Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder.

BACKGROUND: Buprenorphine-naloxone is a medication shown to improve outcomes for individuals seeking treatment for opioid use disorder (OUD); however, outcomes are limited by low medication adherence rates. This is especially true during the early stages of treatment. METHODS: The present study proposes to utilize a sequential multiple assignment randomized trial design to compare two psychological interventions targeting buprenorphine-naloxone adherence: (1) contingency management (CM) and (2) brief motivational interviewing plus substance-free activities session plus mindfulness (BSM). Participants will be N = 280 adults who present to a university-based addictions clinic seeking treatment for OUD. Participants will be randomized to condition to receive 4 sessions of their assigned intervention (CM or BSM). Participants who are adherent, defined as attending physician appointments and having buprenorphine present in urine toxicology, will enter maintenance intervention for an additional 6 months. Those who are not adherent will be re-randomized to receive either the other intervention or both interventions. Follow-up will occur at 8 months post-randomization. CONCLUSIONS: This novel design will examine the benefit of sequential treatment decisions following non-adherence. The primary outcome of this study is buprenorphine-naloxone medication adherence, as assessed by physician visit attendance and presence of buprenorphine in urine. Results will elicit the relative efficacy of CM and BSM compared to one another and whether keeping the initial treatment approach when adding the alternative approach for initially non-adherent individuals is beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04080180.

Effects of acute tryptophan depletion on raphé functional connectivity in depression.

Depression remains a great societal burden and a major treatment challenge. Most antidepressant medications target serotonergic raphé nuclei. Acute tryptophan depletion (ATD) modulates serotonin function. To better understand the raphé's role in mood networks, we studied raphé functional connectivity in depression. Fifteen depressed patients were treated with sertraline for 12 weeks and scanned during ATD and sham conditions. Based on our previous findings in a separate cohort, resting state MRI functional connectivity between raphé and other depression-related regions (ROIs) was analyzed in narrow frequency bands. ATD decreased raphé functional connectivity with the bilateral thalamus within 0.025-0.05 Hz, and also decreased raphé functional connectivity with the right pregenual anterior cingulate cortex within 0.05-0.1 Hz. Using the control broadband filter 0.01-0.1 Hz, no significant differences in raphé-ROI functional connectivity were observed. Post-hoc analysis by remission status suggested increased raphé functional connectivity with left pregenual anterior cingulate cortex in remitters (n=10) and decreased raphé functional connectivity with left thalamus in non-remitters (n=5), both within 0.025-0.05 Hz. Reducing serotonin function appears to alter coordination of these mood-related networks in specific, low frequency ranges. For examination of effects of reduced serotonin function on mood-related networks, specific low frequency BOLD fMRI signals can identify regions implicated in neural circuitry and may enable clinically-relevant interpretation of functional connectivity measures. The biological significance of these low frequency signals detected in the raphé merits further study.

A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility.

BACKGROUND: Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching. METHODS: Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [(18)F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release. RESULTS: The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release. CONCLUSIONS: These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement.

MDMA (Ecstasy) association with impaired fMRI BOLD thalamic coherence and functional connectivity.

BACKGROUND: MDMA exposure is associated with chronic serotonergic dysfunction in preclinical and clinical studies. A recent functional magnetic resonance imaging (fMRI) comparison of past MDMA users to non-MDMA-using controls revealed increased spatial extent and amplitude of activation in the supplementary motor area during motor tasks (Karageorgiou et al., 2009). Blood oxygenation level dependent (BOLD) data from that study were reanalyzed for intraregional coherence and for inter-regional temporal correlations between time series, as functional connectivity. METHODS: Fourteen MDMA users and ten controls reporting similar non-MDMA abuse performed finger taps during fMRI. Fourteen motor pathway regions plus a pontine raphé region were examined. Coherence was expressed as percent of voxels positively correlated with an intraregional index voxel. Functional connectivity was determined using wavelet correlations. RESULTS: Intraregional thalamic coherence was significantly diminished at low frequencies in MDMA users compared to controls (p=0.009). Inter-regional functional connectivity was significantly weaker for right thalamo - left caudate (p=0.002), right thalamo - left thalamus (p=0.007), right caudate - right postcentral (p=0.007) and right supplementary motor area - right precentral gyrus (p=0.011) region pairs compared to controls. When stratified by lifetime exposure, significant negative associations were observed between cumulative MDMA use and functional connectivity in seven other region-pairs, while only one region-pair showed a positive association. CONCLUSIONS: Reported prior MDMA use was associated with deficits in BOLD intraregional coherence and inter-regional functional connectivity, even among functionally robust pathways involving motor regions. This suggests that MDMA use is associated with long-lasting effects on brain neurophysiology beyond the cognitive domain.

Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults.

BACKGROUND: Cannabis dependence is a significant public health problem. Because there are no approved medications for this condition, treatment must rely on behavioral approaches empirically complemented by such lifestyle change as exercise. AIMS: To examine the effects of moderate aerobic exercise on cannabis craving and use in cannabis dependent adults under normal living conditions. DESIGN: Participants attended 10 supervised 30-min treadmill exercise sessions standardized using heart rate (HR) monitoring (60-70% HR reserve) over 2 weeks. Exercise sessions were conducted by exercise physiologists under medical oversight. PARTICIPANTS: Sedentary or minimally active non-treatment seeking cannabis-dependent adults (n = 12, age 25±3 years, 8 females) met criteria for primary cannabis dependence using the Substance Abuse module of the Structured Clinical Interview for DSM-IV (SCID). MEASUREMENTS: Self-reported drug use was assessed for 1-week before, during, and 2-weeks after the study. Participants viewed visual cannabis cues before and after exercise in conjunction with assessment of subjective cannabis craving using the Marijuana Craving Questionnaire (MCQ-SF). FINDINGS: Daily cannabis use within the run-in period was 5.9 joints per day (SD = 3.1, range 1.8-10.9). Average cannabis use levels within the exercise (2.8 joints, SD = 1.6, range 0.9-5.4) and follow-up (4.1 joints, SD = 2.5, range 1.1-9.5) periods were lower than during the run-in period (both P<.005). Average MCQ factor scores for the pre- and post-exercise craving assessments were reduced for compulsivity (P  = .006), emotionality (P  = .002), expectancy (P  = .002), and purposefulness (P  = .002). CONCLUSIONS: The findings of this pilot study warrant larger, adequately powered controlled trials to test the efficacy of prescribed moderate aerobic exercise as a component of cannabis dependence treatment. The neurobiological mechanisms that account for these beneficial effects on cannabis use may lead to understanding of the physical and emotional underpinnings of cannabis dependence and recovery from this disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT00838448].

Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

OBJECTIVE: Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. METHOD: Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. RESULTS: Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. CONCLUSIONS: The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

Prior MDMA (Ecstasy) use is associated with increased basal ganglia-thalamocortical circuit activation during motor task performance in humans: an fMRI study.

MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p=0.02), PSC (p=0.04) and PAV (p=0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose-response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia-thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.