Faculty Bibliography

OBJECTIVE:Fatigue and depression are common and disabling symptoms in people with Multiple Sclerosis (PwMS). This study aimed to examine the relationship between discordant fatigue measures and depression severity in PwMS. METHODS:A retrospective analysis was conducted on 712 PwMS evaluated over 14 years at a comprehensive MS center. All participants completed the Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), and Beck Depression Inventory (BDI) as part of routine clinical care. Fatigue score concordance was defined as both FSS and MFIS being above or below the threshold; discordance was defined as one above and one below. Statistical analyses compared demographic, clinical, and depression-related variables between groups. RESULTS:Of the 712 patients (75.3% female; mean EDSS 2.8), 78.9% demonstrated concordant fatigue scores, while 21.1% showed discordance-most commonly with elevated MFIS and low FSS. The discordant group had significantly higher mean BDI scores (23.0 vs. 9.8; P < 0.0001) and elevated suicidality scores, despite similar clinical characteristics. CONCLUSIONS:PwMS with discordant fatigue profiles, particularly those with higher MFIS than FSS scores, exhibit significantly greater depressive symptoms. Discordance between fatigue measures may serve as a clinical marker for underlying depression, supporting the need for comprehensive psychosocial evaluation in this subgroup.

Cerebral malaria is a major complication of Plasmodium falciparum infection that occurs upon the sequestration of infected red blood cells (iRBCs) in brain capillaries, resulting in the loss of endothelial barrier integrity, brain swelling, and frequently long-term sequelae or death. P. falciparum-iRBCs cause the disruption of human brain microvascular endothelial cell barrier integrity in vitro, mimicking the microenvironment of cerebral malaria, yet the specific mechanisms mediating this process remain unknown. Upon infection of the host RBCs, P. falciparum produces hemozoin, a crystal form of heme generated following the degradation of hemoglobin by the parasite. Here, we show that the endothelial barrier-disrupting activity is found entirely in the hemozoin fraction of P. falciparum-iRBCs. This activity is not caused by the hemozoin crystal itself, which is not able to induce barrier disruption, but by the biomolecules that are associated with it. Treatment of purified P. falciparum hemozoin with proteases inhibits the disruption of endothelial barrier integrity caused by the hemozoin, indicating an important role for proteins in the disruption of the barrier. Conversely, treatment with nucleases did not affect hemozoin barrier-disrupting activity. These results identify a key molecular mechanism in the P. falciparum-mediated brain endothelial barrier disruption during cerebral malaria and may open new avenues for the treatment of this complication.IMPORTANCEWhile several specific biomolecules have been proposed to contribute to the disruption of endothelial barrier integrity in cerebral malaria, no single Plasmodium falciparum- or host-derived factor has been definitively identified as the primary driver of this disruption. Here, we identify the brain endothelial barrier-disruptive P. falciparum-infected red blood cell (iRBC)-derived activity to be caused by biomolecules bound to hemozoin, identifying a key, novel mechanism in the pathogenesis of cerebral malaria. The finding that P. falciparum hemozoin also disrupts a pulmonary endothelial cell barrier opens the possibility that this mechanism underlies other severe malaria complications. The implication of P. falciparum-iRBC-derived proteins in this mechanism is in line with previous reports, providing a novel interpretation of these findings in the context of hemozoin-binding. This knowledge provides a new perspective in the search for specific molecules and mechanisms involved in barrier disruption, which may lead to the development of much-needed specific treatments for cerebral malaria.

Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.

Head computed tomography (CT) imaging is a widely used imaging modality with multitudes of medical indications, particularly in assessing pathology of the brain, skull and cerebrovascular system. It is commonly used as the first-line imaging in neurologic emergencies given its rapidity of image acquisition, safety, cost and ubiquity. Deep learning models may facilitate detection of a wide range of diseases. However, the scarcity of high-quality labels and annotations, particularly among less common conditions, substantially hinders the development of powerful models. To address this challenge, we introduce FM-HCT, a Foundation Model for Head CT for generalizable disease detection, trained using self-supervised learning. Our approach pretrains a deep learning model on a large, diverse dataset of 361,663 non-contrast 3D head CT scans without the need for manual annotations, enabling the model to learn robust, generalizable features. Our results demonstrate that the self-supervised foundation model substantially improves performance on downstream diagnostic tasks compared to models trained from scratch and previous 3D CT foundation models trained on scarce annotated datasets.

Stroke recovery outcomes vary across individuals, motivating the search for biomarkers that can improve prediction. White matter hyperintensities (WMH) volume is a leading biomarker candidate, with FLAIR MRI typically used for WMH segmentation; however, T1-weighted (T1) MRI is often more available. Therefore, we evaluated the performance of two automated WMH segmentation methods (WMH-SynthSeg, SAMSEG) to determine whether WMH volume can be reliably estimated using T1 alone. We analyzed imaging data from 227 stroke patients across three datasets spanning early subacute to chronic recovery, with gold-standard WMH masks and stroke lesion masks manually traced on available T1 and FLAIR scans. WMH was segmented using T1 only as input to WMH-SynthSeg and SAMSEG, as well as using both T1 and FLAIR as input to SAMSEG, as previously implemented in stroke recovery research. Automated WMH segmentations were compared to the gold-standard WMH mask: spatial accuracy was assessed using Dice similarity index (SI) and cluster-level false negative ratio, while volumetric agreement was assessed using intraclass correlation, Pearson's correlation, and volume ratio. We used linear mixed-effects models to evaluate whether SI was influenced by factors such as WMH volume, stroke lesion volume, WMH contrast, age, sex, and days since stroke, with dataset as a random effect. WMH-SynthSeg using T1-only input produced more accurate and reliable WMH segmentations compared to SAMSEG with T1-only input and performed comparably to SAMSEG using both T1 and FLAIR input. WMH-SynthSeg using T1-only input may be used for WMH volume estimation in stroke recovery research in the absence of multimodal imaging.

BACKGROUND:Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. METHODS:We combined finite-element modeling, cadaver measurements (n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long-Evans rats (n = 11 animals, >500 induced seizures analyzed across conditions). RESULTS:Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. CONCLUSIONS:ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.

INTRODUCTION/BACKGROUND:Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI-associated WMH (RHI-WMH). These lesions are punctate, circular, and located at the gray-white matter boundary, an area vulnerable to trauma-related damage. METHODS:We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non-RHI participants. RHI-WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS:Individuals with RHI had greater RHI-WMH by both detection methods in both cohorts. RHI-WMH were associated with plasma neurofilament light and p-tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION/CONCLUSIONS:RHI-WMH may represent a new supportive biomarker for the detection of RHI-related neuropathologies later in life.

BACKGROUND/OBJECTIVES/OBJECTIVE:Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. METHODS:The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. RESULTS: < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. CONCLUSIONS:https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast.

INTRODUCTION/BACKGROUND:Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS:Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS:Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION/CONCLUSIONS:Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.