Faculty Bibliography

OBJECTIVES/OBJECTIVE:Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS:FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS:Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS:Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.

The locus coeruleus (LC) is the primary source of noradrenergic projections to the forebrain, and, in prefrontal cortex, is implicated in decision-making and executive function. LC neurons phase-lock to cortical infra-slow wave oscillations during sleep. Such infra-slow rhythms are rarely reported in awake states, despite their interest, since they correspond to the time scale of behavior. Thus, we investigated LC neuronal synchrony with infra-slow rhythms in awake rats performing an attentional set-shifting task. Local field potential (LFP) oscillation cycles in prefrontal cortex and hippocampus on the order of 0.4 Hz phase-locked to task events at crucial maze locations. Indeed, successive cycles of the infra-slow rhythms showed different wavelengths, as if they are periodic oscillations that can reset phase relative to salient events. Simultaneously recorded infra-slow rhythms in prefrontal cortex and hippocampus could show different cycle durations as well, suggesting independent control. Most LC neurons (including optogenetically identified noradrenergic neurons) recorded here were phase-locked to these infra-slow rhythms, as were hippocampal and prefrontal units recorded on the LFP probes. The infra-slow oscillations also phase-modulated gamma amplitude, linking these rhythms at the time scale of behavior to those coordinating neuronal synchrony. This would provide a potential mechanism where noradrenaline, released by LC neurons in concert with the infra-slow rhythm, would facilitate synchronization or reset of these brain networks, underlying behavioral adaptation.

Bipolar disorder (BD) can be especially challenging to treat due to the dynamic nature of its presentation; there is a critical need for a multimodal approach to adequately address patients"™ symptoms and quality of life concerns. However, most mental health professionals have not implemented a multimodal approach due to limited dissemination of evidence-based psychosocial interventions for BD and bias towards psychopharmacology-centered treatment. This is despite clear findings from numerous studies that medication alone fails to fully address most patients"™ needs and that psychosocial interventions lead to fewer relapses and a higher quality of life. This paper aims to review the evidence in support of psychosocial interventions as a key component of the treatment of BD and to highlight obstacles to the implementation of psychosocial treatment approaches. Additionally, we aim to make a case for an increase in the utilization of psychosocial interventions to improve quality of life and functioning for individuals with BD and their families, and to mitigate societal costs.

Trauma exposure and post-traumatic stress disorder (PTSD) impact emotional and physical well-being, social functioning, and parent-child relationship quality. The effect of parental trauma on parenting and child maltreatment is often overlooked by current child welfare (CW) services. The novel intervention, Parenting-STAIR, was created to address maternal mental health, parenting skills, and child well-being outcomes. Parenting-STAIR is a combination of Skills Training in Affective and Interpersonal Regulation (STAIR) Narrative Therapy and Parent-Child Care (PC-CARE). This open pilot study aimed to examine the feasibility and preliminary impact of Parenting-STAIR in reducing maternal PTSD and increasing positive parenting skills for mothers and families involved in the child welfare system. Parenting-STAIR was delivered to 111 mothers receiving family preservation services in New York City. Of these, 70 completed treatment; statistical and clinically significant changes were observed for maternal PTSD and depression as well as in parenting stress, parenting skills, and child behaviors. These findings provide encouraging initial evidence for the feasibility and impact of this novel PTSD intervention. An evaluation of maltreatment recidivism is needed, as well as implementation of a randomized controlled trial to establish efficacy of the intervention.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.

Introduction: Transitions between sleep and waking and sleep-dependent cortical oscillations are heavily dependent on GABAergic neurons. Importantly, GABAergic neurons are especially sensitive to developmental ethanol exposure, suggesting a potential unique vulnerability of sleep circuits to early ethanol. In fact, developmental ethanol exposure can produce long-lasting impairments in sleep, including increased sleep fragmentation and decreased delta wave amplitude. Here, we assessed the efficacy of optogenetic manipulations of somatostatin (SST) GABAergic neurons in the neocortex of adult mice exposed to saline or ethanol on P7, to modulate cortical slow-wave physiology. Methods: SST-cre × Ai32 mice, which selectively express channel rhodopsin in SST neurons, were exposed to ethanol or saline on P7. This line expressed similar developmental ethanol induced loss of SST cortical neurons and sleep impairments as C57BL/6By mice. As adults, optical fibers were implanted targeting the prefrontal cortex (PFC) and telemetry electrodes were implanted in the neocortex to monitor slow-wave activity and sleep-wake states. Results: Optical stimulation of PFC SST neurons evoked slow-wave potentials and long-latency single-unit excitation in saline treated mice but not in ethanol mice. Closed-loop optogenetic stimulation of PFC SST neuron activation on spontaneous slow-waves enhanced cortical delta oscillations, and this manipulation was more effective in saline mice than P7 ethanol mice. Discussion: Together, these results suggest that SST cortical neurons may contribute to slow-wave impairment after developmental ethanol.

The essence of who we are depends on our brains. They enable us to think, to feel joy and sorrow, communicate through speech, reflect on the moments of our lives, and to anticipate, plan for, and worry about our imagined futures. Although some of our abilities are comparatively new, key features of our behavior have deep roots that can be traced to the beginning of life. By following the story of behavior, step-by-step, over its roughly four-billion-year trajectory, we come to understand both how similar we are to all organisms that have ever lived, and how different we are from even our closest animal relatives. We care about our differences because they are ours. But differences do not make us superior; they simply make us different.

This paper develops a Bayesian model with a flexible link function connecting a binary treatment response to a linear combination of covariates and a treatment indicator and the interaction between the two. Generalized linear models allowing data-driven link functions are often called "single-index models" and are among popular semi-parametric modeling methods. In this paper, we focus on modeling heterogeneous treatment effects, with the goal of developing a treatment benefit index (TBI) incorporating prior information from historical data. The model makes inference on a composite moderator of treatment effects, summarizing the effect of the predictors within a single variable through a linear projection of the predictors. This treatment benefit index can be useful for stratifying patients according to their predicted treatment benefit levels and can be especially useful for precision health applications. The proposed method is applied to a COVID-19 treatment study.

Evidence-based interventions (EBIs) are considered the gold standard but it is unclear if they are effective across settings. Reach Out and Stay Strong, Essentials for new Mothers (ROSE) has been shown to prevent postpartum depression in clinical settings, but has not been implemented or tested in homeless populations. We used the Exploration, Preparation, Implementation and Sustainment (EPIS) model overlaid with the Dynamic Adaptation Process (DAP) to adapt ROSE for implementation in a homeless shelter system in a large U.S. city, using feedback from both the organization and community. The adapted intervention was called Strong in Shelter (SIS). In this paper, we present 4 DAPS (April, 2018- December, 2020); the EPIS stages within each DAP are described. The Exploration Stage is centered around early and ongoing engagement with shelter providers and residents. The Preparation Stage includes adaptations based on learnings from the Exploration and the Implementation Stages from previous DAPs. The Implementation Stage highlights what we learned from implementation and both quantitative and qualitative feedback from shelter staff and residents. Following the DAP cycles, we created scalable plans in the Sustainment Stage. Thematic analysis was used to identify, analyze and report patterns within qualitative data, and descriptive analyses were conducted with quantitative data. Participant engagement and satisfaction were high and facilitators reported implementing SIS with fidelity to ROSE"™s core components. By engaging staff and the participants early and continually, and utilizing an iterative and flexible adaptation process, EBIs such as ROSE can be adapted and implemented with fidelity in new settings.