Faculty Bibliography

FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention-deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger epilepsy and depression. Evidence from human and animal studies supports that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to both disorders and their comorbidity ( Kanner, 2003). Here, we investigate if HPA axis dysfunction may influence epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (Kcc2/Crh KO mice) lacking the K⁺/Cl^- cotransporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced HPA axis hyperactivation ( Melon et al., 2018). We used the Kcc2/Crh KO mice to examine the impact on epilepsy outcomes, including seizure frequency/burden, comorbid behavioral deficits, and sudden unexpected death in epilepsy (SUDEP) risk. We found sex differences in HPA axis dysfunction's effect on chronically epileptic KCC2/Crh KO mice seizure burden, vulnerability to comorbid behavioral deficits, and SUDEP. Suppressing HPA axis hyperexcitability in this model using pharmacological or chemogenetic approaches decreased SUDEP incidence, suggesting that HPA axis dysfunction may contribute to SUDEP. Altered neuroendocrine markers were present in SUDEP cases compared with people with epilepsy or individuals without epilepsy. Together, these findings implicate HPA axis dysfunction in the pathophysiological mechanisms contributing to psychiatric comorbidities in epilepsy and SUDEP.

BACKGROUND:Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disorder that includes intracranial lesions such as unidentified bright objects (UBOs)-areas of increased T2 signal on magnetic resonance imaging (MRI)-and tumors known as gliomas. The presence of these lesions in the corpus callosum (CC) has not been previously studied in a large cohort. METHODS:We reviewed medical records of 681 patients (aged three months to 86 years) followed at our institution from 2000 to 2023 with NF1 and one or more brain MRI. Patients with lesions in the CC were identified, and RAPNO/RANO criteria were used to determine changes in size over time, where a change of 25% in the product of perpendicular measurements indicates growth or shrinkage. RESULTS:Forty-seven patients had CC UBOs, most of which were in the splenium (66.0%). Seventeen patients had CC gliomas (10% of those with any glioma), two of whom had two gliomas. Seventeen of 19 gliomas were in the splenium. Over follow-up, eight of 19 remained stable, three shrunk, and eight grew. The mean percentage change in the product of the dimensions was 311.5% (ranging from -46.7% to 2566.6%). Of the eight lesions that grew, one required treatment. CONCLUSIONS:There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and although some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of CC lesions in NF1 and adds to the growing data to inform appropriate follow-up.

BACKGROUND AND PURPOSE/UNASSIGNED:Sleep disturbance after hemorrhagic stroke (intracerebral or subarachnoid hemorrhage) can impact rehabilitation, recovery, and quality of life. We sought to explore preclinical and clinical factors associated with sleep disturbance after hemorrhagic stroke assessed via the Quality of Life in Neurological Disorders (Neuro-QoL) short form sleep disturbance inventory. METHODS/UNASSIGNED:We telephonically completed the Neuro-QoL short form sleep disturbance inventory 3-months and 12-months after hemorrhagic stroke for patients >18-years-old hospitalized between January 2015 and February 2021. We examined the relationship between sleep disturbance (T-score >50) and social and neuropsychiatric history, systemic and neurological illness severity, medical complications, and temporality. RESULTS/UNASSIGNED:= .046). CONCLUSION/UNASSIGNED:This exploratory analysis did not demonstrate a sustained relationship between any preclinical or clinical factors and sleep disturbance after hemorrhagic stroke. Larger studies that include comparison to patients with ischemic stroke and healthy individuals and utilize additional techniques to evaluate sleep disturbance are needed.

BACKGROUND AND OBJECTIVES/UNASSIGNED:In a retrospective study evaluating the diagnostic approach of definitive neurological infections at a tertiary referral center, we assessed the time to diagnosis from presentation, number of diagnostic tests ordered, and modality of etiologic diagnosis. METHODS/UNASSIGNED:A total of 111 confirmed clinical cases of neurological infections from 2010-2018 were reviewed. Definitive neuroinfectious diagnoses were defined by positive cerebrospinal (CSF) polymerase chain reaction (PCR)/antigen, CSF culture, CSF antibody, serology, or pathology tests. RESULTS/UNASSIGNED:< .001). DISCUSSION/UNASSIGNED:Given the high morbidity and mortality of neuroinfectious disease, specifically meningitis and encephalitis, efficient diagnostic testing is imperative to facilitate the most appropriate clinical course of action with special attention to the specific patient population.

In medication-resistant epilepsy, the goal of epilepsy surgery is to make a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure onset zone (SOZ) and incorporation of neuroimaging findings from MRI, PET, SPECT, and MEG modalities. Resecting cortical tissue generating high-frequency oscillations (HFOs) has been investigated as a more efficacious alternative to targeting the SOZ. In this study, we used a support vector machine (SVM), with four distinct fast ripple (FR: 350-600 Hz on oscillations, 200-600 Hz on spikes) metrics as factors. These metrics included the FR resection ratio (RR), a spatial FR network measure, and two temporal FR network measures. The SVM was trained by the value of these four factors with respect to the actual resection boundaries and actual seizure free labels of 18 patients with medically refractory focal epilepsy. Leave one out cross-validation of the trained SVM in this training set had an accuracy of 0.78. We next used a simulated iterative virtual resection targeting the FR sites that were highest rate and showed most temporal autonomy. The trained SVM utilized the four virtual FR metrics to predict virtual seizure freedom. In all but one of the nine patients seizure free after surgery, we found that the virtual resections sufficient for virtual seizure freedom were larger in volume (p<0.05). In nine patients who were not seizure free, a larger virtual resection made five virtually seizure free. We also examined 10 medically refractory focal epilepsy patients implanted with the responsive neurostimulator system (RNS) and virtually targeted the RNS stimulation contacts proximal to sites generating FR at highest rates to determine if the simulated value of the stimulated SOZ and stimulated FR metrics would trend toward those patients with a better seizure outcome. Our results suggest: 1) FR measures can accurately predict whether a resection, defined by the standard of care, will result in seizure freedom; 2) utilizing FR alone for planning an efficacious surgery can be associated with larger resections; 3) when FR metrics predict the standard of care resection will fail, amending the boundaries of the planned resection with certain FR generating sites may improve outcome; and 4) more work is required to determine if targeting RNS stimulation contact proximal to FR generating sites will improve seizure outcome.

BACKGROUND: METHODS:-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes. RESULTS:A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported. CONCLUSIONS:-SWN. (Funded by the Children's Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).

INTRODUCTION/BACKGROUND:Diverse neurological conditions are reported associated with the SARS-CoV-2 virus; neurological symptoms are the most common conditions to persist after the resolution of acute infection, affecting 20% of patients 6 months after acute illness. The COVID-19 Neuro Databank (NeuroCOVID) was created to overcome the limitations of siloed small local cohorts to collect detailed, curated, and harmonized de-identified data from a large diverse cohort of adults with new or worsened neurological conditions associated with COVID-19 illness, as a scientific resource. METHODS:A Steering Committee including US and international experts meets quarterly to provide guidance. Initial study sites were recruited to include a wide US geographic distribution; academic and non-academic sites; urban and non-urban locations; and patients of different ages, disease severity, and comorbidities seen by a variety of clinical specialists. The NeuroCOVID REDCap database was developed, incorporating input from professional guidelines, existing common data elements, and subject matter experts. A cohort of eligible adults is identified at each site; inclusion criteria are: a new or worsened neurological condition associated with a COVID-19 infection confirmed by testing. De-identified data are abstracted from patients' medical records, using standardized common data elements and five case report forms. The database was carefully enhanced in response to feedback from site investigators and evolving scientific interest in post-acute conditions and their timing. Additional US and international sites were added, focusing on diversity and populations not already described in published literature. By early 2024, NeuroCOVID included over 2,700 patient records, including data from 16 US and 5 international sites. Data are being shared with the scientific community in compliance with NIH requirements. The program has been invited to share case report forms with the National Library of Medicine as an ongoing resource for the scientific community. CONCLUSION/CONCLUSIONS:The NeuroCOVID database is a unique and valuable source of comprehensive de-identified data on a wide variety of neurological conditions associated with COVID-19 illness, including a diverse patient population. Initiated early in the pandemic, data collection has been responsive to evolving scientific interests. NeuroCOVID will continue to contribute to scientific efforts to characterize and treat this challenging illness and its consequences.

This NeuroView assesses the interplay among exposome, One Health, and brain capital in health and disease. Physical and social exposomes affect brain health, and green brain skills are required for environmental health strategies. Ibanez et al. address current gaps and strategies needed in research, policy, and technology, offering a road map for stakeholders.

Biological water-responsive (WR) materials are abundant in nature, and they are used as mechanical actuators for seed dispersal by many plants such as wheat awns and pinecones. WR biomaterials are of interest for applications as high-energy actuators, which can be useful in soft robotics or for capturing energy from natural water evaporation. Recent work on WR silk proteins has shown that β-sheet nanocrystalline domains with high stiffness correlate with the high WR actuation energy density, but the fundamental mechanisms to drive water responsiveness in proteins remain poorly understood. Here, we design, synthesize, and study protein block copolymers consisting of two α-helical domains derived from cartilage oligomeric matrix protein coiled-coil (C) flanking an elastin-like peptide domain (E), namely, CEC. We use these protein materials to create WR actuators with energy densities that outperform mammalian muscle. To elucidate the effect of structure on WR actuation, CEC was compared to a variant, CEC_L44A, in which a point mutation disrupts the α-helical structure of the C domain. Surprisingly, CEC_L44A outperformed CEC, showing higher energy density and less susceptibility to degradation after repeated cycling. We show that CEC_L44A exhibits a higher degree of intermolecular interactions and is stiffer than CEC at high relative humidity (RH), allowing for less energy dissipation during water responsiveness. These results suggest that strong intermolecular interactions and the resulting, relatively steady protein structure are important for water responsiveness.