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.

Successful magnetic resonance-guided focused ultrasound treatment of tremor in patients with a skull density ratio of 0.4 or less.

OBJECTIVE: The use of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor-related disorders and other novel indications has been limited by guidelines advocating treatment of patients with a skull density ratio (SDR) above 0.45 ± 0.05 despite reports of successful outcomes in patients with a low SDR (LSDR). The authors' goal was to retrospectively analyze the sonication strategies, adverse effects, and clinical and imaging outcomes in patients with SDR ≤ 0.4 treated for tremor using MRgFUS. METHODS: Clinical outcomes and adverse effects were assessed at 3 and 12 months after MRgFUS. Outcomes and lesion location, volume, and shape characteristics (elongation and eccentricity) were compared between the SDR groups. RESULTS: A total of 102 consecutive patients were included in the analysis, of whom 39 had SDRs ≤ 0.4. No patient was excluded from treatment because of an LSDR, with the lowest being 0.22. Lesioning temperatures (> 52°C) and therapeutic ablations were achieved in all patients. There were no significant differences in clinical outcome, adverse effects, lesion location, and volume between the high SDR group and the LSDR group. SDR was significantly associated with total energy (rho = -0.459, p < 0.001), heating efficiency (rho = 0.605, p < 0.001), and peak temperature (rho = 0.222, p = 0.025). CONCLUSIONS: The authors' results show that treatment of tremor in patients with an LSDR using MRgFUS is technically possible, leading to a safe and lasting therapeutic effect. Limiting the number of sonications and adjusting the energy and duration to achieve the required temperature early during the treatment are suitable strategies in LSDR patients.

A Drosophila screen identifies a role for histone methylation in ER stress preconditioning.

Stress preconditioning occurs when transient, sublethal stress events impact an organism's ability to counter future stresses. Although preconditioning effects are often noted in the literature, very little is known about the underlying mechanisms. To model preconditioning, we exposed a panel of genetically diverse Drosophila melanogaster to a sublethal heat shock and measured how well the flies survived subsequent exposure to endoplasmic reticulum (ER) stress. The impact of preconditioning varied with genetic background, ranging from dying half as fast to 4 and a half times faster with preconditioning compared to no preconditioning. Subsequent association and transcriptional analyses revealed that histone methylation, and transcriptional regulation are both candidate preconditioning modifier pathways. Strikingly, almost all subunits (7/8) in the Set1/COMPASS complex were identified as candidate modifiers of preconditioning. Functional analysis of Set1 knockdown flies demonstrated that loss of Set1 led to the transcriptional dysregulation of canonical ER stress genes during preconditioning. Based on these analyses, we propose a preconditioning model in which Set1 helps to establish an interim transcriptional "memory" of previous stress events, resulting in a preconditioned response to subsequent stress.

Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes.

Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation. Phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI) anchor biosynthesis. There are over 100 GPI-anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here, we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy but, when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNA sequencing analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here, we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.

Drosophila models of PIGA-CDG mirror patient phenotypes.

Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.

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.

Presumed Silicone Oil Droplets After Intravitreal Pegcetacoplan Injections.

Importance: Recently, intravitreal pegcetacoplan became the first drug to gain US Food and Drug Administration approval for the treatment of geographic atrophy associated with nonexudative age-related macular degeneration, but the administration of this medication may be associated with unanticipated posttreatment complications. Objective: To assess the prevalence of presumed silicone oil droplets in the vitreous cavity after intravitreal injection of pegcetacoplan. Design, Setting, and Participants: This case series study involved a retrospective record review of all 55 patients treated with intravitreal pegcetacoplan, 0.1 mL in 150-mg/mL solution, between March 24 and June 5, 2023, at a single specialty retina practice. All injections were done using needles from the kit supplied by Apellis Pharmaceuticals on a 1-mL McKesson Luer lock syringe. Main Outcomes and Measures: The presence or absence of presumed silicone bubbles detected during dilated biomicroscopic fundus examination and/or on color fundus photographs, the presence or absence of symptoms, change in visual acuity, and/or increase in intraocular pressure. Results: A total of 62 intravitreal pegcetacoplan injections were given to 55 patients (mean [SD] age, 83.8 [7.8] years; 33 women [60%]) from March 24 to June 5, 2023. Of the 55 patients, 16 (29%; mean [SD] age, 83.8 [7.4] years; 9 women [56%]) had presumed intravitreal silicone droplets discovered 2 to 4 weeks after treatment, 3 of which were documented on color fundus photographs. Of the 16 patients, 14 (88%) were symptomatic for new floaters that they described as persistent, while 2 (13%) were asymptomatic. There were no signs of inflammation or infection, no increases in intraocular pressure, and no changes in visual acuity for all 16 patients. Conclusions and Relevance: A substantial percentage of patients had symptomatic floaters from presumed intravitreal silicone oil droplets after injections of pegcetacoplan using a McKesson 1-mL Luer lock syringe. These findings support consideration of informing patients of this potential adverse effect, avoiding use of the McKesson syringe, and considering use of silicone-free syringes for pegcetacoplan injections.

Characterizing genetic variation in the regulation of the ER stress response through computational and cis-eQTL analyses.

Misfolded proteins in the endoplasmic reticulum (ER) elicit the ER stress response, a large transcriptional response driven by 3 well-characterized transcription factors (TFs). This transcriptional response is variable across different genetic backgrounds. One mechanism in which genetic variation can lead to transcriptional variability in the ER stress response is through altered binding and activity of the 3 main TFs: XBP1, ATF6, and ATF4. This work attempts to better understand this mechanism by first creating a computational pipeline to identify potential binding sites throughout the human genome. We utilized GTEx data sets to identify cis-eQTLs that fall within predicted TF binding sites (TFBSs). We also utilized the ClinVar database to compare the number of pathogenic vs benign variants at different positions of the binding motifs. Finally, we performed a cis-eQTL analysis on human cell lines experiencing ER stress to identify cis-eQTLs that regulate the variable ER stress response. The majority of these cis-eQTLs are unique to a given condition: control or ER stress. Some of these stress-specific cis-eQTLs fall within putative binding sites of the 3 main ER stress response TFs, providing a potential mechanism by which these cis-eQTLs might be impacting gene expression under ER stress conditions through altered TF binding. This study represents the first cis-eQTL analysis on human samples experiencing ER stress and is a vital step toward identifying the genetic components responsible for the variable ER stress response.

DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis.

CONTEXT: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea. DESIGN: The study was an observational study. Subjects were recruited at an academic institution. SUBJECTS: Subjects were sisters with primary amenorrhea caused by POI and their parents. Additional subjects included women with POI analyzed previously (n = 291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing, and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool, which identifies genes harboring pathogenic variants in families. We performed functional studies in a Drosophila melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants were identified. RESULTS: The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and severe infertility. CONCLUSIONS: Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3' to 5' exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI.

A Drosophila screen identifies a role for histone methylation in ER stress preconditioning.

Stress preconditioning occurs when transient, sublethal stress events impact an organism's ability to counter future stresses. Although preconditioning effects are often noted in the literature, very little is known about the underlying mechanisms. To model preconditioning, we exposed a panel of genetically diverse Drosophila melanogaster to a sublethal heat shock and measured how well the flies survived subsequent exposure to endoplasmic reticulum (ER) stress. The impact of preconditioning varied with genetic background, ranging from dying half as fast to four and a half times faster with preconditioning compared to no preconditioning. Subsequent association and transcriptional analyses revealed that histone methylation, transcriptional regulation, and immune status are all candidate preconditioning modifier pathways. Strikingly, almost all subunits (7/8) in the Set1/COMPASS complex were identified as candidate modifiers of preconditioning. Functional analysis of Set1 knockdown flies demonstrated that loss of Set1 led to the transcriptional dysregulation of canonical ER stress genes during preconditioning. Based on these analyses, we propose a model of preconditioning in which Set1 helps to establish an interim transcriptional 'memory' of previous stress events, resulting in a preconditioned response to subsequent stress.

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.

Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency.

NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1 deficient fly, was sufficient to partially rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119, lithium, and GSK3 knockdown. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that is regulated by NGLY1 and regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.

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.

The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues.

The genetic regulation of gene expression varies greatly across tissue-type and individuals and can be strongly influenced by the environment. Many variants, under healthy control conditions, may be silent or even have the opposite effect under diseased stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with cellular stress across different tissues. Endoplasmic reticulum stress occurs when misfolded proteins accumulate in the endoplasmic reticulum. This triggers the unfolded protein response, a large transcriptional response which attempts to restore homeostasis. This transcriptional response, despite being a conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study the dynamic effects of genetic variation. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of endoplasmic reticulum stress. The use of different mouse strains and their F1s allow us to also identify context-specific cis- and trans- regulatory variation underlying variable transcriptional responses. We found hundreds of genes that respond to endoplasmic reticulum stress in a tissue- and/or genotype-dependent manner. The majority of the regulatory effects we identified were acting in cis-, which in turn, contribute to the variable endoplasmic reticulum stress- and tissue-specific transcriptional response. This study demonstrates the need for incorporating environmental stressors across multiple different tissues in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the endoplasmic reticulum stress response.

Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency.

CONTEXT: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. DESIGN: The study was an observational study. SETTING: Subjects were recruited at academic institutions. PATIENTS: Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. RESULTS: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). CONCLUSIONS: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

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.

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.

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.