Faculty Bibliography

INTRODUCTION/BACKGROUND:Traumatic brain injury (TBI) is the leading cause of pediatric disability. Most pediatric TBIs are mild but can result in long-term cognitive and functional impairments. Outpatient follow-up is essential to detect post-concussive symptoms and aid recovery. METHODS:All patients 3-18 years of age with positive TBI findings on CT or MRI from 2018-2024 were retrospectively reviewed. Follow-up was defined as an appointment with neurology, neuropsychology, neurosurgery, or physical medicine and rehabilitation within three months of discharge. Analyses were performed with appropriate Chi-squared, Fisher's exact, Mann-Whitney U, or t-tests. RESULTS:Fifty-seven patients (41 male, mean age 11.4 years) were identified, with mild TBIs (GCS 13-15) comprising 41/57 (71.9%). Four patients (7.0%) died from their injury. Of 53 surviving patients, 20 (37.7%) had follow-up appointments scheduled for them at discharge, seven (13.2%) were given a specific date and contact number, 17 (32.1%) received service referrals without a specific date, and eight (15.1%) received nonspecific directions or were directed only to follow-up with non-neuroscience services. Within three months, 32 (60.4%) patients followed up, though only 22/53 (41.5%) patients saw a non-surgical neuroscience discipline. Patients who followed up were more likely to have undergone neurosurgery (p = 0.007) or any surgical procedure at all (p = 0.007). They were also more likely to have a shorter hospital length of stay (p = 0.021). Discharge instruction type was significantly associated with follow-up (p = 0.0013); 62.5% of patients who followed up had an appointment scheduled for them or were given a specific date versus 33.4% of patients who did not follow-up. Conversely, 38.1% of patients without follow-up received nonspecific instructions or were told to follow-up with non-neuroscience specialties. This finding remained significant when excluding patients with severe TBI. Follow-up had no significant associations with demographics, injury severity, or insurance type. CONCLUSION/CONCLUSIONS:Patient-centered discharge instructions with detailed service referrals increase access to critical follow-up care. Children with TBIs should have follow-up care arranged regardless of injury severity. Larger multicenter studies are needed to validate these findings.

OBJECTIVE:Evaluate real-world effectiveness, patient-reported outcomes (PROs), and safety/tolerability of brivaracetam in patients (≥16 years) with focal-onset seizures currently receiving ≥ 1 antiseizure medication (ASM), and with historical or current use of levetiracetam, lamotrigine, oxcarbazepine, and/or carbamazepine. METHODS:EP0088 was a 12-month, prospective, observational study of brivaracetam in a clinical practice setting in the US. Primary study outcome was brivaracetam retention at 12 months after brivaracetam initiation. Effect of brivaracetam on patients' perceptions of their health was assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) short forms and Seizure-Related Disability Assessment Scale (SERDAS). Safety outcomes included incidence of treatment-emergent adverse events (TEAEs). RESULTS:254 patients (mean age: 44.3 years; median duration of epilepsy: 17.3 years) received ≥ 1 brivaracetam dose (Safety Set; SS). Patients had a median of 3.0 historical and 2.0 concomitant ASMs (SS). For all patients (SS), including those who dropped out with unknown brivaracetam treatment status, 12-month brivaracetam retention was 57.1 % (n = 145/254); in patients with known brivaracetam treatment status (post hoc analysis), 12-month brivaracetam retention was 72.1 % (n = 145/201). Slight improvements in mean PROMIS T-scores, and improvements in mean SERDAS scores, were seen by month 1.5, and generally maintained up to 12 months (Full Analysis Set). 49.6 % of patients reported ≥ 1 TEAE, 38.2 % had drug-related TEAEs, and 16.1 % discontinued due to TEAEs (SS). CONCLUSIONS:Brivaracetam was effective in patients with difficult-to-control focal-onset seizures; as shown by brivaracetam retention at 12 months. Improvements in PROs were seen early. Brivaracetam was well-tolerated and no new safety signals were observed.

Naturalistic electrocorticography (ECoG) data are a rare but essential resource for studying the brain's linguistic capabilities. ECoG offers high temporal resolution suitable for investigating processes at multiple temporal timescales and frequency bands. It also provides broad spatial coverage, often along critical language areas. Here, we share a dataset of nine ECoG participants with 1,330 electrodes listening to a 30-minute audio podcast. The richness of this naturalistic stimulus can be used for various research questions, from auditory perception to narrative integration. In addition to the neural data, we extracted linguistic features of the stimulus ranging from phonetic information to large language model word embeddings. We use these linguistic features in encoding models that relate stimulus properties to neural activity. Finally, we provide detailed tutorials for preprocessing raw data, extracting stimulus features, and running encoding analyses that can serve as a pedagogical resource or a springboard for new research.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes. METHODS:Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45). RESULTS:Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies. DISCUSSION/CONCLUSIONS:The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.

Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.

BACKGROUND:Haploinsufficiency of the bromodomain PHD finger transcription factor (BPTF) gene, essential in chromatin remodeling, leads to a neurodevelopmental disorder characterized by dysmorphic facies, distal limb anomalies, neurological disturbances, epilepsy, and gastrointestinal symptoms. METHODS:Families with BPTF-related neurodevelopmental disorders, with or without gastrointestinal symptoms, were recruited through an international collaboration. Data were collected via questionnaires on demographics, clinical features, genetics, and comorbidities, focusing on cyclical vomiting syndrome (CVS). CVS was diagnosed using criteria from the International Classification of Headache Disorders, 3rd edition (ICHD-3). Genetic variants were analyzed for pathogenicity, and effectiveness of therapies was assessed. RESULTS:We enrolled 15 individuals with likely pathogenic/pathogenic BPTF variants (median age: 8.8 years). Three individuals (20%) were diagnosed with CVS, and an additional four individuals (26.7%) met at least three of the ICHD-3 criteria for CVS. Among these seven individuals, the median age at onset of recurrent vomiting episodes was 3 years. In all seven individuals, recurrent vomiting episodes, typically lasting under an hour, were triggered by poor sleep (50%) and fever (66.7%). Acute therapy (ondansetron or domperidone) was administered in 42.8% of cases, and prophylactic therapy was provided in 57.1% of cases with cyproheptadine, levetiracetam combined with lamotrigine, and domperidone; all therapies were associated with clinical benefit. Episodes disrupted families' daily lives, causing emotional stress (85.7%) and routine disruptions (85.7%). CONCLUSIONS:This study broadens the syndromic phenotype associated with BPTF haploinsufficiency, highlighting CVS as a core feature. The findings raise clinician awareness, guide management, and enhance understanding of this rare condition.

BACKGROUND:Febrile seizures occur in 3%-4% of US children aged six months to five years and are considered benign. However, sudden unexplained death in childhood is associated with 10 times increase in febrile seizures. We assessed the characteristics of children with febrile seizure and sudden death to identify factors that confer increased sudden death risk. METHODS:We conducted a case-control analysis of children with febrile seizure and subsequent sudden death versus living controls from December 2021 to June 2023 through an ∼10-minute anonymous online survey. We enrolled parents of children, living or deceased, whose child had experienced a febrile seizure from age six months to six years. Subjects were excluded if the child had an afebrile seizure or parents had not witnessed a febrile seizure. Demographic characteristics, parasomnias, and febrile seizure features were analyzed. RESULTS:A total of 381 completed surveys were received; 53 (14%) cases of febrile seizure with sudden death and 328 (86%) living controls. Cases reported febrile seizure onset >2 months earlier (P = 0.013) and reported developmental concerns (odds ratio [OR] = 2.32, 95% confidence interval [CI] [1.14, 4.71], P = 0.03), less frequent night awakenings (OR = 0.34, 95% CI [0.18, 0.65], P = 0.001), and less restless sleep (OR = 0.37, 95% CI [0.16, 0.85], P = 0.02). Cases were also less likely to drool (OR = 0.442, 95% CI [0.218, 0.900], P = 0.032) or be unresponsive for more than one minute (OR = 0.45, 95% CI [0.238, 0.854], P = 0.021). CONCLUSIONS:We report novel associations of febrile seizure and sudden death related to age, development, sleep, and observed ictal features. Anonymous survey methodology cannot exclude ascertainment bias and any related potential effect on results. Our findings suggest that impaired arousal mechanisms may increase risk of death in subjects with febrile seizure.

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. Analysis of existing pediatric PSGs from clinical studies could enhance the availability of sleep studies in pediatric patients with NDDs towards a better understanding of mechanisms underlying abnormal development in NDDs. Here, we introduce and characterize a retrospective collection of 1527 clinical pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance compared to a generic stager trained primarily on adults. Using consistent staging across cohorts, we derived a panel of EEG micro-architectural features. This unbiased approach replicated broad trajectories previously described in typically developing sleep architecture. Further, we found sleep architecture disruptions in children with Down's Syndrome (DS) that were consistent across independent cohorts. Finally, we built and evaluated a model to predict age from sleep EEG metrics, which recapitulated our previous findings of younger predicted brain age in children with DS. Altogether, by creating a resource pooled from existing clinical data we expanded the available datasets and computational resources to study sleep in pediatric populations, specifically towards a better understanding of sleep in NDDs. This Retrospective Analysis of Sleep in Pediatric (RASP) cohorts dataset, including staging annotation derived from our automated stager, is deposited at https://sleepdata.org/datasets/rasp.

Sentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. It remains a largely untested assumption that the principles of word production generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where ten patients produced six words in isolation (picture naming) and in sentences (scene description). We trained machine learning classifiers to identify the unique brain activity patterns for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings confirm that words share cortical representations across tasks, but reveal a division of labor within the language network. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in prefrontal cortex, the order in which words were processed depended on the syntactic structure of the sentence. In non-canonical sentences (passives), we further observed a spatial code for syntactic roles, with subjects selectively encoded in inferior frontal gyrus (IFG) and objects selectively encoded in middle frontal gyrus (MFG). We suggest that these complex dynamics of prefrontal cortex may impose a subtle pressure on language evolution, potentially explaining why nearly all the world's languages position subjects before objects.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS:In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS:The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION/CONCLUSIONS:We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.