Synopsis

Adolescents with high familial-loading of alcoholism exhibit altered premorbid subcortical and cerebellar brain-volumes compared to their peers. They also differ in brain-activity during executive-functioning, reward, and emotion-processing tasks. However, the changes in the maturation of the cortical thickness during the adolescence in these high-risk (HR) individuals and their relationship with the externalizing-behaviors have never been examined. Our findings reveal wide-spread delays in cortical maturation in HR subjects, which may ultimately contribute to their addiction vulnerability. More importantly, these effects reduce with age by late-adolescence in the absence of substance-misuse. Additionally, cortical thinning was associated with better behavioral control across groups

1. Introduction

1. Methods

2.1. Participants

Eighty alcohol-naïve male HR-offspring of treatment-seeking AUD patients were recruited from a tertiary-care neuropsychiatry hospital. The affected father was required to have established AUD (DSM-IV criteria) before the age of 25 (early-onset) and have at least two further affected first-degree relatives (FDR) with AUD. Seventy alcohol-naïve typically-developing LR-control subjects (without alcohol/ other substance-dependence FH in FDR), matched on age-, education-, sex-, handedness- and socioeconomic-status to the HR group were recruited for comparisons.

2.2. Clinical assessments

All subjects were assessed on SSAGA-II ¹² to compute an externalizing symptoms score (ESS) and to rule out any syndromal psychiatric and substance-use disorders. FIGS ¹³ was used to document alcoholism FH and to screen for other psychiatric disorders. The HR offspring with the mother having diagnosable AUDs or alcohol use during the index pregnancy were excluded, to rule out fetal-alcohol effects.

2.3. MRI acquisition and Processing

The MRI scans of the whole-brain were obtained with a Siemens 3T Skyra-MRI (Erlangen, Germany) using a 32-channel head-coil. A T1-weighted, three-dimensional, high-resolution MPRAGE was performed (TR=1900ms, TE=2.43, TI=900ms, FOV=240*240mm2, slice thickness=0.9mm with no gap) yielding 192 sagittal-slices with voxel size of 1*1*1mm3. All individual images were initially screened for motion-artifacts and gross structural abnormalities. Surface-based CTh reconstruction from T1-weighted MRIs were performed using FreeSurfer Software (v5.3.0, https://surfer.nmr.mgh.harvard.edu/) ^{14, 15}. The CTh maps were smoothed on the surface using a 15mm full-width half-maximum Gaussian kernel. Analyses were conducted using a GLM, controlling for age (linear and quadratic-effects), and head-size (eTIV) to examine the differences in CTh developmental trajectories and effect of ESS. The resulting CTh maps were corrected for multiple-comparisons using a Monte-Carlo-Null-Z simulation, performing 10,000 iterations with a final cluster-wise p <0.05.

Results

2.1. Participant Characteristics

All 150 participants were right-handed, male, substance-naïve, and between 8-25y of age. The groups did not differ in mean age, education, and eTIV. The HR group exhibited significantly greater summative counts of externalizing symptoms and a high family loading of AUDs.

2.2. Comparison of CTh measures

There was no significant group-by-age interaction when only considering the linear growth models. For the quadratic age models, however, there was significantly less age-related thinning observed in HR group in the clusters over left-parsorbitalis, and right ITG, supramarginal and insula regions than LR group. In the background of significant group-by-age interaction, the whole sample was split into three subgroups of pre-adolescents (8-13y), early-adolescents (14-18y) and late-adolescents (19-24y) in order to examine the between-group main-effects within these developmental-spans. In the pre-adolescents group, HR subjects had lesser thinning than LR in bilateral inferior-parietal, left supramarginal regions. In the early-adolescents group, HR subjects had wide spread areas with lesser thinning in comparison to LR controls involving left pars-triangularis, bilateral precentral, and right ITG regions. Interestingly, there were no significant between-group main-effects for the late-adolescent groups.

2.3. Correlation with externalizing symptoms

The entire cortex-wise regression analysis revealed a positive relationship between the ESS and CTh of the left caudal MFG and MTG.

Discussion

Acknowledgements

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