Insomnia symptoms and neurofunctional correlates among adults receiving buprenorphine for opioid use disorder.

OBJECTIVES: Insomnia symptoms are negatively related to opioid use disorder (OUD) treatment outcomes, possibly reflecting the influence of sleep on neurofunctional domains implicated in addiction. Moreover, the intersection between OUD recovery and sleep represents an area well-suited for the development of novel, personalized treatment strategies. This study assessed the prevalence of clinically significant insomnia symptoms and characterized its neurofunctional correlates among a clinical sample of adults with OUD receiving buprenorphine. METHODS: Adults (N = 129) receiving buprenorphine for OUD from an outpatient clinic participated in a cross-sectional survey. Participants completed an abbreviated version of NIDA's Phenotyping Assessment Battery, which assessed 6 neurofunctional domains: sleep, negative emotionality, metacognition, interoception, cognition, and reward. Bivariate descriptive statistics compared those with evidence of clinically significant insomnia symptoms (Insomnia Severity Index [ISI] score of ≥11) to those with minimal evidence of clinically significant insomnia symptoms (ISI score of ≤10) across each of the neurofunctional domains. RESULTS: Roughly 60% of participants reported clinically significant insomnia symptoms (ISI score of ≥11). Experiencing clinically significant insomnia symptoms was associated with reporting greater levels of depression, anxiety, post-traumatic stress, stress intolerance, unhelpful metacognition, and interoceptive awareness (ps<0.05). Participants with evidence of clinically significant insomnia were more likely to report that poor sleep was interfering with their OUD treatment and that improved sleep would assist with their treatment (ps<0.05). CONCLUSIONS: Insomnia was prevalent among adults receiving buprenorphine for OUD. Insomnia was associated with neurofunctional performance, which may impact OUD treatment trajectories. Our findings indicate potential targets in the development of personalized treatment plans for patients with co-morbid insomnia and OUD. To inform the development of novel treatment strategies, more research is needed to understand the potential mechanistic links between sleep disturbances and substance use.

Virtual Hybrid Versus In-Person Administration of Transcending Self Therapy for Veterans with Substance Use Disorders.

Objectives: Veterans with substance use disorder (SUD) can show high severity and are at high risk of relapse due to trauma histories and other comorbid conditions. However, evidence-based SUD therapies may not be available to many veterans due to geographic or transportation constraints. Telehealth approaches have shown promise to improve access to different SUD therapy formats but have not been well-studied in open (rolling-admission) group therapy of in-person patients as administered by a single on-screen therapist. Methods: Social distancing required by the COVID-19 pandemic forced the transition of delivery of Transcending Self Therapy (TST) from an in-person therapist to a single remote (on-screen) therapist. In this virtual model, veterans continued to receive TST but the therapist was off site and provided therapy to veterans who were together in the same room during a 28 day residential Veterans Affairs treatment program. In a program evaluation, we compared their changes in quality of life (QoL), treatment satisfaction ratings and group therapy treatment outcomes with those of Veterans who received TST from an in-person therapist. Results: In both groups, there was a significant increase in QoL Inventory scores from baseline to post-treatment, with no difference in improvement between treatment modalities (i.e., in-person group vs telehealth-delivered group). Veterans professed knowledge of therapy-driven skills at the end of treatment in both groups and overwhelmingly rated TST as helpful and understandable. Conclusions: These data extend previous findings of patient acceptability of remotely-delivered SUD treatment, here with a remote therapist administering open group therapy, as evidenced by improvement in QoL and positive patient feedback about the remote intervention.

Associations between behavioral and self-reported impulsivity, brain structure, and genetic influences in middle childhood.

Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few large-scale studies have assessed associations between impulsivity, brain structure, and genetic susceptibility in children. In 9112 children ages 9-10 from the ABCD study, we explored relationships among impulsivity (UPPS-P impulsive behavior scale; delay discounting), brain structure (cortical thickness (CT), cortical volume (CV), and cortical area (CA)), and polygenic scores for externalizing behavior (PGSEXT). Both higher UPPS-P total scores and more severe delay-discounting had widespread, low-magnitude associations with smaller CA in frontal and temporal regions. No associations were seen between impulsivity and CV or CT. Additionally, higher PGSEXT was associated with both higher UPPS-P scores and with smaller CA and CV in frontal and temporal regions, but in non-overlapping cortical regions, underscoring the complex interplay between genetics and brain structure in influencing impulsivity. These findings indicate that, within large-scale population data, CA is significantly yet weakly associated with each of these impulsivity measures and with polygenic risk for externalizing behaviors, but in distinct brain regions. Future work should longitudinally assess these associations through adolescence, and examine associated functional outcomes, such as future substance use and psychopathology.

Our hands are tied: abortion bans and hesitant medicine.

Trained for decades to analyze risks, benefits, unique body compositions, and complex medical scenarios, healthcare providers are now faced with one of medicine's most trying obstacles: how to practice medicine when new abortion bans contradict best practice standards. Drawn from qualitative interviews with medical providers in Tennessee, USA conducted between October 2022 and December 2022, this study shows how medical providers often must make medical decisions based on legal risks as opposed to standards of care. This is particularly significant as malpractice insurance does not cover criminal charges. In states with abortion bans, often hastily implemented and subject to changes by lawmakers, medical providers are now practicing a new kind of defensive medicine in an effort to protect themselves from legal threats. We call this hesitant medicine, where providers often experience a tension between their own legal protection and the well-being of their patients, making them hesitant to provide necessary abortion care. This has serious, far-reaching consequences. We focus on three distinct arenas impacted by this new form of defensive medicine, specifically: providers' decision-making around patient care, impacts on patient relationships, and finally, what we call the ultimate defense, leaving states with abortion bans to move to states with fewer legal risks. We conclude with commentary on potential ways to reduce the negative impacts of these trends.

Effect of scanning duration and sample size on reliability in resting state fMRI dynamic causal modeling analysis.

Despite its widespread use, resting-state functional magnetic resonance imaging (rsfMRI) has been criticized for low test-retest reliability. To improve reliability, researchers have recommended using extended scanning durations, increased sample size, and advanced brain connectivity techniques. However, longer scanning runs and larger sample sizes may come with practical challenges and burdens, especially in rare populations. Here we tested if an advanced brain connectivity technique, dynamic causal modeling (DCM), can improve reliability of fMRI effective connectivity (EC) metrics to acceptable levels without extremely long run durations or extremely large samples. Specifically, we employed DCM for EC analysis on rsfMRI data from the Human Connectome Project. To avoid bias, we assessed four distinct DCMs and gradually increased sample sizes in a randomized manner across ten permutations. We employed pseudo true positive and pseudo false positive rates to assess the efficacy of shorter run durations (3.6, 7.2, 10.8, 14.4 min) in replicating the outcomes of the longest scanning duration (28.8 min) when the sample size was fixed at the largest (n = 160 subjects). Similarly, we assessed the efficacy of smaller sample sizes (n = 10, 20, …, 150 subjects) in replicating the outcomes of the largest sample (n = 160 subjects) when the scanning duration was fixed at the longest (28.8 min). Our results revealed that the pseudo false positive rate was below 0.05 for all the analyses. After the scanning duration reached 10.8 min, which yielded a pseudo true positive rate of 92%, further extensions in run time showed no improvements in pseudo true positive rate. Expanding the sample size led to enhanced pseudo true positive rate outcomes, with a plateau at n = 70 subjects for the targeted top one-half of the largest ECs in the reference sample, regardless of whether the longest run duration (28.8 min) or the viable run duration (10.8 min) was employed. Encouragingly, smaller sample sizes exhibited pseudo true positive rates of approximately 80% for n = 20, and 90% for n = 40 subjects. These data suggest that advanced DCM analysis may be a viable option to attain reliable metrics of EC when larger sample sizes or run times are not feasible.

Role of PIP39 in oxidative stress response appears conserved in kinetoplastids.

Kinetoplastids, a group of flagellated protists that are often insect intestinal parasites, encounter various sources of oxidative stress. Such stressors include reactive oxygen species, both internally produced within the protist, and induced externally by host immune responses. This investigation focuses on the role of a highly conserved aspartate-based protein phosphatase, PTP-Interacting protein (PIP39) in managing oxidative stress. In addition to its well accepted role in a Trypanosoma brucei life stage transition, there is evidence of PIP39 participation in the T. brucei oxidative stress response. To examine whether this latter PIP39 role may exist more broadly, we aimed to elucidate PIP39's contribution to redox homeostasis in the monoxenous parasite Leptomonas seymouri. Utilizing CRISPR-Cas9-mediated elimination of PIP39 in conjunction with oxidative stress assays, we demonstrate that PIP39 is required for cellular tolerance to oxidative stress in L. seymouri, positing it as a putative regulatory node for adaptive stress responses. We propose that future analysis of L. seymouri PIP39 enzymatic activity, regulation, and potential localization to a specialized organelle termed a glycosome will contribute to a deeper understanding of the molecular mechanisms by which protozoan parasites adapt to oxidative environments. Our study also demonstrates success at using gene editing tools developed for Leishmania for the related L. seymouri.

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Caffeinated Soda Intake in Children Is Associated with Neurobehavioral Risk Factors for Substance Misuse.

BACKGROUND AND OBJECTIVES: Use of psychotropic substances in childhood has been associated with both impulsivity and other manifestations of poor executive function as well as escalation over time to use of progressively stronger substances. However, how this relationship may start in earlier childhood has not been well explored. Here, we investigated the neurobehavioral correlates of daily caffeinated soda consumption in preadolescent children and examined whether caffeinated soda intake is associated with a higher risk of subsequent alcohol initiation. METHODS: Using Adolescent Brain Cognitive Development study data (N = 2,092), we first investigated cross-sectional relationships between frequent caffeinated soda intake and well-known risk factors of substance misuse: impaired working memory, high impulsivity, and aberrant reward processing. We then examined whether caffeinated soda intake at baseline predicts more alcohol sipping at 12 months follow-up using a machine learning algorithm. RESULTS: Daily consumption of caffeinated soda was cross-sectionally associated with neurobehavioral risk factors for substance misuse such as higher impulsivity scores and lower working memory performance. Furthermore, caffeinated soda intake predicted a 2.04 times greater likelihood of alcohol sipping after 12 months, even after controlling for rates of baseline alcohol sipping rates. CONCLUSIONS: These findings suggest that previous linkages between caffeine and substance use in adolescence also extend to younger initiation, and may stem from core neurocognitive features thought conducive to substance initiation.

Relation of Aerobic Activity to Cognition and Well-being in Chronic Mild Traumatic Brain Injury: A LIMBIC-CENC Study.

INTRODUCTION: Because chronic difficulties with cognition and well-being are common after mild traumatic brain injury (mTBI) and aerobic physical activity and exercise (PAE) is a potential treatment and mitigation strategy, we sought to determine their relationship in a large sample with remote mTBI. MATERIALS AND METHODS: The Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study is a national multicenter observational study of combat-exposed service members and veterans. Study participants with positive mTBI histories (n = 1,087) were classified as "inactive" (23%), "insufficiently active" (46%), "active" (19%), or "highly active" (13%) based on the aerobic PAE level. The design was a cross-sectional analysis with multivariable regression. PAE was reported on the Behavioral Risk Factor Surveillance System. Preselected primary outcomes were seven well-validated cognitive performance tests of executive function, learning, and memory: The California Verbal Learning Test-Second Edition Long-Delay Free Recall and Total Recall, Brief Visuospatial Memory Test-Revised Total Recall, Trail-Making Test-Part B, and NIH Toolbox for the Assessment of Neurological Behavior and Function Cognition Battery Picture Sequence Memory, Flanker, and Dimensional Change Card Sort tests. Preselected secondary outcomes were standardized self-report questionnaires of cognitive functioning, life satisfaction, and well-being. RESULTS: Across the aerobic activity groups, cognitive performance tests were not significantly different. Life satisfaction and overall health status scores were higher for those engaging in regular aerobic activity. Exploratory analyses also showed better working memory and verbal fluency with higher aerobic activity levels. CONCLUSIONS: An association between the aerobic activity level and the preselected primary cognitive performance outcome was not demonstrated using this study sample and methods. However, higher aerobic activity levels were associated with better subjective well-being. This supports a clinical recommendation for regular aerobic exercise among persons with chronic or remote mTBI. Future longitudinal analyses of the exercise-cognition relationship in chronic mTBI populations are recommended.

Behavioral and neurocognitive factors distinguishing post-traumatic stress comorbidity in substance use disorders.

Significant trauma histories and post-traumatic stress disorder (PTSD) are common in persons with substance use disorders (SUD) and often associate with increased SUD severity and poorer response to SUD treatment. As such, this sub-population has been associated with unique risk factors and treatment needs. Understanding the distinct etiological profile of persons with co-occurring SUD and PTSD is therefore crucial for advancing our knowledge of underlying mechanisms and the development of precision treatments. To this end, we employed supervised machine learning algorithms to interrogate the responses of 160 participants with SUD on the multidimensional NIDA Phenotyping Assessment Battery. Significant PTSD symptomatology was correctly predicted in 75% of participants (sensitivity: 80%; specificity: 72.22%) using a classification-based model based on anxiety and depressive symptoms, perseverative thinking styles, and interoceptive awareness. A regression-based machine learning model also utilized similar predictors, but failed to accurately predict severity of PTSD symptoms. These data indicate that even in a population already characterized by elevated negative affect (individuals with SUD), especially severe negative affect was predictive of PTSD symptomatology. In a follow-up analysis of a subset of 102 participants who also completed neurocognitive tasks, comorbidity status was correctly predicted in 86.67% of participants (sensitivity: 91.67%; specificity: 66.67%) based on depressive symptoms and fear-related attentional bias. However, a regression-based analysis did not identify fear-related attentional bias as a splitting factor, but instead split and categorized the sample based on indices of aggression, metacognition, distress tolerance, and interoceptive awareness. These data indicate that within a population of individuals with SUD, aberrations in tolerating and regulating aversive internal experiences may also characterize those with significant trauma histories, akin to findings in persons with anxiety without SUD. The results also highlight the need for further research on PTSD-SUD comorbidity that includes additional comparison groups (i.e., persons with only PTSD), captures additional comorbid diagnoses that may influence the PTSD-SUD relationship, examines additional types of SUDs (e.g., alcohol use disorder), and differentiates between subtypes of PTSD.

Development and clinical feasibility study of a brief version of an addiction-focused phenotyping battery in females receiving buprenorphine for opioid use disorder.

INTRODUCTION: We aimed to streamline the NIDA Phenotyping Assessment Battery (PhAB), a package of self-report scales and neurobehavioral tasks used in substance use disorder (SUD) clinical trials, for clinical administration ease. Tailoring the PhAB to shorten administration time for a treatment setting is critical to expanding its acceptability in SUD clinical trials. This study's primary objectives were to develop a brief version of PhAB (PhAB-B) and assess its operational feasibility and acceptability in a female clinical treatment sample. METHODS: Assessments of the original PhAB were evaluated along several criteria to identify a subset for the PhAB-B. Non-pregnant females (N=55) between ages 18-65, stabilized on buprenorphine for opioid use disorder (OUD) at an outpatient addiction clinic, completed this abbreviated battery remotely or after a provider visit in clinic. Participant satisfaction questions were administered. REDCap recorded the time to complete PhAB-B measures. RESULTS: The PhAB-B included 11 measures that probed reward, cognition, negative emotionality, interoception, metacognition, and sleep. Participants who completed the PhAB-B (N =55) were 36.1 ± 8.9 years of age, White (54.5%), Black (34.5%), and non-Latinx (96.0%). Most participants completed the PhAB-B remotely (n = 42, 76.4%). Some participants completed it in-person (n = 13, 23.6%). PhAB-B mean completion time was 23.0 ± 12.0 min. Participant experiences were positive, and 96% of whom reported that they would participate in the study again. CONCLUSION: Our findings support the clinical feasibility and acceptability of the PhAB-B among a female opioid use disorder outpatient addiction treatment sample. Future studies should assess the PhAB-B psychometric properties among broader treatment samples.

Chronic Cocaine Use and White Matter Coherence: A Diffusion Tensor Imaging Study.

OBJECTIVE: Chronic substance use and its effects on brain function and structure has long been of interest to clinicians and researchers. Prior cross-sectional comparisons of diffusion tensor imaging (DTI) metrics have suggested deleterious effects of chronic substance use (i.e., cocaine use) on white matter coherence. However, it is unclear how these effects may replicate across geographic regions when examined with similar technologies. In this study, we sought to conduct a replication of previous work in this area and determine whether there are any patterns of persistent differences in white matter microstructure between individuals with a history of cocaine use disorder (CocUD, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and healthy controls. METHOD: A total of 46 participants (21 healthy controls, 25 chronic cocaine users) were recruited from the Richmond, Virginia metropolitan area. Information regarding past and current substance use was collected from all participants. Participants also completed structural and DTI scans. RESULTS: Consistent with previous DTI studies, significant differences were found between fractional anisotropy (FA) and axial diffusivity (AD) CocUD and controls, with CocUD showing lower FA and AD in the right inferior and superior longitudinal fasciculus, the genu, body, and splenium of the corpus callosum, and the anterior, posterior, and superior corona radiata, among several other regions. These differences were not significant for other diffusivity metrics. Lifetime alcohol consumption was greater in the CocUD group, but lifetime alcohol consumption did not show a significant linear relationship with any of the DTI metrics in within-group regression analyses. CONCLUSIONS: These data align with previously reported declines in white matter coherence in chronic cocaine users. However, it is less clear whether comorbid alcohol consumption results in an additive deleterious effect on white matter microstructure.

Genetic and Environmental Variation in Continuous Phenotypes in the ABCD Study®.

Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9-10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.

Initial Validation of a Behavioral Phenotyping Model for Substance Use Disorder.

Standard nosological systems, such as DSM-5 or ICD-10, are relied upon as the diagnostic basis when developing treatments for individuals with substance use disorder (SUD). Unfortunately, the vast heterogeneity of individuals within a given SUD diagnosis results in a variable treatment response and/or difficulties ascertaining the efficacy signal in clinical trials of drug development. Emerging precision medicine methods focusing on targeted treatments based on phenotypic subtypes rather than diagnosis are being explored as alternatives. The goal of the present study was to provide initial validation of emergent subtypes identified by an addiction-focused phenotyping battery. Secondary data collected as part of a feasibility study of the NIDA phenotyping battery were utilized. Participants completed self-report measures and behavioral tasks across six neurofunctional domains. Exploratory and confirmatory factor analysis (EFA/CFA) were conducted. A three-factor model consisting of negative emotionality, attention/concentration, and interoception and mindfulness, as well as a four-factor model adding a second negative emotion domain, emerged from the EFA as candidate models. The CFA of these models did not result in a good fit, possibly resulting from small sample sizes that hindered statistical power.

Cognitive effort avoidance in veterans with suicide attempt histories.

Suicide attempts (SA) are increasing in the United States, especially in veterans. Discovering individual cognitive features of the subset of suicide ideators who attempt suicide is critical. Cognitive theories attribute SA to facile schema-based negative interpretations of environmental events. Over-general autobiographical memory and facile solutions in problem solving tasks in SA survivors suggest that aversion to expending cognitive effort may be a neurobehavioral marker of SA risk. In veterans receiving care for mood disorder, we compared cognitive effort discounting and evidence-gathering in a beads task between veterans with (SAHx+; n = 26) versus without (SAHx-; n = 22) a history of SA. Groups did not differ in depressed mood or in a proxy metric of premorbid intelligence. Compared to SAHx- participants, SAHx+ participants self-reported significantly more severe cognitive problems in most domains, and also eschewed choice to earn higher monetary reward if earning it required a slightly increased working memory (WM) demand relative to an easy WM task. There was no group difference, however, in extent of evidence-gathering before declaring a conclusion in a beads task. These preliminary data suggest that aversion to expenditure of cognitive effort, potentially as a component of cognitive difficulties, may be a marker for SA risk.

Impulsivity and reduced quality of life in persons with paraplegia.

BACKGROUND: Low Quality of Life (QoL) in persons with paraplegia may stem from impulsive behaviors. Impulsivity in persons with paraplegia and persistently low QoL has seldom been probed but could be targeted with cognitive behavioral therapies. OBJECTIVE: Determine how task-assessed and self-report impulsivity relate to quality of life (QoL) in adults with paraplegia. METHODS: In a preliminary study, 33 adults with paraplegia after traumatic SCI were administered verbal interviews on QoL from the PROMIS item bank at baseline and at six-month follow-up, along with several computerized metrics of impulsivity at baseline. RESULTS: A cluster of (n = 10) participants characterized by high levels of negative affect and low levels of resilience and life satisfaction across both baseline and follow-up showed significantly greater negative urgency impulsivity (p = 0.007) as well as significantly lower mindfulness and self-care in some domains (all p < 0.05), compared to the cluster of participants (n = 23) who showed higher life satisfaction and resilience. Behavioral metrics of delay discounting and rapid-response (motoric) impulsivity did not significantly differ (all p > 0.05) between the two clusters of participants. CONCLUSIONS: These data suggest that novel interventions that reduce trait impulsivity in other disorders could be applied to potentially reduce risk for reduced self-care and QoL in individuals with paraplegia.

Impulsivity and Reflective Thinking in Veterans Seeking Care for Substance Use Disorder.

Objective: Substance use disorder (SUD) is a major public health crisis, with increased overdose deaths in the past decade. This has coincided with a tremendous amount of research on those who misuse substances. However, extensive research on SUD vulnerability characteristics such as impulsivity may be complemented by research on theoretically relevant aspects of cognition. The Cognitive Reflection Test (CRT) was designed to measure a person's ability to subdue quick, intuitive decisions to reflect or deliberate. To some decision making theorists, this measure may help explain why some people are better able to inhibit "gut reactions" than others. Methods: We recruited 140 veterans from a Veterans Affairs medical center; 91 of whom were receiving SUD treatment. Participants completed the CRT and a measure of trait impulsivity (the UPPS-P). We ran planned ANCOVAs assessing differences in the number of correct answers on the CRT and the proportion of errors that were intuitive. Results: Participants who were receiving treatment gave significantly fewer correct, reflective answers on the CRT compared to controls. However, there were no significant differences in the proportion of errors that were due to intuitive responses. These findings did not change when controlling for age and/or trait impulsivity. Conclusion: Those suffering from SUD may exhibit cognitive deficits that do not stem from intuitive thinking. These deficits may, in turn, exacerbate issues arising from elevated impulsivity. Additional research which better incorporates decision making theory may be invaluable in providing clinically-relevant results and positive public health outcomes.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Attentional function and inhibitory control in different substance use disorders.

Attentional function in substance use disorder (SUD) is not well understood. To probe attentional function in SUD as a function of primary substance of abuse, we administered the attentional network task (ANT) to 44 individuals with Cocaine Use Disorder (CoUD), 49 individuals with Cannabis Use Disorder (CaUD), 86 individuals with Opioid Use Disorder (OUD), and 107 controls with no SUD, along with the stop-signal task (SST). The ANT quantifies the effects of (temporal) alerting cues and (spatial) orienting cues to reduce reaction time (RT) to targets, as well as probing how conflicting (target-incongruent) stimuli slow RT. The SST quantifies individuals' ability to inhibit already-initiated motor responses. After controlling for sex representation and age, OUD and CaUD participants showed blunted alerting effects compared to controls, whereas CaUD and CoUD participants showed greater stimulus conflict (flanker) effects. Finally, CoUD participants showed a trend toward increased orienting ability. In SST performance, no SUD group showed a prolonged stop-signal reaction compared to controls. However, the OUD group (and CoUD group at trend level) showed prolonged "go" RT to targets and reduced hit rates. These data indicate differences in attentional function in persons with SUD as a function of the primary substance use.

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine.

Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.