Featured Articles

Hope vs. Hype: Closed loop technology will provide more meaningful improvement vs. directional leads in deep brain stimulation

In this paper, Helen Bronte-Stewart, MD MSE, provides a scientific argument on the advantages of closed-loop deep brain stimulation (DBS) technology over current open-loop systems. Drawing a comparison to cardiac pacemakers, she highlights the limited capabilities of open-loop neurostimulators in sensing and responding to specific symptoms, activity states, and medication levels. In contrast, closed-loop DBS relies on relevant neural or behavioral inputs, such as local field potentials (LFPs), to guide electrode selection, predict outcomes, and identify neuronal oscillation disorders (oscillopathies) associated with movement disorders. We emphasize the relevance of beta oscillopathy in Parkinson's disease and other conditions, showing its bilateral presence in the sensorimotor network, its correlation with disease progression and severity, and its attenuation by both DBS and dopaminergic medication. Furthermore, the author discusses the potential of closed-loop DBS to adapt to medication changes, respond to tremor dynamics, and achieve efficient and superior outcomes compared to open-loop DBS. The evidence presented supports the view that closed-loop DBS technology can address the unmet needs of current open-loop systems. In contrast, Aristide Merola, MD, PhD,  emphasizes the importance of directional DBS leads. The author argues that programming DBS requires detailed anatomical information, best provided by small directional electrodes. Given the small size of DBS targets, such as the subthalamic nucleus (STN), accurate stimulation is crucial to avoid side effects. Directional DBS has improved stimulation accuracy and minimized side effects by modulating the volume of tissue activated (VTA) based on individual anatomy. The author discusses the potential of advanced imaging techniques, such as probabilistic tractography, to identify subregions of interest within the target and modulate specific brain networks without interfering with others. The author contends that directionality in DBS offers greater anatomical precision, modulation of specific brain networks, and clinical efficacy compared to closed-loop approaches.


Bradykinesia and Its Progression Are Related to Interhemispheric Beta Coherence

Bradykinesia is the major cardinal motor sign of Parkinson disease (PD), but its neural underpinnings are unclear. The goal of this study was to examine whether changes in bradykinesia following long-term subthalamic nucleus (STN) deep brain stimulation (DBS) are linked to local STN beta (13–30 Hz) dynamics or a wider bilateral network dysfunction. Higher interhemispheric STN beta coherence, but not contralateral beta power or burst duration, was significantly associated with worse bradykinesia. Bradykinesia worsened off therapy over time. Interhemispheric STN-STN beta coherence also increased over time, whereas beta power and burst duration remained stable. The observed change in bradykinesia was related to the change in interhemispheric beta coherence, with greater increases in synchrony associated with further worsening of bradykinesia. Together, these findings implicate interhemispheric beta synchrony as a neural correlate of the progression of bradykinesia following chronic STN DBS. This could imply the existence of a pathological bilateral network contributing to bradykinesia in PD.


Quantitative Digitography Measures Motor Symptoms and Disease Progression in Parkinson's Disease

Our objective was to investigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD. QDG-RAFT metrics showed differences between PD and controls and provided correlated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment, and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy and showed differences between akinetic-rigid and tremor-dominant phenotypes, as well as people with and without FOG. QDG is a reliable technology, which could be used in the clinic or remotely. This could improve access to care, allow complex remote disease management based on data received in real time, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive motor metrics needed for therapeutic trials


Perspective: Evolution of Control Variables and Policies for Closed-Loop Deep Brain Stimulation for Parkinson’s Disease Using Bidirectional Deep-Brain-Computer Interfaces

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.


Modulation of beta bursts in subthalamic sensorimotor circuits predicts improvement in bradykinesia.  

Clinicians must adjust deep brain stimulation (DBS) parameters for people with Parkinson’s disease based on time-intensive, empirical, and subjective assessments of motor behavior, which presents a critical unmet need for a biomarker that would enable more precise, personalized adjustments of DBS using real-time biomarker feedback in freely moving individuals. The results of this study solve this unmet need by demonstrating for the first time the interdependence of precise location of neuromodulation of sensorimotor networks, optimal restoration of neural signaling and improvement in movement during high frequency subthalamic nucleus (STN) DBS. These results provide valuable insight into the mechanism of STN DBS in Parkinson’s disease in that STN DBS-related improvements in movement are related to the reduction in the beta oscillopathy within the sensorimotor STN. With the advent of commercially available sensing neurostimulators such as the Medtronic Percept PC™ system, these results demonstrate the feasibility and provide the necessary basis for physicians to track patient-specific beta oscillopathies combined with lead locations as a biomarker to adjust clinical neurostimulator settings. Additionally, the development of next generation sensing neurostimulators such as the Summit RC+S™ now allows for the implementation of control policy algorithms based around movement band burst duration driven closed-loop DBS in freely moving people with Parkinson’s disease.

This paper was awarded the Golden Electrode Award of 2020 by the Lead-DBS toolbox.

A brief video summary of the paper can be found on YouTube.


Publications

John E. Cahill Family Professor, Professor of Neurology (Adult Neurology) and, by courtesy, of Neurosurgery

Publications

  • Quantitative DigitoGraphy: a Comprehensive Real-Time Remote Monitoring System for Parkinson's Disease. Research square Hoffman, S. L., Schmiedmayer, P., Gala, A. S., Wilkins, K. B., Parisi, L., Karjagi, S., Negi, A. S., Revlock, S., Coriz, C., Revlock, J., Ravi, V., Bronte-Stewart, H. 2024

    Abstract

    People with Parkinson's disease (PWP) face critical challenges, including lack of access to neurological care, inadequate measurement and communication of motor symptoms, and suboptimal medication management and compliance. We have developed QDG-Care: a comprehensive connected care platform for Parkinson's disease (PD) that delivers validated, quantitative metrics of all motor signs in PD in real time, monitors the effects of adjusting therapy and medication adherence and is accessible in the electronic health record. In this article, we describe the design and engineering of all components of QDG-Care, including the development and utility of the QDG Mobility and Tremor Severity Scores. We present the preliminary results and insights from the first at-home trial using QDG-Care. QDG technology has enormous potential to improve access to, equity of, and quality of care for PWP, and improve compliance with complex time-critical medication regimens. It will enable rapid "Go-NoGo" decisions for new therapeutics by providing high-resolution data that require fewer participants at lower cost and allow more diverse recruitment.

    View details for DOI 10.21203/rs.3.rs-3783294/v1

    View details for PubMedID 38343821

    View details for PubMedCentralID PMC10854288

  • Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements. Frontiers in human neuroscience Johnson, K. A., Dosenbach, N. U., Gordon, E. M., Welle, C. G., Wilkins, K. B., Bronte-Stewart, H. M., Voon, V., Morishita, T., Sakai, Y., Merner, A. R., Lazaro-Munoz, G., Williamson, T., Horn, A., Gilron, R., O'Keeffe, J., Gittis, A. H., Neumann, W., Little, S., Provenza, N. R., Sheth, S. A., Fasano, A., Holt-Becker, A. B., Raike, R. S., Moore, L., Pathak, Y. J., Greene, D., Marceglia, S., Krinke, L., Tan, H., Bergman, H., Potter-Nerger, M., Sun, B., Cabrera, L. Y., McIntyre, C. C., Harel, N., Mayberg, H. S., Krystal, A. D., Pouratian, N., Starr, P. A., Foote, K. D., Okun, M. S., Wong, J. K. 2024; 18: 1320806

    Abstract

    The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

    View details for DOI 10.3389/fnhum.2024.1320806

    View details for PubMedID 38450221

  • Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. Nature medicine Schiff, N. D., Giacino, J. T., Butson, C. R., Choi, E. Y., Baker, J. L., O'Sullivan, K. P., Janson, A. P., Bergin, M., Bronte-Stewart, H. M., Chua, J., DeGeorge, L., Dikmen, S., Fogarty, A., Gerber, L. M., Krel, M., Maldonado, J., Radovan, M., Shah, S. A., Su, J., Temkin, N., Tourdias, T., Victor, J. D., Waters, A., Kolakowsky-Hayner, S. A., Fins, J. J., Machado, A. G., Rutt, B. K., Henderson, J. M. 2023

    Abstract

    Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 .

    View details for DOI 10.1038/s41591-023-02638-4

    View details for PubMedID 38049620

    View details for PubMedCentralID 8126422

  • The digital signature of emergent tremor in Parkinson's disease. Research square Bronte-Stewart, H., Gala, A., Wilkins, K., Pettruci, M., Kehnemouyi, Y., Velisar, A., Trager, M. 2023

    Abstract

    Background: Emergent tremor in Parkinson's disease (PD) can occur during sustained postures or movement that is different from action tremor. Tremor can contaminate the clinical rating of bradykinesia during finger tapping. Currently, there is no reliable way of isolating emergent tremor and measuring the cardinal motor symptoms based on voluntary movements only.Objective: Investigate whether emergent tremor during repetitive alternating finger tapping (RAFT) on a quantitative digitography (QDG) device can be reliably identified and distinguished from voluntary tapping.Methods: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and the Movement Disorders Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III). Visual identification of tremor during QDG-RAFT was labelled by an experienced movement disorders specialist. Two methods of identifying tremor were investigated: 1) physiologically-informed temporal thresholds 2) XGBoost model using temporal and amplitude features of tapping.Results: The XGBoost model showed high accuracy for identifying tremor (area under the precision-recall curve of 0.981) and outperformed temporal-based thresholds. Percent time duration of classifier-identified tremor showed significant correlations with MDS-UPDRS III tremor subscores (r = 0.50, P < 0.0001). There was a significant change in QDG metrics for bradykinesia, rigidity and arrhythmicity after tremor strikes were excluded (p < 0.01).Conclusions: Emergent tremor during QDG-RAFT has a unique digital signature and the duration of tremor correlated with the MDS-UPDRS III tremor items. When involuntary tremor strikes were excluded, the QDG metrics of bradykinesia and rigidity were significantly worse, demonstrating the importance of distinguishing tremor from voluntary movement when rating bradykinesia.

    View details for DOI 10.21203/rs.3.rs-3467667/v1

    View details for PubMedID 37961117

  • An Individualized Tractography Pipeline for the Nucleus Basalis of Meynert Lateral Tract. medRxiv : the preprint server for health sciences Crockett, R. A., Wilkins, K. B., Zeineh, M. M., McNab, J. A., Henderson, J. M., Buch, V. P., Brontë-Stewart, H. M. 2023

    Abstract

    At the center of the cortical cholinergic network, the nucleus basalis of Meynert (NBM) is crucial for the cognitive domains most vulnerable in PD. Preclinical evidence has demonstrated the positive impact of NBM deep brain stimulation (DBS) on cognition but early human trials have had mixed results. It is possible that DBS of the lateral NBM efferent white matter fiber bundle may be more effective at improving cognitive-motor function. However, precise tractography modelling is required to identify the optimal target for neurosurgical planning. Individualized tractography approaches have been shown to be highly effective for accurately identifying DBS targets but have yet to be developed for the NBM.Using structural and diffusion weighted imaging, we developed a tractography pipeline for precise individualized identification of the lateral NBM target tract. Using dice similarity coefficients, the reliability of the tractography outputs was assessed across three cohorts to investigate: 1) whether this manual pipeline is more reliable than an existing automated pipeline currently used in the literature; 2) the inter- and intra-rater reliability of our pipeline in research scans of patients with PD; and 3) the reliability and practicality of this pipeline in clinical scans of DBS patients.The individualized manual pipeline was found to be significantly more reliable than the existing automated pipeline for both the segmentation of the NBM region itself (p<0.001) and the reconstruction of the target lateral tract (p=0.002). There was also no significant difference between the reliability of two different raters in the PD cohort (p=0.25), which showed high inter- (mean Dice coefficient >0.6) and intra-rater (mean Dice coefficient >0.7) reliability across runs. Finally, the pipeline was shown to be highly reliable within the clinical scans (mean Dice coefficient = 0.77). However, accurate reconstruction was only evident in 7/10 tracts.We have developed a reliable tractography pipeline for the identification and analysis of the NBM lateral tract in research and clinical grade imaging of healthy young adult and PD patient scans.

    View details for DOI 10.1101/2023.08.31.23294922

    View details for PubMedID 37693520

    View details for PubMedCentralID PMC10491381

  • The Effect of Deep Brain Stimulation on the Sequence Effect in Speech in Parkinson's Disease Je, G., Wilkins, K. B., Melbourne, J. A., Bronte-Stewart, H. M. WILEY. 2023: S185
  • Transcutaneous Afferent Patterned Stimulation for Essential Tremor: Real-World Evidence with Long Term Follow-Up. Tremor and other hyperkinetic movements (New York, N.Y.) Lu, C., Khosla, D., Kent, A., Bronte-Stewart, H. M., Rosenbluth, K. H. 2023; 13: 29

    Abstract

    Transcutaneous afferent patterned stimulation (TAPS) is a non-invasive neuromodulation therapy for the treatment of hand tremor in patients with essential tremor (ET). This retrospective post-market analysis evaluated the usage, effectiveness, and safety of TAPS in patients using TAPS beyond a 90-day trial period in a real-world setting.Study personnel screened a manufacturer's database for TAPS devices that had been prescribed for the treatment of ET and used beyond a 90-day trial period between August 2019 and January 2023. The device logs were collected to extract the therapy usage, accelerometry measurements, and on-board ratings of tremor improvement. Study personnel also evaluated results of a voluntary survey requested by the manufacturer after the 90-day trial period. Adverse events were assessed from patients' complaints reported to the manufacturer.A total of 1,223 patients in the manufacturer's database met the study criteria. The patients had used therapy between 90 and 1,233 days, with average usage of 5.6 sessions per week. Accelerometry data indicated 89% of patients experienced tremor improvement, with an average 64% improvement. 63% of patients rated at least half of their sessions as improved. No significant habituation was observed in patients who used therapy for more than one year. Approximately 62% of survey respondents either had reduced medication or planned to consult physicians about their medication usage. No serious safety events were reported, and 10% of patients reported minor safety complaints.The analysis demonstrates the real-world effectiveness and safety of TAPS beyond a 90-day trial period over a longer timeframe and in a larger population size than previously published evidence.

    View details for DOI 10.5334/tohm.775

    View details for PubMedID 37663529

    View details for PubMedCentralID PMC10473165

  • No laughing white matter: Reduced integrity of the cortical cholinergic pathways in Parkinson's disease-related cognitive impairment. Neurobiology of disease Crockett, R. A., Wilkins, K. B., Aditham, S., Brontë-Stewart, H. M. 2023: 106243

    Abstract

    Approximately one third of recently diagnosed Parkinson's disease (PD) patients experience cognitive decline. The nucleus basalis of Meynert (NBM) degenerates early in PD and is crucial for cognitive function. The two main NBM white matter pathways include a lateral and medial trajectory. However, research is needed to determine which pathway, if any, are associated with PD-related cognitive decline.Thirty-seven PD patients with no mild cognitive impairment (MCI) were included in this study. Participants either developed MCI at 1-year follow up (PD MCI-Converters; n = 16) or did not (PD no-MCI; n = 21). Mean diffusivity (MD) of the medial and lateral NBM tracts were extracted using probabilistic tractography. Between-group differences in MD for each tract was compared using ANCOVA, controlling for age, sex, and disease duration. Control comparisons of the internal capsule MD were also performed. Associations between baseline MD and cognitive outcomes (working memory, psychomotor speed, delayed recall, and visuospatial function) were assessed using linear mixed models.PD MCI-Converters had significantly greater MD and lower FA (p < .001) of both NBM tracts compared to PD no-MCI. No difference was found in the MD (p = .06) or FA (p = .31) of the control region. Trends were identified between: 1) lateral tract MD and FA with working memory decline; and 2) medial tract MD and reduced psychomotor speed.Reduced integrity of the NBM tracts is evident in PD patients up to one year prior to the development of MCI. Thus, deterioration of the NBM tracts in PD may be an early marker of those at risk of cognitive decline.

    View details for DOI 10.1016/j.nbd.2023.106243

    View details for PubMedID 37524210

  • Kinematic adaptive deep brain stimulation for gait impairment and freezing of gait in Parkinson's disease. Brain stimulation Melbourne, J. A., Kehnemouyi, Y. M., O'Day, J. J., Wilkins, K. B., Gala, A. S., Petrucci, M. N., Lambert, E. F., Dorris, H., Diep, C., Herron, J. A., Bronte-Stewart, H. M. 2023

    View details for DOI 10.1016/j.brs.2023.07.003

    View details for PubMedID 37429355

  • Hope vs. Hype: Closed loop technology will provide more meaningful improvement vs. directional leads in deep brain stimulation. Parkinsonism & related disorders Bronte-Stewart, H., Merola, A. 2023: 105452

    View details for DOI 10.1016/j.parkreldis.2023.105452

    View details for PubMedID 37355400

  • No Laughing White Matter: Cortical Cholinergic Pathways and Cognitive Decline in Parkinson's Disease. medRxiv : the preprint server for health sciences Crockett, R. A., Wilkins, K. B., Aditham, S., Brontë-Stewart, H. M. 2023

    Abstract

    Approximately one third of recently diagnosed Parkinson's disease (PD) patients experience cognitive decline. The nucleus basalis of Meynert (NBM) degenerates early in PD and is crucial for cognitive function. The two main NBM white matter pathways include a lateral and medial trajectory. However, research is needed to determine which pathway, if any, are associated with PD-related cognitive decline.Thirty-seven PD patients with no mild cognitive impairment (MCI) were included in this study. Participants either developed MCI at 1-year follow up (PD MCI-Converters; n=16) or did not (PD no-MCI; n=21). Mean diffusivity (MD) of the medial and lateral NBM tracts were extracted using probabilistic tractography. Between-group differences in MD for each tract was compared using ANCOVA, controlling for age, sex, and disease duration. Control comparisons of the internal capsule MD were also performed. Associations between baseline MD and cognitive outcomes (working memory, psychomotor speed, delayed recall, and visuospatial function) were assessed using linear mixed models.PD MCI-Converters had significantly greater MD of both NBM tracts compared to PD no-MCI (p<.001). No difference was found in the control region (p=.06). Trends were identified between: 1) lateral tract MD, poorer visuospatial performance (p=.05) and working memory decline (p=.04); and 2) medial tract MD and reduced psychomotor speed (p=.03).Reduced integrity of the NBM tracts is evident in PD patients up to one year prior to the development of MCI. Thus, deterioration of the NBM tracts in PD may be an early marker of those at risk of cognitive decline.

    View details for DOI 10.1101/2023.05.01.23289348

    View details for PubMedID 37205443

    View details for PubMedCentralID PMC10187344

  • Adaptive DBS Algorithm for Personalized Therapy in Parkinson's Disease: ADAPT-PD clinical trial methodology and early data Bronte-Stewart, H., Beudel, M., Ostrem, J. L., Fasano, A., Almeida, L., Hassell, T., Moro, E., Gostkowski, M., Mitchell, K. T., Hainque, E., Sarangmat, N., Stanslaski, S., Tonder, L., Summers, R., Raike, R. S., Herrington, T. M. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • The Sequence Effect Worsens Over Time in Parkinson's Disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation. Journal of Parkinson's disease Kehnemouyi, Y. M., Petrucci, M. N., Wilkins, K. B., Melbourne, J. A., Bronte-Stewart, H. M. 2023

    Abstract

    The sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects, or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open-loop deep brain stimulation in people with Parkinson's disease (PD).To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) deep brain stimulation (DBS).Twenty-one people with PD with bilateral subthalamic nucleus (STN) DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS.The sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and closed-loop DBS.Sequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and upon further investigation closed-loop DBS may offer added improvement.

    View details for DOI 10.3233/JPD-223368

    View details for PubMedID 37125563

  • Episodic memory deficit in HIV infection: common phenotype with Parkinson's disease, different neural substrates. Brain structure & function Fama, R., Müller-Oehring, E. M., Levine, T. F., Sullivan, E. V., Sassoon, S. A., Asok, P., Brontë-Stewart, H. M., Poston, K. L., Pohl, K. M., Pfefferbaum, A., Schulte, T. 2023

    Abstract

    Episodic memory deficits occur in people living with HIV (PLWH) and individuals with Parkinson's disease (PD). Given known effects of HIV and PD on frontolimbic systems, episodic memory deficits are often attributed to executive dysfunction. Although executive dysfunction, evidenced as retrieval deficits, is relevant to mnemonic deficits, learning deficits may also contribute. Here, the California Verbal Learning Test-II, administered to 42 PLWH, 41 PD participants, and 37 controls, assessed learning and retrieval using measures of free recall, cued recall, and recognition. Executive function was assessed with a composite score comprising Stroop Color-Word Reading and Backward Digit Spans. Neurostructural correlates were examined with MRI of frontal (precentral, superior, orbital, middle, inferior, supplemental motor, medial) and limbic (hippocampus, thalamus) volumes. HIV and PD groups were impaired relative to controls on learning and free and cued recall trials but did not differ on recognition or retention of learned material. In no case did executive functioning solely account for the observed mnemonic deficits or brain-performance relations. Critically, the shared learning and retrieval deficits in HIV and PD were related to different substrates of frontolimbic mnemonic neurocircuitry. Specifically, diminished learning and poorer free and cued recall were related to smaller orbitofrontal volume in PLWH but not PD, whereas diminished learning in PD but not PLWH was related to smaller frontal superior volume. In PD, poorer recognition correlated with smaller thalamic volume and poorer retention to hippocampal volume. Although memory deficits were similar, the neural correlates in HIV and PD suggest different pathogenic mechanisms.

    View details for DOI 10.1007/s00429-023-02626-x

    View details for PubMedID 37069296

    View details for PubMedCentralID 9804536

  • Bradykinesia and its progression are related to inter-hemispheric beta coherence. Annals of neurology Wilkins, K. B., Kehnemouyi, Y. M., Petrucci, M. N., Anderson, R. W., Parker, J. E., Trager, M. H., Neuville, R. S., Koop, M. M., Velisar, A., Blumenfeld, Z., Quinn, E. J., Bronte-Stewart, H. M. 2023

    Abstract

    OBJECTIVE: Bradykinesia is the major cardinal motor sign of Parkinson's disease (PD), but its neural underpinnings are unclear. The goal of this study was to examine whether changes in bradykinesia following long-term subthalamic nucleus (STN) deep brain stimulation (DBS) are linked to local STN beta (13-30 Hz) dynamics or a wider bilateral network dysfunction.METHODS: Twenty-one individuals with Parkinson's disease implanted with sensing neurostimulators (Activa PC+S, Medtronic, PLC) in the STN participated in a longitudinal 'washout' therapy study every three to six months for an average of three years. At each visit, participants were withdrawn from medication (12/24/48 hours) and had DBS turned off (>60 minutes) before completing a repetitive wrist-flexion extension task, a validated quantitative assessment of bradykinesia, while local field potentials were recorded. Local STN beta dynamics were investigated via beta power and burst duration, while interhemispheric beta synchrony was assessed with STN-STN beta coherence.RESULTS: Higher interhemispheric STN beta coherence, but not contralateral beta power or burst duration, was significantly associated with worse bradykinesia. Bradykinesia worsened off therapy over time. Interhemispheric STN-STN beta coherence also increased over time, whereas beta power and burst duration remained stable. The observed change in bradykinesia was related to the change in interhemispheric beta coherence, with greater increases in synchrony associated with further worsening of bradykinesia.INTERPRETATION: Together, these findings implicate interhemispheric beta synchrony as a neural correlate of the progression of bradykinesia following chronic STN DBS. This could imply the existence of a pathological bilateral network contributing to bradykinesia in PD. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26605

    View details for PubMedID 36641645

  • Unraveling the complexities of programming neural adaptive deep brain stimulation in Parkinson's disease. Frontiers in human neuroscience Wilkins, K. B., Melbourne, J. A., Akella, P., Bronte-Stewart, H. M. 2023; 17: 1310393

    Abstract

    Over the past three decades, deep brain stimulation (DBS) for Parkinson's disease (PD) has been applied in a continuous open loop fashion, unresponsive to changes in a given patient's state or symptoms over the course of a day. Advances in recent neurostimulator technology enable the possibility for closed loop adaptive DBS (aDBS) for PD as a treatment option in the near future in which stimulation adjusts in a demand-based manner. Although aDBS offers great clinical potential for treatment of motor symptoms, it also brings with it the need for better understanding how to implement it in order to maximize its benefits. In this perspective, we outline considerations for programing several key parameters for aDBS based on our experience across several aDBS-capable research neurostimulators. At its core, aDBS hinges on successful identification of relevant biomarkers that can be measured reliably in real-time working in cohesion with a control policy that governs stimulation adaption. However, auxiliary parameters such as the window in which stimulation is allowed to adapt, as well as the rate it changes, can be just as impactful on performance and vary depending on the control policy and patient. A standardize protocol for programming aDBS will be crucial to ensuring its effective application in clinical practice.

    View details for DOI 10.3389/fnhum.2023.1310393

    View details for PubMedID 38094147

  • Quantitative Digitography Measures Motor Symptoms and Disease Progression in Parkinson's Disease. Journal of Parkinson's disease Wilkins, K. B., Petrucci, M. N., Kehnemouyi, Y., Velisar, A., Han, K., Orthlieb, G., Trager, M. H., O'Day, J. J., Aditham, S., Bronte-Stewart, H. 2022

    Abstract

    BACKGROUND: Assessment of motor signs in Parkinson's disease (PD) requires an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous monitoring for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.OBJECTIVE: Investigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD.METHODS: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.RESULTS: QDG-RAFT metrics showed differences between PD and controls and provided correlated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment, and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy and showed differences between akinetic-rigid and tremor-dominant phenotypes, as well as people with and without FOG.CONCLUSIONS: QDG is a reliable technology, which could be used in the clinic or remotely. This could improve access to care, allow complex remote disease management based on data received in real time, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive motor metrics needed for therapeutic trials.

    View details for DOI 10.3233/JPD-223264

    View details for PubMedID 35694934

  • Assessing inertial measurement unit locations for freezing of gait detection and patient preference. Journal of neuroengineering and rehabilitation O'Day, J., Lee, M., Seagers, K., Hoffman, S., Jih-Schiff, A., Kidzinski, L., Delp, S., Bronte-Stewart, H. 2022; 19 (1): 20

    Abstract

    BACKGROUND: Freezing of gait, a common symptom of Parkinson's disease, presents as sporadic episodes in which an individual's feet suddenly feel stuck to the ground. Inertial measurement units (IMUs) promise to enable at-home monitoring and personalization of therapy, but there is a lack of consensus on the number and location of IMUs for detecting freezing of gait. The purpose of this study was to assess IMU sets in the context of both freezing of gait detection performance and patient preference.METHODS: Sixteen people with Parkinson's disease were surveyed about sensor preferences. Raw IMU data from seven people with Parkinson's disease, wearing up to eleven sensors, were used to train convolutional neural networks to detect freezing of gait. Models trained with data from different sensor sets were assessed for technical performance; a best technical set and minimal IMU set were identified. Clinical utility was assessed by comparing model- and human-rater-determined percent time freezing and number of freezing events.RESULTS: The best technical set consisted of three IMUs (lumbar and both ankles, AUROC=0.83), all of which were rated highly wearable. The minimal IMU set consisted of a single ankle IMU (AUROC=0.80). Correlations between these models and human raters were good to excellent for percent time freezing (ICC=0.93, 0.89) and number of freezing events (ICC=0.95, 0.86) for the best technical set and minimal IMU set, respectively.CONCLUSIONS: Several IMU sets consisting of three IMUs or fewer were highly rated for both technical performance and wearability, and more IMUs did not necessarily perform better in FOG detection. We openly share our data and software to further the development and adoption of a general, open-source model that uses raw signals and a standard sensor set for at-home monitoring of freezing of gait.

    View details for DOI 10.1186/s12984-022-00992-x

    View details for PubMedID 35152881

  • Concurrent stimulation and sensing in bi-directional brain interfaces: a multi-site translational experience. Journal of neural engineering Ansó, J., Benjaber, M., Parks, B., Parker, S., Oehrn, C. R., Petrucci, M., Gilron, R., Little, S., Wilt, R., Bronte-Stewart, H., Gunduz, A., Borton, D., Starr, P. A., Denison, T. J. 2022

    Abstract

    To provide a design analysis and guidance framework for the implementation of concurrent stimulation and sensing during adaptive deep brain stimulation (aDBS) with particular emphasis on artifact mitigations.We defined a general architecture of feedback-enabled devices, identified key components in the signal chain which might result in unwanted artifacts and proposed methods that might ultimately enable improved aDBS therapies. We gathered data from research subjects chronically-implanted with an investigational aDBS system, Summit RC+S, to characterize and explore artifact mitigations arising from concurrent stimulation and sensing. We then used a prototype investigational implantable device, DyNeuMo, and a bench-setup that accounts for tissue-electrode properties, to confirm our observations and verify mitigations. The strategies to reduce transient stimulation artifacts and improve performance during aDBS were confirmed in a chronic implant using updated configuration settings.We derived and validated a "checklist" of configuration settings to improve system performance and areas for future device improvement. Key considerations for the configuration include 1) active instead of passive recharge, 2) sense-channel blanking in the amplifier, 3) high-pass filter settings, 4) tissue-electrode impedance mismatch management, 5) time-frequency trade-offs in the classifier, 6) algorithm blanking and transition rate limits. Without proper channel configuration, the aDBS algorithm was susceptible to limit-cycles of oscillating stimulation independent of physiological state. By applying the checklist, we could optimize each block's performance characteristics within the overall system. With system-level optimization, a 'fast' aDBS prototype algorithm was demonstrated to be feasible without reentrant loops, and with noise performance suitable for subcortical brain circuits.We present a framework to study sources and propose mitigations of artifacts in devices that provide chronic aDBS. This work highlights the trade-offs in performance as novel sensing devices translate to the clinic. Finding the appropriate balance of constraints is imperative for successful translation of aDBS therapies.

    View details for DOI 10.1088/1741-2552/ac59a3

    View details for PubMedID 35234664

  • Proceedings of the 10th annual deep brain stimulation think tank: Advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation. Frontiers in human neuroscience Wong, J. K., Mayberg, H. S., Wang, D. D., Richardson, R. M., Halpern, C. H., Krinke, L., Arlotti, M., Rossi, L., Priori, A., Marceglia, S., Gilron, R., Cavanagh, J. F., Judy, J. W., Miocinovic, S., Devergnas, A. D., Sillitoe, R. V., Cernera, S., Oehrn, C. R., Gunduz, A., Goodman, W. K., Petersen, E. A., Bronte-Stewart, H., Raike, R. S., Malekmohammadi, M., Greene, D., Heiden, P., Tan, H., Volkmann, J., Voon, V., Li, L., Sah, P., Coyne, T., Silburn, P. A., Kubu, C. S., Wexler, A., Chandler, J., Provenza, N. R., Heilbronner, S. R., Luciano, M. S., Rozell, C. J., Fox, M. D., de Hemptinne, C., Henderson, J. M., Sheth, S. A., Okun, M. S. 2022; 16: 1084782

    Abstract

    The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

    View details for DOI 10.3389/fnhum.2022.1084782

    View details for PubMedID 36819295

  • Neurofunctional characteristics of executive control in older people with HIV infection: a comparison with Parkinson's disease. Brain imaging and behavior Müller-Oehring, E. M., Hong, J. Y., Poston, K. L., Brontë-Stewart, H. M., Sullivan, E. V., McGlynn, L., Schulte, T. 2022

    Abstract

    Expression of executive dysfunctions is marked by substantial heterogeneity in people living with HIV infection (PLWH) and attributed to neuropathological degradation of frontostriatal circuitry with age and disease. We compared the neurophysiology of executive function in older PLWH and Parkinson's disease (PD), both affecting frontostriatal systems. Thirty-one older PLWH, 35 individuals with PD, and 28 older healthy controls underwent executive task-activated fMRI, neuropsychological testing, and a clinical motor exam. fMRI task conditions distinguished cognitive control operations, invoking a lateral frontoparietal network, and motor control operations, activating a cerebellar-precentral-medial prefrontal network. HIV-specific findings denoted a prominent sensorimotor hypoactivation during cognitive control and striatal hypoactivation during motor control related to CD4+ T cell count and HIV disease duration. Activation deficits overlapped for PLWH and PD, relative to controls, in dorsolateral frontal, medial frontal, and middle cingulate cortices for cognitive control, and in limbic, frontal, parietal, and cerebellar regions for motor control. Thus, despite well-controlled HIV infection, frontostriatal and sensorimotor activation deficits occurred during executive control in older PLWH. Overlapping activation deficits in posterior cingulate and hippocampal regions point toward similarities in mesocorticolimbic system aberrations among older PLWH and PD. The extent of pathophysiology in PLWH was associated with variations in immune system health, neural signature consistent with subclinical parkinsonism, and mild neurocognitive impairment. The failure to adequately engage these pathways could be an early sign for cognitive and motor functional decline in the aging population of PLWH.

    View details for DOI 10.1007/s11682-022-00645-6

    View details for PubMedID 35294979

  • Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury. Frontiers in human neuroscience Wong, J. K., Deuschl, G., Wolke, R., Bergman, H., Muthuraman, M., Groppa, S., Sheth, S. A., Bronte-Stewart, H. M., Wilkins, K. B., Petrucci, M. N., Lambert, E., Kehnemouyi, Y., Starr, P. A., Little, S., Anso, J., Gilron, R., Poree, L., Kalamangalam, G. P., Worrell, G. A., Miller, K. J., Schiff, N. D., Butson, C. R., Henderson, J. M., Judy, J. W., Ramirez-Zamora, A., Foote, K. D., Silburn, P. A., Li, L., Oyama, G., Kamo, H., Sekimoto, S., Hattori, N., Giordano, J. J., DiEuliis, D., Shook, J. R., Doughtery, D. D., Widge, A. S., Mayberg, H. S., Cha, J., Choi, K., Heisig, S., Obatusin, M., Opri, E., Kaufman, S. B., Shirvalkar, P., Rozell, C. J., Alagapan, S., Raike, R. S., Bokil, H., Green, D., Okun, M. S. 2022; 16: 813387

    Abstract

    DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

    View details for DOI 10.3389/fnhum.2022.813387

    View details for PubMedID 35308605

  • Lack of progression of beta dynamics after long-term subthalamic neurostimulation. Annals of clinical and translational neurology Anderson, R. W., Wilkins, K. B., Parker, J. E., Petrucci, M. N., Kehnemouyi, Y., Neuville, R. S., Cassini, D., Trager, M. H., Koop, M. M., Velisar, A., Blumenfeld, Z., Quinn, E. J., Henderson, J., Bronte-Stewart, H. M. 2021

    Abstract

    OBJECTIVE: To investigate the progression of neural and motor features of Parkinson's disease in a longitudinal study, after washout of medication and bilateral subthalamic nucleus deep brain stimulation (STN DBS).METHODS: Participants with clinically established Parkinson's disease underwent bilateral implantation of DBS leads (18 participants, 13 male) within the STN using standard functional frameless stereotactic technique and multi-pass microelectrode recording. Both DBS leads were connected to an implanted investigative sensing neurostimulator (Activa PC+S, Medtronic, PLC). Resting state STN local field potentials (LFPs) were recorded and motor disability, (the Movement Disorder Society-Unified Parkinson's Disease Rating Scale - motor subscale, MDS-UPDRS III) was assessed off therapy at initial programming, and after 6months, 1year, and yearly out to 5years of treatment. The primary endpoint was measured at 3years. At each visit, medication had been held for over 12/24h and DBS was turned off for at least 60min, by which time LFP spectra reached a steady state.RESULTS: After 3years of chronic DBS, there were no increases in STN beta band dynamics (p=0.98) but there were increases in alpha band dynamics (p=0.0027, 25 STNs). Similar results were observed in a smaller cohort out to 5years. There was no increase in the MDS-UPDRS III score.INTERPRETATION: These findings provide evidence that the beta oscillopathy does not substantially progress following combined STN DBS plus medication in moderate to advanced Parkinson's disease.

    View details for DOI 10.1002/acn3.51463

    View details for PubMedID 34636182

  • The effects of mood and cognition on daily functioning and quality of life in older people living with HIV and people with Parkinson's disease. Neuropsychology Patel, S. S., Muller-Oehring, E. M., DeVaughn, S., Fama, R., Bronte-Stewart, H. M., Poston, K. L., Schulte, T. 2021

    Abstract

    OBJECTIVE: In light of the increased longevity of people living with HIV infection (PLWH) undergoing antiretroviral therapy (ART), the present study aimed to determine the effects of mood disturbances alongside cognitive and motor symptoms on activities of daily living (ADLs) and quality of life (QOL) in older PLWH in comparison to an aging control sample without notable medical history (CTL) and individuals with Parkinson's disease (PD).METHOD: Forty-one PLWH, 41 individuals with PD, and 37 CTL, aged 45-79 years, underwent neuropsychological, psychological, and neurological assessment including depressive and anxiety symptoms, physical (ADL-p) and instrumental (ADL-i) daily activities, Unified Parkinson's Disease Rating Scale motor ADLs (ADL-UPDRS-II), QOL, and cognitive and motor functions. Hierarchical regression analyses assessed the relative contribution of predictors including demographics, disease-related factors, comorbid conditions, and mood-related factors for ADL and QOL scales.RESULTS: PLWH and PD participants reported more depressive symptoms and higher anxiety and worse QOL and ADL-i than CTL. The PD group had greater ADL-p and motor-related ADL-UPDRS-II difficulties than PLWH and CTL groups. In PLWH, medical comorbidities and alcohol use disorder (AUD)/substance use disorder (SUD) histories significantly contributed to poor physical and motor ADLs. Mood scores, particularly depressive symptoms, were independent predictors of poor QOL and most ADLs in both clinical groups, above the contribution of cognitive compromise.CONCLUSIONS: Mood symptoms contribute significantly to poor ADLs and QOL in people aging with chronic diseases such as long-term HIV infection and PD. Comprehensive assessment and treatment of mood symptoms are recommended for ensuring optimal functional independence and life quality. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

    View details for DOI 10.1037/neu0000760

    View details for PubMedID 34323563

  • Ramp Rate Evaluation and Configuration for Safe and Tolerable Closed-Loop Deep Brain Stimulation. International IEEE/EMBS Conference on Neural Engineering : [proceedings]. International IEEE EMBS Conference on Neural Engineering Petrucci, M. N., Wilkins, K. B., Orthlieb, G. C., Kehnemouyi, Y. M., O'Day, J. J., Herron, J. A., Bronte-Stewart, H. M. 2021; 2021: 959-962

    Abstract

    Closed-loop deep brain stimulation is a novel form of therapy that has shown benefit in preliminary studies and may be clinically available in the near future. Initial closed-loop studies have primarily focused on responding to sensed biomarkers with adjustments to stimulation amplitude, which is often perceptible to study participants depending on the slew or "ramp" rate of the amplitude changes. These subjective responses to stimulation ramping can result in transient side effects, illustrating that ramp rate is a unique safety parameter for closed-loop neural systems. This presents a challenge to the future of closed-loop neuromodulation systems: depending on the goal of the control policy, clinicians will need to balance ramp rates to avoid side effects and keep the stimulation therapeutic by responding in time to affect neural dynamics. In this paper, we demonstrate the results of an initial investigation into methodology for finding safe and tolerable ramp rates in four people with Parkinson's disease (PD). Results suggest that optimal ramp rates were found more accurately during varying stimulation when compared to simply toggling between maximal and minimal intensity levels. Additionally, switching frequency instantaneously was tolerable at therapeutic levels of stimulation. Future work should focus on including optimization techniques to find ramp rates.

    View details for DOI 10.1109/ner49283.2021.9441336

    View details for PubMedID 35574294

    View details for PubMedCentralID PMC9097241

  • Gait Parameters Measured from Wearable Sensors Reliably Detect Freezing of Gait in a Stepping in Place Task. Sensors (Basel, Switzerland) Diep, C., O'Day, J., Kehnemouyi, Y., Burnett, G., Bronte-Stewart, H. 2021; 21 (8)

    Abstract

    Freezing of gait (FOG), a debilitating symptom of Parkinson's disease (PD), can be safely studied using the stepping in place (SIP) task. However, clinical, visual identification of FOG during SIP is subjective and time consuming, and automatic FOG detection during SIP currently requires measuring the center of pressure on dual force plates. This study examines whether FOG elicited during SIP in 10 individuals with PD could be reliably detected using kinematic data measured from wearable inertial measurement unit sensors (IMUs). A general, logistic regression model (area under the curve = 0.81) determined that three gait parameters together were overall the most robust predictors of FOG during SIP: arrhythmicity, swing time coefficient of variation, and swing angular range. Participant-specific models revealed varying sets of gait parameters that best predicted FOG for each participant, highlighting variable FOG behaviors, and demonstrated equal or better performance for 6 out of the 10 participants, suggesting the opportunity for model personalization. The results of this study demonstrated that gait parameters measured from wearable IMUs reliably detected FOG during SIP, and the general and participant-specific gait parameters allude to variable FOG behaviors that could inform more personalized approaches for treatment of FOG and gait impairment in PD.

    View details for DOI 10.3390/s21082661

    View details for PubMedID 33920070

  • Differential Effects of Pathological Beta Burst Dynamics Between Parkinson's Disease Phenotypes Across Different Movements. Frontiers in neuroscience Neuville, R. S., Petrucci, M. N., Wilkins, K. B., Anderson, R. W., Hoffman, S. L., Parker, J. E., Velisar, A., Bronte-Stewart, H. M. 2021; 15: 733203

    Abstract

    Background: Resting state beta band (13-30 Hz) oscillations represent pathological neural activity in Parkinson's disease (PD). It is unknown how the peak frequency or dynamics of beta oscillations may change among fine, limb, and axial movements and different disease phenotypes. This will be critical for the development of personalized closed loop deep brain stimulation (DBS) algorithms during different activity states. Methods: Subthalamic (STN) and local field potentials (LFPs) were recorded from a sensing neurostimulator (Activa PC + S, Medtronic PLC.) in fourteen PD participants (six tremor-dominant and eight akinetic-rigid) off medication/off STN DBS during 30 s of repetitive alternating finger tapping, wrist-flexion extension, stepping in place, and free walking. Beta power peaks and beta burst dynamics were identified by custom algorithms and were compared among movement tasks and between tremor-dominant and akinetic-rigid groups. Results: Beta power peaks were evident during fine, limb, and axial movements in 98% of movement trials; the peak frequencies were similar during each type of movement. Burst power and duration were significantly larger in the high beta band, but not in the low beta band, in the akinetic-rigid group compared to the tremor-dominant group. Conclusion: The conservation of beta peak frequency during different activity states supports the feasibility of patient-specific closed loop DBS algorithms driven by the dynamics of the same beta band during different activities. Akinetic-rigid participants had greater power and longer burst durations in the high beta band than tremor-dominant participants during movement, which may relate to the difference in underlying pathophysiology between phenotypes.

    View details for DOI 10.3389/fnins.2021.733203

    View details for PubMedID 34858125

  • Ramp Rate Evaluation and Configuration for Safe and Tolerable Closed-Loop Deep Brain Stimulation Petrucci, M. N., Wilkins, K. B., Orthlieb, G. C., Kehnemouyi, Y. M., O'Day, J. J., Herron, J. A., Bronte-Stewart, H. M., IEEE IEEE. 2021: 959-962
  • 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
  • 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

  • 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

  • Safety of Plasma Infusions in Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society Parker, J. E., Martinez, A. n., Deutsch, G. K., Prabhakar, V. n., Lising, M. n., Kapphahn, K. I., Anidi, C. M., Neuville, R. n., Coburn, M. n., Shah, N. 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-α, 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-α 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

  • Data-Driven Prediction of Freezing of Gait Events From Stepping Data. Frontiers in medical technology Parakkal Unni, M., Menon, P. P., Livi, L., Wilson, M. R., Young, W. R., Bronte-Stewart, H. M., Tsaneva-Atanasova, K. 2020; 2: 581264

    Abstract

    Freezing of gait (FoG) is typically a symptom of advanced Parkinson's disease (PD) that negatively influences the quality of life and is often resistant to pharmacological interventions. Novel treatment options that make use of auditory or sensory cues might be optimized by prediction of freezing events. These predictions might help to trigger external sensory cues-shown to improve walking performance-when behavior is changed in a manner indicative of an impending freeze (i.e., when the user needs it the most), rather than delivering cue information continuously. A data-driven approach is proposed for predicting freezing events using Random Forrest (RF), Neural Network (NN), and Naive Bayes (NB) classifiers. Vertical forces, sampled at 100 Hz from a force platform were collected from 9 PD subjects as they stepped in place until they at least had one freezing episode or for 90 s. The F1 scores of RF/NN/NB algorithms were computed for different IL (input to the machine learning algorithm), and GL (how early the freezing event is predicted). A significant negative correlation between the F1 scores and GL, highlighting the difficulty of early detection is found. The IL that maximized the F1 score is approximately equal to 1.13 s. This indicates that the physiological (and therefore neurological) changes leading to freezing take effect at-least one step before the freezing incident. Our algorithm has the potential to support the development of devices to detect and then potentially prevent freezing events in people with Parkinson's which might occur if left uncorrected.

    View details for DOI 10.3389/fmedt.2020.581264

    View details for PubMedID 35047881

    View details for PubMedCentralID PMC8757792

  • Demonstration of Kinematic-Based Closed-loop Deep Brain Stimulation for Mitigating Freezing of Gait in People with Parkinson's Disease O'Day, J. J., Kehnemouyi, Y. M., Petrucci, M. N., Anderson, R. W., Herron, J. A., Bronte-Stewart, H. M., IEEE IEEE. 2020: 3612–16
  • A Closed-loop Deep Brain Stimulation Approach for Mitigating Burst Durations in People with Parkinson's Disease Petrucci, M. N., Anderson, R. W., O'Day, J. J., Kehnemouyi, Y. M., Herron, J. A., Bronte-Stewart, H. M., IEEE IEEE. 2020: 3617–20
  • 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. n., Syrkin-Nikolau, J. n., Anidi, C. n., Kidzinski, L. n., Delp, S. n., Bronte-Stewart, H. n. 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

  • 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

  • Modulation of beta bursts in subthalamic sensorimotor circuits predicts improvement in bradykinesia. Brain : a journal of neurology Kehnemouyi, Y. M., Wilkins, K. B., Anidi, C. M., Anderson, R. W., Afzal, M. F., Bronte-Stewart, H. M. 2020

    Abstract

    No biomarker of Parkinson's disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson's disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson's disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson's disease.

    View details for DOI 10.1093/brain/awaa394

    View details for PubMedID 33301569

  • Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease. Journal of neuropsychology Müller-Oehring, E. M., Fama, R. n., Levine, T. F., Hardcastle, C. n., Goodcase, R. n., Martin, T. n., Prabhakar, V. n., Brontë-Stewart, H. M., Poston, K. L., Sullivan, E. V., Schulte, T. n. 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

  • Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson’s Disease Frontier in Aging Neuroscience Prabhakar, V., Martin, T., Müller-Oehring, E. M., Goodcase, R., Schulte, T., Poston, K. L., Brontë-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

  • Neural Closed loop deep brain stimulation for freezing of Gait. Brain stimulation Petrucci, M. N., Neuville, R. S., Afzal, M. F., Velisar, A. n., 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

  • 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

  • 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
  • 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

  • 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 < 0.001) increased; tremor was below 0.15 rad/sec for 95.4% of the trial and averaged 0.26 rad/sec when present.This is the first study to demonstrate that STN NclDBS is feasible, efficacious and more efficient than olDBS in tremor and bradykinesia dominant PD patients, on long-term DBS, using an implanted clinical neurostimulator and driven by beta power with a novel dual threshold algorithm, based on customized therapeutic voltage windows.

    View details for DOI 10.1016/j.brs.2019.02.020

    View details for PubMedID 30833216

  • 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