2021 Fellows' Scientific Training Day NIMH Intramural Research
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2021 Fellows' Scientific Training Day NIMH Intramural Research Programs September 24, 2021 Anxiety-related striatal connectivity in adolescence and adulthood E. Weiss, C. Gaillard, B. Benson, D. Pine, and M. Ernst Introduction Adolescence is a period marked by a steep increase in the incidence of anxiety. Research suggests that the striatum plays a role in in attention, learning, and motivation, which all show perturbations in anxiety disorders. Given the importance of development and the relative paucity of clinical developmental neuroimaging studies in anxiety, we exploited a large sample of adults and adolescents characterized as either healthy or clinically anxious. Our goal was to examine differences of anxiety-related striatal connectivity deficits between adolescence and adults. We used resting state fMRI data, which provide the basic level of communication of striatal regions with key functional regions. Method Adolescents (44 patients, 63 healthy, age range: 8-18 years) and adults (36 patients, 88 healthy, age range: 18-44 years) completed a resting state scan. All participants were assessed for psychiatric morbidity via KSADS for adolescents and SCID-I for adults. Participants completed questionnaires including Behavioral Inhibition and Activation Scale (BIS/BAS scale), Fear of Negative Evaluation (FNE), and State-Trait Anxiety Inventory (STAI). A General Linear Model (GLM) analysis was run in AFNI with Age and Diagnosis as between-subject factors controlling for scanner, sex, and IQ. Spearman correlation analyses explored brain-behavior associations. Results For this presentation, we focus on the ventral caudate because of its role in motivation, emotion, and cognition and we refer to this connectivity as "iFC". The Age by Diagnosis interaction was significant on the iFC between the ventral caudate (VC) and dorsolateral prefrontal cortex (dlPFC). There was a significantly different pattern in adolescents (t(223) =-2.89, p =0.004) and adults (t(223) =3.41, p =0.002) when comparing anxiety patients to healthy volunteers. For adolescents, the iFC was significantly lower in patients (M= 0.076, SE= 0.020) than in healthy controls (M =0.146, SE =0.017). The adults showed the inverse pattern: the iFC was significantly higher in patients (M =0.154, SE =0.021) than in healthy controls (M =0.067, SE =0.014). When parsing out the two-way interaction by Diagnosis, iFC was significantly higher in anxious adults compared to anxious children (t(223) =2.65, p =0.009), while it was significantly lower in healthy adults compared to healthy children (t(223) =-3.84, p < 0.001). In adults, the iFC was positively correlated with BIS (rs =0.24, p =0.01), FNE (rs =0.20, p =0.02), and STAI-State (rs = 0.29, p < 0.001). In adolescents, the iFC was negatively correlated with BIS (rs = - 0.23, p =0.02). Additionally, the strength of these associations differed significantly (BDI: z =3.52, p < 0.001; FNE: z = 2.46, p =0.01) between adults and adolescents. Discussion Collectively, the reduced connectivity strength in anxious compared to healthy adolescents might represent a delayed maturation of brain regions involved in cognitive control and attentional regulation that govern goal-oriented behaviors. Additionally, the stronger connectivity observed in anxious compared to healthy adults might reflect a compensatory mechanism to alleviate dysfunctional cognitive-emotional processing. Future research should further explore such potential compensatory mechanism that comes on line with maturation, and seek ways to strengthen its efficiency. Acute vs constitutive effects of PACAP gene knockout on behavior, physiology, and the transcriptome D. Bakalar, S. C. SWEAT , G. L. DROSSEL , S. Z. JIANG , B. S. SAMAL , N. STROTH , W. XU , L. ZHANG , H. ZHANG , L. E. EIDEN Effects of gene loss in neuropeptide knockout animals are often interpreted as indicating that the peptide and its receptor(s) are required for the physiological or behavioral responses elicited in wild-type mice at the time of experimental examination. These interpretations presume that peptide/peptide receptor gene deletion affects only the expression of the peptide/receptor itself, and therefore impacts physiological events only at the time at which the experiment is conducted. Here, we show that there is a cohort of genes whose basal expression is affected by constitutive knock-out of the Adcyap1 gene, coding for the neuropeptide PACAP, in C57Bl6/N mice (constitutively PACAP-Regulated Genes, or cPRGs). We show a separate group of genes whose expression in response to physiological challenge, in adults, is altered or impaired in the absence of PACAP expression (acutely PACAP-Regulated Genes, or aPRGs). We also identify a behavioral consequence of Adcyap1 gene loss (repetitive jumping) which does not phenocopy in PACAP receptor (PAC1) knockout mice and does not occur upon tissue-specific postnatal knockout of Adcyap1, suggesting a developmental role of PACAP mediated by something other than its canonical receptor . We are currently using whole-brain clearing in combination with immunostaining for the immediate early gene c-fos to identify the brain locus or loci activated during repetitive jumping, and a conditional whole-brain knockout of Adcyap1 to identify the critical period for PACAP acting to prevent the development of repetitive jumping. Distinguishing constitutive and acute transcriptomic effects of neuropeptide deficiency on physiological function and behavior in mice reveals alternative mechanisms of action, and changing functions of neuropeptides, throughout the lifespan. Assessing the Early Impact of the COVID-19 Pandemic on families with Children with Motor Impairments: Access to Therapies and Well-being S. Francis, E.N. Sutter, DPT*, L.S. Francis, MS, D.H. Lench, PhD, S.T. Nemanich, PhD, L.E. Krach, MD, T. Sukal-Moulton, PhD, DPT, B.T. Gillick, PhD, MSPT, PT Objectives: On March 11, 2020 the World Health Organization declared COVID-19 a global pandemic. Given this historical occurrence, we took the opportunity to investigate the impact of a pandemic event on families with children with motor impairments. Our study investigated the impact of the early "phase" of the pandemic and initial U.S. lockdown on access to rehabilitation therapies and the subsequent impact to the physical and mental well-being of children with motor impairment and their caregivers (Sutter et al, 2021). Design: Caregivers of children younger than 18 years old with childhood-onset motor impairment (primarily cerebral palsy) completed an anonymous survey between May 5 and July 13, 2020. This time frame included the early "phase" of the pandemic and the initial associated lockdown in the U.S. Results: The survey was completed by 102 participants in three Midwest-based national databases and registries. Before the pandemic, 92 of 102 children (90%) were receiving one or more therapies; at the time surveyed, 55 children (54%) were receiving any therapies (P < 0.001). More than 40% of the sample reported increased child stress, decreased physical activity, and/or decline in mobility/movement. Participants who reported a decrease in number of therapies at the time surveyed more frequently reported a decline in child's mobility (P = 0.001) and increased caregiver stress (P= 0.004). Caregiver stress demonstrated a moderate positive correlation with caregiver burden (rho = 0.508, P <.001) and child stress (rho = 0.444, P <.001). Additionally, five qualitative themes were identified from open-ended question responses related to therapy access and well-being. Conclusions: As assessed during the early phase and initial lockdown of the COVID-19 pandemic, access to pediatric rehabilitation therapies was disrupted. Within our survey group, disrupted access was associated with changes in child and caregiver physical and mental health. Child and caregiver feedback are important contributors to the optimization of service delivery, including telehealth modalities, during this pandemic and other future access challenges. * - denotes primary author of Sutter et al, 2021 Reconfiguration of Functional Brain Networks During an Ecologically-Valid Fear Induction Task in Healthy and Anxious Youth J. Galbraith, G. Ringlein, J. Linke, D. Pine, R. Abend Background Pathological anxiety is characterized by excessive anticipatory fears of potential threat and typically emerges in later childhood. Clarifying the neurobiological mechanisms generating threat-anticipatory fears in youth could inform early diagnosis and intervention efforts. Adolescence is a critical period for brain maturation, involving reorganization of localized and network-level connections. Basic neuroscience studies reveal changes in distributed brain regions during threat anticipation, underscoring the need for a network-based approach. Recently, a graph-theoretical approach has been utilized in brain connectomics. This method assumes that the brain is comprised of subnetworks, known as modules, comprised of brain regions (nodes) and their connections (edges). Prior work focusing on efficiency has suggested that a healthy brain maintains a critical balance between integration and segregation to maximize processing and communication, while a faulty balance may underlie psychological disorders. However, few studies have examined how networks reconfigure following presentation of emotional stimuli, typically during rest. Importantly, no study examines reconfiguration during the anticipation of threat. Due to practical and ethical concerns, many neuroimaging studies