Electrophysiological Correlates of Dentate Nucleus Deep Brain Stimulation for Poststroke Motor Recovery.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

A novel restrainer device for acquistion of brain images in awake rats.

Functional neuroimaging methods like fMRI and PET are vital in neuroscience research, but require that subjects remain still throughout the scan. In animal research, anesthetic agents are typically applied to facilitate the acquisition of high-quality data with minimal motion artifact. However, anesthesia can have profound effects on brain metabolism, selectively altering dynamic neural networks and confounding the acquired data. To overcome the challenge, we have developed a novel head fixation device designed to support awake rat brain imaging. A validation experiment demonstrated that the device effectively minimizes animal motion throughout the scan, with mean absolute displacement and mean relative displacement of 0.0256 (SD: 0.001) and 0.009 (SD: 0.002), across eight evaluated subjects throughout fMRI image acquisition (total scanning time per subject: 31 min, 12 s). Furthermore, the awake scans did not induce discernable stress to the animals, with stable physiological parameters throughout the scan (Mean HR: 344, Mean RR: 56, Mean SpO2: 94 %) and unaltered serum corticosterone levels (p = 0.159). In conclusion, the device presented in this paper offers an effective and safe method of acquiring functional brain images in rats, allowing researchers to minimize the confounding effects of anesthetic use.

Uncovering the rate and risk factors of intrathecal baclofen pump-associated complications in the adult population.

OBJECTIVE: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications. METHODS: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications. RESULTS: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation. CONCLUSIONS: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.

Intracranial Bleeding in Deep Brain Stimulation Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Deep brain stimulation (DBS) is a neurosurgical treatment used for the treatment of movement disorders. Surgical and perioperative complications, although infrequent, can result in clinically significant neurological impairment. OBJECTIVES: In this study, we evaluated the incidence and risk factors of intracranial bleeding in DBS surgery. METHOD: Medline, EMBASE, and Cochrane were screened in line with PRISMA 2020 guidelines to capture studies reporting on the incidence of hemorrhagic events in DBS. After removing duplicates, the search yielded 1,510 papers. Abstracts were evaluated by two independent reviewers for relevance. A total of 386 abstracts progressed to the full-text screen and were assessed against eligibility criteria. A total of 151 studies met the criteria and were included in the analysis. Any disagreement between the reviewers was resolved by consensus. Relevant data points were extracted and analyzed in OpenMeta [Analyst] software. RESULTS: The incidence of intracranial bleeding was 2.5% (95% CI: 2.2-2.8%) per each patient and 1.4% (95% CI: 1.2-1.6%) per each implanted lead. There was no statistically significant difference across implantation targets and clinical indications. Patients who developed an intracranial bleed were on average 5 years older (95% CI: 1.26-13.19), but no difference was observed between the genders (p = 0.891). A nonsignificant trend was observed for a higher risk of bleeding in patients with hypertension (OR: 2.99, 95% CI: 0.97-9.19) (p = 0.056). The use of microelectrode recording did not affect the rate of bleeding (p = 0.79). CONCLUSIONS: In this review, we find that the rate of bleeding per each implanted lead was 1.4% and that older patients had a higher risk of hemorrhage.

Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial.

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target. CPMd can offer alternate, bi-hemispheric and ipsilateral connections in support of paretic limb movement. This pilot, randomized clinical trial seeks to investigate whether rTMS delivered to facilitate cPMd in conjunction with rehabilitation produces greater gains in motor function than conventional rTMS delivered to facilitate iM1 in conjunction with rehabilitation in severely impaired stroke survivors. Twenty-four chronic (≥6 months) stroke survivors with severe loss of ipsilesional substrate (defined by the absence of physiologic evidence of excitable residual pathways tested using TMS) will be included. Participants will be randomized to receive rTMS to facilitate cPMd or iM1 in conjunction with task-oriented upper limb rehabilitation given for 2 sessions/week for 6 weeks. Assessments of primary outcome related to motor impairment (upper extremity Fugl-Meyer [UEFM]), motor function, neurophysiology, and functional neuroimaging will be made at baseline and at 6-week end-of-treatment. An additional assessment of motor outcomes will be repeated at 3-month follow-up to evaluate retention. The primary endpoint is 6-week change in UEFM. This pilot trial will provide preliminary evidence on the effects and mechanisms associated with facilitating intact cPMd in chronic severe stroke survivors. The trial is registered on clinicaltrials.gov, NCT03868410.

Directional Stimulation in Parkinson's Disease and Essential Tremor: The Cleveland Clinic Experience.

OBJECTIVE: To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care. MATERIALS AND METHODS: Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables. RESULTS: Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation. CONCLUSIONS: Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.

Stability and Effect of Parkinsonian State on Deep Brain Stimulation Cortical Evoked Potentials.

OBJECTIVES: To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, 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 naïve 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 naïve 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 < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands. CONCLUSIONS: Our findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.

Long-term outcomes of intrathecal baclofen in ambulatory multiple sclerosis patients: A single-center experience.

BACKGROUND: Intrathecal baclofen (ITB) is traditionally reserved for non-ambulatory patients. OBJECTIVE: To investigate outcomes of ITB in ambulatory multiple sclerosis (MS) patients. METHODS: Changes in outcome measures were estimated by a mixed effect model, while the complication rate was calculated using a logistic regression. Predictors of non-ambulatory status were identified by Cox model. RESULTS: In all, 256 patients received an ITB test injection and 170 underwent ITB surgery. Aggregate Modified Ashworth Scale (MAS) scores for the ambulatory ITB cohort decreased from 13.5 ± 6.96 to 4.54 ± 4.18 at 5 years (p < 0.001). There was no significant change in walking speed 1 year post ITB surgery (0.45 m/second ± 0.30 vs 0.38 m/second ± 0.39, p = 0.80) with 77.8% of patients remaining ambulatory which decreased to 41.7% at year 5. Longer MS disease duration (hazard ratio (HR): 1.04; 95% confidence interval (CI): 1.01-1.07; p = 0.018) and lower hip flexor strength (HR: 0.40; 95% CI: 0.27-0.57; p < 0.001) predicted non-ambulatory status after surgery. Complications were more likely in the ambulatory cohort (odds ratio (OR): 3.30, 95% CI: 2.17-5.02; p = 0.017). CONCLUSION: ITB is effective for ambulatory MS patients without compromising short-term walking speed, although a higher complication rate was observed in this cohort.

Biomarker Optimization of Spinal Cord Stimulation Therapies.

OBJECTIVES: We are in the process of designing and testing an intradural stimulation device that will shorten the distance between the location of the electrode array and the targeted neural tissue, thus improving the efficacy of electrical current delivery. Identifying a biomarker that accurately reflects the response to this intervention is highly valued because of the potential to optimize interventional parameters or predict a response before it is clinically measurable. In this report, we summarize the findings pertaining to the study of biomarkers so that we and others will have an up-to-date reference that critically evaluates the current approaches and select one or several for testing during the development of our device. MATERIALS AND METHODS: We have conducted a broad survey of the existing literature to catalogue the biomarkers that could be coupled to intradural spinal cord stimulation. We describe in detail some of the most promising biomarkers, existing limitations, and suitability to managing chronic pain. RESULTS: Chronic, intractable pain is an all-encompassing condition that is incurable. Many treatments for managing chronic pain are nonspecific in action and intermittently administered; therefore, patients are particularly susceptible to large fluctuations in pain control over the course of a day. The absence of a reliable biomarker challenges assessment of therapeutic efficacy and contributes to either incomplete and inconsistent pain relief or, alternatively, intolerable side effects. Fluctuations in metabolites or inflammatory markers, signals captured during dynamic imaging, and genomics will likely have a role in governing how a device is modulated. CONCLUSIONS: Efforts to identify one or more biomarkers are well underway with some preliminary evidence supporting their efficacy. This has far-reaching implications, including improved outcomes, fewer adverse events, harmonization of treatment and individuals, performance gains, and cost savings. We anticipate that novel biomarkers will be used widely to manage chronic pain.

Functional Magnetic Resonance Imaging Correlates of Ventral Striatal Deep Brain Stimulation for Poststroke Pain.

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 < 0.001) in the same regions as healthy controls (thalamus, insula, and operculum) and in additional regions (orbitofrontal and superior convexity cortical areas). DBS significantly reduced activation of these additional regions and introduced foci of significant inhibitory activation (p < 0.001) in the hippocampi when painful stimulation was applied to the affected side. CONCLUSIONS: These findings suggest that DBS of the VS/ALIC modulates affective neural networks.

Prediction of mild parkinsonism revealed by neural oscillatory changes and machine learning.

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.

Spinal Cord Stimulation for Visceral Pain: Present Approaches and Future Strategies.

INTRODUCTION: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges. METHODS: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain. RESULTS: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative. CONCLUSIONS: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy.

An Anatomical Study of the Foramen Ovale for Neuromodulation of Trigeminal Neuropathic Pain.

OBJECTIVE: Neuromodulation for trigeminal pain syndromes such as trigeminal neuropathic pain (TNP) necessitates accurate localization of foramen ovale (FO). The Härtel-type approach is very well-established and safe, ideal for temporary cannulation of the FO for ablative procedures such as balloon microcompression. A key shortcoming of the Hartel approach for placement of neuromodulation leads is the limited opportunity for secure anchoring. The aim of this study is to introduce a novel surgical approach for the treatment of TNP by investigating key osseous landmarks and their spatial relationships to the FO. MATERIALS AND METHODS: Sixteen sides of cadaver heads were dissected to investigate a surgical route of the FO via transoral gingival buccal approach. Alveolar arch of the maxilla and zygomaticomaxillary suture were selected to serve as an osseous landmark for the surgical guidance to the FO. Through the intraoral route, a needle simulating electrode was traversed to aim the FO from the inferior lateral to the superior medial direction to target specific fibers of the aimed division of the nerve. RESULTS: Visual identification and access to the trigeminal nerve at the external opening of FO was successful in all 16 hemifacial cadavers. A needle successfully targeted different regions of the trigeminal nerve by changing the angle of the trajectory allowing the needle to reach a specific division of the trigeminal nerve. CONCLUSIONS: This study provides a novel means of approaching the FO via transoral gingival buccal access.

Patient-Specific Analysis of Neural Activation During Spinal Cord Stimulation for Pain.

OBJECTIVE: Despite the widespread use of spinal cord stimulation (SCS) for chronic pain management, its neuromodulatory effects remain poorly understood. Computational models provide a valuable tool to study SCS and its effects on axonal pathways within the spinal cord. However, these models must include sufficient detail to correlate model predictions with clinical effects, including patient-specific data. Therefore, the goal of this study was to investigate axonal activation at clinically relevant SCS parameters using a computer model that incorporated patient-specific anatomy and electrode locations. METHODS: We developed a patient-specific computer model for a patient undergoing SCS to treat chronic pain. This computer model consisted of two main components: 1) finite element model of the extracellular voltages generated by SCS and 2) multicompartment cable models of axons in the spinal cord. To determine the potential significance of a patient-specific approach, we also performed simulations with standard canonical models of SCS. We used the computer models to estimate axonal activation at clinically measured sensory, comfort, and discomfort thresholds. RESULTS: The patient-specific and canonical models predicted significantly different axonal activation. Relative to the canonical models, the patient-specific model predicted sensory threshold estimates that were more consistent with the corresponding clinical measurements. These results suggest that it is important to account for sources of interpatient variability (e.g., anatomy, electrode locations) in model-based analysis of SCS. CONCLUSIONS: This study demonstrates the potential for patient-specific computer models to quantitatively describe the axonal response to SCS and to address scientific questions related to clinical SCS.

Long-term Outcomes Using Intrathecal Drug Delivery Systems in Complex Regional Pain Syndrome.

OBJECTIVE: Providing durable long-term pain control for patients with complex regional pain syndrome (CRPS) is challenging. A multidisciplinary approach focused on physical therapy is frequently prescribed, with opioids and invasive procedures reserved for those challenged by functional progression. In this study, we examined the long-term efficacy of intrathecal drug delivery systems (IDDS) in patients with CRPS at our institution. METHODS: Patients with CRPS implanted with an IDDS between 2000 and 2013 who had four or more years of continuous follow-up were included in the analysis. The outcome variables of interest were pain intensity and oral opioid intake. The primary predictor of interest was dose of intrathecal opioids, with ziconotide, bupivacaine, and clonidine characterized as binary secondary predictors. RESULTS: Of the 1,653 IDDS identified, 62 were implanted primarily for CRPS-related pain. Of these, 26 had four or more years of complete follow-up data. Pain scores did not significantly decrease over time, and we observed no correlation between pain intensity and use of any intrathecal medication. Although oral opioid intake decreased over time, intrathecal opioid dose did not affect oral opioid consumption. Ziconotide was associated with a hastening of the decrease in oral opioid intake, whereas the presence of bupivacaine paradoxically increased oral opioid intake. CONCLUSIONS: Our study demonstrates that intrathecal opioid dose was not associated with long-term decreases in oral opioid intake. Additionally, ziconotide was associated with a decrease in oral opioid intake over the four-year follow-up, and bupivacaine was associated with an increase in oral opioid intake. Our study examines the long-term effectiveness of intrathecal medications in managing pain in patients with complex regional pain syndrome. We present a detailed follow-up over four years for 26 patients, tracking oral opiate intake, pain scores, and intrathecal pump settings. Our findings suggest that intrathecal opiates may not be effective in reducing oral opiate intake, ziconotide may hasten a decrease in intake, and bupivacaine may lead to an increase in intake.

Durotomy Surrogate and Seals for Intradural Spinal Cord Stimulators: Apparatus and Review of Clinical Methods and Materials.

INTRODUCTION: We are developing a novel intradural spinal cord stimulator for treatment of neuropathic pain and spasticity. A key feature is the means by which it seals the dura mater to prevent leakage of cerebrospinal fluid (CSF). We have built and employed a test rig that enables evaluation of candidate seal materials. METHODS: To guide the design of the test rig, we reviewed the literature on neurosurgical durotomies. The test rig has a mock durotomy slot with a dural substitute serving as the surrogate dura mater and water as the CSF. The primary experimental goal was to evaluate the effectiveness of candidate gasket materials as seals against CSF leakage in an implanted prototype device, at both normal and super-physiologic pressures. A secondary goal was to measure the transmembrane flows in a representative dural substitute material, to establish its baseline aqueous transport properties. RESULTS: The seals prevented leakage of water at the implantation site over periods of ≈ ten days, long enough for the scar tissue to form in the clinical situation. The seals also held at water pressure transients approaching 250 mm Hg. The residual volumetric flux of water through the dura substitute membrane (Durepair®) was δVT /A ≈ 0.24 mm3 /min/cm2 , consistent with expectations for transport through the porous membrane prior to closure and equalization of internal/external pressures. CONCLUSIONS: We have demonstrated the workability of obtaining robust seal against leakage at the implantation site of a novel intradural stimulator using a custom-designed test rig. Extension of the method to in vivo testing in a large animal model will be the next step.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study.

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.

Randomized clinical trial of deep brain stimulation for poststroke pain.

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-Åsberg 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.

Deep brain stimulation of the cerebellum for poststroke motor rehabilitation: from laboratory to clinical trial.

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.

Removal of Intrathecal Catheters Used in Drug Delivery Systems.

INTRODUCTION: Implanted intrathecal drug delivery systems (IDDS) are increasingly used in the treatment of spasticity and in patients with refractory pain. Literature discussing complications associated with intrathecal pump placement is widely available. However, reports of complications following the removal of chronically placed catheters are scarce. We reviewed our series of patients who had surgery to remove the intrathecal catheter. METHODS: Retrospective review was performed for all patients who underwent surgery to remove a catheter linked to an IDDS between 2010 and 2016. Patients older than 18 years were included in final analysis. Demographic (including age at removal, sex, BMI, and comorbidities) and etiologic characteristics (indications of IDDS implant and explant, interval between implant and explant, and concomitant surgery) were analyzed. Simple logistic regression was performed to seek any potential predictor of complications. RESULTS: Fifty-nine patients underwent removal of their intrathecal catheter after variable periods (mean interval of 189 months). On eight occasions, patients developed complications after catheter removal (mean interval between implant and explant was 76 months for these cases). Retained catheter was the cause of complications in half of these occasions. Persistent cerebrospinal fluid leak was the next most common complication, with requirement of an external ventricular drain and lumbar drain to facilitate wound healing on two separate occasions. CONCLUSION: Removal of an intrathecal catheter from IDDS systems may cause complications that in some cases require additional surgery.