State rumination predicts inhibitory control failures and dysregulation of default, salience, and cognitive control networks in youth at risk of depressive relapse: Findings from the RuMeChange trial.

Background: Trait rumination is a habitual response to negative experiences that can emerge during adolescence, increasing risk of depression. Trait rumination is correlated with poor inhibitory control (IC) and altered default mode network (DMN) and cognitive control network (CCN) engagement. Provoking state rumination in high ruminating youth permits investigation of rumination and IC at the neural level, highlighting potential treatment targets. Methods: Fifty-three high-ruminating youth were cued with an unresolved goal that provoked state rumination, then completed a modified Sustained Attention to Response Task (SART) that measures IC (commissions on no-go trials) in a functional MRI study. Thought probes measured state rumination about that unresolved goal and task-focused thoughts during the SART. Results: Greater state rumination during the SART was correlated with more IC failures. CCN engagement increased during rumination (relative to task-focus), including left dorsolateral prefrontal cortex and dorsalmedial prefrontal cortex. Relative to successful response suppression, DMN engagement increased during IC failures amongst individuals with higher state and trait rumination. Exploratory analyzes suggested more bothersome unresolved goals predicted higher left DLPFC activation during rumination. Limitations: The correlational research design did not permit a direct contrast of causal accounts of the relationship between rumination and IC. Conclusions: State rumination was associated with impaired IC and disrupted modulation of DMN and CCN. Increased CCN engagement during rumination suggested effortful suppression of negative thoughts, and this was greater for more bothersome unresolved goals. Relative task disengagement was observed during rumination-related errors. DMN-CCN dysregulation in high-ruminating youth may be an important treatment target.

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.

Early Emergence of Rumination has no Association with Performance on a Non-affective Inhibitory Control Task.

Rumination is a vulnerability for depression and potentially linked to inhibitory control weaknesses. We aimed to replicate the association observed in adults between inhibitory control and rumination in adolescents, and to examine putative moderating roles of childhood maltreatment and perceived family cohesion in an adolescent sample at risk for depression due to familial/personal history. Ninety adolescents aged 11-17 (M = 14.6, SD = 1.8) completed self-report scales of rumination, maltreatment, and family cohesion, and performed a task assessing inhibitory control. Hierarchical regression models showed no significant relation between inhibitory control and moderator variables on rumination. However, adolescents who reported higher levels of maltreatment and who perceived lower family cohesion tended to indicate higher levels of rumination (BChilhood Maltreatment = 27.52, 95% CIs [5.63, 49.41], BFamily Cohesion = -0.40, 95% CIs [-0.65, -0.15]). These findings demonstrate an alternative understanding of factors that increase depression onset risk and recurrence in adolescents.

Relations of gray matter volume to dimensional measures of cognition and affect in mood disorders.

Understanding the relationship between brain measurements and behavioral performance is an important step in developing approaches for early identification of any psychiatric difficulties and interventions to modify these challenges. Conventional methods to identify associations between regional brain volume and behavioral measures are not optimized, either in scale, scope, or specificity. To find meaningful associations between brain and behavior with greater sensitivity and precision, we applied data-driven factor analytic models to identify and extract individual differences in latent cognitive functions embedded across several computerized cognitive tasks. Furthermore, we simultaneously utilized a keyword-based neuroimaging meta-analytic tool (i.e., NeuroSynth), restricted atlas-parcel matching, and factor-analytic models to narrow down the scope of search and to further aggregate gray matter volume (GMV) data into empirical clusters. We recruited an early adult community cross-sectional sample (Total n = 177, age 18-30) that consisted of individuals with no history of any mood disorder (healthy controls, n = 44), those with remitted major depressive disorder (rMDD, n = 104), and those with a diagnosis of bipolar disorder currently in euthymic state (eBP, n = 29). Study participants underwent structural magnetic resonance imaging (MRI) scans and separately completed behavioral testing using computerized measures. Factor-analyzing five computerized tasks used to assess aspects of cognitive and affective processing resulted in seven latent dimensions: (a) Emotional Memory, (b) Interference Resolution, (c) Reward Sensitivity, (d) Complex Inhibitory Control, (e) Facial Emotion Sensitivity, (f) Sustained attention, and (g)Simple Impulsivity/Response Style. These seven dimensions were then labeled with specific keywords which were used to create neuroanatomical maps using NeuroSynth. These masks were further subdivided into GMV clusters. Using regression, we identified GMV clusters that were predictive of individual differences across each of the aforementioned seven cognitive dimensions. We demonstrate that a dimensional approach consistent with core principles of RDoC can be utilized to identify structural variability predictive of critical dimensions of human behavior.

Increased sensitivity of insula to supraliminal faces in adults with histories of mood disorders and self-injury.

BACKGROUND: Mood disorders are associated with neurobiological disruptions in subliminal and supraliminal emotion processing. There may be additional variation based on sex and the presence of self-injurious thoughts and behaviors (SITBs). Examining individuals in remission allows us to understand trait-like emotion processing characteristics that persist in the absence of symptoms. This study investigates neural processing in response to supraliminal and subliminal emotional stimuli based upon mood disorder diagnosis, sex, and SITBs. METHODS: Seventy-five participants with a history of any mood disorder (AMD; 52 female) and 27 healthy controls (HC; 14 female) completed a fMRI task presenting subliminal and supraliminal facial stimuli. Within the AMD group, 20 had no history of SITBs, 26 had histories of suicidal ideation only, and 27 had histories of both SI and self-injurious behavior. We examined activation of salience network regions of interest including the amygdala, insula, and subgenual anterior cingulate cortex (sgACC) during the task. RESULTS: AMD showed greater insula activation in response to happy faces relative to sad faces, which was not seen in the HC group. Males exhibited lower insula activation in response to sad faces relative happy faces, a pattern not seen in females. Individuals with SITBs demonstrated a lack of sgACC blunting during supraliminal versus subliminal trials. CONCLUSIONS: We found different patterns of neural responses related to mood disorder status, sex, and SITBs. Findings highlight the importance of considering heterogeneity within diagnoses and examining neurobiological features in the context of remission.

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.

Shifting research priorities in maternal and child health in the COVID-19 pandemic era in India: A renewed focus on systems strengthening.

BACKGROUND: The remarkable progress seen in maternal and child health (MCH) in India over the past two decades has been impacted by the COVID-19 pandemic. We aimed to undertake a rapid assessment to identify key priorities for public health research in MCH in India within the context and aftermath of the COVID-19 pandemic. METHODS: A web-based survey was developed to identify top research priorities in MCH. It consisted of 26 questions on six broad domains: vaccine preventable diseases, outbreak preparedness, primary healthcare integration, maternal health, neonatal health, and infectious diseases. Key stakeholders were invited to participate between September and November 2020. Participants assigned importance on a 5-point Likert scale, and assigned overall ranks to each sub-domain research priority. Descriptive statistics were used to examine Likert scale responses, and a ranking analysis was done to obtain an "average ranking score" and identify the top research priority under each domain. RESULTS: Amongst the 84 respondents from across 15 Indian states, 37% were public-health researchers, 25% healthcare providers, 20% academic faculty and 13% were policy makers. Most respondents considered conducting systems strengthening research as extremely important. The highest ranked research priorities were strengthening the public sector workforce (vaccine preventable diseases), enhancing public-health surveillance networks (outbreak preparedness), nutrition support through community workers (primary care integration), encouraging at least 4-8 antenatal visits (maternal health), neonatal resuscitation to reduce birth asphyxia (neonatal health) and screening and treatment of tuberculosis (infectious diseases). Common themes identified through open-ended questions primarily included systems strengthening priorities across domains. CONCLUSIONS: The overall focus for research priorities in MCH in India during the COVID-19 pandemic is on strengthening existing services and service delivery, rather than novel research. Our results highlight pivotal steps within the roadmap for advancing and sustaining maternal and child health gains during the ongoing COVID-19 pandemic and beyond.

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.

Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders.

BACKGROUND: Little is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk. METHODS: Participants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups. RESULTS: Several fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1-4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79-88%). CONCLUSIONS: These results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.