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Objective. Electrodes chronically implanted in the brain undergo complex changes over time that can lower the signal to noise ratio (SNR) of recorded signals and reduce the amount of energy delivered to the tissue during therapeutic stimulation, both of which are relevant for the development of robust, closed-loop control systems. Several factors have been identified that link changes in the electrode-tissue interface (ETI) to increased impedance and degraded performance in micro- and macro-electrodes. Previous studies have demonstrated that brief pulses applied every few days can restore SNR to near baseline levels during microelectrode recordings in rodents, a process referred to as electrical rejuvenation. However, electrical rejuvenation has not been tested in clinically relevant macroelectrode designs in large animal models, which could serve as preliminary data for translation of this technique. Here, several variations of this approach were tested to characterize parameters for optimization. Approach . Alternating-current (AC) and direct-current (DC) electrical rejuvenation methods were explored in three electrode types, chronically implanted in two adult male nonhuman primates (NHP) ( Macaca mulatta ), which included epidural electrocorticography (ECoG) electrodes and penetrating deep-brain stimulation (DBS) electrodes. Electrochemical impedance spectroscopy (EIS) was performed before and after each rejuvenation paradigm as a gold standard measure of impedance, as well as at subsequent intervals to longitudinally track the evolution of the ETI. Stochastic error modeling was performed to assess the standard deviation of the impedance data, and consistency with the Kramers-Kronig relations was assessed to evaluate the stationarity of EIS measurement. Main results . AC and DC rejuvenation were found to quickly reduce impedance and minimize the tissue component of the ETI on all three electrode types, with DC and low-frequency AC producing the largest impedance drops and reduction of the tissue component in Nyquist plots. The effects of a single rejuvenation session were found to last from several days to over 1 week, and all rejuvenation pulses induced no observable changes to the animals' behavior. Significance . These results demonstrate the effectiveness of electrical rejuvenation for diminishing the impact of chronic ETI changes in NHP with clinically relevant macroelectrode designs., (© 2024 IOP Publishing Ltd.)

This paper outlines the therapeutic rationale and neurosurgical targeting technique for bilateral, closed-loop, thalamocortical stimulation in Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy. Thalamic stimulation can be an effective treatment for Lennox-Gastaut syndrome, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. We aimed to identify a cortical target by synthesizing prior neuroimaging studies, and to use this knowledge to advance a dual thalamic (centromedian) and cortical (frontal) approach for closed-loop stimulation. Multi-modal brain network maps from three group-level studies of Lennox-Gastaut syndrome were averaged to define the area of peak overlap: simultaneous EEG-functional MRI of generalized paroxysmal fast activity, [ 18 F]fluorodeoxyglucose PET of cortical hypometabolism and diffusion MRI structural connectivity associated with clinical efficacy in a previous trial of thalamic deep brain stimulation. The resulting 'hotspot' was used as a seed in a normative functional MRI connectivity analysis to identify connected networks. Intracranial electrophysiology was reviewed in the first two trial patients undergoing bilateral implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analysed for presence and synchrony of epileptiform activity. The peak overlap was in bilateral premotor cortex/caudal middle frontal gyrus. Functional connectivity of this hotspot revealed a distributed network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-functional MRI and PET. Intracranial electrophysiology showed characteristic epileptiform activity of Lennox-Gastaut syndrome in both the cortical hotspot and thalamus; most detected events occurred first in the cortex before appearing in the thalamus. Premotor frontal cortex shows peak involvement in Lennox-Gastaut syndrome and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for a range of neuromodulation therapies, including thalamocortical stimulation and emerging non-invasive treatments like focused ultrasound or transcranial magnetic stimulation. Compared to thalamus-only approaches, the addition of this cortical target may allow more rapid detections of seizures, more diverse stimulation paradigms and broader modulation of the epileptic network. A prospective, multi-centre trial of closed-loop thalamocortical stimulation for Lennox-Gastaut syndrome is currently underway., Competing Interests: A.E.L.W., M.P.H., L.J.D., E.M.-L., F.L.W.V.J.S., L.A.H., H.S. and K.L.B. have no competing interests to report. C.R.B. has recently served as a consultant for NeuraModix and Abbott and holds intellectual property related to neuromodulation therapy. J.S.A. has received honoraria from Medtronic. R.E.G. received research support from NeuroPace, Medtronic and Boston Scientific, and consulting payments from Medtronic, Boston Scientific, Abbott Labs and Nia Therapeutics, and holds equity interest in Nia Therapeutics; the arrangements are all approved by Emory University. L.J. and M.J.M. have equity ownership with NeuroPace and are employees of NeuroPace, Inc. J.D.R. has received consulting payments from Medtronic, Corlieve and NeuroPace., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: Responsive neurostimulation (RNS) is an established therapy for drug-resistant epilepsy that delivers direct electrical brain stimulation in response to detected epileptiform activity. However, despite an overall reduction in seizure frequency, clinical outcomes are variable, and few patients become seizure-free. The aim of this retrospective study was to evaluate aperiodic electrophysiological activity, associated with excitation/inhibition balance, as a novel electrographic biomarker of seizure reduction to aid early prognostication of the clinical response to RNS., Methods: We identified patients with intractable mesial temporal lobe epilepsy who were implanted with the RNS System between 2015 and 2021 at the University of Utah. We parameterized the neural power spectra from intracranial RNS System recordings during the first 3 months following implantation into aperiodic and periodic components. We then correlated circadian changes in aperiodic and periodic parameters of baseline neural recordings with seizure reduction at the most recent follow-up., Results: Seizure reduction was correlated significantly with a patient's average change in the day/night aperiodic exponent (r = .50, p = .016, n = 23 patients) and oscillatory alpha power (r = .45, p = .042, n = 23 patients) across patients for baseline neural recordings. The aperiodic exponent reached its maximum during nighttime hours (12 a.m. to 6 a.m.) for most responders (i.e., patients with at least a 50% reduction in seizures)., Significance: These findings suggest that circadian modulation of baseline broadband activity is a biomarker of response to RNS early during therapy. This marker has the potential to identify patients who are likely to respond to mesial temporal RNS. Furthermore, we propose that less day/night modulation of the aperiodic exponent may be related to dysfunction in excitation/inhibition balance and its interconnected role in epilepsy, sleep, and memory., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming., Methods: We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements., Results: We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months., Conclusion: MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy., Competing Interests: Conflicts of interest There are potential conflicts of interested related to Medtronic, Boston Scientific, and Abbott, who are the device manufacturers who produced the DBS systems implanted in the study subjects. The University of Florida has received grants from Medtronic, Boston Scientific, and Abbott, but the authors have financial interest in these grants. ARZ serves as a consultant for Medtronic and Boston Scientific. IUH has performed research for Boston Scientific, and has consulted for Boston Scientific and Medtronic. JLO has received grant support from Boston Scientific and Medtronic, has consulted for Medtronic and Abbott, and received non-financial research support from Boston Scientific. MSS has received grant support from Boston Scientific, and honoraria/nonfinancial support as a scientific advisor from Boston Scientific. As the director of the Movement Disorders Fellowship at the University of Florida, CWH has received industry grants for educational support for the fellowship program that are paid directly to the University of Florida and used solely for fellow salary support from Medtronic, Boston Scientific, and Abbott. MHP has received consultation fees from Medtronic, Boston Scientific, and Abbot. MSL has received consulting fees from Boston Scientific. CRB has received consulting feeds from Boston Scientific and Abbott, and he holds intellectual property related to DBS. KDF has received occasional consulting fees from Medtronic and Boston Scientific for DBS related work. University of Florida has received implantable devices for KDF's DBS-related research, but not for this trial, from Medtronic. The University of Florida receives partial funding for KDF's functional neurosurgery fellowship from Medtronic. KDF holds three DBS related patents for which he has received no royalties. KDF has participated as a site implanting surgeon in multicenter DBS-related research studies sponsored by Abbott and Boston Scientific. MV has received consultation fees from Medtronic. PZ has received honorariums as a consultant and part of an advisory panel with Medtronic. JJS has received research support from Medtronic and Abbott, and has received consulting fees from Medtronic, Abbott, and, Boston Scientific. MSO, EM, BJL, CCA, SC, AT, GD, JLW, CG, AB, NN, DS, JC, MH, MA, and AS have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can substantially diminish the quality of life of affected individuals. Evaluating and treating Tourette syndrome is complex, in part due to the heterogeneity of symptoms and comorbidities between individuals. The underlying pathophysiology of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis. Treatment options for Tourette syndrome are expanding with novel pharmacological therapies and increased use of deep brain stimulation for patients with symptoms that are refractory to pharmacological or behavioural treatments. Potential predictors of patient responses to therapies for Tourette syndrome, such as specific networks modulated during deep brain stimulation, can guide clinical decisions. Multicentre data sharing initiatives have enabled several advances in our understanding of the genetics and pathophysiology of Tourette syndrome and will be crucial for future large-scale research and in refining effective treatments., Competing Interests: Declaration of interests KAJ reports receiving fellowship funding from the National Science Foundation and travel grant awards from the International Congress of Parkinson's Disease and Movement Disorders. AG has received grant funding from the National Institutes of Health (NIH; R01NS096008) and the National Science Foundation (NSF PECASE 1553482); support from the Tourette Association of America; device donations from Medtronic under an NIH contract; and serves as a board member of the Brain Computer Interfaces Society. KDF reports receiving research support and fellowship support from Medtronic and Boston Scientific and research support from Functional Neuromodulation. CRB has received support from the NIH (UH3 NS119844) and has served as a consultant for NeuraModix. MSO serves as a medical advisor for the Parkinson's Foundation; has received research grants from NIH, Parkinson's Foundation, the Michael J Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation; has received support for research by NIH (R01 NR014852, R01NS096008, UH3NS119844, and U01NS119562); and is principal investigator of the NIH R25NS108939 Training Grant. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Responsive neurostimulation is an effective therapy for patients with refractory mesial temporal lobe epilepsy. However, clinical outcomes are variable, few patients become seizure-free, and the optimal stimulation location is currently undefined. The aim of this study was to quantify responsive neurostimulation in the mesial temporal lobe, identify stimulation-dependent networks associated with seizure reduction, and determine if stimulation location or stimulation-dependent networks inform outcomes., Methods: We modeled patient-specific volumes of tissue activated and created probabilistic stimulation maps of local regions of stimulation across a retrospective cohort of 22 patients with mesial temporal lobe epilepsy. We then mapped the network stimulation effects by seeding tractography from the volume of tissue activated with both patient-specific and normative diffusion-weighted imaging. We identified networks associated with seizure reduction across patients using the patient-specific tractography maps and then predicted seizure reduction across the cohort., Results: Patient-specific stimulation-dependent connectivity was correlated with responsive neurostimulation effectiveness after cross-validation (p = .03); however, normative connectivity derived from healthy subjects was not (p = .44). Increased connectivity from the volume of tissue activated to the medial prefrontal cortex, cingulate cortex, and precuneus was associated with greater seizure reduction., Significance: Overall, our results suggest that the therapeutic effect of responsive neurostimulation may be mediated by specific networks connected to the volume of tissue activated. In addition, patient-specific tractography was required to identify structural networks correlated with outcomes. It is therefore likely that altered connectivity in patients with epilepsy may be associated with the therapeutic effect and that utilizing patient-specific imaging could be important for future studies. The structural networks identified here may be utilized to target stimulation in the mesial temporal lobe and to improve seizure reduction for patients treated with responsive neurostimulation., (© 2022 International League Against Epilepsy.)

Deep brain stimulation (DBS) has advanced treatment options for a variety of neurologic and neuropsychiatric conditions. As the technology for DBS continues to progress, treatment efficacy will continue to improve and disease indications will expand. Hardware advances such as longer-lasting batteries will reduce the frequency of battery replacement and segmented leads will facilitate improvements in the effectiveness of stimulation and have the potential to minimize stimulation side effects. Targeting advances such as specialized imaging sequences and "connectomics" will facilitate improved accuracy for lead positioning and trajectory planning. Software advances such as closed-loop stimulation and remote programming will enable DBS to be a more personalized and accessible technology. The future of DBS continues to be promising and holds the potential to further improve quality of life. In this review we will address the past, present and future of DBS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frey, Cagle, Johnson, Wong, Hilliard, Butson, Okun and de Hemptinne.)

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury., Competing Interests: RR was employed by Medtronic, Inc. HBo was employed by Boston Scientific Neuromodulation Corporation. DG was employed by the NeuroPace, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wong, Deuschl, Wolke, Bergman, Muthuraman, Groppa, Sheth, Bronte-Stewart, Wilkins, Petrucci, Lambert, Kehnemouyi, Starr, Little, Anso, Gilron, Poree, Kalamangalam, Worrell, Miller, Schiff, Butson, Henderson, Judy, Ramirez-Zamora, Foote, Silburn, Li, Oyama, Kamo, Sekimoto, Hattori, Giordano, DiEuliis, Shook, Doughtery, Widge, Mayberg, Cha, Choi, Heisig, Obatusin, Opri, Kaufman, Shirvalkar, Rozell, Alagapan, Raike, Bokil, Green and Okun.)

Objectives: The spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence-based approach to DBS target identification., Materials and Methods: To classify localized neurostructural changes associated with NP in the SCI population, we compared white matter fiber density (FD) and cross section (FC) between SCI subjects with NP (n = 17) and SCI subjects without NP (n = 15) using diffusion-weighted magnetic resonance imaging (MRI). We then identified theoretical target locations for DBS using fiber bundles connected to significantly altered regions of white matter. Finally, we used computational models of DBS to determine if our theoretical target locations could be used to feasibly activate our fiber bundles of interest., Results: We identified significant increases in FC in the splenium of the corpus callosum in pain subjects when compared to controls. We then isolated five fiber bundles that were directly connected to the affected region of white matter. Our models were able to predict that our fiber bundles of interest can be feasibly activated with DBS at reasonable stimulation amplitudes and with clinically relevant implantation approaches., Conclusions: Altogether, we identified neuroarchitectural changes associated with NP in the SCI cohort and implemented a novel evidence-driven target selection approach for DBS to guide future research in neuromodulation treatment of NP after SCI., (Copyright © 2021. Published by Elsevier Inc.)

Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel 'field-shaping' methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists., (© 2021. The Author(s).)

Background: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients' symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes., Methods: Retrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement., Results: The best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation., Conclusions: Differences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Direct electrocortical stimulation (DECS) with electrocorticography electrodes is an established therapy for epilepsy and an emerging application for stroke rehabilitation and brain-computer interfaces. However, the electrophysiological mechanisms that result in a therapeutic effect remain unclear. Patient-specific computational models are promising tools to predict the voltages in the brain and better understand the neural and clinical response to DECS, but the accuracy of such models has not been directly validated in humans. A key hurdle to modeling DECS is accurately locating the electrodes on the cortical surface due to brain shift after electrode implantation. Despite the inherent uncertainty introduced by brain shift, the effects of electrode localization parameters have not been investigated. The goal of this study was to validate patient-specific computational models of DECS against in vivo voltage recordings obtained during DECS and quantify the effects of electrode localization parameters on simulated voltages on the cortical surface. We measured intracranial voltages in six epilepsy patients during DECS and investigated the following electrode localization parameters: principal axis, Hermes, and Dykstra electrode projection methods combined with 0, 1, and 2 mm of cerebral spinal fluid (CSF) below the electrodes. Greater CSF depth between the electrode and cortical surface increased model errors and decreased predicted voltage accuracy. The electrode localization parameters that best estimated the recorded voltages across six patients with varying amounts of brain shift were the Hermes projection method and a CSF depth of 0 mm ( r = 0.92 and linear regression slope = 1.21). These results are the first to quantify the effects of electrode localization parameters with in vivo intracranial recordings and may serve as the basis for future studies investigating the neuronal and clinical effects of DECS for epilepsy, stroke, and other emerging closed-loop applications., Competing Interests: CB has served as a consultant for NeuroPace, NeuraModix, Advanced Bionics, Boston Scientific, Intelect Medical, Abbott, and Functional Neuromodulation and he holds intellectual property related to neuromodulation therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Charlebois, Caldwell, Rampersad, Janson, Ojemann, Brooks, MacLeod, Butson and Dorval.)

Importance: The travel required to receive deep brain stimulation (DBS) programming causes substantial burden on patients and limits who can access DBS therapy., Objective: To evaluate the efficacy of home health DBS postoperative management in an effort to reduce travel burden and improve access., Design, Settings, and Participants: This open-label randomized clinical trial was conducted at University of Florida Health from November 2017 to April 2020. Eligible participants had a diagnosis of Parkinson disease (PD) and were scheduled to receive DBS independently of the study. Consenting participants were randomized 1:1 to receive either standard of care or home health postoperative DBS management for 6 months after surgery. Primary caregivers, usually spouses, were also enrolled to assess caregiver strain., Interventions: The home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the iPad-based Mobile Application for PD DBS system. Prior to the study, the home health nurse had no experience providing DBS care., Main Outcomes and Measures: The primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. Secondary outcomes included changes from baseline on the Unified Parkinson's Disease Rating Scale part III., Results: Approximately 75 patients per year were scheduled for DBS. Of the patients who met inclusion criteria over the entire study duration, 45 either declined or were excluded for various reasons. Of the 44 patients enrolled, 19 of 21 randomized patients receiving the standard of care (mean [SD] age, 64.1 [10.0] years; 11 men) and 23 of 23 randomized patients receiving home health who underwent a minimum of 1 postoperative management visit (mean [SD] age, 65.0 [10.9] years; 13 men) were included in analysis. The primary outcome revealed that patients randomized to home health had significantly fewer clinic visits than the patients in the standard of care arm (mean [SD], 0.4 [0.8] visits vs 4.8 [0.4] visits; P < .001). We found no significant differences between the groups in the secondary outcomes measuring the efficacy of DBS. No adverse events occurred in association with the study procedure or devices., Conclusions and Relevance: This study provides evidence supporting the safety and feasibility of postoperative home health DBS management., Trial Registration: ClinicalTrials.gov Identifier: NCT02474459.

Neuropathic pain (NP) is a devastating chronic pain condition affecting roughly 80% of the spinal cord injury (SCI) patient population. Current treatment options are largely ineffective and neurophysiological mechanisms of NP are not well-understood. Recent studies in neuroimaging have suggested that NP patients have differential patterns of functional activity that are dependent upon the neurological condition causing NP. We conducted an exploratory pilot study to examine functional activation and connectivity in SCI patients with chronic NP compared to SCI patients without NP. We developed a novel somatosensory attention task to identify short term fluctuations in neural activity related to NP vs. non-painful somatosensation using functional magnetic resonance imaging (fMRI). We also collected high-resolution resting state fMRI to identify connectivity-based correlations over time between the two groups. We observed increased activation during focus on NP in brain regions associated with somatosensory integration and representational knowledge in pain subjects when compared with controls. Similarly, NP subjects showed increased connectivity at rest in many of the same areas of the brain, with positive correlations between somatomotor networks, the dorsal attention network, and regions associated with pain and specific areas of painful and non-painful sensation within our cohort. Although this pilot analysis did not identify statistically significant differences between groups after correction for multiple comparisons, the observed correlations between NP and functional activation and connectivity align with a priori hypotheses regarding pain, and provide a well-controlled preliminary basis for future research in this severely understudied patient population. Altogether, this study presents a novel task, identifies regions of increased task-based activation associated with NP after SCI in the insula, prefrontal, and medial inferior parietal cortices, and identifies similar regions of increased functional connectivity associated with NP after SCI in sensorimotor, cingulate, prefrontal, and inferior medial parietal cortices. This, along with our complementary results from a structurally based analysis, provide multi-modal evidence for regions of the brain specific to the SCI cohort as novel areas for further study and potential therapeutic targeting to improve outcomes for NP patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Black, King, Mahan, Anderson and Butson.)

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank., Competing Interests: SG and MM were employed by companies Medtronic and Boston Scientific Neuromodulation respectively. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vedam-Mai, Deisseroth, Giordano, Lazaro-Munoz, Chiong, Suthana, Langevin, Gill, Goodman, Provenza, Halpern, Shivacharan, Cunningham, Sheth, Pouratian, Scangos, Mayberg, Horn, Johnson, Butson, Gilron, de Hemptinne, Wilt, Yaroshinsky, Little, Starr, Worrell, Shirvalkar, Chang, Volkmann, Muthuraman, Groppa, Kühn, Li, Johnson, Otto, Raike, Goetz, Wu, Silburn, Cheeran, Pathak, Malekmohammadi, Gunduz, Wong, Cernera, Wagle Shukla, Ramirez-Zamora, Deeb, Patterson, Foote and Okun.)

Background: Neuromodulation therapies, such as deep brain stimulation (DBS), spinal cord stimulation (SCS), responsive neurostimulation (RNS), transcranial magnetic stimulation (TMS), transcranial direct stimulation (tDCS), and vagus nerve stimulation (VNS) are used to treat neurological and psychiatric conditions for patients who have failed to benefit from other treatment approaches. Although generally effective, seemingly similar cases often have very different levels of effectiveness. While there is ongoing interest in developing predictors, it can be difficult to aggregate the necessary data from limited cohorts of patients at individual treatment centers., Objective: In order to increase the predictive power in neuromodulation studies, we created an informatics platform called the International Neuromodulation Registry (INR). The INR platform has a data flow process that will allow researchers to pool data across multiple centers to enable population health research., Methods: This custom informatics platform has a Neo4j graph database and includes a harmonization process that allows data from different studies to be aggregated and compared. Users of the INR can download deidentified patient imaging, patient demographic data, device settings, and medical rating scales. The INR supports complex network analysis and patient timeline visualization., Results: The INR currently houses and allows visualization of deidentified imaging and clinical data from hundreds of patients with a wide range of diagnoses and neuromodulation therapies., Conclusion: Ultimately, we believe that widespread adoption of the INR platform will improve population health research in neuromodulation therapy., (Copyright © 2020 Hedges, Hegman, Brown, Wilburn, Chapman and Butson.)

Background: Brain activity is constrained by and evolves over a network of structural and functional connections. Corticocortical evoked potentials (CCEPs) have been used to measure this connectivity and to discern brain areas involved in both brain function and disease. However, how varying stimulation parameters influences the measured CCEP across brain areas has not been well characterized., Objective: To better understand the factors that influence the amplitude of the CCEPs as well as evoked gamma-band power (70-150 Hz) resulting from single-pulse stimulation via cortical surface and depth electrodes., Methods: CCEPs from 4370 stimulation-response channel pairs were recorded across a range of stimulation parameters and brain regions in 11 patients undergoing long-term monitoring for epilepsy. A generalized mixed-effects model was used to model cortical response amplitudes from 5 to 100 ms post-stimulation., Results: Stimulation levels <5.5 mA generated variable CCEPs with low amplitude and reduced spatial spread. Stimulation at ≥5.5 mA yielded a reliable and maximal CCEP across stimulation-response pairs over all regions. These findings were similar when examining the evoked gamma-band power. The amplitude of both measures was inversely correlated with distance. CCEPs and evoked gamma power were largest when measured in the hippocampus compared with other areas. Larger CCEP size and evoked gamma power were measured within the seizure onset zone compared with outside this zone., Conclusion: These results will help guide future stimulation protocols directed at quantifying network connectivity across cognitive and disease states., Competing Interests: Declaration of competing interest The authors confirm there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that influenced its outcome., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate 'reverse' tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Deep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response., Objective: Here we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response., Methods: DTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue., Results: Medial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006)., Conclusions: A wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS., Competing Interests: Declaration of competing interest Dr. Ramasubbu has received honorarium for serving on advisory committees for Astra Zeneca, Lundbeck, Janssen, and Otsuka. He also received investigator-initiated grants from Astra Zeneca and Pfizer. Dr. Kiss reports that Alberta Health Services receives value adds for research and education from Medtronic Canada, the manufacturer of the devices used in the study. These funds are only partially available for research to the authors for research and education through the Neuromodulation program. Medtronic had no involvement in any of this study. Dr. Butson has served as a consultant for NeuroPace, Advanced Bionics, Boston Scientific, Intelect Medical, St. Jude Medical, Functional Neuromodulation and he holds intellectual property related to DBS. Dr. Lebel’s spouse is an employee of General Electric Healthcare, the manufacturer of the MRI scanner. Other authors declare no potential conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Achieving deep brain stimulation (DBS) dose equivalence is challenging, especially with pulse width tuning and directional contacts. Further, the precise effects of pulse width tuning are unknown, and recent reports of the effects of pulse width tuning on neural selectivity are at odds with classic biophysical studies., Methods: We created multicompartment neuron models for two axon diameters and used finite element modeling to determine extracellular influence from standard and segmented electrodes. We analyzed axon activation profiles and calculated volumes of tissue activated., Results: We find that long pulse widths focus the stimulation effect on small, nearby fibers, suppressing distant white matter tract activation (responsible for some DBS side effects) and improving battery utilization when equivalent activation is maintained for small axons. Directional leads enable similar benefits to a greater degree. Reexamining previous reports of short pulse stimulation reducing side effects, we explore a possible alternate explanation: non-dose equivalent stimulation may have resulted in reduced spread of neural activation. Finally, using internal capsule avoidance as an example in the context of subthalamic stimulation, we present a patient-specific model to show how long pulse widths could help increase the biophysical therapeutic window., Discussion: We find agreement with classic studies and predict that long pulse widths may focus the stimulation effect on small, nearby fibers and improve power consumption. While future pre-clinical and clinical work is necessary regarding pulse width tuning, it is clear that future studies must ensure dose equivalence, noting that energy- and charge-equivalent amplitudes do not result in equivalent spread of neural activation when changing pulse width., Competing Interests: Declaration of competing interest Dr. Butson reports personal fees through consulting for Boston Scientific (formerly Advanced Bionics), NeuroPace, Abbott (formerly St Jude Medical), and Functional Neuromodulation, independent of the submitted work. In addition, Dr. Butson holds several US patents relevant to deep brain stimulation parameterization or the computational approaches in the manuscript: numbers 7,346,382, 7,680,526, 7,860,548, 7,904,134, 8,046,077, 8,180,601, 8,209,027, 8,326,433, and 8,379,952., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Clinical outcomes from deep brain stimulation (DBS) can be highly variable, and two critical factors underlying this variability are the location and type of stimulation. In this study we quantified how robustly DBS activates a target region when taking into account a range of different lead designs and realistic variations in placement. The objective of the study is to assess the likelihood of achieving target activation., Approach: We performed finite element computational modeling and established a metric of performance robustness to evaluate the ability of directional and multi-lead configurations to activate target fiber pathways while taking into account location variability. A more robust lead configuration produces less variability in activation across all stimulation locations around the target., Main Results: Directional leads demonstrated higher overall performance robustness compared to axisymmetric leads, primarily 1-2 mm outside of the target. Multi-lead configurations demonstrated higher levels of robustness compared to any single lead due to distribution of electrodes in a broader region around the target., Significance: Robustness measures can be used to evaluate the performance of existing DBS lead designs and aid in the development of novel lead designs to better accommodate known variability in lead location and orientation. This type of analysis may also be useful to understand how DBS clinical outcome variability is influenced by lead location among groups of patients.

Deep brain stimulation (DBS) is an established treatment for movement disorders such as Parkinson's disease or essential tremor. Currently, the selection of optimal stimulation settings is performed by iteratively adjusting the stimulation parameters and is a time consuming procedure that requires multiple clinic visits of several hours. Recently, computational models to predict and visualize the effect of DBS have been developed with the goal to simplify and accelerate this procedure by providing visual guidance and such models have been made available also on mobile devices. However, currently available visualization software still either lacks mobility, i.e., it is running on desktop computers and not easily available in clinical praxis, or flexibility, as the simulations that are visualized on mobile devices have to be precomputed. The goal of the pipeline presented in this paper is to close this gap: Using Duality, a newly developed software for the interactive visualization of simulation results, we implemented a pipeline that allows to compute DBS simulations in near-real time and instantaneously visualize the result on a tablet computer. Therefore, a client-server setup is used, so that the visualization and user interaction occur on the tablet computer, while the computations are carried out on a remote server. We present two examples for the use of Duality, one for postoperative programming and one for the planning of DBS surgery in a pre- or intraoperative setting. We carry out a performance analysis and present the results of a case study in which the pipeline for postoperative programming was applied.

Objective: We performed a retrospective analysis of an optimization algorithm for the computation of patient-specific multipolar stimulation configurations employing multiple independent current/voltage sources. We evaluated whether the obtained stimulation configurations align with clinical data and whether the optimized stimulation configurations have the potential to lead to an equal or better stimulation of the target region as manual programming, while reducing the time required for programming sessions., Approach: For three patients (five electrodes) diagnosed with essential tremor, we derived optimized multipolar stimulation configurations using an approach that is suitable for the application in clinical practice. To evaluate the automatically derived stimulation settings, we compared them to the results of the monopolar review., Main Results: We observe a good agreement between the findings of the monopolar review and the optimized stimulation configurations, with the algorithm assigning the maximal voltage in the optimized multipolar pattern to the contact that was found to lead to the best therapeutic effect in the clinical monopolar review in all cases. Additionally, our simulation results predict that the optimized stimulation settings lead to the activation of an equal or larger volume fraction of the target compared to the manually determined settings in all cases., Significance: Our results demonstrate the feasibility of an automatic determination of optimal DBS configurations and motivate a further evaluation of the applied optimization algorithm.

Background: In patients with Parkinson's disease, stimulation above the subthalamic nucleus (STN) may engage the pallidofugal fibers and directly suppress dyskinesia., Objectives: The objective of this study was to evaluate the effect of interleaving stimulation through a dorsal deep brain stimulation contact above the STN in a cohort of PD patients and to define the volume of tissue activated with antidyskinesia effects., Methods: We analyzed the Core Assessment Program for Surgical Interventional Therapies dyskinesia scale, Unified Parkinson's Disease Rating Scale parts III and IV, and other endpoints in 20 patients with interleaving stimulation for management of dyskinesia. Individual models of volume of tissue activated and heat maps were used to identify stimulation sites with antidyskinesia effects., Results: The Core Assessment Program for Surgical Interventional Therapies dyskinesia score in the on medication phase improved 70.9 ± 20.6% from baseline with noninterleaved settings (P < 0.003). With interleaved settings, dyskinesia improved 82.0 ± 27.3% from baseline (P < 0.001) and 61.6 ± 39.3% from the noninterleaved phase (P = 0.006). The heat map showed a concentration of volume of tissue activated dorsally to the STN during the interleaved setting with an antidyskinesia effect., Conclusion: Interleaved deep brain stimulation using the dorsal contacts can directly suppress dyskinesia, probably because of the involvement of the pallidofugal tract, allowing more conservative medication reduction. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: Computational models are a popular tool for predicting the effects of deep brain stimulation (DBS) on neural tissue. One commonly used model, the volume of tissue activated (VTA), is computed using multiple methodologies. We quantified differences in the VTAs generated by five methodologies: the traditional axon model method, the electric field norm, and three activating function based approaches-the activating function at each grid point in the tangential direction (AF-Tan) or in the maximally activating direction (AF-3D), and the maximum activating function along the entire length of a tangential fiber (AF-Max)., Approach: We computed the VTA using each method across multiple stimulation settings. The resulting volumes were compared for similarity, and the methodologies were analyzed for their differences in behavior., Main Results: Activation threshold values for both the electric field norm and the activating function varied with regards to electrode configuration, pulse width, and frequency. All methods produced highly similar volumes for monopolar stimulation. For bipolar electrode configurations, only the maximum activating function along the tangential axon method, AF-Max, produced similar volumes to those produced by the axon model method. Further analysis revealed that both of these methods are biased by their exclusive use of tangential fiber orientations. In contrast, the activating function in the maximally activating direction method, AF-3D, produces a VTA that is free of axon orientation and projection bias., Significance: Simulating tangentially oriented axons, the standard approach of computing the VTA, is too computationally expensive for widespread implementation and yields results biased by the assumption of tangential fiber orientation. In this work, we show that a computationally efficient method based on the activating function, AF-Max, reliably reproduces the VTAs generated by direct axon modeling. Further, we propose another method, AF-3D as a potentially superior model for representing generic neural tissue activation.

Directional deep brain stimulation (DBS) leads have recently been approved and used in patients, and growing evidence suggests that directional contacts can increase the therapeutic window by redirecting stimulation to the target region while avoiding side-effect-inducing regions. We outline the design, fabrication, and testing of a novel directional DBS lead, the μDBS, which utilizes microscale contacts to increase the spatial resolution of stimulation steering and improve the selectivity in targeting small diameter fibers. We outline the steps of fabrication of the μDBS, from an integrated circuit design to post-processing and validation testing. We tested the onboard digital circuitry for programming fidelity, characterized impedance for a variety of electrode sizes, and demonstrated functionality in a saline bath. In a computational experiment, we determined that reduced electrode sizes focus the stimulation effect on small, nearby fibers. Smaller electrode sizes allow for a relative decrease in small-diameter axon thresholds compared to thresholds of large-diameter fibers, demonstrating a focusing of the stimulation effect within small, and possibly therapeutic, fibers. This principle of selectivity could be useful in further widening the window of therapy. The μDBS offers a unique, multiresolution design in which any combination of microscale contacts can be used together to function as electrodes of various shapes and sizes. Multiscale electrodes could be useful in selective neural targeting for established neurological targets and in exploring novel treatment targets for new neurological indications., (Copyright © 2019 Anderson, Anderson, Lanka, Sharma, Butson, Baker and Dorval.)

Background: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting., Methods: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases., Results: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi., Conclusion: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities., Competing Interests: Competing interests: JLO has received research grant support from the Michael J Fox Foundation, Boston Scientific, Cala Health, NIH, DARPA, PCORI and Biogen, and she has also received training grant support from Boston Scientific and Medtronic, and has served as a consultant for Acadia Pharmaceuticals and Medtronic. AL serves as a consultant for Boston Scientific and holds intellectual property in the field of DBS. JK has received financial support for investigator-initiated trials from Medtronic and grants from the German Research Foundation (KU2665/1-2) and the Marga and Walter Boll Foundation. CZ has received honoraria and travel expenses from the deep brain stimulation industry (Medtronic, PINS, SceneRay). MSO serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MSO DBS research is supported by R01 NR014852 and R01NS096008. MSO has previously received honoraria, but in the past >60 months has received no support from the industry. MSO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients and Cambridge (movement disorders books). MSO is an associate editor for New England Journal of Medicine Journal Watch Neurology. MSO has participated in CME and educational activities on movement disorders (in the last 36 months) sponsored by PeerView, Prime, QuantiaMD, WebMD, Medicus, MedNet, Henry Stewart and by Vanderbilt University. The institution and not MSO receives grants from Medtronic, AbbVie, Allergan and ANS/St Jude, and the PI has no financial interest in these grants. MSO has participated as a site PI and/or co-I for several NIH, foundation and industry sponsored trials over the years but has not received honoraria. CRB has served as a consultant for NeuroPace, Advanced Bionics, Boston Scientific, Intelect Medical, St Jude Medical and Functional Neuromodulation, and he holds intellectual property related to DBS., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Deep brain stimulation (DBS) is an established treatment for Parkinson's Disease (PD). Despite the improvement of motor symptoms in most patients by sub-thalamic nucleus (STN) DBS and its widespread use, the neurobiological mechanisms are not completely understood. The objective of the present study was to elucidate the effects of subthalamic nucleus (STN) DBS in PD on the dopamine system and neural circuitry, employing high-resolution positron emission tomography (PET) imaging. The hypotheses tested were that STN DBS would decrease the striatal vesicular monoamine transporter (VMAT2), secondary to an increase in dopamine concentrations, and would decrease striatal cerebral metabolism and increase cortical cerebral metabolism., Methods: PET imaging of the vesicular monoamine transporter (VMAT2) and cerebral glucose metabolism was performed prior to DBS surgery and after 4-6 months of STN stimulation in seven PD patients (mean age 67 ± 7)., Results: The patients demonstrated significant improvement in motor and neuropsychiatric symptoms after STN DBS. Decreased VMAT2 was observed in the caudate, putamen and associative striatum and in extra-striatal, cortical and limbic regions. Cerebral glucose metabolism was decreased in striatal sub-regions and increased in temporal and parietal cortices and the cerebellum. Decreased striatal VMAT2 was correlated with decreased striatal and increased cortical and limbic metabolism. Improvement of depressive symptoms was correlated with decreased VMAT2 in striatal and extra-striatal regions and with striatal decreases and cortical increases in metabolism., Conclusions: The present results support further investigation of the role of VMAT2, and associated changes in neural circuitry in the improvement of motor and non-motor symptoms with STN DBS in PD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Reliable EEG source analysis depends on sufficiently detailed and accurate head models. In this study, we investigate how uncertainties inherent to the experimentally determined conductivity values of the different conductive compartments influence the results of EEG source analysis. In a single source scenario, the superficial and focal somatosensory P20/N20 component, we analyze the influence of varying conductivities on dipole reconstructions using a generalized polynomial chaos (gPC) approach. We find that in particular the conductivity uncertainties for skin and skull have a significant influence on the EEG inverse solution, leading to variations in source localization by several centimeters. The conductivity uncertainties for gray and white matter were found to have little influence on the source localization, but a strong influence on the strength and orientation of the reconstructed source, respectively. As the CSF conductivity is most accurately determined of all conductivities in a realistic head model, CSF conductivity uncertainties had a negligible influence on the source reconstruction. This small uncertainty is a further benefit of distinguishing the CSF in realistic volume conductor models.

Objective: During deep brain stimulation (DBS), it is well understood that extracellular cathodic stimulation can cause activation of passing axons. Activation can be predicted from the second derivative of the electric potential along an axon, which depends on axonal orientation with respect to the stimulation source. We hypothesize that fiber orientation influences activation thresholds and that fiber orientations can be selectively targeted with DBS waveforms., Approach: We used bioelectric field and multicompartment NEURON models to explore preferential activation based on fiber orientation during monopolar or bipolar stimulation. Preferential fiber orientation was extracted from the principal eigenvectors and eigenvalues of the Hessian matrix of the electric potential. We tested cathodic, anodic, and charge-balanced pulses to target neurons based on fiber orientation in general and clinical scenarios., Main Results: Axons passing the DBS lead have positive second derivatives around a cathode, whereas orthogonal axons have positive second derivatives around an anode, as indicated by the Hessian. Multicompartment NEURON models confirm that passing fibers are activated by cathodic stimulation, and orthogonal fibers are activated by anodic stimulation. Additionally, orthogonal axons have lower thresholds compared to passing axons. In a clinical scenario, fiber pathways associated with therapeutic benefit can be targeted with anodic stimulation at 50% lower stimulation amplitudes., Significance: Fiber orientations can be selectively targeted with simple changes to the stimulus waveform. Anodic stimulation preferentially activates orthogonal fibers, approaching or leaving the electrode, at lower thresholds for similar therapeutic benefit in DBS with decreased power consumption.

Deep brain stimulation (DBS) is an established therapy for treating patients with movement disorders such as Parkinson's disease. Patient-specific computational modelling and visualisation have been shown to play a key role in surgical and therapeutic decisions for DBS. The computational models use brain imaging, such as magnetic resonance (MR) and computed tomography (CT), to determine the DBS electrode positions within the patient's head. The finite resolution of brain imaging, however, introduces uncertainty in electrode positions. The DBS stimulation settings for optimal patient response are sensitive to the relative positioning of DBS electrodes to a specific neural substrate (white/grey matter). In our contribution, we study positional uncertainty in the DBS electrodes for imaging with finite resolution. In a three-step approach, we first derive a closed-form mathematical model characterising the geometry of the DBS electrodes. Second, we devise a statistical framework for quantifying the uncertainty in the positional attributes of the DBS electrodes, namely the direction of longitudinal axis and the contact-centre positions at subvoxel levels. The statistical framework leverages the analytical model derived in step one and a Bayesian probabilistic model for uncertainty quantification. Finally, the uncertainty in contact-centre positions is interactively visualised through volume rendering and isosurfacing techniques. We demonstrate the efficacy of our contribution through experiments on synthetic and real datasets. We show that the spatial variations in true electrode positions are significant for finite resolution imaging, and interactive visualisation can be instrumental in exploring probabilistic positional variations in the DBS lead., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for movement disorders and is being applied to a growing number of disorders. Computational modeling has been successfully used to predict the clinical effects of DBS; however, there is a need for novel modeling techniques to keep pace with the growing complexity of DBS devices. These models also need to generate predictions quickly and accurately. The goal of this project is to develop an image processing pipeline to incorporate structural magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) into an interactive, patient specific model to simulate the effects of DBS. A virtual DBS lead can be placed inside of the patient model, along with active contacts and stimulation settings, where changes in lead position or orientation generate a new finite element mesh and solution of the bioelectric field problem in near real-time, a timespan of approximately 10 seconds. This system also enables the simulation of multiple leads in close proximity to allow for current steering by varying anodes and cathodes on different leads. The techniques presented in this paper reduce the burden of generating and using computational models while providing meaningful feedback about the effects of electrode position, electrode design, and stimulation configurations to researchers or clinicians who may not be modeling experts.

Traumatic brain injury (TBI) is a looming epidemic, growing most rapidly in the elderly population. Some of the most devastating sequelae of TBI are related to depressed levels of consciousness (e.g., coma, minimally conscious state) or deficits in executive function. To date, pharmacological and rehabilitative therapies to treat these sequelae are limited. Deep brain stimulation (DBS) has been used to treat a number of pathologies, including Parkinson disease, essential tremor, and epilepsy. Animal and clinical research shows that targets addressing depressed levels of consciousness include components of the ascending reticular activating system and areas of the thalamus. Targets for improving executive function are more varied and include areas that modulate attention and memory, such as the frontal and prefrontal cortex, fornix, nucleus accumbens, internal capsule, thalamus, and some brainstem nuclei. The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients, while also offering suggestions on directions for future research.

Objective: Deep brain stimulation (DBS) is a growing treatment option for movement and psychiatric disorders. As DBS technology moves toward directional leads with increased numbers of smaller electrode contacts, trial-and-error methods of manual DBS programming are becoming too time-consuming for clinical feasibility. We propose an algorithm to automate DBS programming in near real-time for a wide range of DBS lead designs., Approach: Magnetic resonance imaging and diffusion tensor imaging are used to build finite element models that include anisotropic conductivity. The algorithm maximizes activation of target tissue and utilizes the Hessian matrix of the electric potential to approximate activation of neurons in all directions. We demonstrate our algorithm's ability in an example programming case that targets the subthalamic nucleus (STN) for the treatment of Parkinson's disease for three lead designs: the Medtronic 3389 (four cylindrical contacts), the direct STNAcute (two cylindrical contacts, six directional contacts), and the Medtronic-Sapiens lead (40 directional contacts)., Main Results: The optimization algorithm returns patient-specific contact configurations in near real-time-less than 10 s for even the most complex leads. When the lead was placed centrally in the target STN, the directional leads were able to activate over 50% of the region, whereas the Medtronic 3389 could activate only 40%. When the lead was placed 2 mm lateral to the target, the directional leads performed as well as they did in the central position, but the Medtronic 3389 activated only 2.9% of the STN., Significance: This DBS programming algorithm can be applied to cylindrical electrodes as well as novel directional leads that are too complex with modern technology to be manually programmed. This algorithm may reduce clinical programming time and encourage the use of directional leads, since they activate a larger volume of the target area than cylindrical electrodes in central and off-target lead placements.

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients., (Copyright © 2016 the American Physiological Society.)

Background: Major depressive disorder (MDD) is a public health problem worldwide. There is increasing interest in using non-invasive therapies such as repetitive transcranial magnetic stimulation (rTMS) to treat MDD. However, the changes induced by rTMS on neural circuits remain poorly characterized. The present study aims to test whether the brain regions previously targeted by deep brain stimulation (DBS) in the treatment of MDD respond to rTMS, and whether functional connectivity (FC) measures can predict clinical response., Methods: rTMS (20 sessions) was administered to five MDD patients at the left-dorsolateral prefrontal cortex (L-DLPFC) over 4 weeks. Magnetoencephalography (MEG) recordings and Montgomery-Asberg depression rating scale (MADRS) assessments were acquired before, during and after treatment. Our primary measures, obtained with MEG source imaging, were changes in power spectral density (PSD) and changes in FC as measured using coherence., Results: Of the five patients, four met the clinical response criterion (40% or greater decrease in MADRS) after 4 weeks of treatment. An increase in gamma power at the L-DLPFC was correlated with improvement in symptoms. We also found that increases in delta band connectivity between L-DLPFC/amygdala and L-DLPFC/pregenual anterior cingulate cortex (pACC), and decreases in gamma band connectivity between L-DLPFC/subgenual anterior cingulate cortex (sACC), were correlated with improvements in depressive symptoms., Conclusions: Our results suggest that non-invasive intervention techniques, such as rTMS, modulate the ongoing activity of depressive circuits targeted for DBS, and that MEG can capture these changes. Gamma oscillations may originate from GABA-mediated inhibition, which increases synchronization of large neuronal populations, possibly leading to increased long-range FC. We postulate that responses to rTMS could provide valuable insights into early evaluation of patient candidates for DBS surgery.

Objective: Transcranial magnetic stimulation (TMS) is an effective intervention in noninvasive neuromodulation used to treat a number of neurophysiological disorders. Predicting the spatial extent to which neural tissue is affected by TMS remains a challenge. The goal of this study was to develop a computational model to predict specific locations of neural tissue that are activated during TMS. Using this approach, we assessed the effects of changing TMS coil orientation and waveform., Materials and Methods: We integrated novel techniques to develop a subject-specific computational model, which contains three main components: 1) a figure-8 coil (Magstim, Magstim Company Limited, Carmarthenshire, UK); 2) an electromagnetic, time-dependent, nonhomogeneous, finite element model of the whole head; and 3) an adaptation of a previously published pyramidal cell neuron model. We then used our modeling approach to quantify the spatial extent of affected neural tissue for changes in TMS coil rotation and waveform., Results: We found that our model shows more detailed predictions than previously published models, which underestimate the spatial extent of neural activation. Our results suggest that fortuitous sites of neural activation occur for all tested coil orientations. Additionally, our model predictions show that excitability of individual neural elements changes with a coil rotation of ±15°., Conclusions: Our results indicate that the extent of neuromodulation is more widespread than previous published models suggest. Additionally, both specific locations in cortex and the extent of stimulation in cortex depend on coil orientation to within ±15° at a minimum. Lastly, through computational means, we are able to provide insight into the effects of TMS at a cellular level, which is currently unachievable by imaging modalities., (© 2015 International Neuromodulation Society.)

Background: Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response., Objective: To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS., Methods: Antidepressant-like effects of MFB stimulation at 100 μA, 90 μs and either 130 Hz or 20 Hz were characterized in the forced swim test (FST). Changes in the expression of the immediate early gene (IEG) zif268 were measured with in situ hybridization and used as an index of regional brain activity. Microdialysis was used to measure DBS-induced dopamine and serotonin release in the nucleus accumbens., Results: Stimulation at parameters that approximated those used in clinical practice, but not at lower frequencies, induced a significant antidepressant-like response in the FST. In animals receiving MFB DBS at high frequency, increases in zif268 expression were observed in the piriform cortex, prelimbic cortex, nucleus accumbens shell, anterior regions of the caudate/putamen and the ventral tegmental area. These structures are involved in the neurocircuitry of reward and are also connected to other brain areas via the MFB. At settings used during behavioral tests, stimulation did not induce either dopamine or serotonin release in the nucleus accumbens., Conclusions: These results suggest that MFB DBS induces an antidepressant-like effect in rats and recruits structures involved in the neurocircuitry of reward without affecting dopamine release in the nucleus accumbens., (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.

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The subthalamic nucleus (STN) is a common anatomical target for deep brain stimulation (DBS) for the treatment of Parkinson's disease. However, the effects of stimulation may spread beyond the STN. Ongoing research aims to identify nearby anatomical structures where DBS-induced effects could be associated with therapeutic improvement or side effects. We previously found that DBS lead location determines the rate--abrupt vs. gradual--with which therapeutic effect washes out after stimulation is stopped. Those results suggested that electrical current spreads from the electrodes to two spatially distinct stimulation targets associated with different washout rates. In order to identify these targets we used computational models to predict the volumes of tissue activated during DBS in 14 Parkinson's patients from that study. We then coregistered each patient with a stereotaxic atlas and generated a probabilistic stimulation atlas to obtain a 3-dimensional representation of regions where stimulation was associated with abrupt vs. gradual washout. We found that the therapeutic effect which washed out gradually was associated with stimulation of the zona incerta and fields of Forel, whereas abruptly-disappearing therapeutic effect was associated with stimulation of STN itself. This supports the idea that multiple DBS targets exist and that current spread from one electrode may activate more than one of them in a given patient, producing a combination of effects which vary according to electrode location and stimulation settings.

Background: Effective target regions for deep brain stimulation (DBS) in Parkinson's disease (PD) have been well characterized. We sought to study whether the measured Cartesian coordinates of an implanted DBS lead are predictive of motor outcome(s). We tested the hypothesis that the position and trajectory of the DBS lead relative to the mid-commissural point (MCP) are significant predictors of clinical outcomes. We expected that due to neuroanatomical variation among individuals, a simple measure of the position of the DBS lead relative to MCP (commonly used in clinical practice) may not be a reliable predictor of clinical outcomes when utilized alone., Methods: 55 PD subjects implanted with subthalamic nucleus (STN) DBS and 41 subjects implanted with globus pallidus internus (GPi) DBS were included. Lead locations in AC-PC space (x, y, z coordinates of the active contact and sagittal and coronal entry angles) measured on high-resolution CT-MRI fused images, and motor outcomes (Unified Parkinson's Disease Rating Scale) were analyzed to confirm or refute a correlation between coordinate-based lead locations and DBS motor outcomes., Results: Coordinate-based lead locations were not a significant predictor of change in UPDRS III motor scores when comparing pre- versus post-operative values. The only potentially significant individual predictor of change in UPDRS motor scores was the antero-posterior coordinate of the GPi lead (more anterior lead locations resulted in a worse outcome), but this was only a statistical trend (p<.082)., Conclusion: The results of the study showed that a simple measure of the position of the DBS lead relative to the MCP is not significantly correlated with PD motor outcomes, presumably because this method fails to account for individual neuroanatomical variability. However, there is broad agreement that motor outcomes depend strongly on lead location. The results suggest the need for more detailed identification of stimulation location relative to anatomical targets.