Cerebellar Morphometry and Cognition in the Context of Chronic Alcohol Consumption and Cigarette Smoking.

BACKGROUND: Cerebellar atrophy (especially involving the superior-anterior cerebellar vermis) is among the most salient and clinically significant effects of chronic hazardous alcohol consumption on brain structure. Smaller cerebellar volumes are also associated with chronic cigarette smoking. The present study investigated effects of both chronic alcohol consumption and cigarette smoking on cerebellar structure and its relation to performance on select cognitive/behavioral tasks. METHODS: Using T1-weighted Magnetic Resonance Images (MRIs), the Cerebellar Analysis Tool Kit segmented the cerebellum into bilateral hemispheres and 3 vermis parcels from 4 participant groups: smoking (s) and nonsmoking (ns) abstinent alcohol-dependent treatment seekers (ALC) and controls (CON) (i.e., sALC, nsALC, sCON, and nsCON). Cognitive and behavioral data were also obtained. RESULTS: We found detrimental effects of chronic drinking on all cerebellar structural measures in ALC participants, with largest reductions seen in vermis areas. Furthermore, both smoking groups had smaller volumes of cerebellar hemispheres but not vermis areas compared to their nonsmoking counterparts. In exploratory analyses, smaller cerebellar volumes were related to lower measures of intelligence. In sCON, but not sALC, greater smoking severity was related to smaller cerebellar volume and smaller superior-anterior vermis area. In sALC, greater abstinence duration was associated with larger cerebellar and superior-anterior vermis areas, suggesting some recovery with abstinence. CONCLUSIONS: Our results show that both smoking and alcohol status are associated with smaller cerebellar structural measurements, with vermal areas more vulnerable to chronic alcohol consumption and less affected by chronic smoking. These morphometric cerebellar deficits were also associated with lower intelligence and related to duration of abstinence in sALC only.

Borderline personality disorder symptoms in treatment-naïve actively drinking alcoholics.

Borderline personality disorder (BPD) is often a complicating comorbid factor in alcohol use disorders and substance use disorders. Previous work showed that abstinent alcoholics endorsed lifetime and current symptoms of most of the BPD criteria at much higher rates than controls, with much higher symptom counts for short-term abstinent alcoholic (STAA) women than men, which is consistent with such symptoms negatively affecting female alcoholics' ability to maintain abstinence. Because prior work has also shown that treatment-naïve alcoholics (TNA) are not the same as treated alcoholics observed earlier in their alcohol dependence, but rather are a different population with potentially lower psychiatric comorbidity, in this study we compared BPD symptom criteria between TNA samples of comparable age to the control and STAA samples, including both men and women and individuals dependent on alcohol only or with lifetime dependence on both alcohol and drugs. BPD symptoms were obtained using the SCID-II, and endorsed symptoms were classified as current or lifetime. Logistic regression analyses were used to test for effects of group, sex, presence of a lifetime drug dependence diagnosis, and their interactions for lifetime and current symptom endorsement for each BPD criteria. Groups were compared pairwise (TNA vs. NSAC, and STAA vs. TNA). The effect of a lifetime drug dependence diagnosis was not significant for any BPD symptom variable, consistent with the alcohol groups' BPD symptoms being unaffected by the presence of a comorbid drug dependence. The primary result presented here is that TNA women have borderline symptomatology more similar to that of treated STAA than to NSAC, while TNA men have borderline symptomatology more similar to NSAC than to STAA. A visual examination of co-occurring BPD symptoms showed that while more BPD symptoms are likely to be present in TNA and STAA vs. NSAC, there is no grouping of criteria (i.e., symptom cluster) that is characteristic of TNA or STAA.

EEG coherence related to fMRI resting state synchrony in long-term abstinent alcoholics.

Recent work suggests that faulty co-activation or synchrony of multiple brain regions comprising "networks," or an imbalance between opposing brain networks, is important in alcoholism. Previous studies showed higher fMRI resting state synchrony (RSS) within the executive control (inhibitory control and emotion regulation) networks and lower RSS within the appetitive drive network in long-term (multi-year) abstinent alcoholics (LTAA) vs. non substance abusing controls (NSAC). Our goal was to identify EEG networks that are correlated with the appetitive drive and executive function networks identified with fMRI in our previous alcohol studies. We used parallel ICA for multimodal data fusion for the 20 LTAA and 21 NSAC that had both usable fMRI and 64-channel EEG data. Our major result was that parallel ICA identified a pair of components that significantly separated NSAC from LTAA and were correlated with each other. Examination of the resting-state fMRI seed-correlation map component showed higher bilateral nucleus accumbens seed-correlation in the dorsolateral prefrontal cortex bilaterally and lower seed-correlation in the thalamus. This single component thus encompassed both the executive control and appetitive drive networks, consistent with our previous work. The correlated EEG coherence component showed mostly higher theta and alpha coherence in LTAA compared to NSAC, and lower gamma coherence in LTAA compared to NSAC. The EEG theta and alpha coherence results suggest enhanced top-down control in LTAA and the gamma coherence results suggest impaired appetitive drive in LTAA. Our results support the notion that fMRI RSS is reflected in spontaneous EEG, even when the EEG and fMRI are not obtained simultaneously.

P3b amplitude is not reduced in abstinent alcoholics with a current MDD.

BACKGROUND AND AIMS: In two studies of long-term abstinent alcoholics (LTAAs), we found that about 17% had a current major depressive disorder (MDD). We tested the hypothesis that LTAAs with a current MDD diagnosis do not exhibit the reduced P3b event-related potential amplitude endophenotype for alcoholism. This is consistent with the majority of LTAAs with a current MDD having developed alcohol dependence via self-medication of their MDD rather than their alcohol dependence arising from the alcoholism endophenotype. We revisited the P3b data from the two LTAAs studies, comparing LTAAs with a current MDD vs. LTAAs without a current MDD to each other and to non-substance abusing controls (NSACs). In northern California, 48 LTAAs and 48 non-substance abusing controls were studied, while in Honolulu, 105 LTAAs and 77 NSACs were studied. A total of 26 LTAAs had a current MDD (10 in California and 16 in Honolulu). The difference in P3b amplitude and latency (measured in targets-standards) in a 3-condition visual oddball paradigm was compared to MDD diagnoses gathered using the computerized Diagnostic Interview Schedule. Across both study sites, LTAAs without a current MDD (either with no lifetime MDD or a lifetime, but not current MDD) had lower P3b amplitudes than NSACs. In contrast, P3b amplitudes in LTAAs with a current MDD did not differ from controls. We conclude that alcohol dependence in LTAAs with a current MDD did not derive from the alcoholism endophenotype. This group may not exhibit the externalizing diathesis characterized by impulsive, disinhibited behavior and may have developed alcohol dependence via excessive drinking in an attempt to self-medicate their MDD. These results have major implications for targeted treatments of alcoholism and comorbid MDD.

Resting state synchrony in long-term abstinent alcoholics: Effects of a current major depressive disorder diagnosis.

Alcoholism is characterized by a lack of control over an impulsive and compulsive drive toward excessive alcohol consumption despite significant negative consequences; our previous work demonstrated that successful abstinence is characterized by decreased resting-state synchrony (RSS) as measured with functional magnetic resonance imaging (fMRI), within appetitive drive networks and increased RSS in emotion regulation and inhibitory executive control networks. Our hypothesis is that LTAA (Long-Term Abstinent Alcoholics) with a current major depressive disorder (MDD) drank primarily to deal with the negative affect associated with their MDD and not because of a heightened externalizing diathesis (including heightened appetitive drive), and consequently, in achieving and maintaining abstinence, such individuals would not exhibit the RSS adaptations characteristic of pure alcoholics. We studied 69 NSAC (Non Substance Abusing Controls) and 40 LTAA (8 with current MDD, 32 without a current MDD) using resting-state fMRI and seed based connectivity analyses. In the inhibitory executive control network (nucleus accumbens vs. left dorsolateral prefrontal cortex), LTAA with a current MDD showed increased synchrony compared to NSAC. In the emotion regulation executive control network (subgenual anterior cingulate cortex vs. right dorsolateral prefrontal cortex), LTAA with current MDD did not show increased RSS. In the appetitive drive networks (nucleus accumbens vs, aspects of the caudate nucleus and thalamus), LTAA with a current MDD did not show a reduction of RSS compared to NSAC, but LTAA without a current MDD did. These results suggest different pathways to their alcohol dependence in LTAA with vs. without a current MDD, and different patterns of brain activity in long-term abstinence, suggesting different treatment needs.

Neuroplasticity in Human Alcoholism: Studies of Extended Abstinence with Potential Treatment Implications.

Alcoholism is characterized by a lack of control over excessive alcohol consumption despite significant negative consequences. This impulsive and compulsive behavior may be related to functional abnormalities within networks of brain regions responsible for how we make decisions. The abnormalities may result in strengthened networks related to appetitive drive-or the need to fulfill desires-and simultaneously weakened networks that exercise control over behaviors. Studies using functional magnetic resonance imaging (fMRI) in abstinent alcoholics suggest that abstinence is associated with changes in the tone of such networks, decreasing resting tone in appetitive drive networks, and increasing resting tone in inhibitory control networks to support continued abstinence. Identifying electroencephalographic (EEG) measures of resting tone in these networks initially identified using fMRI, and establishing in longitudinal studies that these abstinence-related changes in network tone are progressive would motivate treatment initiatives to facilitate these changes in network tone, thereby supporting successful ongoing abstinence.

Automated MRI cerebellar size measurements using active appearance modeling.

Although the human cerebellum has been increasingly identified as an important hub that shows potential for helping in the diagnosis of a large spectrum of disorders, such as alcoholism, autism, and fetal alcohol spectrum disorder, the high costs associated with manual segmentation, and low availability of reliable automated cerebellar segmentation tools, has resulted in a limited focus on cerebellar measurement in human neuroimaging studies. We present here the CATK (Cerebellar Analysis Toolkit), which is based on the Bayesian framework implemented in FMRIB's FIRST. This approach involves training Active Appearance Models (AAMs) using hand-delineated examples. CATK can currently delineate the cerebellar hemispheres and three vermal groups (lobules I-V, VI-VII, and VIII-X). Linear registration with the low-resolution MNI152 template is used to provide initial alignment, and Point Distribution Models (PDM) are parameterized using stellar sampling. The Bayesian approach models the relationship between shape and texture through computation of conditionals in the training set. Our method varies from the FIRST framework in that initial fitting is driven by 1D intensity profile matching, and the conditional likelihood function is subsequently used to refine fitting. The method was developed using T1-weighted images from 63 subjects that were imaged and manually labeled: 43 subjects were scanned once and were used for training models, and 20 subjects were imaged twice (with manual labeling applied to both runs) and used to assess reliability and validity. Intraclass correlation analysis shows that CATK is highly reliable (average test-retest ICCs of 0.96), and offers excellent agreement with the gold standard (average validity ICC of 0.87 against manual labels). Comparisons against an alternative atlas-based approach, SUIT (Spatially Unbiased Infratentorial Template), that registers images with a high-resolution template of the cerebellum, show that our AAM approach offers superior reliability and validity. Extensions of CATK to cerebellar hemisphere parcels are envisioned.

Automated cerebellar segmentation: Validation and application to detect smaller volumes in children prenatally exposed to alcohol.

OBJECTIVE: To validate an automated cerebellar segmentation method based on active shape and appearance modeling and then segment the cerebellum on images acquired from adolescents with histories of prenatal alcohol exposure (PAE) and non-exposed controls (NC). METHODS: Automated segmentations of the total cerebellum, right and left cerebellar hemispheres, and three vermal lobes (anterior, lobules I-V; superior posterior, lobules VI-VII; inferior posterior, lobules VIII-X) were compared to expert manual labelings on 20 subjects, studied twice, that were not used for model training. The method was also used to segment the cerebellum on 11 PAE and 9 NC adolescents. RESULTS: The test-retest intraclass correlation coefficients (ICCs) of the automated method were greater than 0.94 for all cerebellar volume and mid-sagittal vermal area measures, comparable or better than the test-retest ICCs for manual measurement (all ICCs > 0.92). The ICCs computed on all four cerebellar measurements (manual and automated measures on the repeat scans) to compare comparability were above 0.97 for non-vermis parcels, and above 0.89 for vermis parcels. When applied to patients, the automated method detected smaller cerebellar volumes and mid-sagittal areas in the PAE group compared to controls (p < 0.05 for all regions except the superior posterior lobe, consistent with prior studies). DISCUSSION: These results demonstrate excellent reliability and validity of automated cerebellar volume and mid-sagittal area measurements, compared to manual measurements. These data also illustrate that this new technology for automatically delineating the cerebellum leads to conclusions regarding the effects of prenatal alcohol exposure on the cerebellum consistent with prior studies that used labor intensive manual delineation, even with a very small sample.

Voxelwise multivariate analysis of multimodality magnetic resonance imaging.

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available.

Voxel-wise co-analysis of macro- and microstructural brain alteration in mild cognitive impairment and Alzheimer's disease using anatomical and diffusion MRI.

BACKGROUND AND PURPOSE: To determine if a voxel-wise "co-analysis" of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer's disease (AD) than voxel-wise analysis of the individual MRI modalities alone. METHODS: Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models. RESULTS: Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe. CONCLUSION: These results suggest that in corpus callosum and temporal regions macro- and microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration.

Not lesser but Greater fractional anisotropy in adolescents with alcohol use disorders.

OBJECTIVE: The objective of this study is to examine white matter microstructure using diffusion tensor imaging (DTI) in a sample of adolescents with alcohol use disorders (AUD) and no psychiatric or substance co-morbidity. METHODS: Fifty adolescents with AUD and fifty non-alcohol abusing controls matched on gender and age were studied with DTI, neurocognitive testing, and a clinical assessment that included measures of alcohol use and childhood trauma. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were computed, registered to a common template, and voxel-wise statistical analysis used to assess group differences. Associations between regions of altered WM microstructure and clinical or neurocognitive measures were also assessed. RESULTS: Compared with controls, adolescent drinkers without co-morbid substance abuse or externalizing disorder, showed 1) no regions of significantly lower FA, 2) increased FA in WM tracts of the limbic system; 3) no MD differences; and 4) within the region of higher FA in AUD, there were no associations between FA and alcohol use, cognition, or trauma. DISCUSSION: The most important observation of this study is our failure to observe significantly smaller FA in this relatively large alcohol abuse/dependent adolescent sample. Greater FA in the limbic regions observed in this study may index a risk for adolescent AUD instead of a consequence of drinking. Drinking behavior may be reinforced in those with higher FA and perhaps greater myelination in these brain regions involved in reward and reinforcement.

Cortical and subcortical volumes in adolescents with alcohol dependence but without substance or psychiatric comorbidities.

Most prior studies of the effects of excessive alcohol intake on the adolescent brain examined alcohol-use-dependent samples with comorbid psychiatric and substance use disorders. In the Cape Town region, we identified a sizeable cohort of adolescents with alcohol use disorders (AUD) without externalizing or other psychiatric disorders. We examined brain morphology in 64 such adolescents compared to age- and gender-matched healthy controls. Magnetic resonance imaging data were analyzed using FSL's FIRST software for subcortical volumes, and cortical gray matter (GM) was analyzed using voxel-based morphometry (VBM) and regions of interest (ROI) analysis. AUD boys had smaller thalamic and putamen volumes compared to non-drinking boys, while AUD girls had larger thalamic and putamen volumes compared to non-drinking girls. VBM revealed a large region of decreased GM density in AUDs compared to controls located in the left lateral frontal, temporal, and parietal lobes, extending medially deep into the parietal lobe. Smaller GM volume in this region was also present when examined using ROI analysis. Our lack of findings in other brain regions, particularly the hippocampus, suggests that reports of smaller brain volumes in adolescent AUDs in the literature are a consequence of psychiatric and substance abuse comorbidities.

Associations among vascular risk factors, carotid atherosclerosis, and cortical volume and thickness in older adults.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate whether the Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness are associated with cortical volume and thickness. METHODS: Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3-T and 4-T MRI at 3 sites. Freesurfer (Version 5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness with cortical volume and thickness. RESULTS: One hundred fifty-two subjects (82 men) were aged 78 (±7) years, 94 had a clinical dementia rating of 0, 58 had a clinical dementia rating of 0.5, and the mean Mini-Mental State Examination was 28±2. Framingham Cardiovascular Risk Profile score was inversely associated with total gray matter volume and parietal and temporal gray matter volume (adjusted P<0.04). Framingham Cardiovascular Risk Profile was inversely associated with parietal and total cerebral gray matter thickness (adjusted P<0.03). Carotid artery intima-media thickness was inversely associated with thickness of parietal gray matter only (adjusted P=0.04). Including history of myocardial infarction or stroke and radiological evidence of brain infarction, or apolipoprotein E genotype did not alter relationships with Framingham Cardiovascular Risk Profile or carotid artery intima-media thickness. CONCLUSIONS: Increased cardiovascular risk was associated with reduced gray matter volume and thickness in regions also affected by Alzheimer disease independent of infarcts and apolipoprotein E genotype. These results suggest a "double hit" toward developing dementia when someone with incipient Alzheimer disease also has high cardiovascular risk.

Changes in brain anatomy during the course of posttraumatic stress disorder.

The goal of this study was to determine whether posttraumatic stress disorder (PTSD) was associated with an increase in time-related decline in macrostructural brain volume and whether these changes were associated with accelerated cognitive decline. To quantify brain structure, three-dimensional T1-weighted MRI scans were performed at baseline and again after a minimum of 24months in 25 patients with PTSD (PTSD+) and 22 controls (PTSD-). Longitudinal changes in brain volume were measured using deformation morphometry. For the group as a whole, PTSD+ patients did not show significant ongoing brain atrophy compared to PTSD-. PTSD+ patients were then subgrouped into those with decreasing or increasing symptoms. We found little evidence for brain markers of accelerated atrophy in PTSD+ veterans whose symptoms improved over time, with only a small left parietal region showing greater ongoing tissue loss than PTSD-. PTSD patients whose symptoms increased over time showed accelerated atrophy throughout the brain, particularly brainstem and frontal and temporal lobes. Lastly, for the sample as a whole, greater rates of brain atrophy were associated with greater rates of decline in verbal memory and delayed facial recognition.

Brain morphology at entry into treatment for alcohol dependence is related to relapse propensity.

BACKGROUND: We examined whether any differences in brain volumes at entry into alcohol dependence treatment differentiate subsequent Abstainers from Relapsers. METHODS: Individuals in alcohol dependence treatment (n = 75) underwent magnetic resonance imaging approximately 6 ± 4 days after their last alcoholic drink, and 40 age-matched nonsmoking light drinkers (LD) were studied as control subjects. At follow-up 7.8 ± 2.6 months later, 23 alcoholics (31%) had abstained from drinking and 52 (69%) had relapsed. Deformation morphometry compared Relapsers, Abstainers, and LD. RESULTS: Compared with LD, future Abstainers had smaller brain tissue volumes in the left amygdala, hippocampal head, and entorhinal cortex and bilaterally in the thalamus and adjacent subcortical white matter (WM) and had larger volume in the left lateral orbitofrontal region. Compared with LD, future Relapsers had smaller brain tissue volumes in the right middle temporal, occipital, and superior frontal WM. Compared with future Abstainers, future Relapsers had smaller tissue volumes primarily in bilateral orbitofrontal cortex and surrounding WM. Results were virtually unaffected after controlling for common comorbidities. CONCLUSIONS: At entry into alcohol dependence treatment, the brain structure of future Relapsers differs from that of future Abstainers. Future Relapsers have smaller brain volumes in regions of the mesocorticolimbic reward system that are critically involved in impulse control, emotional regulation, craving, and evaluation and anticipation of stimulus salience and hedonics. Structural abnormalities of this circuitry might confer greater risk for resumption of hazardous drinking after treatment and might contribute to the definition of a neurobiological relapse risk profile in alcohol dependence.

Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans.

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.

Chronic cigarette smoking and heavy drinking in human immunodeficiency virus: consequences for neurocognition and brain morphology.

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.

Deformation-based morphometry reveals brain atrophy in frontotemporal dementia.

OBJECTIVE: To compare deformation-based maps of local anatomical size between subjects with frontotemporal dementia (FTD) and healthy subjects to identify regions of the brain involved in FTD. DESIGN: Structural magnetic resonance images were obtained from 22 subjects with FTD and 22 cognitively normal, age-matched controls. We applied deformation-based morphometry and compared anatomy between groups using an analysis of covariance model that included a categorical variable denoting group membership and covaried for head size. SETTING: University of California, San Francisco, Memory and Aging Center, and the San Francisco Veterans Affairs Medical Center. PATIENTS: Twenty-two subjects with FTD and 22 cognitively normal, age-matched controls. INTERVENTIONS: Neurological, neuropsychological, and functional evaluations and magnetic resonance imaging. MAIN OUTCOME MEASURE: Deformation maps of local anatomical size. RESULTS: Patients with FTD showed extensive, significant atrophy of the frontal lobes, affecting both gray matter and white matter. Atrophy of similar magnitude but less significance was observed in the anterior temporal lobes. The subcortical and midbrain regions, particularly the thalamus, pons, and superior and inferior colliculi, showed strongly significant atrophy of smaller magnitude. CONCLUSIONS: We confirmed frontal and anterior temporal gray matter atrophy in FTD. The observed white matter loss, thalamic involvement, and midbrain atrophy are consistent with pathological findings in late-stage FTD. Dysfunction of ventral-frontal-brainstem circuitry may underlie some of the unique clinical features of FTD.

Non-treatment-seeking heavy drinkers: effects of chronic cigarette smoking on brain structure.

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.