Estimated Number of Children Who Lost a Parent to Drug Overdose in the US From 2011 to 2021.

Importance: Parents' overdose death can have a profound short- and long-term impact on their children, yet little is known about the number of children who have lost a parent to drug overdose in the US. Objective: To estimate the number and rate of children who have lost a parent to drug overdose from 2011 to 2021 overall and by parental age, sex, and race and ethnicity. Design, Setting, and Participants: This was a cross-sectional study of US community-dwelling persons using data from the National Survey on Drug Use and Health (2010-2014 and 2015-2019) and the National Vital Statistics System (2011-2021). Data were analyzed from January to June 2023. Exposure: Parental drug overdose death, stratified by age group, sex, and race and ethnicity. Main Outcomes and Measures: Numbers, rates, and average annual percentage change (AAPC) in rates of children losing a parent aged 18 to 64 years to drug overdose, overall and by age, sex, and race and ethnicity. Results: From 2011 to 2021, 649 599 adults aged 18 to 64 years died from a drug overdose (mean [SD] age, 41.7 [12.0] years; 430 050 [66.2%] male and 219 549 [33.8%] female; 62 606 [9.6%] Hispanic, 6899 [1.1%] non-Hispanic American Indian or Alaska Native, 6133 [0.9%] non-Hispanic Asian or Pacific Islander, 82 313 [12.7%] non-Hispanic Black, 485 623 [74.8%] non-Hispanic White, and 6025 [0.9%] non-Hispanic with more than 1 race). Among these decedents, from 2011 to 2021, an estimated 321 566 (95% CI, 276 592-366 662) community-dwelling children lost a parent aged 18 to 64 years to drug overdose. The rate of community-dwelling children who lost a parent to drug overdose per 100 000 children increased from 27.0 per 100 000 in 2011 to 63.1 per 100 000 in 2021. The highest rates were found among children of non-Hispanic American Indian or Alaska Native individuals, who had a rate of 187.1 per 100 000 in 2021, more than double the rate among children of non-Hispanic White individuals (76.5 per 100 000) and non-Hispanic Black individuals (73.2 per 100 000). While rates increased consistently each year for all parental age, sex, and race and ethnicity groups, non-Hispanic Black parents aged 18 to 25 years had the largest AAPC (23.8%; 95% CI, 16.5-31.6). Rates increased for both fathers and mothers; however, more children overall lost fathers (estimated 192 459; 95% CI, 164 081-220 838) than mothers (estimated 129 107; 95% CI, 112 510-145 824). Conclusions and Relevance: An estimated 321 566 children lost a parent to drug overdose in the US from 2011 to 2021, with significant disparities evident across racial and ethnic groups. Given the potential short- and long-term negative impact of parental loss, program and policy planning should ensure that responses to the overdose crisis account for the full burden of drug overdose on families and children, including addressing the economic, social, educational, and health care needs of children who have lost parents to overdose.

Associations of cannabis use, use frequency, and cannabis use disorder with violent behavior among young adults in the United States.

BACKGROUND: Most violent crimes (52 %) are committed by adults aged 18-34, who account for 23 % of the US population and have the highest prevalence of cannabis use and cannabis use disorder (CUD). We examined whether and how associations of cannabis use, use frequency, and CUD with violent behavior (i.e., attacking someone with the intent to harm seriously) vary by sex in U.S. young adults. METHODS: Data were from 113,454 participants aged 18-34 in the 2015-2019 US National Surveys on Drug Use and Health, providing nationally representative data on cannabis use, CUD (using DSM-IV criteria), and violent behavior. Descriptive analyses and bivariate and multivariable logistic regression analyses were conducted. RESULTS: Among U.S. adults aged 18-34, 28.9 % (95 % CI = 28.5-29.2 %) reported past-year cannabis use (with/without CUD), including 20.5 % (95 % CI = 20.2-20.8 %) with non-daily cannabis without CUD, 4.7 % (95 % CI = 4.5-4.8 %) with daily cannabis use without CUD, 2.1 % (95 % CI = 1.9-2.2 %) with non-daily cannabis use and CUD, and 1.7 % (95 % CI = 1.5-1.8 %) with daily cannabis use and CUD. Past-year adjusted prevalence of violent behavior was higher among males with daily cannabis use but without CUD (2.9 %, 95 % CI = 2.4-2.7 %; adjusted prevalence ratio (PR) = 1.7, 95 % CI = 1.3-2.2) and males with daily cannabis use and CUD (3.1 %, 95 % CI = 2.3-4.0 %; adjusted PR = 1.8, 95 % CI = 1.3-2.4) than males without past-year cannabis use (1.7 %, 95 % CI = 1.6-1.9 %). Adjusted prevalence of violent behavior was higher among females with cannabis use regardless of daily cannabis use/CUD status (adjusted prevalence = 1.6-2.4 %, 95 % CIs = 0.9-3.2 %; adjusted PRs = 1.6-2.4, 95 % CI = 1.3-3.2) than females without past-year cannabis use (1.0 %, 95 % CI = 0.9-1.1 %). CONCLUSIONS: Research is needed to ascertain the directionality of the associations between cannabis use and violent behavior and underlying sex-specific mechanism(s). Our results point to complex sex-specific relationships between cannabis use frequency, CUD, and violent behavior and highlight the importance of early screening for and treatment of CUD and of preventive interventions addressing cannabis misuse.

Changes in rest-activity rhythms in adolescents as they age: associations with brain changes and behavior in the ABCD study.

Background: Adolescents with disrupted rest-activity rhythms (RAR) including shorter sleep duration, later sleep timing and low physical activity levels have higher risk for mental and behavioral problems. However, it remains unclear whether the same associations can be observed for within-subject changes in RAR. Methods: Our longitudinal investigation on RAR used Fitbit data from the Adolescent Brain Cognitive Development (ABCD) Study at the 2-year (FL2: aged 10-13 years) and 4-year follow-up (FL4: aged 13-16 years). 963 youths had good-quality Fitbit data at both time points. In this study we examined changes in RAR from FL2 to FL4, their environmental and demographic contributors as well as brain and behavioral correlates. Results: From FL2 to FL4, adolescents showed decreases in sleep duration and physical activity as well as delayed sleep timing (Cohen's d .44-.75). The contributions of environmental and demographic factors to RAR changes were greatest to sleep timing (explained 10% variance) and least to sleep duration (explained 1% variance). Delays in sleep timing had stronger correlations with behavioral problems including greater impulsivity and poor academic performance than reductions in sleep duration or physical activity. Additionally, the various brain measures differed in their sensitivity to RAR changes. Reductions in sleep duration were associated with decreased brain functional connectivity between subcortical regions and sensorimotor and cingulo-opercular networks and with enhanced functional connectivity between sensorimotor, visual and auditory networks. Delays in sleep timing were mainly associated with grey matter changes in subcortical regions. Conclusions: The current findings corroborate the role of sleep and physical activity in adolescent's brain neurodevelopment and behavior problems. RAR might serve as biomarkers for monitoring behavioral problems in adolescents and to serve as potential therapeutic targets for mental disorders.

Seasonality in regional brain glucose metabolism.

BACKGROUND: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored. METHODS: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest-activity rhythms/sleep-wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity. RESULTS: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement. CONCLUSIONS: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year.

Associations between handedness and brain functional connectivity patterns in children.

Handedness develops early in life, but the structural and functional brain connectivity patterns associated with it remains unknown. Here we investigate associations between handedness and the asymmetry of brain connectivity in 9- to 10-years old children from the Adolescent Brain Cognitive Development (ABCD) study. Compared to right-handers, left-handers had increased global functional connectivity density in the left-hand motor area and decreased it in the right-hand motor area. A connectivity-based index of handedness provided a sharper differentiation between right- and left-handers. The laterality of hand-motor connectivity varied as a function of handedness in unimodal sensorimotor cortices, heteromodal areas, and cerebellum (P < 0.001) and reproduced across all regions of interest in Discovery and Replication subsamples. Here we show a strong association between handedness and the laterality of the functional connectivity patterns in the absence of differences in structural connectivity, brain morphometrics, and cortical myelin between left, right, and mixed handed children.

Neurovascular effects of cocaine: relevance to addiction.

Cocaine is a highly addictive drug, and its use is associated with adverse medical consequences such as cerebrovascular accidents that result in debilitating neurological complications. Indeed, brain imaging studies have reported severe reductions in cerebral blood flow (CBF) in cocaine misusers when compared to the brains of healthy non-drug using controls. Such CBF deficits are likely to disrupt neuro-vascular interaction and contribute to changes in brain function. This review aims to provide an overview of cocaine-induced CBF changes and its implication to brain function and to cocaine addiction, including its effects on tissue metabolism and neuronal activity. Finally, we discuss implications for future research, including targeted pharmacological interventions and neuromodulation to limit cocaine use and mitigate the negative impacts.

Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study.

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide's potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42-0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46-0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29-0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42-1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.

Obesity is associated with alterations in anatomical connectivity of frontal-corpus callosum.

Obesity has been linked to abnormal frontal function, including the white matter fibers of anterior portion of the corpus callosum, which is crucial for information exchange within frontal cortex. However, alterations in white matter anatomical connectivity between corpus callosum and cortical regions in patients with obesity have not yet been investigated. Thus, we enrolled 72 obese and 60 age-/gender-matched normal weight participants who underwent clinical measurements and diffusion tensor imaging. Probabilistic tractography with connectivity-based classification was performed to segment the corpus callosum and quantify white matter anatomical connectivity between subregions of corpus callosum and cortical regions, and associations between corpus callosum-cortex white matter anatomical connectivity and clinical behaviors were also assessed. Relative to normal weight individuals, individuals with obesity exhibited significantly greater white matter anatomical connectivity of corpus callosum-orbitofrontal cortex, which was positively correlated with body mass index and self-reported disinhibition of eating behavior, and lower white matter anatomical connectivity of corpus callosum-prefrontal cortex, which was significantly negatively correlated with craving for high-calorie food cues. The findings show that alterations in white matter anatomical connectivity between corpus callosum and frontal regions involved in reward and executive control are associated with abnormal eating behaviors.

Stimulant medications in children with ADHD normalize the structure of brain regions associated with attention and reward.

Children with ADHD show abnormal brain function and structure. Neuroimaging studies found that stimulant medications may improve brain structural abnormalities in children with ADHD. However, prior studies on this topic were conducted with relatively small sample sizes and wide age ranges and showed inconsistent results. In this cross-sectional study, we employed latent class analysis and linear mixed-effects models to estimate the impact of stimulant medications using demographic, clinical measures, and brain structure in a large and diverse sample of children aged 9-11 from the Adolescent Brain and Cognitive Development Study. We studied 273 children with low ADHD symptoms and received stimulant medication (Stim Low-ADHD), 1002 children with high ADHD symptoms and received no medications (No-Med ADHD), and 5378 typically developing controls (TDC). After controlling for the covariates, compared to Stim Low-ADHD and TDC, No-Med ADHD showed lower cortical thickness in the right insula (INS, d = 0.340, PFDR = 0.003) and subcortical volume in the left nucleus accumbens (NAc, d = 0.371, PFDR = 0.003), indicating that high ADHD symptoms were associated with structural abnormalities in these brain regions. In addition, there was no difference in brain structural measures between Stim Low-ADHD and TDC children, suggesting that the stimulant effects improved both ADHD symptoms and ADHD-associated brain structural abnormalities. These findings together suggested that children with ADHD appear to have structural abnormalities in brain regions associated with saliency and reward processing, and treatment with stimulant medications not only improve the ADHD symptoms but also normalized these brain structural abnormalities.

Associations among birthweight, adrenarche, brain morphometry and cognitive function in preterm children aged 9-11 years.

BACKGROUND: Preterm infants with low birthweight are at heightened risk of developmental sequelae, including neurological and cognitive dysfunction that can persist into adolescence or adulthood. In addition, preterm birth and low birthweight can provoke changes in endocrine and metabolic processes that likely impact brain health throughout development. However, few studies have examined associations among birthweight, pubertal endocrine process, long-term neurological and cognitive development. METHODS: We investigated the associations between birthweight and brain morphometry, cognitive function, and onset of adrenarche assessed 9 to 11 years later in 3571 preterm and full-term children using the Adolescent Brain Cognitive Development dataset. RESULTS: The preterm children showed lower birthweight and early adrenarche, as expected. Birthweight was positively associated with cognitive function (all︱Cohen's d︱> 0.154, P < 0.005), global brain volumes (all︱Cohen's d︱> 0.170, P < 0.008) and regional volumes in frontal, temporal, and parietal cortices in preterm and full-term children (all︱Cohen's d︱> 0.170, P < 0.0007); and cortical volume in the lateral orbitofrontal cortex (lOFC) partially mediated the effect of low birthweight on cognitive function in preterm children. In addition, adrenal score and cortical volume in the lOFC mediated the associations between birthweight and cognitive function only in preterm children. CONCLUSIONS: These findings highlight the impact of low birthweight on long-term brain structural and cognitive function development, and showed important associations with early onset of adrenarche during the puberty. This understanding may help with prevention and treatment.

Ketogenic diet reduces a neurobiological craving signature in inpatients with alcohol use disorder.

Background and aims: Increasing evidence suggests that a ketogenic (high-fat, low-carbohydrate) diet (KD) intervention reduces alcohol withdrawal severity and alcohol craving in individuals with alcohol use disorder (AUD) by shifting brain energetics from glucose to ketones. We hypothesized that the KD would reduce a neurobiological craving signature when individuals undergoing alcohol detoxification treatment were exposed to alcohol cues. Methods: We performed a secondary analysis of functional magnetic resonance data of 33 adults with an AUD who were randomized to a KD (n = 19) or a standard American diet (SA; n = 14) and underwent 3 weeks of inpatient alcohol detoxification treatment. Once per week, participants performed an alcohol cue-reactivity paradigm with functional magnetic resonance imaging. We extracted brain responses to food and alcohol cues and quantified the degree to which each set of brain images shared a pattern of activation with a recently established 'Neurobiological Craving Signature' (NCS). We then performed a group-by-time repeated measures ANOVA to test for differences in craving signature expression between the dietary groups over the three-week treatment period. We also correlated these expression patterns with self-reported wanting ratings for alcohol cues. Results: For alcohol relative to food cues, there was a main effect of group, such that the KD group showed lower NCS expression across all 3 weeks of treatment. The main effect of time and the group-by-time interaction were not significant. Self-reported wanting for alcohol cues reduced with KD compared to SA but did not correlate with the NCS score. Conclusion: A ketogenic diet reduces self-reported alcohol wanting, and induced lower NCS to alcohol cues during inpatient treatment for AUD. However, in the KD group alcohol wanting continued to decrease across the 3 weeks of abstinence while the NCS scores remained stable, suggesting that this cue-induced NCS may not fully capture ongoing, non-cue-induced alcohol desire.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Association of semaglutide with risk of suicidal ideation in a real-world cohort.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

IUPHAR Review: New strategies for medications to treat substance use disorders.

Substance use disorders (SUDs) and drug overdose are a public health emergency and safe and effective treatments are urgently needed. Developing new medications to treat them is expensive, time-consuming, and the probability of a compound progressing to clinical trials and obtaining FDA-approval is low. The small number of FDA-approved medications for SUDs reflects the low interest of pharmaceutical companies to invest in this area due to market forces, characteristics of the population (e.g., stigma, and socio-economic and legal disadvantages), and the high bar regulatory agencies set for new medication approval. In consequence, most research on medications is funded by government agencies, such as the National Institute on Drug Abuse (NIDA). Multiple scientific opportunities are emerging that can accelerate the discovery and development of new medications for SUDs. These include fast and efficient tools to screen new molecules, discover new medication targets, use of big data to explore large clinical data sets and artificial intelligence (AI) applications to make predictions, and precision medicine tools to individualize and optimize treatments. This review provides a general description of these new research strategies for the development of medications to treat SUDs with emphasis on the gaps and scientific opportunities. It includes a brief overview of the rising public health toll of SUDs; the justification, challenges, and opportunities to develop new medications; and a discussion of medications and treatment endpoints that are being evaluated with support from NIDA.

Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex.

Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which modulate neurovascular coupling-a process that regulates cerebral hemodynamics in response to neuronal activation. However, separating neuronal and astrocytic effects from cocaine's direct vasoactive effects has been challenging, partially due to limitations of neuroimaging techniques able to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions. Here, we used a newly-developed multi-channel fluorescence and optical coherence Doppler microscope (fl-ODM) that allows for simultaneous measurements of neuronal and astrocytic activities (reflected by the intracellular calcium changes in neurons Ca2+N and astrocytes Ca2+A, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca2+ indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca2+ fluorescence and 3D cerebral blood flow velocity (CBFv) in vascular networks in the mouse cortex. We assessed cocaine's effects in the prefrontal cortex (PFC) and found that the CBFv changes triggered by cocaine were temporally correlated with astrocytic Ca2+A activity. Chemogenetic inhibition of astrocytes during the baseline state resulted in blood vessel dilation and CBFv increases but did not affect neuronal activity, suggesting modulation of spontaneous blood vessel's vascular tone by astrocytes. Chemogenetic inhibition of astrocytes during a cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases, but it also attenuated the neuronal Ca2+N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone and consequently blood flow, at baseline and for modulating the vasoconstricting and neuronal activation responses to cocaine in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.

Preterm birth associated alterations in brain structure, cognitive functioning and behavior in children from the ABCD dataset.

BACKGROUND: Preterm birth is a global health problem and associated with increased risk of long-term developmental impairments, but findings on the adverse outcomes of prematurity have been inconsistent. METHODS: Data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) Study. We identified 1706 preterm children and 1865 matched individuals as Control group and compared brain structure (MRI data), cognitive function and mental health symptoms. RESULTS: Results showed that preterm children had higher psychopathological risk and lower cognitive function scores compared to controls. Structural MRI analysis indicated that preterm children had higher cortical thickness in the medial orbitofrontal cortex, parahippocampal gyrus, temporal and occipital gyrus; smaller volumes in the temporal and parietal gyrus, cerebellum, insula and thalamus; and smaller fiber tract volumes in the fornix and parahippocampal-cingulum bundle. Partial correlation analyses showed that gestational age and birth weight were associated with ADHD symptoms, picvocab, flanker, reading, fluid cognition composite, crystallized cognition composite and total cognition composite scores, and measures of brain structure in regions involved with emotional regulation, attention and cognition. CONCLUSIONS: These findings suggest a complex interplay between psychopathological risk and cognitive deficits in preterm children that is associated with changes in regional brain volumes, cortical thickness, and structural connectivity among cortical and limbic brain regions critical for cognition and emotional well-being.