Heightened distractibility in participants with ADHD as indexed by increased reaction time (RT) variability has been hypothesized to be due to a failure to sufficiently suppress activation in the default attention network during cognitively demanding situations. The present study utilized fMRI to examine the relationship between intra-individual variability (IIV) in task RT and suppression of BOLD response in regions of the default network, using a working memory paradigm and two levels of control tasks. IIV was calculated separately for thirteen healthy control and twelve children with ADHD, Combined Type. Children with ADHD displayed significantly more RT variability than controls. Neural measures showed that although both groups displayed a pattern of increasing deactivation of the medial prefrontal cortex (PFC) with increasing task difficulty, the ADHD group was significantly less deactive than controls. Correlations between IIV and brain activation suggested that greater variability was associated with a failure to deactivate ventromedial PFC with increasing task difficulty. T-tests on brain activation between participants with ADHD with low versus high IIV implicated a similar region so that high variability was associated with greater activity in this region. These data provide support for the theory that increased distractibility in at least some participants with ADHD may be due to an inability to sufficiently suppress activity in the default attention network in response to increasing task difficulty.

Patterns of spontaneous brain activity, typically measured in humans at rest with fMRI, are used routinely to assess the brain's functional organization. The mechanisms that generate and coordinate the underlying neural fluctuations are largely unknown. Here we investigate the hypothesis that the nucleus basalis of Meynert (NBM), the principal source of widespread cholinergic and GABAergic projections to the cortex, contributes critically to such activity. We reversibly inactivated two distinct sites of the NBM in macaques while measuring fMRI activity across the brain. We found that inactivation led to strong, regionalized suppression of shared or "global" signal components of cortical fluctuations ipsilateral to the injection. At the same time, the commonly studied resting-state networks retained their spatial structure under this suppression. The results indicate that the NBM contributes selectively to the global component of functional connectivity but plays little if any role in the specific correlations that define resting-state networks.

Background Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuroimaging studies have implicated some regions underlying this disorder, there is little information regarding its large-scale connectivity pattern. This study investigated the within- and between-network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures. Methods Using Probabilistic Independent Component Analysis (PICA) on resting-state fMRI (rs-fMRI) data from 25 alcohol dependent (AD) and 26 healthy control (HC) participants, we compared the within- and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay-discounting task (DDT) was explored. Results Compared to HC, AD exhibited increased within-network FC in salience (SN), default-mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with RECN, anterior DMN (aDMN), and posterior DMN (pDMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, aDMN and SN in AD. Conclusions These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n = 39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized doubleblind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.