI) and of amplitude (CVAMP) during AFT and SFT were measured on an engineered, MRI-compatible keyboard in sixteen PD subjects off medication and in twenty-four age-matched controls.The CVISI and CVAMP of the more affected (MA) and less affected (LA) sides in PD subjects were greater during AFT than SFT (P?
View details for DOI 10.1186/s40734-015-0019-2

View details for PubMedID 26788344

View details for PubMedCentralID PMC4711026
Beta oscillations in freely moving Parkinson's subjects are attenuated during deep brain stimulation. Movement disorders : official journal of the Movement Disorder Society Quinn, E. J., Blumenfeld, Z., Velisar, A., Koop, M. M., Shreve, L. A., Trager, M. H., Hill, B. C., Kilbane, C., Henderson, J. M., Bront�-Stewart, H. 2015; 30 (13): 1750?58
Abstract

Investigations into the effect of deep brain stimulation (DBS) on subthalamic (STN) beta (13-30 Hz) oscillations have been performed in the perioperative period with the subject tethered to equipment. Using an embedded sensing neurostimulator, this study investigated whether beta power was similar in different resting postures and during forward walking in freely moving subjects with Parkinson's disease (PD) and whether STN DBS attenuated beta power in a voltage-dependent manner.Subthalamic local field potentials were recorded from the DBS lead, using a sensing neurostimulator (Activa(�) PC+S, Medtronic, Inc., Food and Drug Administration- Investigational Device Exemption (IDE)-, institutional review board-approved) from 15 PD subjects (30 STNs) off medication during lying, sitting, and standing, during forward walking, and during randomized periods of 140 Hz DBS at 0 V, 1 V, and 2.5/3 V. Continuous video, limb angular velocity, and forearm electromyography recordings were synchronized with neural recordings. Data were parsed to avoid any movement or electrical artifact during resting states.Beta power was similar during lying, sitting, and standing (P = 0.077, n = 28) and during forward walking compared with the averaged resting state (P = 0.466, n = 24), although akinetic rigid PD subjects tended to exhibit decreased beta power when walking. Deep brain stimulation at 3 V and at 1 V attenuated beta power compared with 0 V (P < 0.003, n = 14), and this was voltage dependent (P < 0.001).Beta power was conserved during resting and forward walking states and was attenuated in a voltage-dependent manner during 140-Hz DBS. Phenotype may be an important consideration if this is used for closed-loop DBS.

View details for PubMedID 26360123
The effect of medication and the role of postural instability in different components of freezing of gait (FOG). Parkinsonism & related disorders Nantel, J., Bronte-Stewart, H. 2014; 20 (4): 447-451
Abstract

Freezing of gait (FOG) is associated with gait asymmetry and arrhythmicity, cognitive impairment in Parkinson's disease (PD). However, the role of postural instability (PI) in and the effect of dopaminergic medication (meds) on FOG are unclear. We investigated the effect of meds on FOG using a validated metric, Stepping in Place (SIP) and the relationship between PI and FOG.We assessed static posturography (off meds), SIP, UPDRS-III (off/on meds) and the FOG-questionnaire (FOG-Q) in 15 freezers/15 non-freezers and 14 healthy controls.UPDRS-III, rigidity, tremor (P�<�0.01) and axial subscores (P�<�0.05) improved with meds in freezers. Only UPDRS-III and tremor improved in non-freezers (P�<�0.01). Meds improved freezing episode (FE) frequency, duration and stride duration in freezers (P�<�0.01). Over 73% of freezers did not freeze on meds, although one freezer had more and longer duration FEs. Meds did not improve SIP cycle asymmetry and arrhythmicity, which remained greater in freezers compared to other groups on and off meds (P�<�0.01, P�<�0.05 respectively). Center of pressure (CoP) mediolateral displacement and velocity (VCoP) in both directions were larger in freezers (P�<�0.05). FOG-Q was correlated with CoP anteroposterior displacement and mediolateral VCoP (R�=�0.42; R�=�0.40, P�<�0.05). The improvement of FOG frequency and duration but not of gait asymmetry and arrhythmicity on meds suggests that both dopaminergic and non-dopaminergic networks contribute to FOG. The correlations between postural instability and FOG severity and SIP asymmetry on meds, suggest that as the disease progresses, postural instability interferes with gait symmetry and lead to on meds FOG and falls.

View details for DOI 10.1016/j.parkreldis.2014.01.017

View details for PubMedID 24530016
Perceptual errors increase with movement duration and may contribute to hypokinesia in Parkinson's disease. Neuroscience Koop, M. M., Hill, B. C., Bronte-Stewart, H. M. 2013; 243: 1-13
Abstract

People with Parkinson's disease (PD) perceive that their movement amplitude is greater than what they actually perform. The neural mechanisms underlying one's perception of movement are believed to involve the sensorimotor integration process (SIP). How PD affects the SIP is not well understood. A previous study interrogating the SIP showed healthy adults (HAs) overestimated their limb position in the direction of movement and the error and its variance (VOE) depended on movement duration. We asked if PDs showed errors in perceived limb position and if the dependence on movement duration was different from HAs. We used an existing computational model of the SIP to explore mechanisms for the error and VOE as a function of movement duration. Twenty PDs, off medication, and 20 age-matched HAs were asked to estimate the position of their hand after performing 50, slow, non-visually guided wrist flexion or extension movements for a random period of time (<4.0s). Both groups overestimated the amount they moved; however, the PDs' error and VOE were larger (p<0.001). HAs showed increasing error/VOE for small movement durations that reduced/stabilized for longer movement durations. PDs however showed increasing error/VOE with increasing movement duration that did not significantly improve/stabilize. The model suggested that the basis for such perceptual deficits may be abnormal proprioceptive feedback and/or processing of an abnormal internal impression (prediction) that underestimates movement amplitude. Simulation results imply that the PD's SIP could no longer effectively access sensory (proprioceptive) feedback to correct errors in other components of the SIP due to the abnormal processing of sensory feedback. We suggest from this study that an impaired perception of movement amplitude and sensory processing deficits contribute to hypokinesia in PD.

View details for DOI 10.1016/j.neuroscience.2013.03.026

View details for PubMedID 23542737
Resting Beta Hypersynchrony in Secondary Dystonia and Its Suppression During Pallidal Deep Brain Stimulation in DYT3+ Lubag Dystonia. Neuromodulation Whitmer, D., de Solages, C., Hill, B. C., Yu, H., Bronte-Stewart, H. 2013; 16 (3): 200-205
Abstract

1) To characterize patterns of globus pallidus interna neural synchrony in patients with secondary dystonia; 2) to determine whether neural hypersynchrony in the globus pallidus externa (GPe) and interna (GPi) is attenuated during high frequency deep brain stimulation (HF DBS) in a patient with DYT3+ dystonia and in a patient with secondary dystonia due to childhood encephalitis.We recorded local field potentials from the DBS lead in the GPi of four patients (seven hemispheres) with secondary dystonia and from one patient (two hemispheres) with primary DYT3+ dystonia. In two patients, we also recorded pallidal local field potentials during the administration of 10?sec epochs of HF DBS.Power spectral densities during rest demonstrated visible peaks in the beta band in seven out of nine cases. In DYT3+ dystonia, power in the alpha and beta bands, but not theta band, was attenuated during HF DBS in the GPe and in GPi, and attenuation was most prominent in the high beta band. This patient demonstrated an early and maintained improvement in dystonia. There was no beta peak and the power spectrum was not attenuated during HF DBS in a patient with secondary dystonia due to childhood encephalitis.These results suggest that beta hypersynchrony, demonstrated now in both primary and secondary dystonia, may play a pathophysiological role in pathological hyperkinesis. Further investigation is needed in a larger cohort of well-characterized primary and secondary dystonia patients.

View details for DOI 10.1111/j.1525-1403.2012.00519.x

View details for PubMedID 23094951
Improved efficacy of temporally non-regular deep brain stimulation in Parkinson's disease EXPERIMENTAL NEUROLOGY Brocker, D. T., Swan, B. D., Turner, D. A., Gross, R. E., Tatter, S. B., Koop, M. M., Bronte-Stewart, H., Grill, W. M. 2013; 239: 60-67
Abstract

High frequency deep brain stimulation is an effective therapy for motor symptoms in Parkinson's disease. However, the relative clinical efficacy of regular versus non-regular temporal patterns of stimulation in Parkinson's disease remains unclear. To determine the temporal characteristics of non-regular temporal patterns of stimulation important for the treatment of Parkinson's disease, we compared the efficacy of temporally regular stimulation with four non-regular patterns of stimulation in subjects with Parkinson's disease using an alternating finger tapping task. The patterns of stimulation were also evaluated in a biophysical model of the parkinsonian basal ganglia that exhibited prominent oscillatory activity in the beta frequency range. The temporal patterns of stimulation differentially improved motor task performance. Three of the non-regular patterns of stimulation improved performance of the finger tapping task more than temporally regular stimulation. In the computational model all patterns of deep brain stimulation suppressed beta band oscillatory activity, and the degree of suppression was strongly correlated with the clinical efficacy across stimulation patterns. The three non-regular patterns of stimulation that improved motor performance over regular stimulation also suppressed beta band oscillatory activity in the computational model more effectively than regular stimulation. These data demonstrate that the temporal pattern of stimulation is an important consideration for the clinical efficacy of deep brain stimulation in Parkinson's disease. Furthermore, non-regular patterns of stimulation may ameliorate motor symptoms and suppress pathological rhythmic activity in the basal ganglia more effectively than regular stimulation. Therefore, non-regular patterns of deep brain stimulation may have useful clinical and experimental applications.

View details for DOI 10.1016/j.expneurol.2012.09.008

View details for Web of Science ID 000313765000007

View details for PubMedID 23022917

View details for PubMedCentralID PMC3547657
DEFICITS IN VISUOSPATIAL PROCESSING CONTRIBUTE TO QUANTITATIVE MEASURES OF FREEZING OF GAIT IN PARKINSON'S DISEASE NEUROSCIENCE Nantel, J., McDonald, J. C., Tan, S., Bronte-Stewart, H. 2012; 221: 151-156
Abstract

The aim of this study was to investigate whether an objective measure of freezing of gait (FOG) using a validated alternating stepping in place (SIP) task, is related to executive and/or visuospatial cognitive impairment in Parkinson's disease (PD).We studied prospectively 30 PD subjects with the Unified Parkinson's Disease Rating Scale (UPDRS) III, the FOGq, Trail Making Test Part B (TMTB), Wisconsin Card Sorting, Initiation/Perseveration, Matrix Reasoning (MR) and Block Design (BD). PD subjects performed three, 100s trials of alternative SIP while standing on two force platforms to assess the number and duration of freezing episodes (FE), SIP rhythmicity and symmetry.Freezers had larger cycle asymmetry and arrhythmicity than non-freezers (P<0.05). Performance on BD and MR tests differentiated freezers from non-freezers (P<0.04; P=0.001, respectively). BD performance negatively correlated with the FOGq total (P<0.05), the number and duration of FE (P<0.01), SIP arrhythmicity and asymmetry (P=0.01, P<0.05). MR performance negatively correlated with all FOGq #3 and total as well as SIP FE metrics (P?0.01), except for SIP asymmetry.Deficits in visuospatial perception and reasoning not in executive function differentiated freezers from non-freezers. Deficits in visuospatial processing negatively correlated with all SIP freeze metrics, whereas deficits in executive function were only correlated with SIP arrhythmicity, the FOGq total and the duration of freezing episodes. These results suggest that deficits in visuospatial processing to perform a motor task contribute to FOG and that different cognitive deficits may contribute to different aspects of freezing in PD. This is the first study to our knowledge that has compared metrics of freezing to cognitive tasks in the visuospatial and visual reasoning domains.

View details for DOI 10.1016/j.neuroscience.2012.07.007

View details for Web of Science ID 000308628100015

View details for PubMedID 22796080
High frequency deep brain stimulation attenuates subthalamic and cortical rhythms in Parkinson's disease FRONTIERS IN HUMAN NEUROSCIENCE Whitmer, D., de Solages, C., Hill, B., Yu, H., Henderson, J. M., Bronte-Stewart, H. 2012; 6
Abstract

Parkinson's disease (PD) is marked by excessive synchronous activity in the beta (8-35 Hz) band throughout the cortico-basal ganglia network. The optimal location of high frequency deep brain stimulation (HF DBS) within the subthalamic nucleus (STN) region and the location of maximal beta hypersynchrony are currently matters of debate. Additionally, the effect of STN HF DBS on neural synchrony in functionally connected regions of motor cortex is unknown and is of great interest. Scalp EEG studies demonstrated that stimulation of the STN can activate motor cortex antidromically, but the spatial specificity of this effect has not been examined. The present study examined the effect of STN HF DBS on neural synchrony within the cortico-basal ganglia network in patients with PD. We measured local field potentials dorsal to and within the STN of PD patients, and additionally in the motor cortex in a subset of these patients. We used diffusion tensor imaging (DTI) to guide the placement of subdural cortical surface electrodes over the DTI-identified origin of the hyperdirect pathway (HDP) between motor cortex and the STN. The results demonstrated that local beta power was attenuated during HF DBS both dorsal to and within the STN. The degree of attenuation was monotonic with increased DBS voltages in both locations, but this voltage-dependent effect was greater in the central STN than dorsal to the STN (p < 0.05). Cortical signals over the estimated origin of the HDP also demonstrated attenuation of beta hypersynchrony during DBS dorsal to or within STN, whereas signals from non-specific regions of motor cortex were not attenuated. The spatially-specific suppression of beta synchrony in the motor cortex support the hypothesis that DBS may treat Parkinsonism by reducing excessive synchrony in the functionally connected sensorimotor network.

View details for DOI 10.3389/fnhum.2012.00155

View details for PubMedID 22675296
Effect of medication and STN-DBS on postural control in subjects with Parkinson's disease PARKINSONISM & RELATED DISORDERS Nantel, J., McDonald, J. C., Bronte-Stewart, H. 2012; 18 (3): 285-289
Abstract

To assess the effect of disease severity, dopaminergic medication (med) and STN-DBS on postural stability in Parkinson's disease (PD).Postural sway in quiet stance, and the Unified Parkinson's Disease Rating Scale (motor) (UPDRS III) were evaluated in 129 subjects in the off-med state. A subgroup of 28 subjects was studied on-med and after STN-DBS. Postural sway was measured using center of pressure (CoP) root mean square displacement (RMS(CoP)) and mean velocity (V(CoP)) in the anterior-posterior (AP) and medial-lateral (ML) directions.All CoP parameters were larger in moderate/advanced subjects vs controls (P < 0.001) and early subjects. Only RMS(CoP)ML was larger in early subjects vs controls (P < 0.05). Med, DBS and DBS + med decreased UPDRS III compared to off-med (P < 0.001). RMS(CoP)ML and V(CoP)ML were larger on-med vs off-med and vs DBS (P < 0.001). Compared to controls and PD subjects with normal CoP sway off-med, med increased all CoP parameters (P < 0.01) but DBS returned V(CoP)ML to normal values. For 'abnormal' PD subjects, STN-DBS improved the excessive V(CoP) in ML compared to off and on-med pre-DBS (P < 0.05).Postural sway in quiet stance increased with disease severity. Only ML CoP displacement was abnormal in early stage PD, and this may be a compensatory mechanism. Medication increased ML postural sway. In 'normal' PD subjects, STN-DBS reversed medication induced postural instability. Subjects with abnormal balance in quiet stance did not benefit from medication or DBS, except for improvement in ML CoP velocity from DBS. This may serve to reduce postural instability and falling.

View details for DOI 10.1016/j.parkreldis.2011.11.005

View details for Web of Science ID 000301813200015

View details for PubMedID 22130147
Deep brain stimulation. Neurology. Clinical practice Bronte-Stewart, H. 2012; 2 (1): 67?71
Abstract

High-frequency deep brain stimulation (DBS) is an established therapy for Parkinson disease (PD), essential tremor, and primary dystonia, and is under investigation for several neuropsychiatric diseases. DBS for PD, in the subthalamic nucleus or globus pallidus interna (GPi), improves tremor, bradykinesia, and rigidity, emotional well-being and sleep, and "on" time without dyskinesias, but may not improve axial and cognitive impairment or speech. DBS in motor thalamus may improve or resolve rest, action, and postural tremor. DBS in the GPi results in functional improvement in hyperkinetic greater than tonic aspects of primary and tardive dystonias. Perioperative risks include hemorrhage and stroke (<2%) and infection (8%). The benefit/risk ratio may be optimized with individualized patient selection and the use of an experienced surgical team. DBS is expensive and well-placed unilateral ablation therapy has been shown to be efficacious. Bilateral ablations pose an unacceptable risk of speech impairment and disequilibrium.

View details for PubMedID 29443278
New drugs/devices ? Deep brain stimulation (DBS) Neurology Clin Pract Bronte-Stewart HM 2012; 12 (2): 67 - 71
Maximal subthalamic beta hypersynchrony of the local field potential in Parkinson's disease is located in the central region of the nucleus JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY de Solages, C., Hill, B. C., Yu, H., Henderson, J. M., Bronte-Stewart, H. 2011; 82 (12): 1387-1389
Abstract

A pathological marker of Parkinson's disease is the existence of abnormal synchrony of neuronal activity within the beta frequency range (13-35 Hz) in the subthalamic nucleus (STN). Recent studies examining the topography of this rhythm have located beta hypersynchrony in the most dorsal part of the STN. In contrast, this study of the topography of the local field potential beta oscillations in 18 STNs with a 1 mm spatial resolution revealed that the point of maximal beta hypersynchrony was located at 53 � 24% of the trajectory span from the dorsal to the ventral borders of the STN (corresponding to a 3.0 � 1.6 mm depth for a 5.9 � 0.75 mm STN span). This suggests that maximal beta hypersynchrony is located in the central region of the nucleus and that further investigation should be done before using STN spectral profiles as an indicator for guiding placement of deep brain stimulation leads.

View details for DOI 10.1136/jnnp.2010.223107

View details for PubMedID 21205981
Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives ANESTHESIOLOGY MacIver, M. B., Bronte-Stewart, H. M., Henderson, J. M., Jaffe, R. A., Brock-Utne, J. G. 2011; 115 (2): 254-264
Abstract

During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity.Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects.Neurons discharged at 42 � 9 spikes/s (mean � SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition.These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery.

View details for PubMedID 21701380
Repetitive stepping in place identifies and measures freezing episodes in subjects with Parkinson's disease GAIT & POSTURE Nantel, J., de Solages, C., Bronte-Stewart, H. 2011; 34 (3): 329-333
Abstract

Freezing of gait (FOG) in Parkinson's disease (PD) is challenging to measure. We asked whether a repetitive stepping in place (SIP) task on force plates could identify freezing episodes (FEs) in PD subjects, self-classified as "freezers", using the validated FOG questionnaire (FOG-Q) and whether a computerized algorithm could provide automatic detection of FEs during SIP. Thirty PD subjects and nine age-matched controls completed the SIP task. PD subjects were assessed using the Unified Parkinson's Disease Rating motor Scale (UPDRS-III) and the FOG-Q. The identification of "freezers" using the SIP task correlated with the FOG-Q (r=0.80, P<0.001). The specificity and sensitivity of identifying freezers using the SIP task reached 93% and 87%. The number and duration of FEs detected by the algorithm correlated with visual inspection (r=0.97, r=0.998, P<0.001). Freezers had larger SIP asymmetry compared to controls (P=0.02) and non-freezers (P=0.03) as well as larger arhythmicity (P=0.003 and P<0.001, respectively). UPDRS subscores were higher in freezers compared to non-freezers (P<0.05). These results suggest that the SIP task is a useful tool to detect freezing in PD and is correlated with FOG-Q. SIP cycle asymmetry and stride time variability were worse in freezers, similar to that shown in FOG studies. Detection of the number and duration of FEs using a computerized algorithm correlated with independent visual inspection of records.

View details for DOI 10.1016/j.gaitpost.2011.05.020

View details for Web of Science ID 000295771800007

View details for PubMedID 21715166
Inclusion and Exclusion Criteria for DBS in Dystonia MOVEMENT DISORDERS Bronte-Stewart, H., Taira, T., Valldeoriola, F., Merello, M., Marks, W. J., Albanese, A., Bressman, S., Moro, E. 2011; 26: S5-S16
Abstract

When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of ? 90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS-specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)--have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary--generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures.

View details for DOI 10.1002/mds.23482

View details for Web of Science ID 000291866500003

View details for PubMedID 21692112
Deep Brain Stimulation in "On"-State Parkinson Hyperpyrexia NEUROLOGY Klepitskaya, O., Cole, W., Henderson, J., Bronte-Stewart, H. 2011; 76 (7): S69-S71
View details for Web of Science ID 000287362300014

View details for PubMedID 21321358
Immediate versus delayed switch from levodopa/carbidopa to levodopa/carbidopa/entacapone: effects on motor function and quality of life in patients with Parkinson's disease with end-of-dose wearing off Int J Neurosci Lew MF, Somogyi M, McCague K, Welsh M, Lce Qol Study group 2011; 121 (11): 605 - 13
Deep Brain Stimulation for Parkinson?s Disease. An expert consensus and review of key issues Archives of Neurology Bronstein JM, Tagliati M., Alterman RL, the Deep Brain Study group 2011; 68 (2): 165
Clinical Motor Outcome of Bilateral Subthalamic Nucleus Deep-Brain Stimulation for Parkinson's Disease Using Image-Guided Frameless Stereotaxy NEUROSURGERY Bronte-Stewart, H., Louie, S., Batya, S., Henderson, J. M. 2010; 67 (4): 1088-1093
Abstract

Image-guided neuronavigation has largely replaced stereotactic frames when precise, real-time anatomic localization is required during neurosurgical procedures. However, some procedures, including placement of deep-brain stimulation (DBS) leads for the treatment of movement disorders, are still performed using frame-based stereotaxy. Despite the demonstration of comparable accuracy between frame-based and "frameless" image-guided approaches, the clinical efficacy of frameless DBS placement has never been reported.To analyze the outcomes of subthalamic nucleus (STN) DBS using the frameless technique for the treatment of Parkinson's disease (PD).Of 31 subjects (20 men) with PD for 10 � 4 years, 28 had bilateral STN DBS and 3 had unilateral STN DBS. The Unified Parkinson's Disease Rating Scale (UPDRS) motor scale (III) and total medication doses were assessed before surgery on and off medication and off medication/ON DBS (off/ON) after 6 to 12 months of STN DBS.There was a 58% improvement from bilateral STN DBS in the UPDRS III (40 � 16 preoperatively off, 17 � 11 off/ON) 9.6 � 1.9 months after surgery (P < .001). This compared favorably with the published outcomes using the frame-based technique. All motor subscores improved significantly (P < .01). The mean reduction in medication was 50%. No intraoperative complications occurred, but one subject with hypertension died of a delayed hemorrhage postoperatively. Two subjects developed postoperative infections that required lead removal and antibiotics.Bilateral STN DBS for PD performed by an experienced team using a frameless approach results in outcomes comparable to those reported with the use of the frame-based technique.

View details for DOI 10.1227/NEU.0b013e3181ecc887

View details for PubMedID 20881573
Socioeconomic Trends in Deep Brain Stimulation (DBS) Surgery NEUROMODULATION Lad, S. P., Kalanithi, P. S., Patil, C. G., Itthimathin, P., Batya, S., Bronte-Stewart, H., Boakye, M., Henderson, J. M. 2010; 13 (3): 182-186
Abstract

Objective:? We evaluated trends in deep brain stimulation (DBS) for the 14-year period from 1993 to 2006. Materials and Methods:? We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Results:? A total of 34,792 patients underwent DBS surgery from 1993 to 2006. There were 756 DBS cases performed in 1993 compared with 4200 DBS procedures performed in 2006. Significant increases in nationwide DBS volume coincided with regulatory approval for new indications-Parkinson's disease and dystonia, respectively. Cost of DBS surgery increased from $38,840 in 1993 to $69,329 in 2006. The majority of cases were done in metropolitan areas (97%) at large academic centers (91%) at a national bill of $291 MM. Conclusions:? Future studies will need to include the socioeconomic impact of the technology on disease status, patient access, and costs as it expands to novel indications.

View details for DOI 10.1111/j.1525-1403.2010.00278.x

View details for PubMedID 21992830
Bilateral symmetry and coherence of subthalamic nuclei beta band activity in Parkinson's disease EXPERIMENTAL NEUROLOGY de Solages, C., Hill, B. C., Koop, M. M., Henderson, J. M., Bronte-Stewart, H. 2010; 221 (1): 260-266
Abstract

Abnormal synchronization of neuronal activity in the basal ganglia has been associated with the dysfunction of sensorimotor circuits in Parkinson's disease (PD). In particular, oscillations at frequencies within the beta range (13-35 Hz) are specifically modulated by dopaminergic medication and are correlated with the clinical state of the subjects. While these oscillations have been shown to be coherent ipsilaterally within the basal ganglia and between the basal ganglia nuclei and the ipsilateral motor cortex in PD, the bilateral extent of their coherence has never been characterized. Here we demonstrate for the first time that the beta band oscillations recorded in the local field potential of the subthalamic nuclei (STN), while appearing different across subjects, are occurring at the same frequencies bilaterally (p<0.001) and are coherent between the two STNs of individual PD subjects (11/12 cases, p<0.05). These findings suggest the existence of a bilateral network controlling the beta band activity in the basal ganglia in PD.

View details for DOI 10.1016/j.expneurol.2009.11.012

View details for PubMedID 19944098
Hybrid Cars May Interfere with Implanted Deep Brain Stimulators MOVEMENT DISORDERS Chen, C., Cole, W., Bronte-Stewart, H. M. 2009; 24 (15): 2290-2291
View details for DOI 10.1002/mds.22739

View details for Web of Science ID 000272570000019

View details for PubMedID 19768726
Quantitative Lateralized Measures of Bradykinesia at Different Stages of Parkinson's Disease: The Role of the Less Affected Side MOVEMENT DISORDERS Louie, S., Koop, M. M., Frenklach, A., Bronte-Stewart, H. 2009; 24 (13): 1991-1997
Abstract

The onset of motor abnormalities in Parkinson's disease (PD) is usually unilateral. However, current therapeutic trials do not analyze separately the performance of the more affected (MA) and less affected (LA) limbs. From a cohort of 85 subjects at different stages of PD, we asked whether the relationship between bradykinesia and disease severity was similar on both limbs and if the MA side remained more bradykinetic than the LA side in advanced PD. MA and LA limb determination was made from the history of the side first affected. Twenty-one age-matched subjects were used as controls. The velocities of finger and arm movements on both sides were inversely correlated with disease severity (P < 0.03). The slope of the decline in wrist movement velocity was steeper on the LA side (P = 0.029). When the regression lines were extrapolated to the y-axis (UPDRS III = 0) the performance of the LA side was not different from that of controls (P = 0.954 and P = 0.829 for finger and arm movements, respectively), whereas that of the MA side was slower (P = 0.019 and P = 0.016), suggesting that at the theoretical state of no disease the LA side would reflect less or no contralateral nigral pathology. With increasing disease severity, there was less difference between MA and LA sides in both finger and arm bradykinesia (P < 0.004). These findings highlight the value of analyzing separately the MA and LA sides in subjects with PD, especially for clinical trials of potential disease modifying agents in early stages of disease.

View details for DOI 10.1002/mds.22741

View details for Web of Science ID 000271555700016

View details for PubMedID 19672996
Testing Objective Measures of Motor Impairment in Early Parkinson's Disease: Feasibility Study of an At-Home Testing Device MOVEMENT DISORDERS Goetz, C. G., Stebbins, G. T., Wolff, D., DeLeeuw, W., Bronte-Stewart, H., Elble, R., Hallet, M., Nutt, J., Ramig, L., Sanger, T., Wu, A. D., Kraus, P. H., Blasucci, L. M., Shamim, E. A., Sethi, K. D., Spielman, J., Kubota, K., Grove, A. S., Dishman, E., Taylor, C. B. 2009; 24 (4): 551-556
Abstract

We tested the feasibility of a computer based at-home testing device (AHTD) in early-stage, unmedicated Parkinson's disease (PD) patients over 6 months. We measured compliance, technical reliability, and patient satisfaction to weekly assessments of tremor, small and large muscle bradykinesia, speech, reaction/movement times, and complex motor control. relative to the UPDRS motor score. The AHTD is a 6.5'' x 10'' computerized assessment battery. Data are stored on a USB memory stick and sent by internet to a central data repository as encrypted data packets. Although not designed or powered to measure change, the study collected data to observe patterns relative to UPDRS motor scores. Fifty-two PD patients enrolled, and 50 completed the 6 month trial, 48 remaining without medication. Patients complied with 90.6% of weekly 30-minute assessments, and 98.5% of data packets were successfully transmitted and decrypted. On a 100-point scale, patient satisfaction with the program at study end was 87.2 (range: 80-100). UPDRS motor scores significantly worsened over 6 months, and trends for worsening over time occurred for alternating finger taps (P = 0.08), tremor (P = 0.06) and speech (P = 0.11). Change in tremor was a significant predictor of change in UPDRS (P = 0.047) and was detected in the first month of the study. This new computer-based technology offers a feasible format for assessing PD-related impairment from home. The high patient compliance and satisfaction suggest the feasibility of its incorporation into larger clinical trials, especially when travel is difficult and early changes or frequent data collection are considered important to document.

View details for DOI 10.1002/mds.22379

View details for Web of Science ID 000265003800010

View details for PubMedID 19086085
Excessive Postural Sway and the Risk of Falls at Different Stages of Parkinson's Disease MOVEMENT DISORDERS Frenklach, A., Louie, S., Koop, M. M., Bronte-Stewart, H. 2009; 24 (3): 377-385
Abstract

Excessive postural sway may result in falls in Parkinson's disease (PD). We measured postural sway using the sensory organization test (SOT) of dynamic posturography in static (platform still) and dynamic (sway referenced platform) conditions with normal, no and inappropriate visual feedback in 102 subjects with PD, off medication. Twenty-five healthy subjects were used as age-matched controls. Eighteen very early stage PD subjects had never used dopaminergic medication. Postural sway was normal in those subjects in all conditions, but was abnormal in subjects with more advanced symptoms (UPDRS III > 20, P < 0.01). Postural sway increased with disease severity in all conditions except static, eyes closed (P < 0.0001). We developed the SOT Fall Severity Scale (SOTFSS) from the number of times postural sway was so large that the subject had to take a step (registered as a "fall") and showed that falls mainly occurred in dynamic conditions, and were correlated with disease severity (P < 0.0001). In dynamic conditions the SOTFSS was correlated with the retropulsion score from the UPDRS III (N = 102, P < 0.0001) and with the subjects' self-reported fall frequency from the UPDRS II (N = 62, SOT5: P = 0.0419, SOT6: P = 0.0034).

View details for DOI 10.1002/mds.22358

View details for Web of Science ID 000263747200009

View details for PubMedID 18972546
A comparison of treatment thresholds in two large Parkinson?s disease clinical trial cohorts Movement Disorders Marras C, Lang AE, Eberly SW, Oakes D, Fahn S, Schwid SR, Hyson C, Shoulson I; Parkinson Study Group DATATOP, PRECEPT investigators 2009; 24 (16): 2370 - 8
The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation EXPERIMENTAL NEUROLOGY Bronte-Stewart, H., Barberini, C., Koop, M. M., Hill, B. C., Henderson, J. M., Wingeier, B. 2009; 215 (1): 20-28
Abstract

Producing accurate movements may rely on the functional independence of sensorimotor circuits within basal ganglia nuclei. In parkinsonism there is abnormal synchrony of electrical activity within these circuits that results in a loss of independence across motor channels. Local field potential (LFP) recordings reflect the summation of local electrical fields and an increase in LFP power reflects increased synchrony in local neuronal networks. We recorded LFPs from the subthalamic nucleus (STN) deep brain stimulation (DBS) lead in the operating room in 22 cases from 16 subjects with Parkinson's disease (PD) who were off medication. There was elevated LFP power at beta frequencies (13-35 Hz) at rest. The LFP spectral profile was consistent across several periods of rest that were separated by movement and/or DBS, and appeared to be a relatively stationary phenomenon. The spectral profile and frequencies of the beta-band peak(s) varied among subjects but were similar between the right and left STNs within certain individuals. These results suggest that the LFP spectrum at rest may characterize a "signature" rhythm for an individual with PD. Beta-band power was attenuated after intra-operative STN DBS (p<0.05). The attenuation lasted for 10 s after short periods (30 s) and for up to 50 s after longer periods (5 min) of DBS. The finding that longer periods of DBS attenuated beta power for a longer time suggests that there may be long-acting functional changes to networks in the STN in PD after chronic DBS.

View details for DOI 10.1016/j.expneurol.2008.09.008

View details for PubMedID 18929561
A longitudinal program for biomarker development in Parkinson?s disease: a feasibility study Movement Disorders Ravina B, Tanner C, Dieuliis D, Eberly S, Flagg E, Galpern WR, Fahn S, Goetz CG, Grate S, Kurlan R, Lang AE, Marek K, Kieburtz K, Oakes D, Elliott R, Shoulson I; Parkinson Study Group LABS-PD Investigators 2009; 24 (14): 2081 - 90
Quantitative measures of fine motor, limb, and postural bradykinesia in very early stage, untreated Parkinson's disease MOVEMENT DISORDERS Koop, M. M., Shivitz, N., Bronte-Stewart, H. 2008; 23 (9): 1262-1268
Abstract

Few studies have characterized the motor control abnormalities of very early stage Parkinson's disease (PD), when symptoms are mild and usually unilateral. However, this group is the most targeted for potential disease-modifying therapeutics. We have validated several quantitative measures of bradykinesia with the Unified Parkinson's Disease Rating Scale motor disability score (UPDRS III) and have found these useful in studies of advanced PD. In this study, we asked if quantitative measures of finger, forearm, and postural movement velocity could detect bradykinesia in 20 patients with very early stage, untreated PD. The results revealed evidence of significant finger and forearm bradykinesia of the patient group's more affected side when compared to the nondominant side of 19 age-matched control subjects (P = 0.001 and P < 0.001, respectively). Furthermore, the patient group's forearm movement velocity on the more affected side was significantly slower than their less affected side (P = 0.005), highlighting the importance of using an outcome measure that is lateralized in studies of very early stage PD. In contrast to our previous study that revealed significant postural bradykinesia in patients with advanced PD, we did not detect postural bradykinesia in patients with very early stage, untreated PD. Based on these findings, we suggest that the use of quantitative, lateralized measures of bradykinesia would be useful in studies of very early stage, untreated PD. These measures may improve a study by: increasing efficiency and objectivity of the evaluation, decreasing cost, and decreasing the number of subjects needed for statistical significance.

View details for DOI 10.1002/mds.22077

View details for Web of Science ID 000258421800010

View details for PubMedID 18464283
The Role of Deep Brain Stimulation (DBS) in the Treatment of Postural Instability and Gait Disorders of Parkinson's Disease DEEP BRAIN STIMULATION IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS Bronte-Stewart, H., Tarsy, M. D., Vitek, J. L., Starr, P. A., Okun, M. S. 2008: 333?58
View details for DOI 10.1007/978-1-59745-360-8_19

View details for Web of Science ID 000267559400019
Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson?s disease Neurology The Parkinson's study group, PRECEPT investigators 2007; 69: 1480- 1490
Bilateral subthalamic nucleus deep brain stimulation improves certain aspects of postural control in Parkinson's disease, whereas medication does not MOVEMENT DISORDERS Shivitz, N., Miller Koop, M., Fahimi, J., Heit, G., Bronte-Stewart, H. M. 2006; 21 (8): 1088-1097
Abstract

Postural control requires precise integration of sensory inputs and motor output, but clinical assessments of postural control do not differentiate between these. Previously, we found that this differentiation is important in Parkinson's disease (PD) as there was a dissociated effect of medication versus pallidotomy on sensory aspects of postural instability. In this study, we address several questions that emerged from that work in 28 different patients with PD off and on medication, before and after bilateral subthalamic nucleus deep brain stimulation (B-STN DBS): (1) In a different cohort is there still an unusually large percentage of patients with postural instability in sensory-deprived conditions? (2) Are more specific measures of motor aspects of postural control using dynamic posturography (postural movement velocity [MV] and reaction time [RT]) abnormal in PD as seen clinically using the Postural Instability and Gait Disorder score of the Unified Parkinson's Disease Rating Scale? (3) What is the effect of B-STN DBS versus medication on sensory versus motor aspects of postural instability in PD? The results included (1) substantially more patients (39%) versus controls (5%) exhibited postural instability in conditions of limited sensory feedback; (2) postural MV and postural RT were abnormal off medication preoperatively (N(subset) = 23; P < 0.001 for both); (3) B-STN DBS improved abnormal sensory aspects of postural instability (P < 0.05) and postural MV (P = 0.005), whereas medication did not. Neither B-STN DBS nor medication improved postural RT. For the group as a whole, STN DBS plus medication was better therapy than medication preoperatively for sensory aspects of postural control (P = 0.003).

View details for DOI 10.1002/mds.20905

View details for Web of Science ID 000240081900006

View details for PubMedID 16671073
Improvement in a quantitative measure of bradykinesia after microelectrode recording in patients with Parkinson's disease during deep brain stimulation surgery MOVEMENT DISORDERS Koop, M. M., Andrzejewski, A., Hill, B. C., Heit, G., Bronte-Stewart, H. M. 2006; 21 (5): 673-678
Abstract

It is widely accepted that patients with Parkinson's disease experience immediate but temporary improvement in motor signs after surgical implantation of subthalamic nucleus (STN) deep brain stimulating electrodes before the electrodes are activated, although this has never been formally studied. Based on anecdotal observations that limb mobility improved just after microelectrode recording (MER) during deep brain stimulation (DBS) procedures, we designed a prospective study to measure upper extremity bradykinesia using a quantitative measure of angular velocity. Measurements were made pre- and post-MER and during intraoperative DBS. Analysis of 98 STN DBS procedures performed on 61 patients showed that MER did not create adverse clinical symptoms despite concerns that MER increases morbidity. Quantitative upper extremity bradykinesia improved after MER alone, and further improvement was seen during intraoperative DBS. Electrophysiological data from each case were then compared to the improvement in bradykinesia post-MER alone and a significant correlation was found between the improvement in arm bradykinesia, the number of passes through the STN with somatosensory driving, and also with the number of arm cells with somatosensory driving in the STN, but not with total number of passes, total number of passes through the STN, or total number of cells with somatosensory driving in the STN. This study demonstrates that there is a significant improvement in upper extremity bradykinesia just after MER, before inserting or activating the DBS electrode in patients with Parkinson's disease who undergo STN DBS.

View details for DOI 10.1002/mds.20796

View details for Web of Science ID 000237712700012

View details for PubMedID 16440333
Practice parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology NEUROLOGY Pahwa, R., Factor, S. A., Lyons, K. E., Ondo, W. G., Gronseth, G., Bronte-Stewart, H., Hallett, M., Miyasaki, J., Stevens, J., Weiner, W. J. 2006; 66 (7): 983-995
Abstract

To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS?A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

View details for Web of Science ID 000236673300007

View details for PubMedID 16606909
Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease EXPERIMENTAL NEUROLOGY Wingeier, B., Tcheng, T., Koop, M. M., Hill, B. C., Heit, G., Bronte-Stewart, H. M. 2006; 197 (1): 244-251
Abstract

Power spectra from local field potentials (LFPs) recorded post-operatively from the deep brain stimulation (DBS) macroelectrode show prominence of the beta rhythm (11-30 Hz) in untreated Parkinson's disease (PD). Dopaminergic medication and movement attenuate this beta band in PD. In this pilot study of six sides in four patients, we recorded LFPs from the DBS electrode in untreated PD patients in the operating room. In all cases, there was a peak in the time-frequency spectrogram in the beta frequency range when the patients were at rest, which was associated with attenuation in the same range with movement. The actual frequency range and the strength of the beta peak varied among cases. In two patients, intra-operative constraints permitted recording of LFPs at rest, before and immediately after subthalamic nucleus (STN) DBS. In both patients we documented that STN DBS caused a significant attenuation in power in the beta band at rest that persisted for 15-25 s after DBS had been turned off (P < 0.01). From one case, our data suggest that the beta rhythm attenuation was most prominent within the STN itself. This study shows for the first time that STN DBS attenuates the power in the prominent beta band recorded in the STN of patients with PD. These pilot findings raise the interesting possibility of using this biomarker for closed loop DBS or neuromodulation.

View details for DOI 10.1016/j.expneurol.2005.09.016

View details for Web of Science ID 000234534200025

View details for PubMedID 16289053
Quantitative measurements of alternating finger tapping in Parkinson's disease correlate with UPDRS motor disability and reveal the improvement in fine motor control from medication and deep brain stimulation. Movement disorders Taylor Tavares, A. L., Jefferis, G. S., Koop, M., Hill, B. C., Hastie, T., Heit, G., Bronte-Stewart, H. M. 2005; 20 (10): 1286-1298
Abstract

The Unified Parkinson's Disease Rating Scale (UPDRS) is the primary outcome measure in most clinical trials of Parkinson's disease (PD) therapeutics. Each subscore of the motor section (UPDRS III) compresses a wide range of motor performance into a coarse-grained scale from 0 to 4; the assessment of performance can also be subjective. Quantitative digitography (QDG) is an objective, quantitative assessment of digital motor control using a computer-interfaced musical keyboard. In this study, we show that the kinematics of a repetitive alternating finger-tapping (RAFT) task using QDG correlate with the UPDRS motor score, particularly with the bradykinesia subscore, in 33 patients with PD. We show that dopaminergic medication and an average of 9.5 months of bilateral subthalamic nucleus deep brain stimulation (B-STN DBS) significantly improve UPDRS and QDG scores but may have different effects on certain kinematic parameters. This study substantiates the use of QDG to measure motor outcome in trials of PD therapeutics and shows that medication and B-STN DBS both improve fine motor control.

View details for PubMedID 16001401
Quantitative measurements of Parkinson's disease correlate alternating finger tapping in with UPDRS motor disability and reveal the improvement in fine motor control from medication and deep brain stimulation MOVEMENT DISORDERS Tavares, A. L., Jefferis, G. S., Koop, M., Hill, B. C., Hastie, T., Heit, G., Bronte-Stewart, H. M. 2005; 20 (10): 1286-1298
Abstract

The Unified Parkinson's Disease Rating Scale (UPDRS) is the primary outcome measure in most clinical trials of Parkinson's disease (PD) therapeutics. Each subscore of the motor section (UPDRS III) compresses a wide range of motor performance into a coarse-grained scale from 0 to 4; the assessment of performance can also be subjective. Quantitative digitography (QDG) is an objective, quantitative assessment of digital motor control using a computer-interfaced musical keyboard. In this study, we show that the kinematics of a repetitive alternating finger-tapping (RAFT) task using QDG correlate with the UPDRS motor score, particularly with the bradykinesia subscore, in 33 patients with PD. We show that dopaminergic medication and an average of 9.5 months of bilateral subthalamic nucleus deep brain stimulation (B-STN DBS) significantly improve UPDRS and QDG scores but may have different effects on certain kinematic parameters. This study substantiates the use of QDG to measure motor outcome in trials of PD therapeutics and shows that medication and B-STN DBS both improve fine motor control.

View details for DOI 10.1002/mds.20556

View details for Web of Science ID 000232749300005
The North American survey of placement and adjustment strategies for deep brain stimulation STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Ondo, W. G., Bronte-Stewart, H. 2005; 83 (4): 142-147
Abstract

Deep brain stimulation (DBS) is gaining wide acceptance as treatment for Parkinson's disease (PD), essential tremor, and dystonia.A 40-item questionnaire commissioned by the DBS Study Group was sent to 46 centers that had performed at least 25 DBS implantations. These centers were identified through the DBS Study Group, other professional societies, and with the assistance of the Medtronic Corporation. The results were then tabulated and descriptive analyses were performed.Thirty-six of 47 centers (77%) responded, they had implanted 4,553 patients. The timing for bilaterally implanted patients varied, as 13 sites almost always implanted simultaneously whereas 14 sites almost never implanted simultaneously. Stereotactic frames included Leksell (n = 19), CRW (n = 15) and Compass (n = 2). Post-placement imaging was routinely performed by almost all centers and included MRI (n = 23), CT (n = 4), CT/MRI variably (n = 5), and ventriculography (n = 1). Two centers used more than one electrode per side. The 34 centers that used a single electrode averaged 2.3 +/- 1.4 passes per electrode (range: 1-18 passes). Most centers used macro-stimulation to confirm placement by assessing the intra-operative clinical response (n = 34), and to assess for adverse events (n = 26) at high voltages, averaging 6.7 +/- 2.3 V (range: 4-10). The initial activation averaged 18 +/- 12 days after electrode placement (average range: 11 +/- 10 to 28 +/- 18 days, absolute range: 1-90 days). Most sites had several programmers; however, the primary programmers were neurology staff (n = 15), the neurologist (n = 13), neurosurgery staff (n = 6), the neurosurgeon (n = 2), or a physiatrist (n = 1). Twelve centers automatically reduced PD medications on the day of initial activation, 9 centers reduced them variably, and 16 centers initially did not reduce them. Eventually, 80.4% of patients were reported to have some dose reduction, and 47.1% had a greater than 50% reduction of PD medications.Strategies regarding DBS placement and adjustment vary in North America.

View details for DOI 10.1159/000088654

View details for Web of Science ID 000233954700003

View details for PubMedID 16205106
Microelectrode recording revealing a somatotopic body map in the subthalamic nucleus in humans with Parkinson disease JOURNAL OF NEUROSURGERY Romanelli, P., Heit, G., Hill, B. C., Kraus, A., Hastie, T., Bronte-Stewart, H. M. 2004; 100 (4): 611-618
Abstract

The subthalamic nucleus (STN) is a key structure for motor control through the basal ganglia. The aim of this study was to show that the STN in patients with Parkinson disease (PD) has a somatotopic organization similar to that in nonhuman primates.A functional map of the STN was obtained using electrophysiological microrecording during placement of deep brain stimulation (DBS) electrodes in patients with PD. Magnetic resonance imaging was combined with ventriculography and intraoperative x-ray film to assess the position of the electrodes and the STN units, which were activated by limb movements to map the sensorimotor region of the STN. Each activated cell was located relative to the anterior commissure-posterior commissure line. Three-dimensional coordinates of the cells were analyzed statistically to determine whether those cells activated by movements of the arm and leg were segregated spatially. Three hundred seventy-nine microelectrode tracks were created during placement of 71 DBS electrodes in 44 consecutive patients. Somatosensory driving was found in 288 tracks. The authors identified and localized 1213 movement-related cells and recorded responses from 29 orofacial cells, 480 arm-related cells, 558 leg-related cells, and 146 cells responsive to both arm and leg movements. Leg-related cells were localized in medial (p < 0.0001) and ventral (p < 0.0004) positions and tended to be situated anteriorly (p = 0.063) relative to arm-related cells.Evidence of somatotopic organization in the STN in patients with PD supports the current theory of highly segregated loops integrating cortex-basal ganglia connections. These loops are preserved in chronic degenerative diseases such as PD, but may subserve a distorted body map. This finding also supports the relevance of microelectrode mapping in the optimal placement of DBS electrodes along the subthalamic homunculus.

View details for Web of Science ID 000220440900009

View details for PubMedID 15070113
The functional organization of the sensorimotor region of the subthalamic nucleus STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Romanelli, P., Bronte-Stewart, H., Heit, G., Schaal, D. W., Esposito, V. 2004; 82 (5-6): 222-229
Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is viewed by many as the ultimate therapy targeting severe advanced stages of Parkinson's disease (PD). A fundamental constituent of the mechanisms underlying the therapeutic effects of DBS is clearly the functional organization of the STN; however, there is limited understanding of the organization of this structure in humans. Data from primates suggest that different domains can be identified in the STN, including a sensorimotor area with a segregated body map, as well as nonmotor areas. Recent clinical studies have used microelectrode recording to investigate the presence of a body map in the sensorimotor STN of PD patients. This paper will review and compare experimental and clinical data regarding the functional organization of the STN and discuss the clinical implications for PD patients undergoing STN DBS.

View details for DOI 10.1159/000082778

View details for Web of Science ID 000227207300004

View details for PubMedID 15604597
Possible necessity for deep brain stimulation of both the ventralis intermedius and subthalamic nuclei to resolve Holmes tremor - Case report JOURNAL OF NEUROSURGERY Romanelli, P., Bronte-Stewart, H., COURTNEY, T., Heit, G. 2003; 99 (3): 566-571
Abstract

Holmes tremor is characterized by resting, postural, and intention tremor. Deep brain stimulation (DBS) of both the nucleus ventralis intermedius (Vim) and the subthalamic nucleus (STN) may be required to control these three tremor components. A 79-year-old man presented with a long-standing combination of resting, postural, and intention tremor, which was associated with severe disability and was resistant to medical treatment. Neuroimaging studies failed to reveal areas of discrete brain damage. A DBS device was placed in the Vim and produced an improvement in both the intention and postural tremor, but there was residual resting tremor, as demonstrated by clinical observation and quantitative tremor analysis. Placement of an additional DBS device in the STN resolved the resting tremor. Stimulation of the Vim or STN alone failed to produce global resolution of mixed tremor, whereas combined Vim-STN stimulation produced global relief without creating noticeable side effects. Combined Vim-STN stimulation can thus be a safe and effective treatment for Holmes tremor.

View details for PubMedID 12959446
Surgical therapy for dystonia. Current neurology and neuroscience reports Bronte-Stewart, H. 2003; 3 (4): 296-305
Abstract

Surgical treatments for dystonia have been available since the early 20th century, but have improved in their efficacy to adversity ratio through a combination of technologic advances and better understanding of the role of the basal ganglia in dystonia. The word "dystonia" describes a phenotype of involuntary movement that may manifest from a variety of conditions. Dystonia may affect only certain regions of the body or may be generalized. It appears to be critical to determine whether the etiology underlying the dystonia is "primary" (ie, occurring from a genetic or idiopathic origin) or "secondary" (ie, occurring as a result of structural, metabolic, or neurodegenerative disorders). Secondary dystonias are far more common than primary dystonias. Primary dystonias respond well to pallidotomy or deep brain stimulation of the internal segment of the globus pallidum, whereas secondary dystonias appear to respond partially at best. Limited historic and current data suggest that the thalamus may be a promising target for the treatment of secondary dystonias, but more careful, prospective, randomized studies are needed. Combinations of bilateral targets are possible with the current technology of DBS, but not widely used due to surgical morbidity and expense. This article reviews the surgical treatment of dystonia from past to present, with a focus on separating the outcomes for primary versus secondary and generalized versus cervical dystonia.

View details for PubMedID 12930699
Parkinson's Disease: Surgical Options. Current treatment options in neurology Bronte-Stewart, H. 2003; 5 (2): 131?47
Abstract

Surgical therapy for Parkinson's disease (PD) has been a treatment option for over 100 years. Advances in the knowledge of basal ganglia physiology and in techniques of stereotactic neurosurgery and neuroimaging have allowed more accurate placement of lesions or "brain pacemakers" in the sensorimotor regions of target nuclei. This, in turn, has led to improved efficacy with fewer complications than in the past. Currently, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is the preferred option (and is approved by the US Food and Drug Administration) for the surgical treatment of PD. The most important predictors for outcome for DBS for PD are patient selection and electrode location. Patients should have a documented preoperative improvement from dopaminergic medication of at least 30% in the patient's Unified Parkinson's Disease Rating Scale motor disability scores. A levodopa challenge may be needed to document the best "on" state. Dementia or active cognitive decline must be excluded. Active psychiatric disease should be treated preoperatively. Patients should be motivated, with good support systems, and committed to the postoperative management of DBS therapy. Deep brain stimulation should be considered when the patient begins to experience dyskinesia and on-off fluctuations despite optimal medical therapy. Deep brain stimulation is not a good option at the final stages of the disease because of the increased incidence of dementia and severe comorbidity. The DBS electrode should be placed in the sensorimotor region of the GPi or STN. Subthalamic nucleus and GPi DBS can improve all motor aspects of PD, as well as predictable "on" time, without dyskinesia or fluctuations. On average, STN DBS results in a greater reduction of dopaminergic medication compared with GPi DBS. Because of the smaller size of the target region, the pulse generator battery life is longer with STN then with GPi DBS. Deep brain stimulation programming is a skill that is readily learned and may be required of all neurologists in the future. Emerging surgical therapies are restorative, and they aim to replace or regenerate degenerating dopaminergic neurons. These include embryonic mesencephalic tissue transplantation, human embryonic stem cell transplantation, and gene-derived methods of intracerebral implantation of growth factors and dopamine- producing cell lines. It will be important to determine whether DBS, if performed before the onset of motor response complications to medical therapy, may prevent this stage of disease altogether or delay it for a significant period of time. The same question applies to the future with restorative therapy.

View details for PubMedID 12628062
Postural instability in idiopathic Parkinson's disease: the role of medication and unilateral pallidotomy 52nd Annual Meeting of the American-Academy-of-Neurology Bronte-Stewart, H. M., Minn, A. Y., Rodrigues, K., Buckley, E. L., Nashner, L. M. OXFORD UNIV PRESS. 2002: 2100?2114
Abstract

Postural instability (PI) is common in idiopathic Parkinson's disease (IPD). We measured sensory and motor contributions to PI in 50 patients with advanced IPD, off and on medication and in a subset pre- and 3, 6 and 12 months post-unilateral pallidotomy, using computerized dynamic posturography [specifically, the Sensory Organization Test (SOT) and the Unified Parkinson's Disease Rating Scale (UPDRS) subscale PIGD (Postural Instability and Gait Disorder)]. Off medication, all patients had abnormal PIGD scores. The group could be separated into those with normal SOT equilibrium scores (SOTN) and those, the majority, with abnormal postural control when sensory feedback was limited (SOTABN). Medication improved the PIGD scores but worsened the SOT scores in the majority of patients. Increases in spontaneous sway in some patients contributed to the negative effect of medication on SOT scores. However, this could not explain the detrimental effect of medication on SOT scores in at least 40% of patients. On the other hand, pallidotomy improved both PIGD and SOT scores in both groups. A predictor of good outcome from pallidotomy concerning PI was the degree of worsening of the effect that medication had on SOT5 scores. PI in IPD appears to be multifactorial. We propose that the PIGD score reflects sensory and motor aspects of postural control, with normal sensory feedback, while the SOT equilibrium scores measure the sensory organizational process of postural control in the presence of altered sensory inputs. There is a dissociation between the effects of medication and pallidotomy on motor and sensory components of postural control, which may reflect the underlying pathophysiological mechanism responsible for these different components of PI. We suggest that patients with advanced IPD and PI on medication should consider adjuvant surgical treatment for better postural control.

View details for Web of Science ID 000177504900017

View details for PubMedID 12183355
Outcome of pallidal surgery in primary versus secondary dystonia Kilgore, S. M., Bronte-Stewart, H. LIPPINCOTT WILLIAMS & WILKINS. 2002: A395
View details for Web of Science ID 000174875900998
The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type NEUROLOGY Silverberg, G. D., Heit, G., Huhn, S., Jaffe, R. A., Chang, S. D., Bronte-Stewart, H., Rubenstein, E., Possin, K., Saul, T. A. 2001; 57 (10): 1763-1766
Abstract

To evaluate the production rate of CSF in patients with differing disease states.The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 +/- 4 years, mean +/- SD), nine with PD over age 60 (aged 69 +/- 6 years, mean +/- SD), and seven with dementia of the Alzheimer's type (AD) (aged 72 +/- 9 years, mean +/- SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL.These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 +/- 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 +/- 0.12 mL/minute, and in patients with AD the mean rate was 0.20 +/- 0.06 mL/minute.These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

View details for Web of Science ID 000172334700006

View details for PubMedID 11723260
Superior outcomes of bilateral STN DBS in IPD attributed to precise intraoperative localization techniques Bronte-Stewart, H. M., Hill, B. C., McGuire, K., Minn, A. Y., Courtney, T. A., Heit, G. LIPPINCOTT WILLIAMS & WILKINS. 2001: A279
View details for Web of Science ID 000168270600737
Postural instability is common in patients with essential tremor and is improved after thalamic deep brain stimulation Minn, A. Y., Bronte-Stewart, H. M. LIPPINCOTT WILLIAMS & WILKINS. 2001: A24?A25
View details for Web of Science ID 000168270600061
Postural instability in Parkinson?s Disease: Opposing effects of treatment on sensory and motor components Control of Posture and Gait Nashner LM, Minn AY, Rodrigues K, Buckley EL, Bront-Stewart HM 2001: 737 - 741
A physiological model of the effects of surgery on postural instability in Parkinson?s Disease and in Essential Tremor Control of Posture and Gait Bront-Stewart HM, Minn AY, Nashner LM 2001: 720 - 724
Concurrent Parkinson tremors JOURNAL OF PHYSIOLOGY-LONDON Moore, G. P., Ding, L., Bronte-Stewart, H. M. 2000; 529 (1): 273-281
Abstract

1. Concurrent resting and postural tremors of patients with idiopathic Parkinson's disease were monitored using transducers responding to angular velocity of rotation. Spectra and correlation functions were calculated for each pair of records. 2. When concurrent tremor spectra share indistinguishable fundamental frequencies, have statistically significant peaks in their coherence spectra at those fundamental frequencies, and show significant peaks in their cross-correlation functions near zero delay, they are classified as linearly dependent. When such tremor records are superimposed, their phase-locked behaviour is evident. 3. Pairs of correlated concurrent tremors, of varying duration, have been observed in both hands, both feet and in either hand and the contralateral or ipsilateral foot. Correlated tremors may be concurrent with other tremors that are independent. We hypothesize that correlated Parkinson tremors arise from one or more common (and possibly unilateral) central sources.

View details for Web of Science ID 000165589300025

View details for PubMedID 11080268

View details for PubMedCentralID PMC2270175
Unilateral pallidotomy improves postural instability (PI) in patients with idiopathic Parkinson's disease (IPD) and improves the detrimental effect of medication on the vestibular control of posture Bronte-Stewart, H., Rodrigues, K., Nashner, L. LIPPINCOTT WILLIAMS & WILKINS. 2000: A457?A458
View details for Web of Science ID 000086557801219
Central vestibular mechanisms of balance may be deficient in idiopathic parkinson's disease (IPD) and adversely affected by medication Rodrigues, K., Nashner, L., Bronte-Stewart, H. LIPPINCOTT WILLIAMS & WILKINS. 2000: A446
View details for Web of Science ID 000086557801189
Quantitative digitography (QDG): A sensitive measure of digital motor control in idiopathic Parkinson's disease MOVEMENT DISORDERS Bronte-Stewart, H. M., Ding, L., Alexander, C., Zhou, Y., Moore, G. P. 2000; 15 (1): 36-47
Abstract

This study introduces a new method for studying, quantitatively, the dynamics of finger movement using data obtained from sequences of key strikes on a computer-interfaced piano keyboard. We have called this quantitative digitography (QDG). This initial article introduces the method in a group of patients with Parkinson's disease and in a group of healthy subjects using simple, repetitive, alternating finger-tapping for 60 seconds. Patients with idiopathic Parkinson's disease (IPD) were studied "ON" and "OFF" dopaminergic medication before and after pallidotomy. Customized software allowed the independent analysis of key strike velocity, duration of key strike, and frequency of tapping along with a quantitative measure of the regularity of performance. Quantitative measures of the improvement in performance after medication are presented for each parameter of movement. The technique also reveals correlates of some clinical phenomena of the temporal disturbances of repetitive motion in IPD, such as fatigue, tremor, freezing, and festination. We demonstrate that the performance of 60 seconds of alternating finger tapping on a computerized keyboard yields objective measures of motor performance that are significantly different in patients with IPD "OFF" when compared with "ON" medication and when compared with healthy subjects. This is the first time that such a method has been used in the measurement of specific kinematics of digital motion in Parkinson's disease. The equipment is inexpensive and portable and the data are rapidly and easily collected, making it suitable for the outpatient setting.

View details for PubMedID 10634240
Rhythmic coritcal activity and its relation to movement in normal subjects and patients with movement disorders Journal of Physiology Conway BA, Halliday DA, Farmer SF, Bront-Stewart HM, Rosenberg JR 1999; 518: 32 - 33
NEURAL BASIS FOR MOTOR LEARNING IN THE VESTIBULOOCULAR REFLEX OF PRIMATES .2. CHANGES IN THE RESPONSES OF HORIZONTAL GAZE VELOCITY PURKINJE-CELLS IN THE CEREBELLAR FLOCCULUS AND VENTRAL PARAFLOCCULUS JOURNAL OF NEUROPHYSIOLOGY Lisberger, S. G., PAVELKO, T. A., BRONTESTEWART, H. M., Stone, L. S. 1994; 72 (2): 954-973
Abstract

1. We made extracellular recordings from Purkinje cells in the flocculus and ventral paraflocculus of awake monkeys before and after motor learning in the vestibuloocular reflex (VOR). Three samples were recorded 1) after miniaturizing spectacles had reduced the gain of the VOR (eye speed divided by head speed) to 0.4; 2) when the gain of the VOR was near 1.0; and 3) after magnifying spectacles had increased the gain of the VOR to 1.6. 2. We studied Purkinje cells that showed stronger modulation of simple-spike firing rate during horizontal than during vertical pursuit. These cells corresponded to the previously identified "horizontal gaze velocity Purkinje cells" or HGVP-cells. During pursuit of smooth target motion with the head stationary, HGVP-cells showed strong modulation of firing rate with increases for ipsiversive eye motion (toward the side of recording). When the monkey canceled his VOR by tracking a target that moved exactly with him during sinusoidal head rotation in the horizontal plane, HGVP-cells again showed strong modulation of firing rate with increases for ipsiversive head motion. 3. The responses of HGVP-cells during pursuit with the head stationary and during cancellation of the VOR reveal separate components of firing rate related to eye and head velocity. We used these two behavioral conditions to test for effects of motor learning on the head and eye velocity components of the simple-spike firing of HGVP-cells. Our data confirm the previous observation that motor learning causes the sensitivity to head velocity to be larger when the gain of the VOR is high and smaller when the gain of the VOR is low. Thus we agree with the previous conclusion that changes in the vestibular sensitivity of HGVP-cells, measured during sinusoidal head motion at low frequencies, are in the wrong direction to cause changes in the gain of the VOR. 4. To determine whether the simple-spike output from the HGVP-cells plays a role in the VOR after motor learning, we recorded simple-spike firing during the VOR evoked by transient, rapid changes in head velocity in darkness. When the gain of the VOR was low, firing rate increased during the VOR evoked by ipsiversive head motion and decreased during the VOR evoked by contraversive head motion. When the gain of the VOR was high, the direction selectivity of the responses was reversed.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1994PC60700039

View details for PubMedID 7983548
PHYSIOLOGICAL-PROPERTIES OF VESTIBULAR PRIMARY AFFERENTS THAT MEDIATE MOTOR LEARNING AND NORMAL PERFORMANCE OF THE VESTIBULOOCULAR REFLEX IN MONKEYS JOURNAL OF NEUROSCIENCE BRONTESTEWART, H. M., Lisberger, S. G. 1994; 14 (3): 1290-1308
Abstract

We have used electrical stimulation of the vestibular apparatus to reveal parallels between the physiological responses of the vestibular afferents activated at different currents and the properties of the evoked eye movements before and after magnifying spectacles had been used to cause motor learning in the vestibulo-ocular reflex (VOR). Stimulation with the lowest currents caused little or no eye motion, but activated all the afferents with irregular spontaneous discharge, low sensitivities to head velocity, and highly phasic responses during rapid head turns. Stimulation with moderate currents caused substantial eye motion that was weakly affected by motor learning; these currents activated afferents with a wide range of physiological properties, including many that had intermediate discharge regularity, high sensitivity to head velocity, and clear phasic responses during rapid head turns. Stimulation at still higher currents caused still larger eye movements that were strongly altered by motor learning; these currents activated primarily afferents that had regular spontaneous discharge, lower sensitivities to head velocity, and tonic responses during rapid head turns. Stimulation at the highest currents did not cause any further increment in the amplitude of the evoked eye movement, but activated the afferents with the most regular spontaneous discharge and the lowest sensitivities to head velocity. The data imply that the VOR pathways receive substantial vestibular inputs from afferents with a middle range of thresholds for electrical stimulation. These afferents have a wide range of physiological properties, including a large group that shows substantial phasic responses during rapid head turns. The data also suggest that only a subset of these afferents, primarily those with more regular spontaneous discharge, project into the VOR pathways that are modified in association with motor learning.

View details for Web of Science ID A1994MZ40500030

View details for PubMedID 8120625
EXPRESSION OF MOTOR LEARNING IN THE RESPONSE OF THE PRIMATE VESTIBULOOCULAR REFLEX PATHWAY TO ELECTRICAL-STIMULATION JOURNAL OF NEUROPHYSIOLOGY Broussard, D. M., BRONTESTEWART, H. M., Lisberger, S. G. 1992; 67 (6): 1493-1508
Abstract

1. The vestibuloocular reflex (VOR) undergoes long-term adaptive changes in the presence of persistent retinal image motion during head turns. Previous experiments using natural stimuli have provided evidence that the VOR is subserved by parallel pathways, including some that are modified during learning and some that are not. We have used electrical stimulation of the vestibular labyrinth to investigate the temporal properties of the signals that are transmitted through the modified pathways. 2. Electrodes were implanted chronically in the superior semi-circular canal, the horizontal canal, or the vestibule for electrical activation of the vestibular afferents. Learning was induced by fitting the monkeys with spectacles that magnified or miniaturized vision. Before, during, and after motor learning, we measured the eye movements evoked by electrical stimulation of the labyrinth as well as the gain of the VOR, defined as eye speed divided by head speed during natural vestibular stimulation in the dark. 3. Trains of pulses applied to the labyrinth caused the eyes to move away from the side of stimulation with an initial rapid change in eye velocity followed by a steady-state plateau. Changes in the gain of the VOR caused large changes in the trajectory and magnitude of eye velocity during the plateau, showing that our stimulating electrodes had access to the modified pathways. 4. A single, brief current pulse applied to the labyrinth evoked an eye movement that had a latency of 5 ms and consisted of a pulse of eye velocity away from the side of the stimulation followed by a rebound toward the side of stimulation. To quantify the effect of motor learning on these eye movements, we pooled the data across different VOR gains and computed the slope of the relationship between eye velocity and VOR gain at each millisecond after the stimulus. We refer to the slope as the "modification index." 5. In comparison with the evoked eye velocity, the modification index took longer to return to baseline and showed a large peak at the time of the rebound in eye velocity. Increases in stimulus current increased both the amplitude and the duration of the modification index and revealed several later peaks. These observations suggest that the full expression of motor learning requires activation of multisynaptic pathways and recruitment of primary vestibular afferents with higher thresholds for electrical stimulation. 6. The modification index was almost always positive during the initial deflection in eye velocity, and the latency of the first change in the modification index was usually the same as the latency of the evoked eye movement.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1992HZ90100007

View details for PubMedID 1629760
PROPERTIES OF PATHWAYS THAT MEDIATE MOTOR LEARNING IN THE VESTIBULOOCULAR REFLEX OF MONKEYS SYMP ON THE BRAIN Lisberger, S. G., Broussard, D. M., BRONTESTEWART, H. M. COLD SPRING HARBOR LABORATORY PRESS. 1990: 813?822
View details for Web of Science ID A1990BT68K00074
PROPERTIES OF PATHWAYS THAT MEDIATE MOTOR LEARNING IN THE VESTIBULOOCULAR REFLEX OF MONKEYS COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY Lisberger, S. G., Broussard, D. M., BRONTESTEWART, H. M. 1990; 55: 813-822
View details for Web of Science ID A1990HB91800075

View details for PubMedID 2132858
LACUNAR INFARCTION OF THE BASAL GANGLIA AS A COMPLICATION OF HEMOLYTIC-UREMIC SYNDROME - MRI AND CLINICAL CORRELATIONS CLINICAL PEDIATRICS DiMario, F. J., BRONTESTEWART, H., Sherbotie, J., Turner, M. E. 1987; 26 (11): 586-590
Abstract

Central nervous system (CNS) complications of hemolytic-uremic syndrome (HUS) commonly consist of alterations in mental status, seizures, and rarely hemiparesis. The authors report the clinical evolution of left hemiparesis and later choreo-athetoid movements in a patient who sustained a right lacunar infarction as a complication of HUS. The infarction is demonstrated on magnetic resonance imaging (MRI).

View details for Web of Science ID A1987K862000006

View details for PubMedID 3665330

Helen�Bronte-Stewart, MD, MS

John E. Cahill Family Professor, Professor of Neurology and, by courtesy, of Neurosurgery at the Stanford University Medical Center

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