Abstract

<b>Background:</b> 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. <b>Objective:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.

Abstract

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.

Abstract

<b>Background: </b>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. <b>Objective: </b>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. <b>Methods: </b>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. <b>Results: </b>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. <b>Conclusion: </b>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.

Abstract

<b>Background: </b>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. <b>Methods: </b>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. <b>Results: </b>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. <b>Conclusions: </b>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.

Abstract

</b>Background: </b>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. <b>Aims: </b>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. <b>Methods: </b>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. <b>Results: </b>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. <b>Conclusion: </b>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.

Abstract

<b>Background:</b> 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. <b>Objective:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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). <b>Conclusion:</b> 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.

Abstract

<b>Background: </b>While understanding how corticostriatal connectivity is associated with socioeconomic status (SES), trauma exposure, cognitive function, reward salience, impulsivity, and future substance use is essential to identifying neurobiological pathways that contribute to health disparities and behavioral outcomes, very few studies have tested the role of left caudate resting-state functional connectivity (rsFC) with the cingulo-opercular network as a proxy of corticostriatal connectivity in social, cognitive, and behavioral processes. <b>Objective: </b>This study investigates the associations between left caudate-cingulo-opercular connectivity and multiple biopsychosocial domains, including low SES, high trauma exposure (financial and life events), cognitive function, reward salience, impulsivity, depression, and future substance use (tobacco and marijuana use). <b>Methods: </b>Resting-state functional magnetic resonance imaging (rs-fMRI) data were analyzed to assess connectivity between the left caudate and the cingulo-opercular network. Data on socioeconomic status, trauma exposure, cognitive performance, and mental health were collected from participants. Future substance use behaviors were evaluated through longitudinal follow-ups. Correlation and regression analyses were conducted to examine relationships between corticostriatal connectivity and the targeted domains. <b>Results: </b>Corticostriatal hypoconnectivity was associated with lower SES, higher trauma exposure, poorer cognitive function, heightened reward salience, higher impulsivity, and history of depression. Additionally, corticostriatal hypoconnectivity at baseline predicted future tobacco and marijuana use during follow-up years. <b>Conclusion: </b>Corticostriatal hypoconnectivity, particularly the rsFC between the left caudate and the cingulo-opercular network, may represent a potential mechanism linking a wide range of social, emotional, and behavioral problems in youth. These findings suggest that corticostriatal hypoconnectivity could serve as a neurobiological marker for identifying individuals at risk for depression, low cognitive function, high reward salience, impulsivity, and substance use, emphasizing the interplay between socioeconomic and neurocognitive factors in shaping behavioral health trajectories.

Abstract

<b>Background:</b><b> </b>Low socioeconomic status (SES) has been linked to higher rates of tobacco and marijuana use initiation; however, the contributions of environmental and neurocognitive factors remain underexplored. This study investigates a potential pathway connecting low SES, fine particulate matter (PM2.5) exposure, brain functional connectivity, and inhibitory control to increased tobacco and marijuana use initiation among adolescents. <b>Objectives:</b><b> </b>To examine the mediating roles of PM2.5 exposure, resting-state functional connectivity between the right pallidum and the ventral attention network (P-VAN rsFC), and inhibitory control in the relationship between low SES and tobacco and marijuana use initiation. <b>Methods:</b><b> </b>Data were drawn from the Adolescent Brain Cognitive Development (ABCD) study to assess associations between baseline SES, baseline PM2.5 exposure (based on zip code), baseline P-VAN rsFC, baseline inhibitory control, and subsequent tobacco and marijuana use initiation. Mediation models were used to determine whether PM2.5 exposure and changes in P-VAN rsFC act as pathways linking low SES to diminished inhibitory control and subsequent substance use initiation. <b>Results:</b><b> </b>Low SES was associated with higher PM2.5 exposure, which, in turn, was linked to alterations in P-VAN rsFC. These alterations were correlated with lower inhibitory control, which significantly predicted tobacco and marijuana use initiation over time. Inhibitory control partially mediated the relationship between low SES and substance use initiation, indicating a complex pathway influenced by environmental and neurocognitive factors. <b>Conclusions:</b><b> </b>This study identifies a potential mechanism linking low SES to tobacco and marijuana use initiation through environmental and neurobiological pathways. Understanding how PM2.5 exposure and neurofunctional connectivity impact inhibitory control can provide valuable insights for developing targeted interventions to reduce substance use among adolescents in low SES environments.

Abstract

<b>Background: </b>Socioeconomic status (SES) is a well-established predictor of cognitive function in children, but the neurobiological pathways through which SES influences cognitive outcomes remain underexplored. This study examines the role of the cingulate gyrus (region of the brain that is involved in emotion regulation, decision-making, error detection, and cognitive control) in mediating the relationship between SES and cognitive performance, with a focus on whether these effects vary by sex. <b>Objective: </b>To investigate the role of the cingulate gyrus in mediating the association between social gradients (family SES) and cognitive function in children and assess potential sex differences in these pathways. <b>Methods:</b> Data were drawn from the Adolescent Brain Cognitive Development (ABCD) study. Cognitive function was assessed using a composite measure of executive function and general cognitive ability. Structural MRI data were used to measure the volume of the cingulate gyrus. Path analysis was conducted to examine the mediating role of the cingulate gyrus in the association between SES and cognitive function. Interaction terms were included to test for sex differences. <b>Results:</b> Higher SES was significantly associated with a larger cingulate gyrus volume and better cognitive function. The volume of the left cingulate gyrus partially mediated the relationship between family and neighborhood SES and cognitive function, explaining a portion of the social gradient in cognitive outcomes. No significant sex differences were found in these mediating effects. <b>Conclusions:</b> The cingulate gyrus partially mediates the link between SES and cognitive function in children. These findings suggest that social disparities in cognitive function may operate, in part, through neurobiological changes such as those in the cingulate gyrus, without significant variation by sex.

Abstract

<b>Background:</b> Although some neural mechanisms underlying socioeconomic status (SES) disparities are known, the role of brain-wide resting-state functional connectivity in these effects remains less understood. <b>Aim:</b> This study aims to identify brain-wide resting-state functional connectivity signatures that may mediate the effects of SES on body mass index (BMI) and blood pressure in children, using data from the Adolescent Brain Cognitive Development (ABCD) study. <b>Methods:</b> Data were drawn from the ABCD study, a large, diverse cohort of children aged 9-10. Pre-processed resting-state functional MRI data were used, and factor analysis was conducted to extract a whole-brain connectivity factor. The first factor, capturing the greatest variance in brain-wide resting-state connectivity, was selected for further analysis in a structural equation model (SEM). This connectivity factor was tested as a potential mediator of the relationship between SES (measured by parental education, family income, and neighborhood characteristics) and two indicators of cardiometabolic health: BMI and systolic blood pressure. <b>Results:</b> Factor analysis revealed a robust first factor that accounted for a significant proportion of variance in brain-wide resting-state functional connectivity. This factor was significantly associated with SES, indicating that children from lower SES backgrounds exhibited distinct connectivity patterns. Additionally, the factor was linked to both BMI and systolic blood pressure, suggesting its relevance to cardiometabolic health. Mediation analysis showed that this connectivity factor partially mediated the relationship between SES and both BMI and systolic blood pressure. <b>Conclusions:</b> Brain-wide functional connectivity may be a mediator of SES effects on BMI and blood pressure in children. The first connectivity factor provides a promising neural signature linking SES with cardiometabolic risk. Comprehensive brain-wide approaches to functional connectivity may offer valuable insights into how social determinants of health shape neural and physical development in childhood.

Abstract

<b>Background: </b>Most neuroscience research has predominantly focused on White, middle-class populations, leading to gaps in understanding how socioeconomic status (SES) influences brain development and health behaviors in racially diverse groups. Tobacco use, a major public health concern, is influenced by both family and neighborhood SES, with early initiation during adolescence predicting long-term health outcomes. The Adolescent Brain Cognitive Development (ABCD) study provides a unique opportunity to examine racial disparities in the pathways from SES to brain development and behavior, especially through the lens of Marginalization-Related Diminished Returns (MDRs), where the effects of SES are attenuated for minority groups. <b>Objective: </b>This study investigates racial variation in the associations between SES, cerebral cortical volume, and tobacco use initiation, comparing Black and White youth over 4-6 years of follow-up. <b>Methods: </b>Data from the ABCD study were analyzed to assess pathways from family income to adolescents’ cortical volume via the needs-to-income ratio, and from cortical volume to tobacco use initiation. Structural equation modeling was used to evaluate these pathways, stratified by race, with a focus on comparing Black and White participants. Covariates included family and neighborhood SES, demographic factors, and baseline behavioral measures. <b>Results: </b>We found that the positive association between income (via the needs-to-income ratio) and total cortical volume was significantly weaker for Black youth compared to White youth. Additionally, the link between larger total cortical volume and reduced risk of tobacco initiation was also weaker in Black adolescents. These findings were consistent over 4-6 years of follow-up, suggesting that Black youth experience diminished returns from higher SES in terms of brain development and behavioral outcomes. <b>Conclusions: </b>Our findings highlight significant racial disparities in the pathways from SES to brain development and tobacco use initiation, supporting the Marginalization-Related Diminished Returns (MDRs) framework. While higher SES is associated with larger cortical volumes and lower tobacco use risk in White youth, these associations are attenuated in Black adolescents.

Abstract

Neurodegeneration and aging are pressing issues with significant personal, economic, ethical, and social consequences. However, the underlying biological mechanisms of these conditions remain largely unknown, making the development of effective treatments challenging. The difficulty in early detection and diagnosis of neurodegenerative diseases further compounds the issue. Recent advancements in genetics, genomics, and brain imaging technology hold great promise for improving our understanding of neurodegeneration and aging, as well as the development of personalized medicine and new drugs and therapies. Addressing these challenges will require a multi-disciplinary and collaborative approach from researchers in various fields. This Special Issue offers valuable insights and perspectives on this critical area of research, which can help advance our understanding and improve the health and well-being of our aging population.