Faculty Bibliography

In animal models that mimic human third-trimester fetal development, ethanol causes substantial cellular apoptosis in the brain, but for most brain structures the extent of permanent neuron loss that persists into adulthood is unknown. We injected ethanol into C57BL/6J mouse pups at postnatal day 7 (P7) to model human late-gestation ethanol toxicity, and then used stereological methods to investigate adult cell numbers in several subcortical neurotransmitter systems that project extensively in the forebrain to regulate arousal states. Ethanol treatment caused especially large reductions (34-42%) in the cholinergic cells of the basal forebrain, including cholinergic cells in the medial septal/vertical diagonal band (Ch1/Ch2) and in the horizontal diagonal band/substantia innominata/nucleus basalis (Ch3/Ch4) nuclei. Cell loss was also present in non-cholinergic basal forebrain cells, as demonstrated by 34% reduction of parvalbumin immunolabeled GABA cells and 25% reduction of total Nissl-stained neurons in the Ch1/Ch2 region. In contrast, cholinergic cells in the striatum were reduced only 12% by ethanol, and those of the brainstem pedunculopontine/lateral dorsal tegmental nuclei (Ch5/Ch6) were not significantly reduced. Similarly, ethanol did not significantly reduce dopamine cells of the ventral tegmental area/substantia nigra or serotonin cells in the in the dorsal raphe nucleus. Orexin (hypocretin) cells in the hypothalamus showed a modest reduction (14%). Our findings indicate that the basal forebrain is especially vulnerable to alcohol exposure in the late gestational period. Reduction of cholinergic and GABAergic projection neurons from the basal forebrain that regulate forebrain arousal may contribute to the behavioral and cognitive deficits associated with neonatal ethanol exposure.

Nearly four decades ago, Unclaimed Children documented the gaps in the United States between mental health programs and caregivers' perspectives about those services for their children. This absence of attention to parent or caregiver perspectives, including their satisfaction with these services, was a key finding of the report, which detailed system failure in caring for youth with mental health needs. Since then, the focus on caregiver satisfaction with children's mental health services has been largely overlooked in research, and when examined has been mostly included as an indicator of the feasibility of program implementation. In striking contrast, overall healthcare system reforms have highlighted the importance of improving consumer's direct experience of care. However, caregiver satisfaction remains largely disconnected to these overall health system reforms, even as reforms focus increasingly on value-based, coordinated and integrated care. In this paper, we review literature from 2010 to 2020, revisit the measurement of caregiver satisfaction, identify how and when it is being measured, and delineate a research agenda to both realign it with health system improvements, refine its focus on expectancies and appropriateness, and root it more firmly in the principles of user experience (UX) and human-centered design (HCD).

OBJECTIVE:Comorbidity and subdiagnostic symptoms are understudied for sleep and circadian problems. We evaluated 1) impairment associated with (a) number of sleep and circadian problems and (b) diagnostic threshold (full diagnosis vs. subdiagnostic symptoms), and 2) Transdiagnostic Sleep and Circadian Intervention (TranS-C) outcomes for participants with specific sleep and circadian problems. METHOD/METHODS:Community participants (N = 121) with serious mental illness and sleep and circadian problem(s) were randomized to receive TranS-C plus usual care (TranS-C + UC) or usual care plus delayed TranS-C (UC-DT). Overall impairment, psychiatric symptoms, and sleep and circadian dysfunction were assessed at pre-treatment, post-treatment, and 6-month follow-up. RESULTS: = 0.06-0.15). Diagnostic threshold was not associated with baseline functioning (ps > 0.05). TranS-C + UC versus UC-DT was associated with psychosocial and sleep and circadian improvements for specific sleep and circadian problems (insomnia, hypersomnia, parasomnias, periodic limb movement/restless leg syndrome, circadian rhythm disorders), though improvements varied by problem. TranS-C + UC outcomes were not moderated by number of sleep and circadian problems (ps > 0.05). CONCLUSION/CONCLUSIONS:Higher numbers of sleep and circadian problems, not diagnostic threshold, were associated with greater impairment. Transdiagnostic utility of TranS-C + UC was supported.

Apathy is a common and impairing sequela of traumatic brain injury (TBI). Yet, little is known about the neural mechanisms determining in which patients apathy does or does not develop post-TBI. We aimed to elucidate the impact of TBI on motivational neural circuits and how this shapes apathy over the course of TBI recovery. Resting-state functional magnetic resonance imaging data were collected in patients with subacute mild TBI (n = 44), chronic mild-to-moderate TBI (n = 26), and nonbrain-injured control participants (CTRL; n = 28). We measured ventromedial prefrontal cortex (vmPFC) functional connectivity (FC) as a function of apathy, using an a priori vmPFC seed adopted from a motivated decision-making study in an independent TBI study cohort. Patients reported apathy using a well-validated tool for assaying apathy in TBI. The vmPFC-to-wholebrain FC was contrasted between groups, and we fit regression models with apathy predicting vmPFC FC. Subacute and chronic TBI caused increased apathy relative to CTRL, replicating previous work suggesting that apathy has an enduring impact in TBI. The vmPFC was functionally connected to the canonical default network, and this architecture did not differ between subacute TBI, chronic TBI, and CTRL groups. Critically, in TBI, increased apathy scores predicted decreased vmPFC-dorsal anterior cingulate cortex (dACC) FC. Last, we subdivided the TBI group based on patients above versus below the threshold for "clinically significant apathy," finding that TBI patients with clinically significant apathy demonstrated comparable vmPFC-dACC FC to CTRLs, whereas TBI patients with subthreshold apathy scores demonstrated vmPFC-dACC hyperconnectivity relative to both CTRLs and patients with clinically significant apathy. Post-TBI vmPFC-dACC hyperconnectivity may represent an adaptive compensatory response, helping to maintain motivation and enabling resilience to the development of apathy after neurotrauma. Given the role of vmPFC-dACC circuits in value-based decision making, rehabilitation strategies designed to improve this ability may help to reduce apathy and improve functional outcomes in TBI.

The objective of the current study is to determine robust transdiagnostic brain structural markers for compulsivity by capitalizing on the increasing number of case-control studies examining gray matter volume (GMV) alterations in substance use disorders (SUD) and obsessive-compulsive disorder (OCD). Voxel-based meta-analysis within the individual disorders and conjunction analysis were employed to reveal common GMV alterations between SUDs and OCD. Meta-analytic coordinates and signed brain volumetric maps determining directed (reduced/increased) GMV alterations between the disorder groups and controls served as the primary outcome. The separate meta-analysis demonstrated that SUD and OCD patients exhibited widespread GMV reductions in frontocortical regions including prefrontal, cingulate, and insular. Conjunction analysis revealed that the left inferior frontal gyrus (IFG) consistently exhibited decreased GMV across all disorders. Functional characterization suggests that the IFG represents a core hub in the cognitive control network and exhibits bidirectional (Granger) causal interactions with the striatum. Only OCD showed increased GMV in the dorsal striatum with higher changes being associated with more severe OCD symptomatology. Together the findings demonstrate robustly decreased GMV across the disorders in the left IFG, suggesting a transdiagnostic brain structural marker. The functional characterization as a key hub in the cognitive control network and casual interactions with the striatum suggest that deficits in inhibitory control mechanisms may promote compulsivity and loss of control that characterize both disorders.

OBJECTIVE/UNASSIGNED:Understanding public policy makers' priorities for addressing youth substance use and the factors that influence these priorities can inform the dissemination and implementation of strategies that promote evidence-based decision making. This study characterized the priorities of policy makers in substance use agencies of U.S. states and counties for addressing youth substance use, the factors that influenced these priorities, and the differences in priorities and influences between state and county policy makers. METHODS/UNASSIGNED:In 2020, a total of 122 substance use agency policy makers from 35 states completed a Web-based survey (response rate=22%). Respondents rated the priority of 14 issues related to youth substance use and the extent to which nine factors influenced these priorities. Data were analyzed as dichotomous and continuous variables and for state and county policy makers together and separately. RESULTS/UNASSIGNED:The highest priorities for youth substance use were social determinants of substance use (87%), adverse childhood experiences and childhood trauma (85%), and increasing access to school-based substance use programs (82%). The lowest priorities were increasing access to naloxone for youths (49%), increasing access to medications for opioid use disorder among youths (49%), and deimplementing non-evidence-based youth substance use programs (41%). The factors that most influenced priorities were budget issues (80%) and state legislature (69%), federal (67%), and governor priorities (65%). Issues related to program implementation and deimplementation were significantly higher priorities for state than for county policy makers. CONCLUSIONS/UNASSIGNED:These findings can inform the tailoring of dissemination and implementation strategies to account for the inner- and outer-setting contexts of substance use agencies.

OBJECTIVE:Children with attention-deficit/hyperactivity disorder (ADHD) are at risk for accidental injuries, but little is known about age-related changes in early childhood. We predicted that ADHD would be associated with greater frequency and volume of accidental injuries. We explored associations between ADHD and injury types and examined age-related changes within the preschool period. METHODS:Retrospective chart review data of 21,520 preschool children with accidental injury visits within a large pediatric hospital network were examined. We compared children with ADHD (n = 524) and without ADHD (n = 20,996) on number of injury visits by age, total number of injury visits, injury volume, and injury type. RESULTS:Children with ADHD averaged fewer injury visits at age 3 and 90% more visits at age 6. Children with ADHD had injury visits in more years during the 3-6 age. There were no differences in injury volumes. Among patients with an injury visit at age 3, children with ADHD had 6 times the probability of a subsequent visit at age 6. At age 3, children with ADHD were estimated to have 50% fewer injury visits than children without ADHD, but by age 6, children with ADHD had an estimated 74% more injury visits than children without ADHD. Risk for several injury types for children with ADHD exceeded that for patients without ADHD by at least 50%. CONCLUSIONS:Early identification and treatment of preschool ADHD following accidental injury may prevent subsequent injuries. Clinical implications and future directions are discussed with emphasis on the maintenance of parental monitoring into the older preschool years.

Increasing evidence supports a link between maternal prenatal cannabis use and altered neural and physiological development of the child. However, whether cannabis use relates to altered human brain development prior to birth, and specifically, whether maternal prenatal cannabis use relates to connectivity of fetal functional brain systems, remains an open question. The major objective of this study was to identify whether maternal prenatal cannabis exposure (PCE) is associated with variation in human brain hippocampal functional connectivity prior to birth. Prenatal drug toxicology and fetal fMRI data were available in a sample of 115 fetuses [43 % female; mean age 32.2 weeks (SD = 4.3)]. Voxelwise hippocampal connectivity analysis in a subset of age and sex-matched fetuses revealed that PCE was associated with alterations in fetal dorsolateral, medial and superior frontal, insula, anterior temporal, and posterior cingulate connectivity. Classification of group differences by age 5 outcomes suggest that compared to the non-PCE group, the PCE group is more likely to have increased connectivity to regions associated with less favorable outcomes and to have decreased connectivity to regions associated with more favorable outcomes. This is preliminary evidence that altered fetal neural connectome may contribute to neurobehavioral vulnerability observed in children exposed to cannabis in utero.