Rumination-Focused Cognitive Behavioral Therapy Reduces Rumination and Targeted Cross-network Connectivity in Youth With a History of Depression: Replication in a Preregistered Randomized Clinical Trial.

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 [ps < .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.

Negative association between non-suicidal self-injury in adolescents and default mode network activation during the distraction blocks of a rumination task.

INTRODUCTION: Rumination, or repetitive and habitual negative thinking, is associated with psychopathology and related behaviors in adolescents, including non-suicidal self-injury (NSSI). Despite the link between self-reported rumination and NSSI, there is limited understanding of how rumination is represented at the neurobiological level among youth with NSSI. METHOD: We collected neuroimaging and rumination data from 39 adolescents with current or past NSSI and remitted major depression. Participants completed a rumination induction fMRI task, consisting of both rumination and distraction blocks. We examined brain activation associated with total lifetime NSSI in the context of the rumination versus distraction contrast. RESULTS: Lifetime NSSI was associated with a greater discrepancy in activation during rumination relative to distraction conditions in clusters including the precuneus, posterior cingulate, superior, and middle frontal gyrus, and cerebellum. CONCLUSION: Difficulties associated with rumination in adolescents with NSSI may be related to requiring greater cognitive effort to distract from ruminative content in addition to increased attention in the context of ruminative content. Increasing knowledge of neurobiological circuits and nodes associated with rumination and their relationship with NSSI may enable us to better tailor interventions that can facilitate lasting well-being and neurobiological change.

Using Network Parcels and Resting-State Networks to Estimate Correlates of Mood Disorder and Related Research Domain Criteria Constructs of Reward Responsiveness and Inhibitory Control.

BACKGROUND: Resting-state graph-based network edges can be powerful tools for identification of mood disorders. We address whether these edges can be integrated with Research Domain Criteria (RDoC) constructs for accurate identification of mood disorder-related markers, while minimizing active symptoms of disease. METHODS: We compared 132 individuals with currently remitted or euthymic mood disorder with 65 healthy comparison participants, ages 18-30 years. Subsets of smaller brain parcels, combined into three prominent networks and one network of parcels overlapping across these networks, were used to compare edge differences between groups. Consistent with the RDoC framework, we evaluated individual differences with performance measure regressors of inhibitory control and reward responsivity. Within an omnibus regression model, we predicted edges related to diagnostic group membership, performance within both RDoC domains, and relevant interactions. RESULTS: There were several edges of mood disorder group, predominantly of greater connectivity across networks, different than those related to individual differences in inhibitory control and reward responsivity. Edges related to diagnosis and inhibitory control did not align well with prior literature, whereas edges in relation to reward responsivity constructs showed greater alignment with prior literature. Those edges in interaction between RDoC constructs and diagnosis showed a divergence for inhibitory control (negative interactions in default mode) relative to reward (positive interactions with salience and emotion network). CONCLUSIONS: In conclusion, there is evidence that prior simple network models of mood disorders are currently of insufficient biological or diagnostic clarity or that parcel-based edges may be insufficiently sensitive for these purposes.

Advancing a temporal framework for understanding the biology of nonsuicidal self- injury: An expert review.

Nonsuicidal self-injury (NSSI) is a serious clinical problem, particularly for adolescents and young adults. NSSI is a complex behavior that emerges through the intersecting effects of social, psychological, and biological mechanisms. Although the social and psychological contributions to risk for developing NSSI are relatively well understood and have guided the development of effective psychosocial treatments for self-injury, the biological mechanisms underlying NSSI have just begun to come to light. To evaluate and categorize the biological research conducted on the topic of NSSI, we propose a model that distinguishes between trait and state markers. According to this model, risk factors and mechanisms involved in NSSI can be distinguished into both trait and state factors. We review the existing evidence on distal biological traits (predictors) of NSSI, proximal biological traits (correlates) of NSSI, and biological states directly preceding or following NSSI. We conclude by providing recommendations for future research on the neurobiology of NSSI.

Mechanisms of rumination change in adolescent depression (RuMeChange): study protocol for a randomised controlled trial of rumination-focused cognitive behavioural therapy to reduce ruminative habit and risk of depressive relapse in high-ruminating adolescents.

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.

Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression.

BACKGROUND: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. AIMS: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3ß) in peripheral blood mononuclear cells. METHODS: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers. RESULTS: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3ß signaling. CONCLUSIONS: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3ß as brain flexibility markers and candidate targets for future clinical trials. CLINICAL TRIAL NAME: Ketamine in adolescents with treatment-resistant depressionURL: https://clinicaltrials.gov/ct2/show/NCT02078817Registration number: NCT02078817.