Faculty Bibliography

BACKGROUND:Increasing reports of long-term symptoms following COVID-19 infection, even among mild cases, necessitates systematic investigation into the prevalence and type of lasting illness. Notably, there is limited data regarding the influence of social determinants of health, like perceived discrimination and economic stress, which may exacerbate COVID-19 health risks. The primary goals of this study are to test the bearing of subjective experiences of discrimination, financial security, and quality of care on illness severity and lasting symptom complaints. METHODS:logistic regressions tested social determinants hypothesized to predict neurological, cognitive, or mood symptoms. RESULTS:70.6% of patients reported presence of one or more lasting symptoms after recovery. Neural systems were especially impacted, and 19.4% and 25.1% of patients reported mood or cognitive/memory complaints, respectively. Path models demonstrated that frequency and stress about experiences of discrimination predicted increased illness severity and increased lasting symptom count, even when adjusting for sociodemographic factors and mental/physical health comorbidities. Notably, this effect was specific to stress related to discrimination, and did not extend to general stress levels. Further, perceived but not objective socioeconomic status (SES) was associated with increased lasting symptom complaints after recovery. Finally, associations between discrimination and illness differed with individual perceptions about quality of medical care. CONCLUSIONS:Lasting symptoms after recovery from COVID-19 are highly prevalent and neural systems are significantly impacted. Importantly, psychosocial factors (perceived discrimination and perceived SES) can exacerbate individual health risk. This study provides actionable directions for improved health outcomes by establishing that sociodemographic risk and medical care influence near and long-ranging health outcomes.

First-person accounts of COVID-19 illness and treatment complement and enrich data derived from electronic medical or public health records. With patient-reported data, it is uniquely possible to ascertain in-depth contextual information as well as behavioral and emotional responses to illness. The Novel Coronavirus Illness Patient Report (NCIPR) dataset includes complete survey responses from 1,592 confirmed COVID-19 patients ages 18 to 98. NCIPR survey questions address symptoms, medical complications, home and hospital treatments, lasting effects, anxiety about illness, employment impacts, quarantine behaviors, vaccine-related behaviors and effects, and illness of other family/household members. Additional questions address financial security, perceived discrimination, pandemic impacts (relationship, social, stress, sleep), health history, and coping strategies. Detailed patient reports of illness, environment, and psychosocial impact, proximal to timing of infection and considerate of demographic variation, is meaningful for understanding pandemic-related public health from the perspective of those that contracted the disease.

Background: Autism spectrum disorder (ASD) is a highly prevalent developmental disorder. There is notable disparity in occurrence rates between males and females, with males being 4.5 times as likely as their female counterparts to be diagnosed with the disease. A major objective for improving functional outcomes in ASD is to isolate biomarkers for earlier detection; an area as yet unexplored is whether biomarkers of future ASD symptomology may be observable in the fetal brain. Here, we focus on the amygdala, which shows sex-differential patterns of development and has been implicated in the neurobiology of ASD.
Method(s): We obtained resting-state MRI data in 109 healthy human fetuses (24-39 weeks) and Brief Infant Toddler Social Emotional Assessment (BITSEA) and Child Behavior Checklist (CBCL) measures at child age 3. The average number of frames obtained after scrubbing high-motion frames was N=169, or 5.6 minutes of resting state data (TR=2) with mean XYZ motion 0.9mm (SD=0.3). Subject-specific amygdala connectivity maps were computed and tested in a full factorial model, that included sex, age at scan, and ASD outcome.
Result(s): ASD outcomes were associated with increased amygdala connectivity to prefrontal and sensorimotor cortices, decreased connectivity to anterior insula and cerebellum, and sex interactions were observed in inferior prefrontal and striatal regions (p<0.005 and k min=25).
Conclusion(s): These observations raise exciting new ideas about the advent of risk and the ontogeny of early sex differences. Further analyses will be conducted to examine sex-differential risk and postnatal environmental effects within a multifactorial liability model framework. Supported By: NIMH R01 MH110793 NIDA R34 DA050287 NIMH R01 MH122447 NARSAD Foundation Keywords: Fetal, Autism, Resting-State, Sex Differences
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BACKGROUND:Prenatal development is a time when the brain is acutely vulnerable to insult and alteration by environmental factors (e.g., toxins, maternal health). One important risk factor is maternal obesity (Body Mass Index > 30). Recent research indicates that high maternal BMI during pregnancy is associated with increased risk for numerous physical health, cognitive, and mental health problems in offspring across the lifespan. It is possible that heightened maternal prenatal BMI influences the developing brain even before birth. METHODS:The present study examines this possibility at the level of macrocircuitry in the human fetal brain. Using a data-driven strategy for parcellating the brain into subnetworks, we test whether MRI functional connectivity within or between fetal neural subnetworks varies with maternal prenatal BMI in 109 fetuses between the ages of 26 and 39weeks. RESULTS:We discovered that strength of connectivity between two subnetworks, left anterior insula/inferior frontal gyrus (aIN/IFG) and bilateral prefrontal cortex (PFC), varied with maternal BMI. At the level of individual aIN/IFG-PFC connections, we observed both increased and decreased between-network connectivity with a tendency for increased within-hemisphere connectivity and reduced cross-hemisphere connectivity in higher BMI pregnancies. Maternal BMI was not associated with global differences in network topography based on network-based statistical analyses. CONCLUSIONS:Overall effects were localized in regions that will later support behavioral regulation and integrative processes, regions commonly associated with obesity-related deficits. By establishing onset in neural differences prior to birth, this study supports a model in which maternal BMI-related risk is associated with fetal connectome-level brain organization with implications for offspring long-term cognitive development and mental health.

Child sleep disorders are increasingly prevalent and understanding early predictors of sleep problems, starting in utero, may meaningfully guide future prevention efforts. Here, we investigated whether prenatal exposure to maternal psychological stress is associated with increased sleep problems in toddlers. We also examined whether fetal brain connectivity has direct or indirect influence on this putative association. Pregnant women underwent fetal resting-state functional connectivity MRI and completed questionnaires on stress, worry, and negative affect. At 3-year follow-up, 64 mothers reported on child sleep problems, and in the subset that have reached 5-year follow-up, actigraphy data (N = 25) has also been obtained. We observe that higher maternal prenatal stress is associated with increased toddler sleep concerns, with actigraphy sleep metrics, and with decreased fetal cerebellar-insular connectivity. Specific mediating effects were not identified for the fetal brain regions examined. The search for underlying mechanisms of the link between maternal prenatal stress and child sleep problems should be continued and extended to other brain areas.

Magnetic resonance imaging, histological, and gene analysis approaches in living and nonliving human fetuses and in prematurely born neonates have provided insight into the staged processes of prenatal brain development. Increased understanding of micro- and macroscale brain network development before birth has spurred interest in understanding the relevance of prenatal brain development to common neurological diseases. Questions abound as to the sensitivity of the intrauterine brain to environmental programming, to windows of plasticity, and to the prenatal origin of disorders of childhood that involve disruptions in large-scale network connectivity. Much of the available literature on human prenatal neural development comes from cross-sectional or case studies that are not able to resolve the longitudinal consequences of individual variation in brain development before birth. This review will 1) detail specific methodologies for studying the human prenatal brain, 2) summarize large-scale human prenatal neural network development, integrating findings from across a variety of experimental approaches, 3) explore the plasticity of the early developing brain as well as potential sex differences in prenatal susceptibility, and 4) evaluate opportunities to link specific prenatal brain developmental processes to the forms of aberrant neural connectivity that underlie common neurological disorders of childhood.

Since the first neurodevelopmental models that sought to explain the influx of risky behaviors during adolescence were proposed, there have been a number of revisions, variations and criticisms. Despite providing a strong multi-disciplinary heuristic to explain the development of risk behavior, extant models have not yet reliably isolated neural systems that underlie risk behaviors in adolescence. To address this gap, we screened 2017 adolescents from an ongoing longitudinal study that assessed 15-health risk behaviors, targeting 104 adolescents (Age Range: 17-to-21.4), characterized as high-or-average/low risk-taking. Participants completed the Monetary Incentive Delay (MID) fMRI task, examining reward anticipation to "big win" versus "neutral". We examined neural response variation associated with both baseline and longitudinal (multi-wave) risk classifications. Analyses included examination of a priori regions of interest (ROIs); and exploratory non-parametric, whole-brain analyses. Hypothesis-driven ROI analysis revealed no significant differences between high- and average/low-risk profiles using either baseline or multi-wave classification. Results of whole-brain analyses differed according to whether risk assessment was based on baseline or multi-wave data. Despite significant mean-level task activation, these results do not generalize prior neural substrates implicated in reward anticipation and adolescent risk-taking. Further, these data indicate that whole-brain differences may depend on how risk-behavior profiles are defined.

Childhood trauma is associated with many long-term negative outcomes, and is not limited to the individual experiencing the trauma, but extends to subsequent generations. However, mechanisms underlying the association between maternal childhood trauma and child psychopathology are not well understood. Here, we targeted frontal alpha asymmetry (FAA) as a potential underlying factor of the relationship between maternal childhood trauma and child behavioral problems. Electroencephalography (EEG) was recorded from (N = 45) children (Mean age = 57.9 months, SD = 3.13) during an eyes-closed paradigm in order to evaluate FAA. Mothers reported on their childhood trauma experiences using the Childhood Trauma Questionnaire (CTQ), and on their child's behavior using the child behavior checklist (CBCL). We found that maternal childhood trauma significantly predicted child total, internalizing, and externalizing behavior at age 5 years. We also observed a role for FAA such that it acted as a moderator, but not mediator, for behavioral problems. We found that children with relative more right/less left frontal activity were more at risk to develop behavioral problems when their mother had been exposed to trauma in her childhood. These results indicate that child frontal asymmetry may serve as a susceptibility marker for child behavioral problems.