Background: Identifying functional biomarkers related to treatment success can aid in optimizing therapy and provide a better understanding of the neural mechanisms of treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS). Methods: Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. We identified region-specific oscillatory modulations that both (i) discriminate individuals with TRD (SCC-DBS OFF) from healthy controls and (ii) discriminate responders from non-responders (SCC-DBS ON). The effects of stimulation intensity and frequency were also explored. Results: Discriminative regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power included nodes of the default mode, central executive, and somatomotor networks, Broca’s area, and lingual gyrus. Furthermore, low stimulation frequency had stronger effects on oscillatory modulation. Conclusions: The identified functional biomarkers implicate modulations of TRD-related activity in brain regions involved in emotional control/processing, motor control, and interactions between speech, vision, and memory – all implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations are strengthened by increasing stimulation intensity or reducing frequency, which may benefit SCC-DBS non-responders.

Background: We recently identified four molecular subgroups of meningioma with distinct biology and outcomes. While two (MG3/MG4) are associated with poor outcome, they display divergent transcriptional profiles (enriched in metabolic and cell cycling pathways, respectively) and therapeutic vulnerabilities (MG3 has no clear treatment target). We sought to understand drivers of these key differences at a chromatin level. Methods: We profiled MG3/MG4 meningiomas for common histone marks H3K27me3, H3K27Ac, H3K4me1, H3K4me3, H3K9me3, and H3K36me3. Multiple computational approaches were used to compare MG3 and MG4 tumours including superenhancer ranking, differential binding analysis, and unsupervised clustering. Results: Our cohort includes 11-20 meningiomas per histone mark. Clustering revealed striking separation of subgroups based on multiple histone marks, particularly H3K36me3. FOXC1, a known driver of the epithelial to mesenchymal transition, was identified as a recurrent superenhancer in both groups, whereas MG3-specific superenhancers mapped to immune regulatory networks. Integrated differential binding analysis confirmed an immune-rich microenvironment in MG3 tumours driven by multiple histone marks, suggesting a role for targeting novel immune checkpoint genes CD84 and CD48. Conclusions: This study is the first to apply integrated analysis of multiple histone modifications to aggressive meningioma. We further characterize MG3 tumours by identifying an epigenetically-driven immune phenotype and propose novel treatment targets.

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Background: In early-stage transsylvian aneurysm surgery, achieving brain relaxation is crucial for the safe exposure of aneurysms; however, in cases of tight, hemorrhagic brains, ventricular drainage is often required. Although Paine/Samson initially proposed a ventricular access point in the frontal horn of the lateral ventricle, and numerous points and techniques have been described since, their consistency and success rates have not undergone rigorous evaluation through comparative cadaveric anatomical studies. Methods: We injected 2 cc agar-agar solutions with distinct colors into the lateral ventricles of twelve cadaveric brains, utilizing four described points, followed by refrigeration at 4°C for one hour for each injection. Next, the brains were sectioned in the coronal plane at 2 cm intervals for evaluation. We assessed the efficacy of the injections in reaching the ventricles and measured the ventricular dimensions, in addition to calculating the Evans’ index for each brain. Results: Injections at Paine/Samson’s point achieved a 100% success rate, followed by Hyunn’s point with a 91.6% success rate. The success rates at Temporal point and Park point were 83.3% and 58.3%, respectively. Conclusions: We emphasize the significance of direct ventricle puncture technique and our findings indicate that the classical Paine/Samson point is the most reliable among the evaluated methods.

Background: The drivers that activate endogenous ependymal-derived neural stem/progenitor cells (epNSPCs) remain unknown. Understanding the mechanisms that govern the biology of these cells is critical in developing a therapeutic strategy to harness their regenerative potential after injury. Methods: FoxJ1-CreER-tdTomato reporter mice were used for epNSPC lineage tracing. A conditional genetic knock-out mouse line of glutamate-subtype AMPA receptor (AMPAR) subunits in epNSPCs was generated. Electrophysiological properties were assessed using single cell patch clamp and slice culture recordings. For in vivo studies, mice underwent cervical SCI. To examine the effect of positive modulation of AMPARs, mice received the ampakine CX546 or vehicle and underwent electrophysiological testing, behavioural assessment and spinal cord extraction. Results: Glutamate excitotoxicity, a hallmark in the pathogenesis of acute SCI, drives epNSPCs activation via AMPARs. Genetic knock-out of AMPARs in epNSPCs inhibits their activation following SCI. Positive pharmacological modulation of AMPARs after SCI enhances the migration and differentiation of epNSPCs, increases neuronal sparing and improves long-term locomotor/forelimb function. SCI decreases the excitability of corticospinal tract projections, which is improved with positive AMPAR modulation. Conclusions: Glutamatergic signaling via AMPARs is an important mediator of epNSPC activation after injury. Pharmacological targeting of this mechanism can be used to enhance endogenous regeneration and improve recovery post-SCI.

Background: Canadian Emergency Departments (EDs) are overburdened. Understanding the drivers for postoperative patients to attend the ED allows for targeted interventions thereby reducing demand. We sought to identify “bounce back” patterns for subsequent QI initiatives. Methods: From April 1, 2016 to March 31, 2022, all provincial ED datasets (EDIS, STAR, Meditech) identified patients presenting within 90 days post-spine surgery. Using Canadian Classification of Health Interventions codes, laminectomies (1SC80) and discectomies (1SE87) demonstrated the highest ED visit rates. Comprehensive chart reviews were conducted identifying surgical and medical reasons for presentation within this timeframe. Results: Reviewing a cohort of 2165 post-decompression patients, 42.1% presented to the ED (n=912) with 62.8% of these directly related to surgery. Primary reasons included wound care (31.6%), pain management (31.6%), and bladder issues (retention or UTI, 11.0%). Simple wound evaluation constituted 49.7% of wound-related visits, with surgical site infection 37.6% and dehiscence 6.6% accounting for the remainder. Pain-related presentations resulted in 72.3% discharge with additional medications, and 27.7% necessitating hospital admission. New or worsening neurologic deficits were reported in 8.9% of ED visits. Conclusions: These findings illuminate crucial aspects of postoperative care and ED utilization patterns. Prioritizing patient education, pain management, and wound care could help alleviate the national ED crisis.

Background: This study aimed to investigate the effect of impulsivity on the planning & decision-making of individuals with OCD compared to a control group, focusing on amplitude and latency during the Tower of London (TOL) task. Methods: A sample of a total of 76 (dominantly right-handed & aged between 18-30 yrs) participated. Participants with OCD were assessed with the Y-BOCS & symptom checklist, BIS-11, and the HCs were screened with the GHQ-12. ERP components were measured by using TOL on E-prime 3.0. The amplitude and latency along with the spectral power for each problem-solving task were measured and analyzed. Results: Statistically significant differences were found in the Latency variable in the left frontal area of the brain, indicating distinctive latency patterns in individuals with OCD compared to controls. No statistically significant differences were observed in amplitude or latency for other move sequences. High spectral activity was detected in individuals with OCD for an extended period. Conclusions: Individuals with OCD exhibit higher activity indicative of ambivalence during decision-making which indicates that to overcome impulsive urges, thus they need to put more cognitive effort to maintain the same outcomes. To maintain error-free results obsessive & compulsive behaviors are a necessary evil.

Background: Frontotemporal dementia (FTD) often presents with varying neuropsychiatric symptoms (NPS), which may differ based on genetic mutations. We hypothesized distinct NPS trajectories in FTD progression among carriers of chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) mutations. Methods: We analyzed 1662 participants from ALLFTD, including 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We categorized participants into four stages based on CDR plus NACC FTLD global scores: 1) Presymptomatic (consistent CDR=0), 2) Early conversion (CDR increasing from 0 to 0.5), 3) Advanced conversion (CDR increasing from 0.5 to ≥1.0), and 4) Symptomatic (CDR>1.0). The Neuropsychiatric Inventory-Questionnaire (NPI-Q) assessed NPS changes, analyzed using a mixed-effects model, accounting for age and baseline scores. Results: Our results indicated similar NPS trajectories in the presymptomatic stage for all groups. Notably, during early conversion, C9orf72 and GRN carriers exhibited significantly higher NPI-Q score increases than MAPT carriers, primarily in psychosis and hyperactivity domains. In later stages, increases in NPS were similar across groups. Conclusions: This study suggests familial FTD progression, particularly in TDP-43 pathology, may involve more severe NPS like psychosis or hyperactivity, differing from tau pathology or sporadic FTD. Further research is needed to explore these distinct trajectories.

Background: study patients with PNES’ outcome after their diagnosis in the EMU. Methods: Comparative analyses were carried out on several variables before and after diagnosis: number of participants with daily PNES, number of visits to the emergency department, number of participants who took ASMs or psychotropic drugs, and employment status. Results: 61/103 patients (79% female) participated. The median age at PNES onset was 35 years. 62% were receiving ASMs and 40% psychotropic drugs. The mean stay at the EMU was five days. PNES diagnosis was explained to almost all patients (97%) by the end of their EMU stay and was well accepted by most (89%). When contacted, 46% of participants no longer had PNES; 32% mentioned that their PNES had ceased immediately upon communication of the diagnosis. Fewer patients had daily seizures after the diagnosis. Similarly, the median number of emergency department visits was significantly lower. Only 17 patients consulted their general practitioner and 20 a neurologist after a PNES attack. The use of ASMs was also significantly reduced from 70% to 33%, with only one still taking an ASM for its antiseizure properties. Conclusions: significant reductions in PNES frequency, health care utilization and ASM use.

Background: Since 2018, several CGRP-targeted therapies have entered the migraine market, including eptinezumab. Minimal evidence exists evaluating the real-world effectiveness of switching from a subcutaneous to an intravenous anti-CGRP mAb. Methods: An observational, multi-site (n=4), US-based study, REVIEW evaluated real-world experiences of patients with chronic migraine (CM) treated with eptinezumab using a chart review, patient survey, and physician interviews. Adults (≥18 years) with a diagnosis of CM who had completed ≥2 consecutive eptinezumab infusion cycles were eligible. Results: Enrolled patients were primarily female (83%, 78/94), had a mean age of 49 years and a mean migraine diagnosis duration of 15.4 years. All patients (94/94) self-reported prior preventive therapy with 89% (84/94) reporting prior subcutaneous anti-CGRP mAb use (i.e., fremanezumab, galcanezumab, or erenumab). Regardless of prior exposure to a CGRP ligand or receptor blocker, the number of “good” days/month more than doubled following eptinezumab. Patients experienced a similar mean change in the number of “good” days/month regardless of the number and type of previous subcutaneous anti-CGRP mAb used. Conclusions: This real-world, patient survey showed that patients with prior exposure to subcutaneous anti-CGRP mAbs had high overall satisfaction with the effectiveness of eptinezumab treatment regardless of the number and type of previous therapies used.

Background: This post hoc analysis evaluated the efficacy of eptinezumab vs placebo across 24 weeks of treatment in the placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure. Methods: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo intravenous infusion every 12 weeks. Eligible patients needed documented evidence of 2–4 prior preventive treatment failures within the past 10 years. This post hoc analysis focused on subgroups of patients with prior treatment failure on topiramate, beta blockers, amitriptyline, and/or flunarizine. Results: The full analysis set included 890 patients: 633 previously failed topiramate, 538 failed beta blockers, 508 failed amitriptyline, and 333 failed flunarizine; within each subgroup, most patients had 2 prior treatment failures (51–56%). Across Weeks 1–12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo, with larger reductions observed over Weeks 13–24. Similarly, ≥50% MRRs were higher with eptinezumab than with placebo and increased following a second infusion. Conclusions: Eptinezumab demonstrated greater reductions in MMDs compared with placebo across all subgroups of prior preventive treatment failure, with evidence to suggest that a second dose provides additional benefit.

Background: Migraine affects more than 1 billion people, with attacks triggered by a variety of factors. Knowledge of environmental triggers for migraine attacks is limited, and has mostly been studied via emergency room (ER) visits. There are significant barriers and delays for attending ER for migraine treatment, which create challenges for estimating causal links to environmental exposures. We assessed whether smartphone app records may have fewer barriers and reduced lags. Methods: American and Canadian participants completed an online survey about their migraine attacks, smartphone app use, and ER visits. Results: Among 308 participants, barriers to visiting ER were similar in both countries, except for financial concerns in the US. About half of participants who attended ER also recorded the attack in a diary or app. Whereas migraine patients often present to ER 7+ days after onset, records in a smartphone app dataset were created within 2 days of onset. Conclusions: Although not all severe migraine attacks are recorded by smartphone users, smartphone app records may have fewer barriers to creation and shorter time lags compared to ER visit records, making them a rich source of data for research on transient neurologic health outcomes and environmental exposures.

Background: Healthcare systems incur a significant financial burden through unnecessary neuroimaging, which globally, is in the order of the billions of dollars. Current recommendations suggest avoiding neuroimaging in patients with stable headaches, particularly those meeting the criteria for migraine. Methods: We conducted a retrospective chart review of 100 headache patients in an outpatient neurology clinic. We evaluated the use of CT and MRI imaging and the impact of neuroimaging on clinical management. Results: 55% of patients had a history of migraine. Overall, 74 of 100 patients had either CT or MRI imaging. Imaging was largely normal or identified non-specific, clinically irrelevant findings. There was 1 case of a cerebellopontine angle epidermoid tumor and another of suspected MS. Neuroimaging did not alter headache management. Conclusions: The data is consistent with current guidelines suggesting that neuroimaging is not necessary in patients with stable headaches, particularly migraine. Neuroimaging overuse might reflect lack of awareness of guideline recommendations, insecurity over diagnoses, medicolegal concerns, as well as patients and primary practitioners’ expectations. Resources to help improve public and physician awareness regarding neuroimaging use in patients with stable headache may help reduce unwarranted imaging studies and could have significant financial savings for healthcare systems.

Background: Postural instability is a common symptom of progressive supranuclear palsy (PSP). Retropulsion is one form of postural instability. Spontaneous retropulsion involves loss of balance without external provocation. Others have reported on retropulsion in the clinical setting while testing for postural instability but rates of spontaneous retropulsion in the community have not been described. This study examines the prevalence of spontaneous retropulsion in PSP. Methods: A retrospective chart review examined 60 patients from the Saskatchewan Movement Disorders Program with clinical and pathology-confirmed diagnosis of PSP. We identified patients who endorsed spontaneous retropulsion. The data was analysed with univariate logistic regression. Results: The study included 43 males and 17 females. Spontaneous retropulsion was reported in 18 (30%) patients. Among the variables, only sex showed a statistical significance (p = 0.0184) with females more likely to report spontaneous retropulsion (OR = 4.25). Other variables (PSP onset age, onset age of balance impairment, gait impairment, and disease duration) were not statistically significant. Conclusions: Our data suggest that spontaneous retropulsion is common in PSP, with females being at a significantly higher risk than males. This is useful information when counselling patients on risk-avoidance behaviour to prevent falls.