Reward Responsiveness Research Articles

Cross-species translational paradigms for assessing positive valence system as defined by the RDoC matrix.

Functions associated with processing reward-related information are fundamental drivers of motivation, learning, and goal-directed behavior. Such functions have been classified as the positive valence system under the Research Domain and Criteria (RDoC) criteria and are negatively impacted across a range of psychiatric disorders and mental illnesses. The positive valence system is composed of three comprehensive categories containing related but dissociable functions that are organized into either Reward Responsiveness, Reward Learning, or Reward Valuation. The presence of overlapping behavioral dysfunction across diagnostic mental disorders is in-part what motivated the RDoC initiative, which emphasized that the study of mental illness focus on investigating relevant behavior and cognitive functions and their underlying mechanisms, rather than separating efforts on diagnostic categories (i.e., transdiagnostic). Moreover, the RDoC approach is well-suited for preclinical neuroscience research, as the rise in genetic toolboxes and associated neurotechnologies enables researchers to probe specific cellular targets with high specificity. Thus, there is an opportunity to dissect whether behaviors and cognitive functions are supported by shared or distinct neural mechanisms. For preclinical research to effectively inform our understandings of human behavior however, the cognitive and behavioral paradigms should have predictive, neurobiological, and pharmacological predictive validity to the human test. Touchscreen-based testing systems provide a further advantage for this endeavor enabling tasks to be presented to animals using the same media and task design as in humans. Here, we outline the primary categories of the positive valence system and review the work that has been done cross-species to investigate the neurobiology and neurochemistry underlying reward-related functioning. Additionally, we provide clinical tasks outlined by RDoC, along with validity and/or need for further validation for analogous rodent paradigms with a focus on implementing the touchscreen-based cognitive testing systems.

Functional PET/MRI reveals active inhibition of neuronal activity during optogenetic activation of the nigrostriatal pathway.

The dopaminergic system is a central component of the brain's neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy-d-glucose positron emission tomography approach, simultaneously with blood oxygen level-dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.

Childhood neglect is associated with alterations in neural prediction error signaling and the response to novelty.

One in eight children experience early life stress (ELS), which increases risk for psychopathology. ELS, particularly neglect, has been associated with reduced responsivity to reward. However, little work has investigated the computational specifics of this disrupted reward response - particularly with respect to the neural response to Reward Prediction Errors (RPE) - a critical signal for successful instrumental learning - and the extent to which they are augmented to novel stimuli. The goal of the current study was to investigate the associations of abuse and neglect, and neural representation of RPE to novel and non-novel stimuli. One hundred and seventy-eight participants (aged 10-18, M = 14.9, s.d. = 2.38) engaged in the Novelty task while undergoing functional magnetic resonance imaging. In this task, participants learn to choose novel or non-novel stimuli to win monetary rewards varying from $0 to $0.30 per trial. Levels of abuse and neglect were measured using the Childhood Trauma Questionnaire. Adolescents exposed to high levels of neglect showed reduced RPE-modulated blood oxygenation level dependent response within medial and lateral frontal cortices particularly when exploring novel stimuli (p < 0.05, corrected for multiple comparisons) relative to adolescents exposed to lower levels of neglect. These data expand on previous work by indicating that neglect, but not abuse, is associated with impairments in neural RPE representation within medial and lateral frontal cortices. However, there was no association between neglect and behavioral impairments on the Novelty task, suggesting that these neural differences do not necessarily translate into behavioral differences within the context of the Novelty task.

Associations between polygenic scores for cognitive and non-cognitive factors of educational attainment and measures of behavior, psychopathology, and neuroimaging in the adolescent brain cognitive development study.

Educational attainment (EduA) is correlated with life outcomes, and EduA itself is influenced by both cognitive and non-cognitive factors. A recent study performed a 'genome-wide association study (GWAS) by subtraction,' subtracting genetic effects for cognitive performance from an educational attainment GWAS to create orthogonal 'cognitive' and 'non-cognitive' factors. These cognitive and non-cognitive factors showed associations with behavioral health outcomes in adults; however, whether these correlations are present during childhood is unclear. Using data from up to 5517 youth (ages 9-11) of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and cognition, risk tolerance, decision-making & personality, substance initiation, psychopathology, and brain structure (e.g. volume, fractional anisotropy [FA]). Within-sibling analyses estimated whether observed genetic associations may be consistent with direct genetic effects. Both PGSs were associated with greater cognition and lower impulsivity, drive, and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk tolerance, increased odds of choosing delayed reward, and decreased likelihood of ADHD and bipolar disorder; the non-cognitive PGS was associated with lack of perseverance and reward responsiveness. Cognitive PGS were more strongly associated with larger regional cortical volumes; non-cognitive PGS were more strongly associated with higher FA. All associations were characterized by small effects. While the small sizes of these associations suggest that they are not effective for prediction within individuals, cognitive and non-cognitive PGS show unique associations with phenotypes in childhood at the population level.

Dopamine dynamics are dispensable for movement but promote reward responses.

Dopamine signalling modes differ in kinetics and spatial patterns of receptor activation1,2. How these modes contribute to motor function, motivation and learning has long been debated3-21. Here we show that action-potential-induced dopamine release is dispensable for movement initiation but supports reward-oriented behaviour. We generated mice with dopamine-neuron-specific knockout of the release site organizer protein RIM to disrupt action-potential-induced dopamine release. In these mice, rapid in vivo dopamine dynamics were strongly impaired, but baseline dopamine persisted and fully supported spontaneous movement. Conversely, reserpine-mediated dopamine depletion or blockade of dopamine receptors disrupted movement initiation. The dopamine precursor L-DOPA reversed reserpine-induced bradykinesia without restoring fast dopamine dynamics, a result that substantiated the conclusion that these dynamics are dispensable for movement initiation. In contrast to spontaneous movement, reward-oriented behaviour was impaired in dopamine-neuron-specific RIM knockout mice. In conditioned place preference and two-odour discrimination tasks, the mice effectively learned to distinguish the cues, which indicates that reward-based learning persists after RIM ablation. However, theperformance vigourwas reduced. During probabilistic cue-reward association, dopamine dynamics and conditioned responses assessed through anticipatory licking were disrupted. These results demonstrate that action-potential-induced dopamine release is dispensable for motor function and subsecond precision of movement initiation but promotes motivation and performance during reward-guided behaviours.

Exploring breed differences in discrimination, reversal learning, and resistance to extinction in the domestic dog (Canis familiaris)

Learning is crucial for shaping domestic dogs’ behaviour through life experiences, yet not all breeds exhibit the same learning aptitude towards a particular task. The current study’s objective was to identify differences in behaviour and learning performance across and within five breed clades and elucidate the underlying factors contributing into these variations. Dogs (n = 111) from five breed clades (UK Rural, Retrievers, Asian Spitz, European Mastiff, and New World) participated in a virtual learning task with their owners. Owners completed validated questionnaires of Impulsivity and Reward Responsiveness. The learning task comprised of reinforcing an arbitrary behaviour (hand-touch) through multiple sessions of Acquisition (reinforcing the hand-touch), Discrimination (reinforcing the hand-touch on one of two hands) and Reversal Learning (reinforcing the hand-touch on the opposite hand), followed by a single session of Extinction (hand-touch not reinforced). Results showed notable differences across the studied breed clades in certain learning and behavioural components. However, the observed disparities may not be entirely attributed to inherent cognitive differences among the breed clades but rather potentially influenced by contextual factors such as the human-dog communication dynamics associated with breeds’ cooperativity. Furthermore, breed clades differed in the contributing factors predicting individual learning performances, which could highlight the potential effect of breeds’ historical function.

Autism: A review

Reduced eye contact, facial expressions, and body movements during the first three years of life are among the social behaviors and nonverbal interactions that define autism spectrum disorder (ASD), a collection of neurodevelopmental diseases. It is generally accepted that this condition is a multifactorial disorder resulting from the combination of both hereditary and non-genetic risk factors. It is not a single disorder. Studies on the genetics of ASD have found mutations that disrupt normal neurodevelopment from infancy through childhood. Axon mobility and synaptogenesis have been linked to these gene complexes. Advances in neuroimaging research have yielded numerous significant insights into the pathological alterations that take place in the brains of individuals with ASD while they are living their lives. Numerous neuropathological and neuroimaging studies have demonstrated the significance of the amygdala, a key component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD. The nucleus accumbens is seen as another important structure associated with the social reward response in ASD, in addition to the amygdala. While behavioral and educational interventions have traditionally been the cornerstones of ASD care, pharmaceutical and interventional therapies have also demonstrated some promise in ASD patients. Additionally, a small number of individuals have reportedly improved following deep brain stimulation, one of the interventional treatments.

Dopamine release plateau and outcome signals in dorsal striatum contrast with classic reinforcement learning formulations

We recorded dopamine release signals in centromedial and centrolateral sectors of the striatum as mice learned consecutive versions of visual cue-outcome conditioning tasks. Dopamine release responses differed for the centromedial and centrolateral sites. In neither sector could these be accounted for by classic reinforcement learning alone as classically applied to the activity of nigral dopamine-containing neurons. Medially, cue responses ranged from initial sharp peaks to modulated plateau responses; outcome (reward) responses during cue conditioning were minimal or, initially, negative. At centrolateral sites, by contrast, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. At most sites, we found no evidence for a transition from outcome signaling to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopaminergic neuronal activity. These findings delineate a reshaping of striatal dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.

A Pilot Randomized Control Trial Testing a Smartphone-Delivered Food Attention Retraining Program in Adolescent Girls with Overweight or Obesity.

Attention bias (AB) toward food is associated with obesity, but it is unclear if programs designed to reduce AB can impact adolescents' eating behavior. We investigated whether a two-week, smartphone-delivered attention retraining (AR) program (vs a control program) altered food AB in adolescent girls with overweight. Participants completed three food-cue visual-probe trainings/day. The AR and control programs directed attention away from food stimuli during 100% and 50% of trainings, respectively. Before and after completion of the programs, girls completed a food-cue visual-probe task while undergoing magnetoencephalography (MEG), and then a laboratory test meal. Sixty-eight adolescents were randomized; 58 completed post-program visits. There was minimal effect of condition on AB scores (β [95%CI] = -1.9 [-20.8, 16.9]; d = -0.06). There was a small effect of condition on energy intake (EMMcontrol = 1017 kcal, EMMAR = 1088 kcal, d = 0.29). Within the AR group, there was slightly blunted initial engagement in brain areas associated with reward response and subsequent increased goal-directed attention and action control. We found preliminary support for efficacy of an intensive smartphone-delivered AR program to alter neural correlates of attention processing in adolescent girls with overweight or obesity. Studies with larger sample sizes are needed to elucidate if AR trainings disrupt the link between food AB and eating behavior.

Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation.

Abnormalities in goal-directed behavior, mediated by mesocorticolimbic reward function and structure, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU). In a sham-controlled randomized study design, we measured whether robot-assisted 10Hz transcranial magnetic stimulation (TMS) applied to the prefrontal cortex was able to modulate anterior midcingulate cortex (MCC) electrophysiological response to rewards, in OU and matched healthy controls. We show that OU exhibit a blunted anterior MCC reward response, compared to healthy controls (t(39) = 2.62, p = 0.01, d = 0.84), and that this is normalized following 10-Hz excitatory TMS (t (36) = .82, p = 0.42, d = 0.17). Excitatory TMS modulated the putative reward function of the MCC in OU. Further work with increased sample sizes and TMS sessions is required to determine whether restoring MCC reward function increases reward-directed behaviors, which may enhance treatment success through the maintenance of treatment goals.

8684 Lifetime Duration of Amenorrhea Is Associated With Monetary Decision-Making and Hedonic Eating In Females With a Low-Weight Eating Disorder

Abstract Disclosure: F. Plessow: None. M. Wronski: None. M. Rogers: None. M.G. Turley: None. E.R. Golden: None. M. Slattery: None. J.J. Thomas: None. E.A. Lawson: None. M. Misra: None. K.T. Eddy: None. Background: Low estrogen levels and oligomenorrhea are common characteristics in females with a low-weight eating disorder (LWED). In animal models, estrogen status is associated with neural activity in dopaminergic reward pathways affecting reward processing and decision-making. Whether a similar link exists in humans is unknown but important to understand, as reduced reward-driven behavior and an increased delay of gratification driving decision-making hinder recovery from a LWED. To fill this knowledge gap, we studied the relationship between lifetime duration of amenorrhea and hedonic eating and monetary decision-making in a group of females with a LWED. We hypothesized that longer lifetime duration of amenorrhea is associated with reduced hedonic food intake and a smaller delay discounting rate (indicating an increased delay of gratification) in females with a LWED (independent of age and illness severity). Methods: Fifty-six females with a LWED (mean age±SD: 19.84±2.98 years, range: 13.6-23.5 years) and 34 female healthy controls (HC; 19.08±2.41 years, 13.4-22.2 years) underwent a menstrual history to determine the number of missed menses since menarche, Eating Disorder Examination (EDE) to assess ED psychopathology, anthropometric measurements to calculate body mass index (BMI), Cookie Taste Test as a laboratory-based assessment of reward-related eating beyond satiety, and a monetary Delay Discounting Task to determine their delay discounting rate. Between-group differences were tested using Mann-Whitney U-tests, and associations between duration of amenorrhea and caloric intake at the Cookie Taste Test and delay discounting rate in the LWED group were examined using partial Spearman correlations adjusted for age and BMI as a marker for illness severity. Results: By study design, females with a LWED had a lower BMI (17.97±2.16 vs. 21.71±2.57 kg/m2, U=1,802.50, p&amp;lt;0.001, r=0.75) and more pronounced ED psychopathology (EDE Global Score: 2.38±2.50 vs. 0.00±0.00, U=22.50, p&amp;lt;0.001, r=0.83) than HC. They had missed 16.50±22.64 menses since menarche. When controlling for age and BMI, longer lifetime duration of amenorrhea was correlated with lower caloric intake in the Cookie Taste Test (rs=-0.34, p=0.011) and a smaller delay discounting rate indicating an increased delay of gratification (rs=-0.40, p=0.004). Conclusions: This is the first demonstration that lifetime duration of amenorrhea is associated with hedonic food intake and monetary decision-making in females with a LWED, pointing towards a potential role of cumulative estrogen status in reward processing and decision-making in this population. Future research avenues include investigating whether estrogen replacement can increase reward responsiveness and reduce delay of gratification to promote a faster recovery from a LWED. Presentation: 6/1/2024

8684 Lifetime Duration of Amenorrhea Is Associated With Monetary Decision-Making and Hedonic Eating In Females With a Low-Weight Eating Disorder

Abstract Disclosure: F. Plessow: None. M. Wronski: None. M. Rogers: None. M.G. Turley: None. E.R. Golden: None. M. Slattery: None. J.J. Thomas: None. E.A. Lawson: None. M. Misra: None. K.T. Eddy: None. Background: Low estrogen levels and oligomenorrhea are common characteristics in females with a low-weight eating disorder (LWED). In animal models, estrogen status is associated with neural activity in dopaminergic reward pathways affecting reward processing and decision-making. Whether a similar link exists in humans is unknown but important to understand, as reduced reward-driven behavior and an increased delay of gratification driving decision-making hinder recovery from a LWED. To fill this knowledge gap, we studied the relationship between lifetime duration of amenorrhea and hedonic eating and monetary decision-making in a group of females with a LWED. We hypothesized that longer lifetime duration of amenorrhea is associated with reduced hedonic food intake and a smaller delay discounting rate (indicating an increased delay of gratification) in females with a LWED (independent of age and illness severity). Methods: Fifty-six females with a LWED (mean age±SD: 19.84±2.98 years, range: 13.6-23.5 years) and 34 female healthy controls (HC; 19.08±2.41 years, 13.4-22.2 years) underwent a menstrual history to determine the number of missed menses since menarche, Eating Disorder Examination (EDE) to assess ED psychopathology, anthropometric measurements to calculate body mass index (BMI), Cookie Taste Test as a laboratory-based assessment of reward-related eating beyond satiety, and a monetary Delay Discounting Task to determine their delay discounting rate. Between-group differences were tested using Mann-Whitney U-tests, and associations between duration of amenorrhea and caloric intake at the Cookie Taste Test and delay discounting rate in the LWED group were examined using partial Spearman correlations adjusted for age and BMI as a marker for illness severity. Results: By study design, females with a LWED had a lower BMI (17.97±2.16 vs. 21.71±2.57 kg/m2, U=1,802.50, p&amp;lt;0.001, r=0.75) and more pronounced ED psychopathology (EDE Global Score: 2.38±2.50 vs. 0.00±0.00, U=22.50, p&amp;lt;0.001, r=0.83) than HC. They had missed 16.50±22.64 menses since menarche. When controlling for age and BMI, longer lifetime duration of amenorrhea was correlated with lower caloric intake in the Cookie Taste Test (rs=-0.34, p=0.011) and a smaller delay discounting rate indicating an increased delay of gratification (rs=-0.40, p=0.004). Conclusions: This is the first demonstration that lifetime duration of amenorrhea is associated with hedonic food intake and monetary decision-making in females with a LWED, pointing towards a potential role of cumulative estrogen status in reward processing and decision-making in this population. Future research avenues include investigating whether estrogen replacement can increase reward responsiveness and reduce delay of gratification to promote a faster recovery from a LWED. Presentation: 6/1/2024

Delving into the role of reward and punishment sensitivity in anorexia nervosa: Punishment responsivity as the only predictor of eating disorder symptom persistence in adolescents.

This study differentiated between self-reported punishment responsivity (PR) and motivation to avoid punishment (MP) and examined their relationship with anorexia nervosa (AN) and its course in a combined cross-sectional and longitudinal approach. We explored whether inconsistent findings regarding reward sensitivity may be explained by previous research not differentiating between reward responsivity (RR) and motivation to approach reward (MR). Participants were 69 adolescents with AN and 69 adolescents without AN matched on age, sex and educational level. Eating disorder (ED) symptom severity, PR, MP, RR, and MR were assessed at the start of treatment and 1year later. Only PR was higher in patients with AN than in the comparison group. Both PR and MP decreased over the course of 1year, however, only the reduction in PR was related to the reduction in ED symptoms. Lastly, only higher baseline PR was independently related to less improvement in ED symptoms over the course of 1year. There was no support for the involvement of RS or its specific dimensions in AN. Most critical, the findings suggest that specifically the PR dimension of punishment sensitivity is related to the persistence of AN and could be an important target for treatment.

Depressive Symptoms and Suicidal Ideation in Sexual Minority Adolescents: An Examination of Social Reward Responsiveness and Support as Moderators

Sexual minority (SM) youth are at increased risk of depression and suicidal ideation (SI), due in part to discrimination and other stressors. This raises questions about social factors that may increase risk or resilience to stressors commonly faced by SM youth. The goal of this multimethod study was to examine both neural processing of social feedback and perceived social support as potential moderators of the association between SM identity, depressive symptoms, and endorsement of SI in adolescents. For this study, 165 adolescents aged 14-17 (22.42% identifying as SM) were oversampled for current depression. Participants self-reported social support, depressive symptoms, and SI. Electroencephalogram (EEG) was recorded while participants completed a computerized peer interaction task in which the reward positivity (RewP) component was measured in response to social acceptance vs. rejection feedback. We tested social RewP and social support as moderators of associations between SM identity, depressive symptoms, and whether SI was reported. SM youth reported lower social support and elevated depressive symptoms and were more likely to endorse SI compared to non-SM youth. Social RewP moderated the associations between SM identity, depressive symptoms, and SI such that SM youth with blunted neural responses to social acceptance had higher depression and were more likely to endorse SI. Lower social support was associated with greater depressive symptoms and SI, but social support was not a significant moderator of the association between SM identity and symptoms. This is among the first studies to use affective neuroscience methods to examine social processes in SGM youth and our findings underscore the role of social factors in SGM youth mental health.

Reinforcement Processing as a Predictor of Behavioral Treatment Response in the ADHD Summer Treatment Program

ABSTRACT Background Behavioral interventions for attention-deficit/hyperactivity disorder (ADHD) are well-established interventions, but not all children benefit from these approaches. One factor that may accurately predict treatment outcomes is how individuals process reinforcement. Objective The present study examined the association between reinforcement processing and treatment response to a well-established behavioral intervention for ADHD, the Summer Treatment Program (STP). Methods Participants included two cohorts of patients from a Midwest academic medical center STP (n = 47). Reinforcement processing was assessed via a parent-rated questionnaire and computerized neuropsychological tasks. Behavioral improvement was determined from weekly parent- and counselor-rated measures of children’s behavior over the course of the STP, as well as from STP behavioral data. Repeated measures mixed-linear models were used to determine associations between the reinforcement processing predictors and behavioral ratings. Results Greater parent-rated child impulsive/fun-seeking behavior was significantly associated with both greater counselor- and parent-rated behavioral difficulties. However, greater parent-rated child reward responsiveness was significantly associated with lower counselor-rated behavioral difficulties. Objective, task-based measures did not have any significant associations. Conclusions Impulsive/fun-seeking behaviors appear to be the strongest predictor of behavioral treatment response, with results suggesting that children with high rates of these behaviors might benefit from higher rates or values of positive reinforcement to outweigh the immediate reinforcement gained by negative behavior. Reward responsiveness results suggest that a match between a child’s specific reward preferences and the types of reinforcement provided by a behavioral intervention may also be important to treatment outcomes.

Sex-dependent effects of acute stress and alcohol exposure during adolescence on mRNA expression of brain signaling systems involved in reward and stress responses in young adult rats

BackgroundAdolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.MethodsMale and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.ResultsThe main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.ConclusionsThis study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders.

Genetic associations with neural reward responsivity to food cues in children.

To test associations of candidate obesity-related single nucleotide polymorphisms (SNPs) and obesity polygenic risk scores (PRS) with neural reward reactivity to food cues. After consuming a pre-load meal, 9-12-year-old children completed a functional magnetic resonance imaging (fMRI) paradigm with exposure to food and non-food commercials. Genetic exposures included FTO rs9939609, MC4R rs571312, and a pediatric-specific obesity PRS. A targeted region-of-interest (ROI) analysis for 7 bilateral reward regions and a whole-brain analysis were conducted. Independent associations between each genetic factor and reward responsivity to food cues in each ROI were evaluated using linear models. Analyses included 151 children (M = 10.9 years). Each FTO rs9939609 obesity risk allele was related to a higher food-cue-related response in the right lateral hypothalamus after controlling for covariates including the current BMI Z-score (p < 0.01), however, the association did not remain significant after applying the multiple testing correction. MC4R rs571312 and the PRS were not related to heightened food-cue-related reward responsivity in any examined regions. The whole-brain analysis did not identify additional regions of food-cue-related response related to the examined genetic factors. Children genetically at risk for obesity, as indicated by the FTO genotype, may be predisposed to higher food-cue-related reward responsivity in the lateral hypothalamus in the sated state, which, in turn, could contribute to overconsumption. https://clinicaltrials.gov/study/NCT03766191, identifier NCT03766191.

Response to daratumumab-retreatment in patients with multiple myeloma

AbstractDaratumumab is an effective therapy in multiple myeloma (MM). We assessed whether daratumumab retreatment may re-induce significant responses and which patients do benefit the most. We hypothesized, that there is effective synergism between daratumumab and alternating antimyeloma drug combinations during retreatment and that retreatment is safe and effective. Here, we analyzed 293 consecutive MM patients receiving daratumumab at our institution from 2016 until 2023 retrospectively, and compared responses, side effects and survival of the first daratumumab treatment line and its retreatment. We identified 22/293 (8%) patients with daratumumab retreatment. These patients showed an advanced age and ISS/R-ISS stages, and ≥ 3 lines of prior antimyeloma therapy in 91%. Of note, the median durations of the first and subsequent daratumumab treatment were similarly long. We confirmed a therapy break between daratumumab lines as advantageous. Daratumumab retreatment was effective, with responses declining only gradually from its first use to subsequent first and second retreatment with 64%, 46% and 43%, respectively. Interestingly, comparable progression free survival rates were observed with 11.5, 12 months and not reached, respectively. Consistently, adverse events per daratumumab line did not increase. Our findings suggest that well-selected daratumumab-exposed MM patients may show rewarding responses to daratumumab retreatment, the more with alternating antimyeloma combinations, initial good response and CD38-antibody-treatment pauses, thereby proving CD38-antibody-retreatment as feasible, effective and non-toxic. Confirmatory studies are required to further validate our results.

Investigating the role of mental imagery use in the assessment of anhedonia

ABSTRACT Anhedonia, or a deficit in the liking, wanting, and seeking of rewards, is typically assessed via self-reported “in-the-moment” emotional and motivational responses to reward stimuli and activities. Given that mental imagery is known to evoke emotion and motivational responses, we conducted two studies to investigate the relationship between mental imagery use and self-reported anhedonia. Using a novel Reward Response Scale (adapted from the Dimensional Anhedonia Rating Scale, DARS; Rizvi et al., 2015) modified to assess deliberate and spontaneous mental imagery use, Study 1 (N = 394) compared uninstructed and instructed mental imagery use, and Study 2 (N = 586) conducted a test of replication of uninstructed mental imagery use. Results showed that greater mental imagery use was associated with higher reward response scores (Study 1 & 2), and this relationship was not moderated by whether imagery use was uninstructed or instructed (Study 1). Importantly, mental imagery use moderated the convergence between reward response and depression scale measures of anhedonia, with lower convergence for those reporting higher mental imagery use (Study 1 & 2). Results suggest that higher spontaneous mental imagery use may increase self-reported reward response and reduce the convergence between reward response scale and depression questionnaire measures of anhedonia. [199 / 200 words]

B - 62 Cognitive Training Targeting Reward Responsiveness Promotes more Efficient Affective Processing in an Interference Go/NoGo Task

Abstract Objective Abnormalities in emotional processing are commonly seen in depression and anxiety, disorders also associated with decreased reward sensitivity i.e., anhedonia. We tested a noninvasive, cognitive training program aimed at boosting reward responsiveness and gaged if it may also improve affective processing efficiency. Methods Individuals (N = 50; 54% Female; 18–65 yo) with low hedonic tone (Positive and Negative Affect Scale/PANAS score &amp;lt; 25) and diagnostic levels of depression and/or anxiety (Patient Health Questionnaire-8/PHQ-8 or General Anxiety Disorder-7/GAD-7 score ≥ 10) who responded to community-posted flyers completed an affective go/no-go (AGN) task before and after completing an exploratory reward learning task, i.e., a multi-arm bandit (MAB). Participants were randomly assigned to a high-reward MAB training with either high variance (HV) or low variance (LV) in reward rates, HV being expected to boost reward maximization. In the AGN, participants saw negative and positive pictures and had to respond as fast as possible to pictures of a given target category (positive or negative). Results Following the HV vs LV training MAB, participants were more accurate (higher likelihood of hits), which was more evident in negative target blocks relative to positive target blocks (odds ratio/OR:0.61, 95% CI = [0.38,0.98]; z = −2.045, p = 0.041). Participants exhibited stronger decreases in hits response times following the HV vs LV training MAB, but across all target blocks (B:-37 ms, 95% CI = [−56,-18]; t = −3.806, p &amp;lt; 0.001). Conclusions A novel cognitive training program aimed at boosting reward sensitivity may help improve patients’ processing of emotionally taxing stimuli. Targeting reward sensitivity is a critical component of improving clinical outcomes in depressed and anxious patients..