Faculty Bibliography

Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Ts65Dn mice had unique MSN BFCN transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamatergic, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate this interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.

Background/UNASSIGNED:The Head Start treatment protocols have focused on curing young children with brain tumors while avoiding or delaying radiotherapy through using a combination of high-dose, marrow-ablative chemotherapy and autologous hematopoietic cell transplantation (AuHCT). Late effects data from treatment on the Head Start II (HS II) protocol have previously been published for short-term follow-up (STF) at a mean of 39.7 months post-diagnosis. The current study examines long-term follow-up (LTF) outcomes from the same cohort. Methods/UNASSIGNED:Eighteen HS II patients diagnosed with malignant brain tumors <10 years of age at diagnosis completed a neurocognitive battery and parents completed psychological questionnaires at a mean of 104.7 months' post-diagnosis. Results/UNASSIGNED:There was no significant change in Full Scale IQ at LTF compared to baseline or STF. Similarly, most domains had no significant change from STF, including verbal IQ, performance IQ, academics, receptive language, learning/memory, visual-motor integration, and externalizing behaviors. Internalizing behaviors increased slightly at LTF. Clinically, most domains were within the average range, except for low average mathematics and receptive language. Additionally, performance did not significantly differ by age at diagnosis or time since diagnosis. Of note, children treated with high-dose methotrexate for disseminated disease or atypical teratoid/rhabdoid tumor displayed worse neurocognitive outcomes. Conclusions/UNASSIGNED:These results extend prior findings of relative stability in intellectual functioning for a LTF period. Ultimately, this study supports that treatment strategies for avoiding or delaying radiotherapy using high-dose, marrow-ablative chemotherapy and AuHCT may decrease the risk of neurocognitive and social-emotional declines in young pediatric brain tumor survivors.

OBJECTIVE:Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS:We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS:There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION/CONCLUSIONS:Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Objective/UNASSIGNED:The study examined whether mother-child reciprocity across increasingly challenging contexts moderated the association between household chaos and early childhood behavior problems. Background/UNASSIGNED:Living in a chaotic household is associated with behavioral dysregulation in childhood. An important goal in discordant household contexts is to establish positive aspects of relationships that are associated with more favorable developmental outcomes. Method/UNASSIGNED:The study analyzed data from 127 mother-child dyads participating in the 3-year visit in a study of primarily low-income, African American/Black families in urban areas. Dyads were videotaped during three successive, increasingly challenging, interaction tasks. Multiple regression analyses examined household chaos, dyadic reciprocity, and the interplay of those as predictors of behavior problems. Results/UNASSIGNED:Greater household chaos was associated with more internalizing and externalizing behavior problems. Moderation analyses indicated that dyadic reciprocity during two challenging interaction tasks (but not during free play) attenuated the association between household chaos and internalizing problems. Conclusions/UNASSIGNED:Household chaos was not associated with internalizing problems among dyads who had a connected, supportive relationship in more challenging interactive contexts. Implications/UNASSIGNED:Improving shared positive affect and dyadic harmony in the parent-child relationship may help protect young children against the negative influence of chaotic contexts.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

Observation is a powerful way to learn efficient actions from others. However, the role of observers' motor skill in assessing efficiency of others is unknown. Preschoolers are notoriously poor at performing multi-step actions like grasping the handle of a tool. Preschoolers (N = 22) and adults (N = 22) watched video-recorded actors perform efficient and inefficient tool use. Eye tracking showed that preschoolers and adults looked equally long at the videos, but adults looked longer than children at how actors grasped the tool. Deep learning analyses of participants' eye gaze distinguished efficient from inefficient grasps for adults, but not for children. Moreover, only adults showed differential action-related pupil dilation and neural activity (suppressed oscillation power in the mu frequency) while observing efficient vs. inefficient grasps. Thus, children observe multi-step actions without "seeing" whether the initial step is efficient. Findings suggest that observer's own motor efficiency determines whether they can perceive action efficiency in others.

BACKGROUND:The impact of the 2019 coronavirus pandemic on the&nbsp;mental health of millions worldwide has been well documented, but its&nbsp;impact on prevention and treatment of mental and behavioral health&nbsp;conditions is less clear. The COVID-19 pandemic also created numerous&nbsp;challenges and opportunities to implement health care policies and&nbsp;programs under conditions that are fundamentally different from what&nbsp;has been considered to be usual care.&nbsp;Methods: We conducted a qualitative study to determine the impact of the COVID-19 pandemic on implementation of evidence-based policy and&nbsp;practice by State Mental Health Authorities (SMHA) for prevention and treatment of mental health problems in children and adolescents.&nbsp;Semi-structured interviews were conducted with 29 SMHA&nbsp;representatives of 21 randomly selected states stratified by&nbsp;coronavirus positivity rate and rate of unmet services need. Data&nbsp;analysis with SMHA stakeholders used procedures embedded in the Rapid&nbsp;Assessment Procedure-Informed Community Ethnography methodology.&nbsp;Results: The need for services increased during the pandemic due&nbsp;primarily to family stress and separation from peers. States&nbsp;reporting an increase in demand had high coronavirus positivity and&nbsp;high unmet services need. The greatest impacts were reduced&nbsp;out-of-home services and increased use of telehealth. Barriers to&nbsp;telehealth services included limited access to internet and&nbsp;technology, family preference for face-to-face services, lack of&nbsp;privacy, difficulty using with young children and youth in need of&nbsp;substance use treatment, finding a Health Insurance Portability and Accountability Act (HIPAA)-compliant platform, training&nbsp;providers and clients, and reimbursement challenges. Policy changes&nbsp;to enable reimbursement, internet access, training, and provider&nbsp;licensing resulted in substantially fewer appointment cancellations&nbsp;or no-shows, greater family engagement, reduction in travel time,&nbsp;increased access for people living in remote locations, and increased&nbsp;provider communication and collaboration. States with high rates of&nbsp;coronavirus positivity and high rates of unmet need were most likely&nbsp;to continue use of telehealth post-pandemic. Despite these&nbsp;challenges, states reported successful implementation of policies&nbsp;designed to facilitate virtual services delivery with likely&nbsp;long-term changes in practice.&nbsp;Conclusions: Policy implementation during the pandemic provided&nbsp;important lessons for planning and preparedness for future public&nbsp;health emergencies. Successful policy implementation requires ongoing&nbsp;collaboration among policy makers and with providers.

We assessed the association between anxiety and hypertension in adults via a systematic review/meta-analysis. We searched PubMed, Ovid, and PsycINFO through 27 March 2020 with no language or publication type restrictions and systematically contacted study authors for unpublished information/data. We meta-analysed 59 studies including a total of 4,012,775 participants. Study quality was rated with the Newcastle-Ottawa Scale and random-effects analyses were performed. A significant anxiety-hypertension association was found in cross-sectional (OR = 1.37, 95 % CI = 1.21-1.54) and prospective studies (OR = 1.40, 95 % CI = 1.23-1.59). In sensitivity analyses, results were influenced by method of hypertension diagnosis, but not by study quality, method of anxiety diagnosis, study population, and effect size type. In subgroup analyses, study location, in particular country economic status, but not participant age, influenced the results. Longitudinal data and theoretical literature indicate that anxiety may precede hypertension. These findings have important clinical implications for the early detection and treatment of both anxiety and hypertension. Suggestions for future research are discussed.