Faculty Bibliography

Following intranasal administration of oxytocin (OT), we measured, via functional MRI, changes in brain activity during judgments of socially (Eyes) and nonsocially (Vehicles) meaningful pictures in 17 children with high-functioning autism spectrum disorder (ASD). OT increased activity in the striatum, the middle frontal gyrus, the medial prefrontal cortex, the right orbitofrontal cortex, and the left superior temporal sulcus. In the striatum, nucleus accumbens, left posterior superior temporal sulcus, and left premotor cortex, OT increased activity during social judgments and decreased activity during nonsocial judgments. Changes in salivary OT concentrations from baseline to 30 min postadministration were positively associated with increased activity in the right amygdala and orbitofrontal cortex during social vs. nonsocial judgments. OT may thus selectively have an impact on salience and hedonic evaluations of socially meaningful stimuli in children with ASD, and thereby facilitate social attunement. These findings further the development of a neurophysiological systems-level understanding of mechanisms by which OT may enhance social functioning in children with ASD.

Survival in a dangerous environment requires learning about stimuli that predict harm. Although recent work has focused on the amygdala as the locus of aversive memory formation, the hypothalamus has long been implicated in emotional regulation, and the hypothalamic neuropeptide orexin (hypocretin) is involved in anxiety states and arousal. Nevertheless, little is known about the role of orexin in aversive memory formation. Using a combination of behavioral pharmacology, slice physiology, and optogenetic techniques, we show that orexin acts upstream of the amygdala via the noradrenergic locus coeruleus to enable threat (fear) learning, specifically during the aversive event. Our results are consistent with clinical studies linking orexin levels to aversive learning and anxiety in humans and dysregulation of the orexin system may contribute to the etiology of fear and anxiety disorders.

Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala-PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC-amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and cannabis use are each associated with specific cognitive deficits. Few studies have investigated the neurocognitive profile of individuals with both an ADHD history and regular cannabis use. The greatest cognitive impairment is expected among ADHD Cannabis Users compared to those with ADHD-only, Cannabis use-only, or neither. METHODS: Young adults (24.2+/-1.2 years) with a childhood ADHD diagnosis who did (n=42) and did not (n=45) report past year>/=monthly cannabis use were compared on neuropsychological measures to a local normative comparison group (LNCG) who did (n=20) and did not (n=21) report past year regular cannabis use. Age, gender, IQ, socioeconomic status, and past year alcohol and smoking were statistical covariates. RESULTS: The ADHD group performed worse than LNCG on verbal memory, processing speed, cognitive interference, decision-making, working memory, and response inhibition. No significant effects for cannabis use emerged. Interactions between ADHD and cannabis were non-significant. Exploratory analyses revealed that individuals who began using cannabis regularly before age 16 (n=27) may have poorer executive functioning (i.e., decision-making, working memory, and response inhibition), than users who began later (n=32); replication is warranted with a larger sample. CONCLUSIONS: A childhood diagnosis of ADHD, but not cannabis use in adulthood, was associated with executive dysfunction. Earlier initiation of cannabis use may be linked to poor cognitive outcomes and a significantly greater proportion of the ADHD group began using cannabis before age 16. Regular cannabis use starting after age 16 may not be sufficient to aggravate longstanding cognitive deficits characteristic of ADHD.

The rates of comorbid anxiety as well as the presentation of challenging behaviors are elevated within the autism spectrum disorder (ASD) population. The current study utilizes the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT) to explore the relationship of anxiety/repetitive behavior symptom severity and challenging behaviors in infants and toddlers with ASD. Children with ASD who evinced more severe impairment associated with anxiety/repetitive behavior (n = 94) demonstrated higher rates of overall challenging behaviors than those with ASD who evinced no to minimal anxiety impairment (n = 291). Specifically, a comparison of individual challenging behavior items indicated that the infants and toddlers with moderate to severe anxiety impairment exhibited more significant challenging behaviors under the domains of aggression/destruction, stereotypies, and self-injurious behavior than children with no to minimal impairment. This study adds to the literature evidencing an exacerbation of challenging behaviors by comorbid psychopathology in individuals with ASD. Clinical implications of these results are discussed. (C) 2013 Elsevier Ltd. All rights reserved.

BACKGROUND: Advanced paternal age (APA) is associated with increased risk for schizophrenia, but its effect on treatment response has not been longitudinally studied. METHODS: Association of parental ages at the time of the child's birth with age of onset, initial symptom severity and treatment response (to placebo and three different weight-based doses of paliperidone ER) in adolescents with schizophrenia was assessed in a post-hoc analysis using data from a 6-week double-blind study, the primary results of which are published (NCT00518323). RESULTS: The mean (SD) paternal age was 29.2 (6.2) years, range (16-50) and maternal age was 26.8 (5.7) years, range (17-42) at childbirth for the 201 adolescents (ages 12-17years) included in the analysis. While parental ages were uncorrelated with age of onset or initial symptom severity, both maternal and paternal ages showed significant effects on treatment response (p<0.03) of all paliperidone ER arms versus placebo. Paternal age was significantly correlated to improvement in positive symptoms and maternal age significantly related to negative symptoms, although only paternal age remained significantly associated with the treatment response in analyses that included both parents' ages. CONCLUSIONS: APA was associated with greater treatment response to both paliperidone ER and placebo, but not to age of onset or initial symptom severity in adolescents with schizophrenia. The results support the contention that APA-related schizophrenia has distinct underpinnings from other cases. Further studies are required to explore the role of genetic and environmental factors, and their interactions, in treatment response in this complex disorder.

We examined whether error monitoring, operationalized as the degree to which individuals slow down after committing an error (i.e., posterror slowing), is differentially important in the learning of rule-based versus information-integration category structures. Rule-based categories are most efficiently solved through the application of an explicit verbal strategy (e.g., "sort by color"). In contrast, information-integration categories are believed to be learned in a trial-by-trial, associative manner. Our results indicated that posterror slowing predicts enhanced rule-based but not information-integration category learning. Implications for multiple category-learning systems are discussed.