Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.

Potential optimization of focused ultrasound capsulotomy for obsessive compulsive disorder.

Obsessive-compulsive disorder is a debilitating and often refractory psychiatric disorder. Magnetic resonance-guided focused ultrasound is a novel, minimally invasive neuromodulatory technique that has shown promise in treating this condition. We investigated the relationship between lesion location and long-term outcome in patients with obsessive-compulsive disorder treated with focused ultrasound to discern the optimal lesion location and elucidate the efficacious network underlying symptom alleviation. Postoperative images of 11 patients who underwent focused ultrasound capsulotomy were used to correlate lesion characteristics with symptom improvement at 1-year follow-up. Normative resting-state functional MRI and normative diffusion MRI-based tractography analyses were used to determine the networks associated with successful lesions. Patients with obsessive-compulsive disorder treated with inferior thalamic peduncle deep brain stimulation (n = 5) and lesions from the literature implicated in obsessive-compulsive disorder (n = 18) were used for external validation. Successful long-term relief of obsessive-compulsive disorder was associated with lesions that included a specific area in the dorsal anterior limb of the internal capsule. Normative resting-state functional MRI analysis showed that lesion engagement of areas 24 and 46 was significantly associated with clinical outcomes (R = 0.79, P = 0.004). The key role of areas 24 and 46 was confirmed by (i) normative diffusion MRI-based tractography analysis, showing that streamlines associated with better outcome projected to these areas; (ii) association of these areas with outcomes in patients receiving inferior thalamic peduncle deep brain stimulation (R = 0.83, P = 0.003); and (iii) the connectedness of these areas to obsessive-compulsive disorder-causing lesions, as identified using literature-based lesion network mapping. These results provide considerations for target improvement, outlining the specific area of the internal capsule critical for successful magnetic resonance-guided focused ultrasound outcome and demonstrating that discrete frontal areas are involved in symptom relief. This could help refine focused ultrasound treatment for obsessive-compulsive disorder and provide a network-based rationale for potential alternative targets.

Improving Safety of MRI in Patients with Deep Brain Stimulation Devices.

MRI is a valuable clinical and research tool for patients undergoing deep brain stimulation (DBS). However, risks associated with imaging DBS devices have led to stringent regulations, limiting the clinical and research utility of MRI in these patients. The main risks in patients with DBS devices undergoing MRI are heating at the electrode tips, induced currents, implantable pulse generator dysfunction, and mechanical forces. Phantom model studies indicate that electrode tip heating remains the most serious risk for modern DBS devices. The absence of adverse events in patients imaged under DBS vendor guidelines for MRI demonstrates the general safety of MRI for patients with DBS devices. Moreover, recent work indicates that-given adequate safety data-patients may be imaged outside these guidelines. At present, investigators are primarily focused on improving DBS device and MRI safety through the development of tools, including safety simulation models. Existing guidelines provide a standardized framework for performing safe MRI in patients with DBS devices. It also highlights the possibility of expanding MRI as a tool for research and clinical care in these patients going forward.

Functional MRI Safety and Artifacts during Deep Brain Stimulation: Experience in 102 Patients.

BackgroundWith growing numbers of patients receiving deep brain stimulation (DBS), radiologists are encountering these neuromodulation devices at an increasing rate. Current MRI safety guidelines, however, limit MRI access in these patients.PurposeTo describe an MRI (1.5 T and 3 T) experience and safety profile in a large cohort of participants with active DBS systems and characterize the hardware-related artifacts on images from functional MRI.Materials and MethodsIn this prospective study, study participants receiving active DBS underwent 1.5- or 3-T MRI (T1-weighted imaging and gradient-recalled echo [GRE]-echo-planar imaging [EPI]) between June 2017 and October 2018. Short- and long-term adverse events were tracked. The authors quantified DBS hardware-related artifacts on images from GRE-EPI (functional MRI) at the cranial coil wire and electrode contacts. Segmented artifacts were then transformed into standard space to define the brain areas affected by signal loss. Two-sample t tests were used to assess the difference in artifact size between 1.5- and 3-T MRI.ResultsA total of 102 participants (mean age ± standard deviation, 60 years ± 11; 65 men) were evaluated. No MRI-related short- and long-term adverse events or acute changes were observed. DBS artifacts were most prominent near the electrode contacts and over the frontoparietal cortical area where the redundancy of the extension wire is placed subcutaneously. The mean electrode contact artifact diameter was 9.3 mm ± 1.6, and 1.9% ± 0.8 of the brain was obscured by the coil artifact. The coil artifacts were larger at 3 T than at 1.5 T, obscuring 2.1% ± 0.7 and 1.4% ± 0.7 of intracranial volume, respectively (P < .001). The superficial frontoparietal cortex and deep structures neighboring the electrode contacts were most commonly obscured.ConclusionWith a priori local safety testing, patients receiving deep brain stimulation may safely undergo 1.5- and 3-T MRI. Deep brain stimulation hardware-related artifacts only affect a small proportion of the brain.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Martin in this issue.

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.

Probing responses to deep brain stimulation with functional magnetic resonance imaging.

BACKGROUND: Deep brain stimulation (DBS) is an established treatment for certain movement disorders and has additionally shown promise for various psychiatric, cognitive, and seizure disorders. However, the mechanisms through which stimulation exerts therapeutic effects are incompletely understood. A technique that may help to address this knowledge gap is functional magnetic resonance imaging (fMRI). This is a non-invasive imaging tool which permits the observation of DBS effects in vivo. OBJECTIVE: The objective of this review was to provide a comprehensive overview of studies in which fMRI during active DBS was performed, including studied disorders, stimulated brain regions, experimental designs, and the insights gleaned from stimulation-evoked fMRI responses. METHODS: We conducted a systematic review of published human studies in which fMRI was performed during active stimulation in DBS patients. The search was conducted using PubMED and MEDLINE. RESULTS: The rate of fMRI DBS studies is increasing over time, with 37 studies identified overall. The median number of DBS patients per study was 10 (range = 1-67, interquartile range = 11). Studies examined fMRI responses in various disease cohorts, including Parkinson's disease (24 studies), essential tremor (3 studies), epilepsy (3 studies), obsessive-compulsive disorder (2 studies), pain (2 studies), Tourette syndrome (1 study), major depressive disorder, anorexia, and bipolar disorder (1 study), and dementia with Lewy bodies (1 study). The most commonly stimulated brain region was the subthalamic nucleus (24 studies). Studies showed that DBS modulates large-scale brain networks, and that stimulation-evoked fMRI responses are related to the site of stimulation, stimulation parameters, patient characteristics, and therapeutic outcomes. Finally, a number of studies proposed fMRI-based biomarkers for DBS treatment, highlighting ways in which fMRI could be used to confirm circuit engagement and refine DBS therapy. CONCLUSION: A review of the literature reflects an exciting and expanding field, showing that the combination of DBS and fMRI represents a uniquely powerful tool for simultaneously manipulating and observing neural circuitry. Future work should focus on relatively understudied disease cohorts and stimulated regions, while focusing on the prospective validation of putative fMRI-based biomarkers.

Kilohertz-frequency stimulation of the nervous system: A review of underlying mechanisms.

BACKGROUND: Electrical stimulation in the kilohertz-frequency range has gained interest in the field of neuroscience. The mechanisms underlying stimulation in this frequency range, however, are poorly characterized to date. OBJECTIVE/HYPOTHESIS: To summarize the manifold biological effects elicited by kilohertz-frequency stimulation in the context of the currently existing literature and provide a mechanistic framework for the neural responses observed in this frequency range. METHODS: A comprehensive search of the peer-reviewed literature was conducted across electronic databases. Relevant computational, clinical, and mechanistic studies were selected for review. RESULTS: The effects of kilohertz-frequency stimulation on neural tissue are diverse and yield effects that are distinct from conventional stimulation. Broadly, these can be divided into 1) subthreshold, 2) suprathreshold, 3) synaptic and 4) thermal effects. While facilitation is the dominating mechanism at the subthreshold level, desynchronization, spike-rate adaptation, conduction block, and non-monotonic activation can be observed during suprathreshold kilohertz-frequency stimulation. At the synaptic level, kilohertz-frequency stimulation has been associated with the transient depletion of the available neurotransmitter pool - also known as synaptic fatigue. Finally, thermal effects associated with extrinsic (environmental) and intrinsic (associated with kilohertz-frequency stimulation) temperature changes have been suggested to alter the neural response to stimulation paradigms. CONCLUSION: The diverse spectrum of neural responses to stimulation in the kilohertz-frequency range is distinct from that associated with conventional stimulation. This offers the potential for new therapeutic avenues across stimulation modalities. However, stimulation in the kilohertz-frequency range is associated with distinct challenges and caveats that need to be considered in experimental paradigms.

Global trends in chronic thromboembolic pulmonary hypertension clinical trials and dissemination of results.

Treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) are rapidly expanding. The purpose of this study is to identify trends in CTEPH clinical trials and the publication of results. We performed a worldwide review of completed and ongoing clinical trials through searching the ClinicalTrials.gov database and the World Health Organization International Clinical Trials Registry Platform for "CTEPH" and related terms. Entries were classified as pharmaceutical/procedural interventions (Group 1), all other clinical trials (Group 2) and patient registries (Group 3). Trial characteristics and national affiliation were recorded. PubMed was searched for related publications. There were 117 clinical trials registry entries after removing duplicates and non-target records. Group 1 comprised 29 pharmaceutical, 15 procedural, and four combined interventions starting in 2005, 2010, and 2016, respectively. Riociguat and balloon pulmonary angioplasty were the most frequent pharmaceutical and procedural interventions, respectively. The proportion of procedural trials increased over time from 0% of those in 2005-2009 to 29% in 2010-2014 and 54% in 2015-2020. There were 56 entries in Group 2 and 13 in Group 3. Japan was the most frequent national affiliation and the most frequent participating country, present in 28% of all trials. The proportion of entries with published results was highest with Group 3 (62%) and lowest with Group 1 (27%). Thirty percent of all publications occurred in 2020. In conclusion, CTEPH clinical trials are increasingly procedural based, with growth largely attributable to Japan and balloon pulmonary angioplasty. Most trials have not published, but results from balloon pulmonary angioplasty clinical trials are anticipated soon.

Focused Ultrasound Thalamotomy Sensory Side Effects Follow the Thalamic Structural Homunculus.

OBJECTIVE: Focused ultrasound thalamotomy is an effective treatment for tremor; however, side effects may occur. The purpose of the present study was to investigate the spatial relationship between thalamotomies and specific sensory side effects and their functional connectivity with somatosensory cortex and relationship to the medial lemniscus (ML). METHODS: Sensory adverse effects were categorized into 4 groups based on the location of the disturbance: face/mouth/tongue numbness/paresthesia, hand-only paresthesia, hemibody/limb paresthesia, and dysgeusia. Then, areas of significant risk (ASRs) for each category were defined using voxel-wise mass univariate analysis and overlaid on corresponding odds ratio maps. The ASR associated with the maximum risk was used as a region of interest in a normative functional connectome to determine side effect-specific functional connectivity. Finally, each ASR was overlaid on the ML derived from normative template. RESULTS: Of 103 patients, 17 developed sensory side effects after thalamotomy persisting 3 months after the procedures. Lesions producing sensory side effects extended posteriorly into the principle sensory nucleus of the thalamus or below the thalamus in the ML. The topography of sensory adverse effects followed the known somatotopy of the ML and the sensory nucleus. Functional connectivity patterns between each sensory-specific thalamic seed and the primary somatosensory areas supported the role of the middle insula in processing of gustatory information and in multisensory integration. CONCLUSIONS: Distinct regions in the sensory thalamus and its afferent connections rise to specific sensory disturbances. These findings demonstrate the relationship between the sensory thalamus, ML, and bilateral sensory cortical areas.

A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets.

OBJECTIVE: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature. METHODS: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review. RESULTS: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging. CONCLUSIONS: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.

Evolution of the Neurosurgeon's Role in Clinical Trials for Glioblastoma: A Systematic Overview of the Clinicaltrials.Gov Database.

BACKGROUND: The therapeutic challenge of glioblastoma (GBM) has catalyzed the development of clinical trials to evaluate novel interventions. With increased understanding of GBM biology and technological advances, the neurosurgeon's role in neuro-oncology has evolved. OBJECTIVE: To evaluate the current landscape of procedure-based clinical trials for GBM to characterize this evolution, gain insight into past failures, and accordingly outline implications for future research and practice that may inform future studies. METHODS: The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM. Demographics, specific intervention, trial phase, and main outcome measures were abstracted. RESULTS: A total of 224 of 2311 GBM trials (9.7%) were identified as procedural, with the majority being based in the United States (155/224, 69.2%), single-center (155/224, 69.2%), and not randomized (176/224, 78.6%). Primary and recurrent GBMs were evenly addressed. The leading interventions were local delivery of therapeutics (50.0%), surgical techniques (33.9%), such as image-guided surgery, and novel device applications (14.3%). Phase I designs predominated (82/224, 36.6%). The top primary outcome was safety/tolerability/feasibility (88/224, 39.3%), followed by survival (46/224, 20.5%). Approximately 17% of studies were terminated, withdrawn, or suspended. Fifty-two linked publications were identified, among which 42 were classified as having a positive result. CONCLUSION: Procedural interventions comprised ∼10% of all registered GBM trials. Local delivery of therapeutics, use of surgical imaging techniques and novel device applications, predominantly through phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved reporting of trial designs, outcomes, and results are needed to better inform the field and increase efficiency.

Neuromodulatory treatments for psychiatric disease: A comprehensive survey of the clinical trial landscape.

BACKGROUND: Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions. OBJECTIVE/HYPOTHESIS: We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field. METHODS: ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source. RESULTS: From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased. CONCLUSION(S): These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field.

Identification of neural networks preferentially engaged by epileptogenic mass lesions through lesion network mapping analysis.

Lesion network mapping (LNM) has been applied to true lesions (e.g., cerebrovascular lesions in stroke) to identify functionally connected brain networks. No previous studies have utilized LNM for analysis of intra-axial mass lesions. Here, we implemented LNM for identification of potentially vulnerable epileptogenic networks in mass lesions causing medically-refractory epilepsy (MRE). Intra-axial brain lesions were manually segmented in patients with MRE seen at our institution (EL_INST). These lesions were then normalized to standard space and used as seeds in a high-resolution normative resting state functional magnetic resonance imaging template. The resulting connectivity maps were first thresholded (pBonferroni_cor < 0.05) and binarized; the thresholded binarized connectivity maps were subsequently summed to produce overall group connectivity maps, which were compared with established resting-state networks to identify potential networks prone to epileptogenicity. To validate our data, this approach was also applied to an external dataset of epileptogenic lesions identified from the literature (EL_LIT). As an additional exploratory analysis, we also segmented and computed the connectivity of institutional non-epileptogenic lesions (NEL_INST), calculating voxel-wise odds ratios (VORs) to identify voxels more likely to be functionally-connected with EL_INST versus NEL_INST. To ensure connectivity results were not driven by anatomical overlap, the extent of lesion overlap between EL_INST, and EL_LIT and NEL_INST was assessed using the Dice Similarity Coefficient (DSC, lower index ~ less overlap). Twenty-eight patients from our institution were included (EL_INST: 17 patients, 17 lesions, 10 low-grade glioma, 3 cavernoma, 4 focal cortical dysplasia; NEL_INST: 11 patients, 33 lesions, all brain metastases). An additional 23 cases (25 lesions) with similar characteristics to the EL_INST data were identified from the literature (EL_LIT). Despite minimal anatomical overlap of lesions, both EL_INST and EL_LIT showed greatest functional connectivity overlap with structures in the Default Mode Network, Frontoparietal Network, Ventral Attention Network, and the Limbic Network-with percentage volume overlap of 19.5%, 19.1%, 19.1%, and 12.5%, respectively-suggesting them as networks consistently engaged by epileptogenic mass lesions. Our exploratory analysis moreover showed that the mesial frontal lobes, parahippocampal gyrus, and lateral temporal neocortex were at least twice as likely to be functionally connected with the EL_INST compared to the NEL_INST group (i.e. Peak VOR > 2.0); canonical resting-state networks preferentially engaged by EL_INSTs were the Limbic and the Frontoparietal Networks (Mean VOR > 1.5). In this proof of concept study, we demonstrate the feasibility of LNM for intra-axial mass lesions by showing that ELs have discrete functional connections and may preferentially engage in discrete resting-state networks. Thus, the underlying normative neural circuitry may, in part, explain the propensity of particular lesions toward the development of MRE. If prospectively validated, this has ramifications for patient counseling along with both approach and timing of surgery for lesions in locations prone to development of MRE.

Safety assessment of spine MRI in deep brain stimulation patients.

OBJECTIVE: Many centers are hesitant to perform clinically indicated MRI in patients who have undergone deep brain stimulation (DBS). Highly restrictive guidelines prohibit the use of most routine clinical MRI protocols in these patients. The authors' goals were to assess the safety of spine MRI in patients with implanted DBS devices, first through phantom model testing and subsequently through validation in a DBS patient cohort. METHODS: A phantom was used to assess DBS device heating during 1.5-T spine MRI. To establish a safe spine protocol, routinely used clinical sequences deemed unsafe (a rise in temperature > 2°C) were modified to decrease the rise in temperature. This safe phantom-based protocol was then used to prospectively run 67 spine MRI sequences in 9 DBS participants requiring clinical imaging. The primary outcome was acute adverse effects; secondary outcomes included long-term adverse clinical effects, acute findings on brain MRI, and device impedance stability. RESULTS: The increases in temperature were highest when scanning the cervical spine and lowest when scanning the lumbar spine. A temperature rise < 2°C was achieved when 3D sequences were modified to 2D and when the number of slices was decreased by the minimum amount compared to routine spine MRI protocols (but there were still more slices than allowed by vendor guidelines). Following spine MRI, no acute or long-term adverse effects or acute findings on brain MR images were detected. Device impedances remained stable. CONCLUSIONS: Patients with DBS devices may safely undergo spine MRI with a fewer number of slices compared to those used in routine clinical protocols. Safety data acquisition may allow protocols outside vendor guidelines with a maximized number of slices, reducing the need for radiologist supervision.Clinical trial registration no.: NCT03753945 (ClinicalTrials.gov).