Group behavioral activation with and without a smartphone app in intensive outpatient treatment for substance use disorder: A three-arm randomized controlled trial.

INTRODUCTION: Reward deficits negatively impact recovery from substance use disorder (SUD). LETS ACT, a behavioral activation treatment targeting substance-free reward, has demonstrated effectiveness in reducing post treatment substance use. There remains room for modifications to extend recovery gains, and LETS ACT remains largely untested in outpatient treatment. We tested the effect of LETS ACT when delivered alongside intensive outpatient SUD treatment, with and without a smartphone app designed to extend access to treatment content outside of clinician-administered sessions. METHODS: In this three-arm randomized controlled trial (N = 206; 54 % White, 67 % male), all participants received intensive outpatient SUD treatment as usual (TAU) and either LETS ACT (n = 56), smartphone-enhanced LETS ACT (n = 65), or assessments only (n = 61). Substance use days and substance related problems were assessed through 12 months posttreatment. RESULTS: Generalized estimating equations indicated a significant condition*time interaction for substance use days; Days of substance use significantly declined from pretreatment until 1-month for TAU, 3-months for LETS ACT-SE, and 6-months for LETS ACT. Decreases in substance-related problems were maintained across all conditions through 12 months. CONCLUSIONS: Adding LETS ACT to intensive outpatient treatment resulted in significant decreases in substance use through 6 months posttreatment, yet these gains were not sustained through 12 months posttreatment. A smartphone app did not facilitate superior treatment outcomes. Future studies should consider factors impacting treatment efficacy in outpatient settings and the utility of providing more than six sessions of behavioral activation.

Triple Network Resting State Connectivity Predicts Distress Tolerance and Is Associated with Cocaine Use.

Distress tolerance (DT), a predictor of substance use treatment retention and post-treatment relapse, is associated with task based neural activation in regions located within the salience (SN), default mode (DMN), and executive control networks (ECN). The impact of network connectivity on DT has yet to be investigated. The aim of the present study was to test within and between network resting-state functional connectivity (rsFC) associations with DT, and the impact of cocaine use on this relationship. Twenty-nine adults reporting regular cocaine use (CU) and 28 matched healthy control individuals (HC), underwent resting-state functional magnetic resonance imaging followed by the completion of two counterbalanced, computerized DT tasks. Dual-regression analysis was used to derive within and between network rsFC of the SN, DMN, and lateralized (left and right) ECN. Cox proportional-hazards survival models were used to test the interactive effect of rsFC and group on DT. The association between cocaine use severity, rsFC, and DT was tested within the CU group. Lower LECN and higher DMN-SN rsFC were associated with DT impairment. Greater amount of cocaine use per using day was associated with greater DMN-SN rsFC. The findings emphasize the role of neural resource allocation within the ECN and between DMN-SN on distress tolerance.

Distress tolerance trajectories following substance use treatment.

OBJECTIVE: Distress tolerance (DT), the ability to withstand aversive internal states, represents an important risk factor for substance use relapse and a potential treatment target. Neurobiological research in substance using populations suggests that continued substance use could erode DT, whereas abstinence could bolster it. The current study characterized trajectories of behavioral and self-reported indices of DT and examined the prospective effect of substance use on DT trajectories among those seeking treatment for substance use. METHOD: Individuals (N = 263, Mage = 42.68, SD = 11.8, 70.7% male, 94.7% African American) in residential substance use treatment completed subjective (Distress Tolerance Scale) and behavioral (Mirror Tracing Persistence Task-computerized version) DT measures, as well as report of daily substance use (timeline follow-back) over 5 assessment time-points from pretreatment to 12 months posttreatment. Latent curve modeling estimated DT trajectories and their associations with substance use behavior, including abstinence duration (days until first use) and substance use frequency (percentage of substance use days between assessments). RESULTS: Self-reported and behavioral DT indicators both exhibited positive, nonlinear change over time (standardized slope parameter estimates: Distress Tolerance Scale ß = 0.61, p < .01; Mirror Tracing Persistence Task ß = 0.34, p < .01). Abstinence duration was associated with greater improvement in behavioral (ß = .20, p = .03) DT specifically. Frequency of use was statistically significantly associated with attenuated behavioral DT at 6-month (ß = -.12, p = .03) and 12-month follow-ups (ß = -.08, p = .045). CONCLUSIONS: DT appears to improve appreciably posttreatment, and return to substance use may shape the degree of this improvement. Collectively, these findings support the conceptualization of DT as a malleable treatment target and emphasize the benefit of abstinence on improvement in DT. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Neural reward response to substance-free activity images in opiate use disorder patients with depressive symptoms.

BACKGROUND: Deficits in the ability to experience reward from natural, substance-free activities and stimuli is a common mechanism contributing to both opiate use disorder and depressive symptoms, and is a target of behavioral-focused treatments for substance use and depression. Although the neural response to monetary, positive affect-eliciting and social images has been investigated, the neural response to images representing substance-free activity engagement remains untested. The current study tested the neural response to anticipation and receipt of substance-free activity engagement images and monetary reward in opiate use disorder patients with elevated depressive symptoms compared to healthy controls. METHODS: Sixteen male opiate use disorder detoxification patients with elevated depressive symptoms (Beck Depression Inventory (BDI-II) ≥ 14) (OUDD Mage = 32.19 years, SD = 8.17 years) and seventeen male healthy controls (BDI-II < 14) (HC: Mage = 26.82 years, SD = 5.29 years) completed the Monetary Incentive Delay (MID) and newly developed Activity Incentive Delay (AID) tasks. Within- and between-group whole-brain contrasts tested activation during anticipation ([reward]-[non-reward]) and receipt ([win]-[non-win]) of substance-free activity image, monetary, and substance-free activity relative to monetary (AID-MID), reward. RESULTS: OUDD demonstrated significantly lower activation in reward regions during anticipation and significantly greater activation during receipt of substance-free activity image reward compared to HC. OUDD demonstrated significantly lower activation during anticipation of substance-free activity reward relative to monetary reward, compared to HC. CONCLUSIONS: The observed reduction in frontostriatal response to reward anticipation of substance-free activity engagement images in OUDD, yet increased neural response to reward receipt, supports theory linking reductions in reward processing with deficits in motivation for substance-free activity engagement.

Self-regulatory predictors of eating disorder symptoms: Understanding the contributions of action control and willpower beliefs.

Action orientation, or the ability to regulate both positive and negative affect to perform goal-directed action, has been associated with eating behavior in previous research. Additionally, differences in beliefs about self-control have been shown to influence behavior, but it is unclear how these beliefs impact disordered eating behavior or how they may interact with other self-regulatory mechanisms to predict eating outcomes. In this study, 1128 participants were recruited online via Amazon Mechanical Turk to answer questions about self-regulation constructs and eating behavior. A three-way moderated regression analysis was used to assess relationships between two subtypes of action orientation (failure-related action orientation, or AOF, which describes an ability to up-regulate positive affect, and decision-related action orientation, or AOD, which describes an ability to down-regulate negative affect), willpower beliefs, and binge eating. Results revealed a significant three-way interaction between AOD, AOF, and willpower beliefs such that the interaction between AOF and willpower beliefs was only significant for those with low AOD. These findings suggest an ability to down-regulate negative affect (high AOF) is a protective factor against increased disordered eating, though this may not be the case for individuals with an inability to up-regulate positive affect (low AOD) and simultaneously ascribe to beliefs that willpower is a limited resource.

Relationships Between Craving Beliefs and Abstinence Self-Efficacy are Mediated by Smoking Motives and Moderated by Nicotine Dependence.

INTRODUCTION: Decreased abstinence self-efficacy is linked to increased craving and negative affect, as well as poorer smoking outcomes, such as lapse, relapse, and withdrawal symptom severity. Research suggests that beliefs and cognitions concerning ourselves and the world orient us toward specific goals and thus impact our judgments and behavior. This study serves to investigate whether motives for smoking mediate the relationship between beliefs about craving and abstinence self-efficacy judgments and whether this may differ by nicotine dependence. METHODS: In a sample of 198 smokers (M age = 34.96, 51.8% female, 81.8% Caucasian), self-report measures of craving beliefs, situational abstinence self-efficacy, and smoking motives were measured. We examined the effect of beliefs on abstinence self-efficacy in both craving and negative affect situations, with craving and negative reinforcement smoking motives as mediators, and nicotine dependence as a moderator. RESULTS: Results indicate that craving beliefs predict lower abstinence self-efficacy judgments in craving situations indirectly through increased craving motives. However, this relationship was only significant for less dependent smokers. Additionally, regardless of nicotine dependence, craving beliefs predicted lower abstinence self-efficacy in negative affect situations via increased negative reinforcement smoking motives. CONCLUSIONS: These findings suggest that beliefs concerning the specific nature of craving correlate with smoking motives (ie, smoking goals) and thus abstinence self-efficacy judgments. Furthermore, these associations are stronger for less dependent smokers. Such findings suggest the importance of addressing craving beliefs during smoking cessation treatment, especially for less dependent smokers whose craving beliefs are associated with abstinence self-efficacy across multiple situations.

BDNF val66met polymorphism affects aging of multiple types of memory.

The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). This article is part of a Special Issue entitled Memory & Aging.

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation.

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-beta(2) ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-beta in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-beta receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-beta signaling, with decreased TGF-beta-mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-beta-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-beta-mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-beta receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.