Faculty Bibliography

INTRODUCTION/UNASSIGNED:Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS/UNASSIGNED:We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity. RESULTS/UNASSIGNED:The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. CONCLUSIONS/UNASSIGNED:These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

Toddler visual attention development correlates with subsequent language, cognitive, and social developmental outcomes. This study investigates the association of maternal trauma on toddler looking behaviors in 39 mother-child dyads from the Western Cape Province, South Africa. At 15 months postpartum, maternal trauma was assessed using the Life Events Checklist and toddler multisensory attention skills were measured using the Multisensory Attention Assessment Protocol (MAAP) during eye-tracking. We used two-way mixed ANOVA to analyze the association of maternal trauma and MAAP condition with attention maintenance, intersensory matching, and attention shifting. This study provides support for the MAAP's reliability with a sample of 15-month-old toddlers from a low-income setting. We observed a significant interaction between MAAP condition and maternal trauma group on attention maintenance, but pairwise comparisons did not meet the threshold for statistical significance. In a stratified analysis, toddlers of mothers in the low trauma exposure group demonstrated significant differences in attention maintenance, intersensory matching, and attention shifting by condition. Unexpectedly, toddlers of mothers in the high trauma exposure group did not exhibit significant differences in these attentional skills, potentially indicating attentional adaptations. Further research is needed to explore the relationship between the intergenerational transmission of trauma on infant and toddler multisensory attention skills in low-income settings.

BACKGROUND/UNASSIGNED:Magnetic resonance imaging (MRI) and electroencephalography (EEG) are valuable tools for studying neuroanatomical and electrophysiological features of early brain development. Studies implementing neuroimaging tools in low- and middle-income countries are still rare, and there is limited data on the acceptability of such tools among rural communities. The present study explores the perceptions, feasibility, and acceptability of introducing MRI and EEG for child development research in the rural Amhara region of Ethiopia. METHODS/UNASSIGNED:= 16). A semi-structured interview included four themes: (1) Baseline imaging knowledge, (2) Perceptions of MRI and EEG, (3) Facilitators and barriers to acceptability of MRI and EEG, and (4) Recommendations to improve MRI and EEG uptake. Interviews were conducted in Amharic, the local language. All interviews were transcribed verbatim to Amharic, translated into English, and double-coded. We used thematic analysis to organize data according to predefined and emerging themes. RESULTS/UNASSIGNED:Knowledge of MRI and EEG was limited, and none of the community members had previous experiences with either technology. Broadly, participants responded positively to our introductory videos showing MRI and EEG acquisition and expressed high levels of acceptability. However, participants reported concerns about possible harms related to radiation, electrical shock, and injury from MRI/EEG procedures. Those with lesser education were identified to be less accepting of MRI/EEG. In addition, several mothers expressed that consent from their husbands was necessary for their child's participation in neurodevelopmental research. Potential logistical barriers identified included transportation challenges to the neuroimaging study sites, especially for rural-dwelling families. Creating awareness, using explanatory videos, and engaging community members and clinicians were recommended to facilitate acceptance of EEG and MRI. CONCLUSION/UNASSIGNED:In this formative study, MRI and EEG were viewed as acceptable methods for assessing child neurodevelopment in rural areas of Ethiopia. Community members' and clinicians' views were impacted largely by social, religious, educational, and logistical aspects. Concerns related to MRI radiation, electrical shock, and injuries from EEG can be addressed through awareness creation and education. Engaging community leaders and healthcare providers is key to improving acceptability.

BACKGROUND/UNASSIGNED:Essential tremor (ET) is characterized by often disabling action tremors. No pharmacological agent has been developed specifically for symptomatic treatment. Anecdotal reports describe tremor improvement with cannabis, but no evidence exists to support these claims. We conducted a phase Ib/II double-blind, placebo-controlled, crossover pilot trial in participants with ET to investigate tolerability, safety, and efficacy of Tilray TN-CT120 LM, an oral pharmaceutical-grade formulation containing tetrahydrocannabinol (THC) 5 mg and cannabidiol (CBD) 100 mg. Our objectives were to determine if short-term THC/CBD exposure improved tremor amplitude and was tolerated. METHODS/UNASSIGNED:Participants with ET were randomized (1:1) to receive either TN-CT120 LM or placebo. Dose titration, driven by tolerability, was attempted every 2-3 days to three capsules daily maximum. Participants remained on the highest tolerated dose for two weeks before returning to complete assessments. After completing the first arm, participants titrated off the agent, underwent a three-week washout, and then returned for the same procedures with the alternate compound. The primary endpoint was tremor amplitude change from baseline using digital spiral assessment. Secondary endpoints explored safety and tolerability. RESULTS/UNASSIGNED:Among thirteen participants screened, seven were eligible and enrolled. Five completed all visits; one withdrew following a serious adverse event, and another did not tolerate the lowest dose. Intent-to-treat analyses performed for six participants did not reveal significant effects on primary or secondary endpoints. CONCLUSIONS/UNASSIGNED:This pilot trial did not detect any signals of efficacy of THC/CBD in ET. Although preliminary due to the small sample size, our data do not support anecdotal reports of cannabinoid effectiveness for ET. HIGHLIGHTS/UNASSIGNED:This double-blind, randomized, placebo-controlled efficacy and tolerability pilot trial did not detect any signals of efficacy of oral cannabidiol and tetrahydrocannabinol in reducing essential tremor amplitude using either digital outcome measures or clinical rating scales. The oral cannabinoids were well-tolerated by most (five out of seven) participants.

Allostatic load provides a valuable framework for examining how cumulative stress impacts multiple physiological systems simultaneously, making it a powerful tool for understanding the mechanisms through which stress contributes to adverse pregnancy outcomes. This multisystem perspective is especially important during pregnancy, a period characterized by heightened vulnerability to stress and significant physiological changes that can themselves contribute to allostatic load. Although the impact of allostatic load during pregnancy is well documented, the mechanisms and moderators involved by trimester remain unclear, particularly given wide variation in social, cultural, and structural determinants of maternal health worldwide. In this review, we discuss the progress that has been made over the past two decades in studying prenatal allostatic load and describe the clinical implications of this by highlighting sensitive periods of interest throughout gestation. Despite these advances, key questions remain regarding the intergenerational transmission of risk, the specificity of findings to the pregnancy period, and the role of factors that often accompany elevated allostatic load, such as poor sleep, limited social support, systemic inequities, and comorbid mental or physical health conditions, which may manifest differently across global contexts. Most existing studies have been conducted in high-income settings, yet the burden of adverse pregnancy outcomes is greatest in low- and middle-income countries, where structural, environmental, and social stressors are pervasive. Expanding this framework to include diverse global contexts is essential for understanding how social inequities and chronic stressors shape maternal physiology worldwide. We discuss these issues and offer directions for future research, including the goal of developing a standardized metric for measuring allostatic load - one that we believe will advance the field's understanding of how prenatal allostatic load markers by trimester relate to maternal and infant outcomes.

This pilot study aimed to understand the moderating role of context processing (i.e. encoding and memorizing) when mothers are confronted with threatening stimuli and undergo physiologic monitoring in order to understand a possible mechanism favoring intergenerational transmission of posttraumatic stress. Thirty-one mothers (M age = 33.87 years, SD = 4.14) and their toddlers (M age = 22.66 months, SD = 7.01) participated in the study. Mothers reported adverse life events (ALE), their current posttraumatic stress symptoms (PTSS), as well as regulatory problems of their toddler. Mothers performed a context-encoding and -memory (CEM) task including emotional facial expressions (especially angry faces considered as threatening stimuli) embedded into photo-backgrounds, after which they were asked to recognize both the faces and contexts. Maternal heart rate variability (HRV) was measured during resting state. Maternal current PTSS, but not ALE, had impact on child dysregulation only for mothers with poor context processing (β = 0.014, p = .017). Baseline HRV was negatively correlated with the recognition of contexts previously associated with angry faces (ρ = -.53, p = .006), and marginally with the recognition of angry faces (ρ = -.37, p = .059). This pilot study identifies psychophysiological markers (i.e. CEM, HRV) that may influence the intergenerational transmission of posttraumatic stress. This may open new avenues in early identification and intervention with traumatized mothers and their toddlers.

BACKGROUND/UNASSIGNED:Attention Deficit Hyperactivity Disorder (ADHD) among children younger than 6 years is quite impairing, nearly half these youth with ADHD experience school exclusion from mainstream preschool classes due to related emotional and behavioral outbursts. While a range of behavior rating scales and subjective measures are used to assess these youth, objective methods of assessment and prediction derived from technology have potential to improve therapeutic and academic interventions outcomes for these youths. We hypothesized that biometric sensors would provide objective, highly sensitive and specific information regarding the physiological status of children prior to an impulsive outburst and could be feasibly implemented using a wearable device in the special education classroom. METHODS/UNASSIGNED: = 5 youth from the first grade) of a specialized therapeutic day-school for youth with ADHD and other psychiatric and developmental disorders to examine feasibility of obtaining continuous physiological data associated with behavioral and emotional outbursts through smartwatch use. Children wore a sensor watch during their daily classroom activities for two weeks and trained observers collected data using behavioral logs. Using Ecological Momentary Assessment methodology, to examine correlations between objective sensor data and observer observation. Data collected from parents regarding prior night's sleep was also examined. RESULTS/UNASSIGNED:All participants completed the study. With a few tolerability or palatability issues. Associations were found between physiological and behavioral/questionnaire data. The methodology holds promise for reliably measuring behavioral and emotional outbursts in young children. CONCLUSIONS/UNASSIGNED:among severely dysregulated pre-school aged youth throughout a full school day. This study established the feasibility of utilizing sensor derived physiological data as an objective biomarker of ADHD within the special education therapeutic classroom. Further research with larger samples is required to build a more robust and personalized AI predictive model.

Preterm birth poses a major public health challenge, with significant and heterogeneous developmental impacts. Latent profile analysis was applied to the National Institutes of Health Toolbox performance of 1891 healthy prematurely born children from the Adolescent Brain and Cognitive Development study (970 boys, 921 girls; 10.00 ± 0.61 years; 1.3% Asian, 13.7% Black, 17.5% Hispanic, 57.0% White, 10.4% Other). Three distinct neurocognitive profiles emerged: consistently performing above the norm (19.7%), mixed scores (41.0%), and consistently performing below the norm (39.3%). These profiles were associated with lasting cognitive, neural, behavioral, and academic differences. These findings underscore the importance of recognizing diverse developmental trajectories in prematurely born children, advocating for personalized diagnosis and intervention to enhance care strategies and long-term outcomes for this heterogeneous population.