Reward-related Processes Research Articles

Problematic Gaming and Gambling: A Systematic Review of Task-Specific EEG Protocols.

Even though gaming and gambling bear similar problematic behavioral aspects, there are no recognizable neurophysiological biomarkers or features characterizing and/or distinguishing these conditions. A systematic review of the literature with a focus on methods was performed in PubMed, Scopus, Web of Science (Web of Science Core Collection), EBSCOhost Research Databases (APA PsycINFO; APA PsycArticles; OpenDissertations; ERIC) databases. Following search terms were used to search the databases: ERP, "event related potential*", EP, "evoked potential*", SS, "steady state", EEG, electroencephal*; gam*. Data about the participants (total number, gender, age), main aim of the study and information about the experimental setup (experimental task description, stimuli used, ERPs measured (latency windows and placement of the electrodes), process evaluated) was extracted. A total of 24 studies were revised (problematic gaming - 16, pathological gambling - 8). The experimental protocols could be grouped into 3 main target domains (Cue-reactivity, General Information processing and Reward Processes & Risk Assessment). Sample-related limitations (small sample sizes, gender differences, differences between the groups regarding potential confounding variables) and heterogeneity regarding the experimental tasks, implementation and interpretation reviewed. Gambling-related research is highly focused on the investigation of the reward-related processes, whereas gaming-related research is mostly focused on the altered aspects of more general information processing. A vast heterogeneity regarding the ERP experimental paradigms being usedand lack of clear guidelines and standardized procedures prevents identification of measures capable to reliably discriminate or characterize the population susceptible to addictive behavior or being able to diagnose and monitor these disorders.

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report.

Anorexia nervosa (AN) is a debilitating and potentially chronic eating disorder, characterized by low hedonic drive toward food, which has been linked with perturbations in both reward processing and dopaminergic activity. Neuromelanin-sensitive magnetic resonance imaging (MRI) is an emerging method to index midbrain neuromelanin-a by-product of dopaminergic synthesis. The assessment of midbrain neuromelanin, and its association with AN psychopathology and reward-related processes, may provide critical insights into reward circuit function in AN. This study will incorporate neuromelanin-sensitive MRI into an existing study of appetitive conditioning in those with AN. Specifically, those with acute and underweight AN (N=30), those with weight-restored AN (N=30), and age-matched healthy controls (N=30) will undergo clinical assessment of current and previous psychopathology, in addition to structural neuromelanin-sensitive MRI, diffusion MRI, and functional MRI (fMRI) during appetitive conditioning. This study will be among the first to interrogate midbrain neuromelanin in AN-a disorder characterized by altered dopaminergic activity. Results will help establish whether abnormalities in the midbrain synthesis of dopamine are evident in those with AN and are associated with symptomatic behavior and reduced ability to experience pleasure and reward.

Attention-deficit/hyperactivity disorder is associated with more alcohol problems and less substance-free reinforcement: A behavioral economics daily diary study of college student drinkers.

Behavioral economic theory suggests that alcohol risk is related to elevated alcohol reinforcing efficacy (demand) combined with diminished availability of reinforcing substance-free activities, but little research has examined these reward-related processes at the daily level in association with comorbid conditions that might influence behavioral patterns and reward. Young people with attention-deficit/hyperactivity disorder (ADHD) report high levels of risky drinking, and this risk may be due in part to elevated demand for alcohol and diminished engagement in enjoyable and valued substance-free activities. College student drinkers (N = 101; 48.5% female; 68.3% White; 18-22 years old) with (n = 51) and without (n = 50) ADHD completed 14 consecutive daily diaries (diary entry n = 1,414). We conducted a series of multilevel path models to examine (a) the associations among ADHD and average daily alcohol demand, substance-free enjoyment, and response contingent positive reinforcement (RCPR) for goal-directed behaviors; (b) the associations among concurrent daily alcohol demand, substance-free reinforcement, and RCPR for goal-directed behaviors and daily alcohol use and alcohol-related negative consequences; and (c) the moderating effect of ADHD on these within-day associations. ADHD was significantly associated with more daily alcohol-related negative consequences and less daily substance-free enjoyment and RCPR. Regardless of ADHD status, there were significant associations among behavioral economic risk factors and alcohol use and negative consequences, though effects differed within and between persons. There were no moderating effects of ADHD on within-person associations. Results expose areas of impairment specific to drinkers with ADHD and advance theory on ADHD and hazardous drinking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Common neural dysfunction of economic decision-making across psychiatric conditions

Adaptive decision-making, which is often impaired in various psychiatric conditions, is essential for well-being. Recent evidence has indicated that decision-making capacity in multiple tasks could be accounted for by latent dimensions, enlightening the question of whether there is a common disruption of brain networks in economic decision-making across psychiatric conditions. Here, we addressed the issue by combining activation/lesion network mapping analyses with a transdiagnostic brain imaging meta-analysis. Our findings indicate that there were transdiagnostic alterations in the thalamus and ventral striatum during the decision or outcome stage of decision-making. The identified regions represent key nodes in a large-scale network, which is composed of multiple heterogeneous brain regions and plays a causal role in motivational functioning. The findings suggest that disturbances in the network associated with emotion- and reward-related processing play a key role in dysfunctions of decision‐making observed in various psychiatric conditions. This study provides the first meta-analytic evidence of common neural alterations linked to deficits in economic decision-making.

Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy.The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 μg/μl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Memory-specific encoding activities of the ventral tegmental area dopamine and GABA neurons.

Although the midbrain dopamine (DA) system plays a crucial role in higher cognitive functions, including updating and maintaining short-term memory, the encoding properties of the somatic spiking activity of ventral tegmental area (VTA) DA neurons for short-term memory computations have not yet been identified. Here, we probed and analyzed the activity of optogenetically identified DA and GABA neurons while mice engaged in short-term memory-dependent behavior in a T-maze task. Single-neuron analysis revealed that significant subpopulations of DA and GABA neurons responded differently between left and right trials in the memory delay. With a series of control behavioral tasks and regression analysis tools, we show that firing rate differences are linked to short-term memory-dependent decisions and cannot be explained by reward-related processes, motivated behavior, or motor-related activities. This evidence provides novel insights into the mnemonic encoding activities of midbrain DA and GABA neurons.

Memory-specific encoding activities of the ventral tegmental area dopamine and GABA neurons

Although the midbrain dopamine (DA) system plays a crucial role in higher cognitive functions, including updating and maintaining short-term memory, the encoding properties of the somatic spiking activity of ventral tegmental area (VTA) DA neurons for short-term memory computations have not yet been identified. Here, we probed and analyzed the activity of optogenetically identified DA and GABA neurons while mice engaged in short-term memory-dependent behavior in a T-maze task. Single-neuron analysis revealed that significant subpopulations of DA and GABA neurons responded differently between left and right trials in the memory delay. With a series of control behavioral tasks and regression analysis tools, we show that firing rate differences are linked to short-term memory-dependent decisions and cannot be explained by reward-related processes, motivated behavior, or motor-related activities. This evidence provides novel insights into the mnemonic encoding activities of midbrain DA and GABA neurons.

Sex and pubertal variation in reward-related behavior and neural activation in early adolescents

This study aimed to characterize the role of sex and pubertal markers in reward motivation behavior and neural processing in early adolescence. We used baseline and two-year follow-up data from the Adolescent Brain and Cognitive DevelopmentSM study (15844 observations; 52% from boys; age 9–13). Pubertal development was measured with parent-reported Pubertal Development Scale, and DHEA, testosterone, and estradiol levels. Reward motivation behavior and neural processing at anticipation and feedback stages were assessed with the Monetary Incentive Delay task. Boys had higher reward motivation than girls, demonstrating greater accuracy difference between reward and neutral trials and higher task earnings. Girls had lower neural activation during reward feedback than boys in the nucleus accumbens, caudate, rostral anterior cingulate, medial orbitofrontal cortex, superior frontal gyrus and posterior cingulate. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, although these associations changed when controlling for age. There were no significant associations between pubertal development and neural activation during reward anticipation and feedback. Sex differences in reward-related processing exist in early adolescence, signaling the need to understand their impact on typical and atypical functioning as it unfolds into adulthood.

Hyperdopaminergia in rats is associated with reverse effort-cost dependent performance.

Dopamine is implicated in the effort-based control of motivational processes; however, whether tonic dopamine regulates the effort-cost impact on motivation, is still debated. The rats lacking the dopamine transporter (DAT), which have dramatically increased levels of the synaptic dopamine, were used in the present study to elucidate the role of the synaptic dopamine in motivational processes. To study the reward-related processes, the progressive ratio 3 (PR3) operant schedule of food reinforcement (the ratio increases by 3 after each earned reinforcer) was performed in adult male rats (DAT knockouts (DAT-KO), heterozygotes (DAT-HT) and wild-types (DAT-WT)). During the PR3 session, the response rate of DAT-KO rats was gradually increased following the augmented required number of responses. In contrast, the local response rate of DAT-WT and DAT-HT decreased. d-Amphetamine sulfate salt (3 mg/kg, i.p.) altered the local response rate dynamics in DAT-WT, which became similar to that of DAT-KO. Interestingly, the reduction in response rate at low effort demands was associated with decreased rate of entries into the magazine tray in DAT-WT rats treated with amphetamine (3 mg/kg) but not in DAT-KO rats. Our results suggest that the elevated tonic synaptic dopamine can strongly affect motivation/effort-cost relation in rodents.

THU122 Effects Of A GLP-1 Agonist On Consumption Of Alcohol In Patients Treated For Smoking Cessation

Abstract Disclosure: L.S. Probst: None. S. Monnerat: None. S. Lengsfeld: None. C. Bathelt: None. A. Meienberg: None. T. Burkard: None. M. Christ-crain: None. B.F. Winzeler: None. Introduction: Alcohol use disorder causes high socio-economic costs and has a detrimental impact on health globally, being considered a key factor contributing to non-communicable diseases. In Switzerland four substances are currently approved for treatment of alcohol use disorder with only limited to moderate effects. Thus, the need for new treatment options in alcohol and substance use disorder is evident. Recent research has shed light on a new potential target for treatment of addiction: a body of preclinical studies provide evidence for the attenuating effects of GLP-1 agonists on addictive behavior in rodents and non-human primates. A few studies have shown a link between GLP-1 receptors and reward related processes in humans, and a trial from denmark examined the effect of exenatide in patients treated for alcohol use disorder, however clinical data are scarce and results remain inconclusive. Methods: This is a secondary analysis of the SKIP study, a double-blind, randomized, placebo-controlled trial to evaluate treatment with the GLP-1 agonist dulaglutide (Trulicy®) as a new therapy for smoking cessation. In the present analysis, the primary objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo in alcohol-consuming smokers willing to quit smoking. We selected patients out of the cohort (n=255) who consumed alcohol at baseline and completed 12 weeks of treatment (n= 151). The independent effect of dulaglutide on alcohol consumption was analysed by fitting a multivariate generalized linear regression model with quasipoisson distribution and adjustment for baseline alcohol consumption. Preliminary Results: One hundred and fifty-one patients (placebo n=75, dulaglutide n=76) were included in the primary analysis. Baseline patient characteristics were well balanced between groups. The median age was 42 [IQR 33, 53] years with 61% (n=92) females. At baseline, patients in both treatment groups consumed 3 [IQR 2, 7] standard glasses of alcohol per week on average. At week 12, patients in the dulaglutide group drank an estimated 29% (IRR = 0.71; 95% CI 0.52, 0.97; p=0.04) less compared to the placebo group. For each additional glass consumed at baseline, alcohol consumption at week 12 increased by 6% (95% CI 5, 7; p<0.001). Conclusion: These preliminary findings suggest that in patients who drink, alcohol intake tends to increase during smoking cessation. In the present analysis we were able to show that this increase was attenuated by the addition of a 12-week treatment with dulaglutide to standard smoking cessation therapy. Presentation: Thursday, June 15, 2023

The genetic variant SLC2A1 -rs1105297 is associated with the differential analgesic response to a glucose-based treatment in newborns.

Neonatal pain is a critical issue in clinical practice. The oral administration of glucose-based solutions is currently one of the most common and effective nonpharmacologic strategies for neonatal pain relief in daily minor procedures. However, a varying degree of analgesic efficacy has been reported for this treatment. Environmental, maternal, and genetic factors may explain this variability and potentially allow for a personalized analgesic approach, maximizing therapeutic efficacy and preventing side effects. We investigated the exposome (ie, the set of clinical and anthropometric variables potentially affecting the response to the therapy) and the genetic variability of the noradrenaline transporter gene (solute carrier family 6 member 2 [ SLC6A2 ]) and 2 glucose transporter genes (solute carrier family 2 member 1 [ SLC2A1 ] and 2 [ SLC2A2 ]) in relation to the neonatal analgesic efficacy of a 33% glucose solution. The study population consisted in a homogeneous sample of more than 1400 healthy term newborns. No association for the exposome was observed, whereas a statistically significant association between the G allele of SLC2A1 -rs1105297 and a fourfold decreased probability of responding to the therapy was identified after multiple-testing correction (odds ratio of 3.98, 95% confidence interval 1.95-9.17; P = 4.05 × 10 -4 ). This allele decreases the expression of SLC2A1-AS1 , causing the upregulation of SLC2A1 in the dorsal striatum, which has been suggested to be involved in reward-related processes through the binding of opioids to the striatal mu-opioid receptors. Altogether, these results suggest the involvement of SLC2A1 in the analgesic process and highlight the importance of host genetics for defining personalized analgesic treatments.

Early life stress moderates the relation between systemic inflammation and neural activation to reward in adolescents both cross-sectionally and longitudinally.

Elevated levels of systemic inflammation are associated with altered reward-related brain function in ventral striatal areas of the brain like the nucleus accumbens (NAcc). In adolescents, cross-sectional research indicates that exposure to early life stress (ELS) can moderate the relation between inflammation and neural activation, which may contribute to atypical reward function; however, no studies have tested whether this moderation by ELS of neuroimmune associations persists over time. Here, we conducted a cross-sectional analysis and the first exploratory longitudinal analysis testing whether cumulative severity of ELS moderates the association of systemic inflammation with reward-related processing in the NAcc in adolescents (n = 104; 58F/46M; M[SD] age = 16.00[1.45] years; range = 13.07-19.86 years). For the cross-sectional analysis, we modeled a statistical interaction between ELS and levels of C-reactive protein (CRP) predicting NAcc activation during the anticipation and outcome phases of a monetary reward task. We found that higher CRP was associated with blunted NAcc activation during the outcome of reward in youth who experienced higher levels of ELS (β = -0.31; p = 0.006). For the longitudinal analysis, we modeled an interaction between ELS and change in CRP predicting change in NAcc activation across 2 years. This analysis similarly showed that increasing CRP over time was associated with decreasing NAcc during reward outcomes in youth who experienced higher levels of ELS (β = -0.47; p = 0.022). Both findings support contemporary theoretical frameworks involving associations among inflammation, reward-related brain function, and ELS exposure, and suggest that experiencing ELS can have significant and enduring effects on neuroimmune function and adolescent neurodevelopment.

Brain Networks and Adolescent Alcohol Use

Alcohol misuse in adolescence is a leading cause of disability and mortality in youth and is associated with higher risk for alcohol use disorder. Brain mechanisms underlying risk of alcohol misuse may inform prevention and intervention efforts. To identify neuromarkers of alcohol misuse using a data-driven approach, with specific consideration of neurodevelopmental sex differences. Longitudinal multisite functional magnetic resonance imaging (fMRI) data collected at ages 14 and 19 years were used to assess whole-brain patterns of functional organization associated with current and future alcohol use risk as measured by the Alcohol Use Disorder Identification Test (AUDIT). Primary data were collected by the IMAGEN consortium, a European multisite study of adolescent neurodevelopment. Model generalizability was further tested using data acquired in a single-site study of college alcohol consumption conducted in the US. The primary sample was a developmental cohort of 1359 adolescents with neuroimaging, phenotyping, and alcohol use data. Model generalizability was further assessed in a separate cohort of 114 individuals. Brain-behavior model accuracy, as defined by the correspondence between model-predicted and actual AUDIT scores in held-out testing data, Bonferroni corrected across the number of models run at each time point, 2-tailed α < .008, as determined via permutation testing. Among 1359 individuals in the study, the mean (SD) age was 14.42 (0.40) years, and 729 individuals (54%) were female. The data-driven, whole-brain connectivity approach identified networks associated with vulnerability for future and current AUDIT-defined alcohol use risk (primary outcome, as specified above, future: ρ, 0.22; P < .001 and present: ρ, 0.27; P < .001). Results further indicated sex divergence in the accuracies of brain-behavior models, such that female-only models consistently outperformed male-only models. Specifically, female-only models identified networks conferring vulnerability for future and current severity using data acquired during both reward and inhibitory fMRI tasks. In contrast, male-only models were successful in accurately identifying networks using data acquired during the inhibitory control-but not reward-task, indicating domain specificity of alcohol use risk networks in male adolescents only. These data suggest that interventions focusing on inhibitory control processes may be effective in combating alcohol use risk in male adolescents but that both inhibitory and reward-related processes are likely of relevance to alcohol use behaviors in female adolescents. They further identify novel networks of alcohol use risk in youth, which may be used to identify adolescents who are at risk and inform intervention efforts.

Understanding the benefits of extrinsic emotion regulation in depression.

Depression is a serious psychiatric illness that negatively affects people's feelings, thoughts, and actions. Providing emotion regulation support to others, also termed Extrinsic Emotion Regulation (EER), reduces depressive symptoms such as perseverative thinking and negative mood. In this conceptual review paper, we argue that EER may be especially beneficial for individuals with depression because it enhances the cognitive and affective processes known to be impaired in depression. Behavioral studies have shown that EER recruits processes related to cognitive empathy, intrinsic emotion regulation (IER), and reward, all impaired in depression. Neuroimaging data support these findings by showing that EER recruits brain regions related to these three processes, such as the ventrolateral prefrontal cortex which is associated with IER, the ventral striatum, which is associated with reward-related processes, and medial frontal regions related to cognitive empathy. This conceptual review paper sheds light on the mechanisms underlying the effectiveness of EER for individuals with depression and therefore offers novel avenues for treatment.

Exposure to Multicultural Context Affects Neural Response to Out-Group Faces: A Functional Magnetic Resonance Imaging Study.

Recent migration and globalization trends have led to the emergence of ethnically, religiously, and linguistically diverse countries. Understanding the unfolding of social dynamics in multicultural contexts becomes a matter of common interest to promote national harmony and social cohesion among groups. The current functional magnetic resonance imaging (fMRI) study aimed to (i) explore the neural signature of the in-group bias in the multicultural context; and (ii) assess the relationship between the brain activity and people's system-justifying ideologies. A sample of 43 (22 females) Chinese Singaporeans (M = 23.36; SD = 1.41) was recruited. All participants completed the Right Wing Authoritarianism Scale and Social Dominance Orientation Scale to assess their system-justifying ideologies. Subsequently, four types of visual stimuli were presented in an fMRI task: Chinese (in-group), Indian (typical out-group), Arabic (non-typical out-group), and Caucasian (non-typical out-group) faces. The right middle occipital gyrus and the right postcentral gyrus showed enhanced activity when participants were exposed to in-group (Chinese) rather than out-group (Arabic, Indian, and Caucasian) faces. Regions having a role in mentalization, empathetic resonance, and social cognition showed enhanced activity to Chinese (in-group) rather than Indian (typical out-group) faces. Similarly, regions typically involved in socioemotional and reward-related processing showed increased activation when participants were shown Chinese (in-group) rather than Arabic (non-typical out-group) faces. The neural activations in the right postcentral gyrus for in-group rather than out-group faces and in the right caudate in response to Chinese rather than Arabic faces were in a significant positive correlation with participants' Right Wing Authoritarianism scores (p < 0.05). Furthermore, the activity in the right middle occipital gyrus for Chinese rather than out-group faces was in a significant negative correlation with participants' Social Dominance Orientation scores (p < 0.05). Results are discussed by considering the typical role played by the activated brain regions in socioemotional processes as well as the role of familiarity to out-group faces.

Fear of missing out (FOMO) associates with reduced cortical thickness in core regions of the posterior default mode network and higher levels of problematic smartphone and social media use

Background and aimsFear of missing out (FOMO) promotes the desire or urge to stay continuously connected with a social reference group and updated on their activities, which may result in escalating and potentially addictive smartphone and social media use. The present study aimed to determine whether the neurobiological basis of FOMO encompasses core regions of the reward circuitry or social brain, and associations with levels of problematic smartphone or social media use. MethodsWe capitalized on a dimensional neuroimaging approach to examine cortical thickness and subcortical volume associations in a sample of healthy young individuals (n = 167). Meta-analytic network and behavioral decoding analyses were employed to further characterize the identified regions. ResultsHigher levels of FOMO associated with lower cortical thickness in the right precuneus. In contrast, no associations between FOMO and variations in striatal morphology were observed. Meta-analytic decoding revealed that the identified precuneus region exhibited a strong functional interaction with the default mode network (DMN) engaged in social cognitive and self-referential domains. Discussion and conclusionsTogether the present findings suggest that individual variations in FOMO are associated with the brain structural architecture of the right precuneus, a core hub within a large-scale functional network resembling the DMN and involved in social and self-referential processes. FOMO may promote escalating social media and smartphone use via social and self-referential processes rather than reward-related processes per se.

Sex differences in addiction-relevant behavioral outcomes in rodents following early life stress

In humans, exposure to early life stress (ELS) is an established risk factor for the development of substance use disorders (SUDs) during later life. Similarly, rodents exposed to ELS involving disrupted mother-infant interactions, such as maternal separation (MS) or adverse caregiving due to scarcity-adversity induced by limited bedding and nesting (LBN) conditions, also exhibit long-term alterations in alcohol and drug consumption. In both humans and rodents, there is a range of addiction-related behaviors that are associated with drug use and even predictive of subsequent SUDs. In rodents, these include increased anxiety-like behavior, impulsivity, and novelty-seeking, altered alcohol and drug intake patterns, as well as disrupted reward-related processes involving consummatory and social behaviors. Importantly, the expression of these behaviors often varies throughout the lifespan. Moreover, preclinical studies suggest that sex differences play a role in how exposure to ELS impacts reward and addiction-related phenotypes as well as underlying brain reward circuitry. Here, addiction-relevant behavioral outcomes and mesolimbic dopamine (DA) dysfunction resulting from ELS in the form of MS and LBN are discussed with a focus on age- and sex-dependent effects. Overall, these findings suggest that ELS may increase susceptibility for later life drug use and SUDs by interfering with the normal maturation of reward-related brain and behavioral function.

A structural connectivity atlas of limbic brainstem nuclei.

Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.

Association between inflammation, reward processing, and ibuprofen-induced increases of miR-23b in astrocyte-enriched extracellular vesicles: A randomized, placebo-controlled, double-blind, exploratory trial in healthy individuals

Ibuprofen, a non-steroidal, anti-inflammatory drug, modulates inflammation but may also have neuroprotective effects on brain health that are poorly understood. Astrocyte-enriched extracellular vesicles (AEEVs) facilitate cell-to-cell communication and – among other functions - regulate inflammation and metabolism via microribonucleic acids (miRNAs). Dysfunctions in reward-related processing and inflammation have been proposed to be critical pathophysiological pathways in individuals with mood disorders. This investigation examined whether changes in AEEV cargo induced by an anti-inflammatory agent results in inflammatory modulation that is associated with reward-related processing. Data from a double-blind, randomized, repeated-measures study in healthy volunteers were used to examine the effects of AEEV miRNAs on brain activation during reward-related processing. In three separate visits, healthy participants (N = 20) received a single dose of either placebo, 200 mg, or 600 mg of ibuprofen, completed the monetary incentive delay task during functional magnetic resonance imaging, and provided a blood sample for cytokine and AEEV collection. AEEV miRNA content profiling showed that ibuprofen dose-dependently increased AEEV miR-23b-3p expression with greater increase following the 600 mg administration than placebo. Those individuals who received 600 mg and showed the highest miR-23b-3p expression also showed the (a) lowest serum tumor necrosis factor (TNF) and interleukin-17A (IL-17A) concentrations; and had the (b) highest striatal brain activation during reward anticipation. These results support the hypothesis that ibuprofen alters the composition of miRNAs in AEEVs. This opens the possibility that AEEV cargo could be used to modulate brain processes that are important for mental health.

Dopamine downregulation in novel rodent models useful for the study of postpartum depression.

Postpartum depression (PPD) is the most common psychiatric disorder following childbirth and is characterized by maternal mood disturbances, impaired maternal responses, and disrupted caregiving- all of which negatively impact offspring development. Since PPD has detrimental consequences for both mother and child, clinical and preclinical research has focused on identifying brain changes associated with this disorder. In humans, PPD is linked to dysregulated mesolimbic dopamine (DA) system function and altered neural responses (i.e., decreased reward-related activity) to infant-related cues, which are considered hallmark features of PPD. In accordance, rodent models employing translational risk factors useful for the study of PPD have demonstrated alterations in mesolimbic DA system structure and function, and these changes are reviewed here. We also present two novel rodent models based on postpartum adversity exposure (i.e., pup removal, scarcity-adversity) which result in PPD-relevant behavioral changes (e.g., disrupted mother-infant interactions, deficits in maternal behavior, depressive-like phenotypes) and attenuated ventral tegmental area (VTA) DA neuron activity consistent with a hypodopaminergic state. Furthermore, we highlight open questions and future directions for these rodent models. In sum, human and rodent studies converge in showing blunted mesolimbic DA function (i.e., DA downregulation) in PPD. We propose that reduced activity of VTA DA neurons, resulting in downregulation of the mesolimbic DA system, interferes with reward-related processes necessary for maternal motivation and responsiveness. Thus, the mesolimbic DA system may constitute a therapeutic target for ameliorating reward-related deficits in PPD.