Middlebrooks, Erik H

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

Background Deep brain stimulation (DBS) has been investigated for patients with drug-resistant epilepsy who are not candidates for resective surgery. Because different types of epilepsy involve distinct brain networks, numerous DBS targets have been explored, yet a comprehensive synthesis is lacking. Methods To provide a comprehensive overview of this expanding literature, we conducted a systematic review of studies for DBS in epilepsy, including case series, prospective and retrospective studies. We collected data on surgical targets, individual disease characteristics, outcomes and precise electrode placements. DBS electrode coordinates were gathered into a common template space and related to clinical outcomes. Results We included 124 studies, corresponding to 1210 patients and 20 distinct surgical targets. While the anterior (ANT) and centromedian (CM) nuclei of the thalamus remain the most studied, we also review less commonly used targets that show promise for specific forms of epilepsy and may warrant further investigation. Substantial variability in targeting strategies and electrode placement was observed within each of the target regions. Importantly, significant relationships between stimulation location and outcomes were identified for ANT-DBS and CM-DBS. For ANT-DBS, shorter distance to the mammillothalamic tract junction was associated with greater seizure reduction on both study-level and patient-level analyses (r=−0.55, p<0.001 and r=−0.51, p<0.001, respectively). For CM-DBS, localisation effects may be dependent on the form of epilepsy, with stimulation of the parvocellular CM being associated with better outcomes in generalised epilepsy. Conclusions Our results emphasise the importance of accurate targeting in DBS for epilepsy. Our database and atlas of DBS targets are made publicly available, potentially serving further meta-analytical work. PROSPERO registration number CRD420250649304.

Ultrahigh-field 7-T MRI offers superior resolution and contrast, which enable improved detection of subtle neuroanatomic abnormalities and disease-specific imaging biomarkers, with established clinical applications across a broad range of neurologic disorders.

Background/Objectives: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a safe and established therapy for management of refractory motor fluctuations and dyskinesia in Parkinson’s disease (PD). However, the relationship between stimulation site connectivity and improvement of axial gait symptoms remains poorly understood, particularly when stimulating in the GPi. This study investigated functional and structural connectivity patterns specifically associated with axial symptom outcomes following bilateral GPi-DBS, and, as a secondary exploratory analysis, examined whether Volumes of tissue activated (VTAs)-based connectivity related to overall UPDRS-III change. Methods: We retrospectively analyzed 19 PD patients who underwent bilateral GPi-DBS at the University of Florida (2002–2017). Unified Parkinson’s Disease Rating Scale (UPDRS-III) axial gait subscores were assessed at baseline and 36-month follow-up. VTAs were reconstructed using Lead-DBS and coregistered to Montreal Neurological Institute (MNI) space. Structural connectivity was evaluated with diffusion tractography, and functional connectivity was estimated using normative resting-state fMRI datasets. Correlations between VTA connectivity and clinical improvement were examined using Spearman correlation and voxelwise analyses. Results: Patients with axial improvement in motor scales demonstrated specific VTA connectivity to sensorimotor and supplementary motor networks, particularly lobule V and lobules I–IV of the cerebellum. These associations were specific to axial gait subscores. In contrast, worsening axial gait symptoms correlated with connectivity to cerebellar Crus II, cerebellum VIII, calcarine cortex, and thalamus (p < 0.05). Total UPDRS-III scores did not show a significant positive correlation with supplementary motor area or primary motor cortex connectivity; a non-significant trend was observed for VTA–M1 connectivity (R = 0.41, p = 0.078). Worsening total motor scores were associated with cerebellar Crus II and frontal–parietal networks. These findings suggest that distinct connectivity patterns underlie differential trajectories in axial and global motor outcomes following GPi-DBS. Conclusions: Distinct connectivity profiles might underlie axial gait symptom outcomes following GPi-DBS. Connectivity to motor and sensorimotor pathways supports improvement, whereas involvement of Crus II and occipital networks predicts worsening. Additional studies to confirm and expand on these findings are needed, but our results highlight the value of connectomic mapping for refining patient-specific targeting and developing future programming strategies.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and METHODS This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. RESULTS The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). CONCLUSION Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

Abstract Objective: Reading is a complex cognitive process requiring the integration of orthographic, phonological, and semantic information. The visual word form area, located in the ventral occipitotemporal cortex, is critically involved in orthographic decoding, and damage to this region is known to cause alexia. In contrast, the contributions of white matter pathways supporting reading are less well understood. Method: We present a unique neurosurgical case undergoing awake brain surgery for resection of a metastasis in the left occipitotemporal cortex. A tubular retractor was used to access the lesion and during the insertion of the retractor the patient underwent careful, continuous neuropsychological testing, including evaluation of reading. fMRI language mapping and diffusion MRI were performed preoperatively. Postoperative neuropsychological testing was completed two weeks after surgery to assess cognitive outcome. Results: The patient developed an alexia with letter-by-letter reading in real time during insertion of the tubular retractor. Stealth imaging enabled localization of the tubular retractor at the exact onset of the alexia and, by correlating this with tractography, showed that the tubular retractor was in the vertical occipital fasciculus (VOF). Conclusions: We present the first detailed case report linking the VOF to the acute onset of alexia observed intraoperatively during awake brain surgery. We discuss the connectomics of reading and possible contributions of the VOF in reading.

Background The purpose of this study was to clarify the usefulness of the ‘hot cross bun’ sign (HCBS) as a diagnostic imaging marker in a large cohort of patients with multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Methods This multicentre study included 97 patients with neuropathologically confirmed MSA, and 105 patients with genetically confirmed SCA. Neuroimaging features, including HCBS and middle cerebellar peduncle (MCP) hyperintensities, were assessed. HCBS was graded from 0 to 2: 0, none; 1, only a vertical hyperintense line; and 2, a cruciform hyperintense line. The neuropathological correlates of HCBS were evaluated in 15 patients with MSA with ≤3 months between MRI and autopsy. Results In patients with a disease duration <3 years, grade 1 or 2 HCBS was detected in 100% patients with MSA with predominant cerebellar ataxia (MSA-C) and 39.0% with SCA; whereas grade 2 HCBS was observed in 50% with MSA-C and 2.4% with SCA. Moreover, the coexistence of grade 2 HCBS and MCP hyperintensities exhibited a specificity of 100%. A neuropathological assessment revealed myelin loss, alpha-synuclein aggregates and astrocytic reaction in the MCP, transverse fibres, central zone between longitudinal fasciculi and raphe nucleus, with relative preservation in the longitudinal fasciculi and medial lemniscus in patients with MSA and grade 2 HCBS. Conclusions Grade 1 or 2 HCBS is a highly sensitive finding in patients with MSA-C, and the observation of grade 2 HCBS within 3 years of motor symptom onset has excellent specificity for discriminating MSA-C from SCA, especially when accompanied by MCP hyperintensities.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (&gt;124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.

Deep brain stimulation (DBS) is an established therapeutic intervention for a range of neurological disorders, including Parkinson’s disease, essential tremor, and epilepsy. The efficacy of DBS is predicated on the modulation of dysfunctional neural circuits through the application of electrical pulses. Recent advancements in MRI technology have facilitated the visualization of brain nuclei and their associated networks, which is critical for proper patient-specific targeting of electrodes in surgical procedures. This advancement aims to personalize surgical planning and postoperative programming by integrating patient-specific anatomical and connectivity models. The advent of clinical ultrahigh-field MRI, particularly 7T MRI, significantly enhances the targeting of DBS by improving spatial resolution, signal-to-noise ratio, and tissue contrast. Compared with lower field strengths, 7T MRI provides superior visualization of deeply situated brain nuclei and their extensive cortical projections, including the subthalamic nucleus, globus pallidus internus, and thalamus. This review synthesizes a multi-institutional consensus regarding the technical and clinical applications of 7T MRI, drawing on experience from more than 1000 procedures using 7T DBS. It encompasses both imaging acquisition and postprocessing techniques aimed at optimizing image quality. Our extensive clinical experience informs best practices for correcting distortions, mitigating image artifacts, and employing specific imaging sequences that enhance the visualization of common DBS targets. The insights and recommendations presented are intended to promote the safe and effective utilization of 7T MRI in DBS.

AbstractBackgroundStimulation‐induced dyskinesias (SID) from deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are uncommon; however, they are increasingly recognized. Once considered transient and indicative of effective neuromodulation, SID are now seen as potential therapy‐limiting side effects, akin to internal capsule activation. The mechanism and anatomical basis for SID remain poorly understood.MethodsWe conducted a retrospective study of individuals with Parkinson's disease with STN or GPi DBS who experienced SID in the dopaminergic medication OFF state during the monopolar review 1‐month post‐implantation.ResultsWe analyzed 137 monopolar stimulation observations (105 GPi, 32 STN). In the GPi cohort, discriminative fiber tract analysis showed a strong association between SID and the modulation of subthalamo‐pallidal fibers. This correlation was confirmed using leave‐one‐out and five‐fold cross‐validation. We further validated this model by predicting SID in independent STN and GPi cohorts, with the GPi‐based model accounting for significant variance in SID occurrence in both cohorts.ConclusionsSID from STN or GPi DBS likely shares a common pathway via subthalamo‐pallidal connectivity. DBS modulation of these fibers correlates with SID, as confirmed by multiple cross‐validation methods. These findings suggest that the fibers are part of a more extensive and yet‐to‐be‐fully‐characterized dyskinesia network. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.