Regional cerebral blood flow in opiate dependence relates to substance use and neuropsychological performance.

Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate-dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance-dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol-dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence.

Brain GABA and Glutamate Concentrations Following Chronic Gabapentin Administration: A Convenience Sample Studied During Early Abstinence From Alcohol.

Gabapentin (GBP), a GABA analog that may also affect glutamate (Glu) production, can normalize GABA and Glu tone during early abstinence from alcohol, effectively treating withdrawal symptoms and facilitating recovery. Using in vivo magnetic resonance spectroscopy, we tested the degree to which daily GBP alters regional brain GABA and Glu levels in short-term abstinent alcohol-dependent individuals. Regional metabolite levels were compared between 13 recently abstinent alcohol-dependent individuals who had received daily GBP for at least 1 week (GBP+) and 25 matched alcohol-dependent individuals who had not received GBP (GBP-). Magnetic resonance spectra from up to five different brain regions were analyzed to yield absolute GABA and Glu concentrations. GABA and Glu concentrations in the parieto-occipital cortex were not different between GBP- and GBP+. Glu levels in anterior cingulate cortex, dorsolateral prefrontal cortex, and basal ganglia did not differ between GBP- and GBP+. However, in a subgroup of individuals matched on age, sex, and abstinence duration, GBP+ had markedly lower Glu in the frontal white matter (WM) than GBP-, comparable to concentrations found in light/non-drinking controls. Furthermore, lower frontal WM Glu in GBP+ correlated with a higher daily GBP dose. Daily GBP treatment at an average of 1,600 mg/day for at least 1 week was not associated with altered cortical GABA and Glu concentrations during short-term abstinence from alcohol, but with lower Glu in frontal WM. GBP for the treatment of alcohol dependence may work through reducing Glu in WM rather than increasing cortical GABA.

White matter microstructural correlates of relapse in alcohol dependence.

Identification of neural correlates of relapse to alcohol after treatment is clinically important as it may inform better substance abuse treatment. Few studies have specifically analyzed the white matter microstructure in treatment seekers as it might relate to relapse risk versus long-term abstinence. Using 4 Tesla diffusion tensor imaging, we compared two groups of one-month-abstinent treatment-seekers, who were classified based on their drinking status between six and nine months after treatment initiation. We hypothesized that subsequent relapsers had greater white matter microstructural deficits in specific brain regions than long-term abstainers. At one month of abstinence, 37 future relapsers versus 25 future abstainers had lower fractional anisotropy (a measure of axonal organization and membrane integrity) in the corpus callosum and right stria terminalis/fornix, higher diffusivity in the genu of the corpus callosum, left and right stria terminalis/fornix, and lower diffusivity in left anterior corona radiata. These differences existed despite similar lifetime and recent drinking and smoking histories in the groups. Longer smoking duration in relapsers was associated with lower fractional anisotropy in right stria terminalis/fornix. The study identified specific microstructural biomarkers of alcohol relapse risk in adults, contributing to the definition of a neurobiological relapse risk profile in alcohol use disorder.

Cigarette smoking is associated with amplified age-related volume loss in subcortical brain regions.

BACKGROUND: Magnetic resonance imaging studies of cigarette smoking-related effects on human brain structure have primarily employed voxel-based morphometry, and the most consistently reported finding was smaller volumes or lower density in anterior frontal regions and the insula. Much less is known about the effects of smoking on subcortical regions. We compared smokers and non-smokers on regional subcortical volumes, and predicted that smokers demonstrate greater age-related volume loss across subcortical regions than non-smokers. METHODS: Non-smokers (n=43) and smokers (n=40), 22-70 years of age, completed a 4T MRI study. Bilateral total subcortical lobar white matter (WM) and subcortical nuclei volumes were quantitated via FreeSurfer. In smokers, associations between smoking severity measures and subcortical volumes were examined. RESULTS: Smokers demonstrated greater age-related volume loss than non-smokers in the bilateral subcortical lobar WM, thalamus, and cerebellar cortex, as well as in the corpus callosum and subdivisions. In smokers, higher pack-years were associated with smaller volumes of the bilateral amygdala, nucleus accumbens, total corpus callosum and subcortical WM. CONCLUSIONS: Results provide novel evidence that chronic smoking in adults is associated with accelerated age-related volume loss in subcortical WM and GM nuclei. Greater cigarette quantity/exposure was related to smaller volumes in regions that also showed greater age-related volume loss in smokers. Findings suggest smoking adversely affected the structural integrity of subcortical brain regions with increasing age and exposure. The greater age-related volume loss in smokers may have implications for cortical-subcortical structural and/or functional connectivity, and response to available smoking cessation interventions.

Effects of abstinence and chronic cigarette smoking on white matter microstructure in alcohol dependence: Diffusion tensor imaging at 4T.

BACKGROUND: We previously reported widespread microstructural deficits of brain white matter in alcohol-dependent individuals (ALC) compared to light drinkers in a small 1.5T diffusion tensor imaging study employing tract-based spatial statistics. Using a larger dataset acquired at 4T, the present study is an extension that investigated the effects of alcohol consumption, abstinence from alcohol, and comorbid cigarette smoking on white matter microstructure. METHODS: Tract-based spatial statistics were performed on 20 1-week-abstinent ALC, 52 1-month-abstinent ALC, and 30 controls. Regional measures of fractional anisotropy (FA) and mean diffusivity (MD) in the significant clusters were compared by Analysis of Covariance. The metrics were correlated with substance use history and behavioral measures. RESULTS: 1-week-abstinent ALC showed lower FA than controls in the corpus callosum, right cingulum, external capsule, and hippocampus. At 1 month of abstinence, only the FA in the body of the corpus callosum of ALC remained significantly different from controls. Some regional FA deficits correlated with more severe measures of drinking and smoking histories but only weakly with mood and impulsivity measures. CONCLUSION: White matter microstructure is abnormal during early abstinence in alcohol dependent treatment seekers and recovers into the normal range within about four weeks. The compromised white matter was related to substance use severity, mood, and impulsivity. Our findings suggest that ALC may benefit from interventions that facilitate normalization of DTI metrics to maintain abstinence, via smoking cessation, cognitive-based therapy, and perhaps pharmacology to support remyelination.

Chronic Cigarette Smoking in Healthy Middle-Aged Individuals Is Associated With Decreased Regional Brain N-acetylaspartate and Glutamate Levels.

BACKGROUND: Cigarette smoking is associated with metabolite abnormalities in anterior brain regions, but it is unclear if these abnormalities are apparent in other regions. Additionally, relationships between regional brain metabolite levels and measures of decision making, risk taking, and impulsivity in smokers and nonsmokers have not been investigated. METHODS: In young to middle-aged (predominately male) nonsmokers (n = 30) and smokers (n = 35), N-acetylaspartate (NAA), choline-containing compounds, creatine-containing compounds (Cr), myo-inositol (mI), and glutamate (Glu) levels in the anterior cingulate cortex and right dorsolateral prefrontal cortex (DLPFC) were compared via 4-tesla proton single volume magnetic resonance spectroscopy. Groups also were compared on NAA, choline-containing compounds, Cr, and mI concentrations in the gray matter and white matter of the four cerebral lobes and subcortical nuclei/regions with 1.5-tesla proton magnetic resonance spectroscopy. Associations of regional metabolite levels with neurocognitive, decision-making, risk-taking, and self-reported impulsivity measures were examined. RESULTS: Smokers showed lower DLPFC NAA, Cr, mI and Glu concentrations and lower lenticular nuclei NAA level; smokers also demonstrated greater age-related decreases of DLPFC NAA and anterior cingulate cortex and DLPFC Glu levels. Smokers exhibited poorer decision making and greater impulsivity. Across the sample, higher NAA and Glu in the DLPFC and NAA concentrations in multiple lobar gray matter and white matter regions and subcortical nuclei were associated with better neurocognition and lower impulsivity. CONCLUSIONS: This study provides additional novel evidence that chronic smoking in young and middle-aged individuals is associated with significant age-related neurobiological abnormalities in anterior frontal regions implicated in the development and maintenance of addictive disorders.

Frontal Metabolite Concentration Deficits in Opiate Dependence Relate to Substance Use, Cognition, and Self-Regulation.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. METHODS: Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. RESULTS: Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. CONCLUSION: The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment.

Comparison of Regional Brain Perfusion Levels in Chronically Smoking and Non-Smoking Adults.

Chronic cigarette smoking is associated with numerous abnormalities in brain neurobiology, but few studies specifically investigated the chronic effects of smoking (compared to the acute effects of smoking, nicotine administration, or nicotine withdrawal) on cerebral perfusion (i.e., blood flow). Predominately middle-aged male (47 ± 11 years of age) smokers (n = 34) and non-smokers (n = 27) were compared on regional cortical perfusion measured by continuous arterial spin labeling magnetic resonance studies at 4 Tesla. Smokers showed significantly lower perfusion than non-smokers in the bilateral medial and lateral orbitofrontal cortices, bilateral inferior parietal lobules, bilateral superior temporal gyri, left posterior cingulate, right isthmus of cingulate, and right supramarginal gyrus. Greater lifetime duration of smoking (adjusted for age) was related to lower perfusion in multiple brain regions. The results indicated smokers showed significant perfusion deficits in anterior cortical regions implicated in the development, progression, and maintenance of all addictive disorders. Smokers concurrently demonstrated reduced blood flow in posterior brain regions that show morphological and metabolic aberrations as well as elevated beta amyloid deposition demonstrated by those with early stage Alzheimer disease. The findings provide additional novel evidence of the adverse effects of cigarette smoking on the human brain.

Brain perfusion in polysubstance users: relationship to substance and tobacco use, cognition, and self-regulation.

BACKGROUND: Brain perfusion is altered in both alcohol dependence and stimulant dependence. Although most substance users also abuse/depend on alcohol concurrently (polysubstance users; PSU), rigorous perfusion research in PSU is limited. Also, the relationships of perfusion abnormalities with cognition, impulsivity, or decision making are not well known. METHODS: Arterial spin labeling MRI and neuropsychological measures assessed perfusion levels and neurocognition in 20 alcohol-dependent individuals with comorbid-stimulant dependence (PSU), 26 individuals dependent on alcohol only (ALC), and 31 light/non-drinking controls (LD). The patient groups included smokers and non-smokers. RESULTS: ALC had lower perfusion than LD in subcortical and cortical brain regions including the brain reward/executive oversight system (BREOS). Contrary to our hypothesis, regional perfusion was generally not lower in PSU than ALC. However, smoking PSU had lower perfusion than smoking ALC in several regions, including BREOS. Lower BREOS perfusion related to greater drinking severity in smoking substance users and to greater smoking severity in smoking ALC. Lower regional perfusion in ALC and PSU correlated with worse performance in different cognitive domains; smoking status affected perfusion-cognition relationships in ALC only. Lower BREOS perfusion in both substance using groups related to higher impulsivity. CONCLUSION: Although regional perfusion was not decreased in PSU as a group, the combination of cigarette smoking and polysubstance use is strongly related to hypoperfusion in important cortical and subcortical regions. As lower perfusion relates to greater smoking severity, worse cognition and higher impulsivity, smoking cessation is warranted for treatment-seeking PSU and ALC.

Age-related effects on cortical thickness patterns of the Rhesus monkey brain.

The Rhesus monkey is a useful model for examining age-related as well as other neurological and developmental effects on the brain, because of the extensive neuroanatomical homology to the human brain, the reduced occurrence of neurological diseases such as Alzheimer's disease, and the possibility of obtaining relevant behavioral data and post-mortem tissue for histological analyses. In this study, cortical thickness measurements based on a cortical surface modeling technique were applied for the first time to investigate cortical thickness patterns in the rhesus monkey brain, and were used to evaluate regional age related effects across a wide range of ages. Age related effects were observed in several cortical areas, in particular in the somato-sensory and motor cortices, where a robust negative correlation of cortical thickness with age was observed, similar to that found in humans. In contrast, results for monkeys compared with humans show significant interspecies differences in cortical thickness patterns in the frontal and the inferior temporal regions.