Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal symptoms of Parkinson’s disease (PD). However, the therapeutic mechanisms are incompletely understood. By leveraging patient-specific brain responses to DBS using functional magnetic resonance imaging (fMRI) acquired during stimulation, we identify and validate symptom-specific networks associated with clinical improvement. Methods: Forty PD patients with STN-DBS were enrolled for fMRI using a 30-sec DBS-ON/OFF cycling paradigm. The four cardinal motor outcomes of PD were chosen a priori and measured using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale, part III (MDS-UPDRSIII): axial instability, tremor, rigidity, bradykinesia. Stimulation-dependent changes in blood oxygen level-dependent (BOLD) signal were correlated with each symptom. Results: The relationship between BOLD response and outcomes revealed significant networks of clinical response (p<0.001). Using BOLD responses from the network hubs, each symptom-specific model was significantly predictive of actual improvement: axial instability (R2=0.38, p=0.000026), bradykinesia (R2=0.29, p=0.00033), rigidity (R2=0.40, p=0.000013), tremor (R2=0.26, p=0.00073). Conclusions: Using patient-specific imaging, we provide evidence of an association between DBS-evoked fMRI response and individual symptom improvement. Brain networks associated with clinical improvement were different depending on the PD symptom examined, suggesting the presence of symptom-specific networks of efficacy which may allow personalization of DBS therapy.

Background: Degenerative Cervical Myelopathy (DCM) is the functional derangement of the spinal cord because of compression from degenerate tissues. Typical neurological symptoms of DCM include gait imbalance and upper extremity paresthesia. While it is thought that greater spinal cord compression leads to increased neurological deterioration, our clinical experience suggests a more complex mechanism involving spinal canal diameter (SCD). Methods: 124 MRI scans from 59 non-operative DCM patients underwent manual scoring of cord compression and SCD measurements. Unsupervised machine learning dimensionality reduction techniques and k-means clustering were used to establish patient groups. These patient groups underwent manual inspection of common compression patterns and SCD similarities to define their unique risk criteria. Results: We found that compression pattern is unimportant at SCD extremes (≤14.5 mm or >15.75 mm). Otherwise, stenosis with clear signs of cord compression at two disc levels and stenosis without clear signs of cord compression at two disc levels result in a relatively higher and lower likelihood of deterioration, respectively. We elucidated five patient groups with unique associated risks for neurological deterioration, according to both SCD range and their cord compression pattern. Conclusions: The specific combination of narrow SCD with focal cord compression increases the likelihood of neurological deterioration in non-operative patients with DCM.

Background: There is no guideline for imaging post endovascular therapy (EVT). MRI is considered superior to noncontrast CT for assessment of final infarct volume and to distinguish contrast from hemorrhage. We sought to align the post EVT imaging practices with those after intravenous thrombolysis Methods: We reviewed the EMR records for all EVT patients from Jan 1, 2019 to Dec 31, 2021. We assessed quantity of CT within 24h of EVT, quantity of MRIs performed, and indications listed. We then undertook an educational program targeting stakeholders. The objective was to transition to MRI at 24h for imaging post EVT. Exceptions included neurologic change, need for antiplatelet infusion, or intraoperative complications. Results: Post intervention, a significant reduction in CT within 24h (-28%, P=0.01) and increase in MRIs (+42%, P<0.00). CT within 24h per patient dropped by 50% (1.12 pre vs 0.57 post). Radiation dose per patient dropped by 49%. Average imaging costs increased by 17%, and the number of transfers off unit for imaging increased by 11%. Good functional outcome dropped from 44% preintervention to 34% postintervention (P=0.06). Conclusions: This represents the first systematic evaluation of post EVT imaging in a single center. We demonstrate successful behavior changes for post EVT imaging.

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.