Numerous studies have linked exposure to stress to adverse health outcomes through the effects of cortisol, a product of the stress response system, on cellular aging processes. Accelerated DNA methylation age is a promising epigenetic marker associated with stress and disease risk that may constitute a link from stress response to changes in neural structures. Specifically, elevated glucocorticoid signaling likely contributes to accelerating DNA methylation age, which may signify a maladaptive stress-related cascade that leads to hippocampal atrophy. We examined the relations among diurnal cortisol levels, DNA methylation age and hippocampal volume in a longitudinal study of 46 adolescent girls. We computed area under the curve from two daily cortisol collection periods, and calculated DNA methylation age using previously established methods based on a set of CpG sites associated with chronological age. We computed a residual score by partialling out chronological age; higher discrepancies reflect relatively accelerated DNA methylation age. We assessed hippocampal volume via T1-weighted images and automated volumetric segmentation. We found that greater diurnal cortisol production was associated with accelerated DNA methylation age, which in turn was associated with reduced left hippocampal volume. Finally, accelerated DNA methylation age significantly mediated the association between diurnal cortisol and left hippocampal volume. Thus, accelerated DNA methylation age may be an epigenetic marker linking hypothalamic–pituitary–adrenal axis dysregulation with neural structure. If these findings are replicated, the current study provides a method for advancing our understanding of mechanisms by which glucocorticoid signaling is associated with cellular aging and brain development.

Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

IntroductionMajor depressive disorder (MDD) is primarily characterized by depressed mood and a blunted experience of pleasure (i.e., anhedonia). 1 The disorder is prevalent and chronic and represents a substantial personal, social and economic burden. [2][3][4] Neuroscience promises to elucidate mechanisms under lying depressive pathophysiology, leading to more effective approaches to the prevention and treatment of this debilitating disorder.Considerable evidence indicates that reward processing is dysfunctional in individuals with MDD. 5,6 The basal ganglia (BG) are a set of subcortical structures, including the striatum (caudate and putamen), nucleus accumbens and pallidum, that are critically involved in these reward processing steps. 7Previously research has indicated that depressed individuals have decreased activation in the striatum, 5,6 and some investigators have hypothesized that this abnormal activity affects decision-making. 5 Research in both animals and humans suggests that the dorsal striatum is involved in action selection and initiation and in encoding and integrating sensorimotor, cognitive and motivational/emotional information.8 Current evidence is mixed regarding specific roles of the putamen and caudate in reward processing. The results of several studies using fMRI suggest that whereas the putamen specifi cally encodes reward-related feedback, the caudate encodes both reward and punishment feedback.9,10 Finally, researchers have reported that the putamen is activated most strongly during anticipation of reward, whereas the caudate is activated most strongly during the receipt of reward. 8,10,11 A growing body of research indicates that adults with MDD have smaller volumes of the caudate 12-15 and putamen 13,14,16,17 than healthy controls. Postmortem studies have also reported smaller putamen volumes in depressed than in nondepressed adults. 18 It is important to note that these studies typically include adult samples with a mean age older than 40 years. Depression-associated differences in BG volumes are less consistent in samples of both younger adults 19,20 and adolescents. 21 It appears, therefore, that this discrepancy is associated with age differences in the study Background: Growing evidence indicates that major depressive disorder (MDD) is characterized by accelerated biological aging, including greater age-related changes in physiological functioning. The disorder is also associated with abnormal neural reward circuitry, particularly in the basal ganglia (BG). Here we assessed age-related changes in BG volume in both patients with MDD and healthy control participants. Methods: We obtained whole-brain T 1 -weighted images from patients with MDD and healthy controls. We estimated grey matter volumes of the BG, including the nucleus accumbens, caudate, pallidum and putamen. Volumes were assessed using multivariate analysis of covariance (MANCOVA) with age as a covariate, followed by appropriate post hoc tests. Results: We included 232 individuals (116 patients with MDD) in our analy...

Highlights Non-human animal research shows stress alters amygdala–medial prefrontal cortex (mPFC) connectivity. It is unclear how prenatal stress may alter human infant connectivity. Prenatal stress was associated with decreased amygdala–mPFC functional connectivity. Prenatal stress was associated with increased amygdala–mPFC structural connectivity. This work provides insight into how stress contributes to neurodevelopmental risk.

Researchers are becoming increasingly interested in linking specific forms of early life stress (ELS) to specific neurobiological markers, including alterations in the morphology of stress-sensitive brain regions. We used a person-centered, multi-informant approach to investigate the associations of specific constellations of ELS with hippocampal and amygdala volume in a community sample of 211 9- to 13-year-old early adolescents. Further, we compared this approach to a cumulative risk model of ELS, in which ELS was quantified by the total number of stressors reported. Using latent class analysis, we identified three classes of ELS (labeled typical/low, family instability, and direct victimization) that were distinguished by experiences of family instability and victimization. Adolescents in the direct victimization class had significantly smaller hippocampal volume than did adolescents in the typical/low class; ELS classes were not significantly associated with amygdala volume. The cumulative risk model of ELS had a poorer fit than did the person-centered model; moreover, cumulative ELS was not significantly associated with hippocampal or amygdala volume. Our results underscore the utility of taking a person-centered approach to identify alterations in stress-sensitive brain regions based on constellations of ELS, and suggest victimization is specifically associated with hippocampal hypotrophy observed in early adolescence.

Suicidal ideation (SI), a potent risk factor for suicide attempts, increases in adolescence. While alterations in dopaminergic functioning have been implicated in suicidal acts—particularly in adults—we do not know whether morphological alterations in dopamine-rich regions of the brain, such as the striatum, are vulnerability factors for the emergence of SI in adolescents. At baseline, a community sample of 152 adolescents (89 female; mean age: 11.41 ± 1.01 years) completed a magnetic resonance imaging (MRI) scan that was used to estimate gray matter volumes (GMVs) of three striatal structures: caudate, nucleus accumbens and putamen. At a 24 month follow-up session, participants completed a self-report measure of SI frequency [Suicidal Ideation Questionnaire (SIQ)] and the death version of the Implicit Association Test (IAT). Robust linear regression models were conducted to predict SIQ and IAT scores from striatal GMV. Bilateral putamen and left caudate GMV significantly predicted IAT scores (all Ps < 0.03). No other associations were significant (all Ps > 0.05). Our finding of reduced dorsal striatal GMV predicting implicit SI may indicate that downstream dopaminergic dysfunction is implicated in the development of overt suicidal behaviors. Self-reported SI was not associated with striatal GMV, suggesting that biological correlates of suicide risk may correlate specifically with objective measurements of SI in adolescents.

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five-to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult-infant conversational turns (CTs). Infants completed an rsfMRI scan during natural sleep, and we examined FC among regions of interest (ROIs) previously implicated in language comprehension, including the auditory cortex, the left inferior frontal gyrus (IFG), and the bilateral superior temporal gyrus (STG). Consistent with theory of the ontogeny of the cortical language network (Skeide and Friederici, 2016), we identified two subnetworks posited to have distinct developmental trajectories: a posterior temporal network involving connections of the auditory cortex and bilateral STG and a frontotemporal network involving connections of the left IFG. Independent of socioeconomic status (SES), the quantity of CTs was uniquely associated with FC of these networks. Infants who engaged in a larger number of CTs in daily life had lower connectivity in the posterior temporal language network. These results provide evidence for the role of vocal interactions with caregivers, compared with overheard adult speech, in the function of language networks in infancy.