Faculty Bibliography

OBJECTIVE: The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. METHOD: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. RESULTS: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. CONCLUSIONS: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations

Genetically engineered lymphocytes hold promise for the treatment of genetic disease, viral infections and cancer. However, current methods for genetic transduction of peripheral blood lymphocytes rely on viral vectors, which are hindered by production and safety-related problems. In this study, we demonstrated an efficient novel nonviral platform for gene transfer to lymphocytes. The Sleeping Beauty transposon-mediated approach allowed for long-term stable expression of transgenes at approximately 50% efficiency. Utilizing transposon constructs expressing tumor antigen-specific T-cell receptor genes targeting p53 and MART-1, we demonstrated sustained expression and functional reactivity of transposon-engineered lymphocytes on encountering target antigen presented on tumor cells. We found that transposon- and retroviral-modified lymphocytes had comparable transgene expression and phenotypic function. These results demonstrate the promise of nonviral ex vivo genetic modification of autologous lymphocytes for the treatment of cancer and immunologic disease.

OBJECTIVE: The sociocommunicative abnormalities of young children with Williams syndrome (WS) with limited language were compared with those of children with clinical diagnoses of autism, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), or nonspectrum developmental disability. METHOD: Participants were 30 children with WS and individually matched groups of participants with autism (n = 28), PDD-NOS (n = 17), and mixed etiology nonspectrum developmental disabilities (n = 16). The autism, PDD-NOS, and mixed etiology groups were matched individually to the children with WS for age, sex, and developmental level. All participants were administered the Autism Diagnostic Observation Schedule Module 1 and the Mullen Scales of Early Learning. RESULTS: As a group, children with WS with limited language showed fewer sociocommunicative abnormalities than children with autism, about the same level as children with PDD-NOS, and more abnormalities in reciprocity social interaction than participants in the mixed etiology group. Examination of the subgroup of participants with WS matched and compared with children with PDD-NOS indicated that half of the children showed fewer abnormalities than their individual matches with PDD-NOS, whereas half of the children with WS showed more abnormalities than their matches with PDD-NOS. CONCLUSION: Sociocommunicative difficulties are present for many children with WS and overlap with the autism spectrum. The results of this investigation suggest that these abnormalities are not accounted for by developmental delay alone, and care should be taken to avoid diagnostic overshadowing in young children with WS

This study tested the hypothesis that very young children who received more morphine for acute burns would have larger decreases in posttraumatic symptoms 3 to 6 months later. This has never before been studied in very young children, despite the high frequency of burns and trauma in this age group. Seventy 12- to 48-month-old nonvented children with acute burns admitted to a major pediatric burn center and their parents participated. Parents were interviewed at three time points: during their child's hospitalization, 1 month, and 3 to 6 months after discharge. Measures included the Child Stress Disorders Checklist - Burn Version (CSDC-B). Chart reviews were conducted to obtain children's morphine dosages during hospitalization. Mean equivalency dosages of morphine (mg/kg/d) were calculated to combine oral and intravenous administrations. Eleven participants had complete 3 to 6-month data on the CSDC. The correlation between average morphine dose and amount of decrease in posttraumatic stress disorder symptoms on the CSDC (r = -0.32) was similar to that found in studies with older children. The correlation between morphine dose and amount of decrease in symptoms on the arousal cluster of the CSDC was significant (r = -0.63, P < .05). Findings from the current study suggest that, for young children, management of pain with higher doses of morphine may be associated with a decreasing number of posttraumatic stress disorder symptoms, especially those of arousal, in the months after major trauma. This extends, with very young children, the previous findings with 6- to 16-year olds

Addiction is increasingly understood as a neurobiological illness where repetitive substance abuse corrupts the normal circuitry of rewarding and adaptive behaviors causing drug-induced neuroplastic changes. The addictive process can be examined by looking at the biological basis of substance initiation to the progression of substance abuse to dependence to the enduring risk of relapse. Critical neurotransmitters and neurocircuits underlie the pathological changes at each of these stages. Enhanced dopamine transmission in the nucleus accumbens is part of the common pathway for the positively rewarding aspects of drugs of abuse and for initiation of the addictive process. F-Aminobutyric acid,opioid peptides, serotonin, acetylcholine, the endocannabinoids, and glutamate systems also play a role in the initial addictive process. Dopamine also plays a key role in conditioned responses to drugs of abuse, and addiction is now recognized as a disease of pathological learning and memory. In the path from substance abuse to addiction, the neurochemistry shifts from a dopamine-based behavioral system to a predominantly glutamate-based one marked by dysregulated glutamate transmission from the prefrontal cortex to the nucleus accumbens in relation to drug versus biologically oriented stimuli. This is a core part of the executive dysfunction now understood as one of the hallmark features of addiction that also includes impaired decision making and impulse dysregulation.Understanding the neurobiology of the addictive process allows for a theoretical psychopharmacological approach to treating addictive disorders,one that takes into account biological interventions aimed at particular stages of the illness

Substance use disorders are highly prevalent in the United States and cause considerable damage to our society. They are underrecognized and undertreated despite a vast body of literature demonstrating the efficacy of treatment using both psychosocial and psychopharmacological modalities. For the last decade, research and progress into the biological basis of the addictive process has led to a rapidly growing number of pharmacological agents used to interrupt the addictive process at its various stages such as the initiation of substance abuse, the transition from abuse to dependence, and the prevention of drug reinstatement or relapse. Food and Drug Administration-approved medications exist for nicotine, alcohol, and opioid use disorders, and progress is being made to develop agents for stimulant use disorders. Regarding nicotine use disorders, nicotine replacement therapies,bupropion and varenicline, have Food and Drug Administration approval, and future options exist with endocannabinoid antagonists and immune therapy. Aversive agents, opiate antagonists, and glutamate based interventions are currently approved to treat alcohol use disorders with future promise with GABAergic, serotonergic, and endocannabinoid system agents. Opiate addiction is treated by approved agonist and antagonist mu-opioid medications with the future potential for agents that can modulate the stress systems and the iboga alkaloids. Although no pharmacotherapies are currently approved for cocaine addiction, promising lines of research include agents that affect dopaminergic, GABAergic, serotonergic,and glutamatergic systems as well as the promise for immune therapies

The present study examines the mechanisms by which students' perceptions of family and school experiences moderate the association between their emotionality and their habitual involvement in bullying and victimization. The authors hypothesize that students with internalizing and/or externalizing difficulties are less likely to be categorized as bullies and/or victims if they report coming from more cohesive and adaptable families and attending schools characterized by higher adult monitoring, lower levels of aggression and disorder, and higher levels of school bonding. Home and school environments in which these characteristics are less evident to students were expected to exacerbate the likelihood of being bullies and/or victims. Middle school youth (N = 2,506) and their teachers completed surveys assessing emotionality, peer relationships, academic performance, and home and school contexts. Using multinomial logistic regression, the authors found that perceived climates low in student misconduct increase the likelihood that internalizing difficulties predicted classification as victims. Increased student-reported adult monitoring decreased the likelihood for students with externalizing problems to be characterized as bullies, particularly for girls. These findings have implications for the development of school-based intervention programming

Monkeys separated from their mothers soon after birth and raised with peers display many disturbances in emotional behavior that are similar to human mood and anxiety disorders. In addition to emotional disturbances, both mood and anxiety disorders are often characterized by disruptions in normal sleep-wake cycles, a behavior that has not been well characterized in adversely reared non-human primates. Because polysomnographic measures are difficult to obtain in unrestrained monkeys we used 24-h actigraphy measures to assess probable sleep-wake patterns in juvenile nursery- and mother-reared rhesus macaques (Macaca mulatta, N=16) over several days in the home cage. In addition we assayed plasma cortisol in the morning, afternoon, and evening. Relative to mother-reared (MR) monkeys, actigraphic algorithms indicated that nursery-reared (NR) animals had shorter durations of nocturnal sleep, earlier morning waking, and longer periods of sleep during the active period, specifically in the mid morning. No shift in diurnal patterns of cortisol was observed, but NR animals displayed an overall elevation in cortisol. Finally a significant interaction was found between cortisol and actigraphic determination of sleep efficiency in the two groups. A strong positive relationship (r(2)>0.8) was found between mean cortisol levels and sleep efficiency for the MR monkeys, but a significant negative relationship was found between these same variables for the NR monkeys, indicating a fundamentally different relationship between waking cortisol and actigraphy patterns in these two groups.

BACKGROUND: Increased systemic cytokine levels, modulators of the immune system, have been repeatedly documented in adult and adolescent major depressive disorder (MDD). This preliminary study extends this work to test the role of cytokines in suicidal symptomatology in adolescent MDD. Hypotheses were that acutely suicidal depressed adolescents would have: (1) increased plasma levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, and (2) a proinflammatory/antiinflammatory cytokine imbalance (indexed by plasma IFN-gamma/IL-4), compared to nonsuicidal depressed adolescents and healthy controls. METHODS: Twelve suicidal adolescents with MDD (7 females [58%]; 5 medication-free/naive), 18 nonsuicidal adolescents with MDD (12 females [67%]; 8 medication-free/naive), and 15 controls (8 females [53%]) were enrolled. MDD had to be of at least 6 weeks duration, with a minimum severity score of 40 on the Children's Depression Rating Scale-Revised. Plasma cytokines were examined using enzyme-linked immunosorbent assays. Nonparametric tests were used to compare subject groups. RESULTS: Unexpectedly, suicidal adolescents with MDD had significantly decreased plasma TNF-alpha concentrations compared to nonsuicidal adolescents with MDD (1.33 +/- 2.95 pg/mL versus 30.9 +/- 110.9 pg/mL; p = 0.03). IFN-gamma was increased in both suicidal and nonsuicidal adolescents with MDD compared to controls (2.14 +/- 6.22 and 4.20 +/- 14.48 versus 0.37 +/- 0.64; p < 0.02, p = 0.005). Findings remained evident when controlled for age and gender. CONCLUSIONS: Our preliminary findings suggest that immune system dysregulation may be associated with suicidal symptomatology in adolescent MDD. These findings should be replicated in larger samples with medication-free adolescents