Early life stress (ELS) has been established as a major risk factor for a multitude of psychiatric and medical disorders. ELS is highly prevalent in the general population and constitutes a major public health concern. The current review will focus on the clinical literature that suggests a link between adverse early life experiences and vulnerability for adolescent and adult substance use disorders. It will investigate the characteristics of ELS that appear to increase risk for disorder onset and a more severe disease course, characterized by earlier onset, greater risk of relapse, and treatment resistance. The authors explore how ELS may increase risk for adverse substance use outcomes through long-lasting changes in the HPA axis and development of stress, reward, and executive control brain systems. The review will also discuss potential pathways to substance use disorder following ELS, with a focus on the role of comorbid mood and anxiety disorders and other modifiable traits. Finally, the authors will discuss how the current body of work presents the potential for prevention and intervention strategies to reduce the psychosocial consequences following early life stress and minimize adverse substance use outcomes.

Background: While deep brain stimulation has been successful in treating movement disorders, such as in Parkinson's disease, its potential application in alleviating memory disorders is inconclusive. Objective/Hypothesis: We investigated the role of the location of the stimulating electrode on memory improvement and hypothesized that entorhinal white versus gray matter stimulation would have differential effects on memory. Methods: Intracranial electrical stimulation was applied to the entorhinal area of twenty-two participants with already implanted electrodes as they completed visual memory tasks. Results: We found that stimulation of right entorhinal white matter during learning had a beneficial effect on subsequent memory, while stimulation of adjacent gray matter or left-sided stimulation was ineffective. This finding was consistent across three different visually guided memory tasks. Conclusions: Our results highlight the importance of precise stimulation site on modulation of human hippocampal-dependent memory and suggest that stimulation of afferent input into the right hippocampus may be an especially promising target for enhancement of visual memory.

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Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.

Background: Stress-related mechanisms are implicated in the pathophysiology of bipolar disorder and may contribute to heterogeneity in illness course. Yet, there is a lack of study investigating the neural mechanisms underlying the stress response in this condition. This study investigated changes in amygdala activation and functional connectivity in response to acute psychosocial stress in young adults with bipolar disorder and explored relations with clinical phenotype and prospective mood symptoms.Methods: 42 young adults [19 with bipolar disorder, age mean ± SD =21.4 ± 2.2 years] completed a modified version of the Montreal Imaging Stress Task. Amygdala activation and functional connectivity with prefrontal cortex (PFC) regions of interest was calculated for control and stress conditions. Main effects of group, condition, and group by condition interaction on amygdala activation and connectivity were modeled. A subset of bipolar participants completed 1-year follow-up assessments.Relations between neural responses to stress with concurrent substance use and prospective mood symptoms were explored.Results: There were no between-group differences in amygdala activation or functional connectivity during the control condition. Increased right amygdala-right rostral PFC (rPFC) functional connectivity to stress was observed in bipolar disorder, compared to typically developing controls. In bipolar disorder, greater increase in right amygdala-right rPFC functional connectivity to stress was associated with less frequent cannabis use, and prospectively with shorter duration and lower severity of depression symptoms over follow-up. Conclusion:Results from this preliminary study suggest differences in frontolimbic functional connectivity responses to stress in young adults with bipolar disorder and associations with cannabis use and prospective mood symptoms.