Reward Regions Research Articles

Long read, isoform aware sequencing of mouse nucleus accumbens after chronic cocaine treatment

To better understand the full-length transcriptome of the nucleus accumbens (NAc)—a key brain reward region—in chronic cocaine treatment, we perform the first single molecule, long-read sequencing analysis using the Iso-seq method to detect 42,114 unique transcripts from mouse NAc polyadenylated RNA. Using GENCODE annotation as a reference, we find that over half of the Iso-seq derived transcripts are annotated, while 46% of them harbor novel splicing events in known genes; around 1% of them correspond to other types of novel transcripts, such as fusion, antisense and intergenic. Approximately 34% of the novel transcripts are matched with a compiled transcriptome assembled from published short-read data from various tissues, with the remaining 69% being unique to NAc. These data provide a more complete picture of the NAc transcriptome than existing annotations and can serve as a comprehensive reference for future transcriptomic analyses of this important brain reward region.

Age differences in Neural Activation to Face Trustworthiness: Voxel Pattern and Activation Level Assessments.

Judgment of trustworthiness is an important social ability. Many studies show neural activation differences to variations in face trustworthiness in brain reward regions. A previously published analysis of the present fMRI data showed that older adults' (OA) reward region activation responded significantly to trustworthiness in a set of older and younger faces, whereas younger adults' (YA) activation did not-a finding inconsistent with studies that used only younger faces. We hypothesized that voxel pattern analyses would be more sensitive to YA neural responses to trustworthiness in our set of faces, replicating YA neural discrimination in prior literature. Based on evidence for OA neural dedifferentiation, we also hypothesized that voxel pattern analyses would more accurately classify YA than OA neural responses to face trustworthiness. We reanalyzed the data with two pattern classification models and evaluated the models' performance with permutation testing. Voxel patterns discriminated face trustworthiness levels in both YA and OA reward regions, while allowing better classification of face trustworthiness for YA than OA, the reverse of previous results for neural activation levels. The moderation of age differences by analytic method shines a light on the possibility that voxel patterns uniquely index neural representations of the stimulus information content, consistent with findings of impaired representation with age.

Neural mechanisms of sexual decision-making in women with alcohol use disorder.

The co-occurrence of alcohol consumption and sexual activity is associated with increased risk for sexual assault, sexually transmitted disease, and unplanned pregnancy among young adult women with alcohol use disorder (AUD). There is considerable previous work demonstrating neural reactivity to alcohol cues in AUD. Because alcohol consumption and sexual behavior are both rewarding and tend to co-occur, sexual cues may produce similar neural reactivity in women with AUD, possibly indicating a shared mechanism underlying reactivity to both types of cues. Alternatively, reactivity to alcohol versus sexual cues may be distinct, suggesting domain-specific mechanisms. We investigated whether the decision vulnerabilities in AUD women regarding sexual activity were related to differences in brain activation compared to control women. Women with (n= 15) and without (n= 16) AUD completed a hypothetical decision-making task during fMRI that presented low- or high-risk scenarios involving visual sexual, appetitive, and neutral cues. Results showed that sexual cues were more often endorsed by women with AUD compared to controls and elicited differential brain activation patterns in frontal, visual, and reward regions. During high-risk decisions, women with AUD failed to downregulate activation, causing hyperactivation compared to controls. Visual sexual cues produced reactivity like that previously demonstrated for alcohol cues, suggesting a shared or domain-general mechanism for alcohol and sexual cue reactivity in women with AUD. Riskier sexual decisions in women with AUD may be a consequence of repeatedly pairing alcohol use and sexual activity, a characteristic behavior of this population.

The effect of effort-reward imbalance on brain structure and resting-state functional connectivity in individuals with high levels of schizotypal traits

ABSTRACT Introduction Effort-reward imbalance (ERI) is a typical psychosocial stress. Schizotypal traits are attenuated features of schizophrenia in the general population. According to the diathesis-stress model, schizotypal traits and psychosocial stress contribute to the onset of schizophrenia. However, few studies examined the effects of these factors on brain alterations. This study aimed to examine relationships between ERI, schizotypal traits and brain structures and functions. Methods We recruited 37 (13 male, 24 female) participants with high levels of schizotypal traits and 36 (12 male, 24 female) participants with low levels of schizotypal traits by the Schizotypal Personality Questionnaire (SPQ). The Chinese school version of the effort-reward imbalance questionnaire (C-ERI-S) was used to measure ERI. We conducted the voxel-based morphometry (VBM) and whole brain resting-state functional connectivity (rsFC) analysis using reward or stress-related regions as seeds. Results Participants with high levels of schizotypal traits were more likely to perceive ERI. The severity of ERI was correlated with grey matter volume (GMV) reduction of the left pallidum and altered rsFC among the prefrontal, striatum and cerebellum in participants with high levels of schizotypal traits. Conclusion ERI is associated with GMV reduction and altered rsFC in individuals with high levels of schizotypal traits.

The longitudinal stability of fMRI activation during reward processing in adolescents and young adults

BackgroundThe use of functional neuroimaging has been an extremely fruitful avenue for investigating the neural basis of human reward function. This approach has included identification of potential neurobiological mechanisms of psychiatric disease and examination of environmental, experiential, and biological factors that may contribute to disease risk via effects on the reward system. However, a central and largely unexamined assumption of much of this research is that neural reward function is an individual difference characteristic that is relatively stable and trait-like over time. MethodsIn two independent samples of adolescents and young adults studied longitudinally (Ns = 145 & 139, 100% female and 100% male, ages 15–21 and 20–22, 2–4 scans and 2 scans respectively), we tested within-person stability of reward-task BOLD activation, with a median of 1 and 2 years between scans. We examined multiple commonly used contrasts of active states and baseline in both the anticipation and feedback phases of a card-guessing reward task. We examined the effects of cortical parcellation resolution, contrast, network (reward regions and resting-state networks), region-size, and activation strength and variability on the stability of reward-related activation. ResultsIn both samples, contrasts of an active state relative to a baseline were more stable (ICC: intra-class correlation; e.g., Win>Baseline; mean ICC = 0.13 – 0.33) than contrasts of two active states (e.g., Win>Loss; mean ICC = 0.048 – 0.05). Additionally, activation in reward regions was less stable than in many non-task networks (e.g., dorsal attention), and activation in regions with greater between-subject variability showed higher stability in both samples. ConclusionsThese results show that some contrasts from functional neuroimaging activation during a card guessing reward task have partially trait-like properties in adolescent and young adult samples over 1–2 years. Notably, results suggest that contrasts intended to map cognitive function and show robust group-level effects (i.e. Win > Loss) may be less effective in studies of individual differences and disease risk. The robustness of group-level activation should be weighed against other factors when selecting regions of interest in individual difference fMRI studies.

In Search of the Most Reproducible Neural Vulnerability Factors that Predict Future Weight Gain: Analyses of Data from Six Prospective Studies.

We tested if we could replicate the main effect relations of elevated striatum and lateral orbitofrontal cortex (OFC) response to high-calorie food stimuli to weight gain reported in past papers in six prospective datasets that used similar fMRI paradigms. Participants in Study 1 (N = 37; M age = 15.5), Study 2 (N = 160; M age = 15.3), Study 3 (N = 130; M age = 15.0), Study 4 (N = 175; M age = 14.3), Study 5 (N = 45; M age = 20.8), and Study 6 (N = 49; M age = 31.1) completed fMRI scans at baseline and had their BMI and body fat (Studies 4 and 6 only) measured at baseline and over follow-ups. Elevated striatal response to palatable food images predicted BMI gain in Studies 1 and 6 and body fat gain in Study 6. Lateral OFC activation did not predict weight gain in any of the six studies. Results provide limited support for the hypothesis that elevated reward region responsivity to palatable food images predicts weight gain. Factors that make replication difficult are discussed and potential solutions considered.

Fronto-limbic neuroimaging biomarkers for diagnosis and prediction of treatment responses in major depressive disorder

The neuroimaging is an important tool for understanding the biomarkers and predicting treatment responses in major depressive disorder (MDD). The potential biomarkers and prediction of treatment response in MDD will be addressed in the review article. The brain regions of cognitive control and emotion regulation, such as the frontal and limbic regions, might represent the potential targets for MDD biomarkers. The potential targets of frontal lobes might include anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). For the limbic system, hippocampus and amygdala might be the potentially promising targets for MDD. The potential targets of fronto-limbic regions have been found in the studies of several major neuroimaging modalities, such as the magnetic resonance imaging, near-infrared spectroscopy, electroencephalography, positron emission tomography, and single-photon emission computed tomography. Additional regions, such as brainstem and midbrain, might also play a part in the MDD biomarkers. For the prediction of treatment response, the gray matter volumes, white matter tracts, functional representations and receptor bindings of ACC, DLPFC, OFC, amygdala, and hippocampus might play a role in the prediction of antidepressant responses in MDD. For the response prediction of psychotherapies, the fronto-limbic, reward regions, and insula will be the potential targets. For the repetitive transcranial magnetic stimulation, the DLPFC, ACC, limbic, and visuospatial regions might represent the predictive targets for treatment. The neuroimaging targets of MDD might be focused in the fronto-limbic regions. However, the neuroimaging targets for the prediction of treatment responses might be inconclusive and beyond the fronto-limbic regions.

Modulation of neural fMRI responses to visual food cues by overeating and fasting interventions: A preliminary study.

Neural processing of visual food stimuli is perturbated at extremes of weight. Human fMRI studies investigating diet effects on neural processing of food cues could aid in understanding altered brain activation in conditions of under‐ and overnutrition. In this preliminary study, we examined brain activity changes in response to 10 days of high‐calorie‐diet (HCD), followed by 10 days of fasting, hypothesizing that HCD would decrease activation in homeostatic and reward regions, while fasting would increase activation in homeostatic/reward regions and decrease activation of self‐control regions. Seven adults completed fMRI scanning during a food‐cue paradigm (high‐ and low‐calorie food images and nonfood objects), pre‐ and post‐10‐day HCD. Six adults completed fMRI scanning pre‐ and post‐10‐day fasting. BOLD response changes for contrasts of interest pre‐ versus post‐intervention in regions of interest were examined (peak‐level significance set at p(FWE)<0.05). BMI increased by 6.8% and decreased by 8.1% following HCD and fasting, respectively. Following HCD, BOLD response in the hypothalamus (homeostatic control), was attenuated at trend level in response to high‐ versus low‐calorie foods. Following fasting, BOLD response to food versus objects in inhibitory‐control areas (dorsolateral prefrontal cortex) was reduced, whereas the activation of homeostatic (hypothalamus), gustatory, and reward brain areas (anterior insula and orbitofrontal cortex) increased. Overfeeding and fasting for 10 days modulate brain activity in response to food stimuli, suggesting that in healthy adults, changes in energy balance affect saliency and reward value of food cues. Future studies are required to understand this interaction in states of unhealthy weight.

The Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage.

Manually-administered massage can potently increase endogenous oxytocin concentrations and neural activity in social cognition and reward regions and intranasal oxytocin can increase the pleasantness of social touch. In the present study, we investigated whether intranasal oxytocin modulates behavioral and neural responses to foot massage applied manually or by machine using a randomized placebo-controlled within-subject pharmaco-fMRI design. 46 male participants underwent blocks of massage of each type where they both received and imagined receiving the massage. Intranasal oxytocin significantly increased subjective pleasantness ratings of the manual but not the machine massage and neural responses in key regions involved in reward (orbitofrontal cortex, dorsal striatum and ventral tegmental area), social cognition (superior temporal sulcus and inferior parietal lobule), emotion and salience (amygdala and anterior cingulate and insula) and default mode networks (medial prefrontal cortex, parahippocampal gyrus, posterior cingulate, and precuneus) as well as a number of sensory and motor processing regions. Both neural and behavioral effects of oxytocin occurred independent of whether subjects thought the massage was applied by a male or female masseur. These findings support the importance of oxytocin for enhancing positive behavioral and neural responses to social touch in the form of manually administered massage and that a combination of intranasal oxytocin and massage may have therapeutic potential in autism.Clinical Trials RegistrationThe Effects of Oxytocin on Social Touch; registration ID: NCT03278860; URL: https://clinicaltrials.gov/ct2/show/NCT03278860.

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis.

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, p = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition (p = 0.046) with lower microbial species richness (Chao1) (p = 0.032) and evenness (Shannon) (p = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics (q < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, q = 0.036; brainstem, q = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies.

Hierarchical integrated processing of reward-related regions in obese males: A graph-theoretical-based study

Abnormal activities in reward-related regions are associated with overeating or obesity. Preliminary studies have shown that changes in neural activity in obesity include not only regional reward regions abnormalities but also impairments in the communication between reward-related regions and multiple functional areas. A recent study has shown that the transitions between different neural networks are nonrandom and hierarchical, and that activation of particular brain networks is more likely to occur after other brain networks. The aims of this study were to investigate the key nodes of reward-related regions in obese males and explore the hierarchical integrated processing of key nodes. Twenty-four obese males and 24 normal-weight male controls of similar ages were recruited. The fMRI data were acquired using 3.0 T MRI. The fMRI data preprocessing was performed in DPABI and SPM 12. Degree centrality analyses were conducted using GRETNA toolkit, and Granger causality analyses were calculated using DynamicBC toolbox. Decreased degree centrality was observed in left ventral medial prefrontal cortex (vmPFC) and right parahippocampal/hippocampal gyrus in group with obesity. The group with obesity demonstrated increased effective connectivity between left vmPFC and several regions (left inferior temporal gyrus, left supplementary motor area, right insular cortex, right postcentral gyrus, right paracentral lobule and bilateral fusiform gyrus). Increased effective connectivity was observed between right parahippocampal/hippocampal gyrus and left precentral/postcentral gyrus. Decreased effective connectivity was found between right parahippocampal/hippocampal gyrus and left inferior parietal lobule. This study identified the features of hierarchical interactions between the key reward nodes and multiple function networks. These findings may provide more evidence for the existing view of hierarchical organization in reward processing.

Neural Indicators Of Food Cue Reactivity, Regulation, And Valuation And Their Associations With Body Composition And Daily Eating Behavior.

Exposure to food cues activates the brain's reward system and undermines efforts to regulate impulses to eat. During explicit regulation, lateral prefrontal cortex activates and modulates activity in reward regions and decreases food cravings. However, it is unclear the extent to which between-person differences in recruitment of regions associated with reward processing, subjective valuation, and regulation during food cue exposure-absent instructions to regulate-predict body composition and daily eating behaviors. In this preregistered study, we pooled data from five fMRI samples (N = 262) to examine whether regions associated with reward, valuation, and regulation, as well as whole-brain pattern expression indexing these processes, were recruited during food cue exposure and associated with body composition and real-world eating behavior. Regression models for a single a priori analytic path indicated that univariate and multivariate measures of reward and valuation were associated with individual differences in BMI and enactment of daily food cravings. Specification curve analyses further revealed reliable associations between univariate and multivariate neural indicators of reactivity, regulation, and valuation, and all outcomes. These findings highlight the utility of these methods to elucidate brain-behavior associations and suggest that multiple processes are implicated in proximal and distal markers of eating behavior.

Abnormal functional connectivity within the reward network: a potential neuroimaging endophenotype of bipolar disorder

BackgroundReward circuit dysfunction underlies the pathogenesis of bipolar disorder (BD). This study aims to investigate whether nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC), two key reward regions for BD, have resting-state dysfunctional connectivity with other brain regions in depressed and euthymic BD. Methods40 bipolar depressive (DE), 20 euthymic patients (EU) and 20 healthy controls (HC) were recruited to undergo resting-state functional MRI (rs-fMRI) scanning. Seed-based functional connectivity (FC) was calculated between NAcc/vmPFC and the whole brain. Group differences were calculated and their correlations with clinical characteristics were analyzed. Support vector machine was applied to classify BD patients and HC based on the FC between the cluster of group difference and NAcc/vmPFC. ResultsWhole brain networks of FC identified right anterior insular cortex (AIC) as a significant region with bilateral NAcc when compared among three groups. The right AIC-NAcc FC elevated in both patient groups and was highest in the EU group. Interestingly, vmPFC-based networks also identified the right AIC as a significant cluster. The right AIC-vmPFC FC elevated in both patient groups. However, FC between NAcc and vmPFC did not significantly differ BD patients from HC. Furthermore, the strength of FC between bilateral NAcc and the right AIC was positively associated with the illness course of BD. Notably, the NAcc/vmPFC-right AIC classifier acquired an accuracy of 68.75% and AUC-ROC of 78.17%. LimitationsOur sample size is modest. ConclusionsOur findings indicated that elevated NAcc/vmPFC-right AIC connectivity within the reward circuit could be a neuroimaging endophenotype of BD.

Improvement in Uncontrolled Eating Behavior after Laparoscopic Sleeve Gastrectomy Is Associated with Alterations in the Brain-Gut-Microbiome Axis in Obese Women.

Background: Bariatric surgery is proven to change eating behavior and cause sustained weight loss, yet the exact mechanisms underlying these changes are not clearly understood. We explore this in a novel way by examining how bariatric surgery affects the brain–gut–microbiome (BGM) axis. Methods: Patient demographics, serum, stool, eating behavior questionnaires, and brain magnetic resonance imaging (MRI) were collected before and 6 months after laparoscopic sleeve gastrectomy (LSG). Differences in eating behavior and brain morphology and resting-state functional connectivity in core reward regions were correlated with serum metabolite and 16S microbiome data. Results: LSG resulted in significant weight loss and improvement in maladaptive eating behaviors as measured by the Yale Food Addiction Scale (YFAS). Brain imaging showed a significant increase in brain volume of the putamen (p.adj < 0.05) and amygdala (p.adj < 0.05) after surgery. Resting-state connectivity between the precuneus and the putamen was significantly reduced after LSG (p.adj = 0.046). This change was associated with YFAS symptom count. Bacteroides, Ruminococcus, and Holdemanella were associated with reduced connectivity between these areas. Metabolomic profiles showed a positive correlation between this brain connection and a phosphatidylcholine metabolite. Conclusion: Bariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites.

How ovarian hormones influence the behavioral activation and inhibition system through the dopamine pathway.

The behavioral activation system (BAS) and the behavioral inhibition system (BIS) have been proposed to relate to stable traits that predict inter-individual differences in motivation. Prior reports point dopamine (DA) pathways, mainly including ventral tegmental area (VTA) and substantia nigra (SN), implicate in subserving reward-related functions associated with BAS and inhibitory functions related with BIS. However, as an important factor that affects DA releasing, it remains an open question whether the ovarian hormones may also be related to BIS/BAS. Here, to investigate effects of the estradiol (E2) and progesterone (PROG) on BIS/BAS and related DA pathways, we employed a BIS/BAS scale and the resting-state functional magnetic resonance imaging (fMRI) during the late follicular phase (FP) and the mid-luteal phase (LP). On the behavioral level, when women had high PROG levels, their E2 levels were found positively correlated with BIS scores, but those women whose PROG levels were low, their E2 levels were negative correlation with BIS scores. On the neural level, we demonstrated BAS was related with the VTA pathway, included brain reward regions of nucleus accumbens (NAc) and orbitofrontal cortex (OFC). Meanwhile, the BIS was correlated with the SN-dorsolateral prefrontal cortex (dlPFC) pathway. ROI-based resting-state functional connectivity (RSFC) analyses further revealed that, RSFC between the SN and dlPFC was modulated by ovarian hormones. With higher PROG levels, increased E2 levels among women were accompanied by stronger RSFC of the SN-dlPFC, but when PROG levels were low, E2 levels were negatively correlated with the SN-dlPFC RSFC. These findings revealed a combined enhancement effect of E2 and PROG on BIS, and the SN-dlPFC pathway was mainly involved in this process.

Cocaine-regulated microRNA miR-124 controls poly (ADP-ribose) polymerase-1 expression in neuronal cells

MiR-124 is a highly expressed miRNA in the brain and regulates genes involved in neuronal function. We report that miR-124 post-transcriptionally regulates PARP-1. We have identified a highly conserved binding site of miR-124 in the 3′-untranslated region (3′UTR) of Parp-1 mRNA. We demonstrate that miR-124 directly binds to the Parp-1 3′UTR and mutations in the seed sequences abrogate binding between the two RNA molecules. Luciferase reporter assay revealed that miR-124 post-transcriptionally regulates Parp-1 3′UTR activity in a dopaminergic neuronal cell model. Interestingly, the binding region of miR-124 in Parp-1 3′UTR overlapped with the target sequence of miR-125b, another post-transcriptional regulator of Parp-1. Our results from titration and pull-down studies revealed that miR-124 binds to Parp-1 3′UTR with greater affinity and confers a dominant post-transcriptional inhibition compared to miR-125b. Interestingly, acute or chronic cocaine exposure downregulated miR-124 levels concomitant with upregulation of PARP-1 protein in dopaminergic-like neuronal cells in culture. Levels of miR-124 were also downregulated upon acute or chronic cocaine exposure in the mouse nucleus accumbens (NAc)-a key reward region of brain. Time-course studies revealed that cocaine treatment persistently downregulated miR-124 in NAc. Consistent with this finding, miR-124 expression was also significantly reduced in the NAc of animals conditioned for cocaine place preference. Collectively, these studies identify Parp-1 as a direct target of miR-124 in neuronal cells, establish miR-124 as a cocaine-regulated miRNA in the mouse NAc, and highlight a novel pathway underlying the molecular effects of cocaine.

Novel Virtual Reality System for Auditory Tasks in Head-fixed Mice.

An emerging corpus of research seeks to use virtual realities (VRs) to understand the neural mechanisms underlying spatial navigation and decision making in rodents. These studies have primarily used visual stimuli to represent the virtual world. However, auditory cues play an important role in navigation for animals, especially when the visual system cannot detect objects or predators. We have developed a virtual reality environment defined exclusively by free-field acoustic landmarks for head-fixed mice. We trained animals to run in a virtual environment with 3 acoustic landmarks. We present evidence that they can learn to navigate in our context: we observed anticipatory licking and modest anticipatory slowing preceding the reward region. Furthermore, we found that animals were highly aware of changes in landmark cues: licking behavior changed dramatically when the familiar virtual environment was switched to a novel one, and then rapidly reverted to normal when the familiar virtual environment was re-introduced, all within the same session. Finally, while animals executed the task, we performed in-vivo calcium imaging in the CA1 region of the hippocampus using a modified Miniscope.org system. Our experiments point to a future in which auditory virtual reality can be used to expand our understanding of the neural bases of audition in locomoting animals and the variety of sensory cues which anchor spatial representations in a new virtual environment.

Neuroimaging of Sex/Gender Differences in Obesity: A Review of Structure, Function, and Neurotransmission.

While the global prevalence of obesity has risen among both men and women over the past 40 years, obesity has consistently been more prevalent among women relative to men. Neuroimaging studies have highlighted several potential mechanisms underlying an individual’s propensity to become obese, including sex/gender differences. Obesity has been associated with structural, functional, and chemical alterations throughout the brain. Whereas changes in somatosensory regions appear to be associated with obesity in men, reward regions appear to have greater involvement in obesity among women than men. Sex/gender differences have also been observed in the neural response to taste among people with obesity. A more thorough understanding of these neural and behavioral differences will allow for more tailored interventions, including diet suggestions, for the prevention and treatment of obesity.

Medial Orbitofrontal De-Activation During Tonic Cold Pain Stimulation: A fMRI Study Examining the Opponent-Process Theory.

BackgroundWhile the concomitant administration of painful and rewarding stimuli tends to reduce the perception of one another, recent evidence shows that pleasant pain relief is experience after the interruption of noxious stimuli. On neurobiological grounds, these opponent processes should translate into decreased activity in brain reward regions during nociceptive stimulation and increased activity in these regions after its interruption. While growing evidence supports the latter assumption, evidence is lacking in humans in support of the former.MethodsTwenty-six healthy individuals underwent a functional magnetic resonance imaging (fMRI) session during which they were administered a cold pain stimulation, using a novel paradigm which consisted in a cold gel applied on the right foot of participants.ResultsAfter the interruption of noxious stimulation, participants experienced significant levels of pleasant pain relief. During cold pain stimulation, brain activations were observed in key regions of the pain matrix (eg, thalamus, primary somatosensory cortex and insula). Conversely, the medial orbitofrontal cortex was found to be de-activated. Medial orbitofrontal de-activations were negatively correlated with subclinical pain symptoms.DiscussionOur results show that a key brain reward region (eg, medial orbitofrontal cortex) is de-activated during cold pain stimulation, a result which is consistent with one of the central assumptions of the opponent-process theory. On methodological grounds, our results show that the cold gel applied to the foot can be used to trigger activations in the pain matrix, and that the interruption of the cold pressor test elicits significant levels of pleasant pain relief. fMRI studies on pain–reward interactions in chronic pain patients are warranted.

Adolescent substance use and functional connectivity between the ventral striatum and hippocampus

Neurodevelopmental explanations for adolescent substance use have focused on heightened sensitivity of mesolimbic circuitry, centered on the ventral striatum (VS). Recent evidence suggests that, relative to adults, adolescents show a stronger link between reinforcement learning and episodic memory for rewarding outcomes and greater functional connectivity between the VS and hippocampus, which may reflect a heightened reward modulation of memory. However, a link between VS-hippocampal circuitry and adolescent substance use has yet to be established. Two separate studies were conducted to evaluate whether variation in VS-hippocampal resting-state functional connectivity (rs-FC) predicts subsequent adolescent substance use exposure. A pilot study (Study 1) was conducted in 19 youth recruited from a high sociodemographic risk population (N = 19; mean age = 13.3 SD = 1.4; 14 females; 47% Black Non-Hispanic, 32% White Non-Hispanic). To replicate results of Study 1, Study 2 utilized data from the National Consortium on Adolescent Neurodevelopment and Alcohol (N = 644; mean age = 16.3 SD = 2.5; 339 females; 11% Black Non-Hispanic, 11% Hispanic/Latino, 66% White Non-Hispanic). Resting-state fMRI data were collected at a baseline time point and lifetime and past year self-reported substance use was collected at a follow up visit. Regression models tested whether baseline VS-hippocampal rs-FC predicted substance use exposure at follow up, as measured by an index score reflecting the number of substance classes (e.g., alcohol, marijuana) tried and overall frequency of use. Across both studies, higher VS-hippocampal rs-FC at baseline predicted greater substance use exposure at follow up (pFWE < 0.05). These data provide the first evidence linking increased VS-hippocampal connectivity with greater adolescent substance use exposure. Results fit with the emerging idea that variation in adolescent substance use may relate to not only individual differences in mesolimbic sensitivity to reward, but also to an individuals’ memory sensitivity to reward as measured by connectivity between canonical memory and reward regions.