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.

Connectivity correlates to predict essential tremor deep brain stimulation outcome: Evidence for a common treatment pathway.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) is the most common surgical treatment for essential tremor (ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stimulation "sweet spots," as well as assess the value of structural connectivity in predicting treatment outcomes. MATERIALS AND METHODS: Ninety-seven ET individuals with unilateral thalamic DBS were retrospectively included. Using normative brain connectomes, structural connectivity measures were correlated with the percentage improvement in contralateral tremor, based on the Fahn-Tolosa-Marin tremor rating scale (TRS), after parameter optimization (range 3.1-12.9 months) using a leave-one-out cross-validation in 83 individuals. The predictive feature map was used for cross-validation in a separate cohort of 14 ET individuals treated at another center. Lastly, estimated volumes of tissue activated (VTA) were used to assess a treatment "sweet spot," which was compared to seven previously reported stimulation sweet spots and their relationship to the tract identified by the predictive feature map. RESULTS: In the training cohort, structural connectivity between the VTA and dentato-rubro-thalamic tract (DRTT) correlated with contralateral tremor improvement (R = 0.41; p < 0.0001). The same connectivity profile predicted outcomes in a separate validation cohort (R = 0.59; p = 0.028). The predictive feature map represented the anatomical course of the DRTT, and all seven analyzed sweet spots overlapped the predictive tract (DRTT). CONCLUSIONS: Our results strongly support the possibility that structural connectivity is a predictor of contralateral tremor improvement in ET DBS. The results suggest the future potential for a patient-specific functionally based surgical target. Finally, the results showed convergence in "sweet spots" suggesting the importance of the DRTT to the outcome.

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.

The Functional Role of Thalamocortical Coupling in the Human Motor Network.

The amplitude of high broadband activity in human cortical field potentials indicates local processing and has repeatedly been shown to reflect motor control in the primary motor cortex. In a group of male and female subjects affected by essential tremor and undergoing deep brain stimulation surgery, ventral intermediate nucleus low-frequency oscillations (<30 Hz) entrain the corticomotor high broadband activity (>40 Hz) during rest, relinquishing that role during movement execution. This finding suggests that there is significant cross-rhythm communication between thalamocortical regions, and motor behavior corresponds to changes in thalamocortical phase-amplitude coupling profiles. Herein, we demonstrate that thalamocortical coupling is a crucial mechanism for gating motor behavior.SIGNIFICANCE STATEMENT We demonstrate, for the first time, how thalamocortical coupling is mediating movement execution in humans. We show how the low-frequency oscillation from the ventral intermediate nucleus, known as the motor nucleus of the thalamus, entrains the excitability of the primary motor cortex, as reflected by the phase-amplitude coupling between the two regions. We show that thalamocortical phase-amplitude coupling is a manifestation of a gating mechanism for movement execution mediated by the thalamus. These findings highlight the importance of incorporating cross-frequency relationship in models of motor behavior; and given the spatial specificity of this mechanism, this work could be used to improve functional targeting during surgical implantations in subcortical regions.

Scheduled, intermittent stimulation of the thalamus reduces tics in Tourette syndrome.

INTRODUCTION: Personalized, scheduled deep brain stimulation in Tourette syndrome (TS) may permit clinically meaningful tic reduction while reducing side effects and increasing battery life. Here, we evaluate scheduled DBS applied to TS at two-year follow-up. METHODS: Five patients underwent bilateral centromedian thalamic (CM) region DBS. A cranially contained constant-current device delivering stimulation on a scheduled duty cycle, as opposed to the standard continuous DBS paradigm was utilized. Baseline vs. 24-month outcomes were collected and analyzed, and a responder analysis was performed. A 40% improvement in the Modified Rush Tic Rating Scale (MRTRS) total score or Yale Global Tic Severity Scale (YGTSS) total score defined a full responder. RESULTS: Three of the 4 patients followed to 24 months reached full responder criteria and had a mean stimulation time of 1.85 h per day. One patient lost to follow-up evaluated at the last time point (month 18) was a non-responder. Patients exhibited improvements in MRTRS score beyond the improvements previously reported for the 6 month endpoint; on average, MRTRS total score was 15.6% better at 24 months than at 6 months and YGTSS total score was 14.8% better. Combining the patients into a single cohort revealed significant improvements in the MRTRS total score (-7.6 [5.64]; p = 0.02). CONCLUSION: Electrical stimulation of the centromedian thalamic region in a scheduled paradigm was effective in suppressing tics, particularly phonic tics. Full responders were able to achieve the positive DBS effect with a mean of 2.3 ± 0.9 (SEM) hours of DBS per day.