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Binge drinking and age at first full drink (AFD) of alcohol prior to 21 years (AFD < 21) have been linked to neuroanatomical differences in cortical and subcortical grey matter (GM) volume, cortical thickness, and surface area. Despite the importance of understanding network-level relationships, structural covariation patterns among these morphological measures have yet to be examined in relation to binge drinking and AFD < 21. Here, we used the Joint and Individual Variance Explained (JIVE) method to characterize structural covariation patterns common across and specific to morphological measures in 293 participants (149 individuals with past-12-month binge drinking and 144 healthy controls) from the Human Connectome Project (HCP). An independent dataset (Nathan Kline Institute Rockland Sample; NKI-RS) was used to examine reproducibility/generalizability. We identified a reproducible joint component dominated by structural covariation between GM volume in the brainstem and thalamus proper, and GM volume and surface area in prefrontal cortical regions. Using linear mixed regression models, we found that participants with AFD < 21 showed lower joint component scores in both the HCP (beta = 0.059, p-value = 0.016; Cohen's d = 0.441) and NKI-RS (beta = 0.023, p-value = 0.040, Cohen's d = 0.216) datasets, whereas the individual thickness component associated with binge drinking (p-value = 0.02) and AFD < 21 (p-value < 0.001) in the HCP dataset was not statistically significant in the NKI-RS sample. Our findings were also generalizable to the HCP full sample (n = 880 participants). Taken together, our results show that use of JIVE analysis in high-dimensional, large-scale, psychiatry-related datasets led to discovery of a reproducible cortical and subcortical structural covariation pattern involving brain regions relevant to thalamic-PFC-brainstem neural circuitry which is related to AFD < 21 and suggests a possible extension of existing addiction neurocircuitry in humans.

AbstractPrenatal alcohol exposure (PAE) can alter brain development and impact mental health outcomes, and often occurs in conjunction with postnatal adversity (e.g., maltreatment). However, it is unclear how postnatal adverse exposures may moderate mental health and brain outcomes in children with PAE. T1‐weighted and diffusion magnetic resonance imaging were obtained from 66 participants aged 7–16 years. Twenty‐one participants had PAE and adverse postnatal exposures (PAE+), 12 had PAE without adverse postnatal exposures (PAE−), and 33 were age‐ and gender‐matched controls unexposed to either prenatal alcohol or postnatal adversity. Internalizing and externalizing mental health symptoms were assessed using the Behavioral Assessment System for Children II, Parent‐Rating Scale. ANCOVAs were used to compare mental health symptoms, limbic and prefrontal cortical volumes, and diffusion parameters of cortico‐limbic white matter tracts between groups, and to assess brain‐mental health relationships. Both PAE groups had worse externalizing behavior (higher scores) than controls. The PAE− group had lower fractional anisotropy (FA) in the bilateral cingulum and left uncinate fasciculus, and smaller volumes in the left anterior cingulate cortex than controls and the PAE+ group. The PAE− group also had higher mean diffusivity (MD) in the left uncinate than the PAE+ group, and smaller right anterior cingulate and superior frontal gyrus volumes than controls. These findings show different brain structure and mental health symptom profiles in children with PAE with and without postnatal adversity, highlighting the need to consider adverse postnatal exposures in individuals with PAE.

Abstract Background A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. Results Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. Conclusions Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence.

Prenatal alcohol exposure (PAE) can lead to altered brain function and structure, as well as lifelong cognitive, behavioral, and mental health difficulties. Previous research has shown reduced brain network efficiency in older children and adolescents with PAE, but no imaging studies have examined brain differences in young children with PAE, at an age when cognitive and behavioral problems often first become apparent. The present study aimed to investigate the brain's functional connectome in young children with PAE using passive viewing fMRI. We analyzed 34 datasets from 26 children with PAE aged 2-7 years and 215 datasets from 87 unexposed typically-developing children in the same age range. The whole brain functional connectome was constructed using functional connectivity analysis across 90 regions for each dataset. We examined intra- and inter-participant stability of the functional connectome, graph theoretical measurements, and their correlations with age. Children with PAE had similar inter- and intra-participant stability to controls. However, children with PAE, but not controls, showed increasing intra-participant stability with age, suggesting a lack of variability of intrinsic brain activity over time. Inter-participant stability increased with age in controls but not in children with PAE, indicating more variability of brain function across the PAE population. Global graph metrics were similar between children with PAE and controls, in line with previous studies in older children. This study characterizes the functional connectome in young children with PAE for the first time, suggesting that the increased brain variability seen in older children develops early in childhood, when participants with PAE fail to show the expected age-related increases in inter-individual stability.

Objectives: Most weight loss medications target reductions in energy intake while neglecting energy expenditure, a critical predictor of weight loss/regain. This pilot study examined the effect of short-acting methylphenidate (MPH) on resting energy expenditure (REE), thermic effect of food (TEF), physical activity energy expenditure (PAEE), and how changes in energy expenditure relate to changes in body composition in youth and adults living with obesity. Methods: This study was a randomized, double-blind, placebo-controlled two-parallel arm study. In total, 19 participants were screened, of which 14 participants were randomized into the study, but complete data was only collected for 12, and only analyzed for 10 participants. Those 10 participants aged 28.8 ± 6.9 yrs. (5 Male, 5 Female) were randomized to receive either MPH (0.5 mg/kg) (n = 5) or placebo (n =5) twice daily for 60 days. Participants’ REE and TEF (indirect calorimetry), were measured at baseline (no drug/placebo), and day 60 post-treatment (drug/placebo). Participants’ PAEE (Actical) was measured between screening and baseline for a 1-week period (no drug/placebo), and on day 53 for a 1-week period (drug/placebo). Participants’ anthropometrics were measured using DEXA at baseline, and day 60 post-treatment. Results: From baseline to day 60, MPH showed a relative difference to placebo in relative REE (Relative REE: F(1, 8) = 4.235, p = 0.074, d = 0.83, 2 = 0.346) of 10%, evidenced by a 6% increase in relative REE kcal/kg (18.53 ± 1.97 Kcal/day/kg at baseline, 19.71 ± 2.52 Kcal/day/kg at final) for the MPH group, and a 4% decrease (19.08 2.36 Kcal/day/kg at baseline, 18.26 ± 2.04 Kcal/day/kg at final) in placebo, translating to moderate-effect size (Cohen’s d=0.63) favouring MPH. From baseline to day 60, there were no significant differences between groups on changes in TEF (TEF AUC: F(1, 8) = 0.079, p = 0.785, d = 0.15, 2 = 0.010) or any PAEE variables such as sedentary behavior (SB: F (1, 8) = 0.455, p = 0.52, d = 0.02, 2 = 0.054), light physical activity (LPA: F (1, 8) = 0.504, p = 0.50, d = 0.16, 2 = 0.059), moderate physical activity (MPA: F (1, 8) = 0.281, p = 0.61, d = 0.19, 2 = 0.034), moderate-to-vigorous physical activity (MVPA: F (1, 8) = 0.120, p = 0.74, d = 0.15, 2 = 0.015), or vigorous physical activity (VPA: F (1, 8) = 3.495, p = 0.098, d = 0.91, 2 = 0.304) . Mean change in body weight (kg) resulted in a weight loss of roughly -2.66 ± 2.00 kg in the MPH group and -1.64 ± 1.41 kg in the placebo group, differences that were not statistically significant. Mean change in both groups for body fat% of -0.33 ± 2.08 %, mean change in fat mass of -1.05 ± 2.59 kg, and finally a mean change in fat-free mass of -0.06 ± 1.19 kg was reported. Changes in relative REE were inversely correlated with changes in body weight (r = -0.599, p = 0.067), body fat (r = -0.524, p = 0.12) and fat mass (r = -0.599, p = 0.096). These associations were stronger in the MPH group. Conclusions: Our data suggests that MPH administration may lead to a meaningful increase in relative REE, and these suggested changes were associated with reductions in adiposity among individuals with obesity. These preliminary findings suggest that MPH should be further examined using a larger sample size and study duration to determine its effectiveness in promoting weight loss and maintenance of weight loss in individuals with obesity, a population at high risk of morbidity and premature mortality.

BACKGROUNDThis study examines gene–environment interaction between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled‐analytical approach on four studies that used similar methods.METHODSWe used logistic regression to analyze the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non‐syndromic clefts lip or without cleft palate (CL(P)) and non‐syndromic cleft palate (CP)] and control groups.RESULTSThere was a reduced risk of CL(P) with maternal folic acid use (p = 0.008; OR = 0.70, 95% CI: 0.65–0.94) and with supplements containing folic acid (p = 0.028, OR = 0.80, 95% CI: 0.65–0.94). Maternal smoking increased the risk of both CL(P) (p < 10 e−3; OR = 1.62, 95% CI: 1.35–1.95) and CP (p = 0.028; OR = 1.38, 95% CI: 1.04–1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes.CONCLUSIONThis individual participant data (IPD) meta‐analysis affords greater statistical power and can help alleviate the problems associated with aggregate‐level data‐sharing. The result of this IPD meta‐analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes. Birth Defects Research (Part A) 97:509‐514, 2013. © 2013 Wiley Periodicals, Inc.