Ahmad R. Hariri

Environmental exposures influence the risk of psychiatric disorders, yet the biological mechanisms by which such experiences become embedded in brain structure remain poorly understood. The human cerebral cortex is crucial for cognition and emotional regulation, and variation in cortical thickness (CT) and surface area (SA) is linked to various behavioural and psychiatric traits. Here, we present a large-scale epigenome-wide association study that combines peripheral blood DNA methylation (DNAm) with MRI-derived cortical measures in over 7,400 individuals across 20 cohorts within the ENIGMA consortium. We identify mostly non-overlapping DNAm signatures associated with CT and SA, consistent with their distinct developmental and regulatory architectures. CT-associated CpGs are replicated across independent cohorts and are enriched for environmentally responsive regulatory elements and pathways associated with stress, metabolism, and immune signalling. In contrast, SA-associated CpGs cluster within chromatin-regulatory regions involved in early cortical development. Phenome-wide and Mendelian randomisation analyses reveal pleiotropic associations between DNAm, cortical structure, and psychiatric and cognitive traits. These findings suggest that peripheral DNAm captures environmentally sensitive biological processes that link exposure, cortical organisation, and behavioural vulnerability.

To understand how aging affects functional decline and increases disease risk, it is necessary to develop measures of how fast a person is aging. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain magnetic resonance imaging, that is, the Dunedin Pace of Aging Calculated from NeuroImaging (DunedinPACNI). Exporting this measure to the Alzheimer’s Disease Neuroimaging Initiative, UK Biobank and BrainLat datasets revealed that faster DunedinPACNI predicted cognitive impairment, accelerated brain atrophy and conversion to diagnosed dementia. Faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases and mortality in older adults. When compared to brain age gap, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a next-generation brain magnetic resonance imaging biomarker that can help researchers explore aging effects on health outcomes and evaluate the effectiveness of antiaging strategies.

Mapping individual differences in brain function has been hampered by poor reliability as well as limited interpretability. Leveraging patterns of brain‐wide functional connectivity (FC) offers some promise in this endeavor. In particular, a macroscale principal FC gradient that recapitulates a hierarchical organization spanning molecular, cellular, and circuit level features along a sensory‐to‐association cortical axis has emerged as both a parsimonious and interpretable measure of individual differences in behavior. However, the measurement reliabilities of this FC gradient have not been fully evaluated. Here, we assess the reliabilities of both global and regional principal FC gradient measures using test–retest data from the young adult Human Connectome Project (HCP‐YA) and the Dunedin Study. Analyses revealed that the reliabilities of principal FC gradient measures were (1) consistently higher than those for traditional edge‐wise FC measures, (2) higher for FC measures derived from general FC (GFC) in comparison with resting‐state FC, and (3) higher for longer scan lengths. We additionally examined the relative utility of these principal FC gradient measures in predicting cognition and aging in both datasets as well as the HCP‐aging dataset. These analyses revealed that regional FC gradient measures and global gradient range were significantly associated with aging in all three datasets, and moderately associated with cognition in the HCP‐YA and Dunedin Study datasets, reflecting contractions and expansions of the cortical hierarchy, respectively. Collectively, these results demonstrate that measures of the principal FC gradient, especially derived using GFC, effectively capture a reliable feature of the human brain subject to interpretable and biologically meaningful individual variation, offering some advantages over traditional edge‐wise FC measures in the search for brain–behavior associations.

Self-regulation denotes the processes by which people initiate, maintain, and control their own thoughts, behaviors, or emotions to produce a desired outcome or avoid an undesired outcome. Self-regulation brings the influence of distal factors, such as biology, temperament, and socialization history, onto cognition, motivation, and behavior. Dysfunction in self-regulation represents a contributory causal factor for psychopathology. Accordingly, we previously proposed a risk phenotype model for depression drawing from regulatory focus theory and traditional studies using task-based functional magnetic resonance imaging. In this article, we revise and expand our risk phenotype model using insights from new methodologies allowing quantification of individual differences in task-free macroscale brain organization. We offer a set of hypotheses as examples of how examination of intrinsic macroscale brain organization can extend and enrich investigations of self-regulation and depression. In doing so, we hope to promote a useful heuristic for model development and for identifying transdiagnostic risk phenotypes in psychopathology.

Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7–26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.

Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions of interest, and poor test–retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide functional connectivity in a sample of 1,048 young adult volunteers. Multidimensional matrix regression analysis showed that self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor areas and the right lateral frontal pole. We then demonstrate that trait anger modulates the functional connectivity of these regions with canonical brain networks supporting somatomotor, affective, self-referential, and visual information processes. Our findings offer novel neuroimaging evidence for interpreting trait anger as a greater propensity to provoked action, which supports ongoing efforts to understand its utility as a potential transdiagnostic marker for disordered states characterized by aggressive behavior.

Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO₂Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO₂Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.