We measured in opiate dependent individuals’ metabolite concentrations from the ACC and previously unexplored DLPFC and OFC and related them to quantitative measures of neurocognition, self-regulation, and substance use. Specifically, we compared opiate dependent individuals on buprenorphine maintenance to controls . We also included another control group, a substance-dependent ‘control’ group of 3 week abstinent alcohol dependent individuals , a commonly investigated treatment-seeking group to differentiate opiate dependence from not only control individuals but also individuals with a substance dependence . Our primary hypotheses were that: OD have lower NAA and Glu concentrations than CON in ACC, DLPFC, and OFC, these frontal cortical NAA and Glu deficits are associated with the level of opiate use and cigarette-smoking severity, the frontal NAA and Glu deficits in OD relate to higher impulsivity, poorer executive function, and lower decision making skills, and OD have more pronounced metabolite concentration deficits than ALC. The results of this study will contribute to a better understanding of the neurobiology and neuropsychology in OD, helping to identify novel targets for the treatment of opiate dependence. All participants provided informed consent according to the Declaration of Helsinki and underwent procedures approved by the University of California, San Francisco and San Francisco VA Medical Center 0000006.
Twenty-one chronic cigarette smoking OD,vertical grow rack stable on buprenorphine maintenance therapy for at least 3 months, met DSM-IV criteria for dependence on opiates; they were allowed to meet DSMIV criteria for current abuse or dependence on cocaine, amphetamines, and/or cannabis, but dependence on alcohol or benzodiazepines was exclusionary. OD was part of a buprenorphine treatment program focusing on smoking cessation and they were studied before smoking cessation. For group comparisons of metabolite concentrations specifically in the ACC, DLPFC, and POC and when correlated with neuropsychological variables, there were data from thirty-five cigarette smoking ALC recruited from local treatment programs of the VA and Kaiser Permanente and 28 cigarette smoking CON recruited from the community. The ALC group met DSM-IV criteria for alcohol dependence and was abstinent from alcohol for 21 ± 11 days at time of study. For group comparisons of metabolite concentrations in the OFC and when correlated with neuropsychological variables , smokers and non-smokers were included in the ALC and CON groups: 21 ALC and 19 CON due to a lack of sufficient data in smokers. All participants were studied with structural MRI, 1H MRS, and neuropsychological testing, all were fluent in English and they were allowed to smoke ad libitum before assessment and during breaks. Table 1 contains demographics, tobacco and alcohol use variables, mood measures, and laboratory variables for the three groups. Further exclusion criteria for ALC and CON are described elsewhere.
In brief, ALC and CON participants were excluded for neurological disorders , psychiatric disorders , and medical and vascular risk factors , known to affect neurobiology or cognition as well as for MRI contraindications. In OD and ALC, hepatitis C, type-2 diabetes, hypertension, unipolar mood disorder, or generalized anxiety disorders were not exclusionary due to their high prevalence in addiction. Six OD, 4 ALC and 1 CON had hepatitis C , while 4 OD and 13 ALC had medically-controlled hypertension. All OD were on buprenorphine maintenance therapy averaging 15 ± 9 mg/day. Table 2 depicts their recent and lifetime substance use histories. Overall, OD as a group were all cigarette smokers and had comorbid stimulant and marijuana use over lifetime, which they reduced during the year before study. Only a few OD individuals had drug use within the last 30 days: 3 used opiates and/or cocaine but only 1 used opiates for 20 days, 1 other OD used amphetamines daily, and about one-third of the sample used marijuana. The majority of OD individuals were moderate alcohol drinkers over their lifetime, but they reduced their alcohol consumption during the last year before study; only 3 had consumed alcohol on more than 10 days within the last 30 days. The ALC group for the ACC, DLPFC, and POC VOI analyses were cigarette smokers abstinent from alcohol for about 3 weeks and used other drugs occasionally . Thus, the ALC group for the majority of the analyses and the entire OD group were cigarette-smoking treatment seekers, abstinent from their main drug of abuse for several weeks and they had similarly low levels of drug use within the last month before study.
OD and ALC completed the Structured Clinical Interview for DSM-IV Axis I disorders Patient Edition, v2.0, CON were administered the corresponding screening module. In all groups, alcohol consumption was estimated with the lifetime drinking history interview, nicotine dependence was assessed with the Fagerstrom Tolerance Test for Nicotine Dependence, and lifetime substance use history was assessed with an in-house questionnaire. All participants completed the Beck Depression Inventory and the State-Trait Anxiety Inventory . A neurocognitive battery assessed the major domains affected by opioid and alcohol use disorders and Z-scores were calculated based on corresponding normative data. Cognitive domains were formed from specific neurocognitive tasks . The cognitive domain scores in ALC and CON were calculated according to the shortened neurocognitive battery of tests administered to the OD group and therefore, the constituent measures for cognitive domains in this study are different from our previous publications. All participants completed self-regulation measures, which included the BIS to assess self-reported impulsivity, the Balloon Analogue Risk Task to assess risk taking, and the Iowa Gambling Task to assess decision making. Laboratory tests within 2–3 days of the MR scan evaluated the nutritional status and alcohol-related or other hepatocellular injury in OD and ALC. See Table 1 for laboratory variables, cognitive domain and self-regulation measures for the three groups. Age and years of education did not differ between OD and CON . ALC were equivalent on age to OD and CON, but had fewer years of education. OD had lower hemoglobin and hematocrit than both CON and ALC. There were no significant differences in blood tests of liver function in individuals with and without Hepatitis C within the ALC group and also within the OD group. In addition, none of the individuals with Hepatitis C were taking medications at the time of study for Hepatitis C. Furthermore, the individuals taking hypertension medication did have controlled blood pressure by selfreport but blood pressure levels at time of study were not measured. Nicotine dependence scores were higher in OD than ALC; OD and CON also smoked significantly more cigarettes per day than ALC, but all groups were equivalent on cigarette smoking duration. Gender did not contribute to any group difference or correlation. See Table 1 for drinking severity measures in OD, CON and ALC. This study compared cortical metabolite concentrations, neurocognition,cannabis grow racks and self-regulation between cigarette-smoking opiate dependent individuals on buprenorphine maintenance therapy, treatment-seeking alcohol dependent smokers, and smoking controls. OD had significant metabolite alterations in markers of neuronal integrity , cell membrane turnover/synthesis , glutamate concentration , cellular bio-energetics , and astrocyte integrity in 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 bio-energetics in both the ACC and DLPFC,cananbis grow rack 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 CON and 1 week abstinent ALC vs. mostly nonsmoking CON. However, ACC GABA reductions were reported in abstinent individuals with cocaine and poly substance-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. We also assessed the OFC region previously not investigated in OD. The lateral OFC sub-serves motivation, drive, reward valuation, and aspects of social executive skills, 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 deficits, 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, and dietary/nutritional factors to the neurobiological group effects reported.