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.

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.

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.

Reliability and stability challenges in ABCD task fMRI data.

Trait stability of measures is an essential requirement for individual differences research. Functional MRI has been increasingly used in studies that rely on the assumption of trait stability, such as attempts to relate task related brain activation to individual differences in behavior and psychopathology. However, recent research using adult samples has questioned the trait stability of task-fMRI measures, as assessed by test-retest correlations. To date, little is known about trait stability of task fMRI in children. Here, we examined within-session reliability and long-term stability of individual differences in task-fMRI measures using fMRI measures of brain activation provided by the adolescent brain cognitive development (ABCD) Study Release v4.0 as an individual's average regional activity, using its tasks focused on reward processing, response inhibition, and working memory. We also evaluated the effects of factors potentially affecting reliability and stability. Reliability and stability (quantified as the ratio of non-scanner related stable variance to all variances) was poor in virtually all brain regions, with an average value of 0.088 and 0.072 for short term (within-session) reliability and long-term (between-session) stability, respectively, in regions of interest (ROIs) historically-recruited by the tasks. Only one reliability or stability value in ROIs exceeded the 'poor' cut-off of 0.4, and in fact rarely exceeded 0.2 (only 4.9%). Motion had a pronounced effect on estimated reliability/stability, with the lowest motion quartile of participants having a mean reliability/stability 2.5 times higher (albeit still 'poor') than the highest motion quartile. Poor reliability and stability of task-fMRI, particularly in children, diminishes potential utility of fMRI data due to a drastic reduction of effect sizes and, consequently, statistical power for the detection of brain-behavior associations. This essential issue urgently needs to be addressed through optimization of task design, scanning parameters, data acquisition protocols, preprocessing pipelines, and data denoising methods.

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.

Altered effective connectivity of the reward network during an incentive-processing task in adults with alcohol use disorder.

BACKGROUND: Abnormalities of reward sensitivity and impulsivity are known to be correlated with each other and alcohol use disorder (AUD) risk, but the underlying aberrant neural circuitry involved is not clearly defined. We sought to extend the current knowledge of AUD pathophysiology by studying incentive processing in persons with AUD using functional neuroimaging data. METHODS: We utilized functional MRI data from the Human Connectome Project Database obtained during performance of a number-guessing incentive-processing task with win, loss, and neutral feedback conditions in 78 participants with either DSM-IV alcohol abuse or dependence (combined as the AUD group) and 78 age- and sex-matched control (CON) participants. Within a network consisting of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), insula, ventral striatum, and dorsal striatum (DS) in the right hemisphere, we performed dynamic causal modeling analysis to test group-level differences (AUD vs. CON) in effective directional connectivity (EC) as modulated by "win" and "loss" conditions. We used linear regression analyses to characterize the relations between each EC outcome and measures of cumulative alcohol exposure and impulsivity. RESULTS: During wins, AUD participants had lower ECs from ACC to the other four nodes, greater ECs from insula to the other four nodes, greater ECs from DLPFC to the other four nodes, and greater DS to DS self-connection EC than CON participants. In the total sample, EC from the insula to the DLPFC (insula â†’ DLPFC) during wins was positively correlated with both impulsivity (as measured by the delay-discounting task) and cumulative alcohol exposure. The DS to DS self-connection EC during wins was positively correlated with impulsivity. Many of the altered ECs from the ACC and insula to other nodes were correlated with cumulative alcohol exposure. CONCLUSIONS: Individuals with AUD have disrupted EC in both instrumentally driven and automatized corticostriatal reward circuits during non-alcohol reward feedback. These results point to disrupted corticostriatal EC in both "top-down" and "bottom-up" pathways among individuals with AUD.

Development and Feasibility Study of an Addiction-Focused Phenotyping Assessment Battery.

BACKGROUND AND OBJECTIVES: Current methods of classifying individuals with substance use disorder (SUD) result in vast heterogeneity among persons within a given diagnosis. These approaches, while clinically allowing for distinctions between patient groups, are less than ideal when attempting to recruit a neurobehaviorally defined subset of subjects into clinical trials. To address this gap, alternative strategies have been proposed, including behavioral phenotyping. The NIDA Phenotyping Assessment Battery (PhAB) is a modular package of assessments and neurocognitive tasks that was developed for use in clinical trials. The goal of the present study is to assess the feasibility of the NIDA PhAB with regard to ease of administration and time burden. METHODS: Healthy controls, persons with cocaine use disorder (CocUD), opioid use disorder (OUD), cannabis use disorder (CanUD), and combined opioid and cocaine use disorder (OCUD) were recruited from various sources (N = 595). Participants completed screening and one to three assessment visits. Time to complete the measures was recorded and a satisfaction interview was administered. RESULTS: Of the participants enrolled, 381 were deemed eligible. The majority of eligible participants (83%) completed all assessments. The average completion time was 3 hours. High participant satisfaction ratings were noted, with over 90% of participants endorsing a willingness to participate in a similar study and recommend the study to others. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These findings corroborate the ease with which the PhAB may be easily incorporated into a study assessment visit without undue participant burden. The PhAB is an efficient method for behavioral phenotyping in addiction clinical trials. (Am J Addict 2021;00:00-00).

Impulsivity and Medical Care Utilization in Veterans Treated for Substance Use Disorder.

BACKGROUND: Impulsivity has been defined by acting rashly during positive mood states (positive urgency; PU) or negative mood states (negative urgency; NU) and by excessive de-valuation of deferred rewards. These behaviors reflect a "live in the now" mentality that is not only characteristic of many individuals with severe substance use disorder (SUD) but also impedes medical treatment compliance and could result in repeated hospitalizations or other poor health outcomes. Purpose/objectives: We sought preliminary evidence that impulsivity may relate to adverse health outcomes in the veteran population. Impulsivity measured in 90 veterans receiving inpatient or outpatient SUD care at a Veterans Affairs Medical Center was related to histories of inpatient/residential care costs, based on VA Health Economics Resource Center data. Results: We found that positive urgency, lack of persistence and lack of premeditation, but not sensation-seeking or preference for immediate or risky rewards, were significantly higher in veterans with a history of one or more admissions for VA-based inpatient or residential health care that either included (n = 30) or did not include (n = 29) an admission for SUD care. Among veterans with a history of inpatient/residential care for SUD, NU and PU, but not decision-making behavior, correlated with SUD care-related costs. Conclusions/Importance: In veterans receiving SUD care, questionnaire-assessed trait impulsivity (but not decision-making) related to greater care utilization within the VA system. This suggests that veterans with high impulsivity are at greater risk for adverse health outcomes, such that expansion of cognitive interventions to reduce impulsivity may improve their health.

Image processing and analysis methods for the Adolescent Brain Cognitive Development Study.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice.

The ATP-sensitive K+ channel (KATP) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of KATP channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different KATP channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-KATP channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype KATP channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.

Rapid-Response Impulsivity Predicts Depression and Posttraumatic Stress Disorder Symptomatology at 1-Year Follow-Up in Blast-Exposed Service Members.

OBJECTIVE: To determine if elevated rapid-response impulsivity after blast exposure (as a putative marker of ventral prefrontal cortex [vPFC] damage) is predictive of future elevated affective symptomatology in blast-exposed service members. DESIGN: Longitudinal design with neurocognitive testing at initial assessment and 1-year follow-up assessment of psychiatric symptomatology by telephone interview. SETTING: Veterans Administration medical centers and postdeployment assessment centers at military bases. PARTICIPANTS: Blast-exposed U.S. military personnel (N=84) ages 19 to 39 years old. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Center for Epidemiological Studies-Depression Scale (CES-D) scores, Posttraumatic Stress Disorder Checklist Version 5 (PCL-5) scores, and Alcohol Use Disorders Identification Test-C (AUDIT-C) scores at the 12-month follow-up telephone interview. RESULTS: After controlling for age and affective symptom scores reported at the initial assessment, commission errors on the Continuous Performance Test-II of the initial assessment were predictive of higher symptom scores on the CES-D and PCL-5 at follow-up, but were not predictive of AUDIT-C scores. CONCLUSIONS: Elevated rapid-response impulsivity, as a behavioral marker of reduced top-down frontocortical control, is a risk factor for elevated mood and posttraumatic stress disorder symptoms over time in blast-exposed individuals. Future longitudinal studies with predeployment neurobehavioral testing could enable attribution of this relation to blast-related vPFC damage.

Seasonal changes in brown adipose tissue mitochondria in a mammalian hibernator: from gene expression to function.

Brown adipose tissue (BAT) is a thermogenic organ that is vital for hibernation in mammals. Throughout the hibernation season, BAT mitochondrial uncoupling protein 1 (UCP1) enables rapid rewarming from hypothermic torpor to periodic interbout arousals (IBAs), as energy is dissipated as heat. However, BAT's unique ability to rewarm the body via nonshivering thermogenesis is not necessary outside the hibernation season, suggesting a potential seasonal change in the regulation of BAT function. Here, we examined the BAT mitochondrial proteome and mitochondrial bioenergetics in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) across four time points: spring, fall, torpor, and IBA. Relative mitochondrial content of BAT was estimated by measuring BAT pad mass, UCP1 protein content, and mitochondrial DNA (mtDNA) copy number. BAT mtDNA content was significantly lower in spring compared with torpor and IBA (P < 0.05). UCP1 mRNA and protein levels were highest during torpor and IBA. Respiration rates of isolated BAT mitochondria were interrogated at each complex of the electron transport chain. Respiration at complex II was significantly higher in torpor and IBA compared with spring (P < 0.05), suggesting an enhancement in mitochondrial respiratory capacity during hibernation. Additionally, proteomic iTRAQ labeling identified 778 BAT mitochondrial proteins. Proteins required for mitochondrial lipid translocation and ß-oxidation were upregulated during torpor and IBA and downregulated in spring. These data imply that BAT bioenergetics and mitochondrial content are not static across the year, despite the year-round presence of UCP1.

Cumulative gains enhance striatal response to reward opportunities in alcohol-dependent patients.

Substance use disorder is characterized by a transition from volitional to compulsive responding for drug reward. A possible explanation for this transition may be that alcohol-dependent patients (ADP) show a general propensity for a history of rewarded instrumental responses, and these rewarded responses may boost the activation of motivational neurocircuitry for additional reward. Brain imaging studies of decision-making have demonstrated that ADP relative to controls (CON) often show altered neural activation in response to anticipating and receiving rewards, but the majority of studies have not investigated how past performance affects activation. A potential exists for ADP to show increased sensitivity to reward as a function of reward delivery history. In the current study, we used functional magnetic resonance imaging to investigate the neural correlates of risky decision-making in ADP (n = 18) and CON (n = 18) while they played a two-choice monetary risk-taking game. In addition to investigating general neural recruitment by risky decision-making, we also modeled each participant's running total of monetary earnings in order to determine areas of activation that correlated with cumulative reward. We found that ADP and CON showed few differences in behavior or in mesolimbic activation by choice for, and receipt of, risky gains. However, when including a cumulative-earnings covariate, ADP exhibited heightened striatal activation that correlated with total earnings during the choice event in the task. The heightened contextual sensitivity of striatal responses to cumulative earnings in ADP may represent a general neurobiological affective substrate for development of automatized instrumental behavior.

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.

Developmental differences in striatal recruitment by reward prospects as a function of attentional demand.

Adolescent risk-taking has been attributed to earlier-developing motivational neurocircuitry that is poorly controlled by immature executive-control neurocircuitry. Functional magnetic resonance imaging findings of increased ventral striatum (VS) recruitment by reward prospects in adolescents compared to adults support this theory. Other studies found blunted VS recruitment by reward-predictive cues in adolescents compared to adults. Task features may explain this discrepancy but have never been systematically explored. Adolescents and adults performed a novel reward task that holds constant the expected value of all rewards but varies whether rewards are dependent on vigilance-intensive responding versus making a lucky choice during a relaxed response window. We examined group by sub-task contrast differences in activation of VS and more motoric regions of striatum in response to anticipatory cues. Reward anticipation in both task conditions activated portions of striatum in both groups. In voxel-wise comparison, adults showed greater anticipatory recruitment of VS in trials involving choice during a relaxed time window, not in the more vigilance-demanding trials as hypothesized. In accord with our hypotheses, however, adults showed greater activation in dorsal striatum and putamen volumes of interest during reward anticipation under vigilance-demanding conditions. Following trial outcome notifications, adolescents showed greater activation of the VS during reward notification but lower activation during loss notification. These data extend findings of cross-sectional age-group differences in incentive-anticipatory recruitment of striatum, by demonstrating in adults relatively greater recruitment of motor effector regions of striatum by attentional and motor demands.

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.

Neurocognitive function and medical care utilization in Veterans treated for substance use disorder.

BACKGROUND: Veterans with substance use disorder (SUD) are at high risk for cognitive problems due to neurotoxic effects of chronic drug and alcohol use coupled in many cases with histories of traumatic brain injury (TBI). These problems may in turn result in proneness to SUD relapse and reduced adherence to medical self-care regimens and therefore reliance on health care systems. However, the direct relationship between cognitive function and utilization of Veterans Health Administration (VHA) SUD and other VHA health care services has not been evaluated. We sought initial evidence as to whether neurocognitive performance relates to repeated health care engagement in Veterans as indexed by estimated VHA care costs. METHODS: Neurocognitive performance in 76 Veterans being treated for SUD was assessed using CNS-Vital Signs, a commercial computerized cognitive testing battery, and related to histories of outpatient and inpatient/residential care costs as estimated by the VHA Health Economics Resource Center. RESULTS: After controlling for age, an aggregate metric of overall neurocognitive performance (Neurocognition Index) correlated negatively with total VHA health care costs, particularly with SUD-related outpatient care costs but also with non-mental health-related care costs. Barratt Impulsiveness Scale scores also correlated positively with total VHA care costs. CONCLUSIONS: In Veterans receiving SUD care, higher impulsivity and lower cognitive performance were associated with greater health care utilization within the VHA system. This suggests that veterans with SUD who show lower neurocognitive performance are at greater risk for continued health problems that require healthcare engagement. Cognitive rehabilitation programs developed for brain injury and other neurological conditions could be tried in Veterans with SUD to improve their health outcomes.

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.

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.