Faculty Bibliography

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

Background/UNASSIGNED:(NICHD) funded, cluster randomized-controlled trial to evaluate a combination intervention, titled Suubi + Adherence, aimed at improving ART adherence among HIV perinatally infected adolescents (ages 10-16 at study enrollment) in Uganda. Methods/UNASSIGNED:Suubi + Adherence was evaluated via a two-arm cluster randomized-controlled trial design in 39 health clinics, with a total enrollment of 702 HIV + adolescents (ages 10-16 at enrollment). The study addresses two primary outcomes: 1) adherence to HIV treatment regimen and 2) HIV knowledge and attitudes. Secondary outcomes include family functioning, sexual risk-taking behavior, and financial savings behavior. For potential scale-up, cost effectiveness analysis was employed to compare the relative costs and outcomes associated with each study arm: family economic strengthening comprising matched savings accounts, financial management training and small business development, all intended for family economic security versus bolstered usual care (SOC) comprising enhanced adherence sessions to ensure more standardized and sufficient adherence counseling. Discussion/UNASSIGNED:This study aims to advance knowledge and inform the development of the next generation of programs aimed at increasing adherence to HIV treatment for HIV + adolescents in low-resource regions such as SSA. To our knowledge, the proposed study is the first to integrate and test family economic empowerment and stability-focused interventions for HIV + adolescents in Uganda (and much of SSA)-so families would have the necessary finances to manage HIV/AIDS as a chronic illness. The study would provide crucial evidence about the effects of an economic empowerment program on short and long-term impact, which is essential if such interventions are to be taken to scale. Trial registration/UNASSIGNED:This trial was registered with ClinicalTrials.gov (registration number: NCT01790373) on 13 February 2013.

Background: Reduced endocannabinoid "tone" has been posited in the pathophysiology of ASD animal models; children with ASD have been found to have lower peripheral endocannabinoid levels. Additionally, anecdotal reports suggest cannabinoids may be beneficial for some aspects of ASD.
Method(s): Double-blind placebo-controlled comparison (NCT02956226) of whole plant cannabis extract containing cannabidiol (CBD) and DELTA9-tetrahydrocannabinol (THC) in a 20:1 ratio and (2) purified CBD and THC in the same ratio. Participants were 150 children and adolescents with ASD, both males (80%) and females (mean age 11.8 +/-4.1 yrs). They received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout, and crossed-over to receive another treatment for 12 weeks to further assess tolerability.
Result(s): There were no treatment related severe or serious adverse events. None of the outcomes differed significantly between cannabinoid preparation, in either treatment period. Considering cannabinoids together, in the first period, 43% of 90 children who received cannabinoids were either much or very much improved on the CGI-I compared with 21% of 47 on placebo (p = 0.009). Placebo-cannabinoid differences were not significant on the other primary outcome, the Home Situations Questionnaire for ASD (HSQ-ASD). A positive response on the Social Responsiveness Scale-2 (SRS-2) was defined as 15% decrease or better from baseline. In the first treatment period, 44% of participants who received cannabinoids had a positive response compared with 19% on placebo (p = 0.013). In terms of possible mediators of treatment effects on the SRS-2, male sex and milder ASD symptoms at baseline were independently associated with better response to cannabinoid treatment.
Conclusion(s): Novel pharmacological treatments for the core and comorbid symptoms of ASD are urgently needed. Preclinical studies implicate the endocannabinoid system in the pathophysiology of ASD. In a controlled study of 150 children, a combination of CBD and THC, in a 20:1 ratio, either as a whole plant extract or as pure cannabinoids, improved disruptive behaviors and an index of ASD core symptoms, with relatively few adverse events. These data suggest that further investigation of cannabinoids in ASD is likely to be promising

Background: Serotonin and dopamine are neurotransmitters associated with multiple psychiatric disorders. How they interact during development to affect subsequent behavior remains unknown. Knockout of the serotonin transporter or administration of selective-serotonin-reuptake inhibitors (SSRIs) during early-life lead to novelty-induced exploration deficits in adulthood.
Method(s): Using a combination of optogenetics, behavioral testing and electrophysiology we tested the effects of perinatal exposure to fluoxetine (PN-FLX) on dopaminergic system's function in the adult. Between 10 to 15 mice per group, male and female, were administered with saline or fluoxetine (10 mg/kg IP) from P2 to P11. Mice were tested after 8 weeks of age.
Result(s): Here we show that Raphe nucleus serotonin neurons activate ventral tegmental area (VTA) dopamine neurons via glutamate cotransmission and that this cotransmission is impaired in postnatally SSRI treated animals. Moreover, we show that the SSRI-induced hypolocomotion is mimicked by blocking serotonin neuron glutamate cotransmission. Optogenetic activation of dopamine neurons rescued this hypolocomotor phenotype.
Conclusion(s): Our data demonstrate that serotonin neurons modulate dopaminergic activity via glutamate cotransmission and that this pathway is developmentally malleable, with high serotonin levels during early life blunting this capacity, resulting in reduced novelty-induced exploration in adulthood

Social skills are traditionally viewed as acquired through social environments including parenting. However, biopsychosocial models highlight the importance of genetic influences and gene-environment interactions (G×Es) in child development. Extant G×E investigations often fail to account for developmental changes in the phenotype or rigorously assess the social environment using observational measures. The present study prospectively assessed 110 children (44.5% female) and their parents to explore biologically plausible independent and interactive associations of the serotonin transporter-linked polymorphic region (5-HTTLPR) and observed positive and negative parenting in prediction of (a) initial levels of social skills at school entry (age 6 years) and (b) developmental changes in social skills across the early school years (ages 6-9 years). Overall, the SS (vs. SL/LL) 5-HTTLPR genotype inversely predicted social skills across all domains, although parenting behavior moderated these associations wherein putative G×E effects differed by developmental timing and social skills domain. Positive parenting positively predicted concurrent (age 6) overall social skills for children with SL/LL genotypes, but not the SS genotype. However, for the SS group only, age 6 positive parenting positively predicted prospective growth in social responsibility, although negative parenting positively predicted growth in social cooperation. Findings suggest that 5-HTTLPR may signal differential sensitivities to parenting styles and patterns of social development, which may help to inform targeted intervention approaches to enhance person-environment fit. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

Maternal prenatal stress influences offspring neurodevelopment and birth outcomes including the ratio of males to females born; however, there is limited understanding of what types of stress matter, and for whom. Using a data-driven approach with 27 variables from questionnaires, ambulatory diaries, and physical assessments collected early in the singleton pregnancies of 187 women, 3 latent profiles of maternal prenatal stress emerged that were differentially associated with sex at birth, birth outcomes, and fetal neurodevelopment. Most women (66.8%) were in the healthy group (HG); 17.1% were in the psychologically stressed group (PSYG), evidencing clinically meaningful elevations in perceived stress, depression, and anxiety; and 16% were in the physically stressed group (PHSG) with relatively higher ambulatory blood pressure and increased caloric intake. The population normative male:female secondary sex ratio (105:100) was lower in the PSYG (2:3) and PHSG (4:9), and higher in the HG (23:18), consistent with research showing diminished male births in maternal stress contexts. PHSG versus HG infants were born 1.5 wk earlier (P < 0.05) with 22% compared to 5% born preterm. PHSG versus HG fetuses had decreased fetal heart rate-movement coupling (P < 0.05), which may indicate slower central nervous system development, and PSYG versus PHSG fetuses had more birth complications, consistent with previous findings among offspring of women with psychiatric illness. Social support most strongly differentiated the HG, PSYG, and PHSG groups, and higher social support was associated with increased odds of male versus female births. Stress phenotypes in pregnant women are associated with male vulnerability and poor fetal outcomes.

OBJECTIVE/UNASSIGNED:This cross-sectional study examined the relationship between antipsychotic medication adherence and preventable diabetes-related hospitalizations for individuals with diabetes and schizophrenia. METHODS/UNASSIGNED:Hospitalizations related to diabetes, an ambulatory care sensitive condition, were assessed among Medicaid recipients in New York State with comorbid diabetes and schizophrenia (N=14,365) for three levels of antipsychotic medication adherence: very low to no engagement (two or fewer prescriptions or none in first 6 months), moderate to low adherence, and adherent (proportion of days covered ≥80%). RESULTS/UNASSIGNED:Rates of preventable diabetes hospitalization were highest among individuals with very low to no engagement in antipsychotic treatment (4.7%), followed by those with moderate to low adherence (3.3%). Diabetes hospitalizations among adherent individuals were comparable with those of the total diabetes population (both 2.0%). The odds of a preventable diabetes hospitalization were significantly higher among individuals with very low to no engagement in antipsychotic treatment (adjusted odds ratio [AOR]=2.42) and among those with moderate to low adherence (AOR=1.57) than among adherent individuals. Black individuals were also at increased risk of a preventable diabetes hospitalization after the analyses adjusted for antipsychotic adherence and other variables (AOR=1.38). CONCLUSIONS/UNASSIGNED:This study indicates a relationship between antipsychotic adherence and improved diabetes outcomes among individuals with schizophrenia. Engagement in mental health treatment may be a critical path toward improving health disparities for individuals with schizophrenia. Individuals with very low to no engagement were a particularly vulnerable group, and the exclusion of persons with less than two prescriptions from research and quality measures should be revisited.

Umbilical cord blood transplantation (UCBT) is an alternative for patients who need hematopoietic stem cell transplant (HSCT), but lack HLA-matched adult donors. Rabbit anti-thymoglobulin (ATG) has been used in UCBT conditioning to achieve T cell depletion, but ATG-induced immunosuppression is associated with delayed immune reconstitution, increased infectious complications and higher non-relapse mortality. In a clinical trial of reduced intensity double-unit UCBT (dUCBT), we substituted low dose total body irradiation (TBI) for ATG to determine whether dUCBT without ATG would alter kinetics and quality of immune reconstitution. Thirty-one patients with hematopoietic malignancies and a median age of 58 yr were treated with Flu/Mel/TBI, followed by dUCBT and GVHD prophylaxis with tacrolimus and sirolimus. We examined reconstitution of immune cell populations, thymic regeneration by quantifying T cell receptor excision circles (TREC) and serum cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, IL-12p70, GM-CSF) using the LUNARISTM Human 11-Plex Cytokine BiochipXX from AYOXXA Biosystems. Assessments were done prior to and at 1, 2, 3, 6, 12 and 24 months after dUCBT. Results are based on 28 evaluable patients. The 2-yr overall survival and progression-free survival were 53% and 48%. Median time to neutrophil and platelet engraftment was 25 and 52 days, respectively. Before UCBT, the median values for most leukocyte subsets were below normal limits, except for monocytes. CD3XX cells remained depressed until 2 months post-transplant when gradually began to re-emerge. However, CD4XX subsets had distinct reconstitution kinetics (Figure 1). CD4XX T cells declined at 1 month but gradually increased and exceeded pre-transplant levels by 9 months after UCBT. In contrast, at 9 months, CD8XX lymphocytes remained depressed to 50% of pre-transplant levels, but increased thereafter and reached normal values by 2-yr. NK cells and monocytes reached normal values at 3 months post-UCBT. B cells were mostly undetectable for the first 6 months, followed by a 10-fold increase at 9 months and exceeded the upper normal limit by 2-yr. TREC, which were within normal range before transplant, decreased after UCBT but remained detectable between 1-6 months and recovered to normal levels by 9 months. Among cytokines, only IL-8, IL-6 and TNF-alpha displayed significant changes. IL-8 and IL-6 peaked at day 100 and 9 months, and subsequently declined. In contrast, TNF-alpha increased by day 100 and remained elevated thereafter. To evaluate functional immunity, we assessed correlations between viral reactivation and reconstitution of immune cell populations and thymic function. Nineteen patients experienced 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence of 62%, which was comparable to 53% observed in dUCBT cohorts receiving ATG-containing conditioning. Although there was no difference in CMV, EBV, adenovirus and VZV reactivation, there was a significant increase in the incidence of HHV-6 reactivation. HHV-6 viremia was observed in 24 of 28 (86%) patients during the first month after dUCBT. Six of these 24 (25%) patients developed HHV-6-related encephalitis. There was a correlation between development of encephalitis and HHV-6 viral load >=50.000 copies/ml (p=0.007). Pre-transplant TREC levels >=1.200 copies/ml negatively correlated with subsequent HHV-6 reactivation (p=0.04), indicating that baseline reserve of thymic function has a significant role in post-transplant immune reconstitution. On days 30, 60 and 100 post-transplant, higher TREC levels correlated with lack of HHV-6 viremia (pXX counts in the first 100 days was also observed in patients without HHV-6 reactivation. Neutrophil and platelet engraftment, reconstitution of CD4XX T effectors, NK cells and monocytes, IL-6, IL-8 and TNF-alpha levels, and development of GVHD did not correlate with HHV-6 reactivation or its absence. Our results indicate that substitution of low dose TBI for ATG in the conditioning regimen is characterized by superior recovery of thymopoiesis and reconstitution of CD4XX T cells, both of which have a protective role against HHV-6 reactivation and end organ disease. Further studies will identify why HHV-6 reactivation is selectively increased in UCBT recipients treated with TBI-containing conditioning. [Formula presented] Disclosures: Defilipp: Incyte: Research Funding. Politikos: Angiocrine Bioscience Inc: Research Funding. Armand: Otsuka: Research Funding; Roche: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Sigma Tau: Research Funding; ADC Therapeutics: Consultancy; Tensha: Research Funding; Genentech: Research Funding; Pfizer: Consultancy. Ho: Jazz Pharmaceuticals: Consultancy. Koreth: Amgen: Consultancy; Equillium: Consultancy; Cugene: Consultancy. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexel: Consultancy; Takeda: Consultancy. Rosenblatt: Celgene: Research Funding; Amgen: Other: Advisory Board; Merck: Other: Advisory Board; BMS: Other: Advisory Board; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding. Chen: Abbvie: Consultancy; Incyte: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy. Soiffer: Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Jazz: Consultancy; Cugene: Consultancy. Cutler: Kadmon: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy. Ritz: Equillium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Aleta Biotherapeutics: Consultancy; Celgene: Consultancy; Avrobio: Consultancy; LifeVault Bio: Consultancy; Draper Labs: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy.XXCopyright

Sleep quality varies widely across individuals, especially during normal aging, with impaired sleep contributing to deficits in cognition and emotional regulation. Sleep can also be impacted by a variety of adverse events, including childhood adversity. Here we examined how early life adverse events impacted later life sleep structure and physiology using an animal model to test the relationship between early life adversity and sleep quality across the life span. Rat pups were exposed to an Adversity-Scarcity model from postnatal day 8-12, where insufficient bedding for nest building induces maternal maltreatment of pups. Polysomnography and sleep physiology were assessed in weaning, early adult and older adults. Early life adversity induced age-dependent disruptions in sleep and behavior, including lifelong spindle decreases and later life NREM sleep fragmentation. Given the importance of sleep in cognitive and emotional functions, these results highlight an important factor driving variation in sleep, cognition and emotion throughout the lifespan that suggest age-appropriate and trauma informed treatment of sleep problems.