Brain tract structure predicts relapse to stimulant drug use.

Diffusion tractography allows identification and measurement of structural tracts in the human brain previously associated with motivated behavior in animal models. Recent findings indicate that the structural properties of a tract connecting the midbrain to nucleus accumbens (NAcc) are associated with a diagnosis of stimulant use disorder (SUD), but not relapse. In this preregistered study, we used diffusion tractography in a sample of patients treated for SUD (n = 60) to determine whether qualities of tracts projecting from medial prefrontal, anterior insular, and amygdalar cortices to NAcc might instead foreshadow relapse. As predicted, reduced diffusion metrics of a tract projecting from the right anterior insula to the NAcc were associated with subsequent relapse to stimulant use, but not with previous diagnosis. These findings highlight a structural target for predicting relapse to stimulant use and further suggest that distinct connections to the NAcc may confer risk for relapse versus diagnosis.

INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC): An NIA and VA-sponsored initiative to increase veteran participation in aging and dementia research.

INTRODUCTION: Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers one avenue to advance the field and improve health outcomes. METHODS: To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC), provided funding for five sites and cross-site organizing structure. Diverse and innovative recruitment strategies were used. RESULTS: Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups. CONCLUSIONS: This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans.

Active Cigarette Smoking Is Associated With Increased Age-Related Decline on Measures of Visuospatial Learning and Memory and Executive Function in Alcohol Use Disorder.

AIMS: The goal of this study was to determine if active cigarette smoking in Veterans with alcohol use disorder (AUD) was associated with greater age-related neurocognitive decline. METHODS: Veterans with AUD, in residential treatment (n = 125; 47 ± 14 years of age, min = 24, max = 76, 29 ± 26 days of abstinence), completed measures of executive functions, learning and memory, processing speed and working memory. Actively smoking AUD (AsAUD, n = 47) were active daily cigarette smokers; former smoking AUD (FsAUD, n = 45) were predominately daily smokers prior to study but did not smoke at the time of study; non-smoking AUD (NsAUD, n = 33) never used cigarettes or smoked 'only a few times' during lifetime. RESULTS: AsAUD demonstrated greater age-related decline on measures of visuospatial learning and memory, and response inhibition/cognitive flexibility, primarily relative to NsAUD; there were no age-related differences between FsAUD and NsAUD on any measure. There were few significant mean differences between groups across the 15 neurocognitive measures. In AsAUD, higher scores on indices of smoking severity were associated with poorer performance on measures of auditory-verbal learning and memory, response inhibition, set-shifting and working memory. In FsAUD, longer smoking cessation duration was related to lower PTSD, anxiety and depressive symptomatology. CONCLUSIONS: Active smoking was associated with accelerated age-related decline on cognitive functions implicated in response to common evidence-based AUD interventions. Results suggest that smoking history contributes to the considerable heterogeneity observed in neurocognitive function in early AUD recovery, and reinforce the clinical movement to offer smoking cessation resources concurrent with treatment for AUD.

The association between an inflammatory diet and global cognitive function and incident dementia in older women: The Women's Health Initiative Memory Study.

INTRODUCTION: The Mediterranean and Dietary Approaches to Stop Hypertension diets have been associated with lower dementia risk. We evaluated dietary inflammatory potential in relation to mild cognitive impairment (MCI)/dementia risk. METHODS: Baseline food frequency questionnaires from n = 7085 women (aged 65-79 years) were used to calculate Dietary Inflammatory Index (DII) scores that were categorized into four groups. Cognitive function was evaluated annually, and MCI and all-cause dementia cases were adjudicated centrally. Mixed effect models evaluated cognitive decline on over time; Cox models evaluated the risk of MCI or dementia across DII groups. RESULTS: Over an average of 9.7 years, there were 1081 incident cases of cognitive impairment. Higher DII scores were associated with greater cognitive decline and earlier onset of cognitive impairment. Adjusted hazard ratios (HRs) comparing lower (anti-inflammatory; group 1 referent) DII scores to the higher scores were group 2-HR: 1.01 (0.86-1.20); group 3-HR: 0.99 (0.82-1.18); and group 4-HR: 1.27 (1.06-1.52). CONCLUSIONS: Diets with the highest pro-inflammatory potential were associated with higher risk of MCI or dementia.

Gender effects in alcohol dependence: an fMRI pilot study examining affective processing.

BACKGROUND: Alcohol dependence (AD) has global effects on brain structure and function, including frontolimbic regions regulating affective processing. Preliminary evidence suggests alcohol blunts limbic response to negative affective stimuli and increases activation to positive affective stimuli. Subtle gender differences are also evident during affective processing. METHODS: Fourteen abstinent AD individuals (8 F, 6 M) and 14 healthy controls (9 F, 5 M), ages 23 to 60, were included in this facial affective processing functional magnetic resonance imaging pilot study. Whole-brain linear regression analyses were performed, and follow-up analyses examined whether AD status significantly predicted depressive symptoms and/or coping. RESULTS: Fearful Condition-The AD group demonstrated reduced activation in the right medial frontal gyrus, compared with controls. Gender moderated the effects of AD in bilateral inferior frontal gyri. Happy Condition-AD individuals had increased activation in the right thalamus. Gender moderated the effects of AD in the left caudate, right middle frontal gyrus, left paracentral lobule, and right lingual gyrus. Interactive AD and gender effects for fearful and happy faces were such that AD men activated more than control men, but AD women activated less than control women. Enhanced coping was associated with greater activation in right medial frontal gyrus during fearful condition in AD individuals. CONCLUSIONS: Abnormal affective processing in AD may be a marker of alcoholism risk or a consequence of chronic alcoholism. Subtle gender differences were observed, and gender moderated the effects of AD on neural substrates of affective processing. AD individuals with enhanced coping had brain activation patterns more similar to controls. Results help elucidate the effects of alcohol, gender, and their interaction on affective processing.

Craving is associated with amygdala volumes in adolescent marijuana users during abstinence.

BACKGROUND: Amygdala volume abnormalities have been reported in relation to craving in substance-dependent adults, but it remains unclear if these effects are seen in adolescent marijuana (MJ) users, particularly following abstinence. OBJECTIVES: The aim of this study was to examine the relationship between amygdala volume and craving during 28 days of abstinence in adolescent MJ users. METHODS: MJ-using adolescents (n = 22) aged 16-19 were recruited as part of a larger study on brain function in teen drug users. Craving measures were collected twice per week throughout a 28-day abstinence period. High-resolution anatomical magnetic resonance imaging data were collected at the end of the 28 days of confirmed abstinence. Left and right amygdala volumes were traced by hand (ICC > 0.86). Composite scores for self-reported craving and withdrawal symptoms throughout the 28-day abstinence period were calculated to provide four composite measures of total craving, mood, sleep, and somatic complaints. RESULTS: Results revealed that greater craving during abstinence was significantly associated with smaller left and right amygdala volumes, after controlling for age and gender. Other measures of withdrawal, including mood, somatic complaints and sleep problems, were not related to amygdala morphometry. CONCLUSION: These results are consistent with previous findings in adult alcohol- and cocaine-dependent individuals, who demonstrated a relationship between reduced amygdala volumes and increased craving. Future studies are needed to determine if these brain-behavior relationships are attributable to MJ use or predate the onset of substance use.

Context matters: Exploring the adaptive nature of self-regulation skills in predicting abstinence among veterans with alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is highly prevalent among veterans in the United States. Self-regulation skills (e.g., coping and emotion regulation) are important biopsychosocial factors for preventing relapse. However, how variation in self-regulation skills supports abstinence based on contextual demands is understudied in veterans with AUD. METHODS: In a prospective longitudinal design, treatment-seeking veterans (n = 120; 29 females) aged 23-91 with AUD completed the Alcohol Abstinence Self-Efficacy Scale to assess temptation to drink across several high-risk situations (i.e., negative affect, social/positive emotions, physical concerns, and craving/urges) as well as the Brief-COPE and Emotion Regulation Questionnaire to assess self-regulation skills. Abstinence status was assessed at 6 months. T-tests were used to identify self-regulation skills that differed between abstinent and non-abstinent individuals. Multivariate regression with model selection was performed using all possible interactions between each high-risk situation and the self-regulation skills that significantly differed between groups. RESULTS: Overall, 33.3% of participants (n = 40; nine females) were abstinent at 6 months. Abstinent individuals reported significantly higher use of suppression (p = 0.015), acceptance (p = 0.005), and planning (p = 0.045). Multivariate regression identified significant interactions between (1) planning and physical concerns (p = 0.010) and (2) acceptance, suppression, and craving/urges (p = 0.007). Greater planning predicted abstinence in participants with higher temptation to drink due to physical concerns (e.g., pain). For individuals with lower temptation to drink due to cravings/urges, simultaneous higher suppression and acceptance increased the likelihood of abstinence. Conversely, for participants with higher cravings, greater acceptance with lower suppression was linked to a higher probability of abstinence. CONCLUSIONS: Results suggest that the adaptiveness of self-regulation skills in predicting AUD recovery is dependent on contextual demands and highlight the need for culturally sensitive treatments. Collectively, these findings indicate that further research on coping and regulatory flexibility may be an important avenue for tailoring AUD treatment for veterans.

Transdiagnostic Mood, Anxiety, and Trauma Symptom Factors in Alcohol Use Disorder: Neural Correlates Across 3 Brain Networks.

BACKGROUND: Alcohol use disorder (AUD) is associated with high rates of trauma, mood, and anxiety disorders. Across these diagnoses, individual symptoms substantially overlap, highlighting the need for a transdiagnostic approach. Furthermore, there is limited research on how transdiagnostic psychopathology impacts the neural correlates of AUD. Thus, we aimed to identify symptom factors spanning diagnoses and examine how they relate to the neurocircuitry of addiction. METHODS: Eighty-six veterans with AUD completed self-report measures and reward, incentive salience, and cognitive control functional magnetic resonance imaging tasks. Factor analysis was performed on self-reported trauma, depression, anxiety, and stress symptoms to obtain transdiagnostic symptom compositions. Neural correlates of a priori-defined regions of interest in the 3 networks were assessed. Independent sample t tests were used to compare the same nodes by DSM-5 diagnosis. RESULTS: Four symptom factors were identified: Trauma distress, Negative affect, Hyperarousal, and Somatic anxiety. Trauma distress score was associated with increased cognitive control activity during response inhibition (dorsal anterior cingulate cortex). Negative affect was related to lower activation in reward regions (right caudate) but higher activation in cognitive control regions during response inhibition (left dorsolateral prefrontal cortex). Hyperarousal was related to lower reward activity during monetary reward anticipation (left caudate, right caudate). Somatic anxiety was not significantly associated with brain activation. No difference in neural activity was found by posttraumatic stress disorder, major depressive disorder, or generalized anxiety disorder diagnosis. CONCLUSIONS: These hypothesis-generating findings offer transdiagnostic symptom factors that are differentially associated with neural function and could guide us toward a brain-based classification of psychiatric dysfunction in AUD. Results warrant further investigation of transdiagnostic approaches in addiction.

A pilot, randomized clinical trial: Left dorsolateral prefrontal cortex intermittent theta burst stimulation improves treatment outcomes in veterans with alcohol use disorder.

BACKGROUND: Transcranial magnetic stimulation (TMS) offers a promising treatment avenue to modulate brain function in alcohol use disorder (AUD). To the best of our knowledge, this pilot study is the first randomized, double-blind, sham-controlled trial to deliver intermittent theta burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) among US veterans with AUD. We hypothesized that 20 sessions of real TMS are tolerable and feasible. As a secondary line of inquiry, we hypothesized that, relative to sham TMS, individuals receiving real TMS would experience greater reductions in 6-month relapse rates, anhedonia, and alcohol cue-reactivity. METHODS: Veterans (n = 17, one woman) were enrolled in a double-blind, sham-controlled trial (2-3 sessions/day; 7-10 days; 600 pulses/session; 20 sessions). Pre- and posttreatment assessments included responses to self-report questionnaires and functional magnetic resonance imaging measures of alcohol cue-reactivity. Alcohol consumption was assessed for 6 months. Linear mixed-effects models were constructed to predict posttreatment craving, mood, and cue-reactivity. RESULTS: Individuals who received active iTBS (n = 8) were less likely to relapse within 3 months after treatment than the sham-treated group (n = 9) (OR = 12.0). Greater reductions in anhedonia were observed following active iTBS (Cohen's d = -0.59), relative to sham (d = -0.25). Alcohol cue-reactivity was reduced following active iTBS and increased following sham within the left insula (d = -0.19 vs. 0.51), left thalamus (d = -0.28 vs. 0.77), right insula (d = 0.18 vs. 0.52), and right thalamus (d = -0.06 vs. 0.62). CONCLUSIONS: Relative to sham, we demonstrate that 20 sessions of real left DLPFC iTBS reduced the likelihood of relapse for at least 3 months. The potential utility of this approach is underscored by observed decreases in anhedonia and alcohol cue-reactivity-strong predictors of relapse among veterans. These initial data offer a valuable set of effect sizes to inform future clinical trials in this patient population.

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

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

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

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

Alcohol attenuates activation in the bilateral anterior insula during an emotional processing task: a pilot study.

AIMS: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. METHODS: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. RESULTS: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 µl; corrected P < 0.05). CONCLUSION: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication.

Impact of Adolescent Alcohol and Drug Use on Neuropsychological Functioning in Young Adulthood: 10-Year Outcomes.

BACKGROUND: Alcohol and other substance use disorders (AUD/SUD) are common among youth and often continue into adulthood; therefore, the neurocognitive effects of substance use are of great concern. Because neuromaturation continues into young adulthood, youth with AUD/SUD may be at risk for lasting cognitive decrements. This study prospectively examines neuropsychological functioning over 10 years as a function of AUD/SUD history and outcomes. METHODS: The 51 participants consisted of 18 youth with persisting AUD/SUD, 19 youth with remitted AUD/SUD, and 14 community youth with no AUD/SUD history followed over 10 years (ages 16 to 27 on average) with neuropsychological testing and substance use interviews on 8 occasions. Neuropsychological performance from baseline to 10-year follow-up was compared between the three groups. RESULTS: Despite scoring higher than controls at intake, both AUD/SUD groups showed a relative decline in visuospatial construction at 10-year follow-up (p=.001). Regressions showed that alcohol use (ß=-.33, p < .01) and drug withdrawal symptoms (ß=-.31, p<.05) over follow-up were predictive of year 10 visuospatial function. Alcohol use also predicted verbal learning and memory (ß=-.28, p<.05), while stimulant use predicted visual learning and memory function (ß=-.33, p=.01). More recent substance use was associated with poorer executive function (ß=.28, p<.05). DISCUSSION: These findings confirm prior studies suggesting that heavy, chronic alcohol and other substance use persisting from adolescence to young adulthood may produce cognitive disadvantages, primarily in visuospatial and memory abilities. Youth who chronically consume heavy quantities of alcohol and/or experience drug withdrawal symptoms may be particularly at risk for cognitive deterioration by young adulthood.

Dimensions of Craving Interact with COMT Genotype to Predict Relapse in Individuals with Alcohol Use Disorder Six Months after Treatment.

(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted.

Acute ethanol effects on brain activation in low- and high-level responders to alcohol.

BACKGROUND: A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk of alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption. METHODS: A total of 30 matched high- and low-LR pairs (N = 60 healthy young adults) were recruited from the University of California, San Diego, and administered a structured diagnostic interview and laboratory alcohol challenge followed by two functional magnetic resonance imaging (fMRI) sessions under placebo and alcohol conditions, in randomized order. Task performance and blood oxygen level-dependent response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task were examined across 120 fMRI sessions. RESULTS: Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p < 0.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity. CONCLUSIONS: Alcohol had differential effects on brain activation for low- and high-LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR and identify brain regions that may be associated with the low LR response.

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

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

Heart Rate, Brain Imaging Biomarkers and Cognitive Impairment in Older (≥63 years) Women.

Evidence on the relations between heart rate, brain morphology, and cognition is limited. We examined the associations of resting heart rate (RHR), visit-to-visit heart rate variation (VVHRV), brain volumes and cognitive impairment. The study sample consisted of postmenopausal women enrolled in the Women's Health Initiative Memory Study and its ancillary MRI sub-studies (WHIMS-MRI 1 and WHIMS-MRI 2) without a history of cardiovascular disease, including 493 with one and 299 women with 2 brain magnetic resonance imaging (MRI) scans. HR readings were acquired annually starting from baseline visit (1996-1998). RHR was calculated as the mean and VVHRV as standard deviation of all available HR readings. Brain MRI scans were performed between 2005 and 2006 (WHIMS-MRI 1), and approximately 5 years later (WHIMS-MRI 2). Cognitive impairment was defined as incident mild cognitive impairment or probable dementia until December 30, 2017. An elevated RHR was associated with greater brain lesion volumes at the first MRI exam (7.86 cm3 [6.48, 9.24] vs 4.78 cm3 [3.39, 6.17], p-value <0.0001) and with significant increases in lesion volumes between brain MRI exams (6.20 cm3 [4.81, 7.59] vs 4.28 cm3 [2.84, 5.73], p-value = 0.0168). Larger ischemic lesion volumes were associated with a higher risk for cognitive impairment (Hazard Ratio [95% confidence interval], 2.02 [1.18, 3.47], p-value = 0.0109). Neither RHR nor VVHRV were related to cognitive impairment. In sensitivity analyses, we additionally included women with a history of cardiovascular disease to the study sample. The main results were consistent to those without a history of cardiovascular disease. In conclusion, these findings show an association between elevated RHR and ischemic brain lesions, probably due to underlying subclinical disease processes.

Brain activation to cannabis- and alcohol-related words in alcohol use disorder.

Cannabis abuse commonly co-occurs with alcohol use disorder (AUD). With increased acceptance and accessibility to cannabis in the US, it is imperative to understand the psychological and neural mechanisms of concurrent alcohol and cannabis use. We hypothesized that neural alcohol-cue conditioning may extent to other drug-related stimuli, such as cannabis, and underwrite the loss of control over reward-driven behavior. Task-activated fMRI examined the neural correlates of alcohol- and cannabis-related word cues in 21 abstinent AUD and 18 control subjects. Relative to controls, AUD showed behavioral attentional biases and frontal hypoactivation to both alcohol- and cannabis-related words. This cue-elicited prefrontal hypoactivation was related to higher lifetime alcohol consumption (pcorrected < 0.02) and modulated by past cannabis use histories (p ≦ 0.001). In particular, frontal hypoactivation to both alcohol and cannabis cues was pronounced in AUD without prior cannabis exposure. Overall, frontal control mechanisms in abstinent AUD were not sufficiently engaged to override automatic alcohol and cannabis-related intrusions, enhancing the risk for relapse and potentially for alcohol and cannabis co-use with the increased social acceptance and accessibility in the US.

Association of Neural Responses to Drug Cues With Subsequent Relapse to Stimulant Use.

Importance: Although chronic relapse is a characteristic of addiction to stimulants, conventional measures (eg, clinical, demographic, and self-report) do not robustly identify which individuals are most vulnerable to relapse. Objectives: To test whether drug cues are associated with increased mesolimbic neural activity in patients undergoing treatment for stimulant use disorder and whether this activity is associated with risk for subsequent relapse. Design, Setting, and Participants: This prospective cohort study of 76 participants included a control group for baseline group comparisons. Veteran patients (n = 36) with stimulant use disorders were recruited from a 28-day residential treatment program at the Veterans Affairs Palo Alto Health Care System. Healthy controls (n = 40) were recruited from the surrounding community. Baseline data were collected between September 21, 2015, and January 26, 2018, from patients and healthy controls using functional magnetic resonance imaging during a performance of a reward cue task. Patients' stimulant use was subsequently assessed after treatment discharge (at approximately 1, 3, and 6 months) to assess relapse outcomes. Main Outcomes and Measures: Primary measures included neural responses to drug and food cues in estimated mesolimbic volumes of interest, including the medial prefrontal cortex, nucleus accumbens (NAcc), and ventral tegmental area. The primary outcome variable was relapse (defined as any stimulant use), assessed both dichotomously (3 months after discharge) and continuously (days to relapse). Brain activity measures were contrasted between groups to validate neural measures of drug cue reactivity, which were then used to estimate relapse outcomes of patients. Results: Relative to controls (n = 40; 16 women and 24 men; mean [SD] age, 32.0 [11.6] years), patients (n = 36; 2 women and 34 men; mean [SD] age, 43.4 [13.3] years) showed increased mesolimbic activity in response to drug cues (medial prefrontal cortex, t74 = 2.90, P = .005, Cohen d = 0.66; NAcc, t74 = 2.39, P = .02, Cohen d = 0.54; and ventral tegmental area, t74 = 4.04, P < .001, Cohen d = 0.92). In patients, increased drug cue response in the NAcc (but not other volumes of interest) was associated with time to relapse months later (Cox proportional hazards regression hazard ratio, 2.30; 95% CI, 1.40-3.79). After controlling for age, NAcc response to drug cues classified relapsers (12 patients; 1 woman and 11 men; mean [SD] age, 49.3 [14.1] years) and abstainers (21 patients; 1 woman and 20 men; mean [SD] age, 39.3 [12.3] years) at 3 months with 75.8% classification accuracy. Model comparison further indicated that NAcc responses to drug cues were associated with relapse above and beyond estimations of relapse according to conventional measures. Conclusions and Relevance: Responses in the NAcc to stimulant cues appear to be associated with relapse in humans. Identification of neural markers may eventually help target interventions to the most vulnerable individuals.

Spatial working memory performance and fMRI activation interaction in abstinent adolescent marijuana users.

Previous studies have suggested neural disruption and reorganization in adult marijuana users. However, it remains unclear whether these effects persist in adolescents after 28 days of abstinence and, if they do, what Performance x Brain Response interactions occur. Adolescent marijuana users (n=17) and controls (n=17) aged 16-18 years were recruited from local schools. Functional magnetic resonance imaging data were collected after 28 days' monitored abstinence as participants performed a spatial working memory task. Marijuana users show Performance x Brain Response interactions in the bilateral temporal lobes, left anterior cingulate, left parahippocampal gyrus, and right thalamus (clusters >/=1358 microl; p<.05), although groups do not differ on behavioral measures of task performance. Marijuana users show differences in brain response to a spatial working memory task despite adequate performance, suggesting a different approach to the task via altered neural pathways.