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Background: Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure., Methods: Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002 and 2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus., Results: GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p< or =0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure., Conclusions: These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Diffusion spectrum imaging (DSI) is a generalization of diffusion tensor imaging to map fibrous structure of white matter and potentially very sensitive to alterations of the cingulum bundles in dementia. In this in-vivo 4T study, DSI parameters especially spatial resolution and diffusion encoding bandwidth were optimized on humans to segment the cingulum bundles for tract level measurements of diffusion. The careful tailoring of the DSI acquisitions in conjunction with fiber tracking provided an optimal DSI setting for a reliable quantification of the cingulum bundle tracts. The optimization of tracking the cingulum bundle was verified using fiber tract quantifications, including coefficients of variability of DSI measurements along the fibers between and within healthy subjects in back-to-back studies and variogram analysis of spatial correlations between diffusion orientation distribution functions (ODF) along the cingulum bundle tracts. The results demonstrate that the identification of the cingulum bundle in human brain is reproducible using an optimized DSI parameter for maximum b-value and high spatial resolution of the DSI acquisition with a feasible acquisition time of whole brain in clinical practice. This optimized DSI setting should be useful for detecting alterations along the cingulum bundle in Alzheimer disease and related neurodegenerative disorders., (Published by Elsevier Ireland Ltd.)

Relapse to hazardous levels of alcohol consumption after treatment for alcohol use disorders is common. Investigation of the neurobiological correlates of resumption of hazardous drinking is necessary to clarify the mechanisms contributing to relapse. Fifty-seven treatment-seeking alcohol-dependent participants (ALC) completed arterial spin labeling perfusion MRI of the frontal and parietal gray matter (GM) at 7+/-3 days of abstinence (baseline). ALC participants were restudied after 35+/-11 days of abstinence (assessment point 2: AP2). Twenty-eight nonsmoking, light-drinking control participants (nsLD) from the community were studied with perfusion MRI. ALC participants were followed over 12 months after baseline study and were classified as abstainers (no alcohol consumption; n=19) and resumers (any alcohol consumption; n=38) at follow-up. Cross-sectional and longitudinal perfusion was compared in abstainers, resumers, and nsLD. At baseline, resumers demonstrated significantly lower frontal and parietal GM perfusion than nsLD and abstainers. Abstainers and nsLD were not different on frontal or parietal GM perfusion. No significant longitudinal perfusion changes were observed in abstainers and resumers. At AP2, resumers showed significantly lower frontal GM perfusion than nsLD and abstainers, whereas no group differences were observed for parietal GM. Abstainers and nsLD were not different on frontal GM perfusion. The significantly decreased frontal GM perfusion in resumers compared with both abstainers and nsLD across the assessment interval suggests premorbid and/or acquired neurobiological abnormalities of the frontal GM in resumers., (2010 Elsevier Inc. All rights reserved.)

Recent studies associated excess body weight with brain structural alterations, poorer cognitive function, and lower prefrontal glucose metabolism. We found that higher BMI was related to lower concentrations of N-acetyl-aspartate (NAA, a marker of neuronal integrity) in a healthy middle-aged cohort, especially in frontal lobe. Here, we evaluated whether NAA was also associated with BMI in a healthy elderly cohort. We used 4 Tesla proton magnetic resonance spectroscopy ((1)H MRS) data from 23 healthy, cognitively normal elderly participants (69.4 +/- 6.9 years; 12 females) and measured concentrations of NAA, glutamate (Glu, involved in cellular metabolism), choline-containing compounds (Cho, involved in membrane metabolism), and creatine (Cr, involved in high-energy metabolism) in anterior (ACC) and posterior cingulate cortices (PCC). After adjustment for age, greater BMI was related to lower NAA/Cr and NAA/Cho ratios (beta < -0.56, P < 0.008) and lower Glu/Cr and Glu/Cho ratios (beta < -0.46, P < 0.02) in ACC. These associations were not significant in PCC (beta > -0.36, P > 0.09). The existence of an association between NAA and BMI in ACC but not in PCC is consistent with our previous study in healthy middle-aged individuals and with reports of lower frontal glucose metabolism in young healthy individuals with elevated BMI. Taken together, these results provide evidence that elevated BMI is associated with neuronal abnormalities mostly in frontal brain regions that subserve higher cognitive functions and impulse control. Future studies need to evaluate whether these metabolite abnormalities are involved in the development and maintenance of weight problems.

Objective: This study compared baseline metabolite levels in components of the brain reward system among individuals who remained abstinent and those who resumed hazardous alcohol consumption after treatment for alcohol dependence., Method: Fifty-one treatment-seeking alcohol-dependent individuals (abstinent for approximately 7 days [SD = 3]) and 26 light-drinking nonsmoking controls completed 1.5-T proton magnetic resonance spectroscopic imaging, yielding regional concentrations of N-acetylaspartate, choline-containing compounds, creatine-containing compounds, and myoinositol. Metabolite levels were obtained in the following component of the brain reward system: dorsolateral prefrontal cortex, anterior cingulate cortex, insula, superior corona radiata, and cerebellar vermis. Alcohol-dependent participants were followed over a 12-month period after baseline study (i.e., at 7 days of abstinence [SD = 3]) and were classified as abstainers (no alcohol consumption; n = 18) and resumers (any alcohol consumption; n = 33) at follow-up. Baseline metabolite levels in abstainers and resumers and light-drinking nonsmoking controls were compared in the above regions of interest., Results: Resumers demonstrated significantly lower baseline N-acetylaspartate concentrations than light-drinking nonsmoking controls and abstainers in all regions of interest. Resumers also exhibited lower creatine-containing-compound concentrations than abstainers in the dorsolateral prefrontal cortex, superior corona radiata, and cerebellar vermis. Abstainers did not differ from light-drinking nonsmoking controls on baseline metabolite concentrations in any region of interest., Conclusions: The significantly decreased N-acetylaspartate and creatine-containing-compound concentrations in resumers suggest compromised neuronal integrity and abnormalities in cellular bioenergetics in major neocortical components and white-matter interconnectivity of the brain reward pathway. The lack of metabolite differences between abstainers and light-drinking nonsmoking controls suggests premorbid factors potentially contributed to the baseline brain metabolite abnormalities observed in resumers.

Background: Neuroimaging studies reported cerebral perfusion abnormalities in individuals with alcohol use disorders. However, no longitudinal magnetic resonance imaging (MRI) studies of cerebral perfusion changes during abstinence from alcohol have been reported., Methods: Arterial spin labeling MRI was used to evaluate cortical gray matter perfusion changes in short-term abstinent alcohol dependent individuals in treatment and to assess the impact of chronic cigarette smoking on perfusion changes during abstinence. Seventy-six patients were scanned at least once. Data from 19 non-smoking (17 males, 2 females) and 22 smoking (21 males, 1 female) patients scanned at 1 and 5 weeks of abstinence were used to assess perfusion changes over time. Twenty-eight age-equated healthy controls (25 males, 3 females) were scanned for cross-sectional comparison, 13 of them were scanned twice. Given the age range of the cohort (28 to 68 years), age was used as a covariate in the analyses. Mean perfusion was measured in voxels of at least 80% gray matter in the frontal and parietal lobes and related to neurocognitive and substance use measures., Results: At 1 week of abstinence, frontal and parietal gray matter perfusion in smoking alcoholics was not significantly different from that in non-smoking alcoholics, but each group's perfusion values were significantly lower than in controls. After 5 weeks of abstinence, perfusion of frontal and parietal gray matter in non-smoking alcoholics was significantly higher than that at baseline. However, in smoking alcoholics, perfusion was not significantly different between the time-points in either region. The total number of cigarettes smoked per day was negatively correlated with frontal gray matter perfusion measured at 5 weeks of abstinence. Lobar perfusion measures did not correlate significantly with drinking severity or cognitive domain measures at either time-point., Conclusion: Although cerebral perfusion in alcohol dependent individuals shows improvement with abstinence from alcohol, cigarette smoking appears to hinder perfusion improvement.

Previous diffusion tensor imaging (DTI) studies indicated microstructural disruption of white matter in alcohol dependence. To investigate the microstructure of primary neurocircuitry involved in alcohol use disorders, the present study used Tract-Based Spatial Statistics (TBSS) of DTI measures as well as probabilistic tractography. Eleven recovering alcoholics in their first week of abstinence from alcohol were compared with 10 light-drinking controls; diffusion measures were correlated with measures of neurocognition and drinking severity. Regions characterized by low fractional anisotropy and high mean diffusivity included cortico-striatal fibers and those in frontal white matter and limbic pathways. Greater diffusion abnormalities in sections of commissural fibers (inter-hemispheric connections) were associated with greater drinking severity, and lower fractional anisotropy measures in frontal and limbic fiber tracts correlated with lower visuospatial memory performance. These study findings provide direct evidence of compromised integrity of the motivational brain circuitry in alcohol use disorders. These abnormalities in fiber connections could be partially responsible for deficiencies in executive functions, behavioral regulation, and impulse control commonly described in alcohol dependence.

Our previous proton magnetic resonance spectroscopic imaging ((1)H MRSI) studies showed that the frontal lobe white matter (WM) in smoking recovering alcoholics (sRA) had lower concentrations of N-acetylaspartate (NAA), a marker for neuron viability, compared to both nonsmoking recovering alcoholics (nsRA) and a control group of nonsmoking light drinkers (nsLD). Using diffusion tensor imaging (DTI) in a similar population, we found lower fractional anistropy (FA), a microstructural measure of WM fiber integrity, in regions of specific fiber bundles within frontal WM of recovering alcoholics compared to light drinkers. In this study, we hypothesized that in these regions of lower FA, NAA concentrations in the alcoholic groups are lower than in non-alcoholic controls. We hypothesized further that sRA have lower regional NAA concentrations than nsRA. We retrospectively analyzed existing (1)H MRSI data by quantitating metabolite concentrations from voxels that corresponded to previously identified WM regions of lower FA, and from a control region of normal FA in alcoholics. We found significant NAA concentration differences between groups in regions of abnormal FA. In particular, sRA had significantly lower NAA concentration than nsLD, but in no region was NAA significantly lower in nsRA than nsLD. Furthermore, no NAA group differences were detected in a frontal WM region of normal FA. These results indicate regionally localized NAA loss within the frontal WM, and specifically NAA loss in regions of low FA. Compared to our previous lobar analyses, DTI-guided MRSI analysis allows the selective evaluation of small WM regions with microstructural injury, thereby increasing statistical power to detect relevant pathology and group differences. DTI-guided MRSI analyses promise to contribute to a better understanding of brain injury in alcohol and nicotine dependence and, by extension, perhaps in other neurodegenerative diseases as well., (2009 John Wiley & Sons, Ltd.)

Aims: Resumption of hazardous drinking after treatment is common in alcohol use disorders (AUD). This study examined the ability of multimodality magnetic resonance, neurocognitive, psychiatric and demographic, to predict alcohol consumption after treatment for AUD., Methods: Seventy treatment-seeking participants completed 1.5T magnetic resonance studies, yielding regional gray matter (GM) and white matter (WM) surrogate markers of neuronal integrity (N-acetylaspartate: NAA) and cell membrane turnover/synthesis (choline: Cho), assessment of major psychiatric disorders and comprehensive neurocognitive assessment after approximately 1 month of abstinence. Participants were followed up 6-12 months after treatment and classified as Abstainers (no alcohol consumption; n=26) and Resumers (any alcohol consumption; n=44). Abstainers and Resumers were contrasted on various outcome measures, and those that significantly differed between groups were entered as factors in a logistical regression model to predict drinking status at follow-up., Results: The following variables were independent predictors of resumption of drinking: temporal GM NAA, frontal WM NAA, frontal GM Cho, processing speed and comorbid unipolar mood disorder. With each standard deviation unit decrease in temporal GM NAA, frontal WM NAA, frontal GM Cho and processing speed, the odds of resumption of drinking were increased 3.1, 3.3, 6.4 and 14.2 times, respectively. Diagnosis of a unipolar mood disorder was associated with 14.5-fold increased odds of resumed drinking., Conclusions: The findings suggest that Resumers, relative to Abstainers, demonstrated greater abnormalities in anterior frontal-subcortical circuits involved in mood and behavioral regulation, and development and maintenance of alcohol use disorders, The magnetic resonance-derived variables used in this study may provide additional information regarding the prediction and neurobiological correlates of resumption of hazardous drinking.

Co-morbidities that commonly accompany those afflicted with an alcohol use disorder (AUD) may promote variability in the pattern and magnitude of neurocognitive abnormalities demonstrated. The goal of this study was to investigate the influence of several common co-morbid medical conditions (primarily hypertension and hepatitis C), psychiatric (primarily unipolar mood and anxiety disorders), and substance use (primarily psychostimulant and cannabis) disorders, and chronic cigarette smoking on the neurocognitive functioning in short-term abstinent, treatment-seeking individuals with AUD. Seventy-five alcohol-dependent participants (ALC; 51+/-9 years of age; three females) completed comprehensive neurocognitive testing after approximately 1 month of abstinence. Multivariate multiple linear regression evaluated the relationships among neurocognitive variables and medical conditions, psychiatric, and substance-use disorders, controlling for sociodemographic factors. Sixty-four percent of ALC had at least one medical, psychiatric, or substance-abuse co-morbidity (excluding smoking). Smoking status (smoker or nonsmoker) and age were significant independent predictors of cognitive efficiency, general intelligence, postural stability, processing speed, and visuospatial memory after age-normed adjustment and control for estimated pre-morbid verbal intelligence, education, alcohol consumption, and medical, psychiatric, and substance-misuse co-morbidities. Results indicated that chronic smoking accounted for a significant portion of the variance in the neurocognitive performance of this middle-aged AUD cohort. The age-related findings for ALC suggest that alcohol dependence, per se, was associated with diminished neurocognitive functioning with increasing age. The study of participants who demonstrate common co-morbidities observed in AUD is necessary to fully understand how AUD, as a clinical syndrome, affects neurocognition, brain neurobiology, and their changes with extended abstinence.

Background: Current effort is directed at defining new classification schemes for alcohol use disorders (AUD) based on genetic/biological, physiological, and behavioral endophenotypes., Methods: We describe briefly findings of in vivo brain proton magnetic resonance spectroscopy ((1)H MRS) studies in AUD and propose that they be further explored and expanded regarding their value as a potential endophenotype for AUD., Results: In vivo (1)H MRS, as part of the emerging field of "imaging genomics," may provide readily accessible, objective, functionally significant and region-specific neurobiological measures that successfully link genotypes to neurocognition and to psychiatric symptomatology in relatively small patient cohorts. We discuss several functional gene variants that may affect specific (1)H MRS-detectable metabolites and provide recent data from our own work that supports the view of genetic effects on metabolite measures., Conclusions: MRS-genetics research will not only offer clues to the functional significance and downstream effects of genetic differences in AUD, but, via monitoring and/or predicting the efficacy of pharmacological and behavioral interventions as a function of genotype, has the potential to influence future clinical management of AUD.

Objective: Obesity and being overweight during adulthood have been consistently linked to increased risk for development of dementia later in life, especially Alzheimer's disease. They have also been associated with cognitive dysfunction and brain structural alterations in otherwise healthy adults. Although proton magnetic resonance spectroscopy may distinguish between neuronal and glial components of the brain and may point to neurobiological mechanisms underlying brain atrophy and cognitive changes, no spectroscopic studies have yet assessed the relationships between adiposity and brain metabolites., Methods: We have utilized magnetic resonance imaging and proton magnetic resonance spectroscopic imaging data from 50 healthy middle-aged participants (mean age, 41.7 +/- 8.5 years; 17 women), who were scanned as control subjects for another study., Results: After adjustment for age and sex, greater body mass indices (BMIs) correlated with: (1) lower concentrations of N-acetylaspartate (spectroscopic marker of neuronal viability) in frontal (p = 0.001), parietal (p = 0.006), and temporal (p = 0.008) white matter; (2) lower N-acetylaspartate in frontal gray matter (p = 0.01); and (3) lower concentrations of choline-containing metabolites (associated with membrane metabolism) in frontal white matter (p = 0.05)., Interpretation: These results suggest that increased BMI at midlife is associated with neuronal and/or myelin abnormalities, primarily in the frontal lobe. Because white matter in the frontal lobes is more prone to the effects of aging than in other lobes, our results may reflect accelerated aging in individuals with high levels of adiposity. Thus, greater BMI may increase the odds of developing an age-related disease, such as Alzheimer's disease.

Almost all we know about neurobiological brain injury in alcohol use disorders has been derived from convenience samples of treated alcoholics. Recent research has demonstrated more comorbid conditions, poorer psychosocial functioning, and higher dependence levels in treated alcoholics than in their treatment-naive counterparts. Thus, it is not clear whether neuroimaging results from convenience samples of treated alcoholics can be generalized to the entire population with alcohol use disorders. We compared 35 treated alcoholics at 1 week of abstinence (ALC) and 32 treatment-naive heavy drinkers (HD) on regional brain volumes and metabolite concentrations obtained by in vivo magnetic resonance at 1.5 Tesla to evaluate for potential group differences. Then, we evaluated whether comorbid cigarette smoking and common demographic and clinical variables mediated any existing neurobiological group differences. ALC demonstrated smaller lobar gray matter volumes and thalami than HD, exacerbated by chronic smoking. Furthermore, concentrations of N-acetyl-aspartate (an accepted marker of neuronal viability), choline-containing metabolites (involved in membrane turnover), and myo-inositol (a putative marker of glial cells and osmolyte) were lower in multiple brain regions of ALC compared to HD. The lower N-acetyl-aspartate concentrations in white matter of ALC versus HD were explained by average number of drinks per month over the year preceding study. However, the other group differences were not explained by common drinking, demographic, and clinical variables (used as covariates at the same time) or by excluding participants with comorbid mood disorders. Taken together, this suggests that the degree of brain atrophy, as well as neuronal and membrane injury in clinical samples of alcoholics cannot be generalized to the much larger population with alcohol use disorders that does not seek treatment.

Memory function is largely mediated by the medial temporal lobe (MTL), and its compromise has been observed in alcohol dependence and chronic cigarette smoking. The effects of heavy alcohol consumption and chronic smoking on hippocampal volumes and MTL metabolites and their recovery during abstinence from alcohol have not been assessed. Male alcoholics in treatment (ALC) [13 smokers (sALC) and 11 non-smokers (nsALC)] underwent quantitative magnetic resonance imaging and short-echo proton magnetic resonance spectroscopic imaging at 1 week and 1 month of sobriety. Outcome measures were compared with 14 age-matched, non-smoking light-drinkers and were related to visuospatial learning and memory. Over 1 month of abstinence, N-acetyl-aspartate, a neuronal marker, and membrane-associated choline-containing metabolites normalized in the MTL of nsALC subjects, but remained low in the MTL of sALC subjects. Metabolite concentration changes in both groups were associated with improvements in visuospatial memory. Hippocampal volumes increased in both groups during abstinence, but increasing volumes correlated with visuospatial memory improvements only in nsALC subjects. In summary, chronic cigarette smoking in alcohol-dependent men appears to have adverse effects on MTL metabolite recovery during short-term sobriety. These data may also have implications for other conditions with established MTL involvement and significant smoking co-morbidity, such as schizophrenia-spectrum and mood disorders.

The problem of low signal-to-noise ratio for gamma-aminobutyric acid (GABA) in vivo is exacerbated by inefficient detection schemes and non-optimal experimental parameters. To analyze the mechanisms for GABA signal loss of a MEGA-PRESS J-difference sequence at 4 T, numerical simulations were performed ranging from ideal to realistic experimental implementation, including volume selection and experimental radio frequency (RF) pulse shapes with a macromolecular minimization scheme. The simulations were found to be in good agreement with phantom and in vivo data from human brain. The overall GABA signal intensity for the simulations with realistic conditions for the MEGA-PRESS difference spectrum was calculated to be almost half of the signal simulated under ideal conditions (~43% signal loss). In contrast, creatine was reduced significantly less then GABA (~19% signal loss). The 'four-compartment' distribution due to J-coupling in the PRESS-based localization was one of the most significant sources of GABA signal loss, in addition to imperfect RF profiles for volume selection and editing. An alternative strategy that reduces signal loss due to the four-compartment distribution is suggested. In summary, a detailed analysis of J-difference editing is provided with estimates of the relative amounts of GABA signal losses due to various mechanisms. The numerical simulations presented in this study should facilitate both implementation of the more efficient acquisition and quantification process of J-coupled systems.

Background: Hierarchical linear modeling (HLM) can reveal complex relationships between longitudinal outcome measures and their covariates under proper consideration of potentially unequal error variances. We demonstrate the application of HLM to the study of magnetic resonance imaging (MRI)-derived brain volume changes and cognitive changes in abstinent alcohol-dependent individuals as a function of smoking status, smoking severity, and drinking quantities., Methods: Twenty non-smoking recovering alcoholics (nsALC) and 30 age-matched smoking recovering alcoholics (sALC) underwent quantitative MRI and cognitive assessments at 1 week, 1 month, and 7 months of sobriety. Eight non-smoking light drinking controls were studied at baseline and 7 months later. Brain and ventricle volumes at each time point were quantified using MRI masks, while the boundary shift integral method measured volume changes between time points. Using HLM, we modeled volumetric and cognitive outcome measures as a function of cigarette and alcohol use variables., Results: Different hierarchical linear models with unique model structures are presented and discussed. The results show that smaller brain volumes at baseline predict faster brain volume gains, which were also related to greater smoking and drinking severities. Over 7 months of abstinence from alcohol, sALC compared to nsALC showed less improvements in visuospatial learning and memory despite larger brain volume gains and ventricular shrinkage., Conclusions: Different and unique hierarchical linear models allow assessments of the complex relationships among outcome measures of longitudinal data sets. These HLM applications suggest that chronic cigarette smoking modulates the temporal dynamics of brain structural and cognitive changes in alcoholics during prolonged sobriety.

Alcohol use disorders (AUD) and chronic cigarette smoking are common among individuals with human immunodeficiency virus infection (HIV). Concurrent AUD in HIV is related to greater abnormalities in brain morphology and neurocognition than either condition alone. However, the potential influence of chronic smoking on brain morphology and neurocognition in those concurrently afflicted with AUD and HIV has not been examined. The goal of this retrospective analysis was to determine if chronic smoking affected neurocognition and brain morphology in a subsample of HIV-positive non-treatment-seeking heavy drinking participants (HD+) from our earlier work. Regional volumetric and neurocognitive comparisons were made among age-equivalent smoking HD+(n=17), nonsmoking HD+ (n=27), and nonsmoking HIV-negative light drinking controls (n=27) obtained from our original larger sample. Comprehensive neuropsychological assessment evaluated multiple neurocognitive domains of functioning and for potential psychiatric comorbidities. Quantitative volumetric measures of neocortical gray matter (GM), white matter (WM), subcortical structures, and sulcal and ventricular cerebral spinal fluid (CSF) were derived from high-resolution magnetic resonance images. The main findings were (1) smoking HD+ performed significantly worse than nonsmoking HD+ on measures of auditory-verbal (AV) learning, AV memory, and cognitive efficiency; (2) relative to controls, smoking HD+ demonstrated significantly lower neocortical GM volumes in all lobes except the occipital lobe, while nonsmoking HD+ showed only lower frontal GM volume compared with controls; (3) in the HD+ group, regional brain volumes and neurocognition were not influenced by viremia, highly active antiretroviral treatment, or Center for Disease Control symptom status, and no interactions were apparent with these variables or smoking status. Overall, the findings suggested that the direct and/or indirect effects of chronic cigarette smoking created an additional burden on the integrity of brain neurobiology and neurocognition in this cohort of HIV-positive heavy drinkers.

Background: Approximately 50 to 90% of individuals in North America seeking treatment for alcoholism are chronic smokers. A growing body of evidence suggests that chronic cigarette smokers show a pattern of neurocognitive dysfunction similar to that observed in alcoholic patients. However, previous studies investigating neurocognitive recovery in abstinent alcoholic patients did not specifically consider the potential effects of chronic cigarette smoking., Methods: This study comprehensively compared longitudinal neurocognitive changes over 6 to 9 months of abstinence among 13 nonsmoking recovering alcoholic patients (ALC) and 12 actively smoking ALC. The neurocognitive performance of the alcoholic groups was compared with nonsmoking light-drinking controls (nonsmoking LD)., Results: Nonsmoking ALC exhibited a significantly greater magnitude of longitudinal improvement than smoking ALC on measures of cognitive efficiency, executive skills, visuospatial skills, and working memory. Both nonsmoking ALC and smoking ALC demonstrated equivalent improvement on auditory-verbal learning, auditory-verbal memory, and processing speed. Nonsmoking LD showed no significant changes in neurocognition over time. In cross-sectional comparisons at 6 to 9 months of abstinence, nonsmoking ALC were superior to smoking ALC on measures of auditory-verbal learning, auditory-verbal memory, cognitive efficiency, executive skills, processing speed, and working memory. The longitudinal and cross-sectional neurocognitive differences observed between nonsmoking and smoking ALC remained significant after covarying for group differences in education, estimated premorbid intelligence alcohol consumption, and other potentially confounding variables. In smoking ALC, greater smoking severity was inversely related to longitudinal improvement on multiple neurocognitive measures., Conclusions: These preliminary results suggest that chronic smoking may modulate neurocognitive recovery in abstinent alcoholic patients. More generally, chronic smoking may impact neurocognition in other conditions where is it a prevalent behavior.

Few studies have described the metabolic substrates underlying neuropsychological performance in HIV infection or examined the specificity of these relationships. The authors performed magnetic resonance spectroscopic and neuropsychological evaluations on 61 patients with AIDS dementia complex (stages 1-3) and 39 HIV-positive neurologically asymptomatic individuals. N-acetylaspartate, a marker of mature neurons, choline and myoinositol, both markers of gliosis, and creatine, a reference marker, were measured in the basal ganglia, frontal white matter, and parietal cortex. The neuropsychological evaluation consisted of tests that measured gross and fine motor skills, psychomotor function, information processing speed, and verbal memory. The authors examined performance on individual subtests and an aggregate Z score based on eight subtests (NPZ-8), adjusted for age and education. The NPZ-8 was significantly higher in subjects with greater N-acetylaspartate/creatine in the frontal white matter and was lower in subjects with higher myoinositol/creatine in the basal ganglia. Particularly strong associations were found between measures of gross and fine motor function, which correlated positively with N-acetylaspartate/creatine in the frontal white matter and negatively with myoinositol/creatine in the basal ganglia. Similarly, cognitive processing speed was negatively correlated with myoinositol/creatine in the basal ganglia. In contrast, there were no statistically significant relationships between brain metabolite levels in the parietal cortex and neuropsychological function. This study provides convincing evidence that neuropsychological impairment is associated with reduced markers of mature neurons and increased markers of gliosis in the basal ganglia and frontal white matter. Neural changes as reflected by these metabolite levels may prove useful in identifying individuals at risk for neuropsychological impairment. Prospective studies are needed to elucidate the evolution of these changes in the setting of antiretroviral therapy.

A vast body of research attests to the adverse effects of chronic smoking on cardiac, pulmonary, and vascular function as well as the increased risk for various forms of cancer. However, comparatively little is known about the effects of chronic smoking on human brain function. Although smoking rates have decreased in the developed world, they remain high in individuals with alcohol use disorders. Despite the high prevalence of comorbid chronic smoking in alcohol use disorders, very few studies have addressed the potential neurobiological or neurocognitive effects of chronic smoking in alcohol use disorders. Here, we briefly review the existing literature on the neurobiological and neurocognitive consequences of chronic cigarette smoking and summarize our neuroimaging and neurocognitive studies on the effects of comorbid chronic excessive alcohol consumption and cigarette smoking in treatment-seeking and treatment-naïve populations. Our research suggests comorbid chronic cigarette smoking modulates magnetic resonance-detectable brain injury and neurocognition in alcohol use disorders and that neurobiological recovery in our abstinent alcoholics is adversely affected by chronic smoking. Consideration of the potential separate effects and interactions of chronic smoking and alcohol consumption may foster a better understanding of specific mechanisms and neurocognitive consequences of brain injury in alcoholism and of brain recovery during sustained abstinence from alcohol. The material presented also contributes to ongoing discussions about treatment strategies for comorbid alcoholism and cigarette smoking and will hopefully stimulate further research into the neurobiological and neurocognitive consequences of chronic smoking in alcoholism and other substance use disorders.

Chronic cigarette smoking is associated with adverse effects on cardiac, pulmonary, and vascular function as well as the increased risk for various forms of cancer. However, little is known about the effects of chronic smoking on human brain function. Although smoking rates have decreased in the developed world, they remain high in individuals with alcohol use disorders (AUD) and other neuropsychiatric conditions. Despite the high prevalence of chronic smoking in AUD, few studies have addressed the potential neurobiological or neurocognitive consequences of chronic smoking in alcohol use disorders. Here, we review the the neurobiological and neurocognitive findings in both AUD and chronic cigarette smoking, followed by a review of the effects of comorbid cigarette smoking on neurobiology and neurocognition in AUD. Recent research suggests that comorbid chronic cigarette smoking modulates magnetic resonance-detectable brain injury and neurocognition in alcohol use disorders and adversely affects neurobiological and neurocognitive recovery in abstinent alcoholics.. Consideration of the potential separate and interactive effects of chronic smoking and alcohol use disorders may have significant implications for pharmacological and behavioral treatment interventions.

We previously reported [Cardenas, V.A., Studholme, C., Meyerhoff, D.J., Song, E., Weiner, M.W., 2005. Chronic active heavy drinking and family history of problem drinking modulate regional brain tissue volumes. Psychiatry Res. 138, 115-130] that non-treatment-seeking, active heavy drinkers (HD) demonstrated smaller regional neocortical gray matter volumes compared to light drinking controls; however, the potential effects of chronic cigarette smoking on regional brain volumes were not addressed. The goal of this retrospective analysis was to determine if chronic smoking affected brain structure in the non-treatment-seeking heavy drinking sample from our earlier report (i.e., Cardenas et al., 2005). Regional volumetric comparisons were made among age-matched smoking HD (n=17), non-smoking HD (n=16), and non-smoking light drinkers (nsLD; n=20) from our original sample. Quantitative volumetric measures of neocortical gray matter (GM), white matter (WM), subcortical structures, and cerebral spinal fluid (CSF) were derived from high-resolution magnetic resonance imaging. Smoking HD demonstrated smaller volumes than nsLD in the frontal, parietal, temporal GM, and for total neocortical GM. Smoking HD also demonstrated smaller temporal and total GM volumes than non-smoking HD. Non-smoking HD and nsLD did not differ significantly on GM volumes. Further, the three groups did not differ on lobar WM, subcortical structures or regional CSF volumes. These retrospective analyses indicate neocortical GM volume reductions in non-treatment-seeking smoking HD, but not in non-smoking HD, which are consistent with our studies in recently detoxified treatment-seeking alcohol-dependent samples.

Brain atrophy associated with chronic alcohol consumption is partially reversible after cessation of drinking. Recovering alcoholics (RA, 45+/-8 years) were studied with MRI within 1 week of entering treatment, with follow-up at 8 months. Light drinkers (LD) were studied with MRI twice 1 year apart. For each participant, deformation maps of baseline structure and longitudinal size changes between baseline and follow-up scans were created using nonlinear registration techniques. ANCOVA assessed group differences and regression methods examined relationships between deformation maps and measures of drinking severity or baseline atrophy. At baseline, RA showed significant atrophy in the frontal and temporal lobes. Longitudinally, abstainers recovered tissue volumes significantly faster than LD in parietal and frontal lobes. When comparing abstainers to relapsers, additional regions with significantly greater recovery in abstainers were temporal lobes, thalamus, brainstem, cerebellum, corpus callosum, anterior cingulate, insula, and subcortical white matter. Gray matter volume at baseline predicted volume recovery during abstinence better than white matter. Drinking severity was not significantly related to brain structural changes assessed with this method. Longitudinally, deformation-based morphometry confirmed tissue recovery in RAs who maintain long-term sobriety. Abstinence-associated tissue volume gains are significant in focal parts of the fronto-ponto-cerebellar circuit that is adversely affected by heavy drinking.

Approximately 70-90% of individuals in North America seeking treatment for alcoholism are chronic smokers. A growing body of evidence suggests chronic cigarette smoking alone adversely affects neurocognition in adults. However, few studies on the neurocognitive function of short-term abstinent alcoholics have specifically considered the potential effects of chronic cigarette smoking. In this study, 20 nonsmoking recovering alcoholics (nsRA) and 22 actively smoking recovering alcoholics (sRA) participants, matched on age and education, were contrasted on a comprehensive neurocognitive battery after 34+/-9 days of abstinence. nsRA were superior to sRA on measures of auditory-verbal learning and memory, processing speed, cognitive efficiency, and static postural stability. These group differences were not a function of group disparities in age, education, estimated premorbid verbal intelligence, lifetime alcohol consumption, or other measured comorbid psychiatric or medical factors. In sRA, longer smoking duration was negatively correlated with executive skills, visuospatial learning, general cognitive efficiency, and static postural stability. These results indicate that greater consideration of the potential neurobiological effects of current chronic smoking on neurocognitive functioning is warranted in studies of alcoholism and other conditions where smoking is a common comorbid factor.

Background: Longitudinal studies of brain tissue metabolite recovery in short-term abstinent alcoholics have primarily investigated the frontal lobes and cerebellum with variable results. Preliminary proton magnetic resonance spectroscopic imaging (1H MRSI) suggested that chronic cigarette smoking exacerbates alcohol-induced brain injury in 1-week abstinent alcoholics. However, the potential effects of chronic cigarette smoking on the recovery of alcohol-induced brain injury have not been studied., Methods: Multislice short-echo time 1H MRSI was used to measure longitudinal changes in common brain metabolites in 25 recovering alcohol-dependent individuals (RA), retrospectively assigned to smoking (n = 14) and nonsmoking (n = 11) subgroups. Recovering alcohol-dependent individuals in longitudinal analyses were studied after approximately 7 and 34 days of abstinence from alcohol. In cross-sectional analyses, 36 RA (19 smokers, 17 nonsmokers) with approximately 34 days of sobriety were compared with 29 light drinkers (LD). Relationships between neurocognition and metabolite concentrations in abstinent RA were also examined., Results: Over 1 month of abstinence from alcohol, RA, as a group, showed significant increases of regional N-acetylaspartate (NAA; marker of neuronal viability) and choline-containing compounds (Cho; marker of cell membrane synthesis/turnover) primarily in frontal and parietal lobes. These increases appeared to be driven by nonsmoking RA. Cross-sectional results indicate that metabolite levels in RA at 35 days of sobriety are not significantly different from those in LD in most regions, except for lower NAA and Cho in parietal WM and subcortical structures. However, metabolite levels at that time appear to be strongly modulated by smoking status. The patterns of metabolite-neurocognition relationships were different for nonsmoking and smoking RA., Conclusions: Within the first weeks of sobriety, regional brain NAA and Cho levels increased, but metabolite levels did not normalize in all brain regions after 35 days of sobriety. Neurobiologic recovery in RA appeared to be adversely affected by chronic smoking. Greater consideration of the effects of continued cigarette smoking on the neurobiologic and neurocognitive recovery of alcohol-dependent individuals is warranted.

Background: Recent in vivo research using magnetic resonance spectroscopy demonstrated that chronic cigarette smoking exacerbates regional chronic alcohol-induced brain injury. Other studies associated cigarette smoking with gray matter volume reductions in healthy adults, with greater brain atrophy in aging, and with poorer neurocognition. Although cigarette smoking is common among alcohol-dependent individuals, previous research did not account for the potential effects of chronic smoking on regional brain volumes in alcoholism., Methods: High-resolution T1-weighted magnetic resonance images from one-week-abstinent, alcohol-dependent individuals and light drinkers were automatically segmented into gray matter, white matter, and cerebral spinal fluid of lobes and subcortical structures. A brief neuropsychological test battery was used to assess cognition in alcohol-dependent individuals. The alcoholic and nondrinking groups were retrospectively divided into chronic smokers and nonsmokers, and the volumetric data were analyzed as a function of alcohol and smoking status., Results: Chronic alcohol dependence was associated with smaller volumes of frontal and parietal white matter, parietal and temporal gray matter, and thalami, accompanied by widespread sulcal but not ventricular enlargements. Chronic cigarette smoking was associated with less parietal and temporal gray matter and with more temporal white matter. Among alcoholics, better visuospatial learning and memory and greater visuomotor scanning speed were correlated with larger lobar white matter volumes in the nonsmoking alcohol-dependent group only., Conclusions: These data provide preliminary evidence that comorbid chronic cigarette smoking accounts for some of the variance associated with cortical gray matter loss and appears to alter relationships between brain structure and cognitive functions in alcohol-dependent individuals.

Despite the clinical significance of event-related potential (ERP) latency abnormalities, little attention has focused on the anatomic substrate of latency variability. Volume conduction models do not identify the anatomy responsible for delayed neural transmission between neural sources. To explore the anatomic substrate of ERP latency variability in normal adults using automated measures derived from magnetic resonance imaging (MRI), ERPs were recorded in the visual three-stimulus oddball task in 59 healthy participants. Latencies of the P3a and P3b components were measured at the vertex. Measures of local anatomic size in the brain were estimated from structural MRI, using tissue segmentation and deformation morphometry. A general linear model was fitted relating latency to measures of local anatomic size, covarying for intracranial vault volume. Longer P3b latencies were related to contractions in thalamus extending superiorly into the corpus callosum, white matter (WM) anterior to the central sulcus on the left and right, left temporal WM, the right anterior limb of the internal capsule extending into the lenticular nucleus, and larger cerebrospinal fluid volumes. There was no evidence for a relationship between gray matter (GM) volumes and P3b latency. Longer P3a latencies were related to contractions in left temporal WM, and left parietal GM and WM near the interhemispheric fissure. P3b latency variability is related chiefly to WM, thalamus, and lenticular nucleus, whereas P3a latency variability is not related as strongly to anatomy. These results imply that the WM connectivity between generators influences P3b latency more than the generators themselves do.

We developed a fast method to obtain T1 relaxation maps in magnetic resonance imaging (MRI) based on two inversion recovery acquisitions and a reference acquisition, while maintaining high sensitivity by utilizing the full dynamic range of the MRI signal. Optimal inversion times for estimating T1 in the human brain were predicted using standard error propagation theory. In vivo measurements on nine healthy volunteers yielded T1 values of 1094+/-18 ms in gray matter and 746+/-40 ms in white matter, in reasonable agreement with literature values using conventional approaches. The proposed method should be useful for clinical studies because the T1 maps can be obtained within a few seconds.

The goals of this study were to measure if chronic active heavy drinking is associated with brain volume loss in non-treatment seeking men and women, and to assess the effect of positive family history of problem drinking on brain structure in heavy drinkers. Automated image processing was used to analyze high-resolution T1-weighted magnetic resonance images from 49 active heavy drinkers and 49 age- and sex-matched light drinkers, yielding gray matter, white matter and cerebrospinal fluid (CSF) volumes within the frontal, temporal, parietal and occipital lobes. Regional brain volume measures were compared as a function of group, sex and their interaction. Within heavy drinkers, volumes were correlated with measures of alcohol consumption and compared as a function of family history of problem drinking. Deformation morphometry explored localized patterns of atrophy associated with heavy drinking or severity of drinking. We found significant gray matter volume losses, but no white matter losses, in active heavy drinkers compared with light drinkers. Women had greater gray matter and smaller white matter and CSF volumes as a percentage of intracranial vault than men. Within heavy drinkers, smaller gray matter volumes were associated with higher current levels of drinking and older age, while a positive family history of problem drinking was associated with smaller CSF volumes. Community-dwelling heavy drinkers who are not in alcoholism treatment have dose-related gray matter volume losses, and family history of problem drinking ameliorates some structural consequences of heavy drinking.

Higher rates of alcohol use have been reported in HIV+ individuals compared to the general population. Both heavy alcohol use and HIV infection are associated with increased risk of neuropsychological (NP) impairment. We examined effects of heavy active alcohol use and HIV on NP functioning in a large sample of community-residing HIV+ individuals and HIV- controls. The four main study groups included 72 HIV- light/non-drinkers, 70 HIV- heavy drinkers (>100 drinks per month), 70 HIV+ light/non-drinkers, and 56 HIV+ heavy drinkers. The heavy drinking group was further subdivided to assess effects of the heaviest levels of active alcohol use (>6 drinks per day) on NP functioning. A comprehensive NP battery was administered. Multivariate analysis of covariance was employed to examine the effect of HIV and alcohol on NP functioning after adjusting for group differences in age and estimated premorbid verbal intellectual functioning. The analyses identified main effects of heavy drinking and HIV on NP function, with greatest effects involving the contrast of HIV+ heavy drinkers and the HIV- light drinkers. Synergistic effects of heaviest current drinking and HIV infection were identified in analyses of motor and visuomotor speed. Supplementary analyses also revealed better NP function in the HIV+ group with antiretroviral treatment (ART) and lower level of viral burden, a finding that was consistent across levels of alcohol consumption. Finally, heavy alcohol use and executive functioning difficulties were associated with lower levels of self-reported medication adherence in the HIV+ group. The findings suggest that active heavy alcohol use and HIV infection have additive adverse effects on NP function, that they may show synergistic effects in circumstances of very heavy active alcohol use, and that heavy drinking and executive functioning may mediate health-related behaviors in HIV disease.

Neuropathological and neuroimaging studies show cortical and subcortical volume loss in alcohol-dependent individuals. Using quantitative magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopic imaging ((1)H MRSI), we studied the size and potential cellular injury of the brainstem in untreated heavy alcohol drinkers. The brainstem is considered critical in the development and maintenance of drug and alcohol dependence. Two methods of brainstem size determination were compared: standard volumetry vs. midsagittal MR image area measurement. Heavy drinkers (n=12) and light drinkers (n=10) were compared with MRI; (1)H MRSI brainstem data were obtained from a subset of this cohort. Chronic heavy drinking was associated with significantly smaller midsagittal areas of the brainstem, midbrain, and pons, and with significantly smaller overall brainstem volume. Heavy drinking was also associated with significantly lower ratios of N-acetyl-aspartate and choline-containing metabolites compared with creatine-containing compounds in the brainstem, independent of brainstem atrophy. Additionally, brainstem volume and midsagittal brainstem area were correlated (r=0.78). These structural and metabolite findings are consistent with neuronal injury in the brainstem of untreated chronic heavy drinkers. The results also indicate that the midsagittal MRI brainstem area is an easily determined and reliable indicator of brainstem volume.

Background: Cigarette smoking is common among alcohol-dependent individuals. Nevertheless, previous research has typically not accounted for the potential independent or compounding effects of cigarette smoking on alcohol-induced brain injury and neurocognition., Methods: Twenty-four 1-week-abstinent recovering alcoholics (RAs; 14 smokers and 10 nonsmokers) in treatment and 26 light-drinking controls (7 smokers and 19 nonsmokers) were compared on measures of common brain metabolites in gray matter and white matter of the major lobes, basal ganglia, midbrain, and cerebellar vermis, obtained via multislice short-echo time proton magnetic resonance spectroscopic imaging. Smoking and nonsmoking RAs were also contrasted on measures of neurocognitive functioning, as well as laboratory markers of drinking severity and nutritional status., Results: Chronic alcohol dependence, independent of smoking, was associated with lower concentrations of frontal N-acetylaspartate (NAA) and frontal choline-containing compounds, as well as lower parietal and thalamic choline. Smoking RAs had lower NAA concentrations in frontal white matter and midbrain and lower midbrain choline than nonsmoking RAs. A four-group analysis of covariance also demonstrated that chronic cigarette smoking was associated with lower midbrain NAA and choline and with lower vermian choline. In smoking RAs, heavier drinking was associated with heavier smoking, which correlated with numerous subcortical metabolite abnormalities. The 1-week-abstinent smoking and nonsmoking RAs did not differ significantly on a brief neurocognitive battery. In smoking RAs, lower cerebellar vermis NAA was associated with poorer visuomotor scanning speed and incidental learning, and in nonsmoking RAs lower vermis NAA was related to poorer visuospatial learning and memory., Conclusions: These human in vivo proton magnetic resonance spectroscopic imaging findings indicate that chronic cigarette smoking exacerbates chronic alcohol-induced neuronal injury and cell membrane damage in the frontal lobes of RAs and has independent adverse effects on neuronal viability and cell membranes in the midbrain and on cell membranes of the cerebellar vermis. Higher smoking levels are associated with metabolite concentrations in select subcortical structures. Greater consideration of the potential effects of comorbid cigarette smoking on alcohol-induced brain damage and other diseases affecting the central nervous system is warranted.

The relationship of the cellular changes in the HIV-infected brain to the onset and progression of AIDS dementia complex (ADC) remains uncertain. We undertook an in vivo proton magnetic resonance spectroscopy (MRS) study and used factor analysis to identify specific cellular and regional brain changes that may serve as metabolic markers of ADC. The ratio of N-acetyl aspartate (NAA), choline (Cho), and myoinositol (MI) over creatine (Cr), markers of neuronal and glial cell metabolism, were measured in the basal ganglia, centrum semiovale, and parietal cortex from 100 subjects with and without ADC. Three metabolic patterns were identified, which we termed "inflammatory" (mainly MI/Cr elevations in all three regions plus Cho/Cr increases in the centrum semiovale and parietal cortex), "basal ganglia" (mostly NAA/Cr and Cho/Cr elevations in the basal ganglia), and "neuronal" (primarily NAA/Cr reductions in the centrum semiovale and the parietal cortex). Logistic regression analysis revealed that, adjusted for age, basal ganglia and neuronal pattern scores were strongly associated with ADC but inflammatory levels were not. We conclude that by using factor analysis, we are able to combine multiple metabolites across brain regions in a biologically plausible manner and construct a predictive model of ADC adjusting for relevant factors such as age.

Background: The main goals are to investigate the effects of chronic active heavy drinking on N-acetylaspartate (NAA) and other metabolites throughout the brain and to determine whether they are affected by family history (FH) of alcoholism and long-term drinking pattern., Methods: Forty-six chronic heavy drinkers (HD) and 52 light drinkers (LD) were recruited from the community and compared on measures of regional brain structure using magnetic resonance imaging and measures of common brain metabolites in gray matter (GM) and white matter (WM) of the major lobes, subcortical nuclei, brainstem, and cerebellum using short-echo time magnetic resonance spectroscopic imaging. Regional atrophy-corrected levels of NAA, myoinositol (mI), creatine, and choline-containing metabolites were compared as a function of group, FH of alcoholism, and bingeing., Results: Frontal WM NAA was lower in FH-negative HD than FH-positive HD and tended to be lower in women than men. Creatine-containing metabolites in parietal GM were higher in HD than LD. FH-negative compared with FH-positive HD also had more mI in the brainstem and tended to have lower NAA and more mI in frontal GM. Although parietal GM NAA was not significantly lower in HD than LD, it was lower in non-binge drinkers than bingers. Frontal WM NAA was lower in HD than LD, with the difference driven by a small number of women, FH-negative HD, and older age. Lower frontal WM NAA in HD was associated with lower executive and working memory functions and with lower P3b amplitudes at frontal electrodes., Conclusions: Community-dwelling HD who are not in alcoholism treatment have brain metabolite changes that are associated with lower brain function and are likely of behavioral significance. Age, FH, and binge drinking modulate brain metabolite abnormalities. Metabolite changes in active HD are less pronounced and present with a different spatial and metabolite pattern than reported in abstinent alcoholics.

The contingent negative variation, an event-related potential related to neural activity in the frontal lobe and basal ganglia, neuropsychological tests and structural MRI were used to examine CNS function and structure in HIV-positive patients receiving antiretroviral therapy. Relative to controls, HIV patients had smaller thalamic volume and reduced late contingent negative variation amplitude that correlated with caudal atrophy. Behaviorally, viremic patients were more impaired than virally suppressed patients and controls on neuropsychological measures of psychomotor speed, selective attention and mental flexibility. These results suggest that antiretroviral therapy may not be effective in protecting cortical and subcortical structures against HIV-related neuropathology, regardless of immune function. However, the benefits of antiretroviral therapy on immune function appear to facilitate neurocognitive performance.

Objective: We used the contingent negative variation (CNV), a slow negative shift in the human electroencephalogram, to investigate the effects of heavy chronic alcohol use on frontal lobe function., Methods: Event-related potentials (ERPs) were recorded from 30 heavy drinkers (HD) and 30 age-, sex-, and education-matched light or non-drinkers (LD), using a classical two-stimulus reaction time (RT) paradigm. Structural magnetic resonance images and neuropsychological tests were also administered., Results: The amplitude of the late CNV was significantly reduced in HD relative to light drinkers. Moreover, diminished CNV amplitudes in HD appear to be closely related to the amount of recent alcohol consumption. There were no significant differences in neuropsychological measures of frontal lobe function and frontal lobe volume between light and HD. However, in HD, reduced late CNV amplitudes were associated with decreased frontal lobe gray matter volume and poor performance on the Trail Making Test B. In LD but not in HD, late CNV amplitude correlated positively with RT, suggesting that the late CNV reflects some aspect of motor and cognitive preparation., Conclusions: The inverse relationships between frontal lobe gray matter volume, performance on the Trail Making Test B, and late CNV amplitude in HD suggest that the ERP abnormalities observed in the current study may be indices of alcohol-related damage to the frontal lobe. The lack of a significant relationship between CNV amplitude and RT in HD suggests that chronic heavy alcohol use may disrupt response preparation.

Purpose: To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC)., Materials and Methods: Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects., Results: A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC., Conclusion: This is the first study to ascertain and validate the reliability and reproducibility of a short echo time (1)H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting., (Copyright 2003 Wiley-Liss, Inc.)

Ethanol (EtOH) is believed to exert its neurochemical effects through interactions with brain cellular components, which causes a fraction of brain EtOH to have a lower molecular mobility. This facilitates magnetization transfer to other molecules similarly associated with macromolecules, such as water. It was hypothesized that this effect can be used in vivo to image EtOH indirectly via the much stronger brain tissue water resonance. EtOH-containing bovine serum albumin samples were used to demonstrate magnetic coupling between EtOH and water at 7 T and 1.5 T. Spectroscopy and imaging experiments demonstrated that EtOH signal saturation yielded greater water signal reduction than inversion and that this reduction scaled with EtOH concentration in the BSA samples. In human brain at physiologically relevant brain EtOH concentrations, water signal reductions were measurable when saturating the EtOH resonance. Strengths and limitations of indirectly imaging brain EtOH are discussed., (Copyright 2003 Wiley-Liss, Inc.)

Background: Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. Such samples represent a small proportion of alcoholics in the general population. Such samples may embody a bias (Berkson's fallacy) if the association between variables (for example, alcoholism and cortical gray matter loss) differs between the population of alcoholics in treatment and alcoholics in the general population. Our objective was to determine if treatment-naïve alcoholics show structural brain changes versus controls and to compare our findings with reports evaluating alcoholic samples drawn from treatment populations., Methods: Structural MRI was used to assess whole brain and regional volumes of cortical gray matter and white matter in 24 young to middle-aged treatment-naïve alcohol-dependent males versus 17 controls., Results: Cortical gray matter volumes in alcohol-dependent individuals were negatively associated with age and lifetime duration of alcohol use (which were highly confounded). These subjects showed reduced whole brain (p < 0.05), prefrontal (p < 0.01), and parietal (p < 0.05) cortical gray matter compared with controls. White matter and temporal cortex, tissues that usually show volume reductions in samples drawn from treatment, did not differ between treatment-naïve alcoholics and controls (all p > 0.40)., Conclusions: Our findings are consistent with the hypothesis that structural brain changes in treatment-naïve alcoholics are less severe than those reported in clinical samples of alcoholics, perhaps due to less concomitant psychopathology and a reduced severity of alcoholism in treatment-naïve alcoholics. However, caution must be taken when comparing our findings with results from clinical samples, as we did not directly compare treatment-naïve alcoholics with treated alcoholics and our treatment-naïve sample tended to be younger than the (clinical) samples reported in the literature. Nevertheless, we suggest that most of the reports of the central nervous system consequences of alcoholism may not accurately describe the majority of alcoholic-dependent individuals.

Background: Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse. There is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are present in treated alcohol abusers who achieve long-term abstinence versus treatment-naïve, heavily drinking individuals., Methods: This study compared 12 recovering alcoholics with 8 actively heavily drinking subjects. Participants underwent magnetic resonance (MR) imaging and proton MR spectroscopic imaging of the brain. Semiautomated image segmentation techniques yielded volumes for gray matter, white matter, white matter lesions, and cerebral spinal fluid in multiple brain regions defined by Talairach stereotaxic coordinates. Automated spectral processing methods yielded gray and white matter concentrations of the metabolites N-acetylaspartate, creatine, and choline for the same regions., Results: Recovering alcoholics had greater volumes of frontal white matter, but the opposite was true for white matter in a "remainder" region encompassing the basal frontal and temporal lobes, the cerebellum, and the brainstem. Recovering alcoholics also had smaller volumes of white matter lesions in whole brain, in occipital and mesial parietal regions, and in the remainder region. Recovering alcoholics had greater gray matter volumes in the orbital frontal pole and postcentral gyrus, but smaller gray matter volumes in the anterior cingulate. Whole-brain and regional metabolite concentrations did not differ significantly between the two groups., Conclusions: White and gray matter volumes in different regions of the brain were greater or smaller in recovering, treated alcoholics. The findings suggest region-specific structural recovery from chronic alcohol-induced brain injury, but also region-specific long-term structural damage in abstinent alcoholics. White matter lesions were widespread in active drinkers and may partly resolve during long-term abstinence. Proton MR spectroscopic measures, as applied in this cross-sectional study, were largely ineffective in revealing metabolic effects of abstinence on the alcohol-damaged brain.

The effects of chronic cocaine and alcohol abuse on human brain structure and metabolites are not fully known. We studied controls (n = 13) and abstinent subjects dependent on cocaine (8), alcohol (12), and cocaine and alcohol (17) using quantitative MRI and proton MR spectroscopic imaging. Talairach-based techniques yielded tissue and CSF volumes and gray- and white-matter concentrations of N-acetylaspartate (NAA), creatine and choline metabolites in multiple brain regions. Alcohol dependents had lower gray-matter NAA concentrations and more sulcal CSF than non-alcohol dependents throughout the brain. They also had less subcortical gray matter and (regionally) less white matter. Cocaine dependents compared with non-cocaine dependents had higher posterior parietal white-matter creatine concentration. They also had less gray and white matter in the prefrontal lobes and in a region encompassing the temporal lobes and cerebellum. Structural white-matter deficits in cocaine dependents were greater with longer duration of cocaine use. Subjects with concurrent cocaine and alcohol dependence had less prefrontal white matter, especially in the anterior cingulate, than subjects dependent on only one substance. Chronically abused cocaine and alcohol each leave multiple metabolic and structural brain defects after long-term abstinence. Concurrent dependence on both substances may aggravate white-matter structural defects, primarily in frontal brain.

Background: In vivo phosphorus magnetic resonance spectroscopy (31P MRS) at a magnetic field strength of 1.5 T allows measurement of fairly mobile membrane phospholipids in the human brain. We previously showed that subjects who are heavy drinkers had a smaller signal and a shorter transverse relaxation time (T2) of white matter phospholipids than light drinkers, which suggested lower concentrations and molecular mobility of phospholipids in heavy drinkers. The purpose of the present study was to measure if such chronic alcohol-induced white matter tissue changes are persistent in long-term abstinent alcoholics., Methods: Fourteen abstinent alcoholics (mean age 45 years, seven men and seven women) were studied by localized 31P MRS in the centrum semiovale and were compared with 13 male, alcohol-dependent, heavy drinkers and 23 nondependent light drinkers (17 men, 6 women) of similar age. Methods for measurements of the broad membrane phospholipid signal and its relaxation time were described previously., Results: Phospholipid concentrations and relaxation times in alcoholics abstinent for an average of 31 months were not significantly different from those measured in light drinkers. The contribution of fast and slowly relaxing signal components to the broad phospholipid signal, however, was still different in abstinent alcoholics compared with light drinkers. No effects of sex or of family history of alcoholism were noted on any of our spectroscopic measures within the light-drinking or abstinent groups., Conclusions: Most of our results suggest at least partial recovery of chronic alcohol-induced white matter phospholipid damage with long-term abstinence. They offer myelination changes and/or dendritic rearborization as a possible mechanism for the commonly observed white matter volume gain with prolonged abstinence. But the results also suggest a persistent abnormality in the nature and/or physical properties of white matter phospholipids in long-term abstinent alcoholics.

Background: Phosphorus magnetic resonance spectroscopy (31P MRS) allows for the measurement of phospholipids and their breakdown products in the human brain. Fairly mobile membrane phospholipids give rise to a broad signal that co-resonates with metabolic phosphodiesters. Chronic alcohol exposure increases the rigidity of isolated brain membranes and, thus, may affect the amount and transverse relaxation times (T2) of MRS-detectable phospholipids. We tested the hypothesis that subjects who were heavy drinkers have stiffer membranes than controls who were light drinkers, as reflected in a smaller broad signal component and a shorter T2 of the broad signal in 31P MR spectra of the brain., Methods: Thirteen alcohol-dependent heavy drinkers (mean age 44 years) were studied by localized 31P MRS in the centrum semiovale and compared with 17 nondependent light drinkers of similar age. The broad component signal was separated from the metabolite signal by convolution difference, which is based on the large difference in line widths of these two signals. Longitudinal and T2 relaxation times were measured using standard methods., Results: The broad component integral was 13% lower in the brain of heavy drinkers compared with light drinkers (p < 0.001) and remained significantly smaller after corrections for both longitudinal and transverse relaxations (p < 0.01). The T2 distribution of the broad component consistently showed two resolvable components in both groups. The fast relaxing component had the same T2 in both groups (T2 = 1.9 msec). The slower relaxing component T2 was 0.6 msec shorter in heavy drinkers compared with light drinkers (p = 0.08)., Conclusions: These results, observed in the absence of white matter volume loss, are consistent with biochemical alterations and higher rigidity of white matter phospholipids associated with long-term chronic alcohol abuse. The observed smaller broad signal component in these relatively young heavy drinkers is a sensitive measure of white matter phospholipid damage.

Spectral analysis of short TE in vivo proton magnetic resonance spectroscopic imaging (MRSI) data are complicated by the presence of spectral overlap, low signal to noise and uncharacterized signal contributions. In this study, it is shown that an automated data analysis method can be used to generate metabolite images from MRSI data obtained from human brain at TE = 25 ms and 1.5 T when optimized pulse sequences and a priori metabolite knowledge are used. The analysis approach made use of computer simulation methods to obtain a priori spectral information of the metabolites of interest and utilized a combination of parametric spectral modeling and non-parametric signal characterization for baseline fitting. This approach was applied to data from optimized PRESS-SI and multi-slice spin-echo SI acquisitions, for which sample spectra and metabolite images are shown.

Background: Proton magnetic resonance spectroscopy (1H MRS) allows measurement of alcohol in the human brain after alcohol consumption. However, the quantity of alcohol that can be detected in the brain by 1H MRS pulse sequences has been controversial, with values ranging from about 24% to 94% of the temporally concordant blood alcohol concentrations. The quantitation of brain alcohol is critically affected by the kinetics of alcohol uptake and elimination, by the relaxation times of the protons that give rise to the brain alcohol signal, and by the specifics of both pulse sequence timing and radio frequency pulse applications., Methods: We investigated these factors in 20 light-drinking subjects after oral administration of approximately 0.85 g/kg body weight of alcohol by localized 1H MRS and measurements of blood and breath alcohol concentrations obtained at the same time. Specifically, we measured transverse and longitudinal relaxation times of brain alcohol and its signal saturation on application of on- or off-resonance radio frequency pulses. All 1H MRS measurements were performed at a time after brain and blood alcohol concentrations had equilibrated., Results: 1H MRS measures of brain alcohol were correlated highly with both breath and blood alcohol concentrations after equilibration in brain tissue. The measured 1H MRS relaxation times of brain alcohol were shorter than given in previous reports that were limited by smaller subject numbers, improper use of 1H MRS methods, and estimates rather than measurements. The brain alcohol signal decreased by about 30% on application of on- or off-resonance saturation pulses., Conclusions: 1H MRS allows direct measurement of brain alcohol, formerly only possible indirectly through inferences from breath alcohol levels. Quantitation of brain alcohol levels need to take into account measured relaxation times and alcohol signal attenuation due to presence and timing of standard radio frequency MRS pulses. Saturation experiments give evidence for the existence of more than one compartment of brain alcohol characterized by different molecular environments. They suggest that a fraction of brain alcohol is invisible to 1H MRS.

Chronic abuse of cocaine or alcohol is associated with structural, neuropathological and cognitive impairments that have been documented extensively. Little is known, however, about neurobiochemical changes in chronic substance abusers.We performed MRI and multi-slice brain proton magnetic resonance spectroscopic imaging (MRSI) to assess neuronal viability (via N-acetylaspartate (NAA)) and white matter metabolite status in 22 4-months-abstinent individuals dependent on crack cocaine only and on both crack cocaine and alcohol. Compared to 11 non-dependent controls we found (1) significantly lower NAA measures in the dorsolateral prefrontal cortex of the combined cocaine-dependent groups; (2) comparable spatial distribution and magnitude of these NAA effects for both cocaine-dependent groups; (3) higher choline-containing metabolites in frontal white matter of individuals dependent on both cocaine and alcohol; (4) absence of brain atrophy in both abstinent cocaine-dependent samples; and (5) partial recovery from prefrontal cortical NAA loss, primarily with abstinence from alcohol. The MRSI findings suggest preferential neuronal damage to the frontal cortex of both cocaine-dependent samples and gliosis in frontal white matter of individuals dependent on both alcohol and cocaine, conditions that persist for more than 4 months of abstinence.

Off-resonance or pulsed on-resonance saturation pulses were used together with localized proton magnetic resonance spectroscopy in three brain regions of 20 healthy individuals. Statistically significant signal attenuations were observed for creatine-containing metabolites in posterior-parietal brain (12%), basal ganglia (18%), and cerebellum (15%). N-acetyl- and choline-containing metabolites were not significantly attenuated upon application of saturation pulses in either brain region. The findings are interpreted to reflect possible magnetization transfer between pools of creatine-containing metabolites with different molecular mobility. Magn Reson Med 42:417-420, 1999., (Copyright 1999 Wiley-Liss, Inc.)