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Background:Transcranial direct current stimulation over the dorsolateral prefrontal cortex has been shown to be clinically useful in the treatment of drug addiction.Methods:We conducted a double-blind randomized clinical trial aiming to assess the effects of bilateral dorsolateral prefrontal cortex transcranial direct current stimulation (left cathodal/right anodal) on crack-cocaine addiction. We defined craving as the primary outcome, and other clinical measurements, including depressive and anxiety symtoms, and quality of life, as secondary outcomes. Seventeen male crack-cocaine users (mean age 30.4±9.8 SD) were randomized to receive 5 sessions of active transcranial direct current stimulation (2 mA, 35cm2, for 20 minutes), every other day, and 19 males (mean age 30.3±8.4 SD) to receive sham-transcranial direct current stimulation (placebo) as control group.Results:Craving scores were significantly reduced in the transcranial direct current stimulation group after treatment when compared with sham-transcranial direct current stimulation (P=.028) and baseline values (P=.003), and decreased linearly over 4 weeks (before, during, and after treatment) in the transcranial direct current stimulation group only (P=.047). Changes of anxiety scores towards increase in the sham-transcranial direct current stimulation and decrease in the transcranial direct current stimulation group (P=.03), and of the overall perception of quality of life (P=.031) and of health (P=.048) towards decrease in the sham-transcranial direct current stimulation group and increase in the transcranial direct current stimulation group differed significantly between groups.Conclusions:Repetitive bilateral transcranial direct current stimulation over the dorsolateral prefrontal cortex reduced craving for crack-cocaine use, decreased anxiety, and improved quality of life. We hypothesize that transcranial direct current stimulation effects may be associated with increased prefrontal processing and regulation of craving behavior.

Contemporary neurocognitive models of drug addiction have associated this condition with changes in interoception —namely, the sensing and processing of body signals that fulfill homeostatic functions relevant for the onset and maintenance of addictive behavior. However, most previous evidence is inconsistent, behaviorally unspecific, and virtually null in terms of direct electrophysiological and multimodal markers. To circumvent these limitations, we conducted the first assessment of the relation between cardiac interoception and smoked cocaine dependence (SCD) in a sample of (a) 25 participants who fulfilled criteria for dependence on such a drug, (b) 22 participants addicted to insufflated clorhidrate cocaine (only for behavioral assessment), and (c) 25 healthy controls matched by age, gender, education, and socioeconomic status. We use a validated heartbeat-detection (HBD) task and measured modulations of the heart-evoked potential (HEP) during interoceptive accuracy and interoceptive learning conditions. We complemented this behavioral and electrophysiological data with offline structural (MRI) and functional connectivity (fMRI) analysis of the main interoceptive hubs. HBD and HEP results convergently showed that SCD subjects presented ongoing psychophysiological measures of enhanced interoceptive accuracy. This pattern was associated with a structural and functional tuning of interoceptive networks (reduced volume and specialized network segregation). Taken together, our findings provide the first evidence of an association between cardiac interoception and smoked cocaine, partially supporting models that propose hyper-interoception as a key aspect of addiction. More generally, our study shows that multimodal assessments of interoception could substantially inform the clinical and neurocognitive characterization of psychophysiological and neurocognitive adaptations triggered by addiction.

Cocaine use disorder (CUD) is a worldwide health problem with limited effective treatment options. The therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) is gaining more attention following evidence of its role on craving reduction in CUD. However, the heterogeneity of results underscores a pressing need for biomarkers of treatment outcome. We asked whether brain connectomics together with clinical assessments can predict response to add-on rTMS therapy for CUD better than solely conventional clinical assessments. Forty-four randomly assigned CUD patients underwent the 2-week double-blind acute phase [Sham (n = 20, 2f./18m.) and Active (n = 24, 4f./20m.)], in which they received 2 daily sessions of rTMS on the left dorsolateral prefrontal cortex. Subsequently, 19 and 14 patients continued to an open-label maintenance phase of two weekly rTMS sessions for 3 and 6 months, respectively. Pre and post treatment resting-state brain functional connectivity as well as two clinical scores of craving were measured to predict the subsequent response to rTMS therapy. Two conventional clinical scores, namely Cocaine Craving Questionnaires (CCQ) and Visual Analogue Scale (VAS) were used as craving level assessments. We used a priori seed-driven connectivity of Left Dorsolateral Prefrontal Cortex (LDLPFC) and Anterior Cingulate Cortex (ACC) together with the connectivity from a whole-brain multi-voxel pattern analysis at each time point to predict the reduction in craving after rTMS. The combination of connectivity changes and baseline craving severity improved the prediction of individual craving compared to the prediction with only the initial craving severity. The predictive model from the combination of neuromarkers could explain 45 to 97 percent of variance in craving changes assessed by two different clinical scores. We used leave-one-subject-out cross-validation to support the generalizability of our findings. Our results indicate that employing neuromarkers from resting-state functional connectivity of pre and post condition of CUD patients receiving add-on rTMS therapy increases the power of predicting craving changes and support the idea that neuromarkers may offer improvements in precision medicine approaches.

Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.

Although reward processing appears altered in addiction, few studies track neurofunctional changes following treatment or relate these to measures of reduced drug use. The current study examined neurofunctional alterations in reward processing in cocaine dependence (CD) pretreatment and posttreatment to determine whether these changes relate to clinically meaningful outcome indicators. Treatment-seeking CD outpatients (N=29) underwent functional magnetic resonance imaging while performing a monetary incentive delay task (MIDT) pretreatment and posttreatment. The MIDT parses anticipatory from outcome phases of reward/loss processing. Abstinence indicators (negative urines, days abstinent from cocaine during follow-up) were collected throughout treatment and up to 1 year later. Healthy control (HC) participants (N=28) were also scanned twice with the MIDT. Relative to pretreatment, at posttreatment CD participants demonstrated increased anticipatory reward activity in the midbrain, thalamus, and precuneus (pFWE<0.05). Increased midbrain activity correlated with cocaine abstinence during the 1-year follow-up. Ventral striatal (VS) activity during loss anticipation correlated negatively with negative urine screens. HC group test-retest results showed decreased ventromedial prefrontal cortex activity during winning outcomes. CD-HC group-by-time differences revealed increased left inferior frontal gyrus activity in the CD group during anticipatory phases at posttreatment. In CD participants, increased posttreatment activity in dopamine-innervated regions suggests lowered thresholds in anticipatory signaling for non-drug rewards. Midbrain and VS responses may represent biomarkers associated with CD abstinence. Abstinence-related neurobiological changes occur in similar regions implicated during active use and may possibly be used to track progress during short- and long-term recovery.

Background Cocaine is the most frequently used stimulant worldwide, with increasing consumption rates in Europe. Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regard to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on “real-time” feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery and to reconstitute reward sensitivity to non-drug related reinforcers like, e.g. social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD. Methods We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms. Discussion We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualised and integrated pharmaco-psychotherapy. Trial registration. NCT06125054 ClinicalTrials.gov. Registered on October 26, 2023.

The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic ‘reward’ circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users ( N  = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.

Abstract Background Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. Methods We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.

Abstract Study Objectives: During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed “occult insomnia.” The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Methods: Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Results: Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Conclusions: Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified “occult insomnia” in this population.