Callous and uncaring traits are associated with reductions in amygdala volume among youths with varying levels of conduct problems.

BACKGROUND: The emergence of callous unemotional (CU) traits, and associated externalizing behaviors, is believed to reflect underlying dysfunction in the amygdala. Studies of adults with CU traits or psychopathy have linked characteristic patterns of amygdala dysfunction to reduced amygdala volume, but studies in youths have not thus far found evidence of similar amygdala volume reductions. The current study examined the association between CU traits and amygdala volume by modeling CU traits and externalizing behavior as independent continuous variables, and explored the relative contributions of callous, uncaring, and unemotional traits. METHODS: CU traits and externalizing behavior problems were assessed in 148 youths using the Inventory of Callous Unemotional Traits (ICU) and the Child Behavior Checklist (CBCL). For a subset of participants (n = 93), high-resolution T1-weighted images were collected and volume estimates for the amygdala were extracted. RESULTS: Analyses revealed that CU traits were associated with increased externalizing behaviors and decreased bilateral amygdala volume. These results were driven by the callous and uncaring sub-factors of CU traits, with unemotional traits unrelated to either externalizing behaviors or amygdala volume. Results persisted after accounting for covariation between CU traits and externalizing behaviors. Bootstrap mediation analyses indicated that CU traits mediated the relationship between reduced amygdala volume and externalizing severity. CONCLUSIONS: These findings provide evidence that callous-uncaring traits account for reduced amygdala volume among youths with conduct problems. These findings provide a framework for further investigation of abnormal amygdala development as a key causal pathway for the development of callous-uncaring traits and conduct problems.

Precision Inhibitory Stimulation of Individual-Specific Cortical Hubs Disrupts Information Processing in Humans.

Noninvasive brain stimulation (NIBS) is a promising treatment for psychiatric and neurologic conditions, but outcomes are variable across treated individuals. In principle, precise targeting of individual-specific features of functional brain networks could improve the efficacy of NIBS interventions. Network theory predicts that the role of a node in a network can be inferred from its connections; as such, we hypothesized that targeting individual-specific "hub" brain areas with NIBS should impact cognition more than nonhub brain areas. Here, we first demonstrate that the spatial positioning of hubs is variable across individuals but reproducible within individuals upon repeated imaging. We then tested our hypothesis in healthy individuals using a prospective, within-subject, double-blind design. Inhibition of a hub with continuous theta burst stimulation disrupted information processing during working-memory more than inhibition of a nonhub area, despite targets being separated by only a few centimeters on the right middle frontal gyrus of each subject. Based upon these findings, we conclude that individual-specific brain network features are functionally relevant and could leveraged as stimulation sites in future NIBS interventions.

Externalizing behavior severity in youths with callous-unemotional traits corresponds to patterns of amygdala activity and connectivity during judgments of causing fear.

Callous-unemotional (CU) traits characterize a subgroup of youths with conduct problems who exhibit low empathy, fearlessness, and elevated externalizing behaviors. The current study examines the role of aberrant amygdala activity and functional connectivity during a socioemotional judgment task in youths with CU traits, and links these deficits to externalizing behaviors. Functional magnetic resonance imaging was used to compare neural responses in 18 healthy youths and 30 youths with conduct problems and varying levels of CU traits as they evaluated the acceptability of causing another person to experience each of several emotions, including fear. Neuroimaging analyses examined blood oxygenation level dependent responses and task-dependent functional connectivity. High-CU youths exhibited left amygdala hypoactivation relative to healthy controls and low-CU youths primarily during evaluations of causing others fear. CU traits moderated the relationship between externalizing behavior and both amygdala activity and patterns of functional connectivity. The present data suggest that CU youths' aberrant amygdala activity and connectivity affect how they make judgments about the acceptability of causing others emotional distress, and that these aberrations represent risk factors for externalizing behaviors like rule breaking and aggression. These findings suggest that reducing externalizing behaviors in high-CU youths may require interventions that influence affective sensitivity.

Executive Dysfunction in Autism Spectrum Disorder Is Associated With a Failure to Modulate Frontoparietal-insular Hub Architecture.

BACKGROUND: Comorbid executive dysfunction in autism spectrum disorder (ASD) is a barrier to adaptive functioning, despite remittance of core social-communication symptoms. Network models of ASD address core symptoms but not comorbid executive dysfunction. Following recent demonstrations in healthy adults that, with increasing executive demands, hubs embedded within frontoparietal-insular control networks interact with a more diverse set of networks, we hypothesized that the capability of hubs to do so is perturbed in ASD and predicts executive behavior. METHODS: Seventy-five 7- to 13-year-old children with ASD (n = 35) and age- and IQ-matched typically developing control subjects (n = 40) completed both a resting-state and a selective attention task functional magnetic resonance imaging session. We assessed changes in the participation coefficient, a graph theory metric indexing hubness, of 264 brain regions comprising 12 functional networks between the two sessions. Parent reported executive impairment in everyday life was measured using the Behavior Rating Inventory of Executive Function. RESULTS: The participation coefficient of the frontoparietal-insular cortex, including core nodes of the frontoparietal control and salience networks, significantly increased in typically developing children but not in children with ASD during the task relative to rest. Change in frontoparietal-insular participation coefficient predicted Behavior Rating Inventory of Executive Function scores indexing the ability to attend to task-oriented output, plan and organize, and sustain working memory. CONCLUSIONS: Our results suggest that executive impairments in ASD emerge from a failure of frontoparietal-insular control regions to function as adaptive and integrative hubs in the brain's functional network architecture. Our results also demonstrate the utility of examining dynamic network function for elucidating potential biomarkers for disorders with comorbid executive dysfunction.

Working memory-related changes in functional connectivity persist beyond task disengagement.

We examined whether altered connectivity in functional networks during working memory performance persists following conclusion of that performance, into a subsequent resting state. We conducted functional magnetic resonance imaging (fMRI) in 50 young adults during an initial resting state, followed by an N-back working memory task and a subsequent resting state, in order to examine changes in functional connectivity within and between the default-mode network (DMN) and the task-positive network (TPN) across the three states. We found that alterations in connectivity observed during the N-back task persisted into the subsequent resting state within the TPN and between the DMN and TPN, but not within the DMN. Further, both speed of working memory performance and TPN connectivity strength during the N-back task predicted connectivity strength in the subsequent resting state. Finally, DMN connectivity measured before and during the N-back task predicted individual differences in self-reported inattentiveness, but this association was not found during the post-task resting state. Together, these findings have important implications for models of how the brain recovers following effortful cognition, as well as for experimental designs using resting and task scans.

Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition. OBJECTIVE: To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task. DESIGN, SETTING AND PATIENTS: Nineteen subjects with OTCD and 21 healthy controls participated in a case-control, IRB-approved study at Georgetown University Medical Center. INTERVENTION: An N-back working memory task was performed in a block design using 3T functional magnetic resonance imaging. RESULTS: In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls. CONCLUSIONS: Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub-optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects.