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.

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.

Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.

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 .

Unraveling the complexities of programming neural adaptive deep brain stimulation in Parkinson's disease.

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.

Transcutaneous Afferent Patterned Stimulation for Essential Tremor: Real-World Evidence with Long Term Follow-Up.

Background: 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. Methods: 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. Results: 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. Discussion: 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.

An Individualized Tractography Pipeline for the Nucleus Basalis of Meynert Lateral Tract.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

No laughing white matter: Reduced integrity of the cortical cholinergic pathways in Parkinson's disease-related cognitive impairment.

BACKGROUND: 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. METHODS: 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) and fractional anisotropy (FA) of the medial and lateral NBM tracts were extracted using probabilistic tractography. Between-group differences in MD and FA for each tract was compared using ANCOVA, controlling for age, sex, and disease duration. Control comparisons of the internal capsule MD and FA were also performed. Associations between baseline MD or FA and cognitive outcomes (working memory, psychomotor speed, delayed recall, and visuospatial function) were assessed using linear mixed models. RESULTS: 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. CONCLUSIONS: 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.

The Sequence Effect Worsens Over Time in Parkinson's Disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation.

BACKGROUND: 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). OBJECTIVE: To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) deep brain stimulation (DBS). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

No Laughing White Matter: Cortical Cholinergic Pathways and Cognitive Decline in Parkinson's Disease.

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Episodic memory deficit in HIV infection: common phenotype with Parkinson's disease, different neural substrates.

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.

Bradykinesia and Its Progression Are Related to Interhemispheric Beta Coherence.

OBJECTIVE: 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. METHODS: Twenty-one individuals with PD implanted with sensing neurostimulators (Activa® PC + S, Medtronic, PLC) in the STN participated in a longitudinal 'washout' therapy study every three to 6 months for an average of 3 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. ANN NEUROL 2023;93:1029-1039.

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.

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.

Neurofunctional characteristics of executive control in older people with HIV infection: a comparison with Parkinson's disease.

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.

Differential Effects of Pathological Beta Burst Dynamics Between Parkinson's Disease Phenotypes Across Different Movements.

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.

Lack of progression of beta dynamics after long-term subthalamic neurostimulation.

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 6 months, 1 year, and yearly out to 5 years of treatment. The primary endpoint was measured at 3 years. At each visit, medication had been held for over 12/24 h and DBS was turned off for at least 60 min, by which time LFP spectra reached a steady state. RESULTS: After 3 years 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 5 years. 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.

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.

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) 2022 APA, all rights reserved).

Ramp Rate Evaluation and Configuration for Safe and Tolerable Closed-Loop Deep Brain Stimulation.

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.

Alterations of Brain Signal Oscillations in Older Individuals with HIV Infection and Parkinson's Disease.

More than 30 years 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.

Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease.

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.

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

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.