Trends and disparities in deep brain stimulation utilization in the United States: a Nationwide Inpatient Sample analysis from 1993 to 2017.

Background: Deep brain stimulation (DBS) is an approved treatment option for Parkinson's Disease (PD), essential tremor (ET), dystonia, obsessive-compulsive disorder and epilepsy in the United States. There are disparities in access to DBS, and clear understanding of the contextual factors driving them is important. Previous studies aimed at understanding these factors have been limited by single indications or small cohort sizes. The aim of this study is to provide an updated and comprehensive analysis of DBS utilization for multiple indications to better understand the factors driving disparities in access. Methods: The United States based National Inpatient Sample (NIS) database was utilized to analyze the surgical volume and trends of procedures based on indication, using relevant ICD codes. Predictors of DBS use were analyzed using a logistic regression model. DBS-implanted patients in each indication were compared based on the patient-, hospital-, and outcome-related variables. Findings: Our analysis of 104,356 DBS discharges from 1993 to 2017 revealed that the most frequent indications for DBS were PD (67%), ET (24%), and dystonia (4%). Although the number of DBS procedures has consistently increased over the years, radiofrequency ablation utilization has significantly decreased to only a few patients per year since 2003. Negative predictors for DBS utilization in PD and ET cohorts included age increase and female sex, while African American status was a negative predictor across all cohorts. Significant differences in patient-, hospital-, and outcome-related variables between DBS indications were also determined. Interpretation: Demographic and socioeconomic-based disparities in DBS use are evident. Although racial disparities are present across all indications, other disparities such as age, sex, wealth, and insurance status are only relevant in certain indications. Funding: This work was supported by Alan & Susan Hudson Cornerstone Chair in Neurosurgery at University Health Network.

Magnetic resonance-guided focused ultrasound for the treatment of tremor.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging treatment for tremor and other movement disorders. An incisionless therapy, it is becoming increasingly common worldwide. However, given MRgFUS' relative novelty, there remain limited data on its benefits and adverse effects. AREAS COVERED: We review the current state of evidence of MRgFUS for tremor, highlight its challenges, and discuss future perspectives. EXPERT OPINION: Essential tremor (ET) has been the major indication for MRgFUS since a milestone randomized controlled trial (RCT) in 2016, with substantial evidence attesting to the efficacy and acceptable safety profile of this treatment. Patients with other tremor etiologies are also being treated with MRgFUS, with studies - including an RCT - suggesting parkinsonian tremor in particular responds well to this intervention. Additionally, targets other than the ventral intermediate nucleus, such as the subthalamic nucleus and internal segment of the globus pallidus, have been reported to improve parkinsonian symptoms beyond tremor, including rigidity and bradykinesia. Although MRgFUS is encumbered by certain unique technical challenges, it nevertheless offers significant advantages compared to alternative neurosurgical interventions for tremor. The fast-growing interest in this treatment modality will likely lead to further scientific and technological advancements that could optimize and expand its therapeutic potential.

Connectomic neuromodulation for Alzheimer's disease: A systematic review and meta-analysis of invasive and non-invasive techniques.

Deep brain stimulation (DBS) and non-invasive neuromodulation are currently being investigated for treating network dysfunction in Alzheimer's Disease (AD). However, due to heterogeneity in techniques and targets, the cognitive outcome and brain network connectivity remain unknown. We performed a systematic review, meta-analysis, and normative functional connectivity to determine the cognitive outcome and brain networks of DBS and non-invasive neuromodulation in AD. PubMed, Embase, and Web of Science were searched using three concepts: dementia, brain connectome, and brain stimulation, with filters for English, human studies, and publication dates 1980-2021. Additional records from clinicaltrials.gov were added. Inclusion criteria were AD study with DBS or non-invasive neuromodulation and a cognitive outcome. Exclusion criteria were less than 3-months follow-up, severe dementia, and focused ultrasound intervention. Bias was assessed using Centre for Evidence-Based Medicine levels of evidence. We performed meta-analysis, with subgroup analysis based on type and age at neuromodulation. To determine the patterns of neuromodulation-induced brain network activation, we performed normative functional connectivity using rsfMRI of 1000 healthy subjects. Six studies, with 242 AD patients, met inclusion criteria. On fixed-effect meta-analysis, non-invasive neuromodulation favored baseline, with effect size -0.40(95% [CI], -0.73, -0.06, p = 0.02), while that of DBS was 0.11(95% [CI] -0.34, 0.56, p = 0.63), in favor of DBS. In patients ≥65 years old, DBS improved cognitive outcome, 0.95(95% [CI] 0.31, 1.58, p = 0.004), whereas in patients <65 years old baseline was favored, -0.17(95% [CI] -0.93, 0.58, p = 0.65). Functional connectivity regions were in the default mode (DMN), salience (SN), central executive (CEN) networks, and Papez circuit. The subgenual cingulate and anterior limb of internal capsule (ALIC) showed connectivity to all targets of neuromodulation. This meta-analysis provides level II evidence of a difference in response of AD patients to DBS, based on age at intervention. Brain stimulation in AD may modulate DMN, SN, CEN, and Papez circuit, with the subgenual cingulate and ALIC as potential targets.

Multi-modal investigation of transcranial ultrasound-induced neuroplasticity of the human motor cortex.

INTRODUCTION: There is currently a gap in accessibility to neuromodulation tools that can approximate the efficacy and spatial resolution of invasive methods. Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate cortical and deep brain structures with more focal stimulation compared to existing NIBS modalities. Theta burst TUS (tbTUS, TUS delivered in a theta burst pattern) is a novel repetitive TUS protocol that can induce durable changes in motor cortex excitability, thereby holding promise as a novel neuromodulation tool with durable effects. OBJECTIVE: The aim of the present study was to elucidate the neurophysiologic effects of tbTUS motor cortical excitability, as well on local and global neural oscillations and network connectivity. METHODS: An 80-s train of active or sham tbTUS was delivered to the left motor cortex in 15 healthy subjects. Motor cortical excitability was investigated through transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) using paired-pulse TMS. Magnetoencephalography (MEG) recordings during resting state and an index finger abduction-adduction task were used to assess oscillatory brain responses and network connectivity. The correlations between the changes in neural oscillations and motor cortical excitability were also evaluated. RESULTS: tbTUS to the motor cortex results in a sustained increase in MEP amplitude and decreased SICI, but no change in ICF. MEG spectral power analysis revealed TUS-mediated desynchronization in alpha and beta spectral power. Significant changes in alpha power were detected within the supplementary motor cortex (Right > Left) and changes in beta power within bilateral supplementary motor cortices, right basal ganglia and parietal regions. Coherence analysis revealed increased local connectivity in motor areas. MEP and SICI changes correlated with both local and inter-regional coherence. CONCLUSION: The findings from this study provide novel insights into the neurophysiologic basis of TUS-mediated neuroplasticity and point to the involvement of regions within the motor network in mediating this sustained response. Future studies may further characterize the durability of TUS-mediated neuroplasticity and its clinical applications as a neuromodulation strategy for neurological and psychiatric disorders.

Identifying the neural network for neuromodulation in epilepsy through connectomics and graphs.

Deep brain stimulation is a treatment option for patients with drug-resistant epilepsy. The precise mechanism of neuromodulation in epilepsy is unknown, and biomarkers are needed for optimizing treatment. The aim of this study was to describe the neural network associated with deep brain stimulation targets for epilepsy and to explore its potential application as a novel biomarker for neuromodulation. Using seed-to-voxel functional connectivity maps, weighted by seizure outcomes, brain areas associated with stimulation were identified in normative resting state functional scans of 1000 individuals. To pinpoint specific regions in the normative epilepsy deep brain stimulation network, we examined overlapping areas of functional connectivity between the anterior thalamic nucleus, centromedian thalamic nucleus, hippocampus and less studied epilepsy deep brain stimulation targets. Graph network analysis was used to describe the relationship between regions in the identified network. Furthermore, we examined the associations of the epilepsy deep brain stimulation network with disease pathophysiology, canonical resting state networks and findings from a systematic review of resting state functional MRI studies in epilepsy deep brain stimulation patients. Cortical nodes identified in the normative epilepsy deep brain stimulation network were in the anterior and posterior cingulate, medial frontal and sensorimotor cortices, frontal operculum and bilateral insulae. Subcortical nodes of the network were in the basal ganglia, mesencephalon, basal forebrain and cerebellum. Anterior thalamic nucleus was identified as a central hub in the network with the highest betweenness and closeness values, while centromedian thalamic nucleus and hippocampus showed average centrality values. The caudate nucleus and mammillothalamic tract also displayed high centrality values. The anterior cingulate cortex was identified as an important cortical hub associated with the effect of deep brain stimulation in epilepsy. The neural network of deep brain stimulation targets shared hubs with known epileptic networks and brain regions involved in seizure propagation and generalization. Two cortical clusters identified in the epilepsy deep brain stimulation network included regions corresponding to resting state networks, mainly the default mode and salience networks. Our results were concordant with findings from a systematic review of resting state functional MRI studies in patients with deep brain stimulation for epilepsy. Our findings suggest that the various epilepsy deep brain stimulation targets share a common cortico-subcortical network, which might in part underpin the antiseizure effects of stimulation. Interindividual differences in this network functional connectivity could potentially be used as biomarkers in selection of patients, stimulation parameters and neuromodulation targets.

Idiopathic Parkinson's disease and chronic pain in the era of deep brain stimulation: a systematic review and meta-analysis.

OBJECTIVE: Pain is the most common nonmotor symptom of Parkinson's disease (PD) and is often undertreated. Deep brain stimulation (DBS) effectively mitigates the motor symptoms of this multisystem neurodegenerative disease; however, its therapeutic effect on nonmotor symptoms, especially pain, remains inconclusive. While there is a critical need to help this large PD patient population, guidelines for managing this significant disease burden are absent. Herein, the authors systematically reviewed the literature and conducted a meta-analysis to study the influence of traditional (subthalamic nucleus [STN] and globus pallidus internus [GPi]) DBS on chronic pain in patients with PD. METHODS: The authors performed a systematic review of the literature and a meta-analysis following PRISMA guidelines. Risk of bias was assessed using the levels of evidence established by the Oxford Centre for Evidence-Based Medicine. Inclusion criteria were articles written in English, published in a peer-reviewed scholarly journal, and about studies conducting an intervention for PD-related pain in no fewer than 5 subjects. RESULTS: Twenty-six studies were identified and included in this meta-analysis. Significant interstudy heterogeneity was detected (Cochran's Q test p < 0.05), supporting the use of the random-effects model. The random-effects model estimated the effect size of DBS for the treatment of idiopathic pain as 1.31 (95% CI 0.84-1.79). The DBS-on intervention improved pain scores by 40% as compared to the control state (preoperative baseline or DBS off). CONCLUSIONS: The results indicated that traditional STN and GPi DBS can have a favorable impact on pain control and improve pain scores by 40% from baseline in PD patients experiencing chronic pain. Further trials are needed to identify the subtype of PD patients whose pain benefits from DBS and to identify the mechanisms by which DBS improves pain in PD patients.

Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. OBJECTIVE: The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. METHODS: A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. RESULTS: A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. CONCLUSIONS: Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

Clinical outcomes and complications of peripheral nerve field stimulation in the management of refractory trigeminal pain: a systematic review and meta-analysis.

OBJECTIVE: Peripheral nerve field stimulation (PNFS) is a tool in the armamentarium of treatment options for trigeminal pain. The efficacy of this modality in mitigating trigeminal pain remains unclear. The aim of this study was to examine the existing literature on PNFS and elucidate pain score outcomes associated with its use in patients with trigeminal pain. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA framework. The PubMed, Web of Science, and Scopus databases were queried on June 10, 2020. Studies reporting pain outcomes in more than 5 adult patients treated with PNFS for facial pain were included. The primary outcome of the study was the mean difference in the visual analog scale (VAS) score from the last follow-up to baseline, and it was analyzed by an inverse-variance, random-effect model. The risk of bias was assessed using the Newcastle-Ottawa Scale and a funnel plot. RESULTS: Of the 4597 studies screened for inclusion, 46 relevant full-text articles were assessed for eligibility. Eleven observational cohort studies from the 46 articles were found to be eligible, and reported on a total of 109 patients. In 86% (94/109) of cases, trial stimulation was successful and followed by a permanent system implantation. VAS scores improved by 75% (mean difference 6.32/10 points, 95% CI 5.38-7.27 points) compared to baseline. Seventy-six percent (42/55) of patients became medication free or required lower doses of medications. The complication rate necessitating surgical revision was estimated at 32% per procedure. CONCLUSIONS: These findings support the belief that PNFS provides effective, long-term pain control for trigeminal pain. Statistical heterogeneity was considerable across all studies. Future work should be aimed at conducting double-blind randomized controlled trials to determine the utility of PNFS for treating various forms of trigeminal pain for which limited therapeutic options exist.

Deep brain stimulation targets in epilepsy: Systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

A Network-Based Approach to Glioma Surgery: Insights from Functional Neurosurgery.

The evaluation and manipulation of structural and functional networks, which has been integral to advancing functional neurosurgery, is beginning to transcend classical subspecialty boundaries. Notably, its application in neuro-oncologic surgery has stimulated an exciting paradigm shift from the traditional localizationist approach, which is lacking in nuance and optimization. This manuscript reviews the existing literature and explores how structural and functional connectivity analyses have been leveraged to revolutionize and individualize pre-operative tumor evaluation and surgical planning. We describe how this novel approach may improve cognitive and neurologic preservation after surgery and attenuate tumor spread. Furthermore, we demonstrate how connectivity analysis combined with neuromodulation techniques can be employed to induce post-operative neuroplasticity and personalize neurorehabilitation. While the landscape of functional neuro-oncology is still evolving and requires further study to encourage more widespread adoption, this functional approach can transform the practice of neuro-oncologic surgery and improve the care and outcomes of patients with intra-axial tumors.

Translational Brain Mapping at the University of Rochester Medical Center: Preserving the Mind Through Personalized Brain Mapping.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

Improving the prognosis for patients with glioblastoma: the rationale for targeting Src.

Glioblastoma is the most common and aggressive form of primary brain tumor. The prognosis for patients diagnosed with glioblastoma is poor, with a median survival of 12-14 months and a 5-year survival rate of <5%. The upfront standard treatment for patients with newly diagnosed glioblastoma, consisting of surgery followed by chemotherapy combined with radiotherapy, provides only short-term survival benefits. Recurrent glioblastoma is an extremely challenging therapeutic setting because of the aggressive and resistant nature of the tumor. A set of key molecular targets in oncology is the Src family of non-receptor protein kinases. Dysregulated signaling via the Src kinases has been shown to underlie glioma-related proliferation, angiogenesis, migration, and survival. Here we review the biologic role of Src in malignant glioma and discuss key preclinical studies demonstrating the potential utility of inhibiting Src in glioma. Proof of clinical benefit is forthcoming from the first clinical studies involving the newest generation of small molecule Src inhibitors currently in clinical trials for recurrent glioblastoma. Blocking Src alone will likely not translate into a significant clinical benefit; thus, strategies for combining Src inhibitors with potential synergistic therapeutic modalities will be discussed. This review will focus on dasatinib, the most advanced Src inhibitor being tested in glioblastoma, which is currently in phase I/II trials in this setting.

Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma.

Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC(50) of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G(1) arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide.