Neural mechanisms of inhibitory control in preadolescent irritability: Insights from the ABCD study.

OBJECTIVE: Elevated pediatric irritability is a transdiagnostic symptom that predicts multiple mental health problems in adolescence and adulthood. Altered top-down regulatory networks, such as inhibitory control networks that suppress an impulse in favor of goal-directed behavior, are thought to contribute to high levels of youth irritability. Nevertheless, little work has examined links between youth irritability and neural processes supporting inhibitory control in large diverse samples, nor have they focused on the key period ramping up to adolescence (i.e., preadolescence). METHOD: Functional MRI data from 5380 preadolescents (age M=9.97 years, SD=0.62) in the baseline Adolescent Brain and Cognitive Development (ABCD) Study were analyzed. Parents reported on their preadolescent's irritability. The stop signal task (SST) was leveraged to probe successful and failed inhibitory control. Activation and functional connectivity with amygdala, ventral striatum, and prefrontal seed regions were calculated during the SST and used in whole brain and region of interest (ROI) group-level analyses evaluating irritability effects. RESULTS: Preadolescents with higher levels of irritability displayed decreases in functional connectivity among amygdala, ventral striatum, and prefrontal cortex regions during both successful and failed inhibitory control conditions. These results remained after adjusting for co-occurring anxiety, depression, and attention-deficit/hyperactivity symptoms. CONCLUSIONS: Findings suggest neural aberrations in inhibitory control play a role in the pathophysiology of preadolescent irritability and associations are not merely due to co-occurring symptoms. Neural mechanisms of inhibitory control associated with irritability may provide novel intervention targets.

Neural correlates of irritability symptom relief in adolescents pre- and post-trauma-focused cognitive behavioral therapy: A pilot study on reward processing.

Despite that Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) is a first-line, evidence-based treatment for youths experiencing trauma-related symptoms, treatment responses vary and it remains unclear for whom and how this treatment works. In this context, we examined pre-treatment neural reward processing and pre- vs. post-treatment changes in neural reward processing, in relation to irritability - a transdiagnostic and dimensional feature present in multiple trauma-related syndromes, following TF-CBT. Adolescents (N = 22) with childhood trauma history completed a child-friendly monetary incentive delay task during fMRI acquisition, prior to and after the treatment, and irritability symptoms were assessed at five time points over the course of the treatment. Individual irritability slopes (i.e., irritability change rate) and intercepts (i.e., initial irritability level), generated by linear growth curve modeling, were integrated with fMRI data. Repeated ANCOVAs demonstrated that both pre-treatment neural response to reward and pre- vs. post-treatment changes in neural reward processing correlated with irritability symptom relief, such that opposite baseline neural reward processing profiles and differential changing patterns were observed in individuals showing irritability symptom relief vs. not. Together, our findings provide proof of concept that integrating brain information with clinical information has the potential to identify predictors and mechanisms of symptom relief.

White matter integrity in adolescent irritability: A preliminary study.

Irritability is a prevalent, impairing transdiagnostic symptom, especially during adolescence, yet little is known about irritability's neural mechanisms. A few studies examined the integrity of white matter tracts that facilitate neural communication in irritability, but only with extreme, disorder-related symptom presentations. In this preliminary study, we used a group connectometry approach to identify white matter tracts correlated with transdiagnostic irritability in a community/clinic-based sample of 35 adolescents (mean age = 14 years, SD = 2.0). We found positive and negative associations with irritability in local white matter tract bundles including sections of the longitudinal fasciculus; frontoparietal, parolfactory, and parahippocampal cingulum; corticostriatal and thalamocortical radiations; and vertical occipital fasciculus. Our findings support functional neuroimaging studies that implicate widespread neural pathways, particularly emotion and reward networks, in irritability. Our findings of positive and negative associations reveal a complex picture of what is "good" white matter connectivity. By characterizing irritability's neural underpinnings, targeted interventions may be developed.

Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents.

Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (ß = 0.466 ± 0.199, p = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: ß = -0.906 ± 0.433, p = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.

Default mode and salience network alterations in suicidal and non-suicidal self-injurious thoughts and behaviors in adolescents with depression.

Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide deaths in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents-49 adolescents with depression and 21 healthy controls-to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (all ps < 0.043, uncorrected). Depressed adolescents with NSSI had lower coherence in the anterior DMN and in insula-SN (all ps < 0.030, uncorrected), and higher CEN-DMN connectivity compared to those without NSSI and healthy controls (all ps < 0.030, uncorrected). Lower network coherence in all DMN subnetworks and insula-SN were associated with higher past-month SI and NSSI (all ps < 0.001, uncorrected). Thus, in our sample, both SI and NSSI are related to brain networks associated with difficulties in self-referential processing and future planning, while NSSI specifically is related to brain networks associated with disruptions in interoceptive awareness.

Smaller caudate gray matter volume is associated with greater implicit suicidal ideation in depressed adolescents.

BACKGROUND: Objective biomarkers of cognitive vulnerabilities related to suicidal ideation (SI) may assist in early prevention in adolescents. Previously, we found that smaller gray matter volumes (GMVs) of the dorsal striatum prospectively predicted implicit SI, measured using a computerized implicit association test (IAT) assessing associations between "self" and "death," in a community sample of adolescents. Here, we sought to replicate these findings in an independent sample of depressed adolescents. METHODS: 53 depressed adolescents who varied in severity of suicidal thoughts and behaviors completed high-resolution structural MRI. Caudate, putamen, and nucleus accumbens GMVs were estimated using FreeSurfer 6.0. Robust linear regressions were used to examine associations between striatal GMVs and implicit and explicit SI, covarying for sex, age, total intracranial volume, medication use, and depression severity. Significance was determined using Bonferroni correction. Finally, LASSO regression was used to identify which striatal GMV contributed most to prediction of implicit SI. RESULTS: Smaller bilateral caudate and right nucleus accumbens GMVs were associated with higher IAT scores (all ps<0.001). Smaller putamen and nucleus accumbens GMVs were not associated with implicit or explicit SI. Our LASSO analysis indicated that right caudate GMV contributed most to the prediction of IAT scores. CONCLUSIONS: This study is the first to demonstrate that caudate GMVs are significantly associated with implicit self-associations with death in a sample of depressed adolescents. When considered with our previous work, smaller caudate GMVs may be a robust biomarker of implicit SI in adolescents, with clinical implications for early identification of youth at risk for engaging in suicidal behaviors.

Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER).

This article provides an overview of the study protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) project, a longitudinal study in which we plan to recruit 60 depressed adolescents (ages 13-18 years) and 30 psychiatrically healthy controls in order to examine the inflammatory and glutamatergic pathways that contribute to the recurrence of depression in adolescents. TIGER is the first study to examine the effects of peripheral inflammation on neurodevelopmental trajectories by assessing changes in cortical glutamate in depressed adolescents. Here, we describe the scientific rationale, design, and methods for the TIGER project. This article is intended to serve as an introduction to this project and to provide details for investigators who may be seeking to replicate or extend these methods for other related research endeavors.