Keratosis Pilaris-Like Reaction Associated With Chromatin Remodeling Complex Inhibition in Uveal Melanoma.

This case series describes a constellation of novel adverse reactions in 3 of 9 patients with uveal melanoma receiving treatment targeting activity of the Brahma-associated factor chromatin remodeling complex.

Menstrual Cycle Phase has no Influence on Performance-Determining Variables in Endurance-Trained Athletes: The FENDURA Project.

PURPOSE: To investigate the effect of the MC and endogenous sex hormone concentrations on performance-determining variables in three distinct MC phases in endurance-trained females. METHODS: Twenty-one eumenorrheic trained/highly trained endurance athletes completed a standardized test battery during the early follicular phase (EFP), ovulatory phase (OP), and mid-luteal phase (MLP) for either one (n = 7) or two test cycles (n = 14). MC phases were determined using calendar-based counting, urinary ovulation testing, and verified with serum hormone analysis. MCs were retrospectively classified as eumenorrheic or disturbed. Disturbed MCs were excluded from analysis. The test battery consisted of 4-6 x 5-min submaximal stages with stepwise speed increases, a 30-s all-out double-poling ski ergometer test, and a maximal incremental treadmill running test. RESULTS: At a group level, there was no effect of MC phase or the serum concentrations of estrogen and progesterone on peak oxygen uptake ( O 2peak ), oxygen uptake at 4 mmol·L -1 blood lactate concentration, time-to-exhaustion, running economy, or mean 30-s power output (MPO 30s ). Serum testosterone concentration was positively associated with MPO 30s (p = 0.016). Changes in O 2peak from EFP to MLP were inconsistent between individuals and across cycles. CONCLUSIONS: None of the measured performance-determining variables were influenced by MC phase or serum estrogen or progesterone concentrations. While some individual patterns could be observed, there was no indication that any single MC phase is consistently associated with improved or impaired O 2peak on a group level.

The New Media Landscape and Its Effects on Skin Cancer Diagnostics, Prognostics, and Prevention: Scoping Review.

BACKGROUND: The wide availability of web-based sources, including social media (SM), has supported rapid, widespread dissemination of health information. This dissemination can be an asset during public health emergencies; however, it can also present challenges when the information is inaccurate or ill-informed. Of interest, many SM sources discuss cancer, specifically cutaneous melanoma and keratinocyte cancers (basal cell and squamous cell carcinoma). OBJECTIVE: Through a comprehensive and scoping review of the literature, this study aims to gain an actionable perspective of the state of SM information regarding skin cancer diagnostics, prognostics, and prevention. METHODS: We performed a scoping literature review to establish the relationship between SM and skin cancer. A literature search was conducted across MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from January 2000 to June 2023. The included studies discussed SM and its relationship to and effect on skin cancer. RESULTS: Through the search, 1009 abstracts were initially identified, 188 received full-text review, and 112 met inclusion criteria. The included studies were divided into 7 groupings based on a publication's primary objective: misinformation (n=40, 36%), prevention campaign (n=19, 17%), engagement (n=16, 14%), research (n=12, 11%), education (n=11, 10%), demographics (n=10, 9%), and patient support (n=4, 3%), which were the most common identified themes. CONCLUSIONS: Through this review, we gained a better understanding of the SM environment addressing skin cancer information, and we gained insight into the best practices by which SM could be used to positively influence the health care information ecosystem.

Persistent poverty and incidence-based melanoma mortality in Texas.

PURPOSE: Previous studies have shown that individuals living in areas with persistent poverty (PP) experience worse cancer outcomes compared to those living in areas with transient or no persistent poverty (nPP). The association between PP and melanoma outcomes remains unexplored. We hypothesized that melanoma patients living in PP counties (defined as counties with ≥ 20% of residents living at or below the federal poverty level for the past two decennial censuses) would exhibit higher rates of incidence-based melanoma mortality (IMM). METHODS: We used Texas Cancer Registry data to identify the patients diagnosed with invasive melanoma or melanoma in situ (stages 0 through 4) between 2000 and 2018 (n = 82,458). Each patient's PP status was determined by their county of residence at the time of diagnosis. RESULTS: After adjusting for demographic variables, logistic regression analyses revealed that melanoma patients in PP counties had statistically significant higher IMM compared to those in nPP counties (17.4% versus 11.3%) with an adjusted odds ratio of 1.35 (95% CI 1.25-1.47). CONCLUSION: These findings highlight the relationship between persistent poverty and incidence-based melanoma mortality rates, revealing that melanoma patients residing in counties with persistent poverty have higher melanoma-specific mortality compared to those residing in counties with transient or no poverty. This study further emphasizes the importance of considering area-specific socioeconomic characteristics when implementing place-based interventions to facilitate early melanoma diagnosis and improve melanoma treatment outcomes.

Virtual Reality Application for Vestibular/Ocular Motor Screening: Current Clinical Protocol Versus a Novel Prototype.

BACKGROUND: Virtual reality (VR) has been explored to improve baseline and postinjury assessments in sport-related concussion (SRC). Some experience symptoms related to VR, unrelated to concussion. This may deter use of vestibular/ocular motor screening (VOMS) using VR. Baseline VR VOMS symptomatology differentiates baseline from overall symptomatology. HYPOTHESIS: There will be no difference between current clinical manual VOMS (MAN), a clinical prototype (PRO), and VR for symptom provocation change score (SPCS) and near point of convergence (NPC) average score in a healthy population and sex differences among the 3 modes of administration. STUDY DESIGN: Cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 688 National Collegiate Athletic Association Division I student-athletes completed VOMS using 3 methods (MAN, N = 111; female athletes, N = 47; male athletes, N = 64; average age, 21 years; PRO, N = 365; female athletes, N = 154; male athletes, N = 211; average age, 21 years; VR, N = 212; female athletes, N = 78; male athletes, N = 134; average age = 20 years) over a 3-year period (2019-2021) during annual baseline testing. Exclusion criteria were as follows: self-reported motion sickness in the past 6 months, existing or previous neurological insult, attention deficit hyperactivity disorder, learning disabilities, or noncorrected vision impairment. Administration of MAN followed the current clinical protocols, PRO used a novel prototype, and VR used an HTC Vive Pro Eye head mounted display. Symptom provocation was compared using Mann-Whitney U tests across each VOMS subtest with total SPCS and NPC average by each method. RESULTS: MAN had significantly (P < 0.01) more baseline SPCS (MAN = 0.466 ± 1.165, PRO = 0.163 ± 0.644, VR = 0.161 ± 0.933) and significantly (P < 0.01) and more SPCS (MAN = 0.396 ± 1.081, PRO = 0.128 ± 0.427, VR = 0.48 ± 0.845) when compared with PRO and VR. NPC average measurements for VR (average, 2.99 ± 0.684 cm) were significantly greater than MAN (average, 2.91 ± 3.35 cm; P < 0.01; Cohen's d = 0.03) and PRO (average, 2.21 ± 1.81 cm; P < 0.01; Cohen's d = 0.57). For sex differences, female athletes reported greater SPCS with PRO (female athletes, 0.29 ± 0.87; male athletes, 0.06 ± 0.29; P < 0.01) but not in VR or MAN. CONCLUSION: Using a VR system to administer the VOMS may not elicit additional symptoms, resulting in fewer false positives and is somewhat stable between sexes. CLINICAL RELEVANCE: VOMS may allow for standardization among administrators and reduce possible false positives.

The Influence of Menstrual-Cycle Phase on Measures of Recovery Status in Endurance Athletes: The Female Endurance Athlete Project.

PURPOSE: To investigate the influence of menstrual-cycle (MC) phase on measures of recovery status, that is, resting heart rate, perceived sleep quality, and physical and mental readiness to train, among female endurance athletes. METHODS: Daily data were recorded during 1 to 4 MCs (ie, duration ≥21 and ≤35 d, ovulatory, luteal phase ≥10 d) of 41 trained-to-elite-level female endurance athletes (mean [SD]: age 27 [8] y, weekly training: 9 [3] h). Resting heart rate was assessed daily using a standardized protocol, while perceived sleep quality and physical and mental readiness to train were assessed using a visual analog scale (1-10). Four MC phases (early follicular phase [EFP], late follicular phase, ovulatory phase, and midluteal phase [MLP]) were determined using the calendar-based counting method and urinary ovulation-prediction test. Data were analyzed using linear mixed-effects models. RESULTS: Resting heart rate was significantly higher in MLP (1.7 beats·min-1, P = .006) compared with EFP without significant differences between the other MC phases. Perceived sleep quality was impaired in MLP compared with late follicular phase (-0.3, P = .035). Physical readiness to train was lower both in ovulatory phase (-0.6, P = .015) and MLP (-0.5, P = .026) compared with EFP. Mental readiness to train did not show any significant differences between MC phases (P > .05). CONCLUSIONS: Although significant, the findings had negligible to small effect sizes, indicating that MC phase is likely not the main determinant of changes in measures of recovery status but, rather, one of the many possible stressors.

Understanding Whether and How a Digital Health Intervention Improves Transition Care for Emerging Adults Living With Type 1 Diabetes: Protocol for a Mixed Methods Realist Evaluation.

BACKGROUND: Emerging adults living with type 1 diabetes (T1D) face a series of challenges with self-management and decreased health system engagement, leading to an increased risk of acute complications and hospital admissions. Effective and scalable strategies are needed to support this population to transfer seamlessly from pediatric to adult care with sufficient self-management capability. While digital health interventions for T1D self-management are a promising strategy, it remains unclear which elements work, how, and for which groups of individuals. OBJECTIVE: This study aims to evaluate the design and implementation of a multicomponent SMS text message-based digital health intervention to support emerging adults living with T1D in real-world settings. The objectives are to identify the intervention components and associated mechanisms that support user engagement and T1D health care transition experiences and determine the individual characteristics that influence the implementation process. METHODS: We used a realist evaluation embedded alongside a randomized controlled trial, which uses a sequential mixed methods design to analyze data from multiple sources, including intervention usage data, patient-reported outcomes, and realist interviews. In step 1, we conducted a document analysis to develop a program theory that outlines the hypothesized relationships among "individual-level contextual factors, intervention components and features, mechanisms, and outcomes," with special attention paid to user engagement. Among them, intervention components and features depict 10 core characteristics such as transition support information, problem-solving information, and real-time interactivity. The proximal outcomes of interest include user engagement, self-efficacy, and negative emotions, whereas the distal outcomes of interest include transition readiness, self-blood glucose monitoring behaviors, and blood glucose. In step 2, we plan to conduct semistructured realist interviews with the randomized controlled trial's intervention-arm participants to test the hypothesized "context-intervention-mechanism-outcome" configurations. In step 3, we plan to triangulate all sources of data using a coincidence analysis to identify the necessary combinations of factors that determine whether and how the desired outcomes are achieved and use these insights to consolidate the program theory. RESULTS: For step 1 analysis, we have developed the initial program theory and the corresponding data collection plan. For step 2 analysis, participant enrollment for the randomized controlled trial started in January 2023. Participant enrollment for this realist evaluation was anticipated to start in July 2023 and continue until we reached thematic saturation or achieved informational power. CONCLUSIONS: Beyond contributing to knowledge on the multiple pathways that lead to successful engagement with a digital health intervention as well as target outcomes in T1D care transitions, embedding the realist evaluation alongside the trial may inform real-time intervention refinement to improve user engagement and transition experiences. The knowledge gained from this study may inform the design, implementation, and evaluation of future digital health interventions that aim to improve transition experiences. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46115.

Text message-based intervention, Keeping in Touch (KiT), to support youth as they transition to adult type 1 diabetes care: a protocol for a multisite randomised controlled superiority trial.

INTRODUCTION: Transition from paediatric to adult care can be challenging for youth living with type 1 diabetes (T1D), as many youth feel unprepared to transfer to adult care and are at high risk for deterioration of glycaemic management and acute complications. Existing strategies to improve transition experience and outcomes are limited by cost, scalability, generalisability and youth engagement. Text messaging is an acceptable, accessible and cost-effective way of engaging youth. Together with adolescents and emerging adults and paediatric and adult T1D providers, we co-designed a text message-based intervention, Keeping in Touch (KiT), to deliver tailored transition support. Our primary objective is to test the effectiveness of KiT on diabetes self-efficacy in a randomised controlled trial. METHODS AND ANALYSIS: We will randomise 183 adolescents with T1D aged 17-18 years within 4 months of their final paediatric diabetes visit to the intervention or usual care. KiT will deliver tailored T1D transition support via text messages over 12 months based on a transition readiness assessment. The primary outcome, self-efficacy for diabetes self-management, will be measured 12 months after enrolment. Secondary outcomes, measured at 6 and 12 months, include transition readiness, perceived T1D-related stigma, time between final paediatric and first adult diabetes visits, haemoglobin A1c, and other glycaemia measures (for continuous glucose monitor users), diabetes-related hospitalisations and emergency department visits and the cost of implementing the intervention. The analysis will be intention-to-treat comparing diabetes self-efficacy at 12 months between groups. A process evaluation will be conducted to identify elements of the intervention and individual-level factors influencing implementation and outcomes. ETHICS AND DISSEMINATION: The study protocol version 7 July 2022 and accompanying documents were approved by Clinical Trials Ontario (Project ID: 3986) and the McGill University Health Centre (MP-37-2023-8823). Study findings will be presented at scientific conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05434754.

Exposure to polychlorinated biphenyls selectively dysregulates endothelial circadian clock and endothelial toxicity.

Polychlorinated biphenyls (PCBs) are lipophilic and persistent environmental toxicants, which pose health threats to the exposed population. Among several organs and cell types, vascular tissue and endothelial cells are especially prone to PCB-induced toxicity. Exposure to PCBs can exert detrimental impacts on biological pathways, expression of transcription factors, and tight junction proteins that are integral to the functionality of endothelial cells. Because biological and cellular processes are tightly regulated by circadian rhythms, and disruption of the circadian system may cause several diseases, we evaluated if exposure to PCBs can alter the expression of the major endothelial circadian regulators. In addition, we studied if dysregulation of circadian rhythms by silencing the brain and muscle ARNT-like 1 (Bmal1) gene can contribute to alterations of brain endothelial cells in response to PCB treatment. We demonstrated that diminished expression of Bmal1 enhances PCB-induced dysregulation of tight junction complexes, such as the expression of occludin, JAM-2, ZO-1, and ZO-2 especially at pathologically relevant longer PCB exposure times. Overall, the obtained results imply that dysregulation of the circadian clock is involved in endothelial toxicity of PCBs. The findings provide new insights for toxicological studies focused on the interactions between environmental pollutants and regulation of circadian rhythms.

Preliminary Examination of Guardian Cap Head Impact Data Using Instrumented Mouthguards.

Purpose The objective of this study is to present preliminary on-field head kinematics data for NCAA Division I American football players through closely matched pre-season workouts both with and without Guardian Caps (GCs). Methods 42 NCAA Division I American football players wore instrumented mouthguards (iMMs) for 6 closely matched workouts, 3 in traditional helmets (PRE) and 3 with GCs (POST) affixed to the exterior of their helmets. This includes 7 players who had consistent data through all workouts. Results There was no significant difference between the collapsed mean values for the entire sample between PRE and POST for peak linear acceleration (PLA) (PRE=16.3, POST=17.2Gs; p=0.20), Peak Angular Acceleration (PAA) (PRE=992.1, POST=1029.4rad/s2; p=0.51 and the total amount of impacts (PRE=9.3, POST=9.7; p=0.72). Similarly, no difference was observed between PRE and POST for PLA (PRE=16.1, POST=17.2Gs; p=0.32), PAA (PRE=951.2, POST=1038.0rad/s2; p=0.29 and total impacts (PRE=9.6, POST=9.7; p=0.32) between sessions for the 7 repeated players. Conclusion These data suggest no difference in head kinematics data (PLA, PAA and total impacts) when GCs are worn. This study suggests GCs are not effective in reducing the magnitude of head impacts experienced by NCAA Division I American football players.

Minimal detectable change for the ImPACT test administered remotely.

CONTEXT: The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is one of the most widely used computerized neurocognitive assessment batteries in athletics, serving as both a baseline and post-injury assessment. It has become increasingly popular to administer the ImPACT baseline test in an un-supervised remote environment, however, it is unknown if the lack of supervision affects the test-retest reliability. OBJECTIVE: To establish the minimal detectable change (MDC) of composite scores from the ImPACT test when administered to National Collegiate Athletic Association (NCAA) Division I student-athletes in an un-supervised remote environment before two consecutive athletic seasons. DESIGN: Cross-Sectional. SETTING: Participants were provided with a unique link and detailed written instructions on how to complete the ImPACT test at home. PATIENTS OR OTHER PARTICIPANTS: NCAA Division I student-athletes. MAIN OUTCOME MEASURE(S): Remote ImPACT baseline test results from the 2020-2021 and 2021-2022 athletic seasons were analyzed. The MDC was calculated at the 95%, 90%, and 80% confidence intervals for each of the ImPACT composite scores, as well as the average and standard deviation. RESULTS: The MDC at the 95% confidence interval was found to be 18.6 for the verbal memory composite score, 24.44 for visual memory, 8.76 for visual motor, 0.14 for reaction time, and 6.13 for impulse control. One-way repeated measures MANOVA, repeated measures ANOVA, and Wilcoxon signed-ranks test all suggest no significant difference between the composite scores and impulse control between time points. CONCLUSIONS: The ImPACT test composite scores and impulse control did not significantly change between the two remote testing time points when administered approximately a year between testing. Our study suggests the MDC serve as a clinician's guide for evaluating changes in ImPACT baseline scores and in making clinical judgments on sports-related concussion when the test is administered at home.

A Pilot Implementation-Effectiveness Trial of a Single-Session Telehealth Workshop and Smartphone-Based Cognitive Behavioral Intervention for Managing Emotions Among College Students.

The number of college students who need mental health treatment outpaces the resources available to counseling centers to provide these needed services, presenting a need for low-cost, scalable interventions for college populations. We conducted a pilot implementation-effectiveness trial of a scalable treatment package that consisted of a single (telehealth) workshop plus a companion app that provided ecological momentary intervention. Participants (n = 177) received a workshop provided by counseling center staff and trainees. We were interested in (1) engagement with the app, (2) acceptability of the treatment package, and (3) initial effectiveness of the treatment package. Regarding engagement with the app, we found that participants preferred two reminder prompts per day and identified two key breakpoints when engagement declined significantly: at day 15, when just over half of the sample practiced a skill on the app at least once during the day and at day 41, when just over one third of people practiced a skill on the app each day. Regarding acceptability of the treatment package, students generally reported positive attitudes about the single-session workshop and app, but also noted that the content and assessments in the app needed to be more dynamic to improve how engaging it is. Regarding effectiveness, we found that about 75% of the sample experienced a significant reduction in negative affect from pre- to post-ecological momentary intervention. Moreover, there were significant pre- to post-study decreases in experiential avoidance and symptoms of anxiety and depression and increases in self-efficacy for managing negative emotions. The results of this study are promising in terms of providing initial support for this novel treatment package and provide useful information for researchers planning to develop and test similar interventions.

The Effectiveness of a Brief Telehealth and Smartphone Intervention for College Students Receiving Traditional Therapy: Longitudinal Study Using Ecological Momentary Assessment Data.

BACKGROUND: Brief interventions such as mental health apps and single-session interventions are increasingly popular, efficacious, and accessible delivery formats that may be beneficial for college students whose mental health needs may not be adequately met by college counseling centers. However, no studies so far have examined the effectiveness of these modes of treatment for college students who are already receiving traditional therapy, despite it being common among this population. OBJECTIVE: The aim of this study was to compare the differences in self-reported momentary negative affect between college students in therapy and not in therapy who received a brief single-session intervention delivered by counseling center staff and a supplemental mobile app. METHODS: Data for this study were drawn from E-Manage, a brief mobile health intervention geared toward college students. Participants in the study were 173 college students who indicated whether they had received therapy. We conducted a multilevel model to determine whether there were differences between those in therapy versus not in therapy in negative affect reported throughout the study. Following this, we conducted multilevel models with therapy status as the predictor and negative affect as the outcome. RESULTS: Results of the multilevel model testing showed that the cross-level interaction between the time point (ie, pre- vs postexercise) and therapy status was significant (P=.008), with the reduction in negative affect from pre- to postexercise greater for those in therapy (b=-0.65, 95% CI -0.91 to -0.40; P<.001) than it was for those not in therapy (b=-0.31, 95% CI -0.43 to -0.19; P<.001). Therapy status was unassociated with both the pre-exercise (b=-1.69, 95% CI -3.51 to 0.13; P=.07) and postexercise (b=-1.37, 95% CI -3.17 to 0.43; P=.14) ratings of negative affect. CONCLUSIONS: These findings suggest that app-based and single-session interventions are also appropriate to use among college students who are receiving traditional therapy. A randomized controlled trial comparing students receiving therapy to students receiving therapy and E-Manage will be necessary to determine to what extent E-Manage contributed to the reductions in negative affect that therapy-attending college students experienced.

Promoting Graduate Student Mental Health During COVID-19: Acceptability, Feasibility, and Perceived Utility of an Online Single-Session Intervention.

The COVID-19 outbreak has simultaneously increased the need for mental health services and decreased their availability. Brief online self-help interventions that can be completed in a single session could be especially helpful in improving access to care during the crisis. However, little is known about the uptake, acceptability, and perceived utility of these interventions outside of clinical trials in which participants are compensated. Here, we describe the development, deployment, acceptability ratings, and pre-post effects of a single-session intervention, the Common Elements Toolbox (COMET), adapted for the COVID-19 crisis to support graduate and professional students. Participants (n = 263), who were not compensated, were randomly assigned to two of three modules: behavioral activation, cognitive restructuring, and gratitude. Over 1 week, 263 individuals began and 189 individuals (72%) completed the intervention. Participants reported that the intervention modules were acceptable (93% endorsing), helpful (88%), engaging (86%), applicable to their lives (87%), and could help them manage COVID-related challenges (88%). Participants reported pre- to post-program improvements in secondary control (i.e., the belief that one can control their reactions to objective events; d av = 0.36, d z = 0.50, p < 0.001) and in the perceived negative impact of the COVID-19 crisis on their quality of life (d av = 0.22, d z = 0.25, p < 0.001). On average, differences in their perceived ability to handle lifestyle changes resulting from the pandemic were positive, but small and at the level of a non-significant trend (d av = 0.13, d z = 0.14, p = 0.066). Our results highlight the acceptability and utility of an online intervention for supporting individuals through the COVID-19 crisis.

The Inclusion of Sprints in Low-Intensity Sessions During the Transition Period of Elite Cyclists Improves Endurance Performance 6 Weeks Into the Subsequent Preparatory Period.

PURPOSE: To investigate the effects of including repeated sprints in a weekly low-intensity (LIT) session during a 3-week transition period on cycling performance 6 weeks into the subsequent preparatory period (PREP) in elite cyclists. METHODS: Eleven elite male cyclists (age = 22.0 [3.8] y, body mass = 73.0 [5.8] kg, height = 186 [7] cm, maximal oxygen uptake [VO2max] = 5469 [384] mL·min-1) reduced their training load by 64% and performed only LIT sessions (CON, n = 6) or included 3 sets of 3 × 30-second maximal sprints in a weekly LIT session (SPR, n = 5) during a 3-week transition period. There was no difference in the reduction in training load during the transition period between groups. Physiological and performance measures were compared between the end of the competitive period and 6 weeks into the PREP. RESULTS: SPR demonstrated a 7.3% (7.2%) improvement in mean power output during a 20-minute all-out test at PREP, which was greater than CON (-1.3% [4.6%]) (P = .048). SPR had a corresponding 7.0% (3.6%) improvement in average VO2 during the 20-minute all-out test, which was larger than the 0.7% (6.0%) change in CON (P = .042). No change in VO2max, gross efficiency, or power output at blood lactate concentration of 4 mmol·L-1 from competitive period to PREP occurred in either group. CONCLUSION: Including sprints in a weekly LIT session during the transition period of elite cyclists provided a performance advantage 6 weeks into the subsequent PREP, which coincided with a higher performance VO2.

Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning.

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.

Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.

The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

Domain-Specific Working Memory, But Not Dopamine-Related Genetic Variability, Shapes Reward-Based Motor Learning.

The addition of rewarding feedback to motor learning tasks has been shown to increase the retention of learning, spurring interest in its possible utility for rehabilitation. However, motor tasks using rewarding feedback have repeatedly been shown to lead to great interindividual variability in performance. Understanding the causes of such variability is vital for maximizing the potential benefits of reward-based motor learning. Thus, using a large human cohort of both sexes (n = 241), we examined whether spatial (SWM), verbal, and mental rotation (RWM) working memory capacity and dopamine-related genetic profiles were associated with performance in two reward-based motor tasks. The first task assessed the participant's ability to follow a slowly shifting reward region based on hit/miss (binary) feedback. The second task investigated the participant's capacity to preserve performance with binary feedback after adapting to the rotation with full visual feedback. Our results demonstrate that higher SWM is associated with greater success and an enhanced capacity to reproduce a successful motor action, measured as change in reach angle following reward. In contrast, higher RWM was predictive of an increased propensity to express an explicit strategy when required to make large reach angle adjustments. Therefore, SWM and RWM were reliable, but dissociable, predictors of success during reward-based motor learning. Change in reach direction following failure was also a strong predictor of success rate, although we observed no consistent relationship with working memory. Surprisingly, no dopamine-related genotypes predicted performance. Therefore, working memory capacity plays a pivotal role in determining individual ability in reward-based motor learning.SIGNIFICANCE STATEMENT Reward-based motor learning tasks have repeatedly been shown to lead to idiosyncratic behaviors that cause varying degrees of task success. Yet, the factors determining an individual's capacity to use reward-based feedback are unclear. Here, we assessed a wide range of possible candidate predictors, and demonstrate that domain-specific working memory plays an essential role in determining individual capacity to use reward-based feedback. Surprisingly, genetic variations in dopamine availability were not found to play a role. This is in stark contrast with seminal work in the reinforcement and decision-making literature, which show strong and replicated effects of the same dopaminergic genes in decision-making. Therefore, our results provide novel insights into reward-based motor learning, highlighting a key role for domain-specific working memory capacity.

Phase-Transition Temperature of Gold-Nanorod-Coated Nanodroplets to Microbubbles by Pulsed Laser.

Previously, gold-nanorod-coated perfluorocarbon nanodroplets have been developed as light-activated on-demand drug delivery carriers. When gold nanorods on the perfluorocarbon nanodroplets resonate with a laser wavelength, plasmonic heat is generated and vaporizes the nanodroplets to gas bubbles. Optimal laser parameters such as pulse duration, pulse repetition frequency, and average power are critical to effectively trigger the phase transition of nanodroplets and allow for drug release. This study focused on determining the temperature of a gold-nanorod-coated perfluorocarbon nanodroplet during phase transition to a gas bubble using a femtosecond laser. Two integrated experimental and theoretical methods were explored. First, the theoretical temperature was determined by the Arrhenius equation and the time it took for the phase transition to occur, assuming the phase-transition process followed a first-order kinetic model. The activation energy and Arrhenius constant of the phase-transition process were obtained via light transmittance through a nanodroplet suspension at different temperatures. The time required for phase transition by a femtosecond laser was measured using an optical microscope. The second approach used a classical heat diffusion model. When the pulse peak energy was considered in the model, the temperature predicted matched the experimental observation of phase-transition temperature threshold, while the total energy value failed to predict the temperature threshold. The results suggest that the phase-transition mechanism is triggered by the vaporization of the nanodroplets via photothermal heating, which is influenced by the peak energy of the laser. It also indicates that optimal laser parameters can be determined by a simple calculation using the classical heat diffusion model and peak energy to control phase transition.

Light-Activatable Theranostic Agents for Image-Monitored Controlled Drug Delivery.

A novel drug delivery vehicle using nanodroplets activated by light irradiation for drug release in a controlled manner has been developed. The drug encapsulated in the nanodroplets was released upon phase transition from a liquid droplet to microbubbles (vaporization) by plasmonic photothermal heat from gold nanorods adsorbed on the surface of the nanodroplets. The nanodroplets were stable against aggregation and dissolution at 4 °C over 3 months to date. The phase transition was quantitatively analyzed by ultrasound imaging to examine the amount of drug release noninvasively. In vitro studies showed that cell death occurred only when light irradiation was performed on the drug-encapsulated nanodroplets. Ex vivo studies demonstrated a potential application of the nanodroplets for treating posterior eye diseases. Thus, it has been demonstrated that our gold-nanorod-coated light-activatable nanodroplets can be a candidate for a controlled release and a dosage-monitored drug delivery system.