Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

The neuroscience and context of adolescent depression.

UNLABELLED: Adolescent depression is a growing public health concern with an increased risk of negative health outcomes, including suicide. The use of antidepressants and psychotherapy has not halted its increasing prevalence, and there is a critical need for effective prevention and treatment. We reviewed the neuroscience of adolescent depression, with a focus on the neurocircuitry of sustained threat and summarised contextual factors that have an impact on brain development and the pathophysiology of depression. We also reviewed novel treatment models. CONCLUSION: Attention to the relevant neurocircuitry and contextual factors implicated in adolescent depression is necessary to advance prevention and treatment development.

Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder.

Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.

Stress-Induced Reduction of Dorsal Striatal D2 Dopamine Receptors Prevents Retention of a Newly Acquired Adaptive Coping Strategy.

The inability to learn an adaptive coping strategy in a novel stressful condition leads to dysfunctional stress coping, a marker of mental disturbances. This study tested the involvement of dorsal striatal dopamine receptors in the dysfunctional coping with the Forced Swim test fostered by a previous experience of reduced food availability. Adult male mice were submitted to a temporary (12 days) reduction of food availability [food-restricted (FR)] or continuously free-fed (FF). Different groups of FF and FR mice were used to evaluate: (1) dorsal striatal mRNA levels of the two isoforms of the dopamine D2 receptor (D2S, D2L). (2) Forced Swim-induced c-fos expression in the dorsal striatum; (3) acquisition and 24 h retention of passive coping with Forced Swim. Additional groups of FF mice were tested for 24 h retention of passive coping acquired during a first experience with Forced Swim immediately followed by intra-striatal infusion of vehicle or two doses of the dopamine D2/D3 receptors antagonist sulpiride or the D1/D5 receptors antagonist SCH23390. Previous restricted feeding selectively reduced mRNA levels of both D2 isoforms and abolished Forced Swim-induced c-fos expression in the left Dorsolateral Striatum and selectively prevented 24 h retention of the coping strategy acquired in a first experience of Forced Swim. Finally, temporary blockade of left Dorsolateral Striatum D2/D3 receptors immediately following the first Forced Swim experience selectively reproduced the behavioral effect of restricted feeding in FF mice. In conclusion, the present results demonstrate that mice previously exposed to a temporary reduction of food availability show low striatal D2 receptors, a known marker of addiction-associated aberrant neuroplasticity, as well as liability to relapse into maladaptive stress coping strategies. Moreover, they offer strong support to a causal relationship between reduction of D2 receptors in the left Dorsolateral Striatum and impaired consolidation of newly acquired adaptive coping.

Biobehavioral Mechanisms of Mindfulness as a Treatment for Chronic Stress: An RDoC Perspective.

Mindfulness-based interventions have been heralded as promising means of alleviating chronic stress. While meta-analyses indicate that mindfulness-based interventions significantly reduce global measures of stress, how mindfulness-based interventions modulate the specific mechanisms underpinning chronic stress as operationalized by the National Institute of Mental Health research domain criteria (RDoC) of sustained threat has not yet been detailed in the literature. To address this knowledge gap, this article aims to (1) review evidence that mindfulness-based interventions ameliorate each of the 10 elements of behavioral dysregulation characterizing sustained threat via an array of mindful counter-regulatory strategies; (2) review evidence that mindfulness-based interventions modify biological domains implicated in sustained threat, such as the hypothalamic-pituitary-adrenal axis, as well as brain circuits involved in attentional function, limbic reactivity, habit behavior, and the default mode network; and (3) integrate these findings into a novel conceptual framework of mindful self-regulation in the face of stress-the Mindfulness-to-Meaning Theory. Taken together, the extant body of scientific evidence suggests that the practice of mindfulness enhances a range biobehavioral factors implicated in adaptive stress coping and induces self-referential plasticity, leading to the ability to find meaning in adversity. These mechanistic findings can inform the treatment development process to optimize the next generation of mindfulness-based interventions for greater therapeutic efficacy.