Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson's disease.

Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson's disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.

Responsive deep brain stimulation for the treatment of Tourette syndrome.

To report the results of 'responsive' deep brain stimulation (DBS) for Tourette syndrome (TS) in a National Institutes of Health funded experimental cohort. The use of 'brain derived physiology' as a method to trigger DBS devices to deliver trains of electrical stimulation is a proposed approach to address the paroxysmal motor and vocal tic symptoms which appear as part of TS. Ten subjects underwent bilateral staged DBS surgery and each was implanted with bilateral centromedian thalamic (CM) region DBS leads and bilateral M1 region cortical strips. A series of identical experiments and data collections were conducted on three groups of consecutively recruited subjects. Group 1 (n = 2) underwent acute responsive DBS using deep and superficial leads. Group 2 (n = 4) underwent chronic responsive DBS using deep and superficial leads. Group 3 (n = 4) underwent responsive DBS using only the deep leads. The primary outcome measure for each of the 8 subjects with chronic responsive DBS was calculated as the pre-operative baseline Yale Global Tic Severity Scale (YGTSS) motor subscore compared to the 6 month embedded responsive DBS setting. A responder for the study was defined as any subject manifesting a ≥ 30 points improvement on the YGTSS motor subscale. The videotaped Modified Rush Tic Rating Scale (MRVTRS) was a secondary outcome. Outcomes were collected at 6 months across three different device states: no stimulation, conventional open-loop stimulation, and embedded responsive stimulation. The experience programming each of the groups and the methods applied for programming were captured. There were 10 medication refractory TS subjects enrolled in the study (5 male and 5 female) and 4/8 (50%) in the chronic responsive eligible cohort met the primary outcome manifesting a reduction of the YGTSS motor scale of ≥ 30% when on responsive DBS settings. Proof of concept for the use of responsive stimulation was observed in all three groups (acute responsive, cortically triggered and deep DBS leads only). The responsive approach was safe and well tolerated. TS power spectral changes associated with tics occurred consistently in the low frequency 2-10 Hz delta-theta-low alpha oscillation range. The study highlighted the variety of programming strategies which were employed to achieve responsive DBS and those used to overcome stimulation induced artifacts. Proof of concept was also established for a single DBS lead triggering bi-hemispheric delivery of therapeutic stimulation. Responsive DBS was applied to treat TS related motor and vocal tics through the application of three different experimental paradigms. The approach was safe and effective in a subset of individuals. The use of different devices in this study was not aimed at making between device comparisons, but rather, the study was adapted to the current state of the art in technology. Overall, four of the chronic responsive eligible subjects met the primary outcome variable for clinical effectiveness. Cortical physiology was used to trigger responsive DBS when therapy was limited by stimulation induced artifacts.

Weight and survival after deep brain stimulation for Parkinson's disease.

BACKGROUND: Weight loss in Parkinson's disease (PD) is common and associated with increased mortality. The clinical significance of weight changes following deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is unclear. OBJECTIVES: To address (1) whether PD patients exhibit progressive weight loss, (2) whether staged DBS surgery is associated with weight changes, and (3) whether survival after DBS correlates with post-DBS weight. METHODS: This is a single-center, longitudinal, retrospective cohort study of 1625 PD patients. We examined trends in weight over time and the relationship between weight and years survival after DBS using regression and mixed model analyses. RESULTS: There was a decline in body weight predating motor symptom onset (n = 756, 0.70 ± 0.03% decrease per year, p < 0.001). Weight decline accelerated in the decade preceding death (n = 456, 2.18 ± 0.31% decrease per year, p < 0.001). DBS patients showed a weight increase of 2.0 ± 0.33% at 1 year following the first DBS lead implant (n = 455) and 2.68 ± 1.1% at 3 years if a contralateral DBS lead was placed (n = 249). The bilateral STN DBS group gained the most weight after surgery during 6 years of follow up (vs bilateral GPi, 3.03 ± 0.45% vs 1.89 ± 0.31%, p < 0.01). An analysis of the DBS cohort with date of death available (n = 72) revealed that post-DBS weight (0-12 months after the first or 0-36 months after the second surgery) was positively associated with survival (R2 = 0.14, p < 0.001). DISCUSSION: Though PD is associated with significant weight loss, DBS patients gained weight following surgery. Higher post-operative weight was associated with increased survival. These results should be replicated in other cohorts.

Brain Recording Analysis and Visualization Online (BRAVO): An open-source visualization tool for deep brain stimulation data.

BACKGROUND: Deep brain stimulation (DBS) devices with neural recording capabilities are commercially available and may potentially improve clinical care and advance research. However, tools, to visualize neural recording data have been limited. These tools in general, require custom-made software for processing and analysis. The development of new tools will be critical for clinicians and researchers to fully leverage the latest device capabilities. OBJECTIVE: There is an urgent need for a user-friendly tool for in-depth visualization and analysis of brain signals and of DBS data. METHODS AND RESULTS: The Brain Recording Analysis and Visualization Online (BRAVO) platform was developed to easily import, visualize, and analyze brain signals. This Python-based web interface has been designed and implemented on a Linux server. The tool processes the session files from DBS programming generated by a clinical 'programming' tablet. The platform is capable of parsing and organizing neural recordings for longitudinal analysis. We present the platform and cases exemplifying its application and use. CONCLUSION: The BRAVO platform is an accessible easy-to-use, open-source web interface for clinicians and researchers to apply for analysis of longitudinal neural recording data. The tool can be used for both clinical and research applications.

Globus pallidus internus deep brain stimulation evokes resonant neural activity in Parkinson's disease.

Globus pallidus internus deep brain stimulation is an established therapy for patients with medication-refractory Parkinson's disease. Clinical outcomes are highly dependent on applying stimulation to precise locations in the brain. However, robust neurophysiological markers are needed to determine the optimal electrode location and to guide postoperative stimulation parameter selection. In this study, we evaluated evoked resonant neural activity in the pallidum as a potential intraoperative marker to optimize targeting and stimulation parameter selection to improve outcomes of deep brain stimulation for Parkinson's disease. Intraoperative local field potential recordings were acquired in 22 patients with Parkinson's disease undergoing globus pallidus internus deep brain stimulation implantation (N = 27 hemispheres). A control group of patients undergoing implantation in the subthalamic nucleus (N = 4 hemispheres) for Parkinson's disease or the thalamus for essential tremor (N = 9 patients) were included for comparison. High-frequency (135 Hz) stimulation was delivered from each electrode contact sequentially while recording the evoked response from the other contacts. Low-frequency stimulation (10 Hz) was also applied as a comparison. Evoked resonant neural activity features, including amplitude, frequency and localization were measured and analysed for correlation with empirically derived postoperative therapeutic stimulation parameters. Pallidal evoked resonant neural activity elicited by stimulation in the globus pallidus internus or externus was detected in 26 of 27 hemispheres and varied across hemispheres and across stimulating contacts within individual hemispheres. Bursts of high-frequency stimulation elicited evoked resonant neural activity with similar amplitudes (P = 0.9) but a higher frequency (P = 0.009) and a higher number of peaks (P = 0.004) than low-frequency stimulation. We identified a 'hotspot' in the postero-dorsal pallidum where stimulation elicited higher evoked resonant neural activity amplitudes (P < 0.001). In 69.6% of hemispheres, the contact that elicited the maximum amplitude intraoperatively matched the contact empirically selected for chronic therapeutic stimulation by an expert clinician after 4 months of programming sessions. Pallidal and subthalamic nucleus evoked resonant neural activity were similar except for lower pallidal amplitudes. No evoked resonant neural activity was detected in the essential tremor control group. Given its spatial topography and correlation with postoperative stimulation parameters empirically selected by expert clinicians, pallidal evoked resonant neural activity shows promise as a potential marker to guide intraoperative targeting and to assist the clinician with postoperative stimulation programming. Importantly, evoked resonant neural activity may also have the potential to guide directional and closed-loop deep brain stimulation programming for Parkinson's disease.

Phenomenology and Physiology of Tacrolimus Induced Tremor.

Background: Tacrolimus is a potent immunosuppressant drug commonly used after solid organ transplant surgery. The use of this drug is frequently associated with the emergence of tremors. There is little information on the clinical and physiological characteristics of tacrolimus-induced tremors. Characterizing these tremors is essential as they can promote the development of specific therapies. Methods: We describe four patients placed on tacrolimus immunosuppressant therapy following kidney transplant surgery and who developed tremors impacting their daily functional activities. We describe the clinical and physiological characteristics of the tremor and the response generated after a limb cooling test. Results: A postural and kinetic tremor mainly involving the distal hands was observed in our cohort. In the accelerometer-based assessment, the tremor amplitude was noted to be mild to moderate, and the frequency was 5-6 Hz. Cooling the forearm and the hand led to a temporary albeit significant reduction of tremor amplitude (p = 0.03). Limb cooling lowered the tremor frequency by 1 Hz in two patients with no change in the other two patients, and the statistical comparison was not significant (p > 0.05). Conclusions: Limb cooling may be pursued as a therapeutic option for addressing tacrolimus-induced tremor, as the patients in our cohort benefitted from temporary tremor suppression.

Tachygastria in Preterm Infants: A Longitudinal Cohort Study.

OBJECTIVES: Tachygastria is a gastric dysrhythmia (>4 to ≤9 cycles per minute, cpm) associated with gastric hypomotility and gastrointestinal disorders. Healthy preterm infants spend more time in tachygastria than adults; however, normative values are not defined. We sought to determine the percent of time preterm infants spend in tachygastria. METHODS: We conducted a longitudinal, prospective cohort study with weekly electrogastrography (EGG) recordings in 51 preterm <34 weeks' gestation and 5 term (reference) infants. We calculated percentage recording time in tachygastria (% tachygastria) and determined the mean ± standard deviation (SD) across EGG sessions. Mixed effects model was performed to test weekly variance in % tachygastria and gestational age effect. Successive pre- and post-prandial measurements were obtained to assess reproducibility of % tachygastria. We compared time to achieve full feeds between subjects with % tachygastria within 1 SD from the mean versus % tachygastria >1 SD from mean. RESULTS: Three hundred seventy-six EGG sessions were completed (N = 56). Mean % tachygastria was 40% with SD ±5%. We demonstrated no change in % tachygastria across 9 postnatal weeks (P = 0.70) and no gestational age effect. No difference was demonstrated between successive pre- (P = 0.91) and post-prandial (P = 0.96) % tachygastria. Infants with 35%-45% tachygastria (within 1 SD from mean) had higher gestational age and less time to achieve full feeds than infants with <35% or >45% tachygastria. CONCLUSIONS: EGG is a reproducible tool to assess % tachygastria in preterm infants. Clinical significance of increased or decreased % tachygastria needs further investigation to validate if 35%-45% tachygastria is safe for feeding.

Embedded Human Closed-Loop Deep Brain Stimulation for Tourette Syndrome: A Nonrandomized Controlled Trial.

Importance: Because Tourette syndrome (TS) is a paroxysmal disorder, symptomatic relief in individuals with TS may be possible through the application of stimulation only during the manifestation of human tic neural signatures. This technique could be capable of suppressing both motor and vocal tics and would have similar effectiveness to conventional continuous deep brain stimulation (DBS). Objective: To evaluate the feasibility, safety, and clinical effectiveness of bilateral centromedian-parafascicular complex thalamic closed-loop DBS as a treatment for medication-refractory TS. Design, Setting, and Participants: This single-center double-blinded safety and feasibility trial was conducted between February 2014 and June 2020. Six individuals with TS were screened and recruited from the Norman Fixel Institute at the University of Florida. The primary outcome was measured at 6 months, and participants were followed up for the duration of the neurostimulator battery life. Independent ratings that compared closed-loop and conventional DBS were videotaped. The first 2 of 6 individuals with TS were excluded from the study because the technology for embedded closed-loop capability was not yet available. The date of analysis was August 2020. Interventions: DBS therapy controlled by an embedded closed-loop stimulation system. Main Outcomes and Measures: The primary clinical outcome measure was a minimum of a 40% reduction in the YGTSS score at 6 months following DBS. There was also a comparison of conventional DBS with closed-loop DBS using the Modified Rush Videotape Rating Scale for Tic. Results: The mean (SD) age at TS diagnosis for the cohort was 8.5 (2.9), and the mean (SD) disease duration was 23.7 (5.8) years. Four individuals with TS were analyzed (2 male, 2 female; mean [SD] age, 23.7 [5.8] years). The study showed the closed-loop approach was both feasible and safe. One of the novelties of this study was that a patient-specific closed-loop paradigm was created for each participant. The features and stimulation transition speed were customized based on the signal quality and the tolerance to adverse reactions. The mean (SD) therapeutic outcome with conventional DBS was 33.3% (35.7%) improvement on the YGTSS and 52.8% (21.9%) improvement on the Modified Rush Videotape Rating Scale. Two of 4 participants had a primary outcome variable improvement of 40% meeting the primary efficacy target. When comparing closed-loop DBS with conventional DBS using a Wilcoxon sign-rank test, there was no statistical difference between tic severity score and both approaches revealed a lower tic severity score compared with baseline. The study was feasible in all 4 participants, and there were 25 total reported adverse events with 3 study-related events (12%). The most common adverse events were headache and anxiety. Conclusions and Relevance: Embedded closed-loop deep DBS was feasible, safe, and had a comparable outcome to conventional TS DBS for the treatment of tics. Trial Registration: ClinicalTrials.gov Identifier: NCT02056873.

Past, Present, and Future of Deep Brain Stimulation: Hardware, Software, Imaging, Physiology and Novel Approaches.

Deep brain stimulation (DBS) has advanced treatment options for a variety of neurologic and neuropsychiatric conditions. As the technology for DBS continues to progress, treatment efficacy will continue to improve and disease indications will expand. Hardware advances such as longer-lasting batteries will reduce the frequency of battery replacement and segmented leads will facilitate improvements in the effectiveness of stimulation and have the potential to minimize stimulation side effects. Targeting advances such as specialized imaging sequences and "connectomics" will facilitate improved accuracy for lead positioning and trajectory planning. Software advances such as closed-loop stimulation and remote programming will enable DBS to be a more personalized and accessible technology. The future of DBS continues to be promising and holds the potential to further improve quality of life. In this review we will address the past, present and future of DBS.

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

BACKGROUND: Impulsivity and impulse control disorders are common in Parkinson's disease and lead to increased morbidity and reduced quality of life. Impulsivity is thought to arise from aberrant reward processing and inhibitory control, but it is unclear why deep brain stimulation of either the subthalamic nucleus (STN) or globus pallidus internus (GPi) affects levels of impulsivity. Our aim was to assess the role of the STN and GPi in impulsivity using invasive local field potential (LFP) recordings from deep brain stimulation electrodes. METHODS: We measured LFPs during a simple rewarding Go/NoGo paradigm in 39 female and male human patients with Parkinson's disease manifesting variable amounts of impulsivity who were undergoing unilateral deep brain stimulation of either the STN (18 nuclei) or GPi (28 nuclei). We identified reward-specific LFP event-related potentials and correlated them to impulsivity severity. RESULTS: LFPs in both structures modulated during reward-specific Go and NoGo stimulus evaluation, reward feedback, and loss feedback. Motor and limbic functions were anatomically separable in the GPi but not in the STN. Across participants, LFP reward processing responses in the STN and GPi uniquely depended on the severity of impulsivity. CONCLUSIONS: This study establishes LFP correlates of impulsivity within the STN and GPi regions. We propose a model for basal ganglia reward processing that includes the bottom-up role of the GPi in reward salience and the top-down role of the STN in cognitive control.

The Human Tic Detector: An automatic approach to tic characterization using wearable sensors.

OBJECTIVE: Current rating scales for Tourette syndrome (TS) are limited by recollection bias or brief assessment periods. This proof-of-concept study aimed to develop a sensor-based paradigm to detect and classify tics. METHODS: We recorded both electromyogram and acceleration data from seventeen TS patients, either when voluntarily moving or experiencing tics and during the modified Rush Video Tic Rating Scale (mRVTRS). Spectral properties of voluntary and tic movements from the sensor that captured the dominant tic were calculated and used as features in a support vector machine (SVM) to detect and classify movements retrospectively. RESULTS: Across patients, the SVM had an accuracy, sensitivity, and specificity of 96.69 ± 4.84%, 98.24 ± 4.79%, and 96.03 ± 6.04%, respectively, when classifying movements in the test dataset. Furthermore, each patient's SVM was validated using data collected during the mRVTRS. Compared to the expert consensus, the tic detection accuracy was 85.63 ± 15.28% during the mRVTRS, while overall movement classification accuracy was 94.23 ± 5.97%. CONCLUSIONS: These results demonstrate that wearable sensors can capture physiological differences between tic and voluntary movements and are comparable to expert consensus. SIGNIFICANCE: Ultimately, wearables could individualize and improve care for people with TS, provide a robust and objective measure of tics, and allow data collection in real-world settings.

Suppression and Rebound of Pallidal Beta Power: Observation Using a Chronic Sensing DBS Device.

Pallidal deep brain stimulation (DBS) is an increasingly used therapy for Parkinson's disease (PD). Here, we study the effect of DBS on pallidal oscillatory activity as well as on symptom severity in an individual with PD implanted with a new pulse generator (Medtronic Percept system) which facilitates chronic recording of local field potentials (LFP) through implanted DBS lead. Pallidal LFPs were recorded while delivering stimulation in a monopolar configuration using stepwise increments (0.5 mA, every 20 s). At each stimulation amplitude, the power spectral density (PSD) was computed, and beta power (13-30 Hz) was calculated and correlated with the degree of bradykinesia. Pallidal beta power was reduced when therapeutic stimulation was delivered. Beta power correlated to the severity of bradykinesia. Worsening of parkinsonism when excessive stimulation was applied was associated with a rebound in the beta band power. These preliminary results suggest that pallidal beta power might be used as an objective marker of the disease state in PD. The use of brain sensing from implanted neural interfaces may in the future facilitate clinical programming. Detection of rebound could help to optimize benefits and minimize worsening from overstimulation.

Wearable sensor-driven responsive deep brain stimulation for essential tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. OBJECTIVE: The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. METHODS: Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. RESULTS: Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. CONCLUSIONS: The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.

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

BACKGROUND: The centromedian-parafascicular (Cm-Pf) complex of the thalamus is a common deep brain stimulation (DBS) target for treatment of Tourette syndrome (TS). Currently, there are no standardized functional intraoperative neurosurgical targeting approaches. Collectively, these issues have led to variability in DBS lead placement. Therefore, more defined methods are needed to improve targeting accuracy. OBJECTIVE: The objective of this observational study was to develop and to verify a functional mapping task capable of differentiating the Cm-Pf region from the nearby ventral intermediate (Vim) nucleus region of the thalamus. The overarching goal was to improve the reproducibility of DBS targeting in the Cm-Pf region. METHODS: Seven TS patients completed a modified Go/NoGo task (five in the post-operative setting and two in the intra-operative setting). Post-operative neural signals from Cm-Pf region were collected using sensing-enabled implanted neural stimulators, and intraoperative neural signals from the Cm-Pf region were collected using an external amplifier. Event-related potential (ERP) features were identified by using the grand-average of stimulus onset signals derived from the postoperative participants. These features were correlated with anatomical locations for the specific electrode recordings. The same features were extracted from the intraoperative patients in order to verify electrode positions in the operating room environment. RESULTS: Two features - a positive and a negative deflection - were identified in the average ERP from the post-operative participants. The peak amplitudes of both features were significantly correlated with the electrode depth position (p = 0.025 for positive deflection and p = 0.039 for negative deflection). The same result was reproduced intra-operatively in the two most recent patients, where more ventral electrode contacts revealed stronger peak amplitudes in comparison to the dorsal electrode contacts. CONCLUSION: This process was used to physiologically confirm accurate lead placement in the operating room setting. The modified Go/NoGo task elicited robust neural responses in the Cm-Pf region however the signal was not present in the Vim nucleus region of thalamus along the DBS electrode trajectory. We conclude that the differences in ERP responses may be a potentially novel LFP based functional approach for future targeting of the Cm-Pf complex for TS DBS.

Practical Closed-Loop Strategies for Deep Brain Stimulation: Lessons From Chronic Pain.

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician's perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.

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

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

Lead Repositioning Guided by Both Physiology and Atlas Based Targeting in Tourette Deep Brain Stimulation.

Background: The centromedian (CM) region of the thalamus is a common target for deep brain stimulation (DBS) treatment for Tourette Syndrome (TS). However, there are currently no standard microelectrode recording or macrostimulation methods to differentiate CM thalamus from other nearby structures and nuclei. Case Report: Here we present a case of failed conventional stereotactic targeting in TS DBS. Postoperative local field potential recordings (LFPs) showed features including beta power desynchronization during voluntary movement and thalamo-cortical phase amplitude coupling at rest. These findings suggested that the DBS lead was suboptimally placed in the ventral intermediate (VIM) nucleus of the thalamus rather than the intended CM region. Due to a lack of clinical improvement in tic severity scales three months following the initial surgery, the patient underwent lead revision surgery. Slight repositioning of the DBS leads resulted in a remarkably different clinical outcome. Afterwards, LFPs revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. Follow-up clinical visits documented improvement of the patient's global tic scores. Discussion: This case provides preliminary evidence that combining physiology with atlas based targeting may possibly enhance outcomes in some cases of Tourette DBS. A larger prospective study will be required to confirm these findings. Highlight: This report demonstrates a case of failed centromedian nucleus region deep brain stimulation (DBS). We observed suboptimal tic improvement several months following DBS surgery and subsequent lead revision improved the outcome. The neurophysiology provided an important clue suggesting the possibility of suboptimally placed DBS leads. Repeat LFPs during lead revision revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. There was improvement in tic outcome following slight repositioning during bilateral DBS lead revision. This case provides preliminary evidence supporting the use of physiology to augment the atlas based targeting of Tourette DBS cases.

Florida research open-source synchronization tool (FROST) for electrophysiology experiments.

BACKGROUND: Accurate interpretation of electrophysiological data in cognitive and behavioral experiments requires the acquisition of time labels, such as marking the exact start of a condition or moment a stimulus is presented to a research subject. NEW METHOD: Here we present an inexpensive (∼30 USD) device used as a central relay for multiple peripheral devices, such as a computer screen presenting an experiment, a pressure-sensor push button, a multi-button responder, a pulse oximeter sensor, a light-emitting diode trigger for camera synchronization, and more. We refer to this device as the Florida Research Open-source Synchronization Tool (FROST). FROST allows for easy hardware and Arduino-based firmware modifications that enable a standard platform for the integration of novel peripheral sensors. RESULTS: With two examples, we demonstrate the application of this device during human research experiments: intracranial-electroencephalography (EEG) recordings in a patient with epilepsy and surface-EEG recordings in a healthy participant. We provide an example setup for a rodent experiment as well. We also demonstrate the timing delays of our device. COMPARISON WITH EXISTING METHODS: There is currently very few existing open-source synchronization tools for electrophysiological research that enable customization with new device compatibility. We developed this tool to enable widespread replication for many applications through an open-source platform. CONCLUSIONS: FROST can be easily adapted for research experiments beyond the included example cases. All materials are open-source at github.com/Brain-Mapping-Lab/FROST.

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.

Differentiating tic electrophysiology from voluntary movement in the human thalamocortical circuit.

OBJECTIVES: Tourette syndrome is a neurodevelopmental disorder commonly associated with involuntary movements, or tics. We currently lack an ideal animal model for Tourette syndrome. In humans, clinical manifestation of tics cannot be captured via functional imaging due to motion artefacts and limited temporal resolution, and electrophysiological studies have been limited to the intraoperative environment. The goal of this study was to identify electrophysiological signals in the centromedian (CM) thalamic nucleus and primary motor (M1) cortex that differentiate tics from voluntary movements. METHODS: The data were collected as part of a larger National Institutes of Health-sponsored clinical trial. Four participants (two males, two females) underwent monthly clinical visits for collection of physiology for a total of 6 months. Participants were implanted with bilateral CM thalamic macroelectrodes and M1 subdural electrodes that were connected to two neurostimulators, both with sensing capabilities. MRI scans were performed preoperatively and CT scans postoperatively for localisation of electrodes. Electrophysiological recordings were collected at each visit from both the cortical and subcortical implants. RESULTS: Recordings collected from the CM thalamic nucleus revealed a low-frequency power (3-10 Hz) increase that was time-locked to the onset of involuntary tics but was not present during voluntary movements. Cortical recordings revealed beta power decrease in M1 that was present during tics and voluntary movements. CONCLUSION: We conclude that a human physiological signal was detected from the CM thalamus that differentiated tic from voluntary movement, and this physiological feature could potentially guide the development of neuromodulation therapies for Tourette syndrome that could use a closed-loop-based approach.