Faculty Bibliography

RATIONALE/BACKGROUND:receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES/OBJECTIVE:-mediated sensorimotor deficits. METHODS:receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS:receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS:levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.

Anxiety and eating disorders (EDs) often co-occur, prompting calls to explore anxiety-related maintenance processes in ED samples. Safety behaviors, which function to prevent a feared outcome from occurring or to reduce anxiety associated with a feared stimulus, are observed across anxiety disorders and, along with overt avoidance behaviors, are an important target in treatment. Data suggest that individuals with EDs also engage in safety behaviors. However, no existing assessments provide a comprehensive measure of eating-disorder-specific overt avoidance and safety behaviors. The goal of this Stage 1 Registered Report is to develop a comprehensive self-report measure of ED-specific safety behaviors. In Study 1, we will recruit 50 women with EDs to complete the scale and provide feedback on the response scale. Feedback from these participants will be used to refine the measure. In Study 2, we will evaluate the psychometric properties of the measure in a large sample of women with EDs (n dependent on the size of measurement) and a community sample without current or a history of ED symptoms. We will explore the measure factor structure, known-groups validity by comparing scores from women with EDs to healthy controls, internal consistency, and convergent and divergent validity with other psychological instruments.

Psychophysiological interaction (PPI) was proposed 20 years ago for study of task modulated connectivity on functional MRI (fMRI) data. A few modifications have since been made, but there remain misunderstandings on the method, as well as on its relations to a similar method named beta series correlation (BSC). Here, we explain what PPI measures and its relations to BSC. We first clarify that the interpretation of a regressor in a general linear model depends on not only itself but also on how other effects are modeled. In terms of PPI, it always reflects differences in connectivity between conditions, when the physiological variable is included as a covariate. Secondly, when there are multiple conditions, we explain how PPI models calculated from direct contrast between conditions could generate identical results as contrasting separate PPIs of each condition (a.k.a. "generalized" PPI). Thirdly, we explicit the deconvolution process that is used for PPI calculation, and how is it related to the trial-by-trial modeling for BSC, and illustrate the relations between PPI and those based upon BSC. In particular, when context sensitive changes in effective connectivity are present, they manifest as changes in correlations of observed trial-by-trial activations or functional connectivity. Therefore, BSC and PPI can detect similar connectivity differences. Lastly, we report empirical analyses using PPI and BSC on fMRI data of an event-related stop signal task to illustrate our points.

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20s∼10min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

Early life is a sensitive period in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor, fluoxetine, affects motivation and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task.Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid, but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.Significance StatementThe developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here we show that exposure to the SSRI fluoxetine during a restricted period in early-life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

The social and economic situation in Europe seems to play a role in the migratory flow of doctors and other health professionals within the continent. However, little is known about the particular reality of workforce migration in Spain. The objective of this study was to explore the factors that motivate migration among junior doctors training in psychiatry in Spain. A semistructured questionnaire of 61 items was circulated to psychiatric trainees in Spain to explore the extent and the factors that influence the decisions regarding workforce migration. A total of 95 psychiatric trainees participated in the survey. More than two-thirds (n = 71, 74.7%) had "ever" considered migrating to another country, and more than one-fourth (n = 21, 29.5%) had already taken "practical steps" to go abroad. The main reasons to consider leaving the country were financial (n = 82, 86%) and the opportunity to progress professionally (n = 82, 84%). However, nearly half of the trainees (n = 47, 49%) were satisfied with their current income. While the majority of the psychiatric trainees in this survey had considered migrating abroad, these potential future migrations could lead to a loss of human capital with an important sociosanitary impact.

BACKGROUND:Mind-body integrative health (MBIH) interventions to improve adolescent sleep are lacking. The study characterized sleep quality and bedtime-related psychosocial stressors among urban minority adolescents, explored associations between demographics factors, stressors and sleep quality, and gauged interest in a MBIH sleep intervention. MATERIALS AND METHODS/METHODS:167 school-based health center (SBHC) patients (mean age = 16.3; 64% female; 68% Latino) participated in a needs assessment as part of a quality improvement project. They reported bedtime-related psychosocial stressors using items from the Adolescent Sleep Hygiene Scale (ASHS), sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and interest in a MBIH-based sleep intervention. Chi-square and logistic regression examined associations between demographics, stressors, sleep quality, and interest in the intervention. RESULTS:67% had poor sleep quality. Females, compared to males, had 2.23 higher odds (95% Confidence Interval [CI]: 1.12, 4.42) of having poor sleep quality. Nearly 80% experienced bedtime-related stressors (25% experienced one stressor, 17% two stressors and 37% three or more stressors); relative to those reporting no stressors, those reporting 3+ stressors had 3.15 higher odds (95% CI: 1.27, 7.84) of having poor sleep quality. Most (77%) reported they would participate in an SBHC-based intervention that utilized MBIH modalities preferring both one-on-one and group sessions. CONCLUSIONS:Urban, predominantly Hispanic and Black, SBHC adolescent patients have poor sleep quality and report bedtime-related psychosocial stressors. Their interest in MBIH interventions to address sleep problems represents a unique opportunity for practitioners and complementary therapists to offer MBIH interventions to a population at high-risk for poor sleep quality.

Convergence insufficiency (CI) is the most common binocular vision problem, associated with blurred/double vision, headaches, and sore eyes that are exacerbated when doing prolonged near work, such as reading. The Convergence Insufficiency Neuro-mechanism Adult Population Study (NCT03593031) investigates the mechanistic neural differences between 50 binocularly normal controls (BNC) and 50 symptomatic CI participants by examining the fast and slow fusional disparity vergence systems. The fast fusional system is preprogrammed and is assessed with convergence peak velocity. The slow fusional system optimizes vergence effort and is assessed by measuring the phoria adaptation magnitude and rate. For the fast fusional system, significant differences are observed between the BNC and CI groups for convergence peak velocity, final position amplitude, and functional imaging activity within the secondary visual cortex, right cuneus, and oculomotor vermis. For the slow fusional system, the phoria adaptation magnitude and rate, and the medial cuneus functional activity, are significantly different between the groups. Significant correlations are observed between vergence peak velocity and right cuneus functional activity (p = 0.002) and the rate of phoria adaptation and medial cuneus functional activity (p = 0.02). These results map the brain-behavior of vergence. Future therapeutic interventions may consider implementing procedures that increase cuneus activity for this debilitating disorder.

The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons which inhibit GCs. We used viral delivery of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in mice to implement a gain- and loss of function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENT: The dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

BACKGROUND:Youth in the justice system (YJS) are more likely than youth who have never been arrested to have mental health and substance use problems. However, a low percentage of YJS receive SUD services during their justice system involvement. The SUD care cascade can identify potential missed opportunities for treatment for YJS. Steps along the continuum of the cascade include identification of treatment need, referral to services, and treatment engagement. To address gaps in care for YJS, we will (1) implement a learning health system (LHS) to develop, or improve upon, alliances between juvenile justice (JJ) agencies and community mental health centers (CMHC) and (2) present local cascade data during continuous quality improvement cycles within the LHS alliances. METHODS/DESIGN/METHODS:ADAPT is a hybrid Type II effectiveness implementation trial. We will collaborate with JJ and CMHCs in eight Indiana counties. Application of the EPIS (exploration, preparation, implementation, and sustainment) framework will guide the implementation of the LHS alliances. The study team will review local cascade data quarterly with the alliances to identify gaps along the continuum. The study will collect self-report survey measures longitudinally at each site regarding readiness for change, implementation climate, organizational leadership, and program sustainability. The study will use the Stages of Implementation Completion (SIC) tool to assess the process of implementation across interventions. Additionally, the study team will conduct focus groups and qualitative interviews with JJ and CMHC personnel across the intervention period to assess for impact. DISCUSSION/CONCLUSIONS:Findings have the potential to increase SUD need identification, referral to services, and treatment for YJS.