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.

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.

Leadership Styles Experienced During Military Service Predict Later Anhedonic Depressive Symptoms and Self-Efficacy in Veterans With Alcohol Use Disorder.

INTRODUCTION: Lifetime and past-year alcohol use disorder (AUD) prevalence is significantly higher in US Armed Services Veterans than in non-veterans across adulthood. This study examined the associations of perceived transformational leadership styles (TLS) experienced during military service and anhedonic depression and self-efficacy related to confidence to abstain or reduce alcohol consumption in Veterans seeking treatment for AUD. The ramifications of perceived leadership styles on multiple aspects of follower psychiatric functioning, including depressive and PTSD symptomatology, during and after military service, may be substantial and enduring. Higher anhedonic depression and lower abstinence self-efficacy are related to increased risk of relapse after treatment. We predicted Veterans, in treatment for AUD, who reported higher perceived levels of transformational leadership during military service, demonstrate lower anhedonic depressive symptoms and higher alcohol abstinence self-efficacy. MATERIALS AND METHODS: Veterans with AUD (n = 60; 50 ± 14 years of age) were recruited from residential treatment at the VA Palo Alto Health Care System. All procedures were approved by the VA Palo Alto Health Care System and Stanford University institutional review boards. A series of mediation analyses were completed with The Multifactor Leadership Questionnaire measures of TLS (average across leadership measures [transformational leadership average; TLS average]) as predictor and the Alcohol Abstinence Self-Efficacy Scale, Mood and Anxiety Symptom Questionnaire, anhedonic depression subscale, as dependent measures. PTSD Checklist for DSM-5 score was tested as a mediator variable. RESULTS: Higher reported perceived TLS average during military service was significantly related to lower anhedonic depressive symptoms. Higher TLS average was related to higher self-efficacy to resist alcohol use in contexts involving experience of physical issues and withdrawal/cravings and urges. These relationships were not mediated by PTSD symptomatology or duration of military service, age, education, time since military service, military branch, combat exposure, or current psychiatric diagnosis. CONCLUSIONS: The significant associations of perceived TLS during military service with anhedonic depression and alcohol use self-efficacy are clinically relevant because these measures are associated with relapse risk after AUD treatment. Further study of the implications of perceived TLS during military service for AUD and other substance use disorder treatment outcome is warranted in Veterans.

BDNF rs6265 Met carriers with alcohol use disorder show greater age-related decline of N-acetylaspartate in left dorsolateral prefrontal cortex.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is implicated in neuronal and glial cell growth and differentiation, synaptic plasticity, and apoptotic mechanisms. A single-nucleotide polymorphism of the BDNF rs6265 gene may contribute to the pattern and magnitude of brain metabolite abnormalities apparent in those with an Alcohol Use Disorder (AUD). We predicted that methionine (Met) carriers would demonstrate lower magnetic resonance spectroscopy (MRS) measures of N-acetylaspartate level (NAA) and greater age-related decline in NAA than valine (Val) homozygotes. METHODS: Veterans with AUD (n=95; 46±12 years of age, min = 25, max = 71) were recruited from VA Palo Alto residential treatment centers. Single voxel MRS, at 3 Tesla, was used to obtain NAA, choline (Cho) and creatine (Cr) containing compounds from the left dorsolateral prefrontal cortex (DLPFC). Metabolite spectra were fit with LC Model and NAA and Cho were standardized to total Cr level and NAA was also standardized to Cho. RESULTS: Val/Met (n=35) showed markedly greater age-related decline in left DLPFC NAA/Cr level than Val/Val (n=60); no differences in mean metabolite levels were observed between Val/Met and Val/Val. Val/Met demonstrated greater frequency of history of MDD and higher frequency of cannabis use disorder over 12 months prior to study. CONCLUSIONS: The greater age-related decline in left DLPFC NAA/Cr and the higher frequency of MDD history and Cannabis Use disorder in BDNF rs6265 Met carriers with AUD are novel and may have implications for non-invasive brain stimulation targeting the left DLFPC and other psychosocial interventions typically utilized in the treatment of AUD.

Targeting the Salience Network: A Mini-Review on a Novel Neuromodulation Approach for Treating Alcohol Use Disorder.

Alcohol use disorder (AUD) continues to be challenging to treat despite the best available interventions, with two-thirds of individuals going on to relapse by 1 year after treatment. Recent advances in the brain-based conceptual framework of addiction have allowed the field to pivot into a neuromodulation approach to intervention for these devastative disorders. Small trials of repetitive transcranial magnetic stimulation (rTMS) have used protocols developed for other psychiatric conditions and applied them to those with addiction with modest efficacy. Recent evidence suggests that a TMS approach focused on modulating the salience network (SN), a circuit at the crossroads of large-scale networks associated with AUD, may be a fruitful therapeutic strategy. The anterior insula or dorsal anterior cingulate cortex may be particularly effective stimulation sites given emerging evidence of their roles in processes associated with relapse.

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.

Repetitive Transcranial Magnetic Stimulation as a Treatment for Veterans with Cognitive Impairment and Multiple Comorbidities.

BACKGROUND: Despite decades of research efforts, current treatments for Alzheimer's disease (AD) are of limited effectiveness and do not halt the progression of the disease and associated cognitive decline. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) may improve cognition. OBJECTIVE: We conducted a pilot study to investigate the effect of rTMS on cognitive function in Veterans with numerous medical comorbidities. METHODS: Participants underwent 20 sessions, over the course of approximately 4 weeks, of 10 Hz rTMS at the left dorsolateral prefrontal cortex with intensity of 120% resting motor threshold. Outcome measures including memory, language, verbal fluency, and executive functions were acquired at baseline, end of treatment, and 4 months after the last rTMS session. Twenty-six Veterans completed the study (13 in the active rTMS group, 13 in the sham rTMS group). RESULTS: The study protocol was well-tolerated. Active, compared to sham, rTMS showed improved auditory-verbal memory at the end of treatment and at 4-month follow-up. However, the active rTMS group demonstrated a trend in decreased semantic verbal fluency at the end of treatment and at 4-month follow up. CONCLUSION: These preliminary results show rTMS is safe in general in this elderly Veteran population with multiple co-morbidities. Patients in the sham group showed an expected, slight decline in the California Verbal Learning Test scores over the course of the study, whereas the active treatment group showed a slight improvement at the 4-month post-treatment follow up. These effects need to be confirmed by studies of larger sample sizes.

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.

Predicting relapse after alcohol use disorder treatment in a high-risk cohort: The roles of anhedonia and smoking.

On average, two-thirds of individuals treated for alcohol use disorder (AUD) relapse within six months. There is a critical need to identify modifiable risk factors associated with relapse that can be addressed during AUD treatment. Candidate factors include mood disorders and cigarette smoking, which frequently co-occur with AUD. We predicted that co-occurrence of mood disorders, cigarette smoking, and other modifiable conditions will predict relapse within six months of AUD treatment. Ninety-five Veterans, 23-91 years old, completed assessments of multiple characteristics including demographic information, co-occurring psychiatric disorders, and medical conditions during residential treatment for AUD. Participants' alcohol consumption was monitored over six months after participation. Logistic regression was used to determine if, mood disorders, cigarette smoking status, alcohol consumption, educational level, and comorbid general medical conditions are associated with relapse after AUD treatment. Sixty-nine percent of Veterans (n = 66) relapsed within six months of study while 31% remained abstinent (n = 29). While education, comorbid general medical conditions, and mood disorder diagnoses were not predictors of relapse, Veterans with greater symptoms of anhedonia, active smokers, and fewer days of abstinence prior to treatment showed significantly greater odds for relapse within six months. Anhedonia and cigarette smoking are modifiable risk factors, and effective treatment of underlying anhedonic symptoms and implementation of smoking cessation concurrent with AUD-focused interventions may decrease risk of relapse.

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.

Cigarette smoking history is associated with poorer recovery in multiple neurocognitive domains following treatment for an alcohol use disorder.

Cigarette smoking is associated with neurocognitive dysfunction in various populations, including those seeking treatment for an alcohol use disorder (AUD). This study compared the rate and extent of recovery on measures of processing speed, executive functions, general intelligence, visuospatial skills and working memory in treatment-seeking alcohol dependent individuals (ALC) who were never-smokers (nvsALC), former-smoker (fsALC), and active smokers (asALC), over approximately 8 months of abstinence from alcohol. Methods: ALC participants were evaluated at approximately 1 month of abstinence (AP1; n = 132) and reassessed after 8 months of sobriety (AP2; n = 54). Never-smoking controls (CON; n = 33) completed a baseline and follow-up (n = 19) assessment approximately 9 months later. Domains evaluated were executive functions, general intelligence, processing speed, visuospatial skills and working memory; a domain composite was formed from the arithmetic average of the foregoing domains. nvsALC showed greater improvement than fsALC, asALC and CON on most domains over the AP1-AP2 interval. fsALC demonstrated greater recovery than asALC on all domains except visuospatial skills; fsALC also showed greater improvements than CON on general intelligence, working memory and domain composite. asALC did not show significant improvement on any domain over the AP1-AP2 interval. At 8 months of abstinence, asALC were inferior to CON and nvsALC on multiple domains, fsALC performed worse than nvsALC on several domains, but nvsALC were not different from CON on any domain. Our results provide robust evidence that smoking status influenced the rate and extent of neurocognitive recovery between 1 and 8 months of abstinence in this ALC cohort. Chronic smoking in AUD likely contributes to the considerable heterogeneity observed in neurocognitive recovery during extended abstinence. The findings provide additional strong support for the benefits of smoking cessation and the increasing clinical movement to offer smoking cessation resources concurrent with treatment for AUD.

Evaluation of adding the CANTAB computerized neuropsychological assessment battery to a traditional battery in a tertiary care center for veterans.

Numerous advantages of and concerns about computerized neuropsychological assessment systems have been noted. Here we report a program evaluation of incorporating a computerized system, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in our tertiary assessment center for Veterans. Patients were 23 consecutive referrals to the Western War Related Illness and Injury Study Center, an interdisciplinary assessment center within the Veterans Affairs Healthcare System for Veterans with complex medical presentations. Patients were administered both the CANTAB and a brief traditional neuropsychological battery. The correlation between global composite scores from each method was .71 (p < .05), indicating "good" concordance. Concordance was "fair" to "good" for scores on specific cognitive domains. However, concordance was lower when classifying patients' cognition as "impaired" or "not-impaired" based on a cutoff score. Despite the CANTAB's primarily visuospatial interface, discrepancy between the two methods' scores was not associated with patients' visuospatial abilities. The two methods were similarly sensitive to deficits associated with posttraumatic stress disorder, which is prevalent among the Center's patients. The CANTAB was judged to be a valid and useful complement to, but not an acceptable alternative to a traditional neuropsychologist-administered cognitive assessment battery for the Center's specific patients and needs.

Changes of frontal cortical subregion volumes in alcohol dependent individuals during early abstinence: associations with treatment outcome.

We previously reported that at 1-and-4 weeks of sobriety, those who relapsed after treatment demonstrated significantly smaller total frontal cortical volume than individuals who maintained abstinence for at least 12 months post treatment. The segmentation method employed did not permit examination of frontal subregions that serve as nodes of the executive, salience and emotional regulation networks; structural abnormalities in these circuits are associated with relapse in those seeking treatment for alcohol use disorders (AUD). The primary goal of this study was to determine if frontal cortical subregion volume recovery during early abstinence is associated with long-term abstinence from alcohol. We compared bilateral components of the dorsal prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex and insula volumes, at 1 and 4 weeks of abstinence, between individuals who resumed drinking within 12 months of treatment (Relapsers) those who showed sustained abstinence over 12 months following treatment (Abstainers) and healthy Controls. At 1 and 4 weeks of sobriety, Relapsers demonstrated significantly smaller volumes than Controls in 15 of 20 regions of interest, while Abstainers only had smaller volumes than Controls in 5 of 20 regions. In Relapsers, increasing volumes over 1 month in multiple frontal subregions and the insula were associated with longer duration of abstinence after treatment. The persistent bilateral frontal and insula volume deficits in Relapsers over 4 weeks from last alcohol use may have implications for neurostimulation methods targeting anterior frontal/insula regions, and represent an endophenotype that differentiates those who respond more favorably to available psychosocial and pharmacological interventions.

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.

White matter microstructural correlates of relapse in alcohol dependence.

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

Cigarette smoking is associated with cortical thinning in anterior frontal regions, insula and regions showing atrophy in early Alzheimer's Disease.

BACKGROUND: Magnetic resonance imaging studies of cigarette smoking-related effects on human brain structure primarily focused on cortical volumes. Much less is known about the effects of smoking on cortical thickness. Smokers and Non-smokers were compared on regional cortical thickness. We predicted smokers would demonstrate greater age-related thinning localized to anterior frontal regions that serve as nodes for the executive, salience, and emotional regulation networks (ESER regions) and those demonstrating significant atrophy in early Alzheimer's Disease (AD regions). METHODS: Non-smokers (n = 41) and smokers (n = 41), 22-70 years of age, completed a 4 T MRI study. Regional cortical thickness was quantitated via FreeSurfer. In smokers, associations between smoking severity, decision-making, impulsivity, and regional cortical thickness were examined. RESULTS: Smokers demonstrated cortical thinning in the medial and lateral OFC, insula, entorhinal, fusiform, middle temporal, and Composite AD regions. In Smokers, greater pack-years were associated with thinner lateral OFC, middle temporal, inferior parietal, fusiform, precuneus, and Composite AD regions. In Smokers, poorer decision-making/greater risk taking was related to thinner cortices in caudal ACC, rostral middle frontal and superior frontal gyri, and Composite ESER. Higher self-reported impulsivity was associated with thinner rostral and caudal ACC. CONCLUSIONS: This study provides additional evidence that cigarette smoking is associated with thinner cortices in regions implicated in the development and maintenance of substance use disorders and in regions demonstrating significant atrophy in early AD. The novel structure-function relationships in Smokers further our understanding of the neurobiological substrates potentially underlying the neuropsychological abnormalities documented in smokers.

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.

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

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