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.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer’s disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.

Introduction: Drawing on the seminal work of DeLong, Albin, and Young, we have now entered an era of basal ganglia neuromodulation. Understanding, re-evaluating, and leveraging the lessons learned from neuromodulation will be crucial to facilitate an increased and improved application of neuromodulation in human disease cohorts. Methods: We will focus on deep brain stimulation (DBS)-the most common form of basal ganglia neuromodulation-however, similar principles can apply to other neuromodulation modalities. We start with a brief review of DBS for Parkinson's disease, essential tremor, dystonia, and Tourette syndrome. We then review hallmark studies on basal ganglia circuits and electrophysiology resulting from decades of experience in neuromodulation. The organization and content of this paper follow Dr. Okun's Lecture from the 2018 Parkinsonism and Related Disorders World Congress. Results: Information gained from neuromodulation has led to an expansion of the basal ganglia rate model, an enhanced understanding of nuclei dynamics, an emerging focus on pathological oscillations, a revision of the tripartite division of the basal ganglia, and a redirected focus toward individualized symptom-specific stimulation. Though there have been many limitations of the basal ganglia "box model," the construct provided the necessary foundation to advance the field. We now understand that information in the basal ganglia is encoded through complex neural responses that can be reliably measured and used to infer disease states for clinical translation. Conclusions: Our deepened understanding of basal ganglia physiology will drive new neuromodulation strategies such as adaptive DBS or cell-specific neuromodulation through the use of optogenetics.

Introduction: Although the benefit in motor symptoms for well-selected patients with deep brain stimulation (DBS) has been established, cognitive declines associated with DBS can produce suboptimal clinical responses. Small decrements in cognition can lead to profound effects on quality of life. The growth of indications, the expansion of surgical targets, the increasing complexity of devices, and recent changes in stimulation paradigms have all collectively drawn attention to the need for re-evaluation of DBS related cognitive outcomes. Methods: To address the impact of cognitive changes following DBS, we performed a literature review using PubMed. We searched for articles focused on DBS and cognition. We extracted information about the disease, target, number of patients, assessment of time points, cognitive battery, and clinical outcomes. Diseases included were dystonia, Tourette syndrome (TS), essential tremor (ET), and Parkinson's disease (PD). Results: DBS was associated with mild cognitive issues even when rigorous patient selection was employed. Dystonia studies reported stable or improved cognitive scores, however one study using reliable change indices indicated decrements in sustained attention. Additionally, DBS outcomes were convoluted with changes in medication dose, alleviation of motor symptoms, and learning effects. In the largest, prospective TS study, an improvement in attentional skills was noted, whereas smaller studies reported variable declines across several cognitive domains. Although, most studies reported stable cognitive outcomes. ET studies largely demonstrated deficits in verbal fluency, which had variable responses depending on stimulation setting. Recently, studies have focused beyond the ventral intermediate nucleus, including the post-subthalamic area and zona incerta. For PD, the cognitive results were heterogeneous, although deficits in verbal fluency were consistent and related to the micro-lesion effect. Conclusion: Post-DBS cognitive issues can impact both motor and quality of life outcomes. The underlying pathophysiology of cognitive changes post-DBS and the identification of pathways underpinning declines will require further investigation. Future studies should employ careful methodological designs. Patient specific analyses will be helpful to differentiate the effects of medications, DBS and the underlying disease state, including disease progression. Disease progression is often an underappreciated factor that is important to post-DBS cognitive issues.

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