Multi-modal neuroimaging reveals differences in alcohol-cue reactivity but not neurometabolite concentrations in adolescents who drink alcohol.

BACKGROUND: The objective of this multi-modal neuroimaging study was to identify neuroscience-informed treatment targets for adolescent alcohol use disorder (AUD) by examining potential neural alterations associated with adolescent alcohol use. METHODS: Adolescents (ages 17-19) who heavily used (n=49) or did not use alcohol (n=22) were recruited for a multi-modal neuroimaging protocol, including proton magnetic resonance spectroscopy within the dorsal anterior cingulate cortex (dACC) and an fMRI alcohol cue-reactivity task. The alcohol cue-reactivity task was analyzed across 11 a priori regions-of-interest (ROI), including the dACC, and in an exploratory whole-brain approach. Correlations were run between neurometabolite levels and alcohol cue-reactivity in the dACC. RESULTS: There were no significant group differences in absolute neurometabolite concentrations. Compared to the control group, the alcohol-using group exhibited heightened alcohol cue reactivity in the left amygdala ROI (p=0.04). The whole-brain approach identified higher alcohol cue reactivity in the alcohol-using group compared to controls in the amygdala and occipital regions, and lower reactivity in the parietal lobe. Whole-brain sex effects were noted, with females displaying higher reactivity regardless of group. No significant correlations were found between neurometabolite levels and alcohol cue-reactivity in the dACC. CONCLUSIONS: The null neurometabolic findings may be due to age, relatively low severity of alcohol use, and non-treatment-seeking status of the participants. Females showed overall higher reactivity to alcohol cues, indicating a sex effect regardless of alcohol use history. Higher amygdala reactivity in alcohol-using adolescents suggests that emotional processing related to alcohol cues may be a useful target for future adolescent AUD interventions.

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.

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.

N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial.

Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.

Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies.

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge's g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.

Age-dependent brain morphometry in Major Depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a complex disorder that affects nearly 264 million people worldwide. Structural brain abnormalities in multiple neuroanatomical networks have been implicated in the etiology of MDD, but the degree to which MDD affects brain structure during early to late adulthood is unclear. METHODS: We examined morphometry of brain regions commonly implicated in MDD, including the amygdala, hippocampus, anterior cingulate gyrus, lateral orbitofrontal gyrus, subgenual cortex, and insular cortex subregions, from early to late adulthood. Harmonized measures for gray matter (GM) volume and cortical thickness of each region were estimated cross-sectionally for 305 healthy controls (CTLs) and 247 individuals with MDD (MDDs), collated from four research cohorts. We modeled the nonlinear associations of age with GM volume and cortical thickness using generalized additive modeling and tested for age-dependent group differences. RESULTS: Overall, all investigated regions exhibited smaller GM volume and thinner cortical measures with increasing age. Compared to age matched CTLs, MDDs had thicker cortices and greater GM volume from early adulthood until early middle age (average 35 years), but thinner cortices and smaller GM volume during and after middle age in the lateral orbital gyrus and all insular subregions. Deviations of the MDD and CTL models for both GM volume and cortical thickness in these regions started as early as age 18. CONCLUSIONS: The analyses revealed that brain morphometry differences between MDDs and CTLs are dependent on age and brain region. The significant age-by-group interactions in the lateral orbital frontal gyrus and insular subregions make these regions potential targets for future longitudinal studies of MDD.

Frontocerebellar gray matter plasticity in alcohol use disorder linked to abstinence.

Alcohol use disorder (AUD) is associated with brain-wide gray matter (GM) reduction, but the frontocerebellar circuit seems specifically affected by chronic alcohol consumption. T1 weighted MRI data from 38 AUD patients at one month of sobriety and three months later and from 25 controls were analyzed using voxel-based morphometry (VBM) and a graph theory approach (GTA). We investigated the degree to which the frontocerebellar circuit's integration within the brain's GM network architecture was altered by AUD-related GM volume loss. The VBM analyses did not reveal significant GM volume differences between relapsers and abstainers at either timepoint, but future relapsers at both timepoints had significantly less GM than controls in the frontocerebellar circuit. Abstainers, who at baseline also showed the most pronounced GM loss in the thalamus, showed a significant circuit-wide GM increase with inter-scan abstinence. The post-hoc GTAs revealed a persistent diffuse global atrophy in both AUD groups at follow-up relative to controls and different recovery patterns in the two AUD groups. Our findings suggest that future relapsers do not just present with a more severe expression of the same AUD consequences than abstainers, but that AUD affects the frontocerebellar circuit differently in relapsers and abstainers.

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.

Maladaptive brain organization at 1 month into abstinence as an indicator for future relapse in patients with alcohol use disorder.

Abstinence is a lifelong endeavor, and the risk of a relapse is always present for patients with Alcohol Use Disorder (AUD). The aim of the study was to better understand specific characteristics of the intrinsic whole-brain-network architecture of 34 AUD patients that may support abstinence or relapse. We used Graph Theory Analysis (GTA) of resting-state fMRI data from treatment seekers at 1 month of abstinence and their follow-up data as abstainers or relapsers 3 months later, together with data from 30 light/non-drinking controls scanned at the same interval. We determined the group-specific intrinsic community configurations at both timepoints as well as the corresponding modularity Q, a GTA measure that quantifies how well individual network communities are separated from each other. Both AUD groups at both timepoints had community configurations significantly different from those of controls, but the three groups did not significantly differ in their Q values. However, relapsers showed a maladaptive community configuration at baseline, which became more similar to the controls' community organization after the relapsers had started consuming alcohol again during the study interval. Additionally, successful recovery from AUD was not associated with re-gaining the intrinsic brain organization found in light/non-drinkers, but with a re-configuration resulting in a new brain organization distinctly different from that of healthy controls. Resting-state fMRI provides useful measures reflecting neuroplastic adaptations related to AUD treatment outcome.

The gray matter structural connectome and its relationship to alcohol relapse: Reconnecting for recovery.

Gray matter (GM) atrophy associated with alcohol use disorders (AUD) affects predominantly the frontal lobes. Less is known how frontal lobe GM loss affects GM loss in other regions and how it influences drinking behavior or relapse after treatment. The profile similarity index (PSI) combined with graph analysis allows to assess how GM loss in one region affects GM loss in regions connected to it, ie, GM connectivity. The PSI was used to describe the pattern of GM connectivity in 21 light drinkers (LDs) and in 54 individuals with AUD (ALC) early in abstinence. Effects of abstinence and relapse were determined in a subgroup of 36 participants after 3 months. Compared with LD, GM losses within the extended brain reward system (eBRS) at 1-month abstinence were similar between abstainers (ABST) and relapsers (REL), but REL had also GM losses outside the eBRS. Lower GM connectivities in ventro-striatal/hypothalamic and dorsolateral prefrontal regions and thalami were present in both ABST and REL. Between-networks connectivity loss of the eBRS in ABST was confined to prefrontal regions. About 3 months later, the GM volume and connectivity losses had resolved in ABST, and insula connectivity was increased compared with LD. GM losses and GM connectivity losses in REL were unchanged. Overall, prolonged abstinence was associated with a normalization of within-eBRS connectivity and a reconnection of eBRS structures with other networks. The re-formation of structural connectivities within and across networks appears critical for cognitive-behavioral functioning related to the capacity to maintain abstinence after outpatient treatment.

Substance-Specific and Shared Gray Matter Signatures in Alcohol, Opioid, and Polysubstance Use Disorder.

Substance use disorders (SUD) have been shown to be associated with gray matter (GM) loss, particularly in the frontal cortex. However, unclear is to what degree these regional GM alterations are substance-specific or shared across different substances, and if these regional GM alterations are independent of each other or the result of system-level processes at the intrinsic connectivity network level. The T1 weighted MRI data of 65 treated patients with alcohol use disorder (AUD), 27 patients with opioid use disorder (OUD) on maintenance therapy, 21 treated patients with stimulant use disorder comorbid with alcohol use disorder (polysubstance use disorder patients, PSU), and 21 healthy controls were examined via data-driven vertex-wise and voxel-wise GM analyses. Then, structural covariance analyses and open-access fMRI database analyses were used to map the cortical thinning patterns found in the three SUD groups onto intrinsic functional systems. Among AUD and OUD, we identified both common cortical thinning in right anterior brain regions as well as SUD-specific regional GM alterations that were not present in the PSU group. Furthermore, AUD patients had not only the most extended regional thinning but also significantly smaller subcortical structures and cerebellum relative to controls, OUD and PSU individuals. The system-level analyses revealed that AUD and OUD showed cortical thinning in several functional systems. In the AUD group the default mode network was clearly most affected, followed by the salience and executive control networks, whereas the salience and somatomotor network were highlighted as critical for understanding OUD. Structural brain alterations in groups with different SUDs are largely unique in their spatial extent and functional network correlates.

Does an Over-Connected Visual Cortex Undermine Efforts to Stay Sober After Treatment for Alcohol Use Disorder?

A fine-tuned interplay of highly synchronized activity within and between the brain's communities is a crucial feature of the brain's functional organization. We wanted to investigate in individuals with alcohol use disorder (AUD) the degree to which the interplay of the brain's community-architecture and the extended brain reward system (eBRS) is affected by drinking status (relapse or abstinence). We used Graph Theory Analysis of resting-state fMRI data from treatment seekers at 1 month of abstinence to model the brain's intrinsic community configuration and their follow-up data as abstainers or relapsers 3 months later to quantify the degree of global across-community interaction between the eBRS and the intrinsic communities at both timepoints. After 1 month of abstinence, the ventromedial PFC in particular showed a significantly higher global across-community interaction in the 22 future relapsers when compared to 30 light/non-drinking controls. These differences were no longer present 3 months later when the relapsers had resumed drinking. We found no significant differences between abstainers and controls at either timepoint. Post hoc tests revealed that one eBRS region, the ventromedial PFC, showed a significant global across-community interaction with a community comprising the visual cortex in relapsers at baseline. In contrast, abstainers showed a significant negative association of the ventromedial PFC with the visual cortex. The increased across-community interaction of the ventromedial PFC and the visual cortex in relapsers at timepoint 1 may be an early indicator for treatment failure in a subgroup of AUD patients.

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.

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.

Cortisol, moderated by age, is associated with antidepressant treatment outcome and memory improvement in Major Depressive Disorder: A retrospective analysis.

BACKGROUND: Studies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and depression. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol in association with MDD diagnostic status and mood and memory response to antidepressant treatment. METHODS: Serum cortisol levels in 66 unmedicated patients with MDD and 75 matched healthy controls (HC) were measured at baseline and retrospectively analyzed. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis in the pooled sample of MDD and HC participants. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. RESULTS: Cortisol, moderated by age, was associated with MDD diagnosis (p < .05), treatment-associated reduction of depression symptoms (p < .001) and improvement of delayed recall (p < .001). Modeling the Cortisol × Age interaction suggested that for participants below the median age of our sample, lower cortisol levels were associated with a lower rate of MDD diagnosis and higher antidepressant effects. On the contrary, in those above the median sample age, lower cortisol was associated with a higher rate of MDD and less improvement in depression symptoms and memory performance. CONCLUSIONS: Our results add to the body of literature suggesting that age might be an important factor in moderating the relationship between peripheral cortisol levels, depression, cognition, and prognosis. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the participants studied.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

A Roadmap for Integrating Neuroscience Into Addiction Treatment: A Consensus of the Neuroscience Interest Group of the International Society of Addiction Medicine.

Although there is general consensus that altered brain structure and function underpins addictive disorders, clinicians working in addiction treatment rarely incorporate neuroscience-informed approaches into their practice. We recently launched the Neuroscience Interest Group within the International Society of Addiction Medicine (ISAM-NIG) to promote initiatives to bridge this gap. This article summarizes the ISAM-NIG key priorities and strategies to achieve implementation of addiction neuroscience knowledge and tools for the assessment and treatment of substance use disorders. We cover two assessment areas: cognitive assessment and neuroimaging, and two interventional areas: cognitive training/remediation and neuromodulation, where we identify key challenges and proposed solutions. We reason that incorporating cognitive assessment into clinical settings requires the identification of constructs that predict meaningful clinical outcomes. Other requirements are the development of measures that are easily-administered, reliable, and ecologically-valid. Translation of neuroimaging techniques requires the development of diagnostic and prognostic biomarkers and testing the cost-effectiveness of these biomarkers in individualized prediction algorithms for relapse prevention and treatment selection. Integration of cognitive assessments with neuroimaging can provide multilevel targets including neural, cognitive, and behavioral outcomes for neuroscience-informed interventions. Application of neuroscience-informed interventions including cognitive training/remediation and neuromodulation requires clear pathways to design treatments based on multilevel targets, additional evidence from randomized trials and subsequent clinical implementation, including evaluation of cost-effectiveness. We propose to address these challenges by promoting international collaboration between researchers and clinicians, developing harmonized protocols and data management systems, and prioritizing multi-site research that focuses on improving clinical outcomes.

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.