Therapeutic Deep Brain Stimulation Research Articles

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. 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 DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI.

To characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET). DBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely. A retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores. The therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58). Active DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Evolving characterization of the human hyperdirect pathway.

The hyperdirect pathway (HDP) represents the main glutamatergic input to the subthalamic nucleus (STN), through which the motor and prefrontal cerebral cortex can modulate basal ganglia activity. Further, direct activation of the motor HDP is thought to be an important component of therapeutic deep brain stimulation (DBS), mediating the disruption of pathological oscillations. Alternatively, unintended recruitment of the prefrontal HDP may partly explain some cognitive side effects of DBS therapy. Previous work describing the HDP has focused on non-human primate (NHP) histological pathway tracings, diffusion-weighted MRI analysis of human white matter, and electrophysiology studies involving paired cortical recordings with DBS. However, none of these approaches alone yields a complete understanding of the complexities of the HDP. As such, we propose that generative modeling methods hold promise to bridge anatomy and physiology results, from both NHPs and humans, into a more detailed representation of the human HDP. Nonetheless, numerous features of the HDP remain to be experimentally described before model-based methods can simulate corticosubthalamic activity with a high degree of scientific detail. Therefore, the goals of this review are to examine the experimental evidence for HDP projections from across the primate neocortex and discuss new data which are required to improve the utility of anatomical and biophysical models of the human corticosubthalamic system.

Alterations of resting-state networks of Parkinson‘s disease patients after subthalamic DBS surgery

The implantation of deep brain stimulation (DBS) electrodes in Parkinson’s disease (PD) patients can lead to a temporary improvement in motor symptoms, known as the stun effect. However, the network alterations induced by the stun effect are not well characterized. As therapeutic DBS is known to alter resting-state networks (RSN) and subsequent motor symptoms in patients with PD, we aimed to investigate whether the DBS-related stun effect also modulated RSNs.Therefore, we analyzed RSNs of 27 PD patients (8 females, 59.0 +- 8.7 years) using magnetoencephalography and compared them to RSNs of 24 age-matched healthy controls (8 females, 62.8 +- 5.1 years). We recorded 30 min of resting-state activity two days before and one day after implantation of the electrodes with and without dopaminergic medication. RSNs were determined by use of phase-amplitude coupling between a low frequency phase and a high gamma amplitude and examined for differences between conditions (i.e., pre vs post surgery).We identified four RSNs across all conditions: sensory-motor, visual, fronto-occipital, and frontal. Each RSN was altered due to electrode implantation. Importantly, these changes were not restricted to spatially close areas to the electrode trajectory.Interestingly, pre-operative RSNs corresponded better with healthy control RSNs regarding the spatial overlap, although the stun effect is associated with motor improvement.Our findings reveal that the stun effect induced by implantation of electrodes exerts brain wide changes in different functional RSNs.

O032 / #633 PALLIDAL DEEP BRAIN STIMULATION EVOKES RESONANT NEURAL ACTIVITY IN PARKINSON’S DISEASE: TRACK 2: DEEP BRAIN STIMULATION FOR MOVEMENT DISORDERS

Objective markers of therapeutic deep brain stimulation (DBS) for Parkinson’s disease (PD) are needed to tailor stimulation on a patient-specific basis. Recent studies suggest that subthalamic nucleus DBS evoked resonant neural activity (ERNA) may be used to refine targeting and possibly identify therapeutic stimulation parameters [1]. However, ERNA has not been studied in the pallidum, and whether it could be used to guide intraoperative targeting or stimulation programming is unknown. We aimed to determine if ERNA is present with pallidal DBS and if pallidal ERNA features are correlated with baseline PD neurophysiology.

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice.

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait.

Freezing of gait is a debilitating symptom in advanced Parkinson’s disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson’s disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait.Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson’s disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking.We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials.These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel ‘bandwidth model,’ which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus.

The subthalamic nucleus (STN) controls psychomotor activity and is an efficient therapeutic deep brain stimulation target in individuals with Parkinson's disease. Despite evidence indicating position-dependent therapeutic effects and distinct functions within the STN, the input circuit and cellular profile in the STN remain largely unclear. Using neuroanatomical techniques, we construct a comprehensive connectivity map of the indirect and hyperdirect pathways in the mouse STN. Our circuit- and cellular-level connectivities reveal a topographically graded organization with three types of indirect and hyperdirect pathways (external globus pallidus only, STN only, and collateral). We confirm consistent pathways into the human STN by 7 T MRI-based tractography. We identify two functional types of topographically distinct glutamatergic STN neurons (parvalbumin [PV+/-]) with synaptic connectivity from indirect and hyperdirect pathways. Glutamatergic PV+ STN neurons contribute to burst firing. These data suggest a complex interplay of information integration within the basal ganglia underlying coordinated movement control and therapeutic effects.

337 Neural Network Changes with Loss of Consciousness in Parkinson's Disease

INTRODUCTION: Consciousness is likely mediated by multiple parallel yet interacting cortico-subcortical recurrent networks. The pallidocortical circuit is of particular interest given the putative role of pallidum in consciousness, according to the mesocircuit model, though this has not been well studied. METHODS: We characterized changes in pallidocortical circuits in awake versus propofol-induced unconscious states in humans by directly and simultaneously recording from perirolandic cortices and the pallidum in twelve Parkinson Disease (PD) patients undergoing implantation of therapeutic deep brain stimulation (DBS) leads. RESULTS: Propofol-induced LOC resulted in power increases up to 20 Hz in globus pallidus internus (GPi), 35 Hz in globus pallidus externus (GPe), and 100 Hz in sensorimotor cortices (S1/M1). At a network level, LOC resulted in increased pallidocortical alpha coherence with increases in Granger causality (GC) in the alpha/low beta range from GPe to all other nodes. In contrast, LOC was associated with decreased network-wide beta coherence with decreased GC in the beta range from M1 to the rest of the network. CONCLUSION: These results not only confirm the LOC-related changes in pallidocortical circuitry, but GC results suggest that widely reported LOC-related increases in alpha band power emanate from GPe. These findings support a significant role of the GPe in modulating consciousness. Simultaneous LOC-related suppression of beta synchrony from M1 to other nodes suggests that distinct oscillatory frequencies can act independently, conveying unique network level activity. Given the pathophysiologic role of beta synchrony in PD, LOC-related suppresion of beta synchrony may be amplified in this patient population, but may also highlight a parallel network mediating LOC-related loss of motor control.

Differential modulation of subthalamic projection neurons by short-term and long-term electrical stimulation in physiological and parkinsonian conditions.

The subthalamic nucleus (STN) is one of the best targets for therapeutic deep brain stimulation (DBS) to control motor symptoms in Parkinson's disease. However, the precise circuitry underlying the effects of STN-DBS remains unclear. To understand how electrical stimulation affects STN projection neurons, we used a retrograde viral vector (AAV-retro-hSyn-eGFP) to label STN neurons projecting to the substantia nigra pars reticulata (SNr) (STN-SNr neurons) or the globus pallidus interna (GPi) (STN-GPi neurons) in mice, and performed whole-cell patch-clamp recordings from these projection neurons in ex vivo brain slices. We found that STN-SNr neurons exhibited stronger responses to depolarizing stimulation than STN-GPi neurons. In most STN-SNr and STN-GPi neurons, inhibitory synaptic inputs predominated over excitatory inputs and electrical stimulation at 20-130 Hz inhibited these neurons in the short term; its longer-term effects varied. 6-OHDA lesion of the nigrostriatal dopaminergic pathway significantly reduced inhibitory synaptic inputs in STN-GPi neurons, but did not change synaptic inputs in STN-SNr neurons; it enhanced short-term electrical-stimulation-induced inhibition in STN-SNr neurons but reversed the effect of short-term electrical stimulation on the firing rate in STN-GPi neurons from inhibitory to excitatory; in both STN-SNr and STN-GPi neurons, it increased the inhibition but attenuated the enhancement of firing rate induced by long-term electrical stimulation. Our results suggest that STN-SNr and STN-GPi neurons differ in their synaptic inputs, their responses to electrical stimulation, and their modification under parkinsonian conditions; STN-GPi neurons may play important roles in both the pathophysiology and therapeutic treatment of Parkinson's disease.

The Dostoyevsky effect: epileptogenesis and memory enhancement after kindling stimulation in the primate basolateral amygdala.

Kindling is an electrical stimulation technique used to lower the threshold for epileptogenic activity in the brain. It can also be used as a tool to investigate electrophysiologic alterations that occur as a result of seizures. Epileptiform activity, like seizures and after-discharges (AD; evoked epileptiform activity), commonly cause memory impairment but rarely, can elicit vivid memory retrieval. We kindled the basolateral amygdala of a non-human primate (NHP) once weekly and had him perform a spatial memory task in a 3D virtual environment before, during and after kindling. AD were associated with an initial average performance increase of 46.6%. The enhancement which followed AD persisted up to 2 days. Memory task performance enhancement was accompanied by significant resetting of hippocampal theta oscillations and robust hippocampal potentiation as measured by field evoked potentials. However, neither lasted throughout the duration of performance enhancement. Sharp-wave ripples (SWR), a local field event that supports episodic memory, were generated more often throughout the period of enhancement. SWR rate increased from 14.38 SWR per min before kindling to 24.22 SWR per min after kindling on average. Our results show that kindling can be associated with improved memory. Memory function appears to depend on the particular induction circuit and the resultant excitation/inhibition ratio of the mesial temporal lobe network. Investigating the electrophysiologic underpinnings of this observed memory enhancement is an important step towards understanding the network alterations that occur after seizures and stimulation.Clinical Relevance- Our findings provide new insight into the effects of kindling stimulation in the primate brain. Kindling can cause increase MTL synchrony and the frequency of spontaneous seizures in a primate. This work highlights important considerations for therapeutic deep brain stimulation.

Microelectrode clusters enable therapeutic deep brain stimulation without noticeable side-effects in a rodent model of Parkinson’s disease

BackgroundDeep Brain Stimulation (DBS) is an established treatment for motor symptoms in Parkinson’s disease (PD). However, side effects often limit the usefulness of the treatment. New methodTo mitigate this problem, we developed a novel cluster of ultrathin platinum-iridium microelectrodes (n = 16) embedded in a needle shaped gelatin vehicle. In an established rodent PD-model (6-OHDA unilateral lesion), the clusters were implanted in the subthalamic area for up to 8 weeks. In an open field setting, combinations of microelectrodes yielding therapeutic effects were identified using statistical methods. Immunofluorescence techniques were used for histological assessments of biocompatibility. ResultsIn all rats tested (n = 5), we found subsets of 3–4 microelectrodes which, upon stimulation (160 Hz, 60 μs pulse width, 25–40 μA/microelectrode), prompted normal movements without noticeable side effects. Other microelectrode subsets often caused side effects such as rotation, dyskinesia and tremor. The threshold (per microelectrode) to elicit normal movements strongly depended on the number of activated microelectrodes in the selected subset. The histological analysis revealed viable neurons close to the electrode contacts, minor microglial and astrocytic reactions and no major changes in the vasculature, indicating high biocompatibility. Comparison to existing methods and conclusionBy contrast to the continuous and relatively large stimulation fields produced by existing DBS electrodes, the developed microelectrode cluster enables a fine-tuned granular and individualized microstimulation. This granular type of stimulation pattern provided powerful and specific therapeutic effects, free of noticeable side effects, in a PD animal model.

Dysfunctional Brain Dynamics of Parkinson's Disease and the Effect of Acute Deep Brain Stimulation.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and deep brain stimulation (DBS) can effectively alleviate PD symptoms. Although previous studies have detected network features of PD and DBS, few studies have considered their dynamic characteristics.Objective: We tested two hypotheses. (1) Reduced brain dynamics, as evidenced by slowed microstate dynamic change, is a characteristic of PD and is related to the movement disorders of patients with PD. (2) Therapeutic acute DBS can partially reverse slow brain dynamics in PD to healthy levels.Methods: We used electroencephalography (EEG) microstate analysis based on high density (256-channel) EEG to detect the effects of PD and DBS on brain dynamic changes on a sub-second timescale. We compared 21 healthy controls (HCs) with 20 patients with PD who were in either DBS-OFF or DBS-ON states. Assessment of movement disorder using the Unified Parkinson's Disease Rating Scale III was correlated with microstate parameters.Results: Compared with HCs, patients with PD displayed a longer mean microstate duration with reduced occurrence per second, which were significantly associated with movement disorders. In patients with PD, some parameters of microstate analysis were restored toward healthy levels after DBS.Conclusions: Resting-state EEG microstate analysis is an important tool for investigating brain dynamic changes in PD and DBS. PD can slow down brain dynamic change, and therapeutic acute DBS can partially reverse this change toward a healthy level.

Neurophysiological biomarkers to optimize deep brain stimulation in movement disorders.

Intraoperative neurophysiological information could increase accuracy of surgical deep brain stimulation (DBS) lead placement. Subsequently, DBS therapy could be optimized by specifically targeting pathological activity. In Parkinson’s disease, local field potentials (LFPs) excessively synchronized in the beta band (13–35 Hz) correlate with akinetic-rigid symptoms and their response to DBS therapy, particularly low beta band suppression (13–20 Hz) and high frequency gamma facilitation (35–250 Hz). In dystonia, LFPs abnormally synchronize in the theta/alpha (4–13 Hz), beta and gamma (60–90 Hz) bands. Phasic dystonic symptoms and their response to DBS correlate with changes in theta/alpha synchronization. In essential tremor, LFPs excessively synchronize in the theta/alpha and beta bands. Adaptive DBS systems will individualize pathological characteristics of neurophysiological signals to automatically deliver therapeutic DBS pulses of specific spatial and temporal parameters.

Subcortical short-term plasticity elicited by deep brain stimulation.

ObjectiveTo investigate local short‐term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders.MethodsDuring DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short‐term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models.ResultsDBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P < 0.001) and display absolute and relative refractory periods (0.56 ± 0.08 and 2.94 ± 1.05 msec, respectively). We also identified later oscillatory activity in the subthalamic‐pallidal circuit (4.50 ± 1.11 msec peak latency) that displays paired pulse facilitation (present in 5/8 subthalamic, 4/5 pallidal, and 0/6 thalamic trajectories, P = 0.018, Fisher’s exact test), and correlates with resting beta frequency power (P < 0.001), therapeutic DBS frequencies, and stimulation sites chosen later for therapy in the ambulatory setting (P = 0.031).InterpretationPaired DBS pulses synchronize local circuit electrophysiology and elicit short‐term neuroplasticity in the subthalamic‐pallidal circuit. Collectively, these responses likely represent the earliest detectable interaction between the DBS pulse and local neuronal tissue in humans. Evoked subcortical field potentials could serve as a predictive biomarker to guide the implementation of next‐generation directional and adaptive stimulation devices.

StimVision v2: Examples and Applications in Subthalamic Deep Brain Stimulation for Parkinson’s Disease

ObjectiveSubthalamic deep brain stimulation (DBS) is an established therapy for Parkinson’s disease. Connectomic DBS modeling is a burgeoning subfield of research aimed at characterizing the axonal connections activated by DBS. This article describes our approach and methods for evolving the StimVision software platform to meet the technical demands of connectomic DBS modeling in the subthalamic region. Materials and MethodsStimVision v2 was developed with Visualization Toolkit (VTK) libraries and integrates four major components: 1) medical image visualization, 2) axonal pathway visualization, 3) electrode positioning, and 4) stimulation calculation. ResultsStimVision v2 implemented two key technological advances for connectomic DBS analyses in the subthalamic region. First was the application of anatomical axonal pathway models to patient-specific DBS models. Second was the application of a novel driving-force method to estimate the response of those axonal pathways to DBS. Example simulations with directional DBS electrodes and clinically defined therapeutic DBS settings are presented to demonstrate the general outputs of StimVision v2 models. ConclusionsStimVision v2 provides the opportunity to evaluate patient-specific axonal pathway activation from subthalamic DBS using anatomically detailed pathway models and electrically detailed electric field distributions with interactive adjustment of the DBS electrode position and stimulation parameter settings.

Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation.

Patients with advanced Parkinson's can be treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of 10 Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of DBS strategies to ameliorate gait impairments.SIGNIFICANCE STATEMENT We tested whether the subthalamic nucleus (STN) in humans is causally involved in controlling stepping movements. To this end, we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation (DBS), as in these individuals we can stimulate the STNs in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS (altDBS) could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait.

Deep Brain Stimulation for Chronic Cluster Headache: Meta‐Analysis of Individual Patient Data

Deep brain stimulation (DBS) is a treatment option for refractory chronic cluster headache (CCH). Despite several recent prospective case series reporting a good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long-term pain relief in an individual patient data meta-analysis. Furthermore, we aimed to construct a probabilistic stimulation map of effective DBS. We invited investigators of published cohorts of patients undergoing DBS for CCH, identified by a systematic review of MEDLINE from inception to Febuary 15, 2019, to provide individual patient data on baseline covariates, pre- and postoperative headache scores at median (12-month) and long-term follow-up, in addition to individual imaging data to obtain individual electrode positions. We calculated a stimulation map using voxel-wise statistical analysis. We used multiple regression analysis to estimate predictors of pain relief. Among 40 patients from four different cohorts representing ~50% of all previously published cases, we found a significant 77% mean reduction in headache attack frequency over a mean follow-up of 44 months, with an overall response rate of 75%. Positive outcome was not associated with baseline covariates. We identified 2 hotspots of stimulation covering the midbrain ventral and retrorubral tegmentum. This study supports the hypothesis that DBS provides long-term pain relief for the majority of CCH patients. Our stimulation map of the region of influence of therapeutic DBS identified an optimal anatomical target site that can help surgeons to guide their surgical planning in the future. ANN NEUROL 2020;88:956-969.

Prefrontal - subthalamic pathway supports action selection in a spatial working memory task

Subthalamic nucleus (STN) is the main source of feed-forward excitation in the basal ganglia and a main target of therapeutic deep brain stimulation in movement disorders. Alleviation of motor symptoms during STN stimulation can be accompanied by deterioration of abilities to quickly choose between conflicting alternatives. Cortical afferents to the subthalamic region (ST), comprising STN and zona incerta (ZI), include projections from the medial prefrontal cortex (mPFC), yet little is known about prefrontal-subthalamic coordination and its relevance for decision-making. Here we combined electrophysiological recordings with optogenetic manipulations of projections from mPFC to ST in mice as they performed a spatial working memory task (T-maze) or explored an elevated plus maze (anxiety test). We found that gamma oscillations (30–70 Hz) are coordinated between mPFC and ST at theta (5–10 Hz) and, less efficiently, at sub-theta (2–5 Hz) frequencies. An optogenetic detuning of the theta/gamma cross-frequency coupling between the regions into sub-theta range impaired performance in the T-maze, yet did not affect anxiety-related behaviors in the elevated plus maze. Both detuning and inhibition of the mPFC-ST pathway led to repeated incorrect choices in the T-maze. These effects were not associated with changes of anxiety and motor activity measures. Our findings suggest that action selection in a cognitively demanding task crucially involves theta rhythmic coordination of gamma oscillatory signaling in the prefrontal-subthalamic pathway.

Magnetoelectric Materials for Miniature, Wireless Neural Stimulation at Therapeutic Frequencies

A major challenge for miniature bioelectronics is wireless power delivery deep inside the body. Electromagnetic or ultrasound waves suffer from absorption and impedance mismatches at biological interfaces. On the other hand, magnetic fields do not suffer these losses, which has led to magnetically powered bioelectronic implants based on induction or magnetothermal effects. However, these approaches have yet to produce a miniature stimulator that operates at clinically relevant high frequencies. Here, we show that an alternative wireless power method based on magnetoelectric (ME) materials enables miniature magnetically powered neural stimulators that operate up to clinically relevant frequencies in excess of 100Hz. We demonstrate that wireless ME stimulators provide therapeutic deep brain stimulation in a freely moving rodent model for Parkinson's disease and that these devices can be miniaturized to millimeter-scale and fully implanted. These results suggest that ME materials are an excellent candidate to enable miniature bioelectronics for clinical and research applications.