Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Background We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Methods Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale—24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Results Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Conclusions Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.

Chronically implantable, closed-loop neuromodulation devices with concurrent sensing and stimulation hold promise for better understanding the nervous system and improving therapies for neurological disease. Concurrent sensing and stimulation are needed to maximize usable neural data, minimize time delays for closed-loop actuation, and investigate the instantaneous response to stimulation. Current systems lack concurrent sensing and stimulation primarily because of stimulation interference to neural signals of interest. While careful design of high performance amplifiers has proved useful to reduce disturbances in the system, stimulation continues to contaminate neural sensing due to biological effects like tissue-electrode impedance mismatch and constraints on stimulation parameters needed to deliver therapy. In this work we describe systematic methods to mitigate the effect of stimulation through a combination of sensing hardware, stimulation parameter selection, and classification algorithms that counter residual stimulation disturbances. To validate these methods we implemented and tested a completely implantable system for over one year in a large animal model of epilepsy. The system proved capable of measuring and detecting seizure activity in the hippocampus both during and after stimulation. Furthermore, we demonstrate an embedded algorithm that actuates neural modulation in response to seizure detection during stimulation, validating the capability to detect bioelectrical markers in the presence of therapy and titrate it appropriately. The capability to detect neural states in the presence of stimulation and optimally titrate therapy is a key innovation required for generalizing closed-loop neural systems for multiple disease states.

We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study. Methods: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed. Results: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase).Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years.Overall mortality was 6.9 deaths per 1000 person-years. Significance: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes.Improvement in frequency of the most severe seizure type may reduce SUDEP risk.The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

The need for novel, efficacious, antiseizure therapies is widely acknowledged. This study investigates in humans the feasibility, safety, and efficacy of high-frequency electrical stimulation (HFES; 100-500 Hz) triggered by automated seizure detections. Eight patients were enrolled in this study, which consisted of a control and an experimental phase. HFES was delivered directly to the epileptogenic zone (local closed-loop) in four patients and indirectly, through anterior thalami (remote closed-loop), to the other four patients for every other automated seizure detection made by a validated algorithm. Interphase (control vs experimental phase) and intraphase (stimulated vs nonstimulated) comparisons of clinical seizure rate and relative severity (clinical and electrographic) were performed, and differences were assessed using effect size. Patients were deemed "responders" if seizure rate was reduced by at least 50%; the remaining patients were deemed "nonresponders." All patients completed the study; rescue medications were not required. There were 1,491 HFESs (0.2% triggered after-discharges). Mean change in seizure rate in the local closed-loop group was -55.5% (-100 to +36.8%); three of four responders had a mean change of -86% (-100 to -58.8%). In the remote closed-loop, the mean change of seizure rate was -40.8% (-72.9 to +1.4%); two of four responders had a mean change of -74.3% (-75.6 to -72.9%). Mean effect size was zero in the local closed-loop (responders: beneficial and medium to large in magnitude) and negligible in the remote closed-loop group (responders: beneficial and medium to large). HFES effects on epileptogenic tissue were immediate and also outlasted the stimulation period. This study demonstrates the feasibility and short-term safety of automated HFES for seizure blockage, and also raises the possibility that it may be beneficial in pharmaco-resistant epilepsies.