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Objective. To treat neurological and psychiatric diseases with deep brain stimulation (DBS), a trained clinician must select parameters for each patient by monitoring their symptoms and side-effects in a months-long trial-and-error process, delaying optimal clinical outcomes. Bayesian optimization has been proposed as an efficient method to quickly and automatically search for optimal parameters. However, conventional Bayesian optimization does not account for patient safety and could trigger unwanted or dangerous side-effects. Approach. In this study we develop SAFE-OPT, a Bayesian optimization algorithm designed to learn subject-specific safety constraints to avoid potentially harmful stimulation settings during optimization. We prototype and validate SAFE-OPT using a rodent multielectrode stimulation paradigm which causes subject-specific performance deficits in a spatial memory task. We first use data from an initial cohort of subjects to build a simulation where we design the best SAFE-OPT configuration for safe and accurate searching in silico. Main results. We then deploy both SAFE-OPT and conventional Bayesian optimization without safety constraints in new subjects in vivo , showing that SAFE-OPT can find an optimally high stimulation amplitude that does not harm task performance with comparable sample efficiency to Bayesian optimization and without selecting amplitude values that exceed the subject's safety threshold. Significance. The incorporation of safety constraints will provide a key step for adopting Bayesian optimization in real-world applications of DBS., (Creative Commons Attribution license.)

Objective: The aim of this study was to identify features of responsive neurostimulation (RNS) lead configuration and contact placement associated with greater seizure reduction in mesial temporal lobe epilepsy (MTLE)., Methods: A single-center series of patients with MTLE treated with RNS were retrospectively analyzed to assess the relationship between anatomical targeting and seizure reduction. Targeting was determined according to both the preoperatively conceived lead configuration and the actual placement of RNS contacts. Three lead configurations were used: 1) single bilateral, with 1 depth lead in each hippocampus; 2) single unilateral, with 1 hippocampal depth lead and another implant outside the mesial temporal lobe; and 3) dual unilateral, with 2 leads in 1 hippocampus. Contact placement on postoperative imaging was measured according to the number of hippocampal contacts per targeted hippocampus (contact density) and per patient (contact count), distribution throughout the hippocampus, and proximity to the anteromedial hippocampus., Results: Dual unilateral lead placement resulted in significantly higher hippocampal contact density compared with the single hippocampal approaches, but only showed a nonsignificant trend toward a higher rate of response. However, those patients with more than 4 contacts in a single hippocampus, achievable only with dual unilateral leads, had a significantly higher rate of response. The higher likelihood of response was poorly explained by more widespread hippocampal coverage, but well correlated with proximity to the anteromedial hippocampus., Conclusions: Dual unilateral hippocampal implantation increased RNS contact density in patients with unilateral MTLE, which contributed to improved outcomes, not by stimulating more of the hippocampus, but instead by being more likely to stimulate a latent subtarget in the anterior hippocampus. It remains to be explored whether a single electrode targeted selectively to this region would also result in improved outcomes.

Introduction: Neuromodulation is an important treatment modality for patients with drug-resistant epilepsy who are not candidates for resective or ablative procedures. However, randomized controlled trials and real-world studies reveal that a subset of patients will experience minimal reduction or even an increase in seizure frequency after neuromodulation. We describe our experience with patients who undergo a second intracranial neuromodulation procedure after unsatisfactory initial response to intracranial neuromodulation., Methods: We performed a retrospective chart review to identify all patients who had undergone deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or responsive neurostimulation (RNS), followed by additional intracranial neuromodulatory procedures, with at least 12 months of follow-up. Demographic and clinical data, including seizure frequencies, were collected., Results: All patients had temporal lobe epilepsy. Six patients were treated with concurrent ANT DBS and temporal lobe RNS, and 3 patients transitioned between neuromodulation systems. Of the patients treated concurrently with ANT DBS and temporal lobe RNS, 5 of the 6 patients experienced additional reduction in seizure frequency after adding a second neuromodulation system. Of the patients who switched between neuromodulation modalities, all patients experienced further reduction in seizure frequency., Conclusions: For patients who do not experience adequate benefit from initial therapy with ANT DBS or temporal lobe RNS, the addition of a neuromodulation system or switching to a different form of neuromodulation may allow for additional reduction in seizure frequency. Larger studies will need to be performed to understand whether the use of multiple systems concurrently leads to improved clinical results in patients who are initially treatment resistant to neuromodulation., (© 2024 S. Karger AG, Basel.)

Deep brain stimulation has demonstrated efficacy in reducing seizure frequency in patients with drug-resistant epilepsy who may otherwise not be candidates for other surgical procedures. Recently, a clinical device that can monitor neural activity in the form of local field potentials around the deep brain stimulator lead implant site has been introduced. While this technology has been clinically adopted in other disorders treated with deep brain stimulation, such as Parkinson's disease, its application in epilepsy remains unclear. Previous research using investigational devices has suggested that specific frequency bands may correlate with clinical response to deep brain stimulation in epilepsy, but features of the clinical device may prevent its use. The authors present their experience with using this technology in epilepsy patients and describe some of its limitations. Ultimately, novel biomarkers will need to be identified to elucidate how neural activity at deep brain stimulation sites may change with clinical response., Competing Interests: Disclosure Dr R.E. Gross serves as a consultant to Medtronic, which manufactures products related to the research described in this article, and receives compensation for these services. Additionally, Dr R.E. Gross receives research support for clinical trials from Medtronic. The terms of these arrangements have been reviewed and approved by Emory University in accordance with conflict-of-interest policies. The other authors declare no conflicts of interested related to this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Thalamic deep brain stimulation (DBS) is an effective therapeutic option in patients with drug-resistant epilepsy. Recent DBS devices with sensing capabilities enable chronic, outpatient local field potential (LFP) recordings. Whereas beta oscillations have been demonstrated to be a useful biomarker in movement disorders, the clinical utility of DBS sensing in epilepsy remains unclear. Our aim was to determine LFP features that distinguish ictal from inter-ictal states, which may aid in tracking seizure outcomes with DBS., Methods: Electrophysiology data were obtained from DBS devices implanted in the anterior nucleus (N = 12) or centromedian nucleus (N = 2) of the thalamus. Power spectra recorded during patient/caregiver-marked seizure events were analyzed with a method that quantitatively separates the oscillatory and non-oscillatory/aperiodic components of the LFP using non-parametric statistics, without the need for pre-specification of the frequency bands of interest. Features of the LFP parameterized using this algorithm were compared with those from inter-ictal power spectra recorded in clinic., Results: Oscillatory activity in multiple canonical frequency bands was identified from the power spectra in 86.48% of patient-marked seizure events. Delta oscillations were present in all patients, followed by theta (N = 10) and beta (N = 9). Although there were no differences in oscillatory LFP features between the ictal and inter-ictal states, there was a steeper decline in the 1/f slope of the aperiodic component of the LFP during seizures., Significance: Our work highlights the potential and shortcomings of chronic LFP recordings in thalamic DBS for epilepsy. Findings suggest that no single frequency band in isolation clearly differentiates seizures, and that features of aperiodic LFP activity may be clinically-relevant biomarkers of seizures., (© 2023 International League Against Epilepsy.)

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD) 1 . However, achieving stable recovery is unpredictable 2 , typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting 3 . We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment., (© 2023. The Author(s).)

Objective: Deep brain stimulation (DBS) is a rapidly growing surgical option for patients with drug-resistant epilepsy who are not candidates for resective/ablative surgery. Recent randomized controlled trials have demonstrated efficacy of DBS of the anterior nucleus of the thalamus (ANT), particularly in frontal or temporal epilepsy, whereas DBS of the centromedian (CM) nucleus appears to be most suitable in well-defined generalized epilepsy syndromes. At the authors' institution, DBS candidates who did not fit the populations represented in these trials were managed with DBS of multiple distinct targets, which included ANT, CM, and less-studied nuclei-i.e., mediodorsal nucleus, pulvinar, and subthalamic nucleus. The goal of this study was to present the authors' experience with these types of cases, and to motivate future investigations that can determine the long-term efficacy of multitarget DBS., Methods: This single-center retrospective study of adult patients with drug-resistant epilepsy who underwent multitarget DBS was performed to demonstrate the feasibility and safety of this approach, and to present seizure outcomes. Patients in this cohort had epilepsy with features that were difficult to treat with DBS of the ANT or CM nucleus alone, including multifocal/multilobar, diffuse-onset, and/or posterior-onset seizures; or both generalized and focal seizures., Results: Eight patients underwent DBS of 2-3 distinct thalamic/subthalamic nuclei. DBS was performed with 2 electrodes in each hemisphere. All leads in each patient were implanted with either frontal or parietal trajectories. There were no surgical complications. Among those with > 6 months of follow-up (n = 5; range 7-21 months), all patients were responders in terms of overall seizure frequency and/or convulsive seizure frequency (i.e., ≥ 50% reduction). Two patients had adverse stimulation effects, which resolved with further programming., Conclusions: Multitarget DBS is a procedurally feasible and safe treatment strategy to maximize outcomes in patients with complex epilepsy. The authors highlight their approach to inform future studies that are sufficiently powered to assess its efficacy.

Background: Deep brain stimulation (DBS) is a highly efficacious treatment for appropriately selected patients with advanced, medically refractory Parkinson's disease (PD). It is severely underutilized in Black patients-constituting a major treatment gap. The source of this disparity is unknown, but its identification and correction are necessary to provide equitable care., Objective: To identify sources of racial disparity in DBS for PD., Methods: We predicted the demographics of potential DBS candidates by synthesizing published data on PD and race. We retrospectively examined the clinical course of a cohort including all patients with PD evaluated for DBS at our center from 2016 to 2020, testing whether the rate of DBS use and time from evaluation to surgery differed by race. We also tested whether the geographic distribution of patient catchment was biased relative to racial demographics., Results: Far fewer Black patients were evaluated for DBS than would be expected, given regional demographics. There was no significant difference in the rate at which Black patients evaluated in our clinic were treated with DBS, compared with White patients. Fewer patients were recruited from portions of the surrounding area with larger Black populations., Conclusion: The known underuse of DBS in Black patients with PD was replicated in this sample from a center in a racially diverse metropolitan area, but was not attributable to the presurgical workup. Future work should examine the transition from medical management to surgical evaluation where drivers of disparity are potentially situated. Surgical practices should increase outreach to physicians managing PD in underserved areas., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Deep brain stimulation (DBS) devices capable of measuring differential local field potentials ( ∂ LFP) enable neural recordings alongside clinical therapy. Efforts to identify oscillatory correlates of various brain disorders, or disease readouts, are growing but must proceed carefully to ensure readouts are not distorted by brain environment. In this report we identified, characterized, and mitigated a major source of distortion in ∂ LFP that we introduce as mismatch compression (MC). Using in vivo, in silico, and in vitro models of MC, we showed that impedance mismatches in the two recording electrodes can yield incomplete rejection of stimulation artifact and subsequent gain compression that distorts oscillatory power. We then developed and validated an opensource mitigation pipeline that mitigates the distortions arising from MC. This work enables more reliable oscillatory readouts for adaptive DBS applications.

Objective: Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug-resistant epilepsy. Drug-resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT-DBS or TL-RNS for drug-resistant TLE at our center., Methods: We performed a retrospective review of patients who were treated with either ANT-DBS or TL-RNS for drug-resistant TLE with at least 12 months of follow-up. Along with the clinical characteristics of each patient's epilepsy, seizure frequency was recorded throughout each patient's postoperative clinical course., Results: Twenty-six patients underwent ANT-DBS implantation and 32 patients underwent TL-RNS for drug-resistant TLE. The epilepsy characteristics of both groups were similar. Patients who underwent ANT-DBS demonstrated a median seizure reduction of 58% at 12-15 months, compared to a median seizure reduction of 70% at 12-15 months in patients treated with TL-RNS (p > .05). The responder rate (percentage of patients with a 50% decrease or more in seizure frequency) was 54% for ANT-DBS and 56% for TL-RNS (p > .05). The incidence of complications and stimulation-related side effects did not significantly differ between therapies., Significance: We demonstrate in our single-center experience that patients with drug-resistant TLE benefit similarly from either ANT-DBS or TL-RNS. Selection of either ANT-DBS or TL-RNS may, therefore, depend more heavily on patient and provider preference, as each has unique capabilities and configurations. Future studies will consider subgroup analyses to determine if specific patients have greater seizure frequency reduction from one form of neuromodulation strategy over another., (© 2022 International League Against Epilepsy.)

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial., (© 2022 International League Against Epilepsy.)

Purpose of Review: To summarize current evidence and recent developments in the surgical treatment of drug-resistant generalized epilepsy., Recent Findings: Current surgical treatments of drug-resistant generalized epilepsy include vagus nerve stimulation (VNS), deep brain stimulation (DBS) and corpus callosotomy (CC). Neurostimulation with VNS and/or DBS has been shown to be effective in reducing seizure frequency in patients with generalized epilepsy. DBS for generalized epilepsy is primarily consisted of open-loop stimulation directed at the centromedian (CM) nucleus in the thalamus, though closed-loop stimulation and additional targets are being explored. CC can be effective in treating some seizure types and can be performed using traditional surgical techniques or with the less invasive methods of laser ablation and radiosurgery. This current literature supports the use of VNS, DBS and CC, alone or in combination, as palliative treatments of drug-resistant generalized epilepsy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Neuromodulation of the centromedian nucleus of the thalamus (CM) has unclear effectiveness in the treatment of drug-resistant epilepsy. Prior reports suggest that it may be more effective in the generalized epilepsies such as Lennox-Gastaut syndrome (LGS). The objective of this study was to determine the outcome of CM deep brain stimulation (DBS) at the authors' institution., Methods: Retrospective chart review was performed for all patients who underwent CM DBS at Emory University, which occurred between December 2018 and May 2021. CM DBS electrodes were implanted using three different surgical methods, including frame-based, robot-assisted, and direct MRI-guided. Seizure frequency, stimulation parameters, and adverse events were recorded from subsequent clinical follow-up visits., Results: Fourteen patients underwent CM DBS: 9 had symptomatic generalized epilepsy (including 5 with LGS), 3 had primary or idiopathic generalized epilepsy, and 2 had bifrontal focal epilepsy. At last follow-up (mean [± SEM] 19 ± 5 months, range 4.1-33 months, ≥ 6 months in 11 patients), the median seizure frequency reduction was 91%. Twelve patients (86%) were considered responders (≥ 50% decrease in seizure frequency), including 10 of 12 with generalized epilepsy and both patients with bifrontal epilepsy. Surgical adverse events were rare and included 1 patient with hardware breakage, 1 with a postoperative aspiration event, and 1 with a nonclinically significant intracranial hemorrhage., Conclusions: CM DBS was an effective treatment for drug-resistant generalized and bifrontal epilepsies. Additional studies and analyses may investigate whether CM DBS is best suited for specific epilepsy types, and the relationship of lead location to outcome in different epilepsies.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is a promising intervention for treatment-resistant depression (TRD). Despite the failure of a clinical trial, multiple case series have described encouraging results, especially with the introduction of improved surgical protocols. Recent evidence further suggests that tractography targeting and intraoperative exposure to stimulation enhances early antidepressant effects that further evolve with ongoing chronic DBS. Accelerating treatment gains is critical to the care of this at-risk population, and identification of intraoperative electrophysiological biomarkers of early antidepressant effects will help guide future treatment protocols. Eight patients underwent intraoperative electrophysiological recording when bilateral DBS leads were implanted in the SCC using a connectomic approach at the site previously shown to optimize 6-month treatment outcomes. A machine learning classification method was used to discriminate between intracranial local field potentials (LFPs) recorded at baseline (stimulation-naïve) and after the first exposure to SCC DBS during surgical procedures. Spectral inputs (theta, 4-8 Hz; alpha, 9-12 Hz; beta, 13-30 Hz) to the model were then evaluated for importance to classifier success and tested as predictors of the antidepressant response. A decline in depression scores by 45.6% was observed after 1 week and this early antidepressant response correlated with a decrease in SCC LFP beta power, which most contributed to classifier success. Intraoperative exposure to therapeutic stimulation may result in an acute decrease in symptoms of depression following SCC DBS surgery. The correlation of symptom improvement with an intraoperative reduction in SCC beta power suggests this electrophysiological finding as a biomarker for treatment optimization., (© 2021. The Author(s).)

Background: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites., Objective: To conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings., Methods: Postoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes., Results: Approximately 70% of subjects had "good" bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05)., Conclusion: Consistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy., (© Congress of Neurological Surgeons 2021.)

Objective. Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) but its success depends on a time-consuming process of trial-and-error to identify the optimal stimulation settings for each individual patient. Data-driven optimization algorithms have been proposed to efficiently find the stimulation setting that maximizes a quantitative biomarker of symptom relief. However, these algorithms cannot efficiently take into account stimulation settings that may control symptoms but also cause side effects. Here we demonstrate how multi-objective data-driven optimization can be used to find the optimal trade-off between maximizing symptom relief and minimizing side effects. Approach. Cortical and motor evoked potential data collected from PD patients during intraoperative stimulation of the subthalamic nucleus were used to construct a framework for designing and prototyping data-driven multi-objective optimization algorithms. Using this framework, we explored how these techniques can be applied clinically, and characterized the design features critical for solving this optimization problem. Our two optimization objectives were to maximize cortical evoked potentials, a putative biomarker of therapeutic benefit, and to minimize motor potentials, a biomarker of motor side effects. Main Results. Using this in silico design framework, we demonstrated how the optimal trade-off between two objectives can substantially reduce the stimulation parameter space by 61 ± 19%. The best algorithm for identifying the optimal trade-off between the two objectives was a Bayesian optimization approach with an area under the receiver operating characteristic curve of up to 0.94 ± 0.02, which was possible with the use of a surrogate model and a well-tuned acquisition function to efficiently select which stimulation settings to sample. Significance. These findings show that multi-objective optimization is a promising approach for identifying the optimal trade-off between symptom relief and side effects in DBS. Moreover, these approaches can be readily extended to newly discovered biomarkers, adapted to DBS for disorders beyond PD, and can scale with the development of more complex DBS devices., (© 2021 IOP Publishing Ltd.)

Background: Subthalamic deep brain stimulation (DBS) is an effective surgical treatment for Parkinson's disease and continues to advance technologically with an enormous parameter space. As such, in-silico DBS modeling systems have become common tools for research and development, but their underlying methods have yet to be standardized and validated., Objective: Evaluate the accuracy of patient-specific estimates of neural pathway activations in the subthalamic region against intracranial, cortical evoked potential (EP) recordings., Methods: Pathway activations were modeled in eleven patients using the latest advances in connectomic modeling of subthalamic DBS, focusing on the hyperdirect pathway (HDP) and corticospinal/bulbar tract (CSBT) for their relevance in human research studies. Correlations between pathway activations and respective EP amplitudes were quantified., Results: Good model performance required accurate lead localization and image fusions, as well as appropriate selection of fiber diameter in the biophysical model. While optimal model parameters varied across patients, good performance could be achieved using a global set of parameters that explained 60% and 73% of electrophysiologic activations of CSBT and HDP, respectively. Moreover, restricted models fit to only EP amplitudes of eight standard (monopolar and bipolar) electrode configurations were able to extrapolate variation in EP amplitudes across other directional electrode configurations and stimulation parameters, with no significant reduction in model performance across the cohort., Conclusions: Our findings demonstrate that connectomic models of DBS with sufficient anatomical and electrical details can predict recruitment dynamics of white matter. These results will help to define connectomic modeling standards for preoperative surgical targeting and postoperative patient programming applications., Competing Interests: Declaration of competing interest Bryan Howell is a paid consultant for Abbott Laboratories. Robert E. Gross is a paid consultant for Medtronic, PLC and Abbot Laboratories. Philip A: Starr has research supported by Medtronic, PLC and Boston Scientific, Co. Jon T. Willie is a paid consultant for Medtronic, PLC and Neuropace, Inc. Cameron C. McIntyre is a paid consultant for Boston Scientific, Co., receives royalties from Hologram Consultants, Neuros Medical, and Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, CereGate, Autonomic Technologies, Cardionomic, Enspire DBS. All other authors have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is the surgical method of choice to treat the canonical symptoms of Parkinson disease, occasionally surgical sites become infected or the hardware erodes, necessitating explantation. Usual practice is to remove and reimplant replacement leads after tissue healing, leaving patients without the clinical benefits of DBS for several months, and at risk for DBS withdrawal in some, and some patients are no longer good surgical candidates for reimplantation. Radiofrequency ablation through the DBS lead is an option for these patients., Methods: We performed a retrospective chart review of all patients who underwent radiofrequency ablation of the STN or GPi through indwelling DBS leads performed before hardware removal at our institution. We generated patient-specific anatomic models to determine lesion locations and volumes., Results: Six patients underwent radiofrequency ablation of the STN (n = 4) and GPi (n = 2) through indwelling DBS leads. All 6 of these patients initially showed comparable motor symptom relief to that experienced with DBS before lesioning, with 4 patients sustaining meaningful long-term (≥2 years) improvement. Better outcomes were achieved in those patients with a higher percentage of the planned target lesioned., Conclusions: Radiofrequency ablation through indwelling DBS leads before explantation could be considered a viable alternative to subsequent reimplantation or stereotactic lesion in patients with Parkinson disease in whom hardware explantation is necessary, if the patient achieved substantive symptom relief with DBS. This approach avoids symptom exacerbation while awaiting revision surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes., Objective: The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain., Methods: To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations., Results: Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity., Conclusion: By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity., Competing Interests: Declaration of competing interest M.K. and D.R. have started a company, Nia Therapeutics, Inc., intended to develop and commercialize brain stimulation therapies for memory restoration. Each of them holds >5% equity interest in Nia. R.E.G. serves as a consultant to Medtronic, which was a subcontractor on the RAM project. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. B.J. receives research funding from NeuroPace and Medtronic not relating to this research. G.W. has rights to receive future royalties from the licensing of brain stimulation technology. Mayo Clinic has a financial interest related to brain stimulation technology, and is co-owner of Cadence Neuroscience Inc, the development of which has been assisted by G.W. The remaining authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several studies have shown that direct brain stimulation can enhance memory in humans and animal models. Investigating the neurophysiological changes induced by brain stimulation is an important step towards understanding the neural processes underlying memory function. Furthermore, it paves the way for developing more efficient neuromodulation approaches for memory enhancement. In this study, we utilized a combination of unsupervised and supervised machine learning approaches to investigate how amygdala stimulation modulated hippocampal network activities during the encoding phase. Using a sliding window in time, we estimated the hippocampal dynamic functional network connectivity (dFNC) after stimulation and during sham trials, based on the covariance of local field potential recordings in 4 subregions of the hippocampus. We extracted different network states by combining the dFNC samples from 5 subjects and applying k-means clustering. Next, we used the between-state transition numbers as the latent features to classify between amygdala stimulation and sham trials across all subjects. By training a logistic regression model, we could differentiate stimulated from sham trials with 67% accuracy across all subjects. Using elastic net regularization as a feature selection method, we identified specific patterns of hippocampal network state transition in response to amygdala stimulation. These results offer a new approach to better understanding of the causal relationship between hippocampal network dynamics and memory-enhancing amygdala stimulation.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease., Methods: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396., Findings: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation., Interpretation: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes., Funding: Boston Scientific., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance., Methods: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters., Results: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery., Conclusions: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Objective: We conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor., Methods: Seven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation 'off', three ramped-frequency stimulation (RFS) trains from 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network., Results: Temporally patterned 130 → 60 Hz ramped-frequency trains suppressed tremor relative to stimulation 'off,' but 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions., Conclusion: Frequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism., Significance: Ramping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern., Competing Interests: Declaration of Competing Interest W.M.G. is an inventor on awarded and pending patents related to nonregular patterns of DBS. These patents are owned by Duke University and licensed to Deep Brain Innovations LLC (DBI). W.M.G. is Cofounder, Director, and Chief Scientific Officer of DBI; W.M.G. owns equity in DBI. W.M.G. is Director and Chief scientific Officer of the NDI Healthcare Fund, which is an investor in DBI. These relationships are reported to the Conflict of Interest Committee at Duke University. R.E.G. receives research funding from Medtronic. R.E.G. serves as a consultant to Medtronic, St. Jude Medical, and DBI and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Most medical centers are postponing elective procedures and deferring non-urgent clinic visits to conserve hospital resources and prevent spread of COVID-19. The pandemic crisis presents some unique challenges for patients currently being treated with deep brain stimulation (DBS). Movement disorder (Parkinson's disease, essential tremor, dystonia), neuropsychiatric disorder (obsessive compulsive disorder, Tourette syndrome, depression), and epilepsy patients can develop varying degrees of symptom worsening from interruption of therapy due to neurostimulator battery reaching end of life, device malfunction or infection. Urgent intervention to maintain or restore stimulation may be required for patients with Parkinson's disease who can develop a rare but potentially life-threatening complication known as DBS-withdrawal syndrome. Similarly, patients with generalized dystonia can develop status dystonicus, patients with obsessive compulsive disorder can become suicidal, and epilepsy patients can experience potentially life-threatening worsening of seizures as a result of therapy cessation. DBS system infection can require urgent, and rarely emergent surgery. Elective interventions including new implantations and initial programming should be postponed. For patients with existing DBS systems, the battery status and electrical integrity interrogation can now be performed using patient programmers, and employed through telemedicine visits or by phone consultations. The decision for replacement of the implantable pulse generator to prevent interruption of DBS therapy should be made on a case-by-case basis taking into consideration battery status and a patient's tolerance to potential therapy disruption. Scheduling of the procedures, however, depends heavily on the hospital system regulations and on triage procedures with respect to safety and resource utilization during the health crisis.

Objective: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression., Methods: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years., Results: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides., Conclusions: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

Background: Subcallosal cingulate deep brain stimulation (SCC DBS) is an experimental treatment for severe depression. Surgery is performed with awake patients and intraoperative stimulation produces acute behavioral responses in select contacts. While there have been reports on the relationship between acute intraoperative behaviors and their relation to the location of the contacts, there are no descriptions of the physiological changes that accompany them., Objective: The present study sought to examine these physiological readouts, and their association with the anatomical substrates that generated them., Methods: Nine patients with severe, treatment-resistant depression were tested intraoperatively. The stimulation protocol consisted of 12 three-minute, sham-controlled, double-blind trials. Changes in heart rate and skin conductance were recorded during each stimulation cycle. Probabilistic tractography between the stimulated contacts and predefined regions of the mood regulation network was performed., Results: Acute intraoperative SCC stimulation produced increases in autonomic sympathetic response that correlated with the salience of the behavioral responses. The autonomic changes were observed within seconds of initiating acute stimulation and prior to verbalization of subjective experiences. The probabilistic tractography analysis suggested that structural connectivity between the stimulated area and the midcingulate cortex is the primary pathway that mediates autonomic responsivity to SCC DBS., Conclusions: These findings demonstrate that acute SCC stimulation produces autonomic and behavioral changes in the operating room that are explained by the modulation of networks associated with long term antidepressant response. Intraoperative autonomic recordings paired with careful behavioral observations and precise anatomical mapping aid in the identification and classification of the intraoperative phenomena., (Copyright © 2019. Published by Elsevier Inc.)

Question 1: Is bilateral subthalamic nucleus deep brain stimulation (STN DBS) more, less, or as effective as bilateral globus pallidus internus deep brain stimulation (GPi DBS) in treating motor symptoms of Parkinson's disease, as measured by improvements in Unified Parkinson's Disease Rating Scale, part III (UPDRS-III) scores?, Recommendation: Given that bilateral STN DBS is at least as effective as bilateral GPi DBS in treating motor symptoms of Parkinson's disease (as measured by improvements in UPDRS-III scores), consideration can be given to the selection of either target in patients undergoing surgery to treat motor symptoms. (Level I)., Question 2: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in allowing reduction of dopaminergic medication in Parkinson's disease?, Recommendation: When the main goal of surgery is reduction of dopaminergic medications in a patient with Parkinson's disease, then bilateral STN DBS should be performed instead of GPi DBS. (Level I)., Question 3: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in treating dyskinesias associated with Parkinson's disease?, Recommendation: There is insufficient evidence to make a generalizable recommendation regarding the target selection for reduction of dyskinesias. However, when the reduction of medication is not anticipated and there is a goal to reduce the severity of "on" medication dyskinesias, the GPi should be targeted. (Level I)., Question 4: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in improving quality of life measures in Parkinson's disease?, Recommendation: When considering improvements in quality of life in a patient undergoing DBS for Parkinson's disease, there is no basis to recommend bilateral DBS in 1 target over the other. (Level I)., Question 5: Is bilateral STN DBS associated with greater, lesser, or a similar impact on neurocognitive function than bilateral GPi DBS in Parkinson disease?, Recommendation: If there is significant concern about cognitive decline, particularly in regards to processing speed and working memory in a patient undergoing DBS, then the clinician should consider using GPi DBS rather than STN DBS, while taking into consideration other goals of surgery. (Level I)., Question 6: Is bilateral STN DBS associated with a higher, lower, or similar risk of mood disturbance than GPi DBS in Parkinson's disease?, Recommendation: If there is significant concern about the risk of depression in a patient undergoing DBS, then the clinician should consider using pallidal rather than STN stimulation, while taking into consideration other goals of surgery. (Level I)., Question 7: Is bilateral STN DBS associated with a higher, lower, or similar risk of adverse events compared to GPi DBS in Parkinson's disease?, Recommendation: There is insufficient evidence to recommend bilateral DBS in 1 target over the other in order to minimize the risk of surgical adverse events.  The full guideline can be found at: https://www.cns.org/guidelines/deep-brain-stimulation-parkinsons-disease.

Direct electrical stimulation of the human brain can elicit sensory and motor perceptions as well as recall of memories. Stimulating higher order association areas of the lateral temporal cortex in particular was reported to activate visual and auditory memory representations of past experiences (Penfield and Perot, 1963). We hypothesized that this effect could be used to modulate memory processing. Recent attempts at memory enhancement in the human brain have been focused on the hippocampus and other mesial temporal lobe structures, with a few reports of memory improvement in small studies of individual brain regions. Here, we investigated the effect of stimulation in four brain regions known to support declarative memory: hippocampus, parahippocampal neocortex, prefrontal cortex and temporal cortex. Intracranial electrode recordings with stimulation were used to assess verbal memory performance in a group of 22 patients (nine males). We show enhanced performance with electrical stimulation in the lateral temporal cortex (paired t-test, P = 0.0067), but not in the other brain regions tested. This selective enhancement was observed both on the group level, and for two of the four individual subjects stimulated in the temporal cortex. This study shows that electrical stimulation in specific brain areas can enhance verbal memory performance in humans.awx373media15704855796001.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome., Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome., Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide., Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%])., Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events., Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%])., Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Background: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from preoperatively collected diffusion-weighted imaging (DWI) data. However, brain shift induced by opening burr holes in the skull may alter the position of the target pathways., Objectives: Quantify the effect of electrode location deviations on tractographic representations for stimulating the target pathways using longitudinal clinical imaging datasets., Methods: Preoperative MRI and DWI data (planned) were coregistered with postoperative MRI (1 day, near-term) and CT (3 weeks, long-term) data. Brain shift was measured with anatomical control points. Electrode models corresponding to the planned, near-term, and long-term locations were defined in each hemisphere of 15 patients. Tractography analyses were performed using estimated stimulation volumes as seeds centered on the different electrode positions., Results: Mean brain shift of 2.2 mm was observed in the near-term for the frontal pole, which resolved in the long-term. However, electrode displacements from the planned stereotactic target location were observed in the anterior-superior direction in both the near-term (mean left electrode shift: 0.43 mm, mean right electrode shift: 0.99 mm) and long-term (mean left electrode shift: 1.02 mm, mean right electrode shift: 1.47 mm). DBS electrodes implanted in the right hemisphere (second-side operated) were more displaced from the plan than those in the left hemisphere. These displacements resulted in 3.6% decrease in pathway activation between the electrode and the ventral striatum, but 2.7% increase in the frontal pole connection, compared to the plan. Remitters from six-month chronic stimulation had less variance in pathway activation patterns than the non-remitters., Conclusions: Brain shift is an important concern for SCC DBS surgical targeting and can impact connectomic analyses., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Create a software tool to facilitate tractography-based deep brain stimulation (DBS) electrode targeting within the patient-specific stereotactic coordinate system used in the operating room., Approach: StimVision was developed with Visualization Toolkit libraries and integrates four major components: 1) medical image visualization, 2) tractography visualization, 3) DBS electrode positioning, and 4) DBS activation volume calculation with tractography intersection., Results: Initial applications of StimVision are focused on the study of subcallosal cingulate (SCC) DBS for the treatment of depression. Retrospective modeling results on SCC DBS have suggested that direct stimulation of a specific collection of tractographic pathways are necessary for therapeutic benefit; thereby creating a tractography-based DBS surgical targeting hypotheses. StimVision is the tool we created to facilitate prospective clinical evaluation of that hypothesis., Significance: Retrospective tractography-based analyses are common in DBS research; however, intraoperative software tools for interactive selection of a tractography-based DBS target are not readily available. StimVision provides an academic research tool to assist clinical implementation of new DBS targeting strategies and postoperative evaluation of targeting outcome., (© 2017 International Neuromodulation Society.)

Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies., Competing Interests: The authors declare no conflict of interest.

Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted., Methods: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162., Findings: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery., Interpretation: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy., Funding: Abbott (previously St Jude Medical)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin., Methods: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events., Results: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices)., Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection., (© 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin., Methods: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset., Results: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices., Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex., (© 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

It is estimated that over 160,000 patients worldwide have received deep brain stimulation (DBS) to date predominantly for Parkinson's disease and other movement disorders. With the success of this therapy, a greater appreciation of the clinical benefits and adverse effects is being realized. Neurosurgeons are increasingly paying attention to the technical details of these procedures and optimizing targeting, surgical techniques, and programming to improve outcomes. In this issue, the nuances of surgical techniques for DBS are covered by Dr. House. Dr. Toda et al. and Mr. Chartrain et al. tackle the approach to treating tremors, either essential tremor or Holmes tremor, using either a single target or, in cases of difficult-to-treat tremors, using more than one target and interleaving the stimulation. These abstracts and videos will be appreciated by both those who are being initiated to DBS and the more seasoned practitioners who are looking for helpful hints to tackle challenging cases.

Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy and are refractory to all current medical and surgical therapies in about one-sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the central lateral nucleus of the intralaminar thalamus (CL) and the pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the "network inhibition hypothesis" that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multisite deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy but also those with other disorders of consciousness., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Brain stimulation is a promising therapy for several neurological disorders, including Parkinson's disease. Stimulation parameters are selected empirically and are limited to the frequency and intensity of stimulation. We varied the temporal pattern of deep brain stimulation to ameliorate symptoms in a parkinsonian animal model and in humans with Parkinson's disease. We used model-based computational evolution to optimize the stimulation pattern. The optimized pattern produced symptom relief comparable to that from standard high-frequency stimulation (a constant rate of 130 or 185 Hz) and outperformed frequency-matched standard stimulation in a parkinsonian rat model and in patients. Both optimized and standard high-frequency stimulation suppressed abnormal oscillatory activity in the basal ganglia of rats and humans. The results illustrate the utility of model-based computational evolution of temporal patterns to increase the efficiency of brain stimulation in treating Parkinson's disease and thereby reduce the energy required for successful treatment below that of current brain stimulation paradigms., (Copyright © 2017, American Association for the Advancement of Science.)

Deep brain stimulation (DBS) has shown promise for treating a range of brain disorders and neurological conditions. One recent study showed that DBS in the entorhinal region improved the accuracy of human spatial memory. Based on this line of work, we performed a series of experiments to more fully characterize the effects of DBS in the medial temporal lobe on human memory. Neurosurgical patients with implanted electrodes performed spatial and verbal-episodic memory tasks. During the encoding periods of both tasks, subjects received electrical stimulation at 50 Hz. In contrast to earlier work, electrical stimulation impaired memory performance significantly in both spatial and verbal tasks. Stimulation in both the entorhinal region and hippocampus caused decreased memory performance. These findings indicate that the entorhinal region and hippocampus are causally involved in human memory and suggest that refined methods are needed to use DBS in these regions to improve memory., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We conducted intraoperative measurements of tremor during DBS containing short pauses (⩽50 ms) to determine if there is a minimum pause duration that preserves tremor suppression., Methods: Nine subjects with ET and thalamic DBS participated during IPG replacement surgery. Patterns of DBS included regular 130 Hz stimulation interrupted by 0, 15, 25 or 50 ms pauses. The same patterns were applied to a model of the thalamic network to quantify effects of pauses on activity of model neurons., Results: All patterns of DBS decreased tremor relative to 'off'. Patterns with pauses generated less tremor reduction than regular high frequency DBS. The model revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but pauses in stimulation allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions., Conclusions: The temporal pattern of stimulation influences the efficacy of thalamic DBS. Pauses in stimulation resulted in decreased tremor suppression indicating that masking of pathological bursting is a mechanism of thalamic DBS for tremor., Significance: Pauses in stimulation decreased the efficacy of open-loop DBS for suppression of tremor., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Electrical brain stimulation has shown promise for reducing seizures in drug-resistant epilepsy, but the electrical stimulation parameter space remains largely unexplored. New stimulation parameters, electrode types, and stimulation targets may be more effective in controlling seizures compared to currently available options., Hypothesis: We hypothesized that a novel electrical stimulation approach involving distributed multielectrode microstimulation at the epileptic focus would reduce seizure frequency in the tetanus toxin model of temporal lobe epilepsy., Methods: We explored a distributed multielectrode microstimulation (DMM) approach in which electrical stimulation was delivered through 15 33-µm-diameter electrodes implanted at the epileptic focus (dorsal hippocampus) in the rat tetanus toxin model of temporal lobe epilepsy., Results: We show that hippocampal theta (6-12 Hz brain oscillations) is decreased in this animal model during awake behaving conditions compared to control animals (p < 10(-4)). DMM with biphasic, theta-range (6-12 Hz/electrode) pulses delivered asynchronously on the 15 microelectrodes was effective in reducing seizures by 46% (p < 0.05). When theta pulses or sinusoidal stimulation was delivered synchronously and continuously on the 15 microelectrodes, or through a single macroelectrode, no effects on seizure frequency were observed. High frequency stimulation (>16.66 Hz/per electrode), in contrast, had a tendency to increase seizure frequency., Conclusions: These results indicate that DMM could be a new effective approach to therapeutic brain stimulation for reducing seizures in epilepsy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Importance: The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown., Objective: To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression., Design, Setting, and Participants: Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015., Main Outcomes and Measures: Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes., Results: Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch.", Conclusions and Relevance: This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients., (© 2014 International Parkinson and Movement Disorder Society.)

Objective: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy., Methods: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries., Results: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001)., Conclusion: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population., Classification of Evidence: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years., (© 2015 American Academy of Neurology.)

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures., Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy., Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%)., Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures., Classification of Evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years., (© 2015 American Academy of Neurology.)

Background: Several case reports and small series have indicated that tardive dystonia is responsive to globus pallidus deep brain stimulation. Whether different subtypes or distributions of tardive dystonia are associated with different outcomes remains unknown., Methods: We assessed the outcomes and temporal profile of improvement of eight tardive dystonia patients who underwent globus pallidus deep brain stimulation over the past six years through record review. Due to the retrospective nature of this study, it was not blinded or placebo controlled., Results: Consistent with previous studies, deep brain stimulation improved the overall the Burke-Fahn-Marsden motor scores by 85.1 ± 13.5%. The distributions with best responses in descending order were upper face, lower face, larynx/pharynx, limbs, trunk, and neck. Patients with prominent cervical dystonia demonstrated improvement in the Toronto Western Spasmodic Torticollis Rating Scale but improvements took several months. In four patients the effects of deep brain stimulation on improvement in Burke Fahn Marsden score was rapid, while in four cases there was partial rapid response of neck and trunk dystonia followed by was gradual resolution of residual symptoms over 48 months., Conclusion: Our retrospective analysis shows excellent resolution of tardive dystonia after globus pallidus deep brain stimulation. We found instantaneous response, except with neck and trunk dystonia where partial recovery was followed by further resolution at slower rate. Such outcome is encouraging for using deep brain stimulation in treatment of tardive dystonia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Deep brain stimulation (DBS) treats the symptoms of several movement disorders, but optimal selection of stimulation parameters remains a challenge. The evoked compound action potential (ECAP) reflects synchronized neural activation near the DBS lead, and may be useful for feedback control and automatic adjustment of stimulation parameters in closed-loop DBS systems., Objectives: Determine the feasibility of recording ECAPs in the clinical setting, understand the neural origin of the ECAP and sources of any stimulus artifact, and correlate ECAP characteristics with motor symptoms., Methods: The ECAP and tremor response were measured simultaneously during intraoperative studies of thalamic DBS, conducted in patients who were either undergoing surgery for initial lead implantation or replacement of their internal pulse generator., Results: There was large subject-to-subject variation in stimulus artifact amplitude, which model-based analysis suggested may have been caused by glial encapsulation of the lead, resulting in imbalances in the tissue impedance between the contacts. ECAP recordings obtained from both acute and chronically implanted electrodes revealed that specific phase characteristics of the signal varied systematically with stimulation parameters. Further, a trend was observed in some patients between the energy of the initial negative and positive ECAP phases, as well as secondary phases, and changes in tremor from baseline. A computational model of thalamic DBS indicated that direct cerebellothalamic fiber activation dominated the clinically measured ECAP, suggesting that excitation of these fibers is critical in DBS therapy., Conclusions: This work demonstrated that ECAPs can be recorded in the clinical setting and may provide a surrogate feedback control signal for automatic adjustment of stimulation parameters to reduce tremor amplitude., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.