Sleep as an Important Target or Modifier in Alcohol Use Disorder Clinical Treatment: Example From a Recent Gabapentin Randomized Clinical Trial.

OBJECTIVES: Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. METHODS: This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. RESULTS: Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [P = 0.026] and higher (PDA [P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase (P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. CONCLUSIONS: Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

Predictors of symptom course in alcohol use disorder.

BACKGROUND: Symptoms often play an important role in the scientific inquiry of psychological disorders and have been theorized to play a functional role in the disorders themselves. However, little is known about the course of specific symptoms and individual differences in course. Understanding the course of specific symptoms and factors influencing symptom course can inform psychological theory and future research on course and treatment. METHODS: The current study examined alcohol use disorder (AUD) criteria to explore how etiologically relevant covariates differentially affected the course of individual criteria. The study examined 34,653 participants from Wave 1 (2001-2002) and Wave 2 (2003-2004) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), to analyze the extent to which AUD symptom course is predicted by alcohol consumption patterns, family history of alcoholism, the presence of internalizing and externalizing disorders, and race. RESULTS: The course of all AUD criteria was significantly influenced by these predictors, with the magnitude of the influence varying across different criteria and different aspects of the course (i.e., onset, persistence, recurrence). The strength of the relationship is partially related to the theoretical proximity of a given covariate to AUD symptomatology, with heavy drinking being the strongest and family history of AUD being the weakest. The course of all criteria was strongly associated with the prevalence of the criterion in the overall sample. CONCLUSIONS: The course of AUD criteria is heterogeneous, appearing to be influenced by conceptually proximal predictors, the prevalence of the criterion, and perhaps an underlying common factor. Diagnostic accuracy may be improved by including a criterion related to alcohol consumption. Future work should include exploring the interchangeability of criteria and alternative operationalization of them.

Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.

Cross-sectional and longitudinal AUD symptom networks: They tell different stories.

Modern theoretical models of Alcohol Use Disorder (AUD) highlight the different functional roles played by various mechanisms associated with different symptoms. Symptom network models (SNMs) offer one approach to modeling AUD symptomatology in a way that could reflect these processes and provide important information on the progression and persistence of disorder. However, much of the research conducted using SNMs relies on cross-sectional data, which has raised questions regarding the extent they reflect dynamic processes. The current study aimed to (a) examine symptom networks of AUD and (b) compare the extent to which cross-sectional network models had similar structures and interpretations as longitudinal network models. 17,360 participants from Wave 1 (2001-2002) and Wave 2 (2003-2004) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) were used to model cross-sectional and longitudinal AUD symptom networks. The cross-sectional analyses demonstrate high replicability across waves and central symptoms consistent with other cross-sectional studies on addiction networks. The longitudinal network shared much less similarity than the cross-sectional networks and had a substantially different structure. Given the increasing attention given to the network perspective in psychopathology research, the results of this study raise concerns about interpreting cross-sectional symptom networks as representative of temporal changes occurring within a psychological disorder. We conclude that the psychological symptom network literature should be bolstered with additional research on longitudinal network models.

Epigenetic moderators of naltrexone efficacy in reducing heavy drinking in Alcohol Use Disorder: a randomized trial.

Polymorphisms in genes associated with opioid signaling and dopamine reuptake and inactivation may moderate naltrexone efficacy in Alcohol Use Disorder (AUD), but the effects of epigenetic modification of these genes on naltrexone response are largely unexplored. This study tested interactions between methylation in the µ-opioid receptor (OPRM1), dopamine transporter (SLC6A3), and catechol-O-methyltransferase (COMT) genes as predictors of naltrexone effects on heavy drinking in a 16-week randomized, placebo-controlled trial among 145 treatment-seeking AUD patients. OPRM1 methylation interacted with both SLC6A3 and COMT methylation to moderate naltrexone efficacy, such that naltrexone-treated individuals with lower methylation of the OPRM1 promoter and the SLC6A3 promoter (p = 0.006), COMT promoter (p = 0.005), or SLC6A3 3' untranslated region (p = 0.004), relative to placebo and to those with higher OPRM1 and SLC6A3 or COMT methylation, had significantly fewer heavy drinking days. Epigenetic modification of opioid- and dopamine-related genes may represent a novel pharmacoepigenetic predictor of naltrexone efficacy in AUD.

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.

Determining the optimal pulse number for theta burst induced change in cortical excitability.

Theta-burst stimulation (TBS) is a form of non-invasive neuromodulation which is delivered in an intermittent (iTBS) or continuous (cTBS) manner. Although 600 pulses is the most common dose, the goal of these experiments was to evaluate the effect of higher per-dose pulse numbers on cortical excitability. Sixty individuals were recruited for 2 experiments. In Experiment 1, participants received 600, 1200, 1800, or sham (600) iTBS (4 visits, counterbalanced, left motor cortex, 80% active threshold). In Experiment 2, participants received 600, 1200, 1800, 3600, or sham (600) cTBS (5 visits, counterbalanced). Motor evoked potentials (MEP) were measured in 10-min increments for 60 min. For iTBS, there was a significant interaction between dose and time (F = 3.8296, p = 0.01), driven by iTBS (1200) which decreased excitability for up to 50 min (t = 3.1267, p = 0.001). For cTBS, there was no overall interaction between dose and time (F = 1.1513, p = 0.33). Relative to sham, cTBS (3600) increased excitability for up to 60 min (t = 2.0880, p = 0.04). There were no other significant effects of dose relative to sham in either experiment. Secondary analyses revealed high within and between subject variability. These results suggest that iTBS (1200) and cTBS (3600) are, respectively, the most effective doses for decreasing and increasing cortical excitability.

Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial.

BACKGROUND: While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. METHODS: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes. RESULTS: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers. CONCLUSIONS: These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.

Efficacy of Gabapentin for the Treatment of Alcohol Use Disorder in Patients With Alcohol Withdrawal Symptoms: A Randomized Clinical Trial.

Importance: Although an estimated 30 million people meet criteria for alcohol use disorder (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific, approach might improve efficacy and acceptance. Objective: To examine whether gabapentin would be useful in the treatment of AUD, especially in those with the most alcohol withdrawal symptoms. Design, Setting, and Participants: This double-blind randomized clinical trial conducted between November 2014 and June 2018 evaluated gabapentin vs placebo in community-recruited participants screened and treated in an academic outpatient setting over a 16-week treatment period. A total of 145 treatment-seeking individuals who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for AUD and were not receiving other AUD intervention were screened, and 96 who also met recent alcohol withdrawal criteria were randomized to treatment after 3 abstinent days. Daily drinking was recorded, and percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment. Interventions: Gabapentin up to 1200 mg/d, orally, vs placebo along with 9 medical management visits (20 minutes each). Main Outcomes and Measures: The percentage of individuals with no heavy drinking days and those with total abstinence were compared between treatment groups and further evaluated based on prestudy alcohol withdrawal symptoms. Results: Of 96 randomized individuals, 90 were evaluable (44 in the gabapentin arm and 46 in the placebo arm), with a mean (SD) age of 49.6 (10.1) years; 69 were men (77%) and 85 were white (94%). The evaluable participants had 83% baseline heavy drinking days (4 or more drinks/day for women, 5 or more for men) and met 4.5 alcohol withdrawal criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). More gabapentin-treated individuals had no heavy drinking days (12 of 44 participants [27%]) compared with placebo (4 of 46 participants [9%]), a difference of 18.6% (95% CI, 3.1-34.1; P = .02; number needed to treat [NNT], 5.4), and more total abstinence (8 of 44 [18%]) compared with placebo (2 of 46 [4%]), a difference of 13.8% (95% CI, 1.0-26.7; P = .04; NNT, 6.2). The prestudy high-alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (P < .02; NNT, 3.1) and total abstinence (P = .003; NNT, 2.7) compared with placebo, while within the low-alcohol withdrawal group, there were no significant differences. These findings were similar for other drinking variables, where gabapentin was more efficacious than placebo in the high-alcohol withdrawal group only. Gabapentin caused more dizziness, but this did not affect efficacy. Conclusions and Relevance: These data, combined with others, suggest gabapentin might be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT02349477.

Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder.

BACKGROUND AND AIMS: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment. METHODS: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percentage of heavy drinking days, percentage of days abstinent and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model. RESULTS: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, P = 0.02). However, the effect was not significant when multiple comparisons were taken into account. CONCLUSIONS: From the evidence to date, it remains unclear whether rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

On Ising models and algorithms for the construction of symptom networks in psychopathological research.

During the past 5 to 10 years, an estimation method known as eLasso has been used extensively to produce symptom networks (or, more precisely, symptom dependence graphs) from binary data in psychopathological research. The eLasso method is based on a particular type of Ising model that corresponds to binary pairwise Markov random fields, and its popularity is due, in part, to an efficient estimation process that is based on a series of l1-regularized logistic regressions. In this article, we offer an unprecedented critique of the Ising model and eLasso. We provide a careful assessment of the conditions that underlie the Ising model as well as specific limitations associated with the eLasso estimation algorithm. This assessment leads to serious concerns regarding the implementation of eLasso in psychopathological research. Some potential strategies for eliminating or, at least, mitigating these concerns include (a) the use of partitioning or mixture modeling to account for unobserved heterogeneity in the sample of respondents, and (b) the use of co-occurrence measures for symptom similarity to either replace or supplement the covariance/correlation measure associated with eLasso. Two psychopathological data sets are used to highlight the concerns that are raised in the critique. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Abused Inhalant Toluene Impairs Medial Prefrontal Cortex Activity and Risk/Reward Decision-Making during a Probabilistic Discounting Task.

Inhalant (e.g., toluene) misuse is linked to behavioral and cognitive deficits in humans, yet preclinical studies of the effect of inhalants on higher-order cognition are limited. We addressed this gap in the literature by examining the effect of toluene vapor exposure on risk/reward decision-making in male and female Sprague-Dawley rats using a probabilistic discounting task. In this task, rodents chose a risky/large reward or a safe/small reward, with the odds of risky reinforcement descending or ascending throughout the test session. We observed a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting caused by acute toluene exposure. Rats exposed to toluene vapor during adolescence and tested as adults performed comparably to air-treated controls and were susceptible to the effects of an acute toluene challenge. These behavioral flexibility deficits observed suggests dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients in real-time using in vivo fiber photometry. mPFC activity peaked before either lever press during free-choice trials in toluene- and air-treated animals. During forced-choice trials, GCaMP6f transients shifted from pre-risky to pre-safe choice, an effect mitigated by acute toluene exposure. mPFC activity decreased during rewarded trials, with larger decreases following risky/large wins compared with safe/small wins. Toluene-treated animals also had decreased mPFC activity during rewarded trials, but there was no distinction between risky/large wins and safe/small wins. These results provide physiological evidence for mPFC-dependent behavioral deficits caused by toluene.SIGNIFICANCE STATEMENT Inhalants (e.g., toluene) are an understudied class of drugs of abuse that cause devastating behavioral and cognitive deficits in humans. Understanding the neurobiological interactions of toluene vapor using animal models is important for developing effective treatment strategies for inhalant addicts. Here we find that toluene vapor reduces behavioral flexibility in rodents making risk/reward-based decisions. The medial prefrontal cortex (mPFC) drives behavioral flexibility during this type of decision-making and we show that toluene reduces the ability of mPFC neurons to track optimal choices as reward probabilities change. Toluene also reduces these neurons' ability to distinguish between small and large rewards. A combination of these factors likely leads to the impaired performance in probabilistic discounting following acute toluene exposure.

The influence of sample selection on the structure of psychopathology symptom networks: An example with alcohol use disorder.

Increasingly, the structure of mental disorders has been studied in the form of a network, characterizing how symptoms or criteria interact with and influence each other. Many studies of psychiatric symptoms and diagnostic criteria employ community or population-based surveys using co-occurrence of the symptoms/criteria to form the networks. However, given the overall low prevalence rates of mental disorders and their symptoms in the general population, most of those surveyed may not exhibit or endorse any symptoms and yet are often included in network analyses. Consequently, because network models are built on associations between symptoms/criteria, much of the observed variability is driven by individuals who are asymptomatic. Using data from the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) Wave 2 and NESARC-III, we explore the effect of these "asymptomatic" observations on the estimated relations among diagnostic criteria of alcohol use disorder to determine the effects of such observations on estimated networks. We do so using the eLasso tool, as well as with traditional measures of correlation between binary variables (the Φ coefficient and odds ratio). We find that when the proportion of asymptomatic individuals are systematically culled from the sample, the estimated pairwise relations are often significantly affected, even changing signs in some cases. Our findings indicate that researchers should carefully consider the population(s) included in their sample and the implications it has on their interpretations of pairwise similarity estimates and resulting generalizability and reproducibility of estimates of network structures. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Estimating transdiagnostic symptom networks: The problem of "skip outs" in diagnostic interviews.

Network models of the symptoms of psychological disorders provide a novel lens for examining comorbidity. Viewing symptoms as causal entities in their own right, researchers can attempt to identify specific symptoms that "bridge" diagnostic entities, providing a more granular perspective on comorbidity than the one provided by analysis at the syndromal level. Such analyses could help identify transdiagnostic targets for both research and clinical interventions. Although promising conceptually, extant work using this approach often uses structured diagnostic interview data that employ "skip outs," branching logic conditional on responses to gating questions (which may be criterial or risk markers). We demonstrate that skip outs, where screening items are asked for each disorder before assessing the remaining symptoms, can produce significant problems in interpretation of comorbidity between symptoms and, hence, transdiagnostic network models. The nature and extent of this problem is explored, and suggestions for future network studies of comorbidity are provided. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Criteria Definitions and Network Relations: The Importance of Criterion Thresholds.

Across various structured diagnostic instruments, the criteria used to diagnose alcohol use disorder (AUD) are not assessed consistently. For example, different instruments often pose questions that reflect different thresholds of the underlying symptoms. We consider the criteria for craving and the inability to cut down or stop drinking to demonstrate the influence of using different thresholds for a positive symptom endorsement with respect to the estimated edges of a symptom network. Results indicate that the utilization of these differing thresholds leads to significant differences in edge weights. Generally, higher thresholds relate more strongly to lower prevalence rate criteria, and the reverse for lower thresholds. These findings have implications for reproducibility of effects in symptom networks and their generalization across studies.

Cortical substrates of cue-reactivity in multiple substance dependent populations: transdiagnostic relevance of the medial prefrontal cortex.

Elevated drug-cue elicited brain activity is one of the most widely cited, transdiagnostically relevant traits of substance dependent populations. These populations, however, are typically studied in isolation. The goal of this study was to prospectively investigate the spatial topography of drug-cue reactivity in a large set of individuals dependent on either cocaine, alcohol, or nicotine. Functional MRI data was acquired from 156 substance dependent individuals (55 cocaine, 53 alcohol, and 48 nicotine) as they performed a standardized drug-cue exposure task. Clusters of significant activation to drug-cues relative to neutral cues ('hot spots') were isolated for each individual. K-means clustering was used to classify the spatial topography of the hotspots in the data set. The percentage of hotspots that would be reached at several distances (2-5 cm) of transcranial magnetic stimulation (TMS) were calculated. One hundred and three participants had at least one cluster of significant frontal cortex activity (66%). K-means revealed 3 distinct clusters within the medial prefrontal cortex (MPFC), left inferior frontal gyrus/insula, right premotor cortex. For the group as a whole (and for alcohol users and nicotine users independently), medial prefrontal cortex (BA 10) was the location of the greatest number of hotspots. The frontal pole was cortical location closest to the largest percentage of hotspots. While there is individual variability in the location of the cue-elicited 'hot spot' these data demonstrate that elevated BOLD signal to drug cues in the MPFC may be a transdiagnostic endophenotype of addiction which may also be a fruitful neuromodulation target.

Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and KV7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA KV7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective KV7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that KV7.4 channels are a critical mediator of excessive alcohol drinking.

Author Correction: Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.