Blanchette Rockefeller Neurosciences Institute

Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective treatment for medication‑refractory Parkinson's disease (PD), though outcomes vary widely. The influence of lead location relative to the GPi therapeutic sweetspot has not previously been examined within a multivariable regression framework. This study evaluated the predictive utility of volume-of-tissue-activated (VTA)-sweetspot overlap on postoperative UPDRS‑III outcomes in the CSP #468 cohort receiving bilateral GPi‑DBS, alongside demographic/clinical predictors, using two independently derived sweetspot models. CSP #468 was a multicenter randomized clinical trial with blinded 6‑month outcomes and robust collection of associated features of PD. A prior publication generated a cross validated 6‑month GPi-sweetspot from this dataset. An independent single‑surgeon cohort was used to construct a separate sweetspot uninfluenced by CSP outcomes. Multivariable modeling was completed using backward‑selection linear regression with Bonferroni correction. Models were checked for assumptions, data leakage, and overfitting. Each sweetspot-multivariable model's ability to predict outcomes in the opposite cohort was assessed. Both sweetspots localized to the primary motor GPi. The independent sweetspot multivariable model included VTA‑sweetspot overlap and levodopa response (R²Adj = 0.19) and remained robust under leave-one-out cross validation. The CSP sweetspot multivariable model also predicted outcomes in the independent cohort (p = 0.004), demonstrating meaningful external validity.

IntroductionBrain glucose hypometabolism precedes cognitive decline in Alzheimer's disease, however its role in determining long-term cognitive trajectories remains under studied in current literature in a clear manner. We investigated whether baseline brain glucose metabolism predicts cognitive decline rates and disease conversion risk in a large longitudinal cohort.MethodsWe analyzed 4,732 participants (1,685 with longitudinal cognitive data) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with fluorodeoxyglucose positron emission tomography (FDG-PET), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale (ADAS) measurements over ten years. Mixed-effects models investigated time × brain glucose metabolism interactions on cognitive decline. Cross-validation assessed predictive accuracy for mild cognitive impairment and Alzheimer's disease conversion.ResultsBrain glucose metabolism was found to modulate the cognitive decline rates (time × FDG interaction: MMSE β = 0.746, P-value <0.001; ADAS β = −1.595, P-value <0.001). High versus low glucose metabolism demonstrated 1.49 MMSE points/year and 3.19 ADAS points/year protection. Among cognitively normal participants, low glucose metabolism increased Alzheimer's disease conversion risk four-fold (incidence rate ratio = 3.79, 95%CI: 2.94–4.88). Predictive models achieved high accuracy for Alzheimer's disease conversion (AUC = 0.826) with good calibration (Brier score = 0.092). High-metabolism individuals showed essentially stable cognition over ten years follow-up duration as evident in the ADNI dataset.ConclusionsWe found that brain glucose metabolism is a notable determinant of cognitive decline progression, especially for Alzheimer’s disease risk, providing quantifiable metabolic protection against decline. Our results demonstrate brain glucose hypometabolic findings from baseline FDG-PET as a precision biomarker for therapeutic stratification and support further interventions for cognitive preservation for further research, validation and development purposes that should be further evaluated and investigated in further clinical trials that may lead to better preventive and therapeutic benefits for cognitive functions preservation and prevention of cognitive decline process in high-risk individuals.

Chronic subdural hematoma (cSDH) is a common, age-associated condition driven largely by ground-level falls and the widespread use of antithrombotic agents. Its burden is rising with aging population, and a substantial subset of patients meet practical criteria for middle meningeal artery embolization (MMAE). Contemporary understanding frames cSDH as a vascular-inflammatory disorder with recurrent microhemorrhage from fragile neovessels, largely supplied by branches of the middle meningeal artery. Standard care has traditionally relied on surgical evacuation, yet recurrence and reintervention remain frequent in high-risk cohorts. Over the last several years, randomized trials have evaluated MMAE as an adjunct or alternative to usual care. Three trials-EMBOLISE, STEM, and MEMBRANE-demonstrated reduced treatment failure or reoperation with adjunctive MMAE. These findings, coupled with rapid real-world adoption of MMAE, support embolization as an effective strategy to lower recurrence, especially when used with indicated surgery. Remaining questions include optimal patient selection, choice of embolic agent, target depth and laterality (distal vs. proximal, unilateral vs. bilateral), anesthesia strategy, and standardized angiographic workflows that mitigate anastomotic risks. Addressing these evidence gaps, along with health-system planning for rising volumes, will refine algorithms and improve outcomes in this growing population.

A sequence of muscle actions generates complex movements such as walking or reaching. However, how these coordinated actions subserve complex movements across animals remains unknown. While the sequences of muscle activity have been documented in limb tasks with large animals, the equivalent comprehensive behavioral description of rodent performance is sparse. To this end, we have trained rats to perform precise foot placement, which allows us to assess skilled limb placement during locomotion. Animals were trained on the pegway task, conFigd to impose symmetric or asymmetric (with overstepping) locomotor stepping at the preferred stride length. We collected electromyography from selected representative forelimb muscles implanted with intramuscular differential electrodes and recorded ground reaction forces from the array of force sensors embedded into walkway pegs. The changes in muscle coordination were analyzed for symmetric and asymmetric stepping. The sequence corresponded to the progression of muscle actions responsible for limb lift, flexion and transport, overground clearance, and preparation for ground contact. The stereotyped spatiotemporal sequence of muscle activity was persistent and consistent across asymmetric tasks. These patterns are similar to those observed in cats during locomotion over obstacles and reaching movements. These findings indicate that a temporal sequence of muscle actions is similar across quadrupeds during locomotor tasks with fine stepping control.

In this study we examined neuronal mechanisms associated with chronic headache pain by recruiting a participant diagnosed with New Daily Persistent Headache (NDPH), who had the reliable characteristic that his baseline chronic pain could be immediately and consistently modulated (partially relieved or aggravated) by applying deep pressure to specific locations along his face and head. We sought to map brain regions responsive to modulations of his baseline pain using functional magnetic resonance imaging (fMRI). We constructed customized MRI-compatible 3D-printed face masks and skull plates affixed with syringe plungers that could apply and remove deep pressure to discrete craniofacial locations. Using On/Off block paradigms, we collected fMRI data across nine sessions while pressing on locations that either increased, decreased, or had no effect on his chronic pain. Although displacement artifacts precluded use of relief point data, we did reveal five brain regions that showed significantly increased responses when stimulating locations that aggravated his baseline headache pain, including the right anterior insula, bilateral inferior parietal lobule (IPL) foci, plus bilateral cerebellar regions (lobule VIIIb). Using structural vector autoregression (Granger causality), resting-state functional connectivity MRI analyses of the above somatosensory-related aggravated pain network further revealed effective connectivity (positive effect paths) from the left IPL to the right anterior insula, and these two regions had positive effect paths to the right IPL. This cortical circuit was coupled with the cerebellar foci plus the participant’s anatomically derived periaqueductal gray (PAG) region. Moreover, on days when the participant had greater degrees of baseline chronic headache pain the right IPL and PAG exhibited negative effect paths on the left IPL and left cerebellum, respectively, thereby revealing additional psychophysiological attributes of this circuit. Together, these results not only identified candidate targets for patient-customized neuromodulation therapies but also revealed a novel testable circuit model regarding potential mechanisms underlying one form of neuropathic pain perception.

BackgroundAlzheimer's disease (AD) is a major neurodegenerative disorder affecting millions worldwide, with limited treatment options and significant challenges in drug delivery. Monoclonal antibody (mAb) therapies targeting β‐amyloid plaques have shown promise but are constrained by potential adverse effects, including amyloid‐related imaging abnormalities (ARIA), and extended treatment durations. Low‐Intensity Focused Ultrasound (FUS) has emerged as a promising, non‐invasive approach for targeted BBB opening. FUS‐BBB opening alone has shown small Aβ reductions, with single‐digit SUVR decreases over 9 to 16 weeks in small studies. We have now been investigating targeted mAb therapeutics in conjunction with FUS BBB opening in mild AD (NCT05469009). Our latest findings demonstrate the capability of FUS‐BBB opening to accelerate the therapeutic effects of aducanumab, resulting in an additional 32% SUVr reduction in amyloid plaque within brain regions treated with FUS+mAb compared to mAb therapy alone over 26 weeks. With the FDA approval of Lecanemab, we have expanded our clinical trial to explore the safety and efficacy of combining FUS‐BBB opening with this mAb.MethodsAs the clinical trial progresses (NCT05469009), we continue recruiting amyloid‐positive Mild cognitive impairment participants, who undergo sessions of combining FUS‐BBB opening with Lecanemab. Given the ARIA risk associated with Lecanemab alone we selected patients without ARIA when treated with Lecanemab alone to ensure they could complete the full combination treatment. Neurological and cognitive assessments, along with amyloid PET scans, are performed regularly to evaluate safety, cognitive outcomes and amyloid plaque burden.ResultsWe have successfully recruited and treated two patients with the combination of FUS‐BBB opening and Lecanemab. Up to date safety, Aβ PET results, and cognitive assessment will be presented and discussed at the meeting.ConclusionThe preliminary results suggest safety and feasibility of combining FUS‐BBB opening with Lecanemab for targeted therapy in AD. The study highlights the potential of accelerated amyloid plaque clearance with combined FUS‐BBBO and mAb. Additional studies with more patients and extended follow‐up periods are warranted to validate these initial findings, aid in patient selection, optimized mAB and FUS‐BBB doses, and evaluate the potential clinical benefits of this novel approach.

Brain-infiltrating tumour cells from high-grade glioma remain shielded from drug treatments by the blood-brain barrier, leading to inevitable recurrence. Microbubble-enhanced transcranial focused ultrasound (MB-FUS) enables controlled blood-brain barrier opening (BBBO), permitting localised drug delivery. We aimed to assess safety and feasibility of MB-FUS plus standard-of-care chemotherapy for individuals with high-grade glioma. BT008NA was an open-label, single-arm, phase 1/2 trial conducted at five sites in the USA and Canada (part of the ReFOCUSED Consortium). Key eligibility criteria were participants with newly diagnosed high-grade glioma (glioblastoma as per WHO 2016 classification), aged 18-80 years, with normal organ function, a baseline Karnofsky Performance Status score of 70 or higher, who had received maximal safe resection and 6-week chemoradiotherapy and were to start standard-of-care monthly adjuvant temozolomide chemotherapy (150 mg/m2 of body surface area). MRI-guided, 220 kHz transcranial MB-FUS treatments were delivered in periresectional (tumour-infiltrative) regions, on any of the first 3 days of a 28-day temozolomide cycle, for up to six cycles. Primary outcomes were safety (adverse events) and feasibility (BBBO: new contrast enhancement on post-procedure T1-weighted MRI). Protocol-prespecified secondary outcomes were overall survival and progression-free survival. Analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03551249 (USA) and NCT03616860 (Canada), and is closed to enrolment. Between Oct 16, 2018, and March 9, 2022, we enrolled 34 participants, all evaluable for prespecified primary and secondary endpoints, with a mean age of 51·5 years (SD 13·0) and median follow-up 44·5 months (95% CI 34·9-57·3). By self-reporting, 18 (53%) participants were female and 16 (47%) male, 28 (82%) were White, and 34 (100%) were non-Hispanic. 176 adverse events were captured: 54 (31%) chemotherapy-related, 10 (6%) disease-related, 87 (49%) related to undergoing MB-FUS (40 [46%] grade 1, 46 [53%] grade 2, and one [1%] grade 3), and 25 (14%) unrelated. Two (1%) of the adverse events were grade 5 (disease-related deaths), three (2%) grade 4 (temozolomide-related haematological abnormalities), and eight (5%) grade 3 (three [2%] temozolomide-related, one [1%] MB-FUS-related, three [2%] disease-related, and one [1%] unrelated); these occurred across seven (21%) of 34 participants. No treatment-related deaths occurred during the trial. BBBO was visualised in all treatments. Median overall survival was 31·3 months (95% CI 21·1-not reached) and median progression-free survival was 13·5 months (9·9-26·9) with patient-specific disease courses found concordant with trajectories of MB-FUS-enriched plasma cell-free DNA. MB-FUS plus temozolomide is a safe combinatorial therapeutic approach for individuals with high-grade glioma, with the potential to improve survival and enable non-invasive plasma biomarker-based disease surveillance (sono-liquid biopsy), warranting randomised controlled trials. National Institutes of Health and Insightec.

"Moving toes syndrome" is a rare movement disorder with painful and painless forms. There is a paucity of literature on patients presenting with moving toes syndrome in the first 2 decades. We present 3 cases of moving toes syndrome, with symptom onset between 9 and 19 years. Pain was variable in these patients. Etiologies included minor trauma in 2 patients and a central thalamic-hypothalamic lesion in another. Two of 3 patients required no treatment, and symptoms gradually improved. Similar to adults, children and youth with moving toes syndrome can demonstrate features that overlap with functional movement disorders. Moving toes syndrome presenting in childhood and adolescence appears to be more benign than in adults, with many patients improving over time.