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The biological mediators that support cognitive-control and long-term weight-loss after laparoscopic sleeve gastrectomy (LSG) remain unclear. We measured peripheral appetitive hormones and brain functional-connectivity (FC) using magnetic-resonance-imaging with food cue-reactivity task in 25 obese participants at pre, 1 month, and 6 month after LSG, and compared with 30 normal weight controls. We also used diffusion-tensor-imaging to explore whether LSG increases brain structural-connectivity (SC) of regions involved in food cue-reactivity. LSG significantly decreased BMI, craving for high-calorie food cues, ghrelin, insulin, and leptin levels, and increased self-reported cognitive-control of eating behavior. LSG increased FC between the right dorsolateral prefrontal cortex (DLPFC) and the pregenual anterior cingulate cortex (pgACC) and increased SC between DLPFC and ACC at 1 month and 6 month after LSG. Reduction in BMI correlated negatively with increased FC of right DLPFC-pgACC at 1 month and with increased SC of DLPFC-ACC at 1 month and 6 month after LSG. Reduction in craving for high-calorie food cues correlated negatively with increased FC of DLPFC-pgACC at 6 month after LSG. Additionally, SC of DLPFC-ACC mediated the relationship between lower ghrelin levels and greater cognitive control. These findings provide evidence that LSG improved functional and structural connectivity in prefrontal regions, which contribute to enhanced cognitive-control and sustained weight-loss following surgery.

BACKGROUND AND AIMS Although personality traits are implicated in substance use disorders (SUDs) and obesity, differences and similarities between them have not been assessed. Our main aim was to compare personality traits between people with different SUDs, obese people and healthy controls. DESIGN This was a secondary analysis of personality scores obtained from participants in neuroimaging studies from Brookhaven National Laboratory and the Laboratory of Neuroimaging, National Institutes of Health. SETTING United States. PARTICIPANTS/CASES Individuals with obesity (OB) n = 41, alcohol use disorder (AUD) n = 39, marijuana use disorder (MUD) n = 24, cocaine use disorder (CUD) n = 100, and healthy controls (HC) n = 117 (237 males and 84 females). MEASUREMENTS The Multidimensional Personality Questionnaire, which characterizes positive emotionality (PEM), negative emotionality (NEM) and constraint (CON) traits. Adjusted covariates included cigarette smoking status, age, gender and body mass index (BMI). FINDINGS Multivariate analysis of covariance showed a main group effect (i.e. OB, AUD, MUD, CUD and HC) only on NEM (P 0.05, d = 2.8) relative to HC. CUD showed lower CON (P = 0.015, d = 5.4) and PEM (P = 0.018, d = 4.8) than HC; however, these differences were not significant in the other groups. NEM and CON were negatively correlated for groups combined (r = -0.26, P

OBJECTIVE The aim of this study was to investigate alterations in functional connectivity (FC) within and interactions between resting-state networks involved in salience, executive control, and interoception in participants with obesity (OB). METHODS Using resting-state functional magnetic resonance imaging with independent component analysis and FC, alterations within and interactions between resting-state networks in 35 OB and 35 normal-weight controls (NW) were investigated. RESULTS Compared with NW, OB showed reduced FC strength in the ventromedial prefrontal cortex and posterior cingulate cortex/precuneus within the default-mode network, dorsal anterior cingulate cortex within the salience network (SN), bilateral dorsolateral prefrontal cortex-angular gyrus within the frontoparietal network (FPN), and increased FC strength in the insula (INS) (Pfamilywise error

Objective Obesity is associated with impaired inhibitory control over food intake. We hypothesized that the neural circuitry underlying inhibition of food craving would be impaired in obesity. Here we assessed whether obese men show altered brain responses during attempted cognitive inhibition of craving when exposed to food cues. Methods Sixteen obese men (32 ± 8.7 years old, BMI = 38.6 ± 7.2) were compared with 11 age-matched non-obese men (BMI 24.2 ± 2.5) using PET and FDG. Brain glucose metabolism was evaluated in a food deprived state: no food stimulation, food stimulation with no inhibition (NI), and food stimulation with attempted inhibition (AI), each on a separate day. Individualized favorite food items were presented prior to and after FDG injection for 40 min. For AI, participants were asked to attempt to inhibit their desire for the food presented. Self-reports for hunger and food desire were recorded. Results Food stimulation compared with no stimulation increased glucose metabolism in inferior and superior frontal gyrus, default mode network and cerebellum, in both groups. For both groups, AI compared with NI-suppressed metabolism in right subgenual anterior cingulate, orbitofrontal areas, bilateral insula, and temporal gyri. There was a stimulation-by-group interaction effect in obese (but not in non-obese) men showing increased metabolism in pregenual anterior cingulate cortex (pgACC) and caudate during AI relative to NI. Changes in the food desire from NI to AI correlated negatively with changes in metabolism in pgACC/caudate in obese but not in non-obese men. Conclusions Obese men showed higher activation in pgACC/caudate, which are regions involved with self-regulation and emotion/reward during AI. Behavioral associations suggest that successful AI is an active process requiring more energy in obese but not in non-obese men. The additional required effort to increase cognitive control in response to food stimulation in obese compared with non-obese men may contribute to their uncontrolled eating behavior.

Human telomeres consist of tandem repeats at chromosome ends which protect chromosomal DNA from degradation. Telomere shortening occurs as part of natural aging; however, life stressors, smoking, drug use, BMI, and psychiatric disorders could disrupt cell aging and affect telomere length (TL). In this context, studies have evaluated the effects of alcohol consumption on TL; however, results have been inconsistent, which may reflect diverse drinking cut-offs and categorizations. To help clarify this, the present study addresses the association of TL with alcohol use disorder (AUD), drinking behaviors, lifetime stress, and chronological age. TL was quantified as the telomere to albumin ratio (T/S ratio) obtained from peripheral blood DNA using the quantitative PCR assay, from 260 participants with AUD and 449 non-dependent healthy controls (HC) from an existing National Institute on Alcohol Abuse and Alcoholism (NIAAA) database. AUD participants showed shorter TL compared to HC with both, age, and AUD, as independent predictors as well as a significant AUD with age interaction effect on TL. TL was also associated with impulsiveness in AUD participants. We did not observe an association between TL and chronicity of alcohol use, alcohol doses ingested, or childhood trauma exposures in either AUD or HC, although very few HC reported a history of childhood trauma. Our results support previous findings of telomere shortening with chronic alcohol exposures and show both an effect of AUD on TL that is independent of age as well as a significant AUD by age interaction on TL. These findings are consistent with accelerated cellular aging in AUD.

The “hunger” hormone ghrelin regulates food-intake and preference for high-calorie (HC) food through modulation of the mesocortico-limbic dopaminergic pathway. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery to treat morbid obesity. We tested the hypothesis that LSG-induced reductions in appetite and total ghrelin levels in blood are associated with reduced prefrontal brain reactivity to food cues. A functional magnetic resonance imaging (fMRI) cue-reactivity task with HC and low-calorie (LC) food pictures was used to investigate brain reactivity in 22 obese participants tested before and one month after bariatric surgery (BS). Nineteen obese controls (Ctr) without surgery were also tested at baseline and one-month later. LSG significantly decreased (1) fasting plasma concentrations of total ghrelin, leptin and insulin, (2) craving for HC food, and (3) brain activation in the right dorsolateral prefrontal cortex (DLPFC) in response to HC vs. LC food cues (P(FWE) < 0.05). LSG-induced reduction in DLPFC activation to food cues were positively correlated with reduction in ghrelin levels and reduction in craving ratings for food. Psychophysiological interaction (PPI) connectivity analyses showed that the right DLPFC had stronger connectivity with the ventral anterior cingulate cortex (vACC) after LSG; and changes in BMI were negatively correlated with changes in connectivity between the right DLPFC and vACC in the LSG group only. These findings suggest that LSG-induced weight-loss may be related to reductions in ghrelin, possibly leading to decreased food craving and hypothetically reducing DLPFC response to the HC food cues.

The role of sleep in brain physiology is poorly understood. Recently rodent studies have shown that the glymphatic system clears waste products from brain more efficiently during sleep compared to wakefulness due to the expansion of the interstitial fluid space facilitating entry of cerebrospinal fluid (CSF) into the brain. Here, we studied water diffusivity in the brain during sleep and awake conditions, hypothesizing that an increase in water diffusivity during sleep would occur concomitantly with an expansion of CSF volume - an effect that we predicted based on preclinical findings would be most prominent in cerebellum. We used MRI to measure slow and fast components of the apparent diffusion coefficient (ADC) of water in the brain in 50 healthy participants, in 30 of whom we compared awake versus sleep conditions and in 20 of whom we compared rested-wakefulness versus wakefulness following one night of sleep-deprivation. Sleep compared to wakefulness was associated with increases in slow-ADC in cerebellum and left temporal pole and with decreases in fast-ADC in thalamus, insula, parahippocampus and striatal regions, and the density of sleep arousals was inversely associated with ADC changes. The CSF volume was also increased during sleep and was associated with sleep-induced changes in ADCs in cerebellum. There were no differences in ADCs with wakefulness following sleep deprivation compared to rested-wakefulness. Although we hypothesized increases in ADC with sleep, our findings uncovered both increases in slow ADC (mostly in cerebellum) as well as decreases in fast ADC, which could reflect the distinct biological significance of fast- and slow-ADC values in relation to sleep. While preliminary, our findings suggest a more complex sleep-related glymphatic function in the human brain compared to rodents. On the other hand, our findings of sleep-induced changes in CSF volume provide preliminary evidence that is consistent with a glymphatic transport process in the human brain.

Numerous studies have documented cognitive impairments in multiple domains in patients with an alcohol use disorder (AUD), including perceptuomotor, executive, and visuospatial functions. Although the neural underpinnings of cognitive deficits in AUD have been studied extensively, the neural basis of attention deficits in AUD remains relatively unexplored. Here, we investigated neural responses to a visual attention task (VAT) in 19 recently abstinent patients with AUD and 23 healthy control participants (HC) using functional MRI (fMRI). AUD had a mean number of 62 ± 34SD drinks per week and 29 ± 13 years’ history of alcohol use. Results show that there were no behavioral differences (accuracy or reaction time) between groups during the VAT. For both groups, the VAT activated brain areas associated with visual attention load (i.e., parietal and prefrontal cortices) and visual processing (i.e., occipital cortex), which is in line with previous reports on the same task in healthy volunteers. Despite similar behavioral performances, AUD participants showed decreased VAT activation in regions of the dorsal and ventral attention networks, including parietal and prefrontal cortices, and in the insula as compared to controls. These findings corroborate differences in attention networks in AUD compared to HC that might underlie attention deficits in AUD, whereas impairments in the insula could reflect a disruption of interoception processing as found in other addictions.

Background:Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement ofLRRK2in alcohol dependence (AD).LRRK2expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in theLRRK2gene with AD in multiethnic populations from South and North America.Methods:Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well asin silicofunctional analyses, were also conducted.Results:FourLRRK2variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at theLRRK2locus) found in populations with different genetic backgrounds reinforces the relevance of our findings.Conclusion:Taken together, these results support the notion that genetic variants in theLRRK2locus are risk factors for AD in humans.

A ketogenic diet lowered benzodiazepine use during withdrawal in patients with AUD and blunted alcohol administration in rats., Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower “wanting” and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

Introduction Repeated exposure to high doses of alcohol triggers neuroinflammatory processes that contribute to craving and mood dysfunction in alcohol use disorder (AUD). The upregulation of the translocator protein (TSPO) is considered a biomarker of neuroinflammation, and TSPO ligands have been used as neuroimaging biomarkers of neuroinflammation. Epigenetic mechanisms are also implicated in neuroinflammatory responses to alcohol, and elevated expression of HDAC2 and HDAC6 has been reported in the brain of animals exposed to chronic alcohol. Methods The present study examined the transcriptional regulation of TSPO, HDAC2, and HDAC6 in human postmortem brain tissue from males previously diagnosed with AUD (n = 11) compared to age‐matched nondependent males (n = 13) in four brain regions relevant to AUD: prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus (HPP), and amygdala (AMY). Results Translocator protein mRNA levels in AMY and PFC and HDAC2 and HDAC6 mRNA levels in AMY were upregulated in AUD compared to controls. In AMY, TSPO mRNA levels were positively associated with HDAC2 and HDAC6 mRNA levels, suggesting a possible regulation of TSPO by HDAC2 and HDAC6 in this brain region. In contrast, there were no group differences for TSPO, HDAC2, and HDAC6 in NAc and HPP. Conclusion Our study is the first to find upregulated TSPO mRNA levels in AMY and PFC in postmortem brains from AUD consistent with neuroinflammation, and in the amygdala, they implicate epigenetic regulation of TSPO by HDAC2 and HDAC6., First study to identify TSPO mRNA levels in the postmortem AUD brain. Upregulation of TSPO, HDAC2, and HDAC6 mRNA levels in the amygdala, and upregulation of TSPO in the prefrontal cortex in AUD compared to controls. Positive association between the TSPO, HDAC2, and HDAC6 mRNA levels in amygdala.

Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. Knowing the importance of processes such as neuronal activity, intracellular signal transduction, and synapse plasticity to the development and maintenance of compulsive ethanol drinking, the aim of the present study was to explore and identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake. To do this, we applied a guilt‐by‐association approach, using the GUILDify and ToppGene software, in our previously published microarray data from the prefrontal cortex (PFC) and striatum of inflexible drinker mice. We then tested some of the prioritized genes that showed a tissue‐specific pattern in postmortem brain tissue (PFC and nucleus accumbens (NAc)) from humans with alcohol use disorder (AUD). In the mouse brain, we prioritized 44 genes in PFC and 26 in striatum, which showed opposite regulation patterns in PFC and striatum. The most prioritized of them (i.e., Plcb1 and Prkcb in PFC, and Dnm2 and Lrrk2 in striatum) were associated with synaptic neuroplasticity, a neuroadaptation associated with excessive ethanol drinking. The identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum. Lastly, the differential transcription of IRF4 and LRRK2 in PFC and nucleus accumbens in postmortem brains from AUD compared to control highlights their involvement in compulsive ethanol drinking in humans and mice., Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. To identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake we applied a guilt‐by‐association approach using the GUILDify and ToppGene software. Identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum.

Study Objectives Sleep deprivation and circadian disruptions impair brain function and cognitive performance, but few studies have examined the effect of sleep inconsistency. Here, we investigated how inconsistent sleep duration and sleep timing between weekends (WE) and weekdays (WD) correlated with changes in behavior and brain function during task and at rest in 56 (30 female) healthy human participants. Methods WE–WD differences in sleep duration and sleep midpoint were calculated using 1-week actigraphy data. All participants underwent 3 Tesla blood-oxygen-level-dependent functional Magnetic Resonance Imaging (fMRI) to measure brain activity during a visual attention task (VAT) and in resting-state condition. Results We found that WE–WD inconsistency of sleep duration and sleep midpoint were uncorrelated with each other (r = .08, p = .58) and influenced behavior and brain function differently. Our healthy participants showed relatively small WE–WD differences (WE–WD: 0.59 hours). Longer WE sleep duration (relative to WD sleep duration) was associated with better attentional performance (3-ball: β = .30, t = 2.35, p = .023; 4-ball: β = .30, t = 2.21, p = .032) and greater deactivation of the default mode network (DMN) during VAT (p < .05, cluster-corrected) and greater resting-state functional connectivity (RSFC) between anterior DMN and occipital cortex (p < .01, cluster-corrected). In contrast, later WE sleep timing (relative to WD sleep timing) (WE–WD: 1.11 hours) was associated with worse performance (4-ball: β = −.33, t = −2.42, p = .020) and with lower occipital activation during VAT and with lower RSFC within the DMN. Conclusions Our results document the importance of consistent sleep timing for brain function in particular of the DMN and provide evidence of the benefits of WE catch-up sleep in healthy adults.

Alcohol induces neuroinflammation but its role in cognitive impairment and impulsivity in alcohol use disorder (AUD) has been poorly investigated. We used proton magnetic resonance spectroscopy to measure brain glutamate (Glu) levels and diffusion-weighted imaging to measure functional anisotropy (FA) in the thalamus and ventral anterior cingulate cortex (vACC) in 15 recently detoxified patients with AUD and 14 matched controls. Compared to controls, AUD patients showed higher Glu levels (p = 0.04) and lower FA in the thalamus (p = 0.04) but not in the vACC. In AUD, thalamic Glu levels (r = 0.62, p = 0.019) and FA (r=-0.55, p = 0.034) were associated with severity of drinking (drinks/week). Compared to controls, AUD patients showed higher scores on Conners’ Adult ADHD Rating Scale for impulsivity (p = 0.03), which correlated with glutamate levels in the thalamus (r = 0.58, p = 0.03) and vACC (r = 0.55, p = 0.036). In a second cohort of AUD patients (n = 32), Glu in dorsal ACC (dACC) also correlated with Barrett Impulsiveness Scale total score (r = 0.43, p = 0.014). We interpret the elevated thalamic Glu levels and the parallel reduction in FA in AUD—which correlated with drinking severity—as possible evidence of neurotoxicity from neuroinflammation. The association of Glu with impulsivity suggests that neurotoxic effects of chronic alcohol exposure in the thalamus and dACC may contribute to impulsivity.

Methylphenidate (MPH) is a first line treatment for ADHD and is also misused as a purported cognitive enhancer, yet its effects on brain function are still poorly understood. Recent functional magnetic resonance imaging (fMRI) studies showed that MPH altered cortico-striatal resting functional connectivity (RFC). Here we investigated the effects of MPH in thalamic connectivity since the thalamus modulates striato-cortical signaling. We hypothesized that MPH would increase thalamic connectivity and metabolism, and that this response would be blunted in cannabis abusers. For this purpose, we measured RFC in seven thalamic nuclei using fMRI and brain glucose metabolism using positron emission tomography (PET) and (18)F-fluorodeoxyglucose (FDG) in sixteen healthy controls and thirteen participants with cannabis use disorder (CUD) twice after placebo and after MPH (0.5 mg/kg, iv). MPH significantly increased thalamo-cerebellar connectivity and cerebellar metabolism to the same extent in both groups. Group comparisons revealed that in CUD compared to controls, metabolism in nucleus accumbens was lower for the placebo and MPH measures, that MPH-induced increases in thalamic metabolism were blunted, and that enhanced negative connectivity between thalamus and accumbens in CUD was normalized by MPH (reducing negative connectivity). Our findings identify the thalamus as a target of MPH, which increased its metabolism and connectivity. The reduced metabolism in nucleus accumbens and the disrupted thalamo-accumbens connectivity (enhanced negative connectivity) in CUD is consistent with impaired reactivity of the brain reward’s circuit. MPH’s normalization of thalamo-accumbens connectivity (reduced negative connectivity) brings forth its potential therapeutic value in CUD, which merits investigation.

Central adenosine A1 receptor (A1R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A1R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A1R during the sleep–awake cycle. Although several human A1R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist A1R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial A1R agonist of sub-nanomolar affinity. [11C]22b showed suitable blood–brain barrier (BBB) permeability and test–retest reproducibility. Regional brain uptake of [11C]22b was consistent with known brain A1R...

Dopamine transporters (DAT) are implicated in the pathogenesis and treatment of attention deficit hyperactivity disorder (ADHD) and are upregulated by chronic treatment with methylphenidate, commonly prescribed for ADHD. Methylation of the DAT1 gene in brain and blood has been associated with DAT expression in rodents’ brains. Here we tested the association between methylation of the DAT1 promoter derived from blood and DAT availability in the striatum of unmedicated ADHD adult participants and in that of healthy age-matched controls (HC) using Positron Emission Tomography (PET) and [(11)C]cocaine. Results showed no between-group differences in DAT1 promoter methylation or striatal DAT availability. However, the degree of methylation in the promoter region of DAT1 correlated negatively with DAT availability in caudate in ADHD participants only. DAT availability in VS correlated with inattention scores in ADHD participants. We verified in a post-mortem cohort with ADHD diagnosis and without, that DAT1 promoter methylation in peripheral blood correlated positively with DAT1 promoter methylation extracted from substantia nigra (SN) in both groups. In the cohort without ADHD diagnosis, DAT1 gene expression in SN further correlated positively with DAT protein expression in caudate; however, the sample size of the cohort with ADHD was insufficient to investigate DAT1 and DAT expression levels. Overall, these findings suggest that peripheral DAT1 promoter methylation may be predictive of striatal DAT availability in adults with ADHD. Due to the small sample size, more work is needed to validate whether DAT1 methylation in blood predicts DAT1 methylation in SN in ADHD and controls.

Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and from the substantia nigra (SN) to the dorsal striatum are involved in addiction. However, relatively little is known about the implication of these circuits in Internet gaming disorder (IGD). This study examined the alteration of resting-state functional connectivity (RSFC) and diffusion tensor imaging (DTI) -based structural connectivity of VTA/SN circuits in 61 young male participants (33 IGD and 28 healthy controls). Correlation analysis was carried out to investigate the relationship between the neuroimaging findings and the behavioral Internet Addiction Test (IAT). Both the NAc and medial orbitofrontal cortex (mOFC) showed lower RSFC with VTA in IGD subjects compared with controls. Moreover, the RSFC strength of VTA-right NAc and VTA-left mOFC correlated negatively with IAT in IGD subjects. The IGD subjects also showed lower structural connectivity in bilateral VTA-NAc tracts compared with controls, but the connectivity did not correlate with IAT in IGD. We provide evidence that functional and structural connectivity of the VTA-NAc pathway, and functional connectivity of the VTA-mOFC pathway are implicated in IGD. Since these pathways are important for dopamine reward signals and salience attribution, the findings suggest involvement of the brain DA reward system in the neurobiology of IGD. The association of functional but not structural connectivity of VTA circuits with IAT suggests that while lower structural connectivity might underlie vulnerability for IGD, lower functional connectivity may modulate severity. These results strengthen the evidence that IGD shares similar neuropathology with other addictions.

Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [11C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol’s transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [11C]PBR28 binding. [11C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [11C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [11C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [11C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [11C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.

Significance There has been an emerging interest in sleep and its association with β-amyloid burden as a risk factor for Alzheimer’s disease. Despite the evidence that acute sleep deprivation elevates β-amyloid levels in mouse interstitial fluid and in human cerebrospinal fluid, not much is known about the impact of sleep deprivation on β-amyloid burden in the human brain. Using positron emission tomography, here we show that acute sleep deprivation impacts β-amyloid burden in brain regions that have been implicated in Alzheimer’s disease. Our observations provide preliminary evidence for the negative effect of sleep deprivation on β-amyloid burden in the human brain., The effects of acute sleep deprivation on β-amyloid (Aβ) clearance in the human brain have not been documented. Here we used PET and 18F-florbetaben to measure brain Aβ burden (ABB) in 20 healthy controls tested after a night of rested sleep (baseline) and after a night of sleep deprivation. We show that one night of sleep deprivation, relative to baseline, resulted in a significant increase in Aβ burden in the right hippocampus and thalamus. These increases were associated with mood worsening following sleep deprivation, but were not related to the genetic risk (APOE genotype) for Alzheimer’s disease. Additionally, baseline ABB in a range of subcortical regions and the precuneus was inversely associated with reported night sleep hours. APOE genotyping was also linked to subcortical ABB, suggesting that different Alzheimer’s disease risk factors might independently affect ABB in nearby brain regions. In summary, our findings show adverse effects of one-night sleep deprivation on brain ABB and expand on prior findings of higher Aβ accumulation with chronic less sleep.

Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. Here we evaluate cannabis use through the neurobiological model of addiction proposed by Koob and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated into three distinct stages, each of which perpetuates the cycle of addiction. Here we review previous research on the acute and long-term effects of cannabis use on the brain and behavior, and find that the three-stage framework of addiction applies to CUD in a manner similar to other drugs of abuse, albeit with some slight differences. These findings highlight the urgent need to conduct research that elucidates specific neurobiological changes associated with CUD in humans.

Sugar is highly palatable and rewarding, both in its taste and nutritive input. Excessive sugar consumption, however, may trigger neuroadaptations in the reward system that decouple eating behavior from caloric needs and leads to compulsive overeating. Excessive sugar intake is in turn associated with adverse health conditions, including obesity, metabolic syndrome, and inflammatory diseases. This review aims to use recent evidence to connect sugar's impact on the body, brain, and behavior to elucidate how and why sugar consumption has been implicated in addictive behaviors and poor health outcomes.

Background Alcohol's reinforcement is mediated by dopamine signaling in the ventral striatum, which is modulated by the dopamine transporter (DAT). We hypothesized that methylomic variation in the DAT gene (DAT1/SLC6A3) affects DAT expression, thus contributing to differences in brain reward circuitry in individuals with alcohol dependence (ALC). Methods Blood from 45 recently detoxified ALC and 45 healthy control (HC) individuals was used to assess DNA methylation across 5 functional regions of SLC6A3. Participants completed the monetary incentive delay task in a 3-Tesla magnetic resonance imaging (MRI) scanner. Employing regression models, we examined effects of SLC6A3 methylation on nucleus accumbens (NAc) blood-oxygen-level dependent (BOLD) responses during anticipation of high/low reward/loss. Results Results showed that decreased methylation of the promoter region of SLC6A3 predicted NAc activation during high loss anticipation (p = 0.028) and low loss anticipation (at trend-level; p = 0.057) in HC but not in individuals with ALC. Specifically, percentage of methylation at 2 CpG sites, located −1,001 and −993 base pairs from the transcription start site, accounted for significant variability in NAc activation in the HC group during high (ps ≤ 0.010) and low (ps ≤ 0.006) loss anticipation. There was no effect on reward anticipation. Furthermore, promoter methylation was positively associated with age, which replicates previous findings. Conclusions Our data suggest that methylation in the promoter region of SLC6A3 predicts NAc activation during the anticipation of monetary loss in HCs. However, this effect was not present in the ALC group, suggesting that epigenetic regulation of striatal DAT expression might be disrupted in ALC, which may contribute to previously reported differences in sensitivity to reward and punishment in this population. Alternatively, it is possible that a similar relationship in the ALC group remained undetected possibly due to methodological limitations inherent in functional MRI (e.g., poor spatial resolution, low signal-to-noise ratio) that generally restrict interpretations regarding mechanisms of epigenetic factors involved in group differences in BOLD responses. Future neuroimaging studies are needed to further elucidate the relationship between SLC6A3 methylation and NAc activation in ALC.

The use of Positron emission tomography (PET) to study the effects of acute and chronic alcohol on the human brain has enhanced our understanding of the mechanisms underlying alcohol's rewarding effects, the neuroadaptations from chronic exposure that contribute to tolerance and withdrawal, and the changes in fronto-striatal circuits that lead to loss of control and enhanced motivation to drink that characterize alcohol use disorders (AUD). These include studies showing that alcohol's reinforcing effects may result not only from its enhancement of dopaminergic, GABAergic and opioid signaling but also from its caloric properties. Studies in those suffering from an AUD have revealed significant alterations in dopamine (DA), GABA, cannabinoids, opioid and serotonin neurotransmission and in brain energy utilization (glucose and acetate metabolism) that are likely to contribute to compulsive alcohol taking, dysphoria/depression, and to alcohol-associated neurotoxicity. Studies have also evaluated the effects of abstinence on recovery of brain metabolism and neurotransmitter function and the potential value of some of these measures to predict clinical outcomes. Finally, PET studies have started to provide insights about the neuronal mechanisms by which certain genes contribute to the vulnerability to AUD. These findings have helped identify new strategies for prevention and treatment of AUD. This article is part of the Special Issue entitled "Alcoholism".

Cognitive bias modification (CBM) was first developed as an experimental tool to examine the causal role of cognitive biases, and later developed into complementary interventions in experimental psychopathology research. CBM involves the "re-training" of implicit biases by means of multiple trials of computerized tasks, and has been demonstrated to change anxious, depressive and drug-seeking behavior, including clinically relevant effects. Recently, the field has progressed by combining CBM with neuroimaging techniques, which provides insight into neural mechanisms underlying how CBM affects implicit biases in anxiety, depression, and addiction, and potentially other pathologies. This narrative literature review summarizes the state of the art of studies on the neural effects of CBM and provides directions for future research in the field. A total of 13 published studies were found and discussed: n=9 in anxiety, n=2 in depressive behavior, and n=2 in addiction.

Recent experiments have shown that when individuals with a substance use disorder are confronted with drug-related cues, they exhibit an automatically activated tendency to approach these cues (i.e., drug approach bias). The strength of the drug approach bias has been associated with clinically relevant measures, such as increased drug craving and relapse, and activations in brain reward areas. Retraining the approach bias by means of cognitive bias modification has been demonstrated to decrease relapse rates in patients with an alcohol use disorder and to reduce alcohol cue-evoked limbic activity. Here, we review empirical and theoretical literature on the drug approach bias and explore two distinct models of how the drug approach bias may be embodied. First, we consider the “biological meaning” hypothesis, which grounds the automatic approach bias in the natural meaning of the body. Second, we consider the “sensorimotor hypothesis,” which appeals to the specific sensorimotor loops involved in the instantiation of addictive behaviors as the basis of the automatic approach bias. In order to differentiate between the adequacies of these competing explanations, we present specific, predictions that each model should make.

Automatic processes related to addiction can be directly targeted in novel training paradigms. First studies have demonstrated that Cognitive Bias Modification (CBM) targeting approach biases can enhance treatment outcomes when added to regular treatment. However, the overall efficacy of CBM is debated. We argue that considering the modulating role of motivation and the mediating role of actual bias change are essential to drawing valid conclusions. Findings on mediating cognitive and neural mechanisms underlying clinical effects provide further sources of evidence on CBM. Taken together the literature supports the claim that cognitive bias change can improve clinical outcome, but that there are necessary conditions that must be met. Improved theoretical understanding of changing biases and new techniques such as neuromodulation may be needed to optimally apply CBM to help patients overcome addictive behavior.

The translocator protein (TSPO) transports cholesterol into mitochondria and is involved in steroidogenesis. The TSPO polymorphism rs6971 influences binding of cholesterol and other TSPO ligands including positron-emission tomography (PET) imaging radiotracers. Although it is recognized that alcohol increases plasma high-density lipoproteins (HDLs), its effects on total cholesterol and triglycerides along with its relationship to TSPO genotype have not been assessed. Here, we evaluated whether plasma cholesterol and triglycerides are disrupted in alcohol use disorder (AUD) and their association with rs6971 in 932 AUD participants (DSM IV or 5) and 546 controls. AUD participants compared with controls had significantly higher plasma levels of total cholesterol, HDL, and triglycerides, but not of low-density lipoprotein (LDL). In the AUD group only, TSPO rs6971 had a significant effect on plasma levels of cholesterol, LDL, and triglycerides (AA (n = 62) > AG (n = 319) > GG (n = 551)), but not on HDL levels. Additionally, we showed a significant effect of TSPO rs6971 on withdrawal scores (Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), with higher scores in AA (n = 50) compared with AG (n = 238) and GG (n = 428). CIWA scores in AUD participants correlated negatively with LDL and positively with HDL, but not with total cholesterol or triglycerides. These findings corroborate elevated plasma cholesterol and HDL levels in AUD and document significant increases in triglycerides. We also reveal for the first time an association in AUD participants between TSPO rs6971 genotype and plasma cholesterol, LDL, and triglyceride levels (not for HDL) and with withdrawal severity. Mediation analyses revealed that LDL (but not HDL) influenced the association between TSPO and alcohol withdrawal severity.

Opioid use in the United States has steadily risen since the 1990s, along with staggering increases in addiction and overdose fatalities. With this surge in prescription and illicit opioid abuse, it is paramount to understand the genetic risk factors and neuropsychological effects of opioid use disorder (OUD). Polymorphisms disrupting the opioid and dopamine systems have been associated with increased risk for developing substance use disorders. Molecular imaging studies have revealed how these polymorphisms impact the brain and contribute to cognitive and behavioral differences across individuals. Here, we review the current molecular imaging literature to assess how genetic variations in the opioid and dopamine systems affect function in the brain’s reward, cognition, and stress pathways, potentially resulting in vulnerabilities to OUD. Continued research of the functional consequences of genetic variants and corresponding alterations in neural mechanisms will inform prevention and treatment of OUD.

Excessive alcohol consumption is associated with neuroinflammation, which likely contributes to alcohol-related pathology. However, positron emission tomography (PET) studies using radioligands for the 18-kDa translocator protein (TSPO), which is considered a biomarker of neuroinflammation, reported decreased binding in alcohol use disorder (AUD) participants compared to controls. In contrast, autoradiographic findings in alcohol exposed rats reported increases in TSPO radioligand binding. To assess if these discrepancies reflected differences between in vitro and in vivo methodologies, we compared in vitro autoradiography (using [3 H]PBR28 and [3 H]PK11195) with in vivo PET (using [11 C]PBR28) in male, Wistar rats exposed to chronic alcohol-vapor (dependent n = 10) and in rats exposed to air-vapor (nondependent n = 10). PET scans were obtained with [11 C]PBR28, after which rats were euthanized and the brains were harvested for autoradiography with [3 H]PBR28 and [3 H]PK11195 (n = 7 dependent and n = 7 nondependent), and binding quantified in hippocampus, thalamus, and parietal cortex. Autoradiography revealed significantly higher binding in alcohol-dependent rats for both radioligands in thalamus and hippocampus (trend level for [3 H]PBR28) compared to nondependent rats, and these group differences were stronger for [3 H]PK11195 than [3 H]PBR28. In contrast, PET measures obtained in the same rats showed no group difference in [11 C]PBR28 binding. Our in vitro data are consistent with neuroinflammation associated with chronic alcohol exposure. Failure to observe similar increases in [11 C]PBR28 binding in vivo suggests the possibility that a mechanism mediated by chronic alcohol exposure interferes with [11 C]PBR28 binding to TSPO in vivo. These data question the sensitivity of PBR28 PET as a methodology to assess neuroinflammation in AUD.

BACKGROUND: Inflammatory pathways are known to be negatively affected in patients with alcohol use disorder (AUD). Cognitive bias modification (CBM), an emerging behavioral treatment that involves the ‘re-training’ of cognitive biases using computerized tasks, has been reported to reduce alcohol craving and relapse rates. The aim of this study was to compare peripheral concentrations of the proinflammatory biomarkers IL-18, IL-6, IL-1β, TNF-α and CRP in AUD patients versus controls and to identify whether CBM treatment affected these biomarkers in AUD patients. METHODS: This 3-week double-blind randomized controlled study tested 36 male abstinent AUD patients receiving CBM or placebo-training, who were also compared to 18 male healthy controls. The approach avoidance task (AAT) was used to test the AUD patients before and after training. CBM training took place over 6 sessions, using a joystick-based approach-avoidance task. Blood samples were collected after the pre- and post-AAT test sessions for the AUD groups, and during an outpatient appointment with the controls. RESULTS: AUD patients, versus controls, presented with significantly higher plasma levels of TNF-α (P < 0.0001) and CRP (P = 0.0031). No changes in the CBM versus placebo groups were noted in IL-18, TNF-α and CRP concentrations following pre-post change or within group pretest- posttest analysis. IL-6 and IL-1β levels fell under the lower detection limit, thus were not included in the final analyses. CONCLUSIONS: This study confirms that the inflammatory system is altered in AUD. This was the first study that investigated whether CBM training affected proinflammatory markers in AUD patients.

The response to drugs of abuse is affected by expectation, which is modulated in part by dopamine (DA), which encodes for a reward prediction error. Here we assessed the effect of expectation on methylphenidate (MP)-induced striatal DA changes in 23 participants with an active cocaine use disorder (CUD) and 23 healthy controls (HC) using [11C]raclopride and PET both after placebo (PL) and after MP (0.5 mg/kg, i.v.). Brain dopamine D2 and D3 receptor availability (D2R: non-displaceable binding potential (BPND)) was measured under four conditions in randomized order: (1) expecting PL/receiving PL, (2) expecting PL/receiving MP, (3) expecting MP/receiving PL, and (4) expecting MP/receiving MP. Expecting MP increased pulse rate compared to expecting PL. Receiving MP decreased D2R in striatum compared to PL, indicating MP-induced striatal DA release, and this effect was significantly blunted in CUD versus HC consistent with prior findings of decreased striatal dopamine responses both in active and detoxified CUD. There was a group × challenge × expectation effect in caudate and midbrain, with expectation of MP increasing MP-induced DA release in HC but not in CUD, and expectation of PL showing a trend to increase MP-induced DA release in CUD but not in HC. These results are consistent with the role of DA in reward prediction error in the human brain: decreasing DA signaling when rewards are less than expected (blunted DA increases to MP in CUD) and increasing them when greater than expected (for PL in CUD reflecting conditioned responses to injection). Our findings also document disruption of the expectation of drug effects in dopamine signaling in participants with CUD compared to non-addicted individuals.

The correspondence between cerebral glucose metabolism (indexing energy utilization) and synchronous fluctuations in blood oxygenation (indexing neuronal activity) is relevant for neuronal specialization and is affected by brain disorders. Here, we define novel measures of relative power (rPWR, extent of concurrent energy utilization and activity) and relative cost (rCST, extent that energy utilization exceeds activity), derived from FDG-PET and fMRI. We show that resting-state networks have distinct energetic signatures and that brain could be classified into major bilateral segments based on rPWR and rCST. While medial-visual and default-mode networks have the highest rPWR, frontoparietal networks have the highest rCST. rPWR and rCST estimates are generalizable to other indexes of energy supply and neuronal activity, and are sensitive to neurocognitive effects of acute and chronic alcohol exposure. rPWR and rCST are informative metrics for characterizing brain pathology and alternative energy use, and may provide new multimodal biomarkers of neuropsychiatric disorders., The brain primarily uses glucose to generate energy, but the relationship of neuronal activity to glucose utilization is not necessarily a simple linear one. Here, the authors introduce relative power (rPWR) and relative cost (rCST) as new metrics to quantify how brain activity relates to glucose consumption.

The extent to which cannabis is deleterious to the human brain is not well understood. Here, we test whether cannabis abusers (CA) have impaired frontal function and reactivity to dopaminergic signaling, which are fundamental to relapse in addiction. We measured brain glucose metabolism using PET and [(18)F]FDG both at baseline (placebo) and after challenge with methylphenidate (MP), a dopamine-enhancing drug, in 24 active CA (50% female) and 24 controls (HC; 50% female). Results show that (i) CA had lower baseline glucose metabolism than HC in frontal cortex including anterior cingulate, which was associated with negative emotionality. (ii) MP increased whole-brain glucose metabolism in HC but not in CA; and group by challenge effects were most profound in putamen, caudate, midbrain, thalamus, and cerebellum. In CA, MP-induced metabolic increases in putamen correlated negatively with addiction severity. (iii) There were significant gender effects, such that both the group differences at baseline in frontal metabolism and the attenuated regional brain metabolic responses to MP were observed in female CA but not in male CA. As for other drug addictions, reduced baseline frontal metabolism is likely to contribute to relapse in CA. The attenuated responses to MP in midbrain and striatum are consistent with decreased brain reactivity to dopamine stimulation and might contribute to addictive behaviors in CA. The gender differences suggest that females are more sensitive than males to the adverse effects of cannabis in brain.

Background: The maintenance of harmful alcohol use can be considered a reiterated decision in favour of alcohol in concrete drinking occasions. These decisions are often made despite an intention to quit or reduce alcohol consumption. We tested if a hyperactive reward system and/or an impaired cognitive control system contribute to such unfavourable decision-making. Methods: In this fMRI study, men with modest to harmful drinking behaviour, which was measured using the Alcohol Use Disorders Identification Test (AUDIT), repeatedly made decisions between alcoholic and nonalcoholic drinks. Based on prior individual ratings, decision pairs were created with an alcoholic decision option considered more desirable but less beneficial by the participant. By correlating AUDIT scores with brain activation during decision-making, we determined areas explicitly related to pro-alcohol decisions in men with greater drinking severity. Results: Thirty-eight men participated in our study. Behaviourally, we found a positive correlation between AUDIT scores and the number of decisions for desired alcoholic drinks compared with beneficial nonalcoholic drinks. The fMRI results show that AUDIT scores were positively associated with activation in areas associated with reward and motivation processing (i.e., ventral striatum, amygdala, medial prefrontal cortex) during decisions favouring a desired, nonbeneficial alcoholic drink. Conversely, we did not find hypoactivation in areas associated with self-control (dorsolateral prefrontal cortex). These effects were not present when participants chose a desired, nonbenefical, nonalcoholic drink. Limitations: The men participating in our study had to be abstinent and would potentially consume an alcoholic drink at the end of the experiment. Hence, we did not define manifest alcohol dependence as an inclusion criterion and instead focused on less severely affected individuals. Conclusion: Our results indicate that with growing drinking severity, decisions for alcoholic drinks are associated with increasing activity in reward-associated neural systems, rather than decreasing activity in self-control–associated systems.

Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [(11)C]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p≤0.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p

Adolescence is a period of rapid neural and behavioral development that often precipitates substance use, substance use disorders (SUDs), and other psychopathology. While externalizing disorders have been closely linked to SUD epidemiologically, the comorbidity of internalizing disorders and SUD is less well understood. Neuroimaging studies can be used to measure structural and functional developments in the brain that mediate the relationship between psychopathology and SUD in adolescence. Externalizing disorders and SUD are both associated with structural and functional changes in the basal ganglia and prefrontal cortex in adolescence. The neural mechanisms underlying internalizing disorders and SUD are less clear, but evidence points to involvement of the amygdala and prefrontal cortex. We also highlight independent contributions of SUD, which may vary in certain ways by the substances assessed. A deeper understanding of the neural basis of the relationship between psychopathology and SUD will allow for more informed interventions in this critical developmental stage.

Dysfunctions in frontostriatal circuits have been associated with craving and cognitive control in smokers. However, the relevance of white matter (WM) diffusion properties of the ventral and dorsal frontostriatal tracts for behaviors associated with smoking remains relatively unknown, especially in young adulthood, a critical time period for the development and maintenance of addiction. Here, diffusion tensor imaging (DTI) and probabilistic tractography were used to investigate the WM tracts of the ventral and dorsal frontostriatal circuits in two independent studies (Study1: 36 male smokers (21.3 ± 1.3 years) vs. 35 male nonsmokers (21.2 ± 1.3 years); Study2: 29 male smokers (21.4 ± 1.1 years) vs. 25 male nonsmokers (21.0 ± 1.4 years)). Subjective craving was measured by the Questionnaire on Smoking Urges (QSU) and cognitive control ability was assessed with the Stroop task. In both studies, smokers committed more response errors than nonsmokers during the incongruent condition of the Stroop task. Relative to controls, smokers showed lower fractional anisotropy (FA) and higher radial diffusivity in left medial orbitofrontal cortex-to-nucleus accumbens fiber tracts (ventral frontostriatal path) and also lower FA in right dorsolateral prefrontal cortex-to-caudate fiber tracts (dorsal frontostriatal path). The FA values of the right dorsal fibers were negatively correlated with incongruent response Stroop errors in smokers, whereas the mean diffusivity values of the left ventral fibers were positively correlated with craving in smokers. Thus, WM diffusion properties of the dorsal and ventral frontostriatal tracts were associated with cognitive control and craving, respectively, in young male tobacco smokers. These data highlight the importance of studying WM in relation to neuropsychological changes underlying smoking.

Background Alcohol use disorder (AUD) has been associated with impairments in cognitive and emotional function, including difficulty identifying emotional facial expressions. However, it is unclear whether these deficits are associated with alcohol consumption or related anxious and depressive symptoms. Methods We compared the recognition of emotional faces expressing happiness, surprise, sadness, fear, anger, and disgust in 19 AUD participants and 19 healthy volunteers using the Cambridge Neuropsychological Test Automated Battery Emotion Recognition Task. We analyzed group differences in response latency, accuracy, and misidentification patterns (as defined by the tendency to mislabel facial expressions as exhibiting specific emotions). To assess whether misidentification patterns were associated with drinking severity, we also examined associations with alcohol consumption over the past 90 days. Results There were no differences in response latency or accuracy between groups. However, there were group differences in misidentification patterns. While controls tended to misidentify emotional expressions as happy, those with AUD tended to misidentify expressions as angry or disgusted. In AUD participants, the degree to which individuals were biased toward anger or disgust was positively correlated with the number of drinks they consumed in the past 90 days but was not associated with depression or anxiety scores. Conclusions Our findings suggest that individuals with AUD have a bias toward misidentifying emotional facial expressions as hostile, which is not mediated by associated mood changes. This provides further evidence of disrupted social cognition in AUD.

Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P

Regular alcohol consumption affects cognitive performance and the development of dementia. So far, findings are contradicting, which might be explained in part by dose-related effects. For this narrative review, we undertook a literature search for surveys investigating the impact of alcohol consumption on cognitive performance and the development of dementia. The majority of studies observed a U-shaped relationship between regular alcohol consumption and cognitive function: frequent heavy consumption of alcohol alters brain functions and decreases cognitive performance; regular light and moderate consumption may have protective impact. In many studies, total abstainers show an inferior cognitive performance than people with moderate or light consumption. Nevertheless, policy implications are difficult to draw for at least 2 reasons: (1) the possible risks associated with alcohol consumption and (2) the potential confounders in the group of non-consumers and heavy consumers.

Drugs and food both exert a rewarding effect through the firing of dopamine neurons in the ventral tegmental area, resulting in the release of dopamine into the nucleus accumbens and effects on the mesolimbic pathway. Here, we review the neuroimaging literature to consider the validity of food addiction and the common neurobiological mechanisms that overlap in food and drug addiction. This review paper focuses on findings from Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI) and structural imaging studies, as well as evidence from neuroimaging studies of bariatric surgery and pharmacological interventions on obese individuals. We examine not only functional and structural changes in the mesolimbic pathways, but also in other frontal areas shown to be involved in drug addiction, including the prefrontal cortex, orbitofrontal cortex and anterior cingulate cortex, as well as changes in neurotransmitter systems beyond dopaminergic systems.

Background The control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight-loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC. Methods Thirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire. Results After NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039). Conclusions NB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711.

To assess how tobacco smoking status affects baseline dopamine D2/D3 (D2R) receptor availability and methylphenidate-induced dopamine (DA) release, we retrospectively analyzed D2R availability measures of 8 current smokers, 10 ex-smokers, and 18 nonsmokers who were scanned with positron emission tomography and [11C]raclopride, after administration of an injection of placebo or 0.5 mg/kg i.v. methylphenidate. There was a significant effect of smoking status on baseline striatal D2R availability; with current smokers showing lower striatal D2R availability compared with nonsmokers (caudate, putamen, and ventral striatum) and with ex-smokers (caudate and putamen). Baseline striatal D2R did not differ between nonsmokers and ex-smokers. The effect of smoking status on methylphenidate-induced DA release tended to be lower in smokers but the difference was not significant (p=0.08). For behavioral measures, current smokers showed significantly higher aggression scores compared with both nonsmokers and ex-smokers. These results suggest that with abstinence ex-smokers may recover from low striatal D2R availability and from increased behavioral aggression seen in active smokers. However, longitudinal studies are needed to assess this within abstaining smokers.

Contains fulltext : 169834.pdf (Publisher’s version ) (Open Access) Contains fulltext : 169834pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health. 10 p.

Alcohol-related cues can evoke explicit and implicit motivation to drink alcohol. Concerning the links between explicit and implicit motivation, there are mixed findings. Therefore, we investigated both concepts in 51 healthy 18- to 19-year-old males, who are less affected by neuropsychological deficits in decision-making that are attributed to previous alcohol exposure than older participants. In a randomized crossover design, adolescents were infused with either alcohol or placebo. Self-ratings of alcohol desire, thirst, well-being and alcohol effects comprised our explicit measures of motivation. To measure implicit motivation, we used money and drink stimuli in a Pavlovian conditioning (Pc) task and an Approach-Avoidance Task (AAT). Alcohol administration increased explicit motivation to drink alcohol, reduced Pc choices of alcoholic drink-conditioned stimuli, but had no effect on the AAT. This combination of results might be explained by differences between goal-directed and habitual behavior or a temporary reduction in rewarding outcome expectancies. Further, there was no association between our measures of motivation to drink alcohol, indicating that both self-reported motivation to drink and implicit approach tendencies may independently contribute to adolescents’ actual alcohol intake. Correlations between Alcohol Use Disorders Identification Test (AUDIT) scores and our measures of motivation to drink alcohol suggest that interventions should target high-risk adolescents after alcohol intake. Clinical trials: Project 4: Acute Effects of Alcohol on Learning and Habitization in Healthy Young Adults (LeAD_P4); NCT01858818; https://clinicaltrials.gov/ct2/show/NCT01858818

Negative urgency (NU) and positive urgency (PU) are implicated in several high-risk behaviors, such as eating disorders, substance use disorders, and nonsuicidal self-injury behavior. The current study aimed to explore the possible link between trait of urgency and brain activity at rest. We assessed the amplitude of low-frequency fluctuations (ALFF) of the resting-state functional magnetic resonance imaging (fMRI) signal in 85 healthy volunteers. Trait urgency measures were related to ALFF in the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, ventral and dorsal medial frontal cortex, anterior cingulate, and posterior cingulate cortex/precuneus. In addition, trait urgency measures showed significant correlations with the functional connectivity of the posterior cingulate cortex/precuneus seed with the thalamus and midbrain region. These findings suggest an association between intrinsic brain activity and impulsive behaviors in healthy humans.

The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in theAKT1gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism inAKT1[major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [11C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect ofAKT1genotype on DRD2 availability at baseline for the caudate (F(2,90)= 8.2,p= 0.001) and putamen (F(2,90)= 6.6,p= 0.002), but not the ventral striatum (p= 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect ofAKT1genotype on dopamine increases in the ventral striatum (F(2,53)= 5.3,p= 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p= 0.1) or putamen (p= 0.8) following methylphenidate injection. Our results provide evidence that theAKT1gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterizedAKT1VNTR merits investigation.SIGNIFICANCE STATEMENTTheAKT1gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [11C]raclopride, we identified in theAKT1gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of theAKT1gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTRAKT1variant in schizophrenia and drug-induced psychoses.

Neuroimaging techniques to measure the function and biochemistry of the human brain such as positron emission tomography (PET), proton magnetic resonance spectroscopy ((1)H MRS), and functional magnetic resonance imaging (fMRI), are powerful tools for assessing neurobiological mechanisms underlying the response to treatments in substance use disorders. Here, we review the neuroimaging literature on pharmacological and behavioral treatment in substance use disorder. We focus on neural effects of medications that reduce craving (e.g., naltrexone, bupropion hydrochloride, baclofen, methadone, varenicline) and that improve cognitive control (e.g., modafinil, N-acetylcysteine), of behavioral treatments for substance use disorders (e.g., cognitive bias modification training, virtual reality, motivational interventions) and neuromodulatory interventions such as neurofeedback and transcranial magnetic stimulation. A consistent finding for the effectiveness of therapeutic interventions identifies the improvement of executive control networks and the dampening of limbic activation, highlighting their values as targets for therapeutic interventions in substance use disorders.

Positron emission tomography (PET) has been shown to be an effective imaging technique to study neurometabolic and neurochemical processes involved in addiction. That is, PET has been used to research neurobiological differences in substance abusers versus healthy controls and the pharmacokinetics and pharmacodynamics of abused drugs. Over the past years, the research scope has shifted to investigating neurobiological effects of abstinence and treatment, and their predictive power for relapse and other clinical outcomes. This chapter provides an overview of PET methodology, recent human PET studies on drug addiction and their implications for clinical treatment.