Disruption of Orbitofrontal Cortex Laterality in Offspring from Multiplex Alcohol Dependence Families

Abstract

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.

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

“…Specifically, damage to the orbitofrontal-subcortical circuit disrupts behavioral inhibition (Cummings, 1995) and lesions to lateral and ventral OFC, but not the mPFC, disrupt reversal learning (Bissonette et al, 2008). Human alcoholics often display symptoms similar to patients with OFC damage, including deficits in behavioral inhibition (Verdejo-Garcia et al, 2006) and measures of impulsivity/perseveration (Hill et al, 2009;Tanabe et al, 2009). Chronic alcohol exposure has also been shown to disrupt behavioral flexibility in experimental models of alcohol dependence.…”

Family History Density of Alcoholism Relates to Left Nucleus Accumbens Volume in Adolescent Girls

“…Some of the previously published studies examined differences in brain volume between groups in a dichotomous fashion, such as comparing youth with and without familial alcoholism (Hanson et al, 2010), whereas others took a similar approach but included ultra-high-risk youth with multiplex familial AUDs in the family history group, thereby comparing high-and low-risk groups with very distinct levels of vulnerability toward AUDs (Hill et al, 2001(Hill et al, , 2007(Hill et al, , 2009(Hill et al, , 2011(Hill et al, , 2013a(Hill et al, , 2013b. However, the current study examined the degree of familial risk for alcoholism and its relationship with brain volume in a large cohort of youth all considered at risk because of the presence of at least one second-degree relative with an AUD.…”

“…Lateralized differences in subcortical brain volume between at-risk youth or alcoholics and controls have previously been reported (Hanson et al, 2010;Hill et al, 2001;Makris et al, 2008); therefore, an association between FHD and brain volume in only one hemisphere is not unusual. Genetic susceptibility toward alcoholism could infl uence brain structural characteristics in a lateralized manner (Hanson et al, 2010;Hill et al, 2001Hill et al, , 2009, and sex differences in the development of subcortical structures have been previously documented (Giedd et al, 1997). Thus, it is plausible that sex and family history risk factors may interact to infl uence brain volume in one hemisphere but not the other.…”

“…However, no differences were observed between FHP and FHN female adolescents. In another study, smaller right to left orbitofrontal cortex volume was found in high-risk youth from multiplex alcohol-dependent families compared with controls (Hill et al, 2009). The orbitofrontal cortex is an important structure associated with emotional regulation (Bechara et al, 2000) that has connections with the ventral striatum (Groenewegen et al, 1991).…”

“…For example, interactions with familial history risk status and externalizing disorders were reported in a study that found smaller caudate volume in youth and young adults from multiplex families with AUDs (Hill et al, 2013a). Importantly, studies that have examined brain volume in individuals with familial alcoholism have included samples of youth with little to no experience with alcohol (Benegal et al, 2007;Hanson et al, 2010) or individuals who were largely free of abuse or dependence diagnoses during childhood/adolescence (Hill et al, 2001(Hill et al, , 2007(Hill et al, , 2009(Hill et al, , 2011(Hill et al, , 2013a(Hill et al, , 2013b, thereby controlling for confounding alcohol-related neurotoxic effects on the brain.…”