Background: Adolescence is a critical developmental stage for the emergence of major depressive disorder (MDD). Structural and diffusion neuroimaging studies have highlighted the anterior cingulate cortex (ACC) as a key region implicated in emotion regulation, stress reactivity, and mood processing. However, few studies have examined whether microstructural characteristics of the ACC, reflected by mean diffusivity (MD) within gray matter–white matter (GM–WM) contrast regions, are associated with depression in early adolescence. Objective: To examine whether mean diffusivity (MD) within the GM–WM contrast of the left caudal anterior cingulate cortex (ACC) is associated with a past diagnosis of MDD among adolescents in the Adolescent Brain Cognitive Development (ABCD) Study, after accounting for demographic, socioeconomic, and adversity-related factors. Methods: Data were drawn from adolescents with diffusion MRI–derived mean diffusivity measures and diagnostics. The independent variable was mean diffusivity (MD) of the GM–WM contrast in the left caudal ACC. The primary outcome was past MDD diagnosis based on structured psychiatric assessments. Covariates included age, sex, socioeconomic status (SES), and exposure to adverse childhood experiences (ACEs). Logistic regression models tested the association between ACC MD and past MDD. A secondary model evaluated the relationship between ACC MD and past suicide attempt. Results: Mean diffusivity of the left caudal ACC was associated with the odds of past MDD, independent of age, sex, SES, and adversity exposure. In contrast, ACC mean diffusivity was not associated with a history of suicide attempt. Conclusions: Increased mean diffusivity in the caudal ACC may indicate microstructural alterations associated with depressive vulnerability in adolescence. ACC tissue integrity may serve as a sensitive neural correlate of early-onset depression.

Early-onset neurodegenerative diseases (EO-NDs), such as early-onset Alzheimer’s disease (EOAD), Parkinson’s disease (EOPD), and familial amyotrophic lateral sclerosis (fALS), often stem from monogenic causes and manifest before typical age thresholds. These disorders frequently feature disrupted mitochondrial function and heightened oxidative stress, which together accelerate neuronal damage and degeneration. In this work, the author performs a comprehensive analysis of the literature and data related to mitochondrial dysfunction and redox imbalance in EO-NDs. Bibliometric trends were assessed using R-based tools on PubMed datasets, highlighting keyword networks and publication surges in recent years. Publicly available RNA-seq datasets from GEO and SRA were examined, with example DESeq2 analysis illustrating altered mitochondrial gene expression in EO-ND patient-derived samples. Network modeling of redox pathways using Python’s networkx demonstrates how oxidative stress can propagate through metabolic networks. Together, these computational approaches reinforce that mitochondrial DNA mutations, impaired electron transport chain (ETC) function, and reactive oxygen species (ROS) accumulation play central roles in EO-ND pathogenesis. The discussion further evaluates why antioxidant clinical trials have largely failed and how emerging therapies such as gene replacement, antisense oligonucleotides, and mitochondrial biogenesis modulators may provide more effective interventions.

Background: The sensory-motor network is essential for integrating sensory input with motor function and higher-order cognition. Resting-state functional connectivity (rsFC) within this network undergoes significant developmental changes, and disruptions in these connections have been linked to behavioral and psychiatric outcomes. However, the relationship between sensory-motor connectivity, early-life adversity, and later health behaviors remains understudied. Objective: This study examines the associations between rsFC within the sensory-motor network (mouth and hand regions) and key social, psychological, and behavioral factors, including baseline and past socioeconomic status (SES), trauma exposure, family conflict, impulsivity, major depressive disorder (MDD), and future substance use. Methods: Data were drawn from the Adolescent Brain Cognitive Development (ABCD) Study, a national sample of U.S. children. Resting-state fMRI data were used to assess functional connectivity within the sensory-motor network. Bivariate analyses examined associations between rsFC in the sensory-motor mouth and hand regions and baseline SES, past SES, childhood trauma exposure, family conflict, impulsivity, and MDD. Longitudinal analyses assessed whether baseline rsFC predicted future substance use. Results: Greater rsFC between the sensory-motor mouth and hand regions was significantly associated with lower SES, higher trauma exposure, and greater family conflict. Increased connectivity was also correlated with older age and more advanced puberty status. Higher rsFC between the sensory-motor mouth and hand regions was linked to greater impulsivity, lower cognitive function, an increased likelihood of MDD, and future marijuana use. Conclusion: These findings suggest that sensory-motor connectivity is sensitive to socioeconomic and psychosocial stressors, with potential long-term implications for mental health and substance use risk. The results highlight the importance of early-life environmental factors in shaping neurodevelopmental trajectories and emphasize the need for targeted interventions to mitigate the effects of adversity on brain function and behavior. Future research should further explore the role of sensory-motor network alterations in behavioral health outcomes as a function of environmental stressors.

Background: The hippocampus plays a critical role in memory and decision-making processes, with its resting-state functional connectivity (rsFC) linked to various behavioral outcomes. This study investigates whether baseline brain-wide rsFC of the hippocampus mediates the relationship between impulsivity and subsequent substance use, specifically tobacco and marijuana use, in adolescents. Methods: Data were drawn from the baseline wave of the Adolescent Brain Cognitive Development (ABCD) study. Resting-state fMRI data were used to evaluate the functional connectivity of the hippocampus with key brain networks, including the cingulo-parietal network, visual network, sensory-motor network, and default mode network (DMN). Impulsivity was assessed using validated self-report measures, and substance use (tobacco and marijuana) was evaluated at follow-up. Mediation models were conducted to examine the extent to which hippocampal rsFC explains the association between impulsivity and substance use. Results: Baseline hippocampal rsFC with the cingulo-parietal network, visual network, sensory-motor network, and DMN showed marginal associations with future tobacco and marijuana use. Additionally, hippocampal rsFC was significantly associated with impulsivity, which, in turn, predicted higher substance use at follow-up. These findings suggest that hippocampal rsFC partially mediates the relationship between impulsivity and substance use behaviors. Conclusions: Hippocampal functional connectivity with brain networks may influence the pathway from impulsivity to future substance use in adolescence. These findings emphasize the importance of hippocampal connectivity in understanding the neural mechanisms underlying risk behaviors and may inform the development of targeted interventions to reduce substance use in this vulnerable population.

Background: The Cingulo-Opercular Network (CON) is a crucial executive control network involved in regulating actions and facilitating higher-order cognitive processes. Resting-state functional connectivity between the CON and the Default Mode Network (DMN) plays a vital role in cognitive regulation, enabling the transition between internally focused and externally directed tasks. This study investigates whether resting-state functional connectivity between the CON and DMN mediates the effects of social determinants, such as educational opportunities and family structure, on cognitive outcomes in youth. Aims: This study aims to explore how CON-DMN connectivity influences the relationship between social gradients and cognition in youth. Specifically, it examines whether resting-state functional connectivity between these networks mediates the effects of educational opportunities and family structure on cognitive outcomes and seeks to uncover the neural mechanisms underlying these social gradients. Methods: Data were derived from the Adolescent Brain Cognitive Development (ABCD) study, a large longitudinal dataset of over 11,000 children aged 9–10 years. Cognitive outcomes were assessed using standardized NIH toolbox measures: Total Composite, Fluid Reasoning, Picture Vocabulary, Pattern Recognition, and Card Sorting. Social determinants were operationalized using indicators such as parental education, family composition, and neighborhood educational opportunities (COI). Resting-state functional connectivity (rsFC) between the CON and DMN was measured using functional magnetic resonance imaging (fMRI). Structural equation modeling (SEM) was employed to test whether CON-DMN rsFC mediated the relationship between social determinants and cognitive outcomes, adjusting for potential confounders such as age, sex, and race/ethnicity. Results: Stable family structure and greater educational opportunities were significantly associated with improved cognitive performance. These relationships were mediated by reduced functional connectivity between the CON and DMN. Conclusion: Reduced functional connectivity between the CON and DMN serves as a neural mechanism linking social gradients, such as educational opportunities and family structure, to better cognitive outcomes in youth.

Background: As a central component of the brain's reward system, nucleus accumbens (NAcc) plays a crucial role in reward salience and substance use behaviors. Changes in the NAcc are also relevant to higher rates of substance use of youth and adults from low-income backgrounds. Although resting-state functional connectivity (rsFC) of the NAcc provides valuable insights into the neural mechanisms underlying reward processing and the propensity for self-reported reward salience and substance use, research exploring the association between NAcc rsFC and brain networks beyond the default mode network (DMN) and prefrontal cortex (PFC) is limited. Objective: To investigate the role of the resting-state functional connectivity of the NAcc with the cingulo-opercular network, sensorimotor mouth network, and sensorimotor hand network in the association between socioeconomic status, self-reported reward salience, and future substance use. Methods: Data were obtained from the Adolescent Brain Cognitive Development (ABCD) study. NAcc rsFC with the cingulo-opercular network, sensorimotor mouth network, and sensorimotor hand network was assessed at baseline. Socioeconomic status was measured using family income. Self-reported reward salience was assessed using validated psychometric scales. Substance use outcomes were tracked longitudinally over the study period. Structural Equation Modeling was employed to examine the covariances between family income, NAcc rsFC, reward salience, and subsequent substance use. Results: Higher baseline family income was positively associated with baseline NAcc rsFC (B = 0.092, p < 0.001) and negatively associated with baseline reward salience (B = -0.040, p = 0.036) and future substance use (B = -0.081, p < 0.001). Baseline NAcc rsFC was strongly and positively associated with reward salience (B = 0.734, p < 0.001) and future substance use up to age 13 (B = 0.124, p < 0.001). Additionally, baseline reward salience was positively associated with future substance use (Covariance = 0.176, p < 0.001). Conclusion: The findings suggest that NAcc rsFC with brain networks beyond the DMN or PFC may contribute to the links between low parental socioeconomic status, reward salience, and substance use risk. Expanding the understanding of NAcc rsFC provides new insights into the neural mechanisms underlying these associations. These results have important implications for developing targeted interventions aimed at preventing substance use, particularly among low-income youth with heightened reward salience. Further research is needed to explore causal pathways and moderating factors influencing these relationships.