Faculty Bibliography

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.

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.

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.

OBJECTIVE: We sought to establish prevalence rates and detail patterns of comorbidity for generalized anxiety disorder, separation anxiety disorder, and social phobia in preschool-aged children. METHOD: The Duke Preschool Anxiety Study, a screen-stratified, cross-sectional study, drew from pediatric primary care and oversampled for children at risk for anxiety. A total of 917 parents of preschool children (aged 2-5 years) completed the Preschool Age Psychiatric Assessment. RESULTS: Generalized anxiety disorder, separation anxiety disorder, and social phobia are common in preschool-aged children attending pediatric primary care. Three-fourths of preschoolers with an anxiety disorder only had a single anxiety disorder. Generalized anxiety disorder displayed the greatest degree of comorbidity: with separation anxiety disorder (odds ratio [OR] = 4.1, 95% CI = 2.0-8.5), social phobia (OR = 6.4, 95% CI = 3.1-13.4), disruptive behavior disorders (OR = 5.1, 95% CI = 1.6-15.8), and depression (OR = 3.7, 95% CI = 1.1-12.4). CONCLUSIONS: The weakness of association between generalized anxiety disorder and depression stands in contrast to substantial associations between these 2 disorders reported in older individuals. Attenuated associations in preschool-aged children could translate into clinical opportunities for targeted early interventions, aimed at modifying the developmental trajectory of anxiety disorders.