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The anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC), and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modelling revealed an AIC-to-dACC directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early-relapsers (

The use of psychoactive substances, including cannabis, has accompanied the development of civilization (1). (In the context of this paper, “psychoactive substances” refers specifically to substanc...

Importance The American Medical Association has acknowledged the public health threat posed by racism in medicine. While clinicians in psychiatry have echoed the sentiment, the research community has largely been silent. Current understanding of the biological domains that underlie psychiatric disorders was historically established by studying White populations, often leaving widely used treatments ineffective for Asian, Black, Hispanic, Indigenous, and other racial and ethnic minority individuals. This article addresses how undersampling of racial and ethnic minority individuals has led to overgeneralized physiological findings, the implications for development of psychiatric treatments, and steps to improve service to racially diverse communities. Observations Three primary observations regarding differences associated with race and ethnicity have been addressed in the existing psychiatric research: misdiagnosis, medication nonadherence, and treatment efficacy and expression of adverse effects. While cultural factors have been discussed as potential factors associated with these differences, a lack of understanding of physiologic systems may be foundational to each of these issues. Recent evidence points to race differences in psychophysiological measures, likely attributed to factors including the lived experience of racism as opposed to inherent biological differences. This mounting evidence supports a reassessment of existing work to examine potential divergent patterns within racial and ethnic groups. The following strategies may improve understanding of the influence of racism on physiology, allowing clinicians to better address psychiatric symptoms and improve existing treatment approaches. Thus, psychiatric researchers need to (1) understand the historic and current terminology forraceandethnicityand use appropriate terms and categories as defined by sociologists, population health experts, and databases while respecting individuals’ right to self-identify, (2) refine research questions, and (3) reexamine research data to determine whether patterns observed in largely White populations can extend to other groups. To appropriately implement these steps, researchers must accept the discomfort that accompanies growth, invite scientists from diverse backgrounds to participate, and use resources to increase diversity in recruitment of study participants. This will require a commitment from funding agencies to provide adequate support to recruit and investigate large, diverse samples. Conclusions and Relevance To create more suitable medical treatments and improve the quality of care received by those with psychiatric conditions, further discussion is needed surrounding the physiologic toll that racism has had on multiple generations of racial and ethnic minority groups and how that may alter responsivity to biobehavioral interventions. To better inform psychiatric research, the resources provided must be expanded, basic physiologic studies should be replicated with more diverse samples and adequate analyses, and psychiatry scientists must reconsider approaches to clinical research.

It is reasonable to consider family discord after treatment as a potential target for a next-step intervention, since family discord is often comorbid with substance use disorders.This study evaluated family discord after completing an initial course of treatment as a predictor of substance use and retention in the community treatment program during follow-up.Patients were from two multisite randomized clinical trials implemented through the Clinical Trials Network of the National Institute on Drug Abuse. There were 315 participants from Study 1 (12-week posttreatment follow-up) and 295 participants from Study 2 (8-week posttreatment follow-up). Negative binomial and logistic regression were used to estimate days of substance use and odds of retention in the community treatment program at follow-up, respectively, from family discord status.Family discord was significantly associated with more days of substance use during the posttreatment follow-up period than those without family discord in both Study 1 (9.12 vs. 2.89 days, p =.0001) and Study 2 (5.58 vs. 2.83 days, p =.0062). Family discord was significantly associated with lower retention in the community treatment program at follow-up than those not reporting family discord in Study 1 (47.6% vs. 60.6%; p =.03), but not in Study 2 (55.3% vs. 64.9%; p =.11).Family discord after an initial course of treatment might be a clinically relevant predictor of substance use. There is mixed support for a conclusion that family discord is associated with lower retention in the community treatment program at follow-up.

Cocaine addiction is characterized by notoriously high relapse rates following treatment. Recent efforts to address poor treatment outcomes have turned to potential neural markers of relapse risk. Accordingly, the present study examined resting state functional connectivity (rsFC) within and between three large-scale cortical networks: the default mode network (DMN), salience network (SN) and executive control network (ECN). All three have been implicated in relapse-related phenomena including craving, withdrawal and executive control deficits. Forty-five cocaine-dependent individuals and 22 healthy controls completed 6-min resting fMRI scans, The Wisconsin Card Sorting Task, Continuous Performance Test and Cocaine Craving Questionnaire. Cocaine-dependent individuals completed all measures in the final week of a residential treatment episode. Ten control and 9 abstinent cocaine-dependent individuals returned for 3-6 month follow-up scan visits. A group-level independent component analysis was employed to generate ECN, DMN and SN components. For individuals abstinent up to day 30 post-treatment (n = 21), we found enhanced pre-discharge rsFC between the left ECN and both the right ECN and SN as well as between the right ECN and left ECN. Left ECN rsFC effects remained elevated 3-6 months later among abstinent cocaine-dependent individuals. Relapse was related to fewer years of education and more years smoking but no other demographic, clinical, treatment and neurocognitive characteristics. Findings suggest that interhemispheric ECN and ECN-SN connectivity strength may protect against relapse to cocaine use following treatment. These patterns of enhanced interhemispheric network connectivity may reflect a greater capacity to engage executive control processes when faced with opportunities to use cocaine post-treatment.

Substance use disorders are characterized by a profound intersubject (phenotypic) variability in the expression of addictive symptomatology and propensity to relapse following treatment. However, laboratory investigations have primarily focused on common neural substrates in addiction, and have not yet been able to identify mechanisms that can account for the multifaceted phenotypic behaviors reported in literature. To investigate this knowledge gap theoretically, here we simulated phenotypic variations in addiction symptomology and responses to putative treatments, using both a neural model based on cortico-striatal circuit dynamics, and an algorithmic model of reinforcement learning. These simulations rely on the widely accepted assumption that both the ventral, model-based, goal-directed system and the dorsal, model-free, habitual system are vulnerable to extra-physiologic dopamine reinforcements triggered by drug consumption. We found that endophenotypic differences in the balance between the two circuit or control systems resulted in an inverted U-shape in optimal choice behavior. Specifically, greater unbalance led to a higher likelihood of developing addiction and more severe drug-taking behaviors. Furthermore, endophenotypes with opposite asymmetrical biases among cortico-striatal circuits expressed similar addiction behaviors, but responded differently to simulated treatments, suggesting personalized treatment development could rely on endophenotypic rather than phenotypic differentiations. We propose our simulated results, confirmed across neural and algorithmic levels of analysis, inform on a fundamental and, to date, neglected quantitative method to characterize clinical heterogeneity in addiction.

Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity.To demonstrate a novel, systematic approach to subgroup analyses that avoids these pitfalls.A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n = 127) or placebo (n = 128), and treated with nicotine patch. Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence.Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders (adjusted odds ratio [AOR] 0.27; 95% confidence interval [CI] 0.10-0.74), and (2) more severe ADHD symptoms (baseline score36; AOR 2.64; 95% CI 1.17-5.96). A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence--age 18 to 29 years (AOR 0.23; 95% CI 0.07-0.76).The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.

Stress response biologic systems are altered in alcohol-dependent individuals. Early life stress (ELS) is associated with a heightened risk of alcohol dependence, presumably because of stress-induced neuroplastic changes. This study was designed to assess the contribution of ELS to a stress-induced neural response in alcohol-dependent participants. Fifteen alcohol-dependent men abstinent for 3-5 weeks and 15 age- and race-matched healthy controls were studied. Anticipatory anxiety was induced by a conditioned stimulus paired with an uncertain physically painful unconditioned stressor. Neural response was assessed with functional magnetic resonance imaging. ELS was assessed with the Childhood Adversity Interview. There was a significant interaction between ELS and group on blood-oxygen-level-dependent (BOLD) amplitude during anticipatory anxiety in the right amygdala and bilateral orbitofrontal cortex, posterior putamen and insula. Higher ELS scores were associated with decreased BOLD amplitude during anticipatory anxiety in alcohol-dependent, but not control, participants. These findings suggest that ELS interacts with alcohol dependence to induce a muted cortico-striatal response to high threat stimuli. Allostatic changes due to both ELS and excessive alcohol use may jointly induce persistent changes in the neural response to acute stressors.

Allostatic load from both environmental stressors and persistent glucocorticoid secretion has been associated with disease severity in alcohol dependence. Heightened relapse risk and/or drinking severity, in particular, may be a reaction to alcohol- and withdrawal-induced changes in physiological stress response systems coupled with ongoing life stress, although their shared contributions upon drinking severity have not been assessed. To investigate the combined contribution of hypothalamic-pituitary-adrenal (HPA) reactivity and environmental stressors (e.g., ongoing life stress) to relapse severity in alcohol-dependent men following treatment, plasma adrenocorticotropin (ACTH) and cortisol were obtained in 4-6 weeks abstinent alcohol-dependent men (n=41) following a psychosocial stressor [the Trier Social Stress Test (TSST)] and two pharmacological provocations [ovine corticotropin releasing factor (oCRH) and cosyntropin]. Following treatment discharge, drinking outcomes (primary outcome: drinks per drinking day (DDD); secondary outcomes: total drinks and drinking days) were assessed weekly and ongoing life stress was assessed biweekly for 24 weeks following treatment discharge. Generalized estimating equation models of drinking severity were fit with basal and stimulated ACTH and cortisol concentrations as predictors and ongoing life stress as the moderator. Greater levels of life stress were independently associated with greater drinking intensity (DDD and total drinks) but not frequency (days drinking). Higher basal cortisol:ACTH or provoked cortisol:ACTH ratios were strongly associated with greater post-treatment DDD in individuals who experienced higher levels of ongoing stress. In conclusion, ongoing life stress is associated with post-treatment drinking intensity in alcohol dependent men; stress also strengthens the relationship between adrenocortical sensitivity and post-treatment drinking. Physiological measures of allostatic load and environmental stressors conjointly increase relapse intensity.

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.

Disrupted functioning of biological stress-response systems is thought to underlie stress-induced drinking. Peripherally, both basal reactivity (Sinha et al., 2011) and provoked pituitary–adrenal reactivity to pharmacologic and behavioral stressors (Adinoff et al., 2005b,c) are altered in alcohol-dependent individuals. Centrally, multiple neurotransmitters and neuropeptides are mutually involved in stress reactivity and drinking behaviors, including serotonin, norepinephrine, opioids, corticotropin-releasing factor, neuropeptide Y, and GABA (Brady and Sinha, 2005). Persistent and excessive alcohol use, repeated withdrawal episodes, and recurrent environmental stressors (Heilig et al., 2010), overlaid upon genetic predisposing factors and early life trauma (Schepis et al., 2011), all appear relevant to the induction of stress sensitivity and resultant alcohol intake. Clinically, disruptions in peripheral stress-response systems have been associated with poorer treatment retention (Daughters et al., 2009) and increased relapse rates (Adinoff et al., 2005a; Sinha et al., 2011). The experience and response to stress requires an organism to simultaneously assess, regulate, predict, and respond to anxiety- and/or fear-inducing stimuli. The dorsal–caudal regions of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) appear integral to the appraisal and expression of emotions generated during stress, whereas the ventral–rostral regions regulate these emotions (Etkin et al., 2011). The expression of fear, including conditioned fear, induces amygdalar activation (Sehlmeyer et al., 2009), and both the amygdala and striatum track fearpredictive stimuli (Schiller et al., 2008). Both hippocampal reactivity and amygdalar reactivity are highly correlated with the hypothalamic–pituitary–adrenal (HPA) stress response (Pruessner et al., 2010). Connectivity within the default mode network (DMN), which surveys and assesses internal and external environments (Gusnard et al., 2001), shows decreased coupling in post-traumatic stress disorder (PTSD), a disorder notable for abnormal stress responses (Sripada et al., 2012). Disruptions in these various brain regions have been identified in alcohol-dependent individuals, although whether these alterations are related to stress-response disruptions is uncertain. To further clarify and isolate the neurobiological alterations triggering stress-related drinking, the central processes occurring during stress require real-time assessment. A number of paradigms have been developed to evoke stress while simultaneously monitoring the central nervous system activity in humans. These paradigms include computerized mental arithmetic tasks coupled with negative social comments (Pruessner et al., 2010), verbal serial subtraction with increasing time speed demands (Wang et al., 2005), negative pictures from the International Affective Pictures System (Sarinopoulos et al., 2010), and script-guided imagery (Sinha and Li, 2007). These paradigms utilize a block design, in which stressors are administered for several minutes and compared to a nonstressed condition administered for the same amount of time. Despite the relevance of stress to alcohol use, only Seo and colleagues (2013) have assessed stress reactivity using functional magnetic resonance imaging (fMRI) in alcohol-dependent patients. In that study, stress-induced script-guided imagery paradigm evoked a hyperactive response during neutral-relaxing trials in the patients relative to healthy controls. In order to further clarify the central processes involved in stress reactivity in alcohol dependence, we assessed the blood oxygen level-dependent (BOLD) response with fMRI during anticipatory anxiety in a group of abstinent, alcohol-dependent men and age- and race-matched healthy controls. In an attempt to remove, at least in part, the personalized interpretation and demands of a particular stressor, anxiety was induced by a conditioned stimulus (CS) paired with a painful unconditioned stimulus (US). This approach, adapted from Ploghaus and colleagues (1999), has the advantage of (i) eliciting anxiety in association with an otherwise neutral stimulus, thus disassociating the stimulus from any intrinsic, personalized interpretation; (ii) eliciting anxiety in response to the threat of a universal noxious stimulus (pain); (iii) using a US that can be adjusted for individual differences in pain response; (iv) using a mixed event-related/block design, providing the relatively rapid alteration of a high-anxiety and a low-anxiety CS; and (v) providing real-time, participant anxiety ratings during the presentation of each CS. We have previously reported that this paradigm induces marked striatal–limbic–cortical activation in healthy controls during the high-threat CS relative to a low-threat CS (Yang et al., 2012). In addition, the amplitude of BOLD signal change generally paralleled the subjective rating of anticipatory anxiety (Yang et al., 2012). To avoid the fluctuation in stress-response systems during early withdrawal (Adinoff et al., 1991), alcohol-dependent subjects were studied during 3 to 5 weeks of abstinence.

Frontal systems dysfunction is present in stimulant-dependent patients. However, it is unclear whether this dysfunction is a pre-morbid risk factor or stimulant-induced, is severe enough to be clinically relevant, and if it is relevant to treatment response. These questions were addressed using the Frontal Systems Behavior Scale (FrSBe), a reliable and valid self-report assessment of three neurobehavioral domains associated with frontal systems functioning (Apathy, Disinhibition, and Executive Dysfunction, summed for a Total), that assesses both pre- and post-morbid functioning, and has a specific cutoff for defining clinically significant abnormalities.Six sites evaluating 12-step facilitation for stimulant abusers obtained the FrSBe from 180 methamphetamine- and/or cocaine-dependent participants. Dichotomous treatment response measures included self-reported stimulant use, stimulant urine drug screens, and treatment completion.A substantial percentage of participants retrospectively reported clinically significant neurobehavioral abnormalities prior to lifetime stimulant abuse initiation (e.g., 67.5% on FrSBe-Total) with a significant increase in the proportion reporting such abnormalities for current functioning (86% on FrSBe-Total; p0.0001). Treatment response was significantly worse for participants with, relative to those without, clinically significant Disinhibition as measured by treatment non-completion (31.6% vs. 15.6%, OR=2.51) and self-reported stimulant use during treatment (40.5% vs. 16.7%, OR=3.40).These findings suggest that frontal systems dysfunction is present prior to stimulant-abuse onset and worsens with stimulant use. Disinhibition may be a prime target for intervention in stimulant-dependent individuals.

Objective Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. Methods Participants 55–85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation between the LLD and comparison groups were determined with FMRIB Software Library. Results Despite comparable SST performance measures, LLD participants demonstrated greater blood oxygen level dependent activation relative to the comparison group in predominantly left-lateralized frontostriatal-limbic circuitry that included the bilateral superior frontal cortices and left-hemispheric orbitofrontal gyri, insular cortex, cingulate cortex, caudate, and putamen. Conversely, the healthy comparison group did not exhibit any areas of greater activation than the LLD group. Conclusion Unmedicated participants with LLD activate additional areas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.

While chronic cocaine use is associated with abnormalities in both brain structure and function within and interactions between regions, previous studies have been limited to interrogating structure and function independently, and the detected neural differences have not been applied to independent samples to assess the clinical relevance of results. We investigated consequences of structural differences on resting-state functional connectivity in cocaine addiction and tested whether resting-state functional connectivity of the identified circuits predict relapse in an independent cohort. Subjects included 64 non-treatment-seeking cocaine users (NTSCUs) and 67 healthy control subjects and an independent treatment-completed cohort (n = 45) of cocaine-dependent individuals scanned at the end of a 30-day residential treatment programme. Differences in cortical thickness and related resting-state functional connectivity between NTSCUs and healthy control subjects were identified. Survival analysis, applying cortical thickness of the identified regions, resting-state functional connectivity of the identified circuits and clinical characteristics to the treatment cohort, was used to predict relapse. Lower cortical thickness in bilateral insula and higher thickness in bilateral temporal pole were found in NTSCUs versus healthy control subjects. Whole brain resting-state functional connectivity analyses with these four different anatomical regions as seeds revealed eight weaker circuits including within the salience network (insula seeds) and between temporal pole and elements of the default mode network in NTSCUs. Applying these circuits and clinical characteristics to the independent cocaine-dependent treatment cohort, functional connectivity between right temporal pole and medial prefrontal cortex, combined with years of education, predicted relapse status at 150 days with 88% accuracy. Deficits in the salience network suggest an impaired ability to process physiologically salient events, while abnormalities in a temporal pole-medial prefrontal cortex circuit might speak to the social-emotional functional alterations in cocaine addiction. The involvement of the temporal pole-medial prefrontal cortex circuit in a model highly predictive of relapse highlights the importance of social-emotional functions in cocaine dependence, and provides a potential underlying neural target for therapeutic interventions, and for identifying those at high risk of relapse.

Compulsive tanning despite awareness of ultraviolet radiation (UVR) carcinogenicity may represent an "addictive" behavior. Many addictive disorders are associated with alterations in dopamine (D2/D3) receptor binding and dopamine reactivity in the brain's reward pathway. To determine if compulsive tanners exhibited neurobiologic responses similar to other addictive disorders, this study assessed basal striatal D2/D3 binding and UVR-induced striatal dopamine efflux in ten addicted and ten infrequent tanners. In a double-blind crossover trial, UVR or sham UVR was administered in separate sessions during brain imaging with single photon emission computerized tomography (SPECT). Basal D2/D3 receptor density and UVR-induced dopamine efflux in the caudate were assessed using (123)I-iodobenzamide ((123)I-IBZM) binding potential non-displaceable (BPnd). Basal BPnd did not significantly differ between addicted and infrequent tanners. Whereas neither UVR nor sham UVR induced significant changes in bilateral caudate BPnd in either group, post-hoc analyses revealed left caudate BPnd significantly decreased (reflecting increased dopamine efflux) in the addicted tanners - but not the infrequent tanners - during the UVR session only. Bilateral ∆BPnd correlated with tanning severity only in the addicted tanners. These preliminary findings are consistent with a stronger neural rewarding response to UVR in addicted tanners, supporting a cutaneous-neural connection driving excessive sunbed use.

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P

Complex systems, such as the brain, involve non-linear neuronal interactions. These in turn translate into self-organization and emergence of distinct pat- terns of activity. And although a loss of integrated neuronal activity or increased entropy during anesthesia has been described in the literature, it has not yet been well characterized. These in turn could serve as the basis to better understand pathophysiological states like depression. Task free resting 64 channel EEG recording (Neuroscan, Compumedics) was collected before and during anesthesia with Etomidate (0.2 mg/kg) or Propo- fol (2 mg/kg) from patients scheduled to undergo Electro-Convulsive Therapy (ECT). An 81 second window was chosen for each of the awake and anesthe- sia states. The Symmetric Sensor Difference Series (SSDS) was generated by subtracting sensor pair outputs (e.g. the left frontal F3 sensor from the right frontal F4 sensor) thus resulting in a difference wave from frontal, central, parietal and temporal leads. The following parameters were extracted: power spectral scaling indices (alpha); topological, metric, and fuzzy entropies and Lyapunov exponents. To date, we acquired 38 recordings from 19 patients with major depressive disorder (9 females, age 1/4 47 ± 9 years). Frontal power spectral scaling index (alpha) showed significant differences awake and under anesthesia state (1.79 ± 0.7, 1.97 ± 0.9, p

The orbitofrontal cortex (OFC) is crucial for the inhibition of extraneous stimuli, evaluation of aversive information and emotional regulation-all behaviors impaired in cocaine addiction. Previous studies suggest that cocaine-addicted subjects have decreased basal activity in the OFC. In this study, we examined regional cerebral blood flow (rCBF) during a saline infusion in two independent populations of abstinent cocaine- (and mostly nicotine-) addicted (n=33 and 26) and healthy control (n=35 and 20) men and women. Isolated rCBF decreases (P

Neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) have been implicated in both the stress response and alcohol addiction. However, few studies have assessed the NPY and BDNF response to stress in alcohol-dependent participants and the concurrent measure of NPY and BDNF has not been reported in human participants.The purpose of this study was to concurrently assess serum NPY and BDNF, as well as adrenocorticotropin (ACTH) and cortisol, in control and race- and aged-matched abstinent alcohol-dependent participants in response to a stress-inducing public-speaking task.Basal and post-stress serum values of NPY and BDNF, as well as ACTH and cortisol, were assessed in 14 abstinent alcohol-dependent and ten healthy control male participants.Basal measures were stable over short periods of time and stress induced a significant increase in both NPY (p = 0.002) and BDNF (p = 0.006) as well as ACTH (p 0.001) and cortisol (p 0.007). Alcohol-dependent and control groups did not significantly differ on any basal or stress-induced measure. Basal and delta responses of NPY and BDNF were not significantly correlated, and delta peak responses of NPY and BDNF did not correlate with one another or with their respective ACTH and cortisol responses.These findings reveal that both serum NPY and BDNF are responsive to behavioral stressors, although their regulatory mechanisms appear to differ from one another and those of the hypothalamic-pituitary-adrenal axis. Differences in basal and stress-induced responses of NPY and BDNF were not supported between control and abstinent alcohol-dependent subjects.

Frequent and excessive tanning persists despite a growing understanding of its associated morbidity and mortality, suggesting that ultraviolet radiation may impart rewarding effects beyond the assumed cosmetic benefits. To empirically measure putative centrally rewarding properties of ultraviolet radiation (UVR), we assessed the effects of a commercially available tanning bed upon regional cerebral blood flow (rCBF), a measure of brain activity, using single-photon emission computed tomography (SPECT). Seven frequent salon bed tanners were placed under a UVA/UVB tanning light during two sessions; one session with UVR and the other with filtered UVR (sham UVR). Session order was randomized and subjects were blinded to study order. During the UVR session, relative to sham UVR session, subjects demonstrated a relative increase in rCBF of the dorsal striatum, anterior insula and medial orbitofrontal cortex, brain regions associated with the experience of reward. These changes were accompanied by a decrease in the subjective desire to tan. These findings suggest that UVR may have centrally rewarding properties that encourage excessive tanning.

Objective As the initiation and acceleration of alcohol use commonly occurs during adolescence, the etiological basis for this phenomenon is of critical importance. Using the diathesis-stress model as a framework, this review will evaluate the emerging evidence implicating the limbic-hypothalamic-pituitary-adrenal (LHPA) axis in the development of alcohol use disorder (AUD).

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p

Background: The long-term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone. Methods: Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 agematched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 lg ⁄ kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes. Results: Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone.

The purpose of this review is to summarize the neurobiological factors involved in the etiology of adolescent addiction and present evidence implicating various mechanisms in its development. Adolescents are at heightened risk for experimentation with substances, and early experimentation is associated with higher rates of SUD in adulthood. Both normative (e.g., immature frontal-limbic connections, immature frontal lobe development) and non-normative (e.g., lowered serotonergic function, abnormal hypothalamic-pituitary-adrenal axis function) neurobiological developmental factors can predispose adolescents to a heightened risk for SUD. In addition, a normative imbalance in the adolescent neurobiological motivational system may be caused by the relative underdevelopment of suppressive mechanisms when compared to stimulatory systems. These neurobiological liabilities may correspond to neurobehavioral impairments in decision-making, affiliation with deviant peers and externalizing behavior; these and other cognitive and behavioral traits converge with neurobiological factors to increase SUD risk. The progression to SUD acts as an amplifying feedback loop, where the development of SUD results in reciprocal impairments in neurobehavioral and neurobiological processes. A clearer understanding of adolescent neurobiology is a necessary step in the development of prevention and treatment interventions for adolescent SUD.

Background: It is not clear whether naltrexone is effective in reducing alcohol consumption among patients with clinically significant mood symptoms and whether naltrexone favorably interacts with antidepressant medications when they are co-prescribed. Methods: This study reflects a secondary analysis of the first 13 weeks of VA CSP #425, a study that evaluated the efficacy of naltrexone 50 mg/d in 627 alcohol dependent military veterans receiving Twelve Step Facilitation therapy at 20 VA Medical Centers. This study included patients with comorbid mood and anxiety disorders, providing they did not need treatment for these comorbid conditions at the time of study entry. Sixty patients developed sufficiently severe mood symptoms while on study medication that they required antidepressant treatment. This analysis evaluated whether the efficacy of naltrexone and placebo was influenced by the prescription of antidepressant medications to some study patients for their mood and anxiety symptoms. Results: In patients randomized to placebo (n = 209), prescription of antidepressants was associated with a significantly higher percentage of drinking days (lsmean = 24.4, se = 4.85 vs. lsmean = 12.9, se = 1.69, p = 0.02). Although the group of patients receiving naltrexone (n = 418) was larger than the group assigned to placebo, there were no significant differences in drinking-related outcomes in the groups who did or did not receive antidepressants (lsmean = 11.5, se = 1.18 vs. lsmean = 12.9, se = 1.69, p = 0.47). Among the group of patients receiving antidepressants, naltrexone prescription was associated with a reduction in the percent drinking days compared to placebo [lsmean = 10.1, se = 3.47 vs. lsmean = 24.4, se = 4.85, F(1,556) = 5.84, p = 0.02]. Conclusions: Further investigation will be needed to determine whether naltrexone is efficacious among depressed alcohol dependent patients and whether naltrexone and antidepressant medications show interactive efficacy for treating alcohol dependence.

Background The current study evaluated the bottoming out hypothesis by determining the extent to which composite measures of motivation to change are associated with baseline characteristics among patients seeking treatment for substance dependence. Methods Two hundred treatment-seeking substance-dependent veterans were assessed. Motivation to change was assessed using the composite measures of Readiness to Change (RTC) and Committed Action (CA) derived from the University of Rhode Island Change Assessment. Baseline characteristics included recent life stressors, addiction severity, depression, anxiety and hostility. Linear regression was used to determine the association between baseline characteristics and the composite measures of motivation to change while controlling for age, gender and race. Results Linear regression indicated that RTC and CA were associated with different baseline characteristics. RTC was associated with anger expression (B = −.28; 95% CI = −.6, −.01) and recent life events (B = 1.1; 95% CI = .01, 2.2). CA was associated with alcohol problems (B = −.33; 95% CI = −.62, −.05) and state anxiety (B = −.13; 95% CI = −.21, −.04). Conclusions Our findings suggest that motivation to change was negatively, not positively, associated with greater emotional distress and problem severity. With the exception of recent life events, these findings are contrary to the notion of hitting bottom. Composite measures of RTC and CA also appear to represent different types of motivation to change.

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use.A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale.In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed.Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.

Emotion regulation is the process that controls and modulates internal affective states and emotion-related physiological responses. Healthy and adaptive emotion regulation requires intact functioning of the central nervous system’s physiologic, experiential, and cognitive reactions to given situations. Difficulties in emotion regulation contribute to the development of substance use disorders (SUDs), are more pronounced in individuals with SUD compared to controls, worsen SUD severity, and increase relapse risk.

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the medication groups, but not the placebo group. Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol-dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.

Disruption of Hypothalamic-Pituitary-Adrenal (HPA) axis activity is recognized as a pathophysiological alteration during the intoxicating, withdrawal, and abstinence phases of alcoholism. A number of studies have documented the increase in cortisol secretion during intoxication (Adinoff et al., 2003; Mendelson et al., 1971; Stokes, 1973) and withdrawal (Adinoff et al., 1991; Iranmanesh et al., 1989; Keedwell et al., 2001; Mendelson et al., 1971), occasionally resulting in a hypercortisolemic state mimicking the clinical and biochemical characteristics of Cushing syndrome (Jeffcoate, 1993; Veldman and Meinders, 1996). Concurrent with and after the resolution of this hypercortisolemic state, however, several investigators have observed an attenuation of the axis to pharmacological and psychological stressors. Although the increase in glucocorticoid secretion associated with intoxication and withdrawal resolves within a few days after the cessation of alcohol ingestion (Adinoff et al., 1991), suppression of HPA axis functioning seems to persist for at least the first several weeks of abstinence. Attenuated responsiveness of the HPA axis has been revealed at each level of the axis in both drinking and abstinent alcohol-dependent patients. Central stimuli, including alcohol (Merry and Marks, 1972), operative trauma (Margraf et al., 1967), cold pressor (Errico et al., 1993), insulin-induced hypoglycemia (Chalmers et al., 1978; Costa et al., 1996), nicotine (Coiro and Vescovi, 1999), public speaking (Lovallo et al., 2000), m-chlorophenylpiperazine (Krystal et al., 1996), and hyperthermia (Vescovi et al., 1997) produce a blunted corticotropin and/or cortisol response in alcohol-dependent patients compared with healthy controls. Alcohol-dependent patients also have a muted corticotropin response to naloxone (Inder et al., 1995), an opioid antagonist that blocks the tonic inhibition of endogenous opioids on the hypothalamus. Pituitary stimulation by ovine or human CRH induces a blunted corticotropin and/or cortisol response for at least 3 weeks after drinking cessation (Adinoff et al., 1990; Costa et al., 1996; Ehrenreich et al., 1997). Finally, direct stimulation of the adrenal cortex by exogenously administered adrenocorticotropinα1–24 (cosyntropin) results in a markedly decreased cortisol response in alcohol-dependent individuals (Knudsen et al., 1987; Margraf et al., 1967; Wand and Dobs, 1991). This impressive and consistent literature, however, offers only suggestive clues as to which specific levels of the axis are critical for the hyporesponsive state. Because of both positive and negative organizational loops, interactions between the various components of the HPA axis confound the interpretation of any specific stressor on a given hormonal unit. In addition, increases or decreases in endogenous hormone secretion could alter organ sensitivity to a given stimulus. Finally, many of the studies referenced above have significant confounders that make interpretation of their findings problematic. For example, chronic medical and/or psychiatric conditions (i.e., post–traumatic stress disorder [PTSD], depression) may interfere with HPA axis functioning. To clarify the specific alterations in HPA axis functioning that occur after chronic and excessive use of alcohol, we designed a series of studies to explore basal pulsatile characteristics of corticotropin and cortisol, adrenocortical sensitivity to exogenous stimulation in the presence or absence of endogenous stimulation, and pituitary glucocorticoid sensitivity in 1-month-abstinent alcohol-dependent patients. Secretory characteristics of corticotropin and cortisol were determined by obtaining frequent sampling of plasma corticotropin and cortisol from 2000 to 0800 hr. Adrenocortical sensitivity to an exogenous stimulus was assessed by administering cosyntropin, a corticotropin analog (corticotropinα1–24). To avoid a maximal glucocorticoid response, or ceiling effect, that could obscure potential group differences, we assessed adrenocortical sensitivity with a very low dose (0.01 μg/kg) of cosyntropin. This is approximately 0.3% of the clinically recommended dose (250 μg) used in the cosyntropin stimulation test in the diagnosis of endocrine disorders. In a second test, we isolated the adrenal cortex from its major endogenous input (pituitary corticotropin) by first administering high-dose dexamethasone before the cosyntropin administration. We also determined hypothalamic-pituitary glucocorticoid sensitivity by measuring the corticotropin response to dexamethasone administration. Finally, to assess potential disruptions in adrenosteroid synthesis, we assessed glucocorticoid, minerocorticoid, and androgen hormones (in addition to cortisol) after cosyntropin administration. It was hypothesized that cortisol secretion in response to cosyntropin would be significantly attenuated in alcohol-dependent participants both with and without dexamethasone pretreatment.

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These “hard-wired” changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

Background: Motivation for treatment is generally considered a powerful predictor of treatment seeking and success in patients with alcohol and drug dependence disorders. Objective measures have seldom been used, however, to assess how motivation is altered during treatment, or the impact of depression/anxiety on motivation. Methods: We assessed motivation using the Treatment Motivation Questionnaire (TMQ) in 78 male alcohol- and drug-dependent veterans immediately preceding and following an intensive, 2-week residential substance abuse program. The TMQ assesses four domains of motivation: internal motivation, external motivation, interpersonal help-seeking, and nonconfidence in treatment. Results: Following treatment, only external motivation changed (decreased), whereas the other dimensions of motivation retained the high levels observed pretreatment. Depression (as measured by the Beck Depression Inventory, BDI) was highly correlated with three of the four domains of motivation, while anxiety (as measured by the Spielberger State-Trait Anxiety Inventory, STAI) was highly correlated solely with internal motivation. Conclusions: Our findings suggest that depression and anxiety may differentially effect motivation and that external motivation may be quite transient; treatment implications of these findings are discussed. The usefulness of the TMQ in a residential population was also explored.

Although the alliance between therapist and client in individual therapy is generally considered a significant predictor of treatment success, little is known about how alliance in group therapy affects outcome. We assessed the relationship between group alliance, as measured by the Group Therapy Alliance Scale (GTAS), and group cohesion, as measured by the cohesion scale of the Group Atmosphere Scale (GAS-C) and therapy outcome. Clients were 49 men attending group therapy 3 times per week in a 21-day intensive, residential substance abuse treatment program. Outcome was determined at 30 days after discharge. Although GTAS and GAS-C scores were significantly correlated (r = .66), only group alliance was predictive of client ratings of reduced psychological distress. Neither group alliance nor cohesion was significantly associated with decreased consequences of drug and alcohol use or depressive symptomology.

Impulsivity may underlie the poor treatment retention and high relapse rates observed in cocaine-dependent persons. However, observed differences in measures of impulsivity between cocaine-dependent and healthy control participants often do not reach clinical significance, suggesting that the clinical relevance of these differences may be limited.To examine which measures of impulsivity (i.e. self-report impulsivity, self-report personality, neurocognitive testing) best distinguish cocaine-dependent and healthy control participants (i.e. showing differences at least 1.5 standard deviations [SD] from controls). Optimal measures were considered to demonstrate sufficient classification accuracy.Sixty-five recently abstinent cocaine-dependent and 25 healthy control participants were assessed using select neurocognitive tests and self-report questionnaires including the NEO Personality Inventory-Revised (NEO-PI-R), Temperament and Character Inventory (TCI), Barratt Impulsiveness Scale (BIS-11a), and the Frontal Systems Behavior Scale (FrSBe).When corrected for years of education and gender, neurocognitive measures did not demonstrate clinically significant differences between cocaine-dependent and control participants. The personality measures TCI Purposefulness and Congruent Second Nature and NEO-PI-R Impulsiveness, and the self-rating measures FrSBe Disinhibition and BIS-11 Motor Impulsivity and Total successfully identified clinically meaningful elevations in impulsivity within cocaine-dependent participants (1.5 SDs from controls). Furthermore, these measures achieved 84-93% accuracy in discriminating cocaine-dependent from control participants.Clinically significant neurocognitive impairment in cocaine-dependent participants was not observed in this sample. As the BIS-11 or FrSBe are brief to administer, accurate, and have been shown to predict treatment retention and relapse, these measures appear to be optimal, relative to the personality measures, for examining trait impulsivity in cocaine dependence.

Background Cocaine-induced neuroplastic changes may result in a heightened propensity for relapse. Using regional cerebral blood flow (rCBF) as a marker of basal neuronal activity, this study assessed alterations in rCBF and related resting state functional connectivity (rsFC) to prospectively predict relapse in patients following treatment for cocaine use disorder (CUD). Methods Pseudocontinuous arterial spin labeling functional magnetic resonance imaging and resting blood oxygen level-dependent functional magnetic resonance imaging data were acquired in the same scan session in abstinent participants with CUD before residential treatment discharge and in 20 healthy matched control subjects. Substance use was assessed twice weekly following discharge. Relapsed participants were defined as those who used stimulants within 30 days following treatment discharge ( n = 22); early remission participants ( n = 18) did not. Results Voxel-wise, whole-brain analysis revealed enhanced rCBF only in the left posterior hippocampus (pHp) in the relapsed group compared with the early remission and control groups. Using this pHp as a seed, increased rsFC strength with the posterior cingulate cortex (PCC)/precuneus was seen in the relapsed versus early remission subgroups. Together, both increased pHp rCBF and strengthened pHp-PCC rsFC predicted relapse with 75% accuracy at 30, 60, and 90 days following treatment. Conclusions In CUD participants at risk of early relapse, increased pHp basal activity and pHp-PCC circuit strength may reflect the propensity for heightened reactivity to cocaine cues and persistent cocaine-related ruminations. Mechanisms to mute hyperactivated brain regions and delink dysregulated neural circuits may prove useful to prevent relapse in patients with CUD.

Alcohol dependence is common in bipolar disorder (BPD) and associated with treatment nonadherence, violence, and hospitalization. Quetiapine is a standard treatment for BPD. We previously reported improvement in depressive symptoms, but not alcohol use, with quetiapine in BPD and alcohol dependence. However, mean alcohol use was low and a larger effect size on alcohol-related measures was observed in those with higher levels of alcohol consumption. In this study, efficacy of quetiapine in patients with BPD and alcohol dependence was examined in patients with higher mean baseline alcohol use than in the prior study.Ninety outpatients with bipolar I or II disorders, depressed or mixed mood state, and current alcohol dependence were randomized to 12 weeks of sustained release quetiapine (to 600 mg/d) add-on therapy or placebo. Drinking was quantified using the Timeline Follow Back method. Additional assessment tools included the Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, Penn Alcohol Craving Scale, liver enzymes, and side effects. Alcohol use and mood were analyzed using a declining-effects random-regression model.Baseline and demographic characteristics in the 2 groups were similar. No significant between-group differences were observed on the primary outcome measure of drinks per day or other alcohol-related or mood measures (p0.05). Overall side effect burden, glucose, and cholesterol were similar in the 2 groups. However, a significant weight increase was observed with quetiapine at week 6 (+2.9 lbs [SE 1.4] quetiapine vs. -2.0 lbs [SE 1.4], p = 0.03), but not at week 12. Scores on the Barnes Akathisia Scale increased significantly more (p = 0.04) with quetiapine (+0.40 [SE 0.3]) than placebo (-0.52 [SE 0.3]) at week 6 but not week 12. Retention (survival) in the study was similar in the groups.Findings suggest that quetiapine does not reduce alcohol consumption in patients with BPD and alcohol dependence.

Dysregulated striatal functioning coupled with executive control deficits arising from abnormal frontal cortical function are considered key mechanisms in the development and maintenance of cocaine addiction. The same features are thought to underlie high trait impulsivity observed in cocaine-addicted populations.Employing resting state functional connectivity, the current study sought to identify cortico-striatal circuit alterations in cocaine addiction and examine the degree to which circuit connectivity contributes to relapse risk and impulsivity among cocaine-addicted individuals.Whole-brain resting-state functional magnetic resonance imaging connectivity was assessed in 45 cocaine-addicted individuals relative to 22 healthy controls using seed volumes in the left and right caudate, putamen and nucleus accumbens. Cocaine-addicted individuals completed scans in the final week of a 2-4 weeks residential treatment episode. Relapse by day 30 post-discharge served to separate cocaine-addicted individuals into relapse and non-relapse groups. All participants completed the Barratt Impulsivity Scale (BIS-11a).Cocaine-addicted individuals exhibited reduced positive connectivity between the bilateral putamen and posterior insula and right postcentral gyrus. Group differences were primarily driven by reduced connectivity in relapse individuals relative to controls. No relapse versus non-relapse differences emerged. Impulsivity (BIS-11a) was higher in cocaine-addicted participants, an effect that was partially mediated by reduced putamen-posterior insula connectivity in this group.Cocaine addiction, relapse risk and impulsivity were associated with reduced connectivity in putamen-posterior insula/postcentral gyrus circuits implicated in temporal discounting and habitual responding. Findings provide new insight into the neurobiological mechanisms underlying impulsivity and relapse in cocaine addiction.

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Understanding the biologic systems that underlie the relationship between stress and alcohol consumption may lead to better prevention efforts and more effective treatments for alcoholism. Clinical laboratory studies offer a unique opportunity to examine these relationships by using a controlled environment to study how an acute stressor affects alcohol drinking and alcohol craving, how individuals in recovery or those at risk for alcoholism may respond differently to stressors relative to control subjects, and how alcohol differentially affects stress reactivity in these groups. This article reviews some of the most common physical, psychological, and pharmacological stressors used in stress-induction studies designed to reveal details about the relationship between stress reactivity and alcohol use and abuse.

Anxiety experienced in anticipation of impending aversive events induces striatal-limbic activation. However, previous functional magnetic imaging (fMRI) studies of anticipatory anxiety have utilized post-test measures of anxiety, making a direct association between neural activation and distress problematic. This paradigm was designed to assess the blood-oxygen-level-dependent (BOLD) response to an aversive conditioned stimulus while simultaneously measuring subjective anxiety. Fifteen male healthy subjects (45.5±8.5 years old) were studied. A high-threat conditioned stimulus (CS) was paired with either an unpredictable, highly aversive (painful) or non-aversive (non-painful) unconditioned stimulus and compared to a low-threat CS paired with a predictable, non-aversive stimulus. Neural response was assessed with fMRI, and subjective anxiety (1-4) was recorded upon the presentation of each CS. High subjective ratings of real-time anticipatory anxiety (2-4), relative to low anticipatory anxiety (1), elicited increased activation in the bilateral striatum, bilateral orbital frontal cortex, left anterior insula, and anterior cingulate cortex (ACC) and decreased activation in the posterior cingulate cortex (PCC). The amplitude of BOLD signal change generally paralleled the subjective rating of anxiety. Real-time measures of anticipatory anxiety confirm previous reports, using post-test measures of anxiety, of striatal-limbic activation during anticipatory anxiety while simultaneously demonstrating an increase in BOLD response in parallel with heightened anxiety.

In this concept paper, the authors review the arguments and evidence for the hypothesized link between the alcohol withdrawal syndrome and the anxiety and craving that occurs during abstinence in alcohol-dependent patients. This hypothetical construct suggests that the repeated experience of alcohol withdrawal and its associated limbic-neuronal discharge induces a permanent state of limbic hyperexcitability. This phenomenon has been referred to as “kindling.” Subsequent episodes of limbic discharge may then be precipitated during abstinence by alcohol-related cues or may even occur spontaneously. Subjectively experienced as anxiety or craving, such a neuronal discharge could provoke relapse to drinking in vulnerable subjects. The clinical, neurochemical, and electrophysiologic rationale for this hypothesis will be presented, along with implications for treatment and suggested future studies.

Orbitofrontal cortex regional cerebral blood flow (rCBF) is lower in cocaine-dependent subjects than in non-cocaine-dependent subjects. Performance on the Gambling Task, a test of decision making, is a putative correlate of orbitofrontal cortex activity and is reportedly impaired in drug-dependent subjects. The authors tested the hypothesis that lower Gambling Task scores would be associated with lower resting orbitofrontal cortex rCBF in cocaine-dependent subjects.Fifteen healthy comparison subjects and 13 abstinent cocaine-dependent subjects underwent resting single photon emission computed tomography to measure rCBF, after which they completed the Gambling Task.Resting anterior cingulate and left dorsolateral prefrontal cortex rCBF significantly correlated with performance on the Gambling Task, but orbitofrontal cortex rCBF did not. Left dorsolateral prefrontal cortex rCBF was lower in the cocaine-dependent subjects than in the comparison subjects.Resting anterior cingulate and dorsolateral prefrontal cortex rCBF is significantly related to decision making, as assessed by the Gambling Task.