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Learning causal relationships relies on understanding how often one event precedes another. To investigate how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Conditioned responding was attenuated for the cue-reward contingency that was degraded, as was dopamine neuron activity in the midbrain and dopamine release in the ventral striatum in response to the cue and subsequent reward. Contingency degradation also abolished the trial-by-trial history dependence of the dopamine responses at the time of trial outcome. This profile of changes in cue- and reward-evoked responding is not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.

Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD–DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients. [ABSTRACT FROM AUTHOR]

Background Ventral striatal hypoactivation during reward anticipation has consistently been observed in patients with schizophrenia. In addition, that hypoactivation has been shown to correlate negatively with negative symptoms, and in particular with apathy. However, little is known about the stability of these results over time and their reliability across different centers. Methods In total, 67 patients with schizophrenia (15 females) and 55 healthy controls (13 females) were recruited in 2 centers in Switzerland and Germany. To assess the neural bases of reward anticipation, all participants performed a variant of the Monetary Incentive Delay task while undergoing event-related functional magnetic resonance imaging at baseline and after 3 months. Stability over time was measured using intra-class correlation (ICC(A,1)) and stability between centers was measured with mixed models. Results Results showed the expected ventral striatal hypoactivation in patients compared to controls during reward anticipation. We showed that these results were stable across centers. The primary analysis did not reveal an effect of time. Test-retest reliability was moderate for controls, and poor for patients. We did not find an association between ventral striatal hypoactivation and negative symptoms in patients. Conclusions Our results align with the hypothesis that ventral striatal activation is related to modulation of motivational saliency during reward anticipation. They also confirm that patients with schizophrenia show impaired reward anticipation. However, the poor test-retest reliability and the absence of an association with symptoms suggests that further research is needed before ventral striatal activity can be used as a biomarker on the individual patient level. [ABSTRACT FROM AUTHOR]

BackgroundMotivational impairment associated with deficits in processing the anticipation of future reward is hypothesized to be a cardinal feature of schizophrenia spectrum disorders (SZ). Evidence from short-term follow-up (6-week post-treatment) studies suggests that these deficits may improve or be reversed with treatment, although longer-term outcomes are unknown. Here we examined the one-year trajectory of functional activation in brain circuitry associated with reward anticipation in people with recent onset SZ who participated in coordinated specialty care (CSC) treatment, hypothesizing normalization of brain response mirroring previous short-term findings in first-episode individuals.MethodBlood oxygen level-dependent (BOLD) response in the dorsal anterior cingulate cortex, anterior insula, and ventral striatum (VS) associated with reward anticipation during the Incentivized Control Engagement Task (ICE-T) was analyzed in a baseline sample of 49 healthy controls (HCs) and 52 demographically matched people with SZ, with follow-up data available for 35 HCs and 17 people with SZ.ResultsIn agreement with our hypothesis, significant time × diagnosis interactions were observed across all regions, in which reward anticipation-associated BOLD response increased in SZ to above baseline HC levels at follow-up. Increased VS activation was associated with decreased reality distortion symptoms over the follow-up period. Baseline reward anticipation-associated BOLD response in the right anterior insula was associated with improvement in reality distortion symptoms.ConclusionsThese findings suggest that functional deficits in reward anticipation may be reversed after one year of CSC in recent onset participants with SZ, and that this improvement is associated with reduced positive symptoms in the illness.

Humans adjust their behavioral strategies based on feedback, a process that may depend on intrinsic preferences and contextual factors such as visual salience. In this study, we hypothesized that decision-making based on visual salience is influenced by habitual and goal-directed processes, which can be evidenced by changes in attention and subjective valuation systems. To test this hypothesis, we conducted a series of studies to investigate the behavioral and neural mechanisms underlying visual salience-driven decision-making. We first established the baseline behavioral strategy without salience in Experiment 1 (n = 21). We then highlighted the utility or performance dimension of the chosen outcome using colors in Experiment 2 (n = 30). We demonstrated that the difference in staying frequency increased along the salient dimension, confirming a salience effect. Furthermore, the salience effect was abolished when directional information was removed in Experiment 3 (n = 28), suggesting that the salience effect is feedback-specific. To generalize our findings, we replicated the feedback-specific salience effects using eye-tracking and text emphasis. The fixation differences between the chosen and unchosen values were enhanced along the feedback-specific salient dimension in Experiment 4 (n = 48) but unchanged after removing feedback-specific information in Experiment 5 (n = 32). Moreover, the staying frequency was correlated with fixation properties, confirming that salience guides attention deployment. Lastly, our neuroimaging study (Experiment 6, n = 25) showed that the striatum subregions encoded salience-based outcome evaluation, while the vmPFC encoded salience-based behavioral adjustments. The connectivity of the vmPFC-ventral striatum accounted for individual differences in utility-driven, whereas the vmPFC-dmPFC for performance-driven behavioral adjustments. Together, our results provide a neurocognitive account of how task-irrelevant visual salience drives decision-making by involving attention and the frontal-striatal valuation systems. PUBLIC SIGNIFICANCE STATEMENT: Humans may use the current outcome to make behavior adjustments. How this occurs may depend on stable individual preferences and contextual factors, such as visual salience. Under the hypothesis that visual salience determines attention and subsequently modulates subjective valuation, we investigated the underlying behavioral and neural bases of visual-context-guided outcome evaluation and behavioral adjustments. Our findings suggest that the reward system is orchestrated by visual context and highlight the critical role of attention and the frontal-striatal neural circuit in visual-context-guided decision-making that may involve habitual and goal-directed processes.

Abstract Background Obsessive-compulsive disorder (OCD) is characterized by persistent, unwanted thoughts and repetitive actions. Such repetitive thoughts and/or behaviors may be reinforced either by reducing anxiety or by avoiding a potential threat or harm, and thus may be rewarding to the individual. The possible involvement of the reward system in the symptomatology of OCD is supported by studies showing altered reward processing in reward-related regions, such as the ventral striatum (VS) and the orbitofrontal cortex (OFC), in adults with OCD. However, it is not clear whether this also applies to adolescents with OCD. Methods Using functional magnetic resonance imaging, two sessions were conducted focusing on the anticipation and receipt of monetary reward (1) or loss (2), each contrasted to a verbal (control) condition. In each session, adolescents with OCD (n1=31/n2=26) were compared with typically developing (TD) controls (n1=33/ n2=31), all aged 10-19 years, during the anticipation and feedback phase of an adapted Monetary Incentive Delay task. Results Data revealed a hyperactivation of the VS, but not the OFC, when anticipating both monetary reward and loss in the OCD compared to the TD group. Conclusions These findings suggest that aberrant neural reward and loss processing in OCD is associated with greater motivation to gain or maintain a reward but not with the actual receipt. The greater degree of reward ‘wanting’ may contribute to adolescents with OCD repeating certain actions more and more frequently, which then become habits (i.e., OCD symptomatology).

Background: Affiliating with delinquent peers may stimulate the development of antisocial behavior, especially for adolescents who are sensitive to social rewards. The current study examines whether the association between delinquent peer affiliation (DPA) and disruptive behavior interacts with functional brain correlates of reward sensitivity in early onset male adolescents delinquents. Methods: Childhood arrestees (n = 126, mean age = 17.7 [s.d. 1.6]) completed a DPA questionnaire, and participated in an fMRI study in which reward sensitivity was operationalized through responsiveness of the ventral striatum (VS), amygdala, and medial prefrontal cortex (mPFC) during the monetary incentive delay paradigm (reward anticipation and outcome). Symptoms of disruptive behavior disorders (DBD) were assessed through structured psychiatric interviews (Diagnostic Interview Schedule for Children) with adolescents. Results: DPA had a main effect on DBD symptoms. Adolescents with high VS reward responses showed a stronger significant positive association between DPA and DBD symptoms compared to low VS responders. No evidence for an interaction effect was found for the amygdala and mPFC. Post-hoc analyses revealed the positive association between DPA and DBD was only present in males, with a diminishing effect as age increased. Conclusions: We found evidence for a biosocial interaction between DPA and reward sensitivity of the VS in relation to DBD symptom severity. This study provides the first evidence of an interaction effect between a brain mechanism and an environmental factor in relation to DBD symptoms, implying that susceptibility to influences of delinquent peers may intertwine with individual biological differences. [ABSTRACT FROM AUTHOR]

According to experimental and clinical studies, status epilepticus (SE) causes neurodegenerative morphological changes not only in the hippocampus and other limbic structures, it also affects the thalamus and the neocortex. In addition, several studies reported atrophy, metabolic changes, and neuronal degeneration in the dorsal striatum. The literature lacks studies investigating potential neuronal damage in the ventral component of the striatopallidal complex (ventral striatum [VS] and ventral pallidum) in SE experimentations. To better understand the development of neuronal damage in the striatopallidal complex associated with SE, the detected neuronal degeneration in the compartments of the VS, namely, the nucleus accumbens (NAc) and the olfactory tubercle (OT), was analyzed. The experiments were performed on Wistar rats at age of 25‐day‐old pups and 3‐month‐old adult animals. Lithium–pilocarpine model of SE was used. Lithium chloride (3 mmol/kg, ip) was injected 24 h before administering pilocarpine (40 mg/kg, ip). This presented study demonstrates the variability of post SE neuronal damage in 25‐day‐old pups in comparison with 3‐month‐old adult rats. The NAc exhibited small to moderate number of Fluoro‐Jade B (FJB)‐positive neurons detected 4 and 8 h post SE intervals. The number of degenerated neurons in the shell subdivision of the NAc significantly increased at survival interval of 12 h after the SE. FJB‐positive neurons were evidently more prominent occupying the whole anteroposterior and mediolateral extent of the nucleus at longer survival intervals of 24 and 48 h after the SE. This was also the case in the bordering vicinity between the shell and the core compartments but with clusters of degenerating cells. The severity of damage of the shell subdivision of the NAc reached its peak at an interval of 24 h post SE. Isolated FJB‐positive neurons were detected in the ventral peripheral part of the core compartment. Degenerated neurons persisted in the shell subdivision of the NAc 1 week after SE. However, the quantity of cell damage had significantly reduced in comparison with the aforementioned shorter intervals. The third layer of the OT exhibited more degenerated neurons than the second layer. The FJB‐positive cells in the young animals were higher than in the adult animals. The morphology of those cells was identical in the two age groups except in the OT. [ABSTRACT FROM AUTHOR]

Objectives Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Methods Fifty-eight older adults (mean age = 70.8, SD =  5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. Results Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC–rdlPFC rsFC moderated the association between generative desire and purpose in life. Discussion These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is characterized by persistent, unwanted thoughts and repetitive actions. Such repetitive thoughts and/or behaviors may be reinforced either by reducing anxiety or by avoiding a potential threat or harm, and thus may be rewarding to the individual. The possible involvement of the reward system in the symptomatology of OCD is supported by studies showing altered reward processing in reward-related regions, such as the ventral striatum (VS) and the orbitofrontal cortex (OFC), in adults with OCD. However, it is not clear whether this also applies to adolescents with OCD. Methods: Using functional magnetic resonance imaging, two sessions were conducted focusing on the anticipation and receipt of monetary reward (1) or loss (2), each contrasted to a verbal (control) condition. In each session, adolescents with OCD (n1=31/n2=26) were compared with typically developing (TD) controls (n1=33/ n2=31), all aged 10-19 years, during the anticipation and feedback phase of an adapted Monetary Incentive Delay task. Results: Data revealed a hyperactivation of the VS, but not the OFC, when anticipating both monetary reward and loss in the OCD compared to the TD group. Conclusions: These findings suggest that aberrant neural reward and loss processing in OCD is associated with greater motivation to gain or maintain a reward but not with the actual receipt. The greater degree of reward 'wanting' may contribute to adolescents with OCD repeating certain actions more and more frequently, which then become habits (i.e., OCD symptomatology). [ABSTRACT FROM AUTHOR]

Self-reported sexual orientation of transgender individuals occasionally changes over transition. Using functional magnetic resonance imaging, we tested the hypothesis that neural and behavioral patterns of sexual arousal in transgender individuals would shift from the assigned to the experienced gender (e.g., trans women's responses becoming more dissimilar to those of cis men and more similar to those of cis women). To this aim, trans women (N = 12) and trans men (N = 20) as well as cisgender women (N = 24) and cisgender men (N = 14) rated visual stimuli showing male–female, female–female or male–male intercourse for sexual arousal before and after four months of gender-affirming hormone therapy. A Bayesian framework allowed us to incorporate previous behavioral findings. The hypothesized changes could indeed be observed in the behavioral responses with the strongest results for trans men and female–female scenes. Activation of the ventral striatum supported our hypothesis only for female–female scenes in trans women. The respective application or depletion of androgens in trans men and trans women might partly explain this observation. The prominent role of female–female stimuli might be based on the differential responses they elicit in cis women and men or, in theory, the controversial concept of autogynephilia. We show that correlates of sexual arousal in transgender individuals might change in the direction of the experienced gender. Future investigations should elucidate the mechanistic role of sex hormones and the cause of the differential neural and behavioral findings. The study was registered at ClinicalTrials.gov (NCT02715232), March 22, 2016. [ABSTRACT FROM AUTHOR]

Background: Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms. Methods: In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006–2010, age = 55.0 ± 7.5 [40–70] years; second visit: 2014–2019; age = 62.7 ± 7.5 [44–80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes. Results: Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = −0.032 to −0.023, p = 0.006–0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7–14.3%, p < 0.001− p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10−5) in participants with high v. no SLEs. Conclusions: The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms. [ABSTRACT FROM AUTHOR]

The ventromedial prefrontal cortex (vmPFC) and the ventral striatum are brain regions that are critical for the reward circuit and the maintenance of pleasure. The relationship between these regions and alcohol use disorder has been investigated in the literature in a variety of ways. In this context, it is aimed to determine whether there are structural changes in the vmPFC and ventral striatum regions in patients with alcohol use disorder (AUD) compared to healthy control subjects. Fifteen patients with AUD according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5) diagnostic criteria and seventeen healthy controls participated in our study. The volumes of the vmPFC and ventral striatum were measured in subjects. The mean volumes of both sides of the vmPFC were significantly smaller in patients with AUD than those in the healthy control group whereas both sides of ventral striatum volumes were larger. This study is one of the few to examine structural changes in the vmPFC and ventral striatum together in patients with ACD. Although the contribution of the positive findings to the literature is important, more comprehensive studies are needed to strengthen the existing findings. [ABSTRACT FROM AUTHOR]

The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors, apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine, and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at the highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum. [ABSTRACT FROM AUTHOR]

The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multiregion fiber photometry and machine learning-based analysis to decode dopamine dynamics across the striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running, and grooming on a subsecond-to-minute time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.

BACKGROUND: Poor sleep and anxiety disorders are highly comorbid in youth, and each predicts altered ventral striatum (VS) response to rewards, which may impact mental health risk. Contrasting evidence suggests previously reported negative associations between sleep health and VS response may be stronger or weaker in youth with anxiety, indicating sensitivity to win/loss information or blunted reward processing, respectively. We cross-sectionally examined the role of sleep in VS response to rewards among youth with anxiety versus a no-psychiatric-diagnosis comparison (ND) group. We expected a group*sleep interaction on VS response to rewards but did not hypothesize directionality. METHODS: As part of the pretreatment battery for a randomized clinical trial, 74 youth with anxiety and 31 ND youth (ages 9-14 years; n = 55 female) completed a monetary reward task during fMRI. During the same pretreatment window, actigraphy and diary-estimated sleep were collected over 5 days, and participants and their parents each reported participants total sleep problems. We examined group*sleep interactions on VS response to monetary rewards versus losses via three mixed linear models corresponding to actigraphy, diary, and questionnaires, respectively. RESULTS: Each model indicated group*sleep interactions on VS response to rewards. Actigraphy and diary-estimated time awake after sleep onset predicted reduced VS response in youth with anxiety but not ND youth. Parent-reported sleep problems similarly interacted with group, but simple slopes were nonsignificant. CONCLUSIONS: Wake after sleep onset was associated with blunted reward response in youth with anxiety. These data suggest a potential pathway through which sleep could contribute to perturbed reward function and reward-related psychopathology (e.g., depression) in youth with anxiety.

• Inflammation was associated with higher corticostriatal responsivity to reward. • This relationship was strongest in participants exposed to major early-life stress. • These patterns were specific to stress in early childhood, from ages 0-8. Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood — C-reactive protein, tumor necrosis factor-a, and interleukins-6, −8, and −10 — and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling. [ABSTRACT FROM AUTHOR]

Deciding whether to forego immediate rewards or explore new opportunities is a key component of flexible behavior and is critical for the survival of the species. Although previous studies have shown that different cortical and subcortical areas, including the amygdala and ventral striatum (VS), are implicated in representing the immediate (exploitative) and future (explorative) value of choices, the effect of the motor system used to make choices has not been examined. Here, we tested male rhesus macaques with amygdala or VS lesions on two versions of a three-arm bandit task where choices were registered with either a saccade or an arm movement. In both tasks we presented the monkeys with explore-exploit tradeoffs by periodically replacing familiar options with novel options that had unknown reward probabilities. We found that monkeys explored more with saccades but showed better learning with arm movements. VS lesions caused the monkeys to be more explorative with arm movements and less explorative with saccades, although this may have been due to an overall decrease in performance. VS lesions affected the monkeys' ability to learn novel stimulus-reward associations in both tasks, while after amygdala lesions this effect was stronger when choices were made with saccades. Further, on average, VS and amygdala lesions reduced the monkeys' ability to choose better options only when choices were made with a saccade. These results show that learning reward value associations to manage explore-exploit behaviors is motor system dependent and they further define the contributions of amygdala and VS to reinforcement learning. [ABSTRACT FROM AUTHOR]

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a simple Q-learning model, an asymmetric model with two learning rates, a perseverance model with choice traces, and a perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes, because we noticed that male mice performed frequent magazine nosepokes during PR tasks. The best model was the perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void magazine nosepokes. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of male mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of magazine nosepokes during the PR session without changing the breakpoint. The perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the perseverance model reveals the effects of psychoactive drugs on choice behaviors during PR tasks. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). Background: Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. Methods: Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. Results: Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p =.032), which was positively related to a history of migraines (r =.742, p <.001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r′ =.294, p =.036) and subjective discount rate (r′ =.380, p =.006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non‐triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate. Conclusion: This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network. [ABSTRACT FROM AUTHOR]

Self-enhancement, the tendency to view oneself positively, is a pervasive social motive widely investigated in the psychological sciences. Relatively little is known about the neurocognitive mechanisms underlying this motive, specifically in social-evaluative situations. To investigate whether positive emotion regulation circuitry, circuitry involved in modulating positive affect, relates to the self-enhancement motive in social contexts, we conducted an functional magnetic resonance imaging (fMRI) study in a healthy young adult sample. We hypothesized that self-enhancement indices (state and trait self-esteem) would relate to greater functional connectivity between right ventrolateral prefrontal cortex (RVLPFC), a region implicated in emotion regulation, and the ventral striatum (VS), a region associated with reward-related affect, during a social feedback task. Following social evaluation, participants experienced stable or decreased state self-esteem. Results showed that stable state self-esteem from pre- to post-scan and higher trait self-esteem related to greater RVLPFC-VS connectivity during positive evaluation. Stable-state self-esteem also related to greater RVLPFC-VS connectivity during negative evaluation. Moreover, RVLPFC activation during all types of feedback processing and left VS activation during negative feedback processing was greater for participants with stable-state self-esteem. These findings implicate neurocognitive mechanisms underlying emotion regulation in the self-enhancement motive and highlight a pathway through which self-enhancement may restore feelings of self-worth during threatening situations.

Altered functioning of the brain's threat and reward circuitry has been linked to early life adversity and to symptoms of anxiety and depression. To date, however, these relationships have been studied largely in isolation and in categorical-based approaches. It is unclear to what extent early life adversity and psychopathology have unique effects on brain functioning during threat and reward processing. We examined functional brain activity during a face processing task in threat (amygdala and ventromedial prefrontal cortex) and reward (ventral striatum and orbitofrontal cortex) regions of interest among a sample (N = 103) of young adults (aged 18-19 years) in relation to dimensional measures of early life adversity and symptoms of anxiety and depression. Results demonstrated a significant association between higher scores on the deprivation adversity dimension and greater activation of reward neural circuitry during viewing of happy faces, with the largest effect sizes observed in the orbitofrontal cortex. We found no significant associations between the threat adversity dimension, or symptom dimensions of anxiety and depression, and neural activation in threat or reward circuitries. These results lend partial support to theories of adversity-related alterations in neural activation and highlight the importance of testing dimensional models of adversity and psychopathology in large sample sizes to further our understanding of the biological processes implicated.

Understanding how individuals form and maintain strong social networks has emerged as a significant public health priority as a result of the increased focus on the epidemic of loneliness and the myriad protective benefits conferred by social connection. In this review, we highlight the psychological and neural mechanisms that enable us to connect with others, which in turn help buffer against the consequences of stress and isolation. Central to this process is the experience of rewards derived from positive social interactions, which encourage the sharing of perspectives and preferences that unite individuals. Sharing affective states with others helps us to align our understanding of the world with another's, thereby continuing to reinforce bonds and strengthen relationships. These psychological processes depend on neural systems supporting reward and social cognitive function. Lastly, we also consider limitations associated with pursuing healthy social connections and outline potential avenues of future research. The authors review the psychological and neural mechanisms that foster social connections, highlighting the idea that the rewards derived from positive social interactions facilitate the sharing of perspectives and preferences, which in turn encourages connection with others and promotes well-being. [ABSTRACT FROM AUTHOR]

Humor comprehension (i.e., getting a joke) and humor appreciation (i.e., enjoying a joke) are distinct, cognitively complex processes. Functional magnetic resonance imaging (fMRI) investigations have identified several key cortical regions but have overlooked subcortical structures that have theoretical importance in humor processing. The dorsal striatum (DS) contributes to working memory, ambiguity processing, and cognitive flexibility, cognitive functions that are required to accurately recognize humorous stimuli. The ventral striatum (VS) is critical in reward processing and enjoyment. We hypothesized that the DS and VS play important roles in humor comprehension and appreciation, respectively. We investigated the engagement of these regions in these distinct processes using fMRI. Twenty-six healthy young male and female human adults completed two humor-elicitation tasks during a 3 tesla fMRI scan consisting of a traditional behavior-based joke task and a naturalistic audiovisual sitcom paradigm (i.e., Seinfeld viewing task). Across both humor-elicitation methods, whole-brain analyses revealed cortical activation in the inferior frontal gyrus, the middle frontal gyrus, and the middle temporal gyrus for humor comprehension, and the temporal cortex for humor appreciation. Additionally, with region of interest analyses, we specifically examined whether DS and VS activation correlated with these processes. Across both tasks, we demonstrated that humor comprehension implicates both the DS and the VS, whereas humor appreciation only engages the VS. These results establish the role of the DS in humor comprehension, which has been previously overlooked, and emphasize the role of the VS in humor processing more generally. [ABSTRACT FROM AUTHOR]

Introduction: Deep brain stimulation (DBS) is often effective in treating severe obsessive-compulsive disorder (OCD) when traditional therapeutic approaches have failed. However, optimizing DBS programming is a time-consuming process. Recent research in movement disorders suggests that local field potentials can dramatically speed up the process of identifying the optimal contacts for stimulation, but this has not yet been tested in a patient with OCD. Methods: In a patient with severe OCD, we first determined the optimal contact for stimulation for each hemisphere using traditional monopolar and bipolar review and then tested whether the clinically optimal contact in each hemisphere corresponded to local field potential signals. Results: Overall, we found that clinical efficacy corresponded with the contacts that showed the strongest local field potential signals across multiple frequency bands. Discussion: Our findings are the first indication that local field potentials could guide contact selection in patients with OCD. If validated in a larger sample, this methodology could decrease time to clinical benefit and improve accuracy in patients that are difficult to assess using traditional methods. Further research is needed to determine whether local field potentials could be used to guide finer resolution in programming parameters. [ABSTRACT FROM AUTHOR]

Anger is a powerful and mostly deleterious emotion that can impair an individual's health and social relationships and that imposes considerable costs on society at large. It is a constituent of multiple psychopathologies, most notably intermittent explosive disorder. Excessive anger can drive injurious and even lethal reactive aggression. To understand its biobehavioral origins and develop appropriate therapeutic interventions, an animal model of human anger would be quite useful. The phenomena of aggression provoked by frustrative nonreward (FNR) in other animals, including species of fish, birds, and mammals, resemble those in people in whom it elicits subjectively experienced anger. The brief history presented here traces the original, overgeneralized frustration-aggression hypothesis for humans through to the discovery of operant schedule-induced attack in birds, rodents, and ourselves to the current status of FNR as a crossspecies, transdiagnostic construct within the National Institute of Health Research Domain Criteria. Brain circuitry that is activated by frustration, generates felt anger and motivates reactive aggression includes discomfort reactions likely instantiated in the insula and cingulate gyrus of the salience network and reward expectancy/prediction error mediated by the ventral striatum and other structures. Caveats in establishing a paradigm for other animals that most closely matches FNR-induced anger in people include avoiding confounds with other aggression-provoking stimuli and situations, providing evidence for aggressive motivation, as well as behavior, and demonstrating activation of homologous brain structures. With appropriate regard for these caveats, developing such paradigms appears to be the best route to advancing psychopharmacological and deep brain stimulation treatments for excessive anger. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) is still an experimental treatment modality for psychiatric disorders including treatment-resistant depression (TRD). There is preliminary evidence that stimulation of brain reward circuit structures including the ventral striatum (VS) may exert an antidepressant effect. The main nucleus of the reward circuit is the nucleus accumbens (NAc). The NAc is a major structure of VS that plays a critical role in reward-seeking behavior, motivation, and addiction. Aims: This study aimed to review the current studies including randomized clinical trials, open-label trials, and case reports of NAc/VS and VC DBS for TRD in humans. Method: The literature was reviewed using a medical database--Medical Literature, Analysis, and Retrieval System Online (MEDLINE) on NAc/VS or VC DBS in TRD. The identified studies were assessed based on the patient's characteristics, clinical outcomes, and adverse events related to DBS as well as the stereotactic technique used to guide the implantation of DBS electrodes. The inclusion and exclusion criteria of DBS for TRD were presented and discussed. Results: The searched literature revealed one case report, three open-label studies (OLS), one multicenter open-label study (mOLS), and two randomized clinical trials (RCTs). There were three additional studies reporting the clinical outcomes in the long term in TRD patients included in the two mentioned RCTs. The total number of patients with TRD treated by NAc/VS or VC is estimated to be 85 individuals worldwide. The response rate to DBS defined as a 50% reduction of postoperative Montgomery-Asberg Depression Rating Scale (MADRS) scores was achieved in 39.8% of the operated patients (range, 23-53%). The remission defined as MADRS scores of < 10 was found in 17.8% after DBS (range, 0-40%). The mean follow-up was 19.7 months (range 3.7-24 months). Conclusion: The current results of NAc/VS and VC DBS are still limited by a relatively small number of patients treated worldwide. Nevertheless, the results suggest that NAc/VS and VC can be regarded as promising and efficacious targets for DBS, taking into account the response and remission rates among TRD patients with no other treatment option. The adverse events of NAc/VS and VC DBS are reversible due to the adjustment of stimulation parameters. The most common adverse events were hypomanic/manic states, suicidal thoughts/attempts, and suicides. Patients with TRD after NAc/VS and VC DBS should be strictly followed to prevent or diminish these stimulation-induced adverse events. [ABSTRACT FROM AUTHOR]

Background: Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level. Methods: We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data. Results: Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function. Conclusions: These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers. [ABSTRACT FROM AUTHOR]

Objective This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). Background Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. Methods Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. Results Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p

Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory behavior and periods of dietary restraint, suggesting extremes of under and overcontrol that may be metabolic-state related. This study examined the influence of hunger and satiety on impulsivity and neural responding during decision-making. Twenty-three women remitted from BN (RBN) and 20 healthy comparison women (CW) performed a delay discounting task after a 16-hr fast and following a standardized meal during functional neuroimaging. A dual-systems approach examined reward valuation (decision trials where the early reward option was available immediately) and cognitive control (all decision trials). Interactions of Group × Visit (Hungry, Fed) for immediate reward revealed that CW had greater activation when hungry versus fed in the ventral striatum and dorsal caudate, whereas RBN had greater response when fed versus hungry in the dorsal caudate. Compared to CW, RBN showed decreased response when hungry within the left dorsal caudate and ventral striatum and increased response when fed in bilateral dorsal caudate. No differences were found within cognitive control regions or with choice behavior. Reward sensitivity is normally increased when hungry and decreased when fed; our findings in CW provide further support of hunger-based reward sensitivity within the striatum. However, RBN showed no differences for hunger and satiety in the ventral striatum and greater activation in the dorsal caudate when fed compared to hungry. This suggests RBN may be less sensitive to reward when hungry but do not devalue reward when satiated, indicating altered metabolic modulation of self-regulatory control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

ImportanceEating disorders are severe psychiatric disorders; however, disease models that cross subtypes and integrate behavior and neurobiologic factors are lacking.ObjectiveTo assess brain response during unexpected receipt or omission of a salient sweet stimulus across a large sample of individuals with eating disorders and healthy controls and test for evidence of whether this brain response is associated with the ventral striatal-hypothalamic circuitry, which has been associated with food intake control, and whether salient stimulus response and eating disorder related behaviors are associated.Design, setting, and participantsIn this cross-sectional functional brain imaging study, young adults across the eating disorder spectrum were matched with healthy controls at a university brain imaging facility and eating disorder treatment program. During a sucrose taste classic conditioning paradigm, violations of learned associations between conditioned visual and unconditioned taste stimuli evoked the dopamine-related prediction error. Dynamic effective connectivity during expected sweet taste receipt was studied to investigate hierarchical brain activation between food intake relevant brain regions. The study was conducted from June 2014 to November 2019. Data were analyzed from December 2019 to February 2020.Main outcomes and measuresPrediction error brain reward response across insula and striatum; dynamic effective connectivity between hypothalamus and ventral striatum; and demographic and behavior variables and their correlations with prediction error brain response and connectivity edge coefficients.ResultsOf 317 female participants (197 with eating disorders and 120 healthy controls), the mean (SD) age was 23.8 (5.6) years and mean (SD) body mass index was 20.8 (5.4). Prediction error response was elevated in participants with anorexia nervosa (Wilks λ, 0.843; P = .001) and in participants with eating disorders inversely correlated with body mass index (left nucleus accumbens: r = -0.291; 95% CI, -0.413 to -0.167; P

IntroductionDeep brain stimulation (DBS) is often effective in treating severe obsessive-compulsive disorder (OCD) when traditional therapeutic approaches have failed. However, optimizing DBS programming is a time-consuming process. Recent research in movement disorders suggests that local field potentials can dramatically speed up the process of identifying the optimal contacts for stimulation, but this has not yet been tested in a patient with OCD.MethodsIn a patient with severe OCD, we first determined the optimal contact for stimulation for each hemisphere using traditional monopolar and bipolar review and then tested whether the clinically optimal contact in each hemisphere corresponded to local field potential signals.ResultsOverall, we found that clinical efficacy corresponded with the contacts that showed the strongest local field potential signals across multiple frequency bands.DiscussionOur findings are the first indication that local field potentials could guide contact selection in patients with OCD. If validated in a larger sample, this methodology could decrease time to clinical benefit and improve accuracy in patients that are difficult to assess using traditional methods. Further research is needed to determine whether local field potentials could be used to guide finer resolution in programming parameters.

The ventral striatum (VS) and amygdala are two structures often implicated as essential structures for learning. The literature addressing the contribution of these areas to learning, however, is not entirely consistent. We propose that these inconsistencies are due to learning environments and the effect they have on motivation. To differentiate aspects of learning from environmental factors that affect motivation, we ran a series of experiments with varying task factors. We compared monkeys (Macaca mulatta) with VS lesions, amygdala lesions, and unoperated controls on reinforcement learning (RL) tasks that involve learning from both gains and losses as well as from deterministic and stochastic schedules of reinforcement. We found that for all three groups, performance varied by experiment. All three groups modulated their behavior in the same directions, to varying degrees, across the three experiments. This behavioral modulation is why we find deficits in some experiments, but not others. The amount of effort animals exhibited differed depending on the learning environment. Our results suggest that the VS is important for the amount of effort animals will give in rich deterministic and relatively leaner stochastic learning enivornments. We also showed that monkeys with amygdala lesions can learn stimulus-based RL in stochastic environments and environments with loss and conditioned reinforcers. These results show that learning environments shape motivation and that the VS is essential for distinct aspects of motivated behavior. [ABSTRACT FROM AUTHOR]

BackgroundDeep brain stimulation (DBS) is still an experimental treatment modality for psychiatric disorders including treatment-resistant depression (TRD). There is preliminary evidence that stimulation of brain reward circuit structures including the ventral striatum (VS) may exert an antidepressant effect. The main nucleus of the reward circuit is the nucleus accumbens (NAc). The NAc is a major structure of VS that plays a critical role in reward-seeking behavior, motivation, and addiction.AimsThis study aimed to review the current studies including randomized clinical trials, open-label trials, and case reports of NAc/VS and VC DBS for TRD in humans.MethodThe literature was reviewed using a medical database—Medical Literature, Analysis, and Retrieval System Online (MEDLINE) on NAc/VS or VC DBS in TRD. The identified studies were assessed based on the patient's characteristics, clinical outcomes, and adverse events related to DBS as well as the stereotactic technique used to guide the implantation of DBS electrodes. The inclusion and exclusion criteria of DBS for TRD were presented and discussed.ResultsThe searched literature revealed one case report, three open-label studies (OLS), one multicenter open-label study (mOLS), and two randomized clinical trials (RCTs). There were three additional studies reporting the clinical outcomes in the long term in TRD patients included in the two mentioned RCTs. The total number of patients with TRD treated by NAc/VS or VC is estimated to be 85 individuals worldwide. The response rate to DBS defined as a 50% reduction of postoperative Montgomery-Asberg Depression Rating Scale (MADRS) scores was achieved in 39.8% of the operated patients (range, 23–53%). The remission defined as MADRS scores of < 10 was found in 17.8% after DBS (range, 0–40%). The mean follow-up was 19.7 months (range 3.7–24 months).ConclusionThe current results of NAc/VS and VC DBS are still limited by a relatively small number of patients treated worldwide. Nevertheless, the results suggest that NAc/VS and VC can be regarded as promising and efficacious targets for DBS, taking into account the response and remission rates among TRD patients with no other treatment option. The adverse events of NAc/VS and VC DBS are reversible due to the adjustment of stimulation parameters. The most common adverse events were hypomanic/manic states, suicidal thoughts/attempts, and suicides. Patients with TRD after NAc/VS and VC DBS should be strictly followed to prevent or diminish these stimulation-induced adverse events.

Stimulants like methamphetamine (MA) affect motivated behaviors via actions on circuits mediating mood, attention, and reward. Few studies examined the effects of single doses of stimulants on reward circuits during anticipation and receipt of rewards and losses. Here, we examined the effects of MA (20 mg) or placebo in a within-subject, double-blind study with healthy adults (n  = 43). During 2 fMRI sessions, participants completed the monetary incentive delay task. Primary outcome measures were BOLD activation in selected regions of interest during anticipation and receipt of monetary rewards and losses. Secondary analyses included behavioral measures, whole brain analysis, and arterial spin labeling. MA produced its expected behavioral effects and increased neural activation in the ventral striatum and anterior insula during anticipation of monetary loss versus non-loss. MA did not affect activation during anticipation of gains, or during receipt of wins or losses. MA significantly reduced cerebral blood flow in the striatum and insula. The present finding that a stimulant enhances the responses of striatal and insular regions to upcoming loss suggests that this system may be sensitive to the salience of upcoming events. The finding adds to a complex body of evidence regarding the effects of stimulant drugs on neural processes during motivated behaviors. [ABSTRACT FROM AUTHOR]

Background: Across multiple levels of investigation, there appear to be convergent neuronal processes underlying substance use and other motivated behaviors (i.e., the pursuit and consumption of rewarding substances). The consumption of alcohol and sweet, high‐fat food engages many of the same brain regions, especially, the ventral striatum. In the current study, we hypothesized that ventral striatal local field potentials (LFPs) recorded during self‐administration sessions could be used to detect when the consumption of 10% ethanol or sweet‐fat food (SF) was occurring compared to all other behaviors, including naturalistic controls (i.e., water or house‐chow). Methods: We used an intermittent limited access approach to condition Sprague–Dawley rats to consume either ethanol or SF while we recorded LFPs. We used machine learning and simple logistic regressions to determine whether LFP features could classify when consumption of each substance was occurring, and whether a general model could predict consumption of both substances. We report performance as the average area under the receiver operator characteristic curve (AUROC). Results: Consumption of a single substance was differentiable from all other behaviors, as evidenced by the AUROC (ethanol = 0.84 and SF = 0.83, p < 0.01). Models built from the combined dataset (general) did modestly overall (general → general = 0.68, p < 0.05), and did not detect the consumption of the two substances similarly (general → SF = 0.5 and general → ethanol = 0.63, p > 0.05). Conclusions: Models successfully classified ethanol and SF consumption versus all other behavior/naturalistic controls. However, the findings highlight differences in how the ventral striatum represents the consumption of ethanol and SF and show that, although there is potential for finding biomarkers related to substance use, it may be difficult to build a model that performs well detecting multiple substances. [ABSTRACT FROM AUTHOR]

The subcallosal cingulate (SCC) area is a putative hub in the brain network underlying depression. Deep brain stimulation (DBS) targeting a particular subregion of SCC, identified as the intersection of forceps minor (FM), uncinate fasciculus (UCF), cingulum and fronto-striatal fiber bundles, may be critical to a therapeutic response in patients with severe, treatment-resistant forms of major depressive disorder (MDD). The pattern and variability of the white matter anatomy and organization within SCC has not been extensively characterized across individuals. The goal of this study is to investigate the variability of white matter bundles within the SCC that structurally connect this region with critical nodes in the depression network. Structural and diffusion data from 100 healthy subjects from the Human Connectome Project database were analyzed. Anatomically defined SCC regions were used as seeds to perform probabilistic tractography and to estimate the connectivity from the SCC to subject-specific target areas believed to be involved in the pathology of MDD including ventral striatum (VS), UCF, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC). Four distinct areas of connectivity were identified within SCC across subjects: (a) postero-lateral SCC connectivity to medial temporal regions via UCF, (b) postero-medial connectivity to VS, (c) superior-medial connectivity to ACC via cingulum bundle, and (d) antero-lateral connectivity to mPFC regions via forceps minor. Assuming white matter connectivity is critical to therapeutic response, the improved anatomic understanding of SCC as well as an appreciation of the intersubject variability are critical to developing optimized therapeutic targeting for SCC DBS.

BackgroundAlcohol use disorder (AUD) is heterogenous. One approach to parsing this heterogeneity is to phenotype individuals by their underlying motivation to drink, specifically drinking for reward (i.e., positive reinforcement) or for relief (i.e., negative reinforcement/normalizing). Reward- versus relief-motivated behavior is thought to be associated with a shift from ventral to dorsal striatal (DS) signaling. The present study examined whether reward and relief drinking were differentially associated with other clinical characteristics and with alcohol cue-elicited activation of the ventral and dorsal striatum.MethodsNon-treatment-seeking heavy drinkers (N = 184; 61 female, 123 male) completed the UCLA Reward, Relief, Habit Drinking Scale (RRHDS) and the Reasons for Heavy Drinking Questionnaire (RHDQ), to categorize drinking motivation. Measures of alcohol use, alcohol problems, mood, and craving were also collected. A subset of participants (N = 45; 17 female, 28 male) also completed a functional neuroimaging alcohol cue reactivity task.ResultsRRHDS-designated relief/habit drinkers scored lower than reward drinkers on the RHDQ Reinforcement subscale (p = 0.04) and higher on the RHDQ Normalizing subscale (p = 0.004). Relief/habit drinkers also demonstrated greater AUD severity on a host of clinical measures. Relief/habit drinkers displayed higher cue-elicited DS activation compared with reward drinkers (p = 0.04), while ventral striatal cue-elicited activation did not significantly differ between groups.ConclusionsOur findings support and extend the differentiation of reward from relief/habit-motivated drinking and suggest that differences in DS response to conditioned alcohol cues may underlie this distinction. Elucidating neurobiological and clinical differences between these subtypes may facilitate treatment matching and precision medicine for AUD.

Self-affirmation can buffer stress responses across different contexts, yet the neural mechanisms for these effects are unknown. Self-affirmation has been shown to increase activity in reward-related neural regions, including the ventral striatum and ventromedial prefrontal cortex (VMPFC). Given that reward-related prefrontal cortical regions such as the VMPFC are involved in reducing neurobiological and behavioral responses to stress, we hypothesized that self-affirmation would activate VMPFC and also reduce neural responses to stress in key neural threat system regions such as the dorsal anterior cingulate cortex (dACC) and anterior insula (AI). We explored this hypothesis using self-affirmation and evaluative stress tasks following a within-subjects design in the fMRI scanner. Consistent with prior work, self-affirmation blocks led to lower self-reported stress and improved performance. With respect to neural activity, compared to control blocks, self-affirmation blocks led to greater VMPFC activity, and subsequently less left AI (but not dACC) activity during stress task blocks. Functional connectivity analyses revealed greater connectivity between the VMPFC and left and right AI during self-affirmation compared to control. These findings begin to articulate the neural circuits involved in self-affirmations effects during exposure to stressors, and more broadly specify neural reward-based responses to stressful situations.

Self-affirmation can buffer stress responses across different contexts, yet the neural mechanisms for these effects are unknown. Self-affirmation has been shown to increase activity in reward-related neural regions, including the ventral striatum and ventromedial prefrontal cortex (VMPFC). Given that reward-related prefrontal cortical regions such as the VMPFC are involved in reducing neurobiological and behavioral responses to stress, we hypothesized that self-affirmation would activate VMPFC and also reduce neural responses to stress in key neural threat system regions such as the dorsal anterior cingulate cortex (dACC) and anterior insula (AI). We explored this hypothesis using self-affirmation and evaluative stress tasks following a within-subjects design in the fMRI scanner. Consistent with prior work, self-affirmation blocks led to lower self-reported stress and improved performance. With respect to neural activity, compared to control blocks, self-affirmation blocks led to greater VMPFC activity, and subsequently less left AI (but not dACC) activity during stress task blocks. Functional connectivity analyses revealed greater connectivity between the VMPFC and left and right AI during self-affirmation compared to control. These findings begin to articulate the neural circuits involved in self-affirmation's effects during exposure to stressors, and more broadly specify neural reward-based responses to stressful situations.

Background: Alcohol use disorder (AUD) is associated with exaggerated preference for immediate rewards, a candidate endophenotype for use disorders. Addiction symptomology is often well-described by the preference for immediate intoxication over other delayed prosocial rewards. We measured brain activation in AUD-implicated regions during a cross-commodity delay discounting (CCD) task with choices for immediate alcohol and delayed money. Methods: Heavy drinkers (n=24) experienced a brief intravenous alcohol infusion prime, regained sobriety, then chose between ‘One Shot’ and delayed money in an adjusting delay CCD task (sober and intoxicated); also during fMRI (sober). Participants also performed a behavioral sensation seeking task and completed self-report inventories of other risk factors. We assessed brain activation to choices representing immediate intoxication versus delayed money rewards in a priori regions of interest defined within the framework of Addictions NeuroImaging Assessment. Results: Activation to CCD choice versus control trials activated paralimbic and ventral frontal cortical regions, including orbital and medial prefrontal cortex, posterior cingulate/retrosplenial cortex, angular and superior frontal gyri. We detected no differences between immediate or delayed choices. Left medial orbitofrontal cortex activation correlated with alcohol-induced wanting for alcohol; females showed greater activation than males. Behavioral sensation seeking correlated with right nucleus accumbens task engagement. Conclusions: Alcohol decision-making elicited activation in regions governing reward, introspection, and executive decision-making in heavy drinkers, demonstrating the utility of laboratory tasks designed to better model real-world choice. Our findings suggest that the brain processes subserving immediate and delayed choices are mostly overlapping, even with varied commodities.

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.

Social jetlag (SJL), a form of circadian rhythm disturbance, is linked to depressive symptoms; however, it is unclear what role the brain network, particularly the reward and cognitive control circuits, plays in this association. To address this issue, employing the ventral striatum (VS) and dorsolateral prefrontal cortex (DLPFC) as seeds, we used voxel-level whole-brain functional connectivity (FC) to determine the neural basis of the association between SJL and depressive tendency. Behavioral results indicated that SJL was positively associated with depression scores. Functional connection results showed that higher SJL was linked with decreased FC between the inferior orbitofrontal cortex and the VS. For DLPFC, we discovered changed FC in frontal, parietal, and occipital lobes related to SJL. More importantly, the mediation analysis revealed that the DLPFC-cuneus FC significantly mediated the relationship between SJL and depression scores. According to our study, higher SJL showed abnormal FC from the VS and DLPFC, which may involve attention impairments, cognitive control and reward function. Our results suggest that brain FC involving visual attention may explain the relationship between SJL and depressive tendency. This may offer new insights into the neural underpinnings of how circadian misalignment leads to mood issues. [ABSTRACT FROM AUTHOR]

The ventrolateral striatum (VLS), a subregion of the ventral striatum (VS), possesses distinct neuronal Ca2+ activities and functions in reward-oriented behavior, compared with the ventromedial striatum (VMS) based on the anatomical feature. We hypothesized that the VLS exhibits unique neuronal activity and function in nociceptive processing, a part of aversive processing. Using fiber photometry to monitor the neuronal Ca2+ activities, we demonstrated that acute noxious mechanical stimuli like tail-pinch increased the Ca2+ activity of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) in the VLS in correlation with the stimulus intensities in mice, whereas mechanical stimuli increased the VMS D2-MSN activity independent of the stimulus intensities. Likewise, thermal stimuli decreased the VLS and VMS D2-MSN Ca2+ activities during nociceptive behaviors in the hot plate test. Furthermore, the VLS D2-MSNs increased their Ca2+ activity accompanied by formalin-induced nociceptive behaviors in mice, whereas the VMS D2-MSNs decreased it. The optogenetic inhibition of VLS D2-MSN activity increased the formalin-induced pain-related behavior in mice, thus suggesting the inhibitory effect of VLS D2-MSN activity on chemical nociceptive behavior, in contrast to previous reports that the VMS D2-MSNs could not involve the behavior. Therefore, the VLS D2-MSNs exhibited region-specific roles in nociception. • VLS/VMS D2-MSNs show region-specific Ca2+ activities depending on pain stimulus type. • VLS D2-MSNs encode intensity of acute noxious mechanical stimuli but not VMS D2-MSNs. • Noxious thermal stimuli reduces both VLS/VMS D2-MSNs Ca2+ activities. • VLS/VMS D2-MSNs show opposite Ca2+ activity patterns during pain behavior by formalin. • Photoinhibition of VLS D2-MSNs increases total time of formalin-induced pain behavior. [ABSTRACT FROM AUTHOR]

Interaction between Pavlovian and instrumental control systems is key for adaptive motivated behavior, but also plays an important role in various neuropsychiatric disorders, including depression, addiction, and anxiety. Here, we employed the flouorodopa positron emission tomography ([18F]-DOPA PET) in healthy participants (N = 100) to assess whether dopamine synthesis capacity (Ki), specifically in the ventral striatum, accounts for individual variation in Pavlovian-to-instrumental transfer (PIT). Surprisingly, this was not the case. Rather, the relationship of ventral striatal Ki with PIT depended on working memory (WM) capacity. Ventral striatal dopamine boosted the effects of Pavlovian cues on instrumental responding to a greater degree in participants with higher WM capacity. Caution is warranted to interpret this post hoc four-way interaction given the modest sample size. Nonetheless, these results chime with prior findings demonstrating that dopaminergic drugs boost Pavlovian biases to a greater degree in participants with greaterWMcapacity and highlight the importance of interactions between striatal dopamine and WM capacity. [ABSTRACT FROM AUTHOR]

Background: Personality traits contribute to the risks of smoking. The striatum has been implicated in nicotine addiction and nicotine deprivation is associated with alterations in resting state functional connectivity (rsFC) of the ventral (VS) and dorsal (DS) striatum. However, it remains unclear how striatal rsFC may change following overnight abstinence or how these shorter-term changes in interregional connectivity relate to personality traits. Methods: In the current study, 28 smokers completed assessments with Fagerström Test of Nicotine Dependence, Tridimensional Personality Questionnaire (TPQ), as well as resting state functional magnetic resonance imaging (fMRI) scans during satiety and after overnight abstinence. We processed imaging data with published routines and evaluated the results with a corrected threshold. Results: Smokers showed increases in the VS-insula rsFC but no significant changes in the DS rsFC after overnight abstinence as compared to satiety. The difference in the VS-insula rsFC (abstinence minus satiety) was negatively correlated with harm avoidance. Conclusions: These findings highlighted striatal connectivity correlates of very short-term abstinence from smoking and how the VS-insula rsFC may vary with individual personality traits, interlinking neural markers and personality risk factors of cigarette smoking at the earliest stage of abstinence. [ABSTRACT FROM AUTHOR]

Background: Medication overuse headache shares several characteristics with substance use disorders. However, key features of substance use disorders such as increased impulsivity and alterations in reward processing remain little explored in medication overuse headache. Methods: Temporal discounting and impulsive decision making behavior and the associated brain mechanisms were assessed in 26 chronic migraine patients with medication overuse headache and in 28 healthy controls. Regions-of-interest analyses were first performed for task-related regions, namely the ventral striatum and the ventromedial and dorsomedial prefrontal cortices. Resting-state functional connectivity between these regions were then explored. An additional 27 chronic migraine patients without medication overuse headache were included for comparison in the latter analysis. Results: Patients with medication overuse headache showed steeper temporal discounting behavior than healthy controls. They also showed weaker subjective value representations in the dorsomedial prefrontal cortex, when accepting larger delayed rewards, and in ventral striatum and ventromedial prefrontal cortex, when accepting the smaller immediate reward. Resting-state functional connectivity was reduced among the valuation regions when comparing patients with medication overuse headache to the other two control groups. Conclusions: Patients with medication overuse headache were characterized by altered processing and dysconnectivity in the reward system during intertemporal choices and in the resting-state. [ABSTRACT FROM AUTHOR]

BackgroundHuman laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory.MethodsNon-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm.ResultsMultilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes.ConclusionsNeuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.