Reward Processing Research Articles

Effects of urban living environments on mental health in adults

Urban-living individuals are exposed to many environmental factors that may combine and interact to influence mental health. While individual factors of an urban environment have been investigated in isolation, no attempt has been made to model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors. Using the data of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation analyses to investigate the relationships between urban environments and psychiatric symptoms. We found an environmental profile of social deprivation, air pollution, street network and urban land-use density that was positively correlated with an affective symptom group (r = 0.22, Pperm < 0.001), mediated by brain volume differences consistent with reward processing, and moderated by genes enriched for stress response, including CRHR1, explaining 2.01% of the variance in brain volume differences. Protective factors such as greenness and generous destination accessibility were negatively correlated with an anxiety symptom group (r = 0.10, Pperm < 0.001), mediated by brain regions necessary for emotion regulation and moderated by EXD3, explaining 1.65% of the variance. The third urban environmental profile was correlated with an emotional instability symptom group (r = 0.03, Pperm < 0.001). Our findings suggest that different environmental profiles of urban living may influence specific psychiatric symptom groups through distinct neurobiological pathways.

A new synthesis of aberrant reward processing in frontotemporal dementias

AbstractBackgroundAberrant reward processing is a cardinal feature of frontotemporal dementias (FTD), driving abnormal socio‐emotional behaviours that define these diseases clinically. However, the hedonic architecture of FTD remains poorly characterised. Here we addressed this issue for a multimodal spectrum of hedonic behaviours in a large patient cohort representing all major syndromes of FTD.MethodTwenty‐seven patients with behavioural variant (bv)FTD and 58 with primary progressive aphasia (PPA) (24 non‐fluent variant (nfvPPA), 22 semantic (svPPA), 12 logopenic (lvPPA)) were studied in relation to 34 patients with typical Alzheimer’s disease (AD) and 42 healthy controls. Patients’ caregivers completed a questionnaire recording changes in liking and/or interest in stimuli or activities with primary (appetite/sweet tooth, sex) or non‐primary (music, religion, art, colour) reward value. We applied multiple correspondence analysis (MCA) to map the relationships between hedonic domains and extract core factors defining aberrant hedonic phenotypes. Voxel‐based morphometry (VBM) was used to define neuroanatomical substrates across the patient cohort.ResultThe most striking hedonic phenotypes defined bvFTD and svPPA: whereas both syndromes were characterised by altered hedonic valuation of food, they were polarised by their profiles in other hedonic domains (bvFTD ‐ decreased interest in sex and music, altered interest in art and colour; svPPA ‐ increased interest in sex, religion and music). Across the combined participant cohort, one MCA factor largely accounted for the presence of hedonic alterations: this factor was linked to a diverse repertoire of appetitive and socio‐emotional behaviours (apathy, disinhibition, inappropriate humour and affection) and underpinned by grey matter loss in a distributed frontotemporal and subcortical network anchored in right anterior temporal cortex. A second MCA factor largely determined the polarity of altered hedonic valuation (approach vs avoidance).ConclusionOur findings define new, multimodal hedonic phenotypes of bvFTD and svPPA and suggest a neurobiological synthesis in which involvement of right anterior temporal lobe and its connections drives the phenotypic expression of aberrant reward processing across the FTD and AD spectrum. This work has implications for the development of novel hedonic instruments and biomarkers in neurodegenerative diseases.

Deficits in consummatory reward relate to severity of cocaine use

Background and aimsIdentifying modifiable neuropsychological factors associated with more severe CUD could improve CUD treatment. Impairments in processing of non-drug rewards may be one such factor. This study assessed the relationship between reward functioning and cocaine use severity using multi-modal measures of three distinct reward functions: consummatory reward (pleasure or “liking”); motivational reward (“wanting”) and reward learning. MethodsFifty-three adults with at least moderate CUD completed self-report and behavioral measures of consummatory reward, motivational reward and reward learning, and a composite cocaine use severity measure including quantity, frequency and life impacts of cocaine use. We conducted parallel Frequentist and Bayesian multiple regressions with measures of reward functioning as predictors of cocaine use severity. ResultsLess self-reported ability to experience pleasure, a hypothesized measure of consummatory reward, significantly predicted greater severity after adjustment for covariates and multiple hypothesis testing, β = 0.39, t(38) = 2.86, p = 0.007. Bayesian analyses confirmed a highly likely association between severity and ability to experience pleasure, and provided moderate evidence for associations with willingness to exert effort and reward learning. ConclusionsOur results suggest that less experience of subjective pleasure is related to greater cocaine use severity. This cross-sectional study cannot establish whether differences in consummatory reward are pre-existing, a result of CUD, or both. However, these results suggest interventions focused on increasing subjective pleasure, such as mindful “savoring”, should be investigated for CUD.

Agmatine reduces alcohol drinking and produces antinociceptive effects in rodent models of alcohol use disorder.

Alcohol use disorder (AUD) is a chronic, relapsing disorder characterized by an escalation of drinking and the emergence of negative affective states over time. Within this framework, alcohol may be used in excessive amounts to alleviate withdrawal-related symptoms, such as hyperalgesia. Future effective therapeutics for AUD may need to exhibit the ability to reduce drinking as well as to alleviate co-morbid conditions such as pain, and to take mechanistic sex differences into consideration. Agmatine is an endogenous neuromodulator that has been previously implicated in the regulation of reward and pain processing. In the current set of studies, we examined the ability of agmatine to reduce escalated ethanol drinking in complementary models of AUD where adult male and female mice and rats were made dependent via chronic, intermittent ethanol vapor exposure (CIE). We also examined the ability of agmatine to modify thermal and mechanical sensitivity in alcohol-dependent male and female rats. Agmatine reduced alcohol drinking in a dose-dependent fashion, with somewhat greater selectivity in alcohol-dependent female mice (versus non-dependent female mice), but equivalent efficacy across male mice and both groups of male and female rats. In mice and female rats, this efficacy did not extend to sucrose drinking, indicating some selectivity for ethanol reinforcement. Female rats made dependent on alcohol demonstrated significant hyperalgesia symptoms, and agmatine produced dose-dependent antinociceptive effects across both sexes. While additional mechanistic studies into agmatine are necessary, these findings support the broad-based efficacy of agmatine to treat co-morbid excessive drinking and pain symptoms in the context of AUD.

Distinct influence of inter- versus intra-trial feedback on the brain response to subsequent feedback: Evidence from event-related potentials

Substantial evidence indicates that feedback processing not only varies with the valence of feedback, but is also highly dependent on contextual factors. Even so, the influence of prior outcome history on current outcome evaluation is far from clear. To investigate this issue, we conducted two event-related potential (ERP) experiments using a modified gambling task whereby each trial was associated with two consequences. In experiment 1, two instances of feedback indicated participant performance on two dimensions of a single decision, within a trial. In experiment 2, participants made two decisions in each trial, and then received two instances of feedback. We examined the feedback-related negativity (FRN) as an index of feedback processing. When both instances of feedback were relevant to the same trial (intra-trial), the FRN to the second was affected by the valence of the immediately previous feedback: The FRN was amplified to losses following wins. This was observed in both experiment 1 and experiment 2. When two instances of feedback were relevant to two different trials (inter-trial), the effect of immediately previous feedback on the FRN was inconsistent. In experiment 1 there was no effect of feedback from the previous trial on the FRN. However, in Experiment 2 there was an effect of inter-trial feedback on the FRN that was opposite to the effect of intra-trial feedback: The FRN was amplified when losses followed losses. Taken together, the findings suggest that the neural systems involved in reward processing dynamically and continuously integrate preceding feedback for the evaluation of present feedback.

Delay discounting in adults with and without chronic pain: Differentiation across commodity and sign.

Delay discounting is a component of reward processing that affects decision-making in various health behavior domains. This study examined the discounting of gains and losses for monetary and pain outcomes among adults with and without chronic pain. Pain severity and pain catastrophizing (PC) were examined as additional moderators. This study assessed the discounting rates of 138 adults with chronic pain and 147 adults without chronic pain using online convenience sampling. Delay discounting was measured using an adjusting amount procedure, which titrates discounting rates based on participants' responses to identify points of indifference. Adults with and without chronic pain discounted losses more than gains and discounted pain outcomes more than monetary outcomes. There were no differences between groups based on chronic pain status or average self-reported pain severity. Post hoc analyses show that, on average, adults with chronic pain and high pain catastrophizing discounted monetary losses less than adults without chronic pain and low pain catastrophizing. This finding suggests that a tendency to defer immediate losses in favor of even larger delayed losses is dependent on high pain catastrophizing in the context of chronic pain. If pain catastrophizing is a more robust predictor of discounting rates than other pain metrics, then catastrophizing may be the construct that predicts risky decision-making. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Drinking alcohol by mid-adolescence is related to reduced reward reactivity: Novel evidence of positive valence system alterations in early initiating female youth

Initiation of alcohol use at younger ages is prognostic of later drinking problems. Reward system dysfunction is theorized to contribute to early initiation and escalation of drinking, but existing evidence supports both hyposensitivity and hypersensitivity as risk-markers; research employing effective indices of reward processing is needed for clarification. The reward positivity (RewP) is a well-established neurophysiological index of hedonic “liking,” an important aspect of reward processing. Adult research has yielded conflicting findings, with different studies reporting reduced, enhanced, or null associations of RewP with engagement in or risk for harmful alcohol use. No study has examined relations between RewP and multiple indices of drinking in youth. Here, we examined how RewP measured in a gain/loss feedback task related to self-reported drinking initiation and past-month drinking, when accounting for age along with depression and externalizing symptoms, in 250 mid-adolescent females. Analyses showed that (1) compared to not-yet drinkers, adolescents endorsing drinking initiation responded less strongly to monetary gain (RewP) but not loss feedback (FN), and (2) past-month drinking was unrelated to both RewP and FN magnitude. These findings provide evidence for reduced hedonic “liking” as a concomitant of early drinking initiation in adolescent females and warrant further research with mixed-sex adolescent samples exhibiting greater drinking variability.

The central blockade of the dopamine DR4 receptor decreases sucrose consumption by modifying the microstructure of drinking behavior in male rats.

Sugar solutions promote hedonic feeding and increase the risk of obesity and binge-type behavior. In rodents, ingestion of sugar solutions enhances dopamine release to mesolimbic regions, suggesting changes in hedonic intake and brain reward processes. Moreover, dopaminergic D2R/D3R receptors contribute to the hedonic intake of palatable solutions. Although the experimental evidence indicate that the dopaminergic D4 receptor (D4R) modulates feeding at homeostatic levels, it is currently unknown whether D4R also regulate the hedonic intake of sugar solutions. In this study, we evaluated the effect of the central blockade of D4R on the consumption of a 20% sucrose solution, the drinking microstructure parameters, and levels of locomotor activity in sated rats. In the first experiment, male Wistar rats were daily exposed to a 20% sugar solution in the first hour of the light phase of the light:dark cycle. On day 10, rats received i.c.v injections of the D4R antagonist, L-745870 (0, 1 or 2µg/5µl) and sucrose consumption and drinking microstructure parameters (latency to start drinking, bouts, drinking duration, bout size, inter-bout interval, time in activity and time in resting) were evaluated. In the second experiment, rats were trained to receive the 20% sucrose solution as described in experiment 1. On day 10, after the 1h of sucrose access, the rats were placed in the open field for 5-min (habituation phase). Then, rats received i.c.v injections of L-745870 (0, 1 or 2µg/ 5µl), and were placed again in the open-field test for 10-min (pharmacological phase). The number or crosses trough squares and number of rears were scored for both the habituation and pharmacological phase. Here we found that administration of L-745870 decreased the consumption of sucrose in a dose-depended manner. Moreover, L-745870-treated rats displayed microstructural changes, including greater number of bouts and reduced drinking duration, bout size and inter-bout intervals. Furthermore, the number of crosses and number of rears in the open field test remained unchanged for habituation and pharmacological phase. Finally, present findings suggest that D4R modulates the consumption of sugar solutions by alteration of hedonic responses, but the contribution of homeostatic systems is discussed. These results open perspectives for the potential use of the D4R antagonists for treating obesity or binge-eating behavior.

Development and validation of an fMRI-informed EEG model of reward-related ventral striatum activation

Reward processing is essential for our mental-health and well-being. In the current study, we developed and validated a scalable, fMRI-informed EEG model for monitoring reward processing related to activation in the ventral-striatum (VS), a significant node in the brain's reward system. To develop this EEG-based model of VS-related activation, we collected simultaneous EEG/fMRI data from 17 healthy individuals while listening to individually-tailored pleasurable music – a highly rewarding stimulus known to engage the VS. Using these cross-modal data, we constructed a generic regression model for predicting the concurrently acquired Blood-Oxygen-Level-Dependent (BOLD) signal from the VS using spectro-temporal features from the EEG signal (termed hereby VS-related-Electrical Finger Print; VS-EFP). The performance of the extracted model was examined using a series of tests that were applied on the original dataset and, importantly, an external validation dataset collected from a different group of 14 healthy individuals who underwent the same EEG/FMRI procedure. Our results showed that the VS-EFP model, as measured by simultaneous EEG, predicted BOLD activation in the VS and additional functionally relevant regions to a greater extent than an EFP model derived from a different anatomical region. The developed VS-EFP was also modulated by musical pleasure and predictive of the VS-BOLD during a monetary reward task, further indicating its functional relevance. These findings provide compelling evidence for the feasibility of using EEG alone to model neural activation related to the VS, paving the way for future use of this scalable neural probing approach in neural monitoring and self-guided neuromodulation.

Transcranial direct current stimulation alters the process of reward processing in children with ADHD: Evidence from cognitive modeling

BackgroundThe ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are the neural underpinnings of reward processing, which is impaired in individuals with attention deficit hyperactivity disorder (ADHD). In the present study, we aimed to explore the impact of the vmPFC and the dlPFC regulation on reward processing. MethodsTwenty-six children with ADHD performed the balloon analogue risk-taking task (BART) and chocolate delay discounting task (CDDT) during five different sessions of transcranial direct current stimulation (tDCS), separated by a one-week interval: anodal left dlPFC/cathodal right vmPFC, the reversed electrode positioning, anodal left dlPFC stimulation with extracranial return electrode, anodal right vmPFC stimulation with extracranial return electrodes, and sham stimulation. Four-parameter and constant-sensitivity models were used to model the data. ResultsIn the BART, anodal dlPFC/cathodal vmPFC stimulation facilitated conservative decision making, anodal tDCS over dlPFC with extracranial return electrode increased positive beliefs about the explosion of a balloon, and anodal vmPFC/cathodal dlPFC stimulation reduced ongoing learning in the process of decision making. In the CDDT, anodal vmPFC stimulation with extracranial return electrode decreased impatience in the process of the task. ConclusionThese results suggest a role of the left dlPFC and right vmPFC in the outcome of decision making and the process of risky decision making and delay discounting.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained themin adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

Depressive and anxiety symptoms, and neural correlates of reward and punishment anticipation in female athletes with amenorrhea.

Studies in estrogen deficiency states such as primary ovarian insufficiency and Turner syndrome suggest that estrogen status may be an important modulator of mood and emotions. In this study we compared depressive and anxiety symptoms between adolescent and young adult female oligo-amenorrheic athletes (AA) and eumenorrheic females (EM), and explored structural, and functional changes in related brain areas during reward processing, a behavioral construct that is altered in depression and anxiety. We included (i) 24 AA participating in ≥4 hours/week of aerobic exercise or running ≥20 miles/week for ≥6 months in the preceding year, with lack of menstrual cycles for ≥3 months within at least 6 preceding months of oligo-amenorrhea, OR in premenarchal girls, absence of menses at >15 years), and (ii) 27 EM aged 14-25 years. Participants completed the Beck Depression Inventory-II (BDI-II), State and Trait Anxiety Inventory (STAI), and Mood and Anxiety Symptoms Questionnaire (MASQ). Structural MRI and brain activation during a functional MRI (fMRI) task that probes reward and punishment processing was examined in a subset of 10 AA and 23 EM. Median (IQR) age and BMI of AA and EM groups were 20.6 (19.0-22.6) vs. 20.6 (19.2-23.7) years, p=0.6 and v 20.3 (18.8-21.5) vs. 21.9 (19.6-23.5) kg/m2, p=0.005, respectively. While groups did not differ for BDI-II scores, AA had higher anhedonic depression MASQ scores (p=0.04), and STAI (p=0.03) scores vs. EM. In the fMRI subset, AA had higher caudate volumes vs. EM [F(1, 29)=9.930, p=0.004]. Lower activation observed in the right caudate during reward anticipation in AA compared with EM (p=0.036) suggests blunted reward processing in the striatum in estrogen deficient states. Athletes with amenorrhea had higher depressive and anxiety symptomatology compared to eumenorrheic young women. Exploratory analyses demonstrated increased caudate volumes and decreased caudate activation during reward processing in athletes with amenorrhea suggesting that estrogen may play a role in reward processing.

Consumption of ultra-processed foods is associated with depression, mesocorticolimbic volume, and inflammation

BackgroundThe consumption of ultra-processed foods and drinks (UPF) has been associated with depression and inflammation and preclinical studies showed that some UPF components disrupt the amygdala-hippocampal complex. We combine diet, clinical and brain imaging data to investigate the relationship between the UPF consumption, depressive symptoms, and brain volumes in humans, considering interactions with obesity, and the mediation effect of inflammation biomarkers. MethodsOne-hundred fifty-two adults underwent diet, depressive symptoms, anatomic magnetic resonance imaging assessments and laboratory tests. Relationships between the % of UPF consumption (in grams) of the total diet, depressive symptoms, and gray matter brain volumes were explored using several adjusted regression models, and in interaction with the presence of obesity. Whether inflammatory biomarkers (i.e., white blood cell count, lipopolysaccharide-binding protein, c-reactive protein) mediate the previous associations was investigated using R mediation package. ResultsHigh UPF consumption was associated with higher depressive symptoms in all participants (β = 0.178, CI = 0.008–0.261) and in those with obesity (β = 0.214, CI = −0.004–0.333). Higher consumption was also associated with lower volumes in the posterior cingulate cortex and the left amygdala, which in the participants with obesity also encompassed the left ventral putamen and the dorsal frontal cortex. White blood count levels mediated the association between UPF consumption and depressive symptoms (p = 0.022). LimitationsThe present study precludes any causal conclusions. ConclusionsUPF consumption is associated with depressive symptoms and lower volumes within the mesocorticolimbic brain network implicated in reward processes and conflict monitoring. Associations were partially dependent on obesity and white blood cell count.

Paediatric obesity and metabolic syndrome associations with cognition and the brain in youth: Current evidence and future directions.

Obesity and components of the metabolic syndrome (MetS) are associated with differences in brain structure and function and in general and food-related cognition in adults. Here, we review evidence for similar phenomena in children and adolescents, with a focus on the implications of extant research for possible underlying mechanisms and potential interventions for obesity and MetS in youth. Current evidence is limited by a relative reliance on small cross-sectional studies. However, we find that youth with obesity and MetS or MetS components show differences in brain structure, including alterations in grey matter volume and cortical thickness across brain regions subserving reward, cognitive control and other functions, as well as in white matter integrity and volume. Children with obesity and MetS components also show some evidence for hyperresponsivity of food reward regions and hyporesponsivity of cognitive control circuits during food-related tasks, altered brain responses to food tastes, and altered resting-state connectivity including between cognitive control and reward processing networks. Potential mechanisms for these findings include neuroinflammation, impaired vascular reactivity, and effects of diet and obesity on myelination and dopamine function. Future observational research using longitudinal measures, improved sampling strategies and study designs, and rigorous statistical methods, promises to further illuminate dynamic relationships and causal mechanisms. Intervention studies targeted at modifiable biological and behavioural factors associated with paediatric obesity and MetS can further inform mechanisms, as well as test whether brain and behaviour can be altered for beneficial outcomes.

Abnormality of Reward Sensitivity in Major Depressive Disorder and Bipolar Disorder

Bipolar disorder (BD) and major depressive disorder (MDD) are two major psychiatric disorders that both involve a reward system abnormality. This paper reviews studies on the hyper/hyposensitivity model, also known as the Behavior Approach System (BAS), that emphasize the role of abnormal reward processing in patients with BD and MDD. The paper concludes that BD patients' extremely high reward sensitivity causes manic-related symptoms as well as bipolar depressive symptoms. On the contrary, MDD patients' extremely low reward sensitivity leads to unipolar depressive symptoms such as anhedonia and loss of motivation. Furthermore, this paper discusses the hyper/hyposensitivity model's utility in three areas: how it can aid in disease differentiation and prediction, and how it can be used to develop potential treatments. Because reward sensitivity can be measured using reward tasks, predicting the onset of BD and MDD, making the correct diagnosis, and developing treatments will be easier if the relationship between sensitivity and diseases is clear.

Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present. Since both the infralimbic cortex (IL) and amygdala have each been shown to be important for fear regulation to safety cues, we tested the necessity of specific IL projections to the basolateral amygdala (BLA) or central amygdala (CeA) during safety recall. Male Long Evans rats were used since prior work showed female Long Evans rats did not acquire the safety discrimination task used in this study. Here, we show the infralimbic projection to the central amygdala was necessary for suppressing fear cue-induced freezing in the presence of a learned safety cue, and the projection to the basolateral amygdala was not. The loss of discriminative fear regulation seen specifically during IL->CeA inhibition is similar to the behavioral disruption seen in PTSD individuals that fail to regulate fear in the presence of a safety cue.

Study directions and development of cognitive theory of depression.

Aaron T. Beck's cognitive model of depression became the basis for the analysis of cognitive factors as significant correlates and predictors of depression. Psychological mechanisms of depression related to the depressive cognitive triad, the specificity of cognitive schemas and errors in cognitive processing determined the directions of further research on depression. The presented analysis of selected studies confirms and extends Beck's assumptions about the role of cognitive factors in the development and maintenance of depressive symptoms. The analysis of psychological, neuroimaging and biochemical studies provides a broader perspective of understanding both the etiology and mechanisms that sustain the symptoms of depression. The development of neuroimaging research has broadened the knowledge about the brain mechanisms of depression - the presented research combine the theoretical constructs of the cognitive concept of depression with the characteristics of the activity of brain structures and their functional connections. The following conclusions seem to be particularly important for clinical practice: 1) impairment of the cognitive inhibition function in depression reduces the control of negative automatic thoughts - strengthening working memory is important; 2) different brain mechanisms for processing rewards and punishments in people suffering from depression and in healthy people explain the formation of self-esteem - this knowledge can be an important element of psychoeducation in therapeutic work; 3) neuroimaging studies indicate neuronal correlates of cognitive distortions observed in depression - for further research on depression, it would be particularly important to monitor changes in brain activity in the course of its treatment.

The impact of cannabidiol treatment on resting state functional connectivity, prefrontal metabolite levels and reward processing in recent-onset patients with a psychotic disorder

The first clinical trials with cannabidiol (CBD) as treatment for psychotic disorders have shown its potential as an effective and well-tolerated antipsychotic agent. However, the neurobiological mechanisms underlying the antipsychotic profile of CBD are currently unclear. Here we investigated the impact of 28-day adjunctive CBD or placebo treatment (600 mg daily) on brain function and metabolism in 31 stable recent-onset psychosis patients (<5 years after diagnosis). Before and after treatment, patients underwent a Magnetic Resonance Imaging (MRI) session including resting state functional MRI, proton Magnetic Resonance Spectroscopy (1H-MRS) and functional MRI during reward processing. Symptomatology and cognitive functioning were also assessed. CBD treatment significantly changed functional connectivity in the default mode network (DMN; time × treatment interaction p = 0.037), with increased connectivity in the CBD (from 0.59 ± 0.39 to 0.80 ± 0.32) and reduced connectivity in the placebo group (from 0.77 ± 0.37 to 0.62 ± 0.33). Although there were no significant treatment effects on prefrontal metabolite concentrations, we showed that decreased positive symptom severity over time was associated with both diminishing glutamate (p = 0.029) and N-acetyl-aspartate (NAA; neuronal integrity marker) levels (p = 0.019) in the CBD, but not the placebo group. CBD treatment did not have an impact on brain activity patterns during reward anticipation and receipt or functional connectivity in executive and salience networks. Our results show that adjunctive CBD treatment of recent-onset psychosis patients induced changes in DMN functional connectivity, but not prefrontal metabolite concentrations or brain activity during reward processing. These findings suggest that DMN connectivity alteration may be involved in the therapeutic effects of CBD.

Neural responses to reward valence and magnitude from pre- to early adolescence

BackgroundNeural activation during reward processing is thought to underlie critical behavioral changes that take place during the transition to adolescence (e.g., learning, risk-taking). Though literature on the neural basis of reward processing in adolescence is booming, important gaps remain. First, more information is needed regarding changes in functional neuroanatomy in early adolescence. Another gap is understanding whether sensitivity to different aspects of the incentive (e.g., magnitude and valence) changes during the transition into adolescence. We used fMRI from a large sample of preadolescent children to characterize neural responses to incentive valence vs. magnitude during anticipation and feedback, and their change over a period of two years. MethodsData were taken from the Adolescent Cognitive and Brain DevelopmentSM (ABCD®) study release 3.0. Children completed the Monetary Incentive Delay task at baseline (ages 9–10) and year 2 follow-up (ages 11–12). Based on data from two sites (N = 491), we identified activation-based Regions of Interest (ROIs; e.g., striatum, prefrontal regions, etc.) that were sensitive to trial type (win $5, win $0.20, neutral, lose $0.20, lose $5) during anticipation and feedback phases. Then, in an independent subsample (N = 1470), we examined whether these ROIs were sensitive to valence and magnitude and whether that sensitivity changed over two years. ResultsOur results show that most ROIs involved in reward processing (including the striatum, prefrontal cortex, and insula) are specialized, i.e., mainly sensitive to either incentive valence or magnitude, and this sensitivity was consistent over a 2-year period. The effect sizes of time and its interactions were significantly smaller (0.002≤η2≤0.02) than the effect size of trial type (0.06≤η2≤0.30). Interestingly, specialization was moderated by reward processing phase but was stable across development. Biological sex and pubertal status differences were few and inconsistent. Developmental changes were mostly evident during success feedback, where neural reactivity increased over time. ConclusionsOur results suggest sub-specialization to valence vs. magnitude within many ROIs of the reward circuitry. Additionally, in line with theoretical models of adolescent development, our results suggest that the ability to benefit from success increases from pre- to early adolescence. These findings can inform educators and clinicians and facilitate empirical research of typical and atypical motivational behaviors during a critical time of development.

Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations.

Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations. In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors. Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis. Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant. Key Technological Projects of Guangdong Province grant 2018B030335001. NCT05265806.