Active Cigarette Smoking Is Associated With Increased Age-Related Decline on Measures of Visuospatial Learning and Memory and Executive Function in Alcohol Use Disorder.

AIMS: The goal of this study was to determine if active cigarette smoking in Veterans with alcohol use disorder (AUD) was associated with greater age-related neurocognitive decline. METHODS: Veterans with AUD, in residential treatment (n = 125; 47 ± 14 years of age, min = 24, max = 76, 29 ± 26 days of abstinence), completed measures of executive functions, learning and memory, processing speed and working memory. Actively smoking AUD (AsAUD, n = 47) were active daily cigarette smokers; former smoking AUD (FsAUD, n = 45) were predominately daily smokers prior to study but did not smoke at the time of study; non-smoking AUD (NsAUD, n = 33) never used cigarettes or smoked 'only a few times' during lifetime. RESULTS: AsAUD demonstrated greater age-related decline on measures of visuospatial learning and memory, and response inhibition/cognitive flexibility, primarily relative to NsAUD; there were no age-related differences between FsAUD and NsAUD on any measure. There were few significant mean differences between groups across the 15 neurocognitive measures. In AsAUD, higher scores on indices of smoking severity were associated with poorer performance on measures of auditory-verbal learning and memory, response inhibition, set-shifting and working memory. In FsAUD, longer smoking cessation duration was related to lower PTSD, anxiety and depressive symptomatology. CONCLUSIONS: Active smoking was associated with accelerated age-related decline on cognitive functions implicated in response to common evidence-based AUD interventions. Results suggest that smoking history contributes to the considerable heterogeneity observed in neurocognitive function in early AUD recovery, and reinforce the clinical movement to offer smoking cessation resources concurrent with treatment for AUD.

GABA concentrations in the anterior cingulate and dorsolateral prefrontal cortices: Associations with chronic cigarette smoking, neurocognition, and decision making.

Chronic cigarette smoking is associated with regional metabolite abnormalities in choline-containing compounds, creatine-containing compounds, glutamate, and N-acetylaspartate. The effects of cigarette smoking on anterior frontal cortical gamma-aminobutyric acid (GABA) concentration are unknown. This study compared chronic smokers (n = 33) and nonsmokers (n = 31) on anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC) GABA+ (the sum of GABA and coedited macromolecules) concentrations and associations of GABA+ levels in these regions with seven neurocognitive domains of functioning, decision making, and impulsivity measures. Smokers had significantly lower right DLPFC GABA+ concentration than nonsmokers, but groups were equivalent on ACC GABA+ level. Across groups, greater number of days since end of menstrual cycle was related to higher GABA+ level in the ACC but not right DLPFC GABA+ concentration. In exploratory correlation analyses, higher ACC and right DLPFC GABA+ levels were associated with faster processing speed and better auditory-verbal memory, respectively, in the combined group of smokers and nonsmokers; in smokers only, higher ACC GABA+ was related to better decision making and auditory-verbal learning. This study contributes additional novel data on the adverse effects of chronic cigarette smoking on the adult human brain and demonstrated ACC and DLPFC GABA+ concentrations were associated with neurocognition and decision making/impulsivity in active cigarette smokers. Longitudinal studies on the effects of smoking cessation on regional brain GABA levels, with a greater number of female participants, are required to determine if the observed metabolite abnormalities are persistent or normalize with smoking cessation.

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.

Medical Conditions Linked to Atherosclerosis Are Associated With Magnified Cortical Thinning in Individuals With Alcohol Use Disorders.

AIMS: Magnetic resonance imaging (MRI) studies report widespread cortical thinning in individuals with alcohol use disorder (AUD), but did not consider potential effects of pro-atherogenic conditions such as hypertension, type 2 diabetes mellitus, hepatitis C seropositivity and hyperlipidemia on cortical thickness. The conditions are associated with regional cortical thinning in those without AUD. We predicted that individuals with concurrent AUD and pro-atherogenic conditions demonstrate the greatest regional cortical thinning in areas most vulnerable to decreased perfusion. METHODS: Treatment-seeking individuals with AUD (n = 126) and healthy controls (CON; n = 49) completed a 1.5 T MRI study. Regional cortical thickness was quantitated via FreeSurfer. Individuals with AUD and pro-atherogenic conditions (Atherogenic+), AUD without pro-atherogenic conditions (Atherogenic-) and CON were compared on regional cortical thickness. RESULTS: Individuals with AUD showed significant bilateral cortical thinning compared to CON, but Atherogenic+ demonstrated the most widespread and greatest magnitude of regional thinning, while Atherogenic- had reduced thickness primarily in anterior frontal and posterior parietal lobes. Atherogenic+ also showed a thinner cortex than Atherogenic- in lateral orbitofrontal and dorso/dorsolateral frontal cortex, mesial and lateral temporal and inferior parietal regions. CONCLUSIONS: Our results demonstrate significant bilateral cortical thinning in individuals with AUD relative to CON, but the distribution and magnitude were influenced by comorbid pro-atherogenic conditions. The magnitude of cortical thinning in Atherogenic+ strongly corresponded to cortical watershed areas susceptible to decreased perfusion, which may result in morphometric abnormalities. The findings indicate that pro-atherogenic conditions may contribute to cortical thinning in those seeking treatment for AUD.

Regional Brain Volume Changes in Alcohol-Dependent Individuals During Short-Term and Long-Term Abstinence.

BACKGROUND: Widespread brain atrophy in alcohol-dependent individuals (ALC) has been consistently documented in pathological and magnetic resonance imaging (MRI) studies. Longitudinal MRI studies have shown that the regional brain volume losses in ALC are partially reversible during abstinence from alcohol. The goal of this study was to determine volume reductions in cortical and subcortical regions functionally important to substance use behavior and their changes during short-term (1 week to 1 month) and long-term abstinence (1 to 7 months) from alcohol. The regions of interest (ROIs) were as follows: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), insula, amygdala, and hippocampus. METHODS: A total of 85 unique ALC were assessed at 1 week (n = 65), 1 month (n = 82), and 7 months (n = 36) of abstinence. In addition, 17 light/nondrinking healthy controls (CON) were assessed at baseline and follow-up over a 10-month interval. Regional brain volumes were derived from FreeSurfer. Cross-sectional statistical analyses using 1-way analysis of variance or Fisher's exact test were applied to identify group differences. Longitudinal statistical analyses using linear mixed models were applied to identify regional volume increases and nonlinear volume recovery trajectories. RESULTS: We demonstrated significant regional volume reductions in ACC, DLPFC, and hippocampus. Older age was associated with smaller DLPFC and OFC, and higher average monthly drinking over 1 year prior to study was associated with smaller OFC. We also demonstrated significant volume increases of all ROIs except amygdala in ALC and significant nonlinear volume recovery trajectories of DLPFC, OFC, and insula. CONCLUSIONS: Results showed significant volume reductions in key regions of the executive control, salience, and emotion networks in ALC at entry into treatment and significant volume increases during short-term and long-term abstinence that were nonlinear over the entire abstinence period for the DLPFC, OFC, and insula. This gray matter plasticity during alcohol abstinence may have important neurobiological and neurocognitive implications in ALC, and it may contribute to an individual's ability to maintain abstinence from alcohol at different phases.

Differences in White Matter Microstructure and Connectivity in Nontreatment-Seeking Individuals with Alcohol Use Disorder.

BACKGROUND: Diffusion-weighted imaging (DWI) has been widely used to investigate the integrity of white matter (WM; indexed by fractional anisotropy [FA]) in alcohol dependence and cigarette smoking. These disorders are highly comorbid, yet cigarette use has often not been adequately controlled in neuroimaging studies of alcohol-dependent populations. In addition, information on WM deficits in currently drinking, nontreatment-seeking (NTS) individuals with alcohol dependence is limited. Therefore, the aim of this work was to investigate WM microstructural integrity in alcohol use disorder by comparing matched samples of cigarette smoking NTS and social drinkers (SD). METHODS: Thirty-eight smoking NTS and 19 smoking SD subjects underwent DWI as well as structural magnetic resonance imaging. After an in-house preprocessing of the DWI data, FA images were analyzed with tract-based spatial statistics (TBSS). FA obtained from the TBSS skeleton was tested for correlation with recent alcohol consumption. RESULTS: Smoking NTS had lower FA relative to smoking SD, predominantly in the left hemisphere (p < 0.05, family-wise error rate corrected across FA skeleton). Across the full sample, FA and number of drinks per week were negatively related (ρ = -0.348, p = 0.008). Qualitative analyses of the structural connections through compromised WM as identified by TBSS showed differential connectivity of gray matter in NTS compared to SD subjects of left frontal, temporal, and parietal regions. CONCLUSIONS: NTS subjects had lower WM FA than SD, indicating compromised WM integrity in the NTS population. The inverse relationship of entire WM skeleton FA with self-reported alcohol consumption supports previous evidence of a continuum of detrimental effects of alcohol consumption on WM. These results provide additional evidence that alcohol dependence is associated with reduced WM integrity in currently drinking NTS alcohol-dependent individuals, after controlling for the key variable of cigarette smoking.

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

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

Psychiatric, Demographic, and Brain Morphological Predictors of Relapse After Treatment for an Alcohol Use Disorder.

BACKGROUND: Relapse in alcohol use disorders (AUD) is related to a complex interplay among multiple biological, psychiatric, psychological, and psychosocial factors, which may change dynamically during and after treatment. At treatment entry for AUD, morphological abnormalities in anterior frontal regions and the insula have been observed in those who ultimately relapse following treatment. The goal of this study was to determine whether anterior frontal and insula measures of brain thickness, surface area, and volume predict posttreatment drinking status (i.e., relapser or abstainer) over an extended period after outpatient treatment for AUD, while concurrently considering common psychiatric, psychological, and psychosocial factors previously associated with relapse. METHODS: Alcohol-dependent individuals (n = 129) were followed for 18 months after treatment to determine posttreatment drinking status (abstainers [n = 47] or relapsers [n = 82]). Brain morphometrics were derived from FreeSurfer. Receiver operating characteristic (ROC) curve analysis was used to identify the regional brain thickness, surface area, and volume (all scaled to intracranial volume), demographic, psychiatric, other substance use (e.g., cigarette smoking), and alcohol consumption variables, obtained at entry into treatment, that best predicted posttreatment drinking status. Survival analyses determined variables that were related to duration of abstinence after treatment. RESULTS: ROC analyses indicated that mood disorders, education, and volumes of the right caudal anterior cingulate cortex (ACC), right rostral ACC, and total right frontal gray matter were significant predictors of posttreatment drinking status. Among relapsers, survival analyses showed smokers and individuals with a comorbid medical condition relapsed earlier after treatment. Additionally, a greater frequency of smokers relapsed within 6 months of AUD treatment. CONCLUSIONS: Results reinforce that relapse in AUD is a function of multiple biological, psychiatric, psychological, and psychosocial factors. Effective treatment of depressive disorders and cigarette smoking concurrent with AUD-focused interventions may promote better treatment outcomes.

Regional brain volume changes in alcohol-dependent individuals during early abstinence: associations with relapse following treatment.

Cross-sectional structural magnetic resonance (MR) imaging studies of individuals with an alcohol use disorder (AUD) report that those who relapse after treatment, relative to individuals who maintain a period of extended abstinence, show greater morphological abnormalities in multiple brain regions near the inception of treatment, particularly in the frontal lobe. However, given the cross-sectional design of previous studies, it is unclear if the baseline morphological differences between future abstainers and relapsers were maintained over the course of early recovery. The primary goal of this study was to determine if frontal lobe tissue volume recovery during early abstinence is associated with long-term abstinence from alcohol. We compared frontal, parietal, temporal and occipital grey matter (GM) and white matter (WM) volumes, at 1 and 4 weeks of abstinence, among individuals who resumed alcohol consumption within 12 months of treatment (Relapsers) and those who showed sustained abstinence over 12 months following treatment (Abstainers). At 1 and 4 weeks of sobriety, both Abstainers and Relapsers demonstrated significantly smaller GM volumes than Controls in the majority of ROIs, but Relapsers exhibited significantly smaller bilateral frontal GM volumes than Abstainers. No significant group differences were observed for any WM region of interest. The persistent bilateral frontal GM volume deficits in Relapsers over 4 weeks from last alcohol use may represent an endophenotype that differentiates those who respond more favorably to the typical psychosocial and pharmacological interventions provided for AUD.

Interaction of Cigarette Smoking History With APOE Genotype and Age on Amyloid Level, Glucose Metabolism, and Neurocognition in Cognitively Normal Elders.

INTRODUCTION: Chronic cigarette smoking is associated with increased risk for Alzheimer's disease (AD). The goal of this study was to determine if smoking history moderated the associations of age and APOE genotype (the most robust risk factors for AD) on brain amyloid deposition, glucose metabolism, and neurocognition in cognitively-normal elders. METHODS: Participants (n = 264) were grouped according to their APOE ε4 carrier status (ε4 carrier: APOE4+; non-ε4 carrier: APOE4-) and smoking status (smokers: at least 1 year of smoking during lifetime; never-smokers: no history of smoking). Approximately 89% of the smoking sample was former-smokers. We specifically tested for interactions of smoking status with APOE ε4 carrier status and age on measures of cortical amyloid deposition, glucose metabolism, and neurocognition. RESULTS: (1) smoking status interacted with APOE ε4 carrier status, where smoker APOE4+ showed lower glucose metabolism and poorer auditory-verbal learning and memory than never-smoking APOE4-, never-smoking APOE4+, and smoking APOE4-; (2) smoking status interacted with age on measures of semantic fluency, processing speed/set-shifting and global neurocognition; smokers, irrespective of APOE ε4 carrier status, demonstrated poorer performance with increasing age than never-smokers; and (3) smoking APOE4+ and never-smoking APOE4+ showed greater cortical amyloid deposition than never-smoking APOE4- and smoking APOE4-. CONCLUSIONS: The findings indicate consideration of smoking history is essential to both better understand the factors associated with neurobiological and neurocognitive abnormalities in elders, and the risk for development of AD-related neuropathology.

Serial longitudinal magnetic resonance imaging data indicate non-linear regional gray matter volume recovery in abstinent alcohol-dependent individuals.

The trajectory of regional volume changes during the first year of sustained abstinence in those recovering from an alcohol use disorder is unclear because previous research typically employed only two assessment points. To better understand the trajectory of regional brain volume recovery in treatment-seeking alcohol-dependent individuals (ALC), regional brain volumes were measured after 1 week, 1 month and 7.5 months of sustained abstinence via magnetic resonance imaging at 1.5 T. ALC showed significant volume increases in frontal, parietal and occipital gray matter (GM) and white matter (WM), total cortical GM and total lobar WM, thalamus and cerebellum, and decreased ventricular volume over 7.5 months of abstinence. Volume increases in regional GM were significantly greater over 1 week to 1 month than from 1 month to 7.5 months of abstinence, indicating a non-linear rate of change in regional GM over 7.5 months. Overall, regional lobar WM showed linear volume increases over 7.5 months. With increasing age, smoking ALC showed lower frontal and total cortical GM volume recovery than non-smoking ALC. Despite significant volume increases, ALC showed smaller GM volumes in all regions, except the frontal cortex, than controls after 7.5 months of abstinence. ALC and controls showed no regional WM volume differences at any assessment point. In non-smoking ALC only, increasing regional GM and WM volumes were related to improving processing speed. Findings may indicate a differential rate of recovery of cell types/cellular components contributing to GM and WM volume during early abstinence, and that GM volume deficits persist after 7.5 months of sustained sobriety in this ALC cohort.

Effects of cigarette smoking history on neurocognitive recovery over 8 months of abstinence in alcohol-dependent individuals.

BACKGROUND: This study compared the rate and extent of recovery on measures of learning and memory, processing speed, and working memory in treatment-seeking alcohol-dependent individuals (ALC) who were never smokers (nvsALC), former smokers (fsALC), and active smokers (asALC) over the first 8 months of sustained abstinence from alcohol. Assessments after 1 week, 1 month, and 8 months of abstinence in ALC enabled a comparison of the rates of neurocognitive changes from 1 week to 1 month versus 1 to 8 months of abstinence. METHODS: ALC and never-smoking controls were administered standardized measures of auditory-verbal and visuospatial learning and memory, processing speed, and working memory. Controls completed a baseline assessment and a follow-up approximately 9 months later. RESULTS: Over 8 months of abstinence, asALC showed poorer recovery than nvsALC on visuospatial learning, and both fsALC and asALC recovered less than nvsALC on processing speed measures. The corresponding recovery rates for the ALC group, as a whole, were greater from 1 week to 1 month than from 1 to 8 months of abstinence; these findings were largely driven by improvements in nvsALC. The recovery levels for fsALC on most measures were similar to those in asALC. Additionally, over 8 months, asALC showed significantly less improvement with increasing age than nvsALC on measures of processing speed and learning and memory. At 8 months of abstinence, asALC were inferior to controls and nvsALC on multiple measures, fsALC performed worse than nvsALC on several tests, but nvsALC were not different from controls on any measure. CONCLUSIONS: Overall, ALC showed rapid improvement on measures of visuospatial learning and processing speed during the first month of abstinence from alcohol. Results also provide robust evidence that smoking status influenced the rate and level of neurocognitive recovery over 8 months of abstinence in this ALC cohort.

Postural stability in cigarette smokers and during abstinence from alcohol.

BACKGROUND: Static postural instability is common in alcohol-dependent individuals (ALC). Chronic alcohol consumption has deleterious effects on the neural and perceptual systems subserving postural stability. However, little is known about the effects of chronic cigarette smoking on postural stability and its changes during abstinence from alcohol. METHODS: A modified Fregly ataxia battery was administered to a total of 115 smoking (sALC) and nonsmoking ALC (nsALC) and to 71 smoking (sCON) and nonsmoking light/nondrinking controls (nsCON). Subgroups of abstinent ALC were assessed at 3 time points (TPs; approximately 1, 5, 34 weeks of abstinence from alcohol); a subset of nsCON was retested at 40 weeks. We tested whether cigarette smoking affects postural stability in CON and in ALC during extended abstinence from alcohol, and we used linear mixed effects modeling to measure change across TPs within ALC. RESULTS: Chronic smoking was associated with reduced performance on the Sharpened Romberg eyes-closed task in abstinent ALC at all 3 TPs and in CON. The test performance of nsALC increased significantly between 1 and 32 weeks of abstinence, whereas the corresponding increases for sALC between 1 and 35 weeks were nonsignificant. With long-term abstinence from alcohol, nsALC recovered into the range of nsCON and sALC recovered into the range of sCON. Static postural stability decreased with age and correlated with smoking variables but not with drinking measures. CONCLUSIONS: Chronic smoking was associated with reduced static postural stability with eyes closed and with lower increases of postural stability during abstinence from alcohol. Smoking cessation in alcohol dependence treatment may facilitate recovery from static postural instability during abstinence.

Interactive effects of chronic cigarette smoking and age on brain volumes in controls and alcohol-dependent individuals in early abstinence.

Chronic alcohol-use disorders (AUDs) have been shown to interact with normal age-related volume loss to exacerbate brain atrophy with increasing age. However, chronic cigarette smoking, a highly co-morbid condition in AUD and its influence on age-related brain atrophy have not been evaluated. We performed 1.5 T quantitative magnetic resonance imaging in non-smoking controls [non-smoking light drinking controls (nsCONs); n = 54], smoking light drinking controls (sCONs, n = 34), and one-week abstinent, treatment-seeking alcohol-dependent (ALC) non-smokers (nsALCs, n = 35) and smokers (sALCs, n = 43), to evaluate the independent and interactive effects of alcohol dependence and chronic smoking on regional cortical and subcortical brain volumes, emphasizing the brain reward/executive oversight system (BREOS). The nsCONs and sALCs showed greater age-related volume losses than the nsALCs in the dorsal prefrontal cortex (DPFC), total cortical BREOS, superior parietal lobule and putamen. The nsALCs and sALCs demonstrated smaller volumes than the nsCONs in most cortical region of interests (ROIs). The sCONs had smaller volumes than the nsCONs in the DPFC, insula, inferior parietal lobule, temporal pole/parahippocampal region and all global cortical measures. The nsALCs and sALCs had smaller volumes than the sCONs in the DPFC, superior temporal gyrus, inferior and superior parietal lobules, precuneus and all global cortical measures. Volume differences between the nsALCs and sALCs were observed only in the putamen. Alcohol consumption measures were not related to volumes in any ROI for ALC; smoking severity measures were related to corpus callosum volume in the sCONs and sALCs. The findings indicate that consideration of smoking status is necessary for a better understanding of the factors contributing to regional brain atrophy in AUD.

Smoking and increased Alzheimer's disease risk: a review of potential mechanisms.

BACKGROUND: Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. METHODS: A systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. RESULTS: Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. CONCLUSIONS: A reduction in the incidence of smoking will likely reduce the future prevalence of AD.

Regional cortical thickness recovery with extended abstinence after treatment in those with alcohol use disorder.

Several cross-sectional investigations reported widespread cortical thinning in those with alcohol use disorder (AUD). The few longitudinal studies investigating cortical thickness changes during abstinence are limited to the first month of sobriety. Consequently, cortical thickness changes during extended abstinence in those with AUD is unclear. In this study, AUD participants were studied at approximately 1 week (n = 68), 1 month (n = 88), and 7.3 months (n = 40) of abstinence. Forty-five never-smoking controls (CON) completed a baseline study, and 15 were reassessed after approximately 9.6 months. Participants completed magnetic resonance imaging studies at 1.5T, and cortical thickness for 34 bilateral regions of interest (ROI) was quantitated with FreeSurfer. AUD participants demonstrated significant linear thickness increases in 25/34 ROI over 7.3 months of abstinence. The rate of change from 1 week to 1 month was greater than 1 month to 7.3 months in 19/34 ROIs. Proatherogenic conditions were associated with lower thickness recovery in anterior frontal, inferior parietal, and lateral/mesial temporal regions. After 7.3 months of abstinence, AUD participants were statistically equivalent to CON on cortical thickness in 24/34 ROIs; the cortical thickness differences between AUD and CON in the banks superior temporal gyrus, post central, posterior cingulate, superior parietal, supramarginal, and superior frontal cortices were driven by thinner cortices in AUD with proatherogenic conditions relative to CON. In actively smoking AUD, increasing pack-years was associated with decreasing thickness recovery primarily in the anterior frontal ROIs. Widespread bilateral cortical thickness recovery over 7.3 months of abstinence was the central finding for this AUD cohort. The longitudinal and cross-sectional findings for AUD with proatherogenic suggests alterations in perfusion or vascular integrity may relate to structural recovery in those with AUD. These results support the adaptive and beneficial effects of sustained sobriety on brain structural recovery in people with AUD.

Regional cortical brain volumes at treatment entry relates to post treatment WHO risk drinking levels in those with alcohol use disorder.

BACKGROUND: Abstinence following treatment for alcohol use disorder (AUD) is associated with significant improvements in psychiatric and physical health, however, recent studies suggest resumption of low risk levels of alcohol use can also be beneficial. The present study assessed whether post-treatment levels of alcohol use were associated with cortical brain volumedifferences at treatment entry. METHODS: Individuals seeking treatment for AUD (n=75) and light/non-drinking controls (LN, n=51) underwent 1.5T magnetic resonance imaging. The volumes of 34 bilateral cortical regions of interest (ROIs) were quantitated via FreeSurfer. Individuals with AUD were classified according to post-treatment alcohol consumption using the WHO risk drinking levels (abstainers: AB; low risk: RL; or higher risk: RH). Regional volumes for AB, RL and RH, at treatment entry, were compared to LN. RESULTS: Relative to LN, AB demonstrated smaller volumes in 18/68 (26%), RL in 24/68 (35%) and RH in 34/68 (50%) ROIs with the largest magnitude volume differences observed between RH and LN. RH and RL reported a higher frequency of depressive disorders than AB. Among RH and RL, level of depressive and anxiety symptomatology were associated with daily number of drinks consumed after treatment. CONCLUSIONS: Volumetric differences, at treatment entry, in brain regions implicated in executive function and salience networks corresponded with post-treatment alcohol consumption levels suggesting that pre-existing differences in neural integrity may contribute to treatment outcomes. Depressive and anxiety symptomatology was also associated with brain morphometrics and alcohol use patterns, highlighting the importance of effectively targeting these conditions during AUD treatment.

A pilot, randomized clinical trial: Left dorsolateral prefrontal cortex intermittent theta burst stimulation improves treatment outcomes in veterans with alcohol use disorder.

BACKGROUND: Transcranial magnetic stimulation (TMS) offers a promising treatment avenue to modulate brain function in alcohol use disorder (AUD). To the best of our knowledge, this pilot study is the first randomized, double-blind, sham-controlled trial to deliver intermittent theta burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) among US veterans with AUD. We hypothesized that 20 sessions of real TMS are tolerable and feasible. As a secondary line of inquiry, we hypothesized that, relative to sham TMS, individuals receiving real TMS would experience greater reductions in 6-month relapse rates, anhedonia, and alcohol cue-reactivity. METHODS: Veterans (n = 17, one woman) were enrolled in a double-blind, sham-controlled trial (2-3 sessions/day; 7-10 days; 600 pulses/session; 20 sessions). Pre- and posttreatment assessments included responses to self-report questionnaires and functional magnetic resonance imaging measures of alcohol cue-reactivity. Alcohol consumption was assessed for 6 months. Linear mixed-effects models were constructed to predict posttreatment craving, mood, and cue-reactivity. RESULTS: Individuals who received active iTBS (n = 8) were less likely to relapse within 3 months after treatment than the sham-treated group (n = 9) (OR = 12.0). Greater reductions in anhedonia were observed following active iTBS (Cohen's d = -0.59), relative to sham (d = -0.25). Alcohol cue-reactivity was reduced following active iTBS and increased following sham within the left insula (d = -0.19 vs. 0.51), left thalamus (d = -0.28 vs. 0.77), right insula (d = 0.18 vs. 0.52), and right thalamus (d = -0.06 vs. 0.62). CONCLUSIONS: Relative to sham, we demonstrate that 20 sessions of real left DLPFC iTBS reduced the likelihood of relapse for at least 3 months. The potential utility of this approach is underscored by observed decreases in anhedonia and alcohol cue-reactivity-strong predictors of relapse among veterans. These initial data offer a valuable set of effect sizes to inform future clinical trials in this patient population.

Loss in connectivity among regions of the brain reward system in alcohol dependence.

A recently developed measure of structural brain connectivity disruption, the loss in connectivity (LoCo), is adapted for studies in alcohol dependence. LoCo uses independent tractography information from young healthy controls to project the location of white matter (WM) microstructure abnormalities in alcohol-dependent versus nondependent individuals onto connected gray matter (GM) regions. LoCo scores are computed from WM abnormality masks derived at two levels: (1) groupwise differences of alcohol-dependent individuals (ALC) versus light-drinking (LD) controls and (2) differences of each ALC individual versus the LD control group. LoCo scores based on groupwise WM differences show that GM regions belonging to the extended brain reward system (BRS) network have significantly higher LoCo (i.e., disconnectivity) than those not in this network (t = 2.18, P = 0.016). LoCo scores based on individuals' WM differences are also higher in BRS versus non-BRS (t = 5.26, P = 3.92 × 10(-6) ) of ALC. These results suggest that WM alterations in alcohol dependence, although subtle and spatially heterogeneous across the population, are nonetheless preferentially localized to the BRS. LoCo is shown to provide a more sensitive estimate of GM involvement than conventional volumetric GM measures by better differentiating between brains of ALC and LD controls (rates of 89.3% vs. 69.6%). However, just as volumetric measures, LoCo is not significantly correlated with standard metrics of drinking severity. LoCo is a sensitive WM measure of regional cortical disconnectivity that uniquely characterizes anatomical network disruptions in alcohol dependence.

Effects of fat on MR-measured metabolite signal strengths: implications for in vivo MRS studies of the human brain.

Recent MRS studies have indicated that a higher body mass index (BMI) is associated with lower brain metabolite levels. Generally, individuals with higher BMIs have more body fat deposits than individuals with normal BMIs. This single-voxel spectroscopy (SVS) study investigated possible effects of fat on MR-measured metabolite signal areas, which may at least partly explain the observed associations of BMI with MR-measured brain metabolite levels in vivo. SVS data were acquired at 4 T from a phantom containing N-acetylaspartate, glutamate and creatine, as well as from three healthy male adults. Back fat obtained from pig was used to assess the effects of fat on metabolite signals. With the same voxel size and placement, the phantom was first scanned without fat (baseline), and then with 0.7-cm- and 1.4-cm-thick fat layers placed on it. Each participant was also scanned first without fat and then with two 0.7-cm fat layers, one placed beneath the occiput and the other on the forehead. Two spectra were acquired per participant from the anterior cingulate and the parieto-occipital cortices. The metabolite resonance and corresponding water peak areas were then fitted and metabolite to water signal ratios were used for analyses. In both phantom and in vivo experiments, the metabolite-to-water ratios decreased in the presence of fat relative to baseline metabolite-to-water ratios. The reduced metabolite signals in the presence of fat reported here are reminiscent of the negative correlations observed between BMI and MR-measured metabolite levels. These apparent physical effects of fat have potentially far-reaching consequences for the accuracy of MR measurements of brain metabolite levels and their interpretation, particularly when large fat stores exist around the skull, such as in individuals with higher BMI.