Faculty Bibliography

In neonatal brain development there is a period of normal apoptotic cell death that regulates adult neuron number. At approximately the same period, ethanol exposure can cause a dramatic spike in apoptotic cell death. While ethanol-induced apoptosis has been shown to reduce adult neuron number, questions remain about the regional selectivity of the ethanol effect, and whether the brain might have some capacity to overcome the initial neuron loss. The present study used stereological cell counting to compare cumulative neuron loss 8 h after postnatal day 7 (P7) ethanol treatment to that of animals left to mature to adulthood (P70). Across several brain regions we found that the reduction of total neuron number after 8 h was as large as that of adult animals. Comparison between regions revealed that some areas are more vulnerable, with neuron loss in the anterior thalamic nuclei > the medial septum/vertical diagonal band, dorsal subiculum, and dorsal lateral geniculate nucleus > the mammillary bodies and cingulate cortex > whole neocortex. In contrast to estimates of total neuron number, estimates of apoptotic cell number in Nissl-stained sections at 8 h after ethanol treatment provided a less reliable predictor of adult neuron loss. The findings show that ethanol-induced neonatal apoptosis often causes immediate neuron deficits that persist in adulthood, and furthermore suggests that the brain may have limited capacity to compensate for ethanol-induced neuron loss.

The commentaries by Ren, de Carvalho, Gabriel, Reber and BaluÅ¡ka raise interesting and timely questions about the views I expressed in The Deep History of Ourselves. I begin my response with an Overview of my perspective, and how it has changed in the three years since publication. This is important since some of the commentators"™ concerns may be assuaged by some of these points. Other specific issues raised by each commentator are addressed separately. I greatly appreciate the time and effort they put into their comments on The Deep History of Ourselves.

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.

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.

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.

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.