Although perceived threats in a child’s social environment, including in the family, school, and neighborhood, are known to increase risk for adolescent psychopathology, the underlying biological mechanisms remain unclear. To investigate, we examined whether perceived social threats were associated with the functional connectivity of large-scale cortical networks in early adolescence, and whether such connectivity differences mediated the development of subsequent mental health problems in youth.

Structural equation models were used to analyze data from 8,690 youth (50% female, 45% non-White, age 9–10 years) drawn from the large-scale, nationwide Adolescent Brain Cognitive Development study that has 21 clinical and research sites across the United States. Data were collected from 2016 to 2018.

Consistent with Social Safety Theory, perceived social threats were prospectively associated with mental health problems both 6 months (standardized $ \beta =0.27,p<.001 $) and 30 months ($ \beta =0.14,p<.001 $) later. Perceived social threats predicted altered connectivity patterns within and between the default mode (DMN), dorsal attention (DAN), frontoparietal (FPN), and cingulo-opercular (CON) networks. In turn, hypoconnectivity within the DMN and FPN – and higher (i.e., less negative) connectivity between DMN-DAN, DMN-CON, and FPN-CON – mediated the association between perceived social threats and subsequent mental health problems.

Perceiving social threats in various environments may alter neural connectivity and increase the risk of psychopathology in youth. Therefore, parenting, educational, and community-based interventions that bolster social safety may be helpful.

Midlife adults are experiencing a crisis of deaths of despair (i.e. deaths from suicide, drug overdose, and alcohol-related liver disease). We tested the hypothesis that a syndrome of despair-related maladies at midlife is preceded by psychopathology during adolescence.

Participants are members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972–73 and followed to age 45 years, with 94% retention. Adolescent mental disorders were assessed in three diagnostic assessments at ages 11, 13, and 15 years. Indicators of despair-related maladies across four domains – suicidality, substance misuse, sleep problems, and pain – were assessed at age 45 using multi-modal measures including self-report, informant-report, and national register data.

We identified and validated a syndrome of despair-related maladies at midlife involving suicidality, substance misuse, sleep problems, and pain. Adults who exhibited a more severe syndrome of despair-related maladies at midlife tended to have had early-onset emotional and behavioral disorders [β = 0.23, 95% CI (0.16–0.30), p < 0.001], even after adjusting for sex, childhood SES, and childhood IQ. A more pronounced midlife despair syndrome was observed among adults who, as adolescents, were diagnosed with a greater number of mental disorders [β = 0.26, 95% CI (0.19–0.33), p < 0.001]. Tests of diagnostic specificity revealed that associations generalized across different adolescent mental disorders.

Midlife adults who exhibited a more severe syndrome of despair-related maladies tended to have had psychopathology as adolescents. Prevention and treatment of adolescent psychopathology may mitigate despair-related maladies at midlife and ultimately reduce deaths of despair.