Lateral thinking: Neurodegeneration of the cortical cholinergic system in Alzheimer's disease.

INTRODUCTION: Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression. METHODS: 187 participants were included in this study who were either healthy controls (HC; n = 50) or had early mild cognitive impairment (EMCI; n = 50), late MCI (LMCI; n = 37), or AD (n = 50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed. RESULTS: NBM volume was smallest in AD followed by LMCI (p < 0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p < 0.01). Both MCI groups had higher lateral tract MD compared to HC (p < 0.05). Medial tract MD was higher in LMCI (p = 0.008), but not EMCI (p = 0.09) compared to HC. Higher lateral tract MD was associated with executive function (p = 0.001) and language (p = 0.02). DISCUSSION: Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.

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.

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.

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.

Limited capacity for ipsilateral secondary motor areas to support hand function post-stroke.

KEY POINTS: Ipsilateral-projecting corticobulbar pathways, originating primarily from secondary motor areas, innervate the proximal and even distal portions, although they branch more extensively at the spinal cord. It is currently unclear to what extent these ipsilateral secondary motor areas and subsequent cortical projections may contribute to hand function following stroke-induced damage to one hemisphere. In the present study, we provide both structural and functional evidence indicating that individuals increasingly rely on ipsilateral secondary motor areas, although at the detriment of hand function. Increased activity in ipsilateral secondary motor areas was associated with increased involuntary coupling between shoulder abduction and finger flexion, most probably as a result of the low resolution of these pathways, making it increasingly difficult to open the hand. These findings suggest that, although ipsilateral secondary motor areas may support proximal movements, they do not have the capacity to support distal hand function, particularly for hand opening. ABSTRACT: Recent findings have shown connections of ipsilateral cortico-reticulospinal tract (CRST), predominantly originating from secondary motor areas to not only proximal, but also distal muscles of the arm. Following a unilateral stroke, CRST from the ipsilateral side remains intact and thus has been proposed as a possible backup system for post-stroke rehabilitation even for the hand. We argue that, although CRST from ipsilateral secondary motor areas can provide control for proximal joints, it is insufficient to control either hand or coordinated shoulder and hand movements as a result of its extensive spinal branching compared to contralateral corticospinal tract. To address this issue, we combined magnetic resonance imaging, high-density EEG, and robotics in 17 individuals with severe chronic hemiparetic stroke and 12 age-matched controls. We tested for changes in structural morphometry of the sensorimotor cortex and found that individuals with stroke demonstrated higher grey matter density in secondary motor areas ipsilateral to the paretic arm compared to controls. We then measured cortical activity when participants were attempting to generate hand opening either supported on a table or when lifting against a shoulder abduction load. The addition of shoulder abduction during hand opening increased reliance on ipsilateral secondary motor areas in stroke, but not controls. Crucially, the increased use of ipsilateral secondary motor areas was associated with decreased hand opening ability when lifting the arm as a result of involuntary coupling between the shoulder and wrist/finger flexors. Taken together, this evidence implicates a compensatory role for ipsilateral (i.e. contralesional) secondary motor areas post-stroke, although with no apparent capacity to support hand function.

Coordination of multiple joints increases bilateral connectivity with ipsilateral sensorimotor cortices.

Although most activities of daily life require simultaneous coordination of both proximal and distal joints, motor preparation during such movements has not been well studied. Previous results for motor preparation have focused on hand/finger movements. For simple hand/finger movements, results have found that such movements typically evoke activity primarily in the contralateral motor cortices. However, increasing the complexity of the finger movements, such as during a distal sequential finger-pressing task, leads to additional recruitment of ipsilateral resources. It has been suggested that this involvement of the ipsilateral hemisphere is critical for temporal coordination of distal joints. The goal of the current study was to examine whether increasing simultaneous coordination of multiple joints (both proximal and distal) leads to a similar increase in coupling with ipsilateral sensorimotor cortices during motor preparation compared to a simple distal movement such as hand opening. To test this possibility, 12 healthy individuals participated in a high-density EEG experiment in which they performed either hand opening or simultaneous hand opening while lifting at the shoulder on a robotic device. We quantified within- and cross-frequency cortical coupling across the sensorimotor cortex for the two tasks using dynamic causal modeling. Both hand opening and simultaneous hand opening while lifting at the shoulder elicited coupling from secondary motor areas to primary motor cortex within the contralateral hemisphere exclusively in the beta band, as well as from ipsilateral primary motor cortex. However, increasing the task complexity by combining hand opening while lifting at the shoulder also led to an increase in cross-frequency coupling within the ipsilateral hemisphere including theta, beta, and gamma frequencies, as well as a change in the coupling frequency of the interhemispheric coupling between the primary motor and premotor cortices. These findings demonstrate that increasing the demand of joint coordination between proximal and distal joints leads to increases in communication with the ipsilateral hemisphere as previously observed in distal sequential finger tasks.

Gait variability is linked to the atrophy of the Nucleus Basalis of Meynert and is resistant to STN DBS in Parkinson's disease.

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.

Lateral Thinking: Pathway Specific Neurodegeneration of the Cortical Cholinergic System in Alzheimer's Disease.

INTRODUCTION: Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression. METHODS: 187 participants were included in this study who were either healthy controls (HC; n=50) or had early mild cognitive impairment (EMCI; n=50), late MCI (LMCI; n=37), or AD (n=50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed. RESULTS: NBM volume was smallest in AD followed by LMCI (p<0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p<0.001). Both MCI groups had higher lateral tract MD compared to HC (p<0.05). Medial tract MD was higher in LMCI (p=0.008), but not EMCI (p=0.09) compared to HC. Higher lateral tract MD was associated with executive function (p=0.001) and language (p=0.02). DISCUSSION: Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.

The digital signature of emergent tremor in Parkinson's disease.

Emergent tremor in Parkinson's disease (PD) can occur during sustained postures or movements that are 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. In this study, we investigated whether emergent tremor during repetitive alternating finger tapping (RAFT) on a quantitative digitography (QDG) device could be reliably identified and distinguished from voluntary tapping. 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 labeled 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. 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). The results demonstrate that 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.

Quantitative DigitoGraphy: a Comprehensive Real-Time Remote Monitoring System for Parkinson's Disease.

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.

Comprehensive real time remote monitoring for Parkinson's disease using Quantitative DigitoGraphy.

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 an 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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.