Melinda Westlund Schreiner

Multilevel assessment of the neurobiological threat system in depressed adolescents: Interplay between the limbic system and hypothalamic-pituitary-adrenal axis

Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12-19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

Abnormal striatal resting-state functional connectivity in adolescents with obsessive–compulsive disorder

Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed.

Conceptualizing the neurobiology of non-suicidal self-injury from the perspective of the Research Domain Criteria Project

Non-suicidal self-injury (NSSI) commonly starts in adolescence and is associated with an array of negative outcomes. Neurobiological research investigating NSSI is in its early stages and most studies have examined this behavior within the context of specific diagnoses. However, the Research Domain Criteria (RDoC) initiative encourages researchers to examine brain-behavior relationships across diagnoses. This review on the neurobiology associated with NSSI is organized using the domains proposed by RDoC: Negative Valence, Positive Valence, Cognitive, Social Processes, and Arousal/Regulatory Systems. Evidence of neurobiological anomalies is found in each of these domains. We also propose future research directions, especially in regard to human development. Future NSSI studies should address this behavior independent of diagnosis, examine relevant constructs across multiple units of analysis, and assess how systems change across development and course of illness. These advances will be essential for guiding neurobiologically informed intervention and prevention strategies to target NSSI. In doing so, we may prevent the associated negative outcomes across the lifespan.

Multi-modal neuroimaging of adolescents with non-suicidal self-injury: Amygdala functional connectivity

BACKGROUND Non-suicidal self-injury (NSSI) is a significant mental health problem among adolescents. Research is needed to clarify the neurobiology of NSSI and identify candidate neurobiological targets for interventions. Based on prior research implicating heightened negative affect and amygdala hyperactivity in NSSI, we pursued a systems approach to characterize amygdala functional connectivity networks during rest (resting-state functional connectivity [RSFC)]) and a task (task functional connectivity [TFC]) in adolescents with NSSI. METHOD We examined amygdala networks in female adolescents with NSSI and healthy controls (n = 45) using resting-state fMRI and a negative emotion face-matching fMRI task designed to activate the amygdala. Connectivity analyses included amygdala RSFC, amygdala TFC, and psychophysiological interactions (PPI) between amygdala connectivity and task conditions. RESULTS Compared to healthy controls, adolescents with NSSI showed atypical amygdala-frontal connectivity during rest and task; greater amygdala RSFC in supplementary motor area (SMA) and dorsal anterior cingulate; and differential amygdala-occipital connectivity between rest and task. After correcting for depression symptoms, amygdala-SMA RSFC abnormalities, among others, remained significant. LIMITATIONS This studys limitations include its cross-sectional design and its absence of a psychiatric control group. CONCLUSIONS Using a multi-modal approach, we identified widespread amygdala circuitry anomalies in adolescents with NSSI. While deficits in amygdala-frontal connectivity (driven by depression symptoms) replicates prior work in depression, hyperconnectivity between amygdala and SMA (independent of depression symptoms) has not been previously reported. This circuit may represent an important mechanism underlying the link between negative affect and habitual behaviors. These abnormalities may represent intervention targets for adolescents with NSSI.

Neural and neuroendocrine predictors of pharmacological treatment response in adolescents with depression: A preliminary study

Objective: Typically, about 30 to 50% of adolescents with depression fail to respond to evidence‐based treatments, including antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). Efforts for identifying predictors and moderators of treatment response are needed to begin to address critical questions relevant to personalized care in adolescent depression. In this pilot study, we aim to identify biological predictors of response to antidepressant treatment. Method: We used a multiple levels of analysis approach to evaluate threat system functioning (fronto‐limbic system and the associated hormonal cascade) to determine if key biological indexes at baseline could predict improvement in depressive symptoms after eight weeks of antidepressant treatment in adolescents with depression. Results: Neural predictors of favorable treatment response included lower amygdala connectivity with left supplementary motor area and with right precentral gyrus, and greater amygdala connectivity with right central opercular cortex and Heschls gyrus connectivity during rest. During an emotion task, neural predictors of treatment response were greater activation of the bilateral anterior cingulate cortex and left medial frontal gyrus. Additionally, different patterns of salivary cortisol obtained in the context of a modified Trier Social Stress Test were associated with those whose depressive symptoms remitted as compared to those whose symptoms persisted. Conclusions: This approach shows significant promise for identifying predictors of treatment response in adolescents with depression. Future work is needed that incorporates sufficiently powered, randomized control trials to provide the basis by which both predictors and moderators of treatment response are identified. The hope is that this work will inform the development of methods that can guide clinician decision‐making in assigning beneficial treatments for adolescents who are suffering from depression. HighlightsTreatments are available for adolescent depression.Few guidelines are available for guiding treatment selection.This study sets out to identify possible predictors of treatment response.Preliminary results support the use of neural circuitry and neuroendocrine indexes.The hope is to optimize the match between the individual and the treatment.

Brain structural thickness and resting state autonomic function in adolescents with major depression

Abstract 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.

Increases in orbitofrontal cortex thickness following antidepressant treatment are associated with changes in resting state autonomic function in adolescents with major depression – Preliminary findings from a pilot study

In adults with major depressive disorder (MDD), effective treatment has been associated with increases in both heart rate variability (HRV) and cortical thickness. However, the impact of treatment on these indices has not yet been examined in adolescents. Cortical thickness and HRV were measured in twelve adolescents with MDD before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). We examined treatment-related changes in depression symptoms, HRV, heart rate (HR), and cortical thickness, and analyzed correlations among these change indices. At follow-up, patients showed significantly decreased depression severity, increased HRV and increased thickness of the left medial orbitofrontal cortex (OFC). Clinical improvement was associated with increased HRV and decreased HR. Increased HRV was associated with increased cortical thickness of left lateral OFC and superior frontal cortex. Due to the small sample size, results represent preliminary findings that need replication. Further, in the absence of a placebo arm, we cannot confirm that the observed effects are due solely to medication. These preliminary findings suggest that SSRI treatment in adolescents impacts both cortical thickness and autonomic functioning. Confirmation of these findings would support OFC thickness and HRV as neurobiological mediators of treatment outcome.

Multi-level Analysis of the Functioning of the Neurobiological Threat System in Adolescents: Implications for Suicide and Nonsuicidal Self-Injury

Purpose of ReviewAdvancement in knowledge of the neurobiological underpinnings of suicide and nonsuicidal self-injury (NSSI) will require multi-level approaches to understand the typical and atypical developmental processes in systems that are relevant to these aberrant behaviors. Here we focus on the threat system as a prototype, with the goal of integrating research investigating both the central and peripheral arms of this system, as well as the interplay between the brain and the body, during adolescence.Recent FindingsAn examination of research on the central and peripheral measures of the threat system in typically and atypically developing populations illustrates how the integration of multiple levels of analysis can be optimal in the comprehensive assessment of a system’s functioning. Further, this examination of the literature to date highlights important considerations for future work incorporating populations that engage in self-harm.SummaryFuture adolescent research investigating the neurobiology implicated in suicide and NSSI would benefit from the application of multiple units of analysis that is embedded in a developmental psychopathology perspective.