Faculty Bibliography

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2^-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.

Interoceptive accuracy, the ability to correctly perceive internal body signals such as heartbeats, has been empirically and theoretically linked to stress. However, issues with the measurement of both interoceptive accuracy and stress have led to lack of clarity regarding this relationship. This systematic review and meta-analysis aimed to clarify whether interoceptive accuracy is associated with different facets of stress, including - physical, cognitive and self-reported stressors and the physiological stress response. A systematic search identified 2014 abstracts. Twenty-eight authors were contacted to request data for eligible studies, which yielded a final sample of 20 studies. Results revealed a positive association between heartbeat counting task (HCT) performance and acute physical stressors, and a negative association between HCT performance and physiological stress responses. No significant relationships were observed between stress and interoceptive accuracy assessed by the heartbeat discrimination task. While these findings offer tentative support for stress-interoceptive accuracy associations, they must be interpreted with caution given substantial heterogeneity in stress measures, limited use of interoception tasks beyond the HCT, and ongoing concerns regarding task validity. Implications for future research and methodological recommendations are discussed.

BACKGROUND/UNASSIGNED:Complementary and integrative health (CIH) services enhance physiological and psychological wellbeing, while potentially reducing medical costs. Despite these benefits, use of inpatient CIH services remains poorly characterized, impeding efforts to develop equitable and effective healthcare. OBJECTIVE/UNASSIGNED:This retrospective case-control study examined characteristics of patients likely to receive CIH referrals and consults. METHOD/UNASSIGNED:Electronic health records were analyzed from patients hospitalized at a large metropolitan academic medical center from September 2022 to February 2024. RESULTS/UNASSIGNED:values <0.001). Among those referred, 72% received at least one CIH consult, with lower odds of completing a consult for male patients. CONCLUSION/UNASSIGNED:Disparities underscore the need for equitable CIH services access in healthcare systems. Future research will test how to broaden services to male patients, those with non-English language preference, and less medical complexity, to ensure greater benefit from holistic healthcare.

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.

The development of racial identity in Black boys is a critical aspect of their overall mental health and well-being. This article explores the unique societal and cultural challenges faced by Black boys in the context of identity formation and mental health outcomes. It critiques the one size fits all approach in clinical settings and advocates for an equitably tailored approach that emphasizes cultural competence, cultural responsiveness, and the importance of understanding the lived experiences of Black youth. By integrating these elements into clinical practice, mental health professionals can provide more effective and compassionate care promoting their mental health and resilience.

Adverse childhood experiences (ACE) are common risk factors for many psychiatric disorders. Their underlying biological mechanisms may involve oxidative stress (OS), which has deleterious effects on cells through its own actions and through its interactions with inflammation and the stress axes, particularly in the brain. In order to assess the role of OS in the association between ACE and psychopathology, we performed a systematic review of animal and human research (PROSPERO CRD42023378418 and CRD42022378376), funded by the Swiss National Science Foundation (grant number 204033). PubMed, Web of Science, PsycInfo, Scopus and Embase were searched from inception until 31 October 2024. We included 130 studies involving animal models exposed to stressor-paradigms recognized as ACE analogs before they reached adulthood, or human participants with a history of ACE and assessment of psychopathology, and reporting outcomes on OS-related markers. Animal studies overall show increased OS and psychopathology after stress, thus supporting the hypothesis that OS mediates the relationship between ACE and psychopathology. Human studies are heterogeneous and less conclusive. Although the association between ACE exposure and OS, in animals and humans, was likely affected by the nature, the timing, and the intensity of the exposure, these parameters were only evaluated in a small fraction of studies. Similarly, though some studies hinted at sex differences in the OS response to ACE in animals, the majority of studies did not address this issue. Further research, using longitudinal designs and more thorough examination of ACE history in participants, is therefore needed.

Narrative is an important communication skill for sharing personal experiences and connecting with others. Narrative skills are often impacted in autism spectrum disorder (ASD) and have important consequences for social interactions and relationships. Subtle differences in narrative have also been reported among first-degree relatives of autistic individuals, suggesting that narrative may also be an etiologically important language-related skill that is influenced by genes associated with ASD. This study examined narrative ability and related visual attention during narration in ASD and first-degree relatives of individuals with ASD (siblings and parents) to understand how narrative and related attentional styles may be variably impacted across the spectrum of ASD genetic influence. Participants included 56 autistic individuals, 42 siblings of autistic individuals, 49 controls, 161 parents of autistic individuals, and 61 parent controls. Narratives were elicited using a wordless picture book presented on an eye tracker to record concurrent gaze. Findings revealed parallel patterns of narrative differences among ASD and sibling groups in the use of causal language to connect story elements and the use of cognitive and affective language. More subtle differences within the domain of causal language were evident in ASD parents. Parallel patterns in the ASD and sibling groups were also found for gaze during narration. Findings implicate causal language as a critical narrative skill that is impacted in ASD and may be reflective of ASD genetic influence in relatives. Gaze patterns during narration suggest similar attentional mechanisms associated with narrative among ASD families.

INTRODUCTION/UNASSIGNED:Assessing sustained attention presents methodological challenges, particularly when spanning diverse populations whose baseline sensorimotor functioning may vary significantly. METHODS/UNASSIGNED:This study introduces the Continuous Performance Critical Stability Task (cpCST), a novel paradigm combining high-density sampling of behavior (30 Hz), individualized calibration, and fixed-difficulty assessment to measure attentional control. In a sample of 166 adults (ages 18-76), we evaluated the psychometric properties of the cpCST's instantaneous reaction time (iRT) metric derived through dynamic time warping. RESULTS/UNASSIGNED:The cpCST demonstrated exceptional reliability (bootstrap split-half r = 0.999) and predictive validity for cognitive performance (flanker and Woodcock-Johnson) and cardiorespiratory fitness (VO2submax). The task achieved high temporal efficiency, with just 2 min of data correlating at r = 0.94 with full-task performance, outperforming a standard arrow-based flanker task. The cpCST's individualized calibration effectively isolated attentional control processes from baseline sensorimotor function, eliminating age-related slowing effects typically observed in reaction time tasks. DISCUSSION/UNASSIGNED:This approach offers methodological advantages for lifespan studies, clinical populations, integration with neurophysiological measures, and computational modeling approaches while addressing limitations of existing attention assessment paradigms.

INTRODUCTION/BACKGROUND:The impact of maternal SARS-CoV-2 infection on fetal brain development during pregnancy remains unclear. Prior research has associated other antenatal infections with adverse neurodevelopmental outcomes in offspring. OBJECTIVE:To compare neurodevelopmental outcomes in infants born to mothers infected with SARS-CoV-2 during pregnancy (COVID+) to infants without congenital exposure (COVID-). METHODS:This study included 77 COVID+ infants and 157 COVID- infants assessed at 6 and/or 12 months. Outcomes were based on maternal self-report, observed infant behavior and brain fMRI. RESULTS:Overall, COVID+ and COVID- infant groups showed no significant differences across a range of neurobehavioral measures. However, analyses not adjusted for multiple comparisons revealed differences: fewer night awakenings at 6 (t(154) = 2.24, p < 0.03) and 12 months (t(107) = 1.94, p < 0.05), and reduced duration of orienting at 12 months (t(55.38) = 2.15, p < 0.04) in COVID+ infants. Neural differences were noted in posterior-anterior midline, insular-frontal, insular-posterior cingulate, and frontal-cingulate regions at an uncorrected threshold of p < 0.01. CONCLUSION/CONCLUSIONS:This study of multi-level infant development suggests that infants born to mothers infected with COVID during pregnancy are not experiencing harmful effects of that exposure. IMPACT/CONCLUSIONS:This study contributes comprehensive data on infant neurodevelopmental outcomes following prenatal SARS-CoV-2 exposure, evaluating a wide range of behavioral and neural measures to address gaps in previous research. Findings suggest that congenital exposure to SARS-CoV-2 does not result in significant neurodevelopmental impairments in infants, offering reassurance amidst concerns about potential long-term effects of maternal prenatal COVID-19 infection. Results indicate that any observed differences, such as fewer night awakenings and functional neural connectivity patterns, may reflect a more mature developmental profile in the exposed group. Continued longitudinal research is necessary to understand behaviorally relevant and lasting neurodevelopmental effects of prenatal SARS-CoV-2 exposure.