Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Impact of acquisition and modeling parameters on the test-retest reproducibility of edited GABA.

Literature values vary widely for within-subject test-retest reproducibility of gamma-aminobutyric acid (GABA) measured with edited magnetic resonance spectroscopy (MRS). Reasons for this variation remain unclear. Here, we tested whether three acquisition parameters-(1) sequence complexity (two-experiment MEscher-GArwood Point RESolved Spectroscopy [MEGA-PRESS] vs. four-experiment Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy [HERMES]); (2) editing pulse duration (14 vs. 20 ms); and (3) scanner frequency drift (interleaved water referencing [IWR] turned ON vs. OFF)-and two linear combination modeling variations-(1) three different coedited macromolecule models (called "1to1GABA", "1to1GABAsoft", and "3to2MM" in the Osprey software package); and (2) 0.55- versus 0.4-ppm spline baseline knot spacing-affected the within-subject coefficient of variation of GABA + macromolecules (GABA+). We collected edited MRS data from the dorsal anterior cingulate cortex from 20 participants (mean age: 30.8 ± 9.5 years; 10 males). Test and retest scans were separated by removing the participant from the scanner for 5-10 min. Each acquisition consisted of two MEGA-PRESS and two HERMES sequences with editing pulse durations of 14 and 20 ms (referred to here as MEGA-14, MEGA-20, HERMES-14, and HERMES-20; all TE = 80 ms, 224 averages). We identified the best test-retest reproducibility following postprocessing with a composite model of the 0.9- and 3-ppm macromolecules ("3to2MM"); this model performed particularly well for the HERMES data. Furthermore, sparser (0.55- compared with 0.4-ppm) spline baseline knot spacing yielded generally better test-retest reproducibility for GABA+. Replicating our prior results, linear combination modeling in Osprey compared with simple peak fitting in Gannet resulted in substantially better test-retest reproducibility. However, reproducibility did not consistently differ for MEGA-PRESS compared with HERMES, for 14- compared with 20-ms editing pulses, or for IWR-ON versus IWR-OFF. These results highlight the importance of model selection for edited MRS studies of GABA+, particularly for clinical studies that focus on individual patient differences in GABA+ or changes following an intervention.

Alcohol Cue Processing in Co-Occurring Bipolar Disorder and Alcohol Use Disorder.

Importance: Reward circuitry dysfunction is a candidate mechanism of co-occurring bipolar disorder and alcohol use disorder (BD + AUD) that remains understudied. This functional magnetic resonance imaging (fMRI) research represents the first evaluation of alcohol cue reward processing in BD + AUD. Objective: To determine how alcohol cue processing in individuals with BD + AUD may be distinct from that of individuals with AUD or BD alone. Design, Setting, and Participants: This cross-sectional case-control study (April 2013-June 2018) followed a 2 × 2 factorial design and included individuals with BD + AUD, AUD alone, BD alone, and healthy controls. A well-validated visual alcohol cue reactivity fMRI paradigm was administered to eligible participants following their demonstration of 1 week or more of abstinence from alcohol and drugs assessed via serial biomarker testing. Study procedures were completed at the Medical University of South Carolina. Analysis took place between June and August 2022. Main Outcomes and Measures: Past-week mood symptoms were rated by clinicians using the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. The Alcohol Dependence Scale, Obsessive-Compulsive Drinking Scale, and Barratt Impulsiveness Scale were included questionnaires. Functional MRI whole-brain data were analyzed along with percent signal change within a priori regions of interest located in the ventral striatum, dorsal striatum, and ventromedial prefrontal cortex. Exploratory analyses of associations between cue reactivity and select behavioral correlates (alcohol craving, impulsivity, maximum number of alcohol drinks on a single occasion, and days since last alcohol drink) were also performed. Results: Of 112 participants, 28 (25.0%) had BD + AUD, 26 (23.2%) had AUD alone, 31 (27.7%) had BD alone, and 27 (24.1%) were healthy controls. The mean (SD) age was 38.7 (11.6) years, 50 (45.5%) were female, 33 (30%) were smokers, and 37 (34.9%) reported recent alcohol consumption. Whole-brain analyses revealed a BD × AUD interaction (F = 10.64; P = .001; η2 = 0.09) within a cluster spanning portions of the right inferior frontal gyrus and insula. Region of interest analyses revealed a main association of BD (F = 8.02; P = .006; η2 = 0.07) within the dorsal striatum. In each instance, individuals with BD + AUD exhibited reduced activation compared with all other groups who did not significantly differ from one another. These hypoactivations were associated with increased impulsivity and obsessive-compulsive alcohol craving exclusively among individuals with BD + AUD. Conclusion and Relevance: The findings of this study suggest conceptualizing reward dysfunction in BD + AUD by the potential interaction between blunted reward responsivity and deficient inhibitory control may help guide treatment development strategies. To this end, reduced right inferior frontal gyrus and insula alcohol cue reactivity represents a novel candidate biomarker of BD + AUD that may respond to pharmacological interventions targeting impulsivity-related neural mechanisms for improved executive control.

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.

More than one-half of the variance in in vivo proton MR spectroscopy metabolite estimates is common to all metabolites.

The present study characterized associations among brain metabolite levels, applying bivariate and multivariate (i.e., factor analysis) statistical methods to total creatine (tCr)-referenced estimates of the major Point RESolved Spectroscopy (PRESS) proton MR spectroscopy (1 H-MRS) metabolites (i.e., total NAA/tCr, total choline/tCr, myo-inositol/tCr, glutamate + glutamine/tCr) acquired at 3 T from medial parietal lobe in a large (n = 299), well-characterized international cohort of healthy volunteers. Results supported the hypothesis that 1 H-MRS-measured metabolite estimates are moderately intercorrelated (Mr = 0.42, SDr = 0.11, ps < 0.001), with more than one-half (i.e., 57%) of the total variability in metabolite estimates explained by a single common factor. Older age was significantly associated with lower levels of the identified common metabolite variance (CMV) factor (ß = -0.09, p = 0.048), despite not being associated with levels of any individual metabolite. Holding CMV factor levels constant, females had significantly lower levels of total choline (i.e., unique metabolite variance; ß = -0.19, p < 0.001), mirroring significant bivariate correlations between sex and total choline reported previously. Supplementary analysis of water-referenced metabolite estimates (i.e., including tCr/water) demonstrated lower, although still substantial, intercorrelations among metabolites, with 37% of total metabolite variance explained by a single common factor. If replicated, these results would suggest that applied 1 H-MRS researchers shift their analytical framework from examining bivariate associations between individual metabolites and specialty-dependent (e.g., clinical, research) variables of interest (e.g., using t-tests) to examining multivariable (i.e., covariate) associations between multiple metabolites and specialty-dependent variables of interest (e.g., using multiple regression).

Impact of acquisition and modeling parameters on test-retest reproducibility of edited GABA.

Literature values for within-subject test-retest reproducibility of gamma-aminobutyric acid (GABA), measured with edited magnetic resonance spectroscopy (MRS), vary widely. Reasons for this variation remain unclear. Here we tested whether sequence complexity (two-experiment MEGA-PRESS versus four-experiment HERMES), editing pulse duration (14 versus 20 ms), scanner frequency drift (interleaved water referencing (IWR) turned ON versus OFF), and linear combination modeling variations (three different co-edited macromolecule models and 0.55 versus 0.4 ppm spline baseline knot spacing) affected the within-subject coefficient of variation of GABA + macromolecules (GABA+). We collected edited MRS data from the dorsal anterior cingulate cortex from 20 participants (30.8 ± 9.5 years; 10 males). Test and retest scans were separated by removing the participant from the scanner for 5-10 minutes. Each acquisition consisted of two MEGA-PRESS and two HERMES sequences with editing pulse durations of 14 and 20 ms (referred to here as: MEGA-14, MEGA-20, HERMES-14, and HERMES-20; all TE = 80 ms, 224 averages). Reproducibility did not consistently differ for MEGA-PRESS compared with HERMES or for 14 compared with 20 ms editing pulses. A composite model of the 0.9 and 3 ppm macromolecules (particularly for HERMES) and sparser (0.55 compared with 0.4 ppm) spline baseline knot spacing yielded generally better test-retest reproducibility for GABA+. Replicating our prior results, linear combination modeling in Osprey compared with simple peak fitting in Gannet resulted in substantially better test-retest reproducibility. These results highlight the importance of model selection for edited MRS studies of GABA+, particularly for clinical studies which focus on individual patient differences in GABA+ or changes following an intervention.

Importance of Linear Combination Modeling for Quantification of Glutathione and γ-Aminobutyric Acid Levels Using Hadamard-Edited Magnetic Resonance Spectroscopy.

Background: J-difference-edited 1H-MR spectra require modeling to quantify signals of low-concentration metabolites. Two main approaches are used for this spectral modeling: simple peak fitting and linear combination modeling (LCM) with a simulated basis set. Recent consensus recommended LCM as the method of choice for the spectral analysis of edited data. Purpose: The aim of this study is to compare the performance of simple peak fitting and LCM in a test-retest dataset, hypothesizing that the more sophisticated LCM approach would improve quantification of Hadamard-edited data compared with simple peak fitting. Methods: A test-retest dataset was re-analyzed using Gannet (simple peak fitting) and Osprey (LCM). These data were obtained from the dorsal anterior cingulate cortex of twelve healthy volunteers, with TE = 80 ms for HERMES and TE = 120 ms for MEGA-PRESS of glutathione (GSH). Within-subject coefficients of variation (CVs) were calculated to quantify between-scan reproducibility of each metabolite estimate. Results: The reproducibility of HERMES GSH estimates was substantially improved using LCM compared to simple peak fitting, from a CV of 19.0-9.9%. For MEGA-PRESS GSH data, reproducibility was similar using LCM and simple peak fitting, with CVs of 7.3 and 8.8%. GABA + CVs from HERMES were 16.7 and 15.2%, respectively for the two models. Conclusion: LCM with simulated basis functions substantially improved the reproducibility of GSH quantification for HERMES data.

A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus.

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

Disrupted brain gamma-aminobutyric acid (GABA)/glutamate homeostasis is a promising target for pharmacological intervention in co-occurring bipolar disorder (BD) and cannabis use disorder (CUD). Gabapentin is a safe and well-tolerated medication, FDA-approved to treat other neurological diseases, that restores GABA/glutamate homeostasis, with treatment studies supporting efficacy in treating CUD, as well as anxiety and sleep disorders that are common to both BD and CUD. The present manuscript represents the primary report of a randomized, double-blind, placebo-controlled, crossover (1-week/condition), multimodal-MRI (proton-MR spectroscopy, functional MRI) pilot study of gabapentin (1200 mg/day) in BD + CUD (n = 22). Primary analyses revealed that (1) gabapentin was well tolerated and adherence and retention were high, (2) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels and (3) gabapentin increased activation to visual cannabis cues in the posterior midcingulate cortex (pMCC, a region involved in response inhibition to rewarding stimuli). Exploratory evaluation of clinical outcomes further found that in participants taking gabapentin versus placebo, (1) elevations of dACC GABA levels were associated with lower manic/mixed and depressive symptoms and (2) elevations of rBG glutamate levels and pMCC activation to cannabis cues were associated with lower cannabis use. Though promising, the findings from this study should be interpreted with caution due to observed randomization order effects on dACC glutamate levels and identification of statistical moderators that differed by randomization order (i.e. cigarette-smoking status on rBG glutamate levels and pMCC cue activation). Nonetheless, they provide the necessary foundation for a more robustly designed (urn-randomized, parallel-group) future study of adjuvant gabapentin for BD + CUD.

Effects of Gabapentin on Dorsal Anterior Cingulate Cortex GABA and Glutamate Levels and Their Associations With Abstinence in Alcohol Use Disorder: A Randomized Clinical Trial.

OBJECTIVE: Although gabapentin has demonstrated efficacy in mitigating alcohol withdrawal symptoms and preventing relapse drinking in individuals with alcohol use disorder (AUD), the neurobiological mechanisms of action underlying these therapeutic effects remain unknown. The present study evaluated changes in GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) as candidate mechanisms of action. METHODS: In a 16-week randomized clinical trial, 68 adults with AUD, including a history of alcohol withdrawal syndrome, received 1,200 mg/day of gabapentin (N=37) or placebo (N=31) and nine medical management visits after ≥72 hours of abstinence. Proton MR spectroscopy (1H-MRS) estimates of dACC levels of GABA (N=67) and glutamate (N=64) were acquired before start of treatment and again approximately 14 days after randomization. Percent days abstinent was reported via timeline followback interview. RESULTS: The effects of gabapentin on GABA and glutamate levels were significantly associated with participants' percent days abstinent during early treatment. Specifically, gabapentin was associated with greater increases in glutamate and greater decreases in GABA levels in participants who remained mostly or entirely abstinent, and yet the opposite in participants who drank on more than half of the days preceding the second scan. Furthermore, gabapentin-treated participants with greater increases in glutamate levels during early treatment had significantly more percent days abstinent across the remainder of the study, relative to placebo-treated participants. CONCLUSIONS: In addition to providing insight into the mechanisms through which gabapentin may promote abstinence in individuals with AUD, this study also provides evidence for a biomarker of efficacious treatment that may be used to evaluate other glutamatergic or GABAergic medications for AUD and related conditions.

A Multimethod Examination of Sensitivity to Reward and Sensitivity to Punishment in Bipolar Disorder and Alcohol Dependence: Results from a 2 × 2 Factorial Design.

INTRODUCTION: Shared neurobehavioral characteristics of bipolar disorder (BD) and alcohol dependence (AD), including heightened sensitivity to reward (SR), may account for high rates of BD and AD co-occurrence (BD + AD). However, empirical research is lacking. The present multimethod investigation examined SR and sensitivity to punishment (SP) among these patient groups using a reliable and well-validated self-report questionnaire of SR and SP along with a laboratory task specifically designed to distinguish SR and SP activation. METHODS: One-hundred participants formed 4 groups: BD + AD (n = 40), BD (n = 18), AD (n = 25), and healthy controls (n = 17). Clinical interviews were administered, and participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSR-Q) and the Point Score Reaction Test behavioral task. Pearson correlations, hierarchical linear regression, and 2 × 2 factorial general linear modeling with Bonferroni-corrected pairwise comparisons were performed. RESULTS: BD and AD main effects were significant on self-reported SR and SP; however, BD × AD interactions were not. BD + AD individuals were significantly higher on self-reported SR than BD and AD individuals, yet all clinical groups were similar on SP. Behavioral response times did not distinguish groups nor did they associate with self-report data. DISCUSSION/CONCLUSION: BD and AD had additive, rather than interactive, effects on self-reported SR and SP. The methods employed, paired with their application to the present sample, may account for a lack of positive findings with behavioral data.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Intraindividual changes in brain GABA, glutamate, and glutamine during monitored abstinence from alcohol in treatment-naive individuals with alcohol use disorder.

Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in treatment-seeking individuals with moderate-severe alcohol use disorder (AUD) following acute withdrawal. In contrast, few studies have investigated neurochemical changes across early abstinence in less severe, treatment-naïve AUD. The present study, which represents the primary report of a research grant from ABMRF/The Alcohol Research Fund, measured dorsal anterior cingulate cortex (dACC) GABA, glutamate, and glutamine levels in treatment-naïve AUD (n = 23) via three 1 H-MRS scans spaced across a planned week of abstinence from alcohol. In addition to AUD participants, 12 light drinkers completed two scans, separated by 48 hours, to ensure that results in AUD were not produced by between-scan differences other than abstinence from alcohol. 1 H-MRS spectra were acquired in dACC at each scan using 2D J-resolved point-resolved spectroscopy. Linear mixed modeling results demonstrated a significant increase in GABA, but not glutamate or glutamine (Ps = .237-.626), levels between scans 1 and 2 (+8.88%, .041), with no difference between scans 2 and 3 (+1.00%, .836), in AUD but not LD (F = 1.24, .290) participants. Exploratory regression analyses tentatively revealed a number of significant prospective associations between changes in glutamine levels and heavy drinking, craving, and withdrawal symptoms. Most notably, the present study demonstrated return from abnormally low to normal GABA levels in treatment-naïve AUD within 3 days of their last drink; the pattern of results was consistent with glutamate and glutamine disturbances being exclusive to relatively more severe AUD.

An evaluation of the reproducibility of 1H-MRS GABA and GSH levels acquired in healthy volunteers with J-difference editing sequences at varying echo times.

Recent advances in J-difference-edited proton magnetic resonance spectroscopy (1H MRS) data acquisition and processing have led to the development of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) techniques, which enable the simultaneous measurement of ɣ-aminobutyric acid (GABA), the primary inhibitory amino acid neurotransmitter in the central nervous system, and of glutathione (GSH), the most abundant antioxidant in living tissue, at the commonly available magnetic field strength of 3 T. However, the reproducibility of brain levels of GABA and GSH measured across multiple scans in human subjects using HERMES remains to be established. In the present study, twelve healthy volunteers completed two consecutive HERMES scans of the dorsal anterior cingulate cortex (dACC) to assess the test-retest reproducibility of the technique for GABA and GSH measurements at TE = 80 ms. Eleven of the twelve participants additionally completed two consecutive MEGA-PRESS scans at TE = 120 ms, with editing pulses configured for GSH acquisition, to compare the reliability of GSH in the same voxel measured using the standard MEGA-PRESS at TE = 120 ms. The primary findings of study were that, 1) the coefficient of variation (CV) of measuring GABA with HERMES was 16.7%, which is in agreement with the reliability we previously reported for measuring GABA using MEGA-PRESS; and 2) the reliability of measuring GSH with MEGA-PRESS at TE = 120 ms was more than twice as high as that for measuring the antioxidant with HERMES at TE = 80 ms (CV = 7.3% vs. 19.0% respectively). These findings suggest that HERMES and MEGA-PRESS offer similar reliabilities for measuring GABA, while MEGA-PRESS at TE = 120 ms is more reliable for measuring GSH relative to HERMES at TE = 80 ms.

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics.

Evidence for a unique association between fronto-cortical glycine levels and recent heavy drinking in treatment naïve individuals with alcohol use disorder.

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy (1H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using 1H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (ß = -0.44, t = -3.09, p = 0.004) and glycine (ß = -0.68, t = -5.72, p < 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (ß = -0.11, t = -0.81, p = 0.42) whereas the effect of glycine remained significant (ß = -0.62, t = -4.38, p < 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.

Delay discounting and reward sensitivity in a 2 × 2 study of bipolar disorder and alcohol dependence.

BACKGROUND AND AIMS: Separate studies have shown increased delay discounting in people with bipolar disorder (BD) and people with alcohol dependence (AD) relative to people without mental health problems. Delay discounting was compared in people with no mental health problems, AD, BD and AD plus BD. Associations of delay discounting with self-reported impulsivity and reward sensitivity were also assessed. DESIGN: The study was a two-by-two factorial comparative observational design. SETTING: Data were collected at baseline diagnostic visits as part of a neuroimaging study at a medical university in South Carolina, USA. PARTICIPANTS: Twenty-two BD + AD, 33 BD, 28 AD and 27 people without mental health problems participated. MEASUREMENTS: Diagnostic and clinician-rated symptom measures, self-report questionnaires and a computerized delay discounting task were administered. Two-by-two general linear univariate models were tested to examine between-group differences on discounting rates, and bivariate correlations and hierarchical regression analyses were performed to examine associations between discounting rates and self-reported reward sensitivity and impulsivity. FINDINGS: There was a significant main effect of AD (P = 0.006, η2  = 0.068). The main effect of BD and the BD × AD interaction terms were non-significant (P ≥ 0.293, η2  ≤ 0.010). Reward sensitivity and impulsivity were not significantly associated with discounting rates after adjustment for the other (P ≥ 0.089). CONCLUSIONS: People with alcohol dependence appear to have higher delay discounting, while previously found associations between bipolar disorder and delay discounting may be secondary to alcohol use disorder.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

An evaluation of the impact of co-occurring anxiety and substance use disorder on bipolar disorder illness outcomes in STEP-BD.

BACKGROUND: Anxiety disorder (AD) and substance use disorder (SUD) highly co-occur with bipolar disorder (BD). AD and/or SUD co-occurrence is associated with poorer clinical outcomes in BD. However, respective associations between AD and/or SUD diagnoses and BD outcomes require clarification. Baseline data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were therefore utilized to investigate independent and simultaneous contributions of ADs and SUDs on clinical variables in BD. METHODS: Two latent factors, "pathological anxiety" and "substance use problems," were derived from presence/absence of lifetime AD and SUD diagnoses. Latent dimensions' associations with clinical variables, obtained from the Affective Disorders Evaluation, Mini-International Neuropsychiatric Interview and Range of Impaired Functioning, were estimated via structural equation modeling (SEM). RESULTS: Modeled independently, pathological anxiety and substance use problems were significantly associated with several variables. Yet when modeled simultaneously, pathological anxiety's associations with functional impairment, past-year rapid cycling, and past-year %time spent anxious and depressed remained while most variables' associations with substance use problems became non-significant. The only significant latent-factor interaction evidenced was for age of BD onset. LIMITATIONS: Analyses were limited to lifetime diagnoses and causality may not be inferred given cross-sectional data. CONCLUSIONS: ADs and SUDs impact on BD was mostly additive rather than synergistic. Findings highlight the potentially understated importance of treating inter-episodic anxiety in BD as it may exacerbate mood symptoms, increasing functional impairment and risk for subsequent mood episodes.

Identification and initial validation of empirically derived bipolar symptom states from a large longitudinal dataset: an application of hidden Markov modeling to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.

BACKGROUND: Although bipolar disorder (BD) is a fundamentally cyclical illness, a divided model of BD that emphasizes polarity over cyclicity has dominated modern psychiatric diagnostic systems since their advent in the 1980s. However, there has been a gradual return to conceptualizations of BD which focus on longitudinal course in the research community due to emerging supportive data. Advances in longitudinal statistical methods promise to further progress the field. METHODS: The current study employed hidden Markov modeling to uncover empirically derived manic and depressive states from longitudinal data [i.e. Young Mania Rating Scale and Montgomery-Asberg Depression Rating Scale responses across five occasions from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study], estimate participants' probabilities of transitioning between these states over time (n = 3918), and evaluate whether clinical variables (e.g. rapid cycling and substance dependence) predict participants' state transitions (n = 3229). RESULTS: Analyses identified three empirically derived mood states ('euthymic,' 'depressed,' and 'mixed'). Relative to the euthymic and depressed states, the mixed state was less commonly experienced, more temporally unstable, and uniquely associated with rapid cycling, substance use, and psychosis. Individuals assigned to the mixed state at baseline were relatively less likely to be diagnosed with BD-II (v. BD-I), more likely to present with a mixed or (hypo)manic episode, and reported experiencing irritable and elevated mood more frequently. CONCLUSIONS: The results from the current study represent an important step in defining, and characterizing the longitudinal course of, empirically derived mood states that can be used to form the foundation of objective, empirical attempts to define meaningful subtypes of affective illness defined by clinical course.