Background: There is emerging evidence that the increased susceptibility to developing alcohol and substance use dis- orders in those with a family history of Alcohol Dependence (AD) may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing. Externalizing disorders of childhood including Attention Deficit Hyperactivity Disorder, Conduct and Oppositional Disorders are a prominent feature of those with a positive family history. The caudate nuclei have been implicated in both the salience of rewards and in the pathophysiology of alcohol dependence and these often antecedent childhood disorders. Methods: Adolescent/young adult high and low-risk for AD offspring (N = 130) were studied using magnetic resonance imaging. Volumes of the caudate nucleus were obtained using manual tracing with BRAINS2 software and neuropsychological functioning determined. Childhood disorders were assessed as part of a long-term longitudinal follow-up that includes young adult assessment. Dopaminergic variation was assessed using genotypic variation in the catechol-O-methyltransferase (COMT) and DRD2 genes. Results: High-risk subjects showed poorer Working Memory functioning. Caudate volume did not differ between high and low-risk subjects, but those with externalizing disorders of childhood showed reduced caudate volume. Variation in COMT and DRD2 genes was associated with Working Memory performance and caudate volume. Conclusions: Caudate volume is reduced in association with externalizing disorders of childhood/adolescence. Working Memory deficits appear in familial high-risk offspring and those with externalizing disorders of childhood. The dopaminergic system appears to be involved in both working memory performance and externalizing disorders of childhood.

Offspring from families with alcohol dependence (AD) have been shown to exhibit brain morphological alterations that appear to be related to their familial/genetic risk for AD. Greater susceptibility for developing AD may be related to structural underpinnings of behavioral traits that predispose to AD. We examined white matter (WM) integrity in 81 individuals with either a high density of AD in their families (N=44) or without a family history for either alcohol or drug dependence (N=37). Magnetic resonance images were acquired on a Siemens 3 T scanner with fractional anistropy (FA) and the apparent diffusion coefficient (ADC), along with radial diffusivity (RD) and longitudinal (axial) diffusivity calculated for major white matter tracts in both hemispheres. Extensive personal histories of alcohol and drug use were available from longitudinal collection of data allowing for reliable estimates of alcohol and drug exposure. We found that the interaction of personal exposure to alcohol and familial risk for AD predicts reduction in WM integrity for the inferior longitudinal fasciculus (ILF) and the superior longitudinal fasciculus (SLF) in the left hemisphere and the forceps major tract. Only one tract showed a significant difference for exposure alone, the anterior thalamic radiation.

BACKGROUND:The increased susceptibility for developing alcohol dependence seen in offspring from families with alcohol dependence may be related to structural and functional differences in brain circuits that influence emotional processing. Early childhood environment, genetic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR) of the SLCA4 gene and allelic variation in the Brain Derived Neurotrophic Factor (BDNF) gene have each been reported to be related to volumetric differences in the temporal lobe especially the amygdala.METHODS:Magnetic resonance imaging was used to obtain amygdala volumes for 129 adolescent/young adult individuals who were either High-Risk (HR) offspring from families with multiple cases of alcohol dependence (N=71) or Low-Risk (LR) controls (N=58). Childhood family environment was measured prospectively using age-appropriate versions of the Family Environment Scale during a longitudinal follow-up study. The subjects were genotyped for Brain-Derived Neurotrophic Factor (BDNF) Val66Met and the serotonin transporter polymorphism (5-HTTLPR). Two family environment scale scores (Cohesion and Conflict), genotypic variation, and their interaction were tested for their association with amygdala volumes. Personal and prenatal exposure to alcohol and drugs were considered in statistical analyses in order to more accurately determine the effects of familial risk group differences.RESULTS:Amygdala volume was reduced in offspring from families with multiple alcohol dependent members in comparison to offspring from control families. High-Risk offspring who were carriers of the S variant of the 5-HTTLPR polymorphism had reduced amygdala volume in comparison to those with an LL genotype. Larger amygdala volume was associated with greater family cohesion but only in Low-Risk control offspring.CONCLUSIONS:Familial risk for alcohol dependence is an important predictor of amygdala volume even when removing cases with significant personal exposure and covarying for prenatal exposure effects. The present study provides new evidence that amygdala volume is modified by 5-HTTLPR variation in High-Risk families.

Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence (AD) and related substance use disorders. Greater susceptibility for developing these disorders may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing and AD susceptibility. We examined the cerebellum of 71 adolescent/young adult high-risk (HR) offspring from families with multiple cases of alcohol dependence (multiplex families), and 60 low-risk (LR) controls with no family history of alcohol or drug dependence who were matched for age, gender, socioeconomic status and IQ, with attention given to possible effects of personal use of substances and maternal use during pregnancy. Magnetic resonance images were acquired on a General Electric 1.5-Tesla scanner and manually traced (BRAINS2) blind to clinical information. GABRA2 and BDNF variation were tested for their association with cerebellar volumes. High-risk offspring from multiplex AD families showed greater total volume of the cerebellum and total gray matter (GM), in comparison with LR controls. An interaction between allelic variation in GABRA2 and BDNF genes was associated with GM volumes, suggesting that inherited variation in these genes may promote early developmental differences in neuronal proliferation of the cerebellum.

Background: Despite the importance of understanding the long-term outcome for children of alcohol dependent (AD) women, the available literature is largely based on offspring of AD fathers and few have utilized prospective designs that include child, adolescent and young adult assessments. Multiplex AD families in which multiple cases of AD are present provide an ideal setting for understanding developmental variants of the adult phenotype.Method: Offspring from multiplex AD families identified through the mother or control families were evaluated multiple times during childhood and followed to young adulthood. Familial risk status and the presence of specific child/adolescent disorders were used as predictors of substance use disorder outcome by young adulthood.Results: Offspring who were members of maternal multiplex families had elevated rates of child and young adulthood disorders. High risk offspring of alcohol dependent women were at increased risk for externalizing (Conduct Disorder and ADHD) and internalizing disorders (Major Depressive Disorder (MDD) and Anxiety Disorders). By young adulthood, offspring from these multiplex families had significantly greater odds of developing alcohol abuse or dependence (odds ratio [OR] = 3.63 [CI 1.36-9.641) and drug abuse or dependence (OR = 4.23 [CI 1.73-10.32]). The prospective design of the study revealed that specific childhood disorders (Conduct Disorder, ADHD, MOD) increased the odds of subsequent development of substance use disorder (SLID).Conclusions: Multiplex familial risk for alcohol dependence is a significant predictor of substance use disorders by young adulthood. Familial risk and an earlier childhood disorder may set the stage for later development of SLID. (C) 2010 Elsevier Ltd. All rights reserved.

It was of interest to determine if hemispheric differences in orbitofrontal cortex (OFC) volume would be related to behavioral inhibition observed in a peer-play setting. Magnetic resonance imaging (MRI) was carried out in 23 individuals (19 males and 4 females) at an average age of 14.87±1.14years who were either at high or low risk for alcohol dependence. All subjects had previously been evaluated in a preschool peer play paradigm (5.03±0.78years) assessing behavioral inhibition. Region of interest measures were traced for the OFC and the amygdala, and confirmed with voxel based morphometry. Behavioral inhibition, a behavioral tendency that often occurs in a novel setting in reaction to strangers, includes the following: greater time spent next to the mother, greater time staring at another child, and longer latency to begin play with another child. A significant relationship was seen between greater right OFC volume and indicators of behavioral inhibition including greater time spent proximal to their mother and greater time staring at the other child. Also, larger amygdala volume was associated with more time spent proximal to the mother. Behavioral control, including both over- and under-control, is likely to be subserved by neural circuitry associated with emotion regulation including the right OFC and the amygdala.

BACKGROUND:Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the orbitofrontal cortex (OFC) in regulating emotional processing is increasingly being recognized along with its association with impulsive behavior. METHODS:Magnetic resonance imaging was used to measure the OFC in 107 high- and low-risk offspring (mean age 17.6 +/- 4.69 years) from either multiplex AD families or control families. Region of interest measures including segmented values were obtained by reliable raters using BRAINS2 software. Statistical analyses were adjusted for intracranial volume, age, socioeconomic status (SES), IQ, and handedness. The Multidimensional Personality Questionnaire (MPQ) was administered to determine scale scores for Control. Genotyping was performed for the serotonin transporter (5-HTT) gene and the brain-derived neurotrophic factor (BDNF) gene. RESULTS:High-risk offspring from multiplex for AD families showed decreased right/left OFC volumes in comparison with control subjects. Smaller volume in the right hemisphere was significantly associated with variation in the 5-HTT and BDNF genes. White matter (WM) ratios showed a positive correlation with MPQ Control scale scores, indicating that reduced OFC WM is related to greater impulsivity. CONCLUSIONS:Offspring from multiplex families for AD manifest genetic susceptibility by exhibiting disruption in the laterality of the OFC volume that is related to greater impulsivity (lower Control scale scores). This disruption in OFC laterality is related to variation in genes associated with neuronal growth.

Multiplex families ascertained through multiple alcohol dependent individuals appear to transmit alcohol and drug use disorders at higher rates than randomly selected families of alcoholics. Our goal was to investigate the risk of developing specific psychiatric diagnoses during childhood or adolescence in association with familial risk status (high-risk [HR] or low-risk [LR]) and parental diagnosis. Using a prospective longitudinal design, HR offspring from three generation multiplex alcohol dependence families and LR control families were followed yearly. Data analysis was based on consensus diagnoses from 1738 yearly evaluations conducted with the offspring and a parent using the K-SADS, and separately modeled the effects of familial susceptibility and exposure to parental alcohol dependence. Multiplex family membership and parental alcohol and drug dependence significantly increased the odds that offspring would experience some form of psychopathology during childhood or adolescence, particularly externalizing disorders. Additionally, parental alcohol dependence increased the odds that adolescent offspring would have major depressive disorder (MDD). While it is well known that parental substance dependence is associated with externalizing psychopathology, the increased risk for MDD seen during adolescence in the present study suggests the need for greater vigilance of these children.

Background: Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the cerebellum in regulating cognitive functions is being increasingly recognized along with its well-known influence on motor performance. Additionally, developmental changes in cerebellar volume during adolescence have been reported.Methods. Magnetic resonance imaging was used to measure the cerebellum in 17 high-risk adolescent and young adult offspring from multiplex alcohol dependence families and 16 control subjects matched for gender, age, and IQ.Results: High-risk (HR) adolescents/young adults showed increased total cerebellum volume and total grey in comparison with control subjects. Age-related decreases in total grey volume were seen with age, a pattern that was not seen in HR offspring.Conclusions: Qffspring from multiplex families for AD manifest genetic susceptibility by having larger cerebellar volume, which seems to be related to lesser grey matter pruning for age. Larger cerebellar volumes in adult obsessive compulsive disorder (OCD) patients have been reported. This suggests a possible similarity in structural underpinnings for alcohol dependence and OCD.

BACKGROUND Increased susceptibility for developing alcohol dependence (AD) may be related to structural and functional differences in brain circuits that influence social cognition and more specifically, theory of mind (ToM). Alcohol dependent individuals have a greater likelihood of having deficits in social skills and greater social alienation. These characteristics may be related to inherited differences in the neuroanatomical network that comprises the social brain. METHODS Adolescent/young adult participants from multiplex AD families and controls (n = 16) were matched for gender, age, IQ, education, and handedness and administered the Eyes Task of Baron-Cohen during functional magnetic resonance imaging (fMRI). RESULTS High-risk (HR) subjects showed significantly diminished blood oxygen level dependent (BOLD) response in comparison with low-risk control young adults in the right middle temporal gyrus (RMTG) and the left inferior frontal gyrus (LIFG), areas that have previously been implicated in ToM tasks. CONCLUSIONS Offspring from multiplex families for AD may manifest one aspect of their genetic susceptibility by having a diminished BOLD response in brain regions associated with performance of ToM tasks. These results suggest that those at risk for developing AD may have reduced ability to empathize with others' state of mind, possibly resulting in diminished social skill.