Sera from people with HIV and depression induce commensurate metabolic alterations in astrocytes: toward precision diagnoses and therapies.

Objectives: People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH. Methods: Human astrocytes were exposed to sera from PWH (n=40) with varying degrees of depressive symptomatology and cognitive function. MitoTrackerTM Deep Red FM (MT) was used to visualize mitochondrial activity and glial fibrillary acidic protein (GFAP) as an indicator of astrocyte reactivity using the high-throughput fluorescent microscopy and image analyses platform, CellInsight CX5 (CX5). The Seahorse platform was used to assess glycolytic and mitochondrial metabolism. Results: More severe depression, as indexed by higher Beck's Depression Inventory (BDI-II) scores, was associated with lower MT signal measures. Better cognitive function, as assessed by neuropsychiatric testing t-scores, was associated with increased MT signal measures. GFAP intensity negatively correlated with several cognitive t-scores. Age positively correlated with (higher) MT signal measures and GFAP intensity. Worse depressive symptoms (higher BDI-II scores) were associated with decreased oxygen consumption rate and spare respiratory capacity, concomitant with increased extracellular acidification rate in astrocytes. Conclusions: These findings show that factors in the sera of PWH alter mitochondrial activity in cultured human astrocytes, suggesting that mechanisms that alter mitochondrial and astrocyte homeostasis can be detected peripherally. Thus, in vitro cultures may provide a model to identify neuropathogenic mechanisms of depression or neurocognitive impairment in PWH and test personalized therapeutics for neurologic and psychiatric disorders.

Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain.

Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

Behavioral and Physical Activity Interventions for HAND.

Approximately 30-50% of persons living with HIV manifest some degree of neurocognitive impairment. Even mild-to-moderate forms of HIV-associated neurocognitive disorders (HAND) can result in difficulties with everyday functioning, such as suboptimal medication adherence and impaired driving. Despite the pervasive presence and consequences of HAND, there is a significant unmet need to develop effective behavioral strategies to reduce the incidence and consequences of HAND. Although there is an absence of evidence-based behavioral interventions specific to HAND, the literature reviewed in this chapter suggest the following modifiable lifestyle factors as intervention targets: physical activity, diet, sleep, and antiretroviral medication adherence. Adoption and maintenance of these healthy lifestyle factors may reduce inflammation and oxidative stress, which, in turn, may reduce the incidence and/or severity of HAND.

Cannabis use is associated with greater total sleep time in middle-aged and older adults with and without HIV: A preliminary report utilizing digital health technologies.

Current literature on the effect of cannabis use on sleep quality is mixed, and few studies have used objectively-measured sleep measures or real-time sampling of cannabis use to examine this relationship. The prevalence of cannabis use among older adults and persons living with HIV has increased in recent years, and poor sleep quality is elevated in these populations as well. However, research examining cannabis-sleep relationships in these populations is lacking. Thus, we aimed to examine the relationship between daily cannabis use and subsequent objectively-measured sleep quality in middle-aged and older adults with and without HIV. In this pilot study, seventeen (11 HIV+, 6 HIV-) adults aged 50-70 who consumed cannabis completed four daily smartphone-based surveys for 14 days, in which they reported their cannabis use (yes/no) since the last survey. Participants also wore actigraphy watches during the 14-day period to objectively assess sleep quality (i.e., efficiency, total sleep time, and sleep fragmentation). In linear mixed-effects models, cannabis use was significantly associated with greater subsequent total sleep time (ß=0.56; p=0.046). Cannabis use was not related to a change in sleep efficiency (ß=1.50; p=0.46) nor sleep fragmentation (ß=0.846, p=0.756) on days with cannabis use versus days without cannabis use. These preliminary results indicate cannabis use may have a positive effect on sleep duration in middle-aged and older adults. However, future studies with larger sample sizes that assess cannabis use in more detail (e.g., route of administration, dose, reason for use) are needed to further understand this relationship.

Greater Well-Being in More Physically Active Cancer Patients Who Are Enrolled in Supportive Care Services.

Background: Cancers are one of the leading causes of mortality worldwide. Cancer patients are increasingly seeking integrative care clinics to promote their health and well-being during and after treatment. Aim: To examine relationships between physical activity (PA) and quality of life (QoL) in a sample of cancer patients enrolling in integrative care in a supportive care clinic. Also, to explore circulating inflammatory biomarkers and heart rate variability (HRV) in relationship to PA and QoL. Methods: A cross-sectional design of adult patients who sought care in the InspireHealth clinic, Vancouver, British Columbia, Canada. Patients with complete PA data (n = 118) answered psychosocial questionnaires, provided blood samples, and received HRV recordings before enrollment. Patients were stratified into "less" versus "more" active groups according to PA guidelines (150 minutes of moderate or 75 minutes of vigorous PA or an equivalent combination). Results: Breast (33.1%) and prostate (10.2%) cancers were the most prevalent primary diagnoses. Patients engaging in more PA reported better physical (U = 1265.5, P = .013), functional (U = 1306.5, P = .024), and general QoL (U = 1341, P = .039), less fatigue (U = 1268, P = .014), fewer physical cancer-related symptoms (U = 2.338, P = .021), and less general distress (U = 2.061, P = .021). Between PA groups, type of primary cancer diagnosis differed (χ2 = 41.79, P = .014), while stages of cancer did not (χ2 = 3.95, P = .412). Fewer patients reported depressed mood within the more active group (χ2 = 6.131, P = .047). More active patients were also less likely to have ever used tobacco (χ2 = 7.41, P = .025) and used fewer nutritional supplements (χ2 = 39.74, P ≤ .001). An inflammatory biomarker index was negatively correlated with vigorous PA (rs = -0.215, P = .022). Multivariable linear regression (R2 = 0.71) revealed that age (ß = 0.22; P = .001), fatigue (ß = -0.43; P ≤ .001), anxiety (ß = -0.14; P = .048), and social support (ß = 0.38; P = .001) were significant correlates of QoL.

Barriers and Facilitators to PrEP Initiation and Adherence Among Transgender and Gender Non-Binary Individuals in Southern California.

While transgender and gender non-binary (trans/nb) individuals are disproportionately affected by HIV, pre-exposure prophylaxis (PrEP) uptake remains low in this underserved population. We conducted four focus groups with 37 trans/nb individuals in San Diego and Los Angeles to assess barriers and facilitators of PrEP usage. Transcripts were coded for qualitative themes. Although overall PrEP awareness was high, participants reported limited knowledge and misinformation about PrEP. Barriers to PrEP use included: structural access (e.g., discrimination from health care providers, lack of trans-inclusive services, financial barriers), mental health struggles limiting ability to access PrEP, and concerns about potential side effects, drug-drug interactions with hormone therapy, and lack of other STI protection. Facilitators of PrEP usage included: increased PrEP availability, prior experience taking daily medications, and motivation to have active and healthy lives without fear of contracting HIV. Addressing both structural and psychosocial/behavioral factors in trans-affirming health care environments is crucial to designing inclusive, effective PrEP interventions.

Focus groups inform a mobile health intervention to promote adherence to a Mediterranean diet and engagement in physical activity among people living with HIV.

BACKGROUND: A personalized mobile health intervention (iSTEP) aims to promote a Mediterranean diet and increase physical activity, thereby improving neurocognitive functioning among persons living with HIV (PLWH). This article describes a qualitative study conducted to develop iSTEP for PLWH, including assessment of diet habits and preferences for tracking physical activity. METHOD: Two focus groups, with seven and 13 PLWH respectively, discussed barriers and facilitators of a healthy diet and provided feedback to refine iSTEP components, including the feasibility of using a Fitbit and the content of text messages designed to encourage improved diet and physical activity. RESULTS: Focus group discussions revealed several healthy diet barriers, including housing instability, time required for food preparation, cost of healthy food, depression, gastrointestinal issues, physical disability, and changes in appetite since HIV diagnosis. Participant-identified healthy diet facilitators included affordable price options for healthy food, a structured food plan, desire to modify appearance or weight, access to medical professionals, motivation for disease prevention, and social support. Participants endorsed wearing a Fitbit on the wrist and receiving text messages as useful methods to monitor and encourage a better diet and greater physical activity. CONCLUSIONS: These findings assisted the expansion of a mobile health intervention that promotes health behaviors in order to improve neurocognitive outcomes among PLWH. TRIAL REGISTRATION: NCT03123731 , prospectively registered on ClinicalTrials.gov, April 21, 2017.

A Longitudinal Analysis of the Impact of Physical Activity on Neurocognitive Functioning Among HIV-Infected Adults.

Higher levels of physical activity (PA) have been linked to better neurocognitive functioning in many populations. The current study examines the longitudinal association between PA and neurocognitive functioning among HIV-infected and HIV-uninfected persons. Community-dwelling adults (N = 291) self-reported level of PA and completed a comprehensive neuropsychological battery at two to four study visits (Mean follow-up time = 2.6 years). Participants were divided into three PA groups: "No PA" (no PA at any visit), "consistent PA" (PA at ≥50% of visits), and "inconsistent PA" (PA < 50% of visits). A mixed effect model, adjusting for significant covariates showed that all PA groups had statistically significant, yet modest, neurocognitive decline over time; and, the consistent PA group began with, and maintained, significantly better neurocognitive function compared to the other two PA groups. This effect was evident among both HIV-uninfected and HIV-infected persons, despite the fact that HIV-infected persons showed lower baseline neurocognitive function. PA is a modifiable lifestyle behavior that may help to protect against neurocognitive impairment regardless of HIV status, however, given the proportion of HIV-infected individuals who evidence neurocognitive difficulties, a focus on increasing PA seems warranted.

RESUMEN: La actividad física (AF) ha sido asociada con un mejor funcionamiento neurocognitivo en varios grupos. Este estudio examinó la asociación longitudinal entre la AF y el funcionamiento neurocognitivo en personas con y sin infección del VIH. Adultos viviendo en la comunidad (N = 291) proporcionaron información acerca de sus niveles de AF y completaron una batería neuropsicológica exhaustiva. Los participantes completaron entre dos y cuatro visitas relacionadas con el estudio (tiempo de seguimiento promedio = 2,6 años) y fueron divididos en tres grupos de AF: "Ninguna AF" (Ninguna AF durante todas las visitas del estudio), "AF Consistente" (AF durante 50% o más de las visitas del estudio), y "AF Inconsistente" (AF durante menos del 50% de las visitas del estudio). Un modelo estadístico mixto, ajustando por el efecto de variables externas, indicó que hubo una reducción estadísticamente significativa, pero poco pronunciada, en el funcionamiento neurocognitivo en todos los grupos. Además, el grupo con AF Consistente demostró un mejor funcionamiento neurocognitivo en comparación con los otros dos grupos de AF al comienzo del estudio, el cual se mantuvo durante el seguimiento. A pesar de que las personas con VIH demostraron un funcionamiento neurocognitivo más bajo al comienzo del estudio que las personas sin VIH, el efecto de AF fue demostrado en los dos grupos. Es importante recalcar que la AF es un factor de vida modificable que podría proteger contra los daños neurocognitivos independientemente de si las personas tienen o no VIH. Dada la proporción de personas con VIH que demuestran problemas neurocognitivos relacionados con esta enfermedad, será importante enfocar los esfuerzos investigativos en desarrollar formas de incrementar la AF en este grupo de personas.

Amphetamine Modestly Improves Conners' Continuous Performance Test Performance in Healthy Adults.

OBJECTIVES: Amphetamine improves vigilance as assessed by continuous performance tests (CPT) in children and adults with attention deficit hyperactivity disorder (ADHD). Less is known, however, regarding amphetamine effects on vigilance in healthy adults. Thus, it remains unclear whether amphetamine produces general enhancement of vigilance or if these effects are constrained to the remediation of deficits in patients with ADHD. METHODS: We tested 69 healthy adults (35 female) on a standardized CPT (Conner's CPT-2) after receiving 10- or 20-mg d-amphetamine or placebo. To evaluate potential effects on learning, impulsivity, and perseveration, participants were additionally tested on the Iowa Gambling Task (IGT) and Wisconsin Card Sorting Task (WCST). RESULTS: Participants receiving placebo exhibited the classic vigilance decrement, demonstrated by a significant reduction in attention (D') across the task. This vigilance decrement was not observed, however, after either dose of amphetamine. Consistent with enhanced vigilance, the 20-mg dose also reduced reaction time variability across the task and the ADHD confidence index. The effects of amphetamine appeared to be selective to vigilance since no effects were observed on the IGT, WCST, or response inhibition/perseveration measures from the CPT. CONCLUSIONS: The present data support the premise that amphetamine improves vigilance irrespective of disease state. Given that amphetamine is a norepinephrine/dopamine transporter inhibitor and releaser, these effects are informative regarding the neurobiological substrates of attentional control. (JINS, 2018, 24, 283-293).

Everyday functional ability in HIV and methamphetamine dependence.

BACKGROUND: Methamphetamine (METH) use is a risk factor for the transmission of HIV. Each is associated with neurocognitive impairment and subsequent problems in everyday functioning, yet additive effects of HIV and METH are not consistently observed. This study used the UCSD Performance-Based Skills Assessment (UPSA-2) to assess whether METH use disorder and HIV together resulted in poorer functional outcome than either condition alone. METHOD: Participants in the Translational Methamphetamine AIDS Research Center (TMARC) cohort were stratified based upon HIV infection and METH use disorder: HIV-/METH- (n=49), HIV-/METH+ (n=48), HIV+/METH- (n=37), and HIV+/METH+ (n=38). They were administered the UPSA-2 which measures abilities in six domains of everyday functioning. Main effects and interactions of HIV and METH were examined, as were relationships between UPSA-2 scores and disease characteristics. RESULTS: Significant HIV-by-METH interactions were observed for the UPSA-2 total score and Comprehension/Planning and Financial subscales such that METH was associated with lower scores in HIV- participants but not HIV+ participants. METH was associated with lower scores on the Communications subscale. All three risk groups had lower scores than HIV-/METH- participants. Recency and frequency of METH use were associated with lower scores. Lower Medication Management scores were related to lower nadir CD4 counts. CONCLUSIONS: METH use disorder and HIV each impair functional performance, but there is no additive effect when the two conditions occur together. The neurocognitive sequelae of combined HIV infection and METH use are complex and warrant further study, as do the potential effects of compensatory strategies and other factors.

Diagnosis and characterization of mania: Quantifying increased energy and activity in the human behavioral pattern monitor.

Increased energy or activity is now an essential feature of the mania of Bipolar Disorder (BD) according to DSM-5. This study examined whether objective measures of increased energy can differentiate manic BD individuals and provide greater diagnostic accuracy compared to rating scales, extending the work of previous studies with smaller samples. We also tested the relationship between objective measures of energy and rating scales. 50 hospitalized manic BD patients were compared to healthy subjects (HCS, n=39) in the human Behavioral Pattern Monitor (hBPM) which quantifies motor activity and goal-directed behavior in an environment containing novel stimuli. Archival hBPM data from 17 schizophrenia patients were used in sensitivity and specificity analyses. Manic BD patients exhibited higher motor activity than HCS and higher novel object interactions. hBPM activity measures were not correlated with observer-rated symptoms, and hBPM activity was more sensitive in accurately classifying hospitalized BD subjects than observer ratings. Although the findings can only be generalized to inpatient populations, they suggest that increased energy, particularly specific and goal-directed exploration, is a distinguishing feature of BD mania and is best quantified by objective measures of motor activity. A better understanding is needed of the biological underpinnings of this cardinal feature.

Pilot Randomized Study of a Gratitude Journaling Intervention on Heart Rate Variability and Inflammatory Biomarkers in Patients With Stage B Heart Failure.

OBJECTIVE: Stage B, asymptomatic heart failure (HF) presents a therapeutic window for attenuating disease progression and development of HF symptoms, and improving quality of life. Gratitude, the practice of appreciating positive life features, is highly related to quality of life, leading to development of promising clinical interventions. However, few gratitude studies have investigated objective measures of physical health; most relied on self-report measures. We conducted a pilot study in Stage B HF patients to examine whether gratitude journaling improved biomarkers related to HF prognosis. METHODS: Patients (n = 70; mean [standard deviation] age = 66.2 [7.6] years) were randomized to an 8-week gratitude journaling intervention or treatment as usual. Baseline (T1) assessments included the six-item Gratitude Questionnaire, resting heart rate variability (HRV), and an inflammatory biomarker index. At T2 (midintervention), the six-item Gratitude Questionnaire was measured. At T3 (postintervention), T1 measures were repeated but also included a gratitude journaling task. RESULTS: The gratitude intervention was associated with improved trait gratitude scores (F = 6.0, p = .017, η = 0.10), reduced inflammatory biomarker index score over time (F = 9.7, p = .004, η = 0.21), and increased parasympathetic HRV responses during the gratitude journaling task (F = 4.2, p = .036, η = 0.15), compared with treatment as usual. However, there were no resting preintervention to postintervention group differences in HRV (p values > .10). CONCLUSIONS: Gratitude journaling may improve biomarkers related to HF morbidity, such as reduced inflammation; large-scale studies with active control conditions are needed to confirm these findings. TRIAL REGISTRATION: Clinicaltrials.govidentifier:NCT01615094.

Preliminary Findings Describing Participant Experience With iSTEP, an mHealth Intervention to Increase Physical Activity and Improve Neurocognitive Function in People Living With HIV.

We assessed the feasibility and acceptability of using text messages to monitor and encourage physical activity in the first 21 participants enrolled in an ongoing randomized controlled trial evaluating a 16-week Short Message Service/Multimedia Message Service (SMS/MMS) intervention (iSTEP) designed to increase moderate physical activity and improve neurocognition in persons with HIV-associated neurocognitive disorders (HAND; iSTEP, n = 11; control group, n = 10). Data were collected during the intervention and from interviews conducted at the 16-week postintervention visits. Text message response rates for both iSTEP and control participants were high (89% and 85%, respectively). Pedometer self-monitoring, step count goals, and milestone achievement texts were reported to facilitate physical activity. All iSTEP participants (100%) and 70% of control participants indicated that they would recommend the study to other people living with HIV. The results indicate that it is feasible to administer an SMS/MMS physical activity intervention to persons with HAND.

Amphetamine increases activity but not exploration in humans and mice.

RATIONALE: Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as bipolar disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. OBJECTIVES: The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. METHODS: Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n = 25), 10 mg d-amphetamine (n = 18), or 20 mg amphetamine (n = 23). Eighty mice were administered one of four doses of d-amphetamine or vehicle. Humans and mice were tested in the behavioral pattern monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. RESULTS: In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. CONCLUSIONS: Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases.

Development of an mHealth Intervention (iSTEP) to Promote Physical Activity among People Living with HIV.

A randomized controlled trial is being conducted in the United States to test the efficacy of a personalized interactive mobile health intervention (iSTEP) designed to increase physical activity (PA) and improve neurocognitive functioning among HIV-positive persons. This article describes an initial qualitative study performed to develop iSTEP for the HIV-positive population, including assessment of PA barriers and facilitators. Two focus groups, with 9 and 12 unique HIV-positive individuals, respectively, were administered to evaluate barriers limiting PA and potential iSTEP content created to encourage greater PA. Group discussions revealed prominent PA barriers, including HIV symptoms (neuropathy, lipoatrophy), antiretroviral medication effects, and fatigue; significant PA facilitators included self-monitoring and family support. Participants provided feedback on strategies to increase PA and expressed positive support for a mobile intervention adapted to personal priorities. These findings will assist the development of novel PA interventions focused on treating the epidemic of HIV-associated neurocognitive disorders.

Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies.

Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments.

Physical Activity is Associated with Better Neurocognitive and Everyday Functioning Among Older Adults with HIV Disease.

We examined the association between physical activity (PA), neurocognitive impairment (NCI), and instrumental activities of daily living (IADLs) among older HIV+ persons. One hundred older HIV+ adults completed the International Physical Activity Questionnaire, a neurocognitive battery, and IADL scale. Higher levels of moderate PA were associated with lower odds of NCI (p = 0.01), even when covariates were modeled. The association between moderate PA and NCI was driven by executive function (p = 0.04). Higher levels of moderate PA were also associated with lower odds of IADL Dependence (p = 0.03), although this fell to a trend (p = 0.08) when including covariates. Follow-up analysis showed those with both NCI and IADL Dependence had lower moderate PA than those with neither (p = 0.03). While these cross-sectional findings suggest PA is associated with better neurocognitive and everyday functioning in older HIV+ adults, longitudinal studies utilizing objective PA methods are needed to evaluate directionality and mechanisms.

Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning.

Methamphetamine (MA) dependence is associated with executive dysfunction, but no studies have evaluated MA-related elevations in neurocognitive intraindividual variability (IIV), an expression of cognitive dyscontrol linked to poor daily functioning in populations with frontal systems injury. We examined IIV during a vigilance task in a well-characterized sample of 35 MA-dependent (MA+) and 55 non-MA using comparison participants (MA-) as part of a larger neuropsychological battery that included self-report and performance-based measures of everyday functioning. A mixed model ANOVA was conducted while controlling for covariates, including factors that differed between the groups (e.g., education) and those with conceptual relevance to IIV: mean reaction time, global cognitive performance, and HIV-infection (which was comparable across groups; p=0.32). This analysis revealed significantly elevated IIV among MA+ relative to MA- individuals that was comparable in magnitude across all trial blocks of the vigilance task. Within the MA group, elevated IIV was associated with executive dysfunction, psychomotor slowing, and recency of MA use, as well as poorer automobile driving simulator performance, worse laboratory-based functional skills, and more cognitive complaints. MA-users are vulnerable to IIV elevation, likely due to cognitive dyscontrol, which may increase their risk of real-world problems.

Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder.

Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n = 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n = 31) and wild-type (n = 28) mice) and acute (C57BL/6J mice (n = 89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by high-reward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies.