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The impact of pulse timing is an important factor in our understanding of how to effectively modulate the basal ganglia thalamocortical (BGTC) circuit. Single pulse low-frequency DBS-evoked potentials generated through electrical stimulation of the subthalamic nucleus (STN) provide insight into circuit activation, but how the long-latency components change as a function of pulse timing is not well-understood. We investigated how timing between stimulation pulses delivered in the STN region influence the neural activity in the STN and cortex. DBS leads implanted in the STN of five patients with Parkinson's disease were temporarily externalized, allowing for the delivery of paired pulses with inter-pulse intervals (IPIs) ranging from 0.2 to 10 ms. Neural activation was measured through local field potential (LFP) recordings from the DBS lead and scalp EEG. DBS-evoked potentials were computed using contacts positioned in dorsolateral STN as determined through co-registered post-operative imaging. We quantified the degree to which distinct IPIs influenced the amplitude of evoked responses across frequencies and time using the wavelet transform and power spectral density curves. The beta frequency content of the DBS evoked responses in the STN and scalp EEG increased as a function of pulse-interval timing. Pulse intervals 4 ms produced modest, but non-significant growth. Beta frequency activity in the scalp EEG and STN LFP response was maximal when IPIs were between 1.5 and 4.0 ms. These results demonstrate that long-latency components of DBS-evoked responses are pre-dominantly in the beta frequency range and that pulse interval timing impacts the level of BGTC circuit activation.

OBJECTIVE Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain. MATERIALS AND METHODS Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps. RESULTS In response to pain, patients in the DBS OFF state showed significant activation (p

We aim to provide a comprehensive review of the current scientific evidence supporting the use of invasive neurostimulation in the treatment of deficits associated with traumatic brain injury (TBI), as well as to identify future directions for research and highlight important questions that remain unaddressed. Neurostimulation is a treatment modality with expanding applications in modern medical practice. Targeted electrical stimulation of specific brain regions has been shown to increase synaptogenesis and enhance structural reorganization of neuronal networks. This underlying therapeutic effect might be of high value for patients suffering from TBI because it could modulate neuronal connectivity and function of areas that are partially or completely spared after injury. The current published literature exploring the application of invasive neurostimulation for the treatment of functional deficits associated with TBI is scarce but promising. Rodent models have shown that targeted stimulation of the hippocampus or connecting structures can result in significant cognitive recovery, while stimulation of the motor cortex and deep cerebellar nuclei is associated with motor improvements. Data from clinical studies are extremely limited; single-patient reports and case series found neurostimulation to be effective in relieving motor symptoms, improving visuospatial memory, and supporting emotional adjustment. Looking forward, it will be important to identify stimulation targets and paradigms that can maximize improvement over multiple functional domains. It will also be important to corroborate the observed behavioral improvements with histological, electrophysiological, and radiological evidence. Finally, the impact of biological variables such as sex and age on the treatment outcomes needs to be explored.

Parkinson’s disease is a neurological disease with cardinal motor signs including bradykinesia and tremor. Although beta-band hypersynchrony in the cortico-basal ganglia network is thought to contribute to disease manifestation, the resulting effects on network connectivity are unclear. We examined local field potentials from a non-human primate across the naïve, mild, and moderate disease states (model was asymmetric, left-hemispheric dominant) and probed power spectral density as well as cortico-cortical and cortico-subthalamic connectivity using both coherence and Granger causality, which measure undirected and directed effective connectivity, respectively. Our network included the left subthalamic nucleus (L-STN), bilateral primary motor cortices (L-M1, R-M1), and bilateral premotor cortices (L-PMC, R-PMC). Results showed two distinct peaks (Peak A at 5–20 Hz, Peak B at 25–45 Hz) across all analyses. Power and coherence analyses showed widespread increases in power and connectivity in both the Peak A and Peak B bands with disease progression. For Granger causality, increases in Peak B connectivity and decreases in Peak A connectivity were associated with the disease. Induction of mild disease was associated with several changes in connectivity: (1) the cortico-subthalamic connectivity in the descending direction (L-PMC to L-STN) decreased in the Peak A range while the reciprocal, ascending connectivity (L-STN to L-PMC) increased in the Peak B range; this may play a role in generating beta-band hypersynchrony in the cortex, (2) both L-M1 to L-PMC and R-M1 to R-PMC causalities increased, which may either be compensatory or a pathologic effect of disease, and (3) a decrease in connectivity occurred from the R-PMC to R-M1. The only significant change seen between mild and moderate disease was increased right cortical connectivity, which may reflect compensation for the left-hemispheric dominant moderate disease state.

Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in participants (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN, and their interaction as a function of motor impairment and performance. Our results indicate the following: (1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low beta band, with moderately and severely impaired participants showing desynchronization and synchronization, respectively; and (2) significant CCC was observed during the isometric hold period in the low beta band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low beta band during motor control across all impairment levels, which encourages the exploitation of the cerebello–thalamo–cortical pathway as a neuromodulation target to promote rehabilitation. SIGNIFICANCE STATEMENT Cerebral infarct because of stroke can lead to lasting reduction in cerebellar metabolism, resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology, as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate the development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke survivors performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low beta band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

PURPOSE OF REVIEW: This paper reviews the current preclinical and clinical evidence for cerebellar deep brain stimulation for stroke rehabilitation. RECENT FINDINGS: We have demonstrated the effectiveness of cerebellar stimulation for stroke rehabilitation in rodent models, which has been reproduced by other groups. Synaptogenesis, neurogenesis, and vicariation of function in the perilesional cortex likely contribute to the mechanistic underpinnings of the effectiveness of this therapy. A Phase I clinical trial investigating dentate nucleus stimulation for improvement of hemiparesis due to stroke is currently underway, and results thus far are encouraging. SUMMARY: Activation of the rodent cerebellar dentate nucleus promotes functional motor recovery following stroke. Although results of a Phase I clinical trial are pending, substantial preclinical evidence indicates that deep brain stimulation of the dentate nucleus is a promising therapeutic modality.

Introduction Deep brain stimulation (DBS) is a widely accepted therapy for Parkinson's disease. While outcome predictors such as levodopa-response are well established, there remains a need for objective and unbiased predictors in clinical practice. We performed an exploratory study to examine whether cortical thickness, derived from preoperative MRI, correlates with postoperative outcome. Methods Using freesurfer, we retrospectively measured cortical thickness on the preoperative MRI of 38 patients who underwent bilateral STN-DBS for PD during a 4-year period. The Unified Parkinson Disease Rating motor (UPDRS III) and experiences of daily living subscales (UPDRS II) were collected at baseline and six months after surgery. As an initial analysis, a series of partial correlations was conducted to evaluate the association between postoperative outcome scores and average cortical thickness from predefined regions of interest, adjusting for candidate confounders, without correcting for multiple comparisons. A confirmatory vertex-wise analysis was performed using a cluster-wise correction for multiple comparisons. Results Based on the ROI analysis, the strongest correlation with motor outcome was found to be with the left lateral-occipital cortex. Patients with greater cortical thickness in this area presented with greater improvements in motor scores. This relationship was also supported by the vertex-wise analysis. Greater cortical thickness in frontal and temporal regions may be correlated with greater post-operative improvements in UPDRS II, but this was not confirmed in the vertex-wise analysis. Conclusions Our data indicate that greater cortical thickness in visuo-motor areas is correlated with motor outcomes after DBS for PD. Further prospective investigations are needed to confirm our findings and better-investigate potential image biomarkers.

Stroke is a leading cause of disability in the Western world. Current post-stroke rehabilitation treatments are only effective in approximately half of the patients. Therefore, there is a pressing clinical need for developing new rehabilitation approaches for enhancing the recovery process, which requires the use of appropriate animal models. Here, we demonstrate the use of nonlinear microscopy of calcium sensors in the rat brain to study the effects of ischemic stroke injury on cortical activity patterns. We longitudinally recorded from thousands of neurons labeled with a genetically-encoded calcium indicator before and after an ischemic stroke injury in the primary motor cortex. We show that this injury has an effect on the activity patterns of neurons not only in the motor and somatosensory cortices, but also in the more distant visual cortex, and that these changes include modified firing rates and kinetics of neuronal activity patterns in response to a sensory stimulus. Changes in neuronal population activity provided animal-specific, circuit-level information on the post-stroke cortical reorganization process, which may be essential for evaluating the efficacy of new approaches for enhancing the recovery process.

Stroke is a leading cause of disability in the Western world. Current post-stroke rehabilitation treatments are only effective in approximately half of the patients. Therefore, there is a pressing clinical need for developing new rehabilitation approaches for enhancing the recovery process, which requires the use of appropriate animal models. Here we study the activity patterns of multiple cortical regions in the rat brain using two-photon microscopy. We longitudinally recorded the fluorescence signal from thousands of neurons labeled with a genetically-encoded calcium indicator before and after an ischemic stroke injury, and found substantial functional changes across motor, somatosensory, and visual cortical regions during the post-stroke cortical reorganization period. We show that a stroke injury in the primary motor cortex has an effect on the activity patterns of neurons not only in the motor and somatosensory cortices, but also in the more distant visual cortex, and that these changes include modified firing rates and kinetics of neuronal activity patterns in response to a sensory stimulus. Changes in neuronal population activity provided animal-specific, circuit-level information on the poststroke cortical reorganization process, which may be essential for evaluating the efficacy of new approaches for enhancing the recovery process.

OBJECTIVES To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naive, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming. MATERIALS AND METHODS Serial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naive followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement. RESULTS In the naive state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45-0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p

Deep brain stimulation (DBS) is one of the most important clinical therapies for neurological disorders. DBS also has great potential to become a great tool for clinical neuroscience research. Recently, the National Engineering Laboratory for Neuromodulation at Tsinghua University held an international Deep Brain Stimulation Initiative workshop to discuss the cutting-edge technological achievements and clinical applications of DBS. We specifically addressed new clinical approaches and challenges in DBS for movement disorders (Parkinson's disease and dystonia), clinical application toward neurorehabilitation for stroke, and the progress and challenges toward DBS for neuropsychiatric disorders. This review highlighted key developments in (1) neuroimaging, with advancements in 3-Tesla magnetic resonance imaging DBS compatibility for exploration of brain network mechanisms; (2) novel DBS recording capabilities for uncovering disease pathophysiology; and (3) overcoming global healthcare burdens with online-based DBS programming technology for connecting patient communities. The successful event marks a milestone for global collaborative opportunities in clinical development of neuromodulation to treat major neurological disorders.

Neural oscillatory changes within and across different frequency bands are thought to underlie motor dysfunction in Parkinson’s disease (PD) and may serve as biomarkers for closed-loop deep brain stimulation (DBS) approaches. Here, we used neural oscillatory signals derived from chronically implanted cortical and subcortical electrode arrays as features to train machine learning algorithms to discriminate between naive and mild PD states in a nonhuman primate model. Local field potential (LFP) data were collected over several months from a 12-channel subdural electrocorticography (ECoG) grid and a 6-channel custom array implanted in the subthalamic nucleus (STN). Relative to the naive state, the PD state showed elevated primary motor cortex (M1) and STN power in the beta, high gamma, and high-frequency oscillation (HFO) bands and decreased power in the delta band. Theta power was found to be decreased in STN but not M1. In the PD state there was elevated beta-HFO phase-amplitude coupling (PAC) in the STN. We applied machine learning with support vector machines with radial basis function (SVM-RBF) kernel and k-nearest neighbors (KNN) classifiers trained by features related to power and PAC changes to discriminate between the naive and mild states. Our results show that the most predictive feature of parkinsonism in the STN was high beta (∼86% accuracy), whereas it was HFO in M1 (∼98% accuracy). A feature fusion approach outperformed every individual feature, particularly in the M1, where ∼98% accuracy was achieved with both classifiers. Overall, our data demonstrate the ability to use various frequency band power to classify the clinical state and are also beneficial in developing closed-loop DBS therapeutic approaches. NEW & NOTEWORTHY Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson’s disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

The remarkable clinical effectiveness of deep brain stimulation (DBS) for the treatment of an expanding range of neurological dysfunction will have profound implications. DBS has given emphasis to a whole new approach utilizing the electrical nature of brain function. Quite the contrary, evidence shows that high frequency DBS drives the output of the simulated structures. Ashby et al. provided evidence that excitation of axons by subthalamic DBS mediates DBS effects on electromyographic activity, while Baker et al. demonstrated the axonal mediation of subthalamic DBS-evoked scalp poten-tials. The current model, as described above, for the physiology and pathophysiology of the basal ganglia is in need of radical revision if not outright elimination. The previous anatomically based metaphor has resulted in simplistic notions that, unfortunately, have been found to be epiphenomenonally true as special cases and has created false local minima in our ignorance of basal ganglia physiology and pathophysiology.

Many studies suggest that Parkinson’s disease (PD) is associated with changes in neuronal activity patterns throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts the presupplementary motor area (pre-SMA) and SMA proper (SMAp), cortical areas known to be involved in movement planning and motor control. In this study, local field potentials (LFPs) were recorded in the pre-SMA/SMAp of a nonhuman primate during a visually cued reaching task. Recordings were made in the same subject in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism. We found that in the naive animal, well before a go-cue providing instruction of reach onset and direction was given, LFP activity was dynamically modulated in both high (20–30 Hz) and low beta (10–20 Hz) bands, and the magnitude of this modulation (e.g., decrease/increase in beta amplitude for each band, respectively) correlated linearly with reaction time (RT) on a trial-to-trial basis, suggesting it may predictively encode for RT. Consistent with this hypothesis, we observed that this activity was more prominent within the pre-SMA compared with SMAp. In the parkinsonian state, however, pre-SMA/SMAp beta band modulation was disrupted, particularly in the high beta band, such that the predictive encoding of RT was significantly diminished. In addition, the predictive encoding of RT preferentially within pre-SMA over SMAp was lost. These findings add to our understanding of the role of pre-SMA/SMAp in motor behavior and suggest a fundamental role of these cortical areas in early preparatory and premovement processes that are altered in parkinsonism. NEW & NOTEWORTHY Goal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in parkinsonism is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in pre-SMA/SMAp beta band modulation to the pathogenesis of motor disturbances in parkinsonism.

5-bromo-2′-dexoyuridine (BrdU) is often used in neuroscience research as a marker of newly-divided cells. However, several studies suggest that BrdU can produce unwanted side effects, including changes in animal behavior and cellular function. In this study, we investigated the effect of BrdU injections on locomotor behavior in a rodent model of ischemic stroke. Ischemic strokes were induced in adult rats, and 50 mg/kg BrdU was intraperitoneally injected over 5 days beginning 2 weeks post-stroke, while control animals received vehicle. Locomotor activity was evaluated by videotaping the rats in their home cages for 30 min, beginning one hour after BrdU injection. BrdU-injected rats showed a nearly three-fold increase in locomotor activity compared to control animals. These findings suggest that BrdU induces a hyperlocomotor effect in rats following brain injury, pointing to the need for caution when interpreting behavioral results in such studies.

Objectives We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia. Methods Five patients with SCA with cortical atrophy (ages 60‐69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET. Results Postsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%). Interpretation Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello‐thalamo‐cortical network.

Background Chronic deep brain stimulation of the rodent lateral cerebellar nucleus (LCN) has been demonstrated to enhance motor recovery following cortical ischemia. This effect is concurrent with synaptogenesis and expression of long-term potentiation markers in the perilesional cerebral cortex. Objective To further investigate the cellular changes associated with chronic LCN stimulation in the ischemic rodent by examining neurogenesis along the cerebellothalamocortical pathway. Methods Rats were trained on the pasta matrix task, followed by induction of cortical ischemia and electrode implantation in the contralesional LCN. Electrical stimulation was initiated 6 wk after stroke induction and continued for 4 wk prior to sacrifice. Neurogenesis was examined using immunohistochemistry. Results Treated animals showed enhanced performance on the pasta matrix task relative to sham controls. Increased cell proliferation colabeled with 5'-Bromo-2'-deoxyuridine and neurogenic markers (doublecortin) was observed in the perilesional cortex as well as bilateral mediodorsal and ventrolateral thalamic subnuclei in treated vs untreated animals. The neurogenic effect at the level of motor cortex was selective, with stimulation-treated animals showing greater glutamatergic neurogenesis but significantly less GABAergic neurogenesis. Conclusion These findings suggest that LCN deep brain stimulation modulates postinjury neurogenesis, providing a possible mechanistic foundation for the associated enhancement in poststroke motor recovery.

A number of studies suggest that Parkinson’s disease (PD) is associated with alterations of neuronal activity patterns in the basal-ganglia-thalamocortical circuit. There are limited electrophysiological data, however, describing how the premotor cortex, which is involved in movement and decision-making, is likely impacted in PD. In this study, spontaneous local field potential (LFP) and single unit neuronal activity were recorded in the dorsal premotor area of nonhuman primates in both the naïve and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In both animals, we observed a shift of power in LFP power spectral densities (1−350 Hz) from higher to lower frequency bands; parkinsonism resulted in increased power in frequencies 30 Hz. A comparable but not identical trend was observed in the power spectral analysis of single unit spike trains: alpha power increased in both animals and gamma power decreased in one; power in other frequency bands remaining unchanged. Although not consistent across animals, we also observed changes in discharge rates and bursting activity. Overall, the LFP and single unit analysis suggest that abnormalities in premotor neural activity are a feature of parkinsonism, although specific details of those abnormalities may differ between subjects. This study further supports the concept that PD is a network disorder that induces abnormal spontaneous neural activities across the basal-ganglia-thalamocortical circuit including the premotor cortex and provides foundational knowledge for future studies regarding the relationship between changes in neuronal activity in this region and the development of motor deficits in PD. NEW & NOTEWORTHY This study begins to fill a gap in knowledge regarding how Parkinson’s disease (PD) may cause abnormal functioning of the premotor cortex. It is novel as the premotor activity is examined in both the naïve and parkinsonian states, in the same subjects, at the single unit and LFP level. It provides foundational knowledge on which to build future studies to explore the relationships between premotor activities and specific parkinsonian motor and cognitive deficits.

Objective The experience with deep brain stimulation (DBS) for pain is largely based on uncontrolled studies targeting the somatosensory pathways, with mixed results. We hypothesized that targeting limbic neural pathways would modulate the affective sphere of pain and alleviate suffering. Methods We conducted a prospective, double-blinded, randomized, placebo-controlled, crossover study of DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) in 10 patients with poststroke pain syndrome. One month after bilateral DBS, patients were randomized to active DBS or sham for 3 months, followed by crossover for another 3-month period. The primary endpoint was a ≥50% improvement on the Pain Disability Index in 50% of patients with active DBS compared to sham. This 6-month blinded phase was followed by an 18-month open stimulation phase. Results Nine participants completed randomization. Although this trial was negative for its primary and secondary endpoints, we did observe significant differences in multiple outcome measures related to the affective sphere of pain (eg, Montgomery–Asberg Depression Rating Scale, Beck Depression Inventory, Affective Pain Rating Index of the Short-Form McGill Pain Questionnaire). Fourteen serious adverse events were recorded and resolved. Interpretation VS/ALIC DBS to modulate the affective sphere of pain represents a paradigm shift in chronic pain management. Although this exploratory study was negative for its primary endpoint, VS/ALIC DBS demonstrated an acceptable safety profile and statistically significant improvements on multiple outcome measures related to the affective sphere of pain. Therefore, we believe these results justify further work on neuromodulation therapies targeting the affective sphere of pain. Ann Neurol 2017;81:653–663

OBJECTIVE Deep brain stimulation (DBS) is an effective therapy for different neurological diseases, despite the lack of comprehension of its mechanism of action. The use of nonhuman primates (NHPs) has been historically important in advancing this field and presents a unique opportunity to uncover the therapeutic mechanisms of DBS, opening the way for optimization of current applications and the development of new ones. To be informative, research using NHPs should make use of appropriate electrode implantation tools. In the present work, the authors report on the feasibility and accuracy of targeting different deep brain regions in NHPs using a commercially available frameless stereotactic system (microTargeting platform). METHODS Seven NHPs were implanted with DBS electrodes, either in the subthalamic nucleus or in the cerebellar dentate nucleus. A microTargeting platform was designed for each animal and used to guide implantation of the electrode. Imaging studies were acquired preoperatively for each animal, and were subsequently analyzed by two independent evaluators to estimate the electrode placement error (EPE). The interobserver variability was assessed as well. RESULTS The radial and vector components of the EPE were estimated separately. The magnitude of the vector of EPE was 1.29 ± 0.41 mm and the mean radial EPE was 0.96 ± 0.63 mm. The interobserver variability was considered negligible. CONCLUSIONS These results reveal the suitability of this commercial system to enhance the surgical insertion of DBS leads in the primate brain, in comparison to rigid traditional frames. Furthermore, our results open up the possibility of performing frameless stereotaxy in primates without the necessity of relying on expensive methods based on intraoperative imaging.

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.

Electrophysiologic mapping remains an integral component of deep brain stimulation (DBS) surgical procedures, particularly in movement disorder cases where functional maps are used to guide DBS lead placement in patients with Parkinson's disease, dystonia, or tremor. Overall, the goal of the surgical procedure is to implant the distal end of a chronic, multicontact depth electrode into a specific brain region for the purpose of delivering therapeutic electrical stimulation. Regions that are currently targeted for patients with movement disorders include the subthalamic nucleus, the ventral intermediate nucleus of the thalamus, and the globus pallidus. Multiple imaging modalities are used initially to derive a stereotactic plan and guide the initial microelectrode trajectory. Changes in neuronal firing rate and pattern, both spontaneous and in response to somatosensory stimulation, are used to establish the location of the tip of the microelectrode(s), while acute stimulation can be used to estimate the proximity of neighboring brain regions. In this chapter, we will provide an overview of the microelectrode recording process as it is commonly applied to refine image-based targeting of lead placement for DBS surgery.

Background Incorporating feedback controls based on real-time measures of pathological brain activity may improve deep brain stimulation (DBS) approaches for the treatment of Parkinson's disease (PD). Excessive beta oscillations in subthalamic nucleus (STN) local field potentials (LFP) have been proposed as a potential biomarker for closed-loop DBS (CL-DBS). Objective In a non-human primate PD model we compared CL-DBS, which delivered stimulation only when STN LFP beta activity was elevated, to traditional continuous DBS (tDBS). Methods Therapeutic effects of CL-DBS and tDBS relative to the Off-DBS condition were evaluated via a clinical rating scale and objective measures of movement speed during a cued reaching task. Results CL-DBS was comparable to tDBS at reducing rigidity, while reducing the amount of time DBS was on by ≈50%; however, only tDBS improved bradykinesia during the reaching behavior. This was likely due to reach-related reductions in beta amplitude that influence the timing and duration of stimulation in the CL-DBS condition. Conclusion These results illustrate the potential utility of closed-loop DBS devices for PD based on STN beta LFP levels. They also point to possible consequences in behavioral tasks when restricting real-time sensing to a single LFP frequency that itself is modulated during performance of such tasks. The present study provides data that suggest alternate algorithms or more than one physiological biomarker may be required to optimize the performance of behavioral tasks and demonstrates the value of using multiple objective measures when evaluating the efficacy of closed-loop DBS systems.

Background Novel deep brain stimulation (DBS) paradigms are being explored in an effort to further optimize therapeutic outcome for patients with Parkinson's disease (PD). One approach, termed ‘Coordinated Reset’ (CR) DBS, was developed to target pathological oscillatory network activity. with desynchronizing effects and associated therapeutic benefit hypothesized to endure beyond cessation of stimulus delivery. Objective To characterize the acute and carry-over effects of low-intensity CR DBS versus traditional DBS (tDBS) in the region of the subthalamic nucleus (STN). Methods A within-subject, block treatment design involving the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate model of parkinsonism was used. Each treatment block consisted of five days of daily DBS delivery followed by a one week minimum post-treatment observation window. Motor behavior was quantified using a modified rating scale for both animals combined with an objective, upper-extremity reach task in one animal. Results Both animals demonstrated significant motor improvements during acute tDBS; however, within-session and post-treatment carry-over was limited. Acute motor improvements were also observed in response to low-intensity CR DBS; however, both within- and between-session therapeutic carry-over enhanced progressively following each daily treatment. Moreover, in contrast to tDBS, five consecutive days of CR DBS treatment yielded carry-over benefits that persisted for up to two weeks without additional intervention. Notably, the magnitude and time-course of CR DBS' effects on each animal varied with daily dose-duration, pointing to possible interaction effects involving baseline parkinsonian severity. Conclusion Our results support the therapeutic promise of CR DBS for PD, including its potential to induce carryover while reducing both side effect risk and hardware power consumption.

Electrophysiologic mapping remains an integral component of deep brain stimulation (DBS) surgical procedures, particularly in movement disorder cases where functional maps are used to guide DBS lead placement in patients with Parkinson's disease, dystonia, or tremor. Overall, the goal of the surgical procedure is to implant the distal end of a chronic, multicontact depth electrode into a specific brain region for the purpose of delivering therapeutic electrical stimulation. Regions that are currently targeted for patients with movement disorders include the subthalamic nucleus, the ventral intermediate nucleus of the thalamus, and the globus pallidus. Multiple imaging modalities are used initially to derive a stereotactic plan and guide the initial microelectrode trajectory. Changes in neuronal firing rate and pattern, both spontaneous and in response to somatosensory stimulation, are used to establish the location of the tip of the microelectrode(s), while acute stimulation can be used to estimate the proximity of neighboring brain regions. In this chapter, we will provide an overview of the microelectrode recording process as it is commonly applied to refine image-based targeting of lead placement for DBS surgery.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson’s disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward., SCOPUS: re.j, info:eu-repo/semantics/published

Ischemic stroke is a leading cause of disability worldwide, with profound economic costs. Poststroke motor impairment is the most commonly encountered deficit resulting in significant disability and is the primary driver of stroke-associated healthcare expenditures. Although many patients derive some degree of benefit from physical rehabilitation, a significant proportion continue to suffer from persistent motor impairment. Noninvasive brain stimulation, vagal nerve stimulation, epidural cortical stimulation, and deep brain stimulation (DBS) have all been studied as potential modalities to improve upon the benefits derived from physical therapy alone. These neuromodulatory therapies aim primarily to augment neuroplasticity and drive functional reorganization of the surviving perilesional cortex.The authors have proposed a novel and emerging therapeutic approach based on cerebellar DBS targeted at the dentate nucleus. Their rationale is based on the extensive reciprocal connectivity between the dentate nucleus and wide swaths of cerebral cortex via the dentatothalamocortical and corticopontocerebellar tracts, as well as the known limitations to motor rehabilitation imposed by crossed cerebellar diaschisis. Preclinical studies in rodent models of ischemic stroke have shown that cerebellar DBS promotes functional recovery in a frequency-dependent manner, with the most substantial benefits of the therapy noted at 30-Hz stimulation. The improvements in motor function are paralleled by increased expression of markers of synaptic plasticity, synaptogenesis, and neurogenesis in the perilesional cortex. Given the findings of preclinical studies, a first-in-human trial, Electrical Stimulation of the Dentate Nucleus Area (EDEN) for Improvement of Upper Extremity Hemiparesis Due to Ischemic Stroke: A Safety and Feasibility Study, commenced in 2016. Although the existing preclinical evidence is promising, the results of this Phase I trial and subsequent clinical trials will be necessary to determine the future applicability of this therapy.

Background Many traumatic brain injury (TBI) survivors live with persistent disability from chronic motor deficits despite contemporary rehabilitation services, underscoring the need for novel treatment. Objective/Hypothesis We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) can enhance post-stroke motor recovery and increase the expression of markers of long-term potentiation in perilesional cerebral cortex. We hypothesize that a similar beneficial effect will be for motor deficits induced by unilateral fluid percussion injury (FPI) in rodents through long-term potentiation- and anti-inflammatory based mechanisms. Methods Male Long Evans rats with a DBS macroelectrode in the LCN underwent FPI over contralateral primary motor cortex. After 4 weeks of spontaneous recovery, DBS treatment was applied for 4 weeks, with the pasta matrix, cylinder, and horizontal ladder tests used to evaluate motor performance. All animals were euthanized and tissue harvested for further analysis by histology, immunohistochemistry, RNA microarray assay and Western Blot. Results LCN DBS-treated animals experienced a significantly greater rate of motor recovery than untreated surgical controls, with treated animals showing enhanced expression of RNA and protein for excitability related genes, suppressed expression of pro-inflammatory genes, suppressed microglial and astrocytic activation, but proliferation of c-fos positive cells. Finally, our data suggest a possible role for anti-apoptotic effects with LCN DBS. Conclusion LCN DBS enhanced the motor recovery following TBI, possibly by elevating the neuronal excitability at the perilesional area and mediating anti-apoptotic and anti-inflammatory effects.

Goal: Develop and characterize the functionality of a novel thin-film probe technology with a higher density of electrode contacts than are currently available with commercial deep brain stimulation (DBS) lead technology. Such technology has potential to enhance the spatial precision of DBS and enable a more robust approach to sensing local field potential activity in the context of adaptive DBS strategies. Methods: Thin-film planar arrays were microfabricated and then assembled on a cylindrical carrier to achieve a lead with 3-D conformation. Using an integrated and removable stylet, the arrays were chronically implanted in the subthalamic nucleus and globus pallidus in two parkinsonian nonhuman primates. Results: This study provides the first in vivo data from chronically implanted DBS arrays for translational nonhuman primate studies. Stimulation through the arrays induced a decrease in parkinsonian rigidity, and directing current around the lead showed an orientation dependence for eliciting motor capsule side effects. The array recordings also showed that oscillatory activity in the basal ganglia is heterogeneous at a smaller scale than detected by the current DBS lead technology. Conclusion: These 3-D DBS arrays provide an enabling tool for future studies that seek to monitor and modulate deep brain activity through chronically implanted leads. Significance: DBS lead technology with a higher density of electrode contacts has potential to enable sculpting DBS current flow and sensing biomarkers of disease and therapy.

The firing patterns of neurons in the basal ganglia are known to become more oscillatory and synchronized from healthy to parkinsonian conditions. Similar changes have been observed with local field potentials (LFPs). In this study, we used an unbiased machine learning approach to investigate the utility of pallidal LFPs for discriminating the stages of a progressive parkinsonian model. A feature selection algorithm was used to identify subsets of LFP features that provided the most discriminatory information for severity of parkinsonian motor signs. Prediction errors 50%. These results suggest that pallidal oscillations can be predictive biomarkers of parkinsonian severity, but the features are more complex than spectral power in individual frequency bands, such as the beta band. Additionally, the best feature set was subject specific, which highlights the pathophysiological heterogeneity of parkinsonism and the importance of subject specificity when designing closed-loop system controllers dependent on such features.

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.

Ischemic stroke is a leading cause of permanent disability worldwide. While intensive rehabilitation has the potential to improve motor function in some patients in the chronic phase of stroke, a large proportion of patients are left with significant motor deficits. Several noninvasive and invasive neuromodulatory approaches have been investigated as adjunctive therapies to augment motor recovery in the chronic phase. These modalities are aimed at modulation of the surviving perilesional cortex or remote cortical areas. Noninvasive neuromodulatory strategies, including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrated the ability to produce significant improvements in motor function when combined with rehabilitation and are important investigational tools in elucidating mechanisms of recovery in human subjects. Invasive strategies that have been investigated include epidural cortical stimulation (ECS), vagal nerve stimulation (VNS), and deep brain stimulation (DBS). ECS of the motor cortex (MCS) demonstrated promise in preclinical studies using both rodent and nonhuman primate models of stroke. While Phase I and Phase II studies showed apparent benefits, a pivotal Phase III randomized controlled clinical trial (RCT) failed to demonstrate improvements when compared to rehabilitation alone. VNS has shown efficacy in recent studies and a Phase I clinical trial recently conducted in the United Kingdom demonstrated safety and promising benefits. Our group has investigated the use of DBS, targeting the dentatothalamocortical (DTC) pathway output. We have shown that DBS of the DTC augments motor recovery in rodent models of large and focal ischemic strokes. In addition, we have shown that DBS of the DTC increased expression of markers of synaptic plasticity in the perilesional cortex as well as synaptogenesis and significant reorganization of motor representation. A Phase I clinical trial of cerebellar DBS is currently underway. While significant research efforts are still needed before neurostimulation becomes a standard treatment for poststroke rehabilitation, several investigational approaches have shown promising data.

Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson’s disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8–30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed-loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance. NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson’s disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson’s disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers.

Objectives To review the current state of cerebral stimulation for neuropathic pain and to propose that cerebral stimulation should aim also at the affective sphere of chronic pain rather than solely focusing on the primary sensory-discriminative sphere. Methods The past and current goals of cerebral stimulation are reviewed as well as its limitations. A novel deep brain stimulation approach is proposed to evaluate this conceptual shift from somatosensory to affective sphere of pain targeting. Approach Thalamic and other central pain syndromes are typically intractable to current treatment methods, including cerebral neuromodulation of somatosensory pathways, leading to long-term distress and disability. Our modern understanding of chronic pain pathophysiology is based largely on the neuromatrix theory, where cognitive, affective, and sensory-discriminative spheres contribute equally to the overall pain experience. During the last decade, the safety and feasibility of chronic stimulation of neural pathways related to mood and affect has been explored with promising results. Here, we propose a novel approach to modulate the affective sphere of chronic pain by targeting similar networks in patients with treatment-refractory central pain. Our primary goal is not to produce (or measure) analgesia, but rather to modulate the affective burden of chronic pain. Discussion Cerebral neuromodulation for neuropathic pain has had limited efficacy thus far. Shifting our aim to neural networks related to the affective sphere of pain may allow us to reduce pain conditioning and pain-related disability. Our ultimate goal is to promote rehabilitation from chronic pain—social and occupational.

Summary Electrical brain stimulation is used in a variety of clinical situations, including cortical mapping for epilepsy surgery, cortical stimulation therapy to terminate seizure activity in the cortex, and in deep brain stimulation therapy. However, the effects of stimulus parameters are not fully understood. In this study, we systematically tested the impact of various stimulation parameters on the generation of motor symptoms and afterdischarges (ADs). Focal electrical stimulation was delivered at subdural cortical, intracortical, and hippocampal sites in a rat model. The effects of stimulus parameter on the generation of motor symptoms and on the occurrence of ADs were examined. The effect of stimulus irregularity was tested using random or regular 50Hz stimulation through subdural electrodes. Hippocampal stimulation produced ADs at lower thresholds than neocortical stimulation. Hippocampal stimulation also produced significantly longer ADs. Both in hippocampal and cortical stimulation, when the total current was kept constant with changing pulse width, the threshold for motor symptom or AD was lowest between 50 and 100Hz and higher at both low and high frequencies. However, if the pulse width was fixed, the threshold did not increase above 100Hz and it apparently continued to decrease through 800Hz even if the difference did not reach statistical significance. There was no significant difference between random and regular stimulation. Overall, these results indicate that electrode location and several stimulus parameters including frequency, pulse width, and total electricity are important in electrical stimulation to produce motor symptoms and ADs.