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Background: Rumination-focused cognitive behavioral therapy (RF-CBT) is designed to reduce depressive rumination or the habitual tendency to dwell on experiences in a repetitive, negative, passive, and global manner. RF-CBT uses functional analysis, experiential exercises, and repeated practice to identify and change the ruminative habit. This preregistered randomized clinical trial (NCT03859297, R61) is a preregistered replication of initial work. We hypothesized a concurrent reduction of both self-reported rumination and cross-network connectivity between the left posterior cingulate cortex and right inferior frontal and inferior temporal gyri., Methods: Seventy-six youths with a history of depression and elevated rumination were randomized to 10 to 14 sessions of RF-CBT ( n  = 39; 34 completers) or treatment as usual ( n  = 37; 28 completers). Intent-to-treat analyses assessed pre-post change in rumination response scale and in functional connectivity assessed using two 5 minute, 12 second runs of resting-state functional magnetic resonance imaging., Results: We replicated previous findings: a significant reduction in rumination response scale and a reduction in left posterior cingulate cortex to right inferior frontal gyrus/inferior temporal gyrus connectivity in participants who received RF-CBT compared with those who received treatment as usual. Reductions were large ( z change = 0.84; 0.73, respectively [ p s < .05])., Conclusions: This adolescent clinical trial further demonstrates that depressive rumination is a brain-based mechanism that is modifiable via RF-CBT. Here, we replicated that RF-CBT reduces cross-network connectivity, a possible mechanism by which rumination becomes less frequent, intense, and automatic. This National Institute of Mental Health-funded fast-fail study continues to the R33 phase during which treatment-specific effects of RF-CBT will be compared with relaxation therapy., (© 2023 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.)

Precision medicine approaches hold tremendous promise to advance current clinical practice by providing information about which individuals will benefit from which treatments. This pilot study evaluated if baseline structure and function of the salience and emotion brain regions implicated in adolescent depression, specifically the amygdala and anterior cingulate cortex (ACC), predict response to Interpersonal Psychotherapy for Depressed Adolescents (IPT-A). Adolescents ( n = 15; mean age = 14.5 (1.6); 80.0% female) diagnosed with a depressive disorder completed brain scans before the start of a 16 week trial of IPT-A. Clinical measures assessing depressive symptoms were completed before, during, and after a trial of therapy. Results show that at baseline, greater ACC activation in the context of an emotion-matching task and greater amygdala-ACC resting-state functional connectivity was related to greater improvement in depression symptoms. There was minimal evidence that brain structure predicted changes in depressive symptoms. The present study is the first to evaluate neural predictors of IPT-A response. While the results are preliminary, these findings suggest some avenues for future research to pursue in the hopes that more will benefit from treatment.

Strategies to link impulsivity and self-injurious behaviors (SIBs) show highly variable results, and may differ depending on the impulsivity measure used. To better understand this lack of consistency, we investigated correlations between self-report and behavioral impulsivity, inhibitory control, SIBs, and rumination. We included participants aged 13-17 years with either current or remitted psychopathology who have ( n = 31) and who do not have ( n = 14) a history of SIBs. Participants completed self-report measures of impulsivity, the Rumination Responsiveness Scale (RRS), and two behavioral measures of impulsivity: the Balloon Analogue Risk Task (BART) and Parametric Go/No-Go (PGNG). Lifetime SIBs were positively associated with self-reported impulsivity, specifically positive and negative urgency. However, individuals with greater lifetime SIBs demonstrated greater risk aversion (lower impulsivity) as measured by the BART, whereas there was no relation between lifetime SIBs and PGNG performance. There was no relation between rumination and behavioral impulsivity, although greater rumination was associated with higher negative urgency. Future research examining the role of SIBs in the context of active versus remitted psychopathology is warranted. Because most adolescents were remitted from major depressive disorder at the time of study, follow-up studies can determine if lower risk-taking may aid individuals with more prior SIBs to achieve and maintain a remitted state.

Investigation of brain changes in functional connectivity and functional network topology from receiving 8-week selective serotonin reuptake inhibitor (SSRI) treatments is conducted in 12 unmedicated adolescents with major depressive disorder (MDD) by using wavelet-filtered resting-state functional magnetic resonance imaging (fMRI). Changes are observed in frontal-limbic, temporal, and default mode networks. In particular, topological analysis shows, at the global scale and in the 0.12-0.25 Hz band, that the normalized clustering coefficient and smallworldness of brain networks decreased after treatment. Regional changes in clustering coefficient and efficiency were observed in the bilateral caudal middle frontal gyrus, rostral middle frontal gyrus, superior temporal gyrus, left pars triangularis, putamen, and right superior frontal gyrus. Furthermore, changes of nodal centrality and changes of connectivity associated with these frontal and temporal regions confirm the global topological alternations. Moreover, frequency dependence is observed from FDR-controlled subnetworks for the limbic-cortical connectivity change. In the high-frequency band, the altered connections involve mostly frontal regions, while the altered connections in the low-frequency bands spread to parietal and temporal areas. Due to the limitation of small sample sizes and lack of placebo control, these preliminary findings require confirmation with future work using larger samples. Confirmation of biomarkers associated with treatment could suggest potential avenues for clinical applications such as tracking treatment response and neurobiologically informed treatment optimization.

Background: Adolescent-onset depression often results in a chronic and recurrent course, and is associated with worse outcomes relative to adult-onset depression. Targeting habitual depressive rumination, a specific known risk factor for relapse, may improve clinical outcomes for adolescents who have experienced a depressive episode. Randomized controlled trials (RCTs) thus far have demonstrated that rumination-focused cognitive behavioral therapy (RFCBT) reduces depressive symptoms and relapse rates in patients with residual depression and adolescents and young adults with elevated rumination. This was also observed in a pilot RCT of adolescents at risk for depressive relapse. Rumination can be measured at the self-report, behavioral, and neural levels- using patterns of connectivity between the Default Mode Network (DMN) and Cognitive Control Network (CCN). Disrupted connectivity is a putative important mechanism for understanding reduced rumination via RFCBT. A feasibility trial in adolescents found that reductions in connectivity between DMN and CCN regions following RFCBT were correlated with change in rumination and depressive symptoms., Method: This is a phase III two-arm, two-stage, RCT of depression prevention. The trial tests whether RFCBT reduces identified risk factors for depressive relapse (rumination, patterns of neural connectivity, and depressive symptoms) in adolescents with partially or fully remitted depression and elevated rumination. In the first stage, RFCBT is compared to treatment as usual within the community. In the second stage, the comparator condition is relaxation therapy. Primary outcomes will be (a) reductions in depressive rumination, assessed using the Rumination Response Scale, and (b) reductions in resting state functional magnetic resonance imaging connectivity of DMN (posterior cingulate cortex) to CCN (inferior frontal gyrus), at 16 weeks post-randomization. Secondary outcomes include change in symptoms of depression following treatment, recurrence of depression over 12 months post-intervention period, and whether engagement with therapy homework (as a dose measure) is related to changes in the primary outcomes., Discussion: RFCBT will be evaluated as a putative preventive therapy to reduce the risk of depressive relapse in adolescents, and influence the identified self-report, behavioral, and neural mechanisms of change. Understanding mechanisms that underlie change in rumination is necessary to improve and further disseminate preventive interventions., Trial Registration: ClinicalTrials.gov Identifier: NCT03859297 , registered 01 March 2019.

Background: Non-suicidal self-injury (NSSI) is a growing public health concern that commonly begins in adolescence, and can persist into young adulthood. A promising approach for advancing our understanding of NSSI in youth is to examine white matter microstructure using diffusion magnetic resonance imaging (dMRI)., Method: The present study examined whole-brain group differences in structural connectivity (as measured by generalized fractional anisotropy [GFA]) between 28 female adolescents and young adults ages 13-21 years with NSSI and 22 age-matched healthy controls (HC). We also explored the association between clinical characteristics including NSSI severity and duration, impulsivity, emotion regulation and personality traits within the NSSI group and GFA of the uncinate fasciculus and cingulum., Results: Compared to the HC group, participants with NSSI had lower GFA in several white matter tracts, including the uncinate fasciculus, cingulum, bilateral superior and inferior longitudinal fasciculi, anterior thalamic radiation, callosal body, and corticospinal tract. When controlling for depressive symptoms, the NSSI group showed an association between NSSI duration (time since initiating NSSI behavior) and lower GFA in the left cingulum. Higher levels of attentional impulsivity were related to lower GFA in the left uncinate fasciculus within the NSSI group., Conclusions: We found evidence suggesting widespread white matter microstructure deficits in adolescents and young adults with NSSI versus HC. We also report inverse associations between white matter integrity and clinical characteristics (duration of NSSI and attentional impulsivity). These white matter microstructural deficits may represent a possible neurobiologically-based vulnerability to developing maladaptive coping mechanisms, such as NSSI. Additionally, results suggest that this white matter disorganization may either worsen with prolonged engagement in NSSI or predict persistent NSSI; thereby highlighting the importance of early intervention targeting this behavior., (Copyright © 2020 Westlund Schreiner, Mueller, Klimes-Dougan, Begnel, Fiecus, Hill, Lim and Cullen.)

Major depressive disorder (MDD) has been associated with abnormalities in cortical thickness and autonomic function. Adolescence is a time notable for brain development and MDD onset. In healthy adolescents, greater resting state vagal activity (RVA) is associated with lower cortical thickness. The relationship between brain structural thickness and RVA in adolescents with MDD has not previously been studied. This secondary analysis drew on a sample of 37 non-depressed controls and 53 adolescents with MDD. Resting state heart rate and two indices of RVA (HF-HRV and RMSSD) were recorded during a neuroimaging session. Cortical thickness within fronto-limbic regions of interest was measured using Freesurfer analysis of T1-weighted high-resolution structural images. Self-reports of depression severity showed a significant interaction with cortical thickness of the right insula in predicting RMSSD [t = 2.22, P=0.030, β = 5.44; model fit of the interaction term as indicated by the 'Bayes Factor' (BF): 7.58] and HF-HRV (t = 2.09, P=0.041, β = 4.72; BF: 7.94). Clinician ratings of depression severity showed further interactions. Findings underscore the important relationships between RVA and cortical development, suggesting two possible explanations: (i) in adolescent MDD, greater fronto-limbic thickness is compensatory for deficits in autonomic regulation or (ii) increased autonomic arousal results in delayed fronto-limbic maturation. Longitudinal research is necessary to further clarify the nature of the relationship between autonomic functioning and cortical development.