OD had significant metabolite alterations in markers of neuronal integrity , cell membrane turnover/synthesis , glutamate concentration , cellular bio-energetics , and astrocyte integrityin frontal lobe regions implicated in the development and maintenance of addictive disorders. OD had lower NAA, Glu, Cr and mI concentrations than CON in the DLPFC and lower NAA, Cr and mI in the ACC. The metabolite concentration deficits in OD were most pronounced in the DLPFC, were associated with various substance use measures, and correlated with worse performance on measures of global cognition, executive and visuospatial functioning. However, OD and CON were equivalent in regional GABA concentrations, most cognitive domains, and self-regulation measures. Relative to 3 week abstinent ALC, OD had significantly lower NAA, Cr, Cho and mI concentrations in the DLPFC, with NAA and Cho deficits having cognitive ramifications. Consistent with most previous reports, we found metabolite deficits in the ACC of OD. In addition, OD had similar deficits in NAA, Cr, and Glu concentrations in the DLPFC. This suggests reduced neuronal and astrocyte viability and cellular bioenergetics in both the ACC and DLPFC, with additional glutamatergic injury in the DLPFC. ACC Glu and also DLPFC NAA and Cho metabolite abnormalities related to poorer cognitive function, which, however, did not differ significantly from CON. Of note, GABA concentrations in ACC and DLPFC of OD were equivalent to those in smoking CON, similar to findings in 3-week abstinent ALC versus smoking CONand 1 week abstinent ALC vs. mostly nonsmoking CON. However, ACC GABA reductions were reported in abstinent individuals with cocaine- and polysubstance-dependence. The POC and occipital region have been used as control regions in MRS studies as they are typically not altered in addiction. This appears to be true also for OD, who showed the most pronounced metabolite deficits in anterior frontal brain regions.The lateral OFC sub-serves motivation, drive, reward valuation, and aspects of social executive skills,vertical grow system is affected in opiate dependence and other drug abuse, and the OFC has altered brain activity in decision making task-based fMRI studies of individuals with substance use disorders.
OFC metabolite concentrations did not differ between OD and CON, the latter including mostly non-smokers. However, and in contrast to DLPFC and ACC findings, OD showed elevated Glu and Cho concentrations in the OFC when compared to a subset of CON, the small group of smoking CON. Although the small group size warrants caution when interpreting results, our finding of lower OFC Cho concentration in smoking vs. nonsmoking CON is consistent with lower Cho measured in frontal, midbrain and vermis regions of smoking vs. non-smoking controls. In OD, lower DLPFC Glu and strong trends for lower ACC GABA correlated with greater severity and duration of opiate use. These findings are congruent with other neuroimaging studies that reported lower DLPFC GM density and poorer functional connectivity between DLPFC and parietal regions associated with greater duration of opiate use. ACC Glu and NAA were not related to opiate use, consistent with previous reports. However, greater cocaine and marijuana misuse in our OD group was associated with significantly lower metabolite concentrations, commensurate with findings in other substance using/ dependent populations. Metabolite concentrations in the DLPFC and ACC of OD related to executive function, visuospatial skills, global cognition and working memory, but not to self-regulation measures. Previous 1H MRS studies in opiate dependence did not report on such relationships, but studies in marijuana-dependent and recreational ecstasy users reported relationships between altered frontal metabolite levels and impaired cognition or higher impulsivity. Although previous research in opiate addicts reported neuropsychological deficit, our OD group performed in the average range across various cognitive domains and self-regulation measures. There is some evidence that buprenorphine maintenance is associated with better cognition compared to other maintenance drugs, and buprenorphine has been shown to improve brain perfusion in cocaine dependence; correspondingly, buprenorphine may have had an effect on cognitive performance in OD in this study. Future studies on the effects of buprenorphine on brain function and cognition in OD may be useful to inform effective treatment.
Our study showed that OD on maintenance therapy had greater anterior frontal brain metabolite abnormalities than 3 week abstinent ALC, and we found previously that even 1 week abstinent ALC did not show metabolite abnormalities in the DLPFC. The greater DLPFC metabolite abnormalities in OD may relate to the greater relapse rate in opiate than alcohol dependence, which may require differently tailored approaches for treatment of OD and ALC. Metabolite deficits in the DLPFC of OD are more reminiscent of 1H MRS results in poly-substance users, recreational cannabis users, and methamphetamine dependent individuals. The DLPFC is critically involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. As such, DLPFC brain metabolite abnormalities, in addition to those in ACC, may be promising targets to monitor the efficacy of cognitive behaviour therapy in OD treatment, especially as they correlate with cognition and substance use behaviour. This study has limitations. Drug use histories were based on self-report and gender effects across groups could not be assessed due to the small number of females . Menstrual cycle appears to affect brain GABA levels, but data on the time since last menstrual cycle was not collected. However, excluding the female participants from statistical analyses did not alter the finding of no significant GABA differences between groups. The number of analysed spectra for some comparisons was relatively small, especially those involving smoking CON with OFC and POC VOIs; therefore, these analyses need to be considered hypothesis generating rather than definitive. Further, differences to previous metabolite and neuropsychological research in OD may relate to differences in comorbid tobacco, alcohol, marijuana and stimulant abuse as pointed out previously. Of note in this context is the relatively low lifetime and current alcohol use in our OD sample. An additional limitation is that the duration of buprenorphine maintenance therapy was not assessed, although OD had to be on therapy for at least 3 months. Furthermore, the results may not be generalizable to OD who are not on buprenorphine therapy. Finally, we cannot rule out the possible contributions of premorbid, developmental,cannabis grow tray and dietary/nutritional factors to the neurobiological group effects reported.
That genetic factors have an age-specific influence on the onset of alcohol dependence is suggested by the findings that there are strong genetic effects contributing to risk for alcohol dependence particularly connected with early onset of drinking activity . Correspondingly, the rate of adult alcohol dependence is significantly greater among those who start drinking at a relatively early age than among those who start drinking after the age of 19. Studies of adolescent brain development point to neurophysiological factors that could enhance the likelihood of substance use/abuse in those between 14 years of age and 17 years of age . Significant changes in the dopaminergic system occur during adolescence, as well as growth and refinement of prefrontal and limbic circuitry . As a result of the early enhanced activity of the mesolimbic system in contrast to the more slowly maturing prefrontal control systems and their connections to other brain regions, changes in the adolescent brain may lead to enhanced risk taking compared to earlier and later stages of maturation. specifically, these changes may lead to a reduced cognitive control of the reward system in the brain in early to middle adolescence, leading to increased risk for alcohol and other substance abuse disorders . Alcohol dependence and risk for alcoholism in both adults and adolescents is associated with reduced power in event related oscillations in a number of different experiments which elicit a P3 or P300 response. ERO power in a task that elicits a P3 response is also associated with a number of SNPs in the CHRM2 gene . Alcohol dependence in adults was found to be associated with a number of SNPs in the cholinergic M2 receptor genein two studies . A refinement of the study of Wang et al.showed that the association was present only in those subjects who had comorbid illicit drug dependence . This group of subjects and their family members form a genetically vulnerable group, that is, a group whose alcohol dependent members have a more heritable form of the disorder. The alcohol dependent members of this group had a significantly earlier age of onset of drinking compared to the alcohol dependent subjects without comorbid drug dependence. A generalized measure of externalizing psychopathology including alcohol dependence and illicit drug dependence is associated with the same group of SNPs in the CHRM2 gene . Additionally, there is variation in the genetic factors associated with alcohol dependence; multiple genetic factors were found to contribute to a DSM-IV diagnosis of alcohol dependence in adults . Some differences were found between genetic factors involved in alcohol consumption in adolescents and in young adults in twin study models. In order to investigate the age specificity of the genetic and endophenotypic factors noted above on the early onset of alcohol use and dependence, we studied adolescents and young adults drawn from the Collaborative Studies on the Genetics of Alcoholism sample . Because we wanted to understand the processes which lead from non-drinking to regular drinking to alcohol dependence we used both the onset of regular alcohol use and of alcohol dependence as dependent variables.
As we noted above, more severe cases of alcohol dependence in adults were found associated with earlier ages of onset of drinking and are more likely to be the result of genetic factors, thus we hypothesized that specific genetic and related neurophysiological endophenotypes would have a greater predictive power in those with the earliest ages of onset. Discrete time survival analysis was used to investigate the contribution of genetic variants in CHRM2, ERO power, and environmental factors to the onset of regular alcohol use and of alcohol dependence in adolescents and young adults, to deal with the first two items of investigation. DTSA provides age-specific measures for the effects associated with predictive variables. Additional statistical tests, including both genetic and endophenotypic independent variables, were used to link the onset of regular alcohol use to the onset of alcohol dependence, to deal with the third item of investigation. To deal with the fourth item, the same DTSA methodology as was used for the entire sample was applied to a behaviorally defined sub-sample, the definition of which is discussed subsequently . The results of the DTSA calculations suggested further investigation of age related changes in the genotypic distributions of those who became alcohol dependent. A further test was made to determine whether there was an effect of alcohol use on our endophentypic covariates.Data were analyzed in a cross sectional sample of subjects who were assessed at least once when they were between the ages of 12 and 25 years. They were drawn from multiplex alcoholic families and a set of community families in the Collaborative Studies on Genetics of Alcoholism . Written informed consent was obtained from all subjects, and the Institutional Review Boards of each collaborative site approved all procedures. The procedures used by COGA for diagnostic interviews and recording and analyzing EEG data have been described previously . A detailed description of population characteristics of alcohol use and dependence are given in ‘‘Population description’’ section.A substantial literature indicates that alcohol dependence and risk for alcoholism are associated with reduced levels of brain activity when subjects respond to infrequent target stimuli within a sequence of non-target stimuli . Representation of this response in terms of brain rhythms or EROs has proved fruitful . The ERO amplitudes used in this study were obtained from responses to rare target stimuli that elicited a P3 component in a visual oddball experiment at three midline leads . Three leads were chosen because of topographical variation in the significance of results in previous studies . The amplitudes were calculated using the S-transform applied to the recorded data for the delta frequency band extending from 300 to 700 ms post-stimulus. Jones et al.provides a complete description of the experiment and the calculation of the values. The values were log transformed and non-parametric age regression was performed on the variables and the standardized residuals used for further analysis.