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Background Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. Methods Sapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks). Results Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance). Conclusions In OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

The motivation to strive for and consume primary rewards such as palatable food is bound by devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Devaluation procedures with repeated exposure to reward combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreasing hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference with repeated receipt, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that—in contrast to primary reinforcers—secondary reinforcers, i.e. money, can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.

Objective The current study aims to investigate whether computer generated (CG) expressions of emotion evoke similar emotional appraisal processing in the lateral orbitofrontal cortex (lOFC) compared to real human expressions, as well as how speech cues would influence the processing. Methods Functional near-infrared spectroscopy was used to measure the neural activations in the prefrontal cortex during emotion recognition task. Thirty normal participants were asked to view videos of dynamic facial expressions and selected the emotions that were best matches with the expressions. Results CG expressions evoked less activation in the lOFC comparing to real human expressions. Furthermore, speech cues increased the activation in the lOFC for CG expressions but not real expressions. Conclusion Comparing to real expressions, CG expressions evoked less appraisal processing related to motivational values although this disadvantage can be compensated to some extent by presenting the expressions with speech cues.

Parcellation of the orbitofrontal cortex, anterior cingulate cortex, and inferior frontal gyrus based on their functional connectivity with the whole brain in resting state fMRI with 654 participants was performed to investigate how these regions with different functions in reward, emotion and their disorders are functionally connected to each other and to the whole brain. The human medial and lateral orbitofrontal cortex, the ventromedial prefrontal cortex, the anterior cingulate cortex, and the right and left inferior frontal gyrus have different functional connectivity with other brain areas and with each other; and each of these regions has several parcels with different functional connectivity with other brain areas. In terms of functional connectivity, the lateral orbitofrontal cortex extends especially on the right into the orbital part of the inferior frontal gyrus and provides connectivity with premotor cortical areas. The orbitofrontal cortex, especially the lateral orbitofrontal cortex, has connectivity not only with language-related areas in the inferior frontal gyrus (Broca's area), but also with the angular and supramarginal gyri. In this context, whereas the connectivity of the orbitofrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex is symmetrical, the connectivity of the inferior frontal gyrus triangular and opercular parts is asymmetrical for the right and the left hemispheres. These findings have implications for understanding the neural bases of human emotion and decision-making, and for their disorders including depression.

Studies of neural dynamics in lateral orbitofrontal cortex (lOFC) have shown that subsets of neurons that encode distinct aspects of behavior, such as value, may project to common downstream targets. However, it is unclear whether reward history, which may subserve lOFC’s well-documented role in learning, is represented by functional subpopulations in lOFC. Previously, we analyzed neural recordings from rats performing a value-based decision-making task, and we documented trial-by-trial learning that required lOFC (Constantinople et al., 2019). Here, we characterize functional subpopulations of lOFC neurons during behavior, including their encoding of task variables. We found five distinct clusters of lOFC neurons, either based on clustering of their trial-averaged peristimulus time histograms (PSTHs), or a feature space defined by their average conditional firing rates aligned to different task variables. We observed weak encoding of reward attributes, but stronger encoding of reward history, the animal’s left or right choice, and reward receipt across all clusters. Only one cluster, however, encoded the animal’s reward history at the time shortly preceding the choice, suggesting a possible role in integrating previous and current trial outcomes at the time of choice. This cluster also exhibits qualitatively similar responses to identified corticostriatal projection neurons in a recent study (Hirokawa et al., 2019), and suggests a possible role for subpopulations of lOFC neurons in mediating trial-by-trial learning.

Early adolescence is a critical period for eating behaviors as children gain autonomy around food choice and peer influences increase in potency. From a neurodevelopmental perspective, significant structural changes take place in the prefrontal cortex during this time, including the orbitofrontal cortex (OFC), which is involved in socially contextualized decision-making. We examined the morphological features of the OFC in relation to food choice in a sample of 10 309 early adolescent children from the Adolescent Brain and Cognitive Development Study. Structural parameters of the OFC and insula were examined for relationships with two important aspects of food choice: limiting the consumption of fast/fried food and maximizing the consumption of nutritious foods. Raw, partially adjusted and fully adjusted models were evaluated. Findings revealed that a larger surface area of the lateral OFC was associated with higher odds of limiting fast/fried food consumption in raw [odds ratio (OR) = 1.07, confidence interval (CI): 1.02, 1.12, P = 0.002, PFDR = 0.012], partially adjusted (OR = 1.11, CI: 1.03, 1.19, P = 0.004, PFDR = 0.024) and fully adjusted models (OR = 1.11, CI: 1.03, 1.19, P = 0.006, PFDR = 0.036). In contrast, a larger insula volume was associated with lower odds of maximizing healthy foods in raw (OR = 0.94, CI: 0.91, 0.97, P

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain systems that differentially contribute to the repetition of rewarded choices and the avoidance of punished choices., Whether maximizing rewards and minimizing punishments rely on distinct brain learning systems remains debated. Here, using intracerebral recordings in humans, the authors provide evidence for brain regions differentially engaged in signaling reward and punishment prediction errors that prescribe repetition versus avoidance of past choices.

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the rewards they predict. Here, we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC→BLA and BLA→lOFC pathways form a functional circuit regulating the encoding (lOFC→BLA) and subsequent use (BLA→lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

Objective Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome. Method Using 3 Tesla MRI scanner, we obtained T1-weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes. Results We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6-month follow-up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects. Conclusion The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.

1AbstractStudies of neural dynamics in lateral orbitofrontal cortex (lOFC) have shown that subsets of neurons that encode distinct aspects of behavior, such as value, may project to common downstream targets. However, it is unclear whether reward history, which may subserve lOFC’s well-documented role in learning, is represented by functional subpopulations in lOFC. Previously, we analyzed neural recordings from rats performing a value-based decision-making task, and we documented trial-by-trial learning that required lOFC (Constantinople et al., 2019). Here we characterize functional subpopulations of lOFC neurons during behavior, including their encoding of task variables. We found five distinct clusters of lOFC neurons, either based on clustering of their trial-averaged peristimulus time histograms (PSTHs), or a feature space defined by their average conditional firing rates aligned to different task variables. We observed weak encoding of reward attributes, but stronger encoding of reward history, the animal’s left or right choice, and reward receipt across all clusters. Only one cluster, however, encoded the animal’s reward history at the time shortly preceding the choice, suggesting a possible role in integrating previous and current trial outcomes at the time of choice. This cluster also exhibits qualitatively similar responses to identified corticostriatal projection neurons in a recent study (Hirokawa et al., 2019), and suggests a possible role for subpopulations of lOFC neurons in mediating trial-by-trial learning.

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the reward they predict. Here we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and an outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so that they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition to perform a serial circuit disconnection, we found that activity in lOFC[->]BLA projections regulates the encoding of the same components of the stimulus-outcome memory that are later used to allow cues to guide choice via activity in BLA[->]lOFC projections. Thus, the lOFC[->]BLA[->]lOFC circuit regulates the encoding (lOFC[->]BLA) and subsequent use (BLA[->]lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

BackgroundPatients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment.MethodsSapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks).ResultsBaseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, modulation in response to reversal learning and compulsive behavior are independent, as reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance).ConclusionsIn OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct and independent roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

Increased appetite and body weight are core features of atypical depression. While previous research has consistently highlighted the presence of distinct immunometabolic profiles in atypical depression, little is still known about the neural correlates of atypical symptoms in major depression. Even though obesity and increased body-mass index have frequently been associated with prefrontal brain structural alterations first and foremost in the orbitofrontal cortex (OFC) in healthy and depressed subjects, it is unclear if conceptually related atypical depressive symptoms are associated with similar neural signatures. Here we aimed to investigate associations between appetite and weight change in major depression and OFC morphometry using a multimodal structural neuroimaging approach. We found that increased appetite was associated with significantly lower cortical thickness and lower gray matter density specifically in the right lateral OFC. Further, Bayesian model comparison showed that appetite change was a more informative predictor for changes in cortical thickness and gray matter density compared to body mass index. No conclusive association between appetite change and white matter tracts connected to the right lateral OFC was found. Our findings highlight the relevance of the right lateral OFC for future investigation of the neurobiological underpinnings of the atypical depressive symptom dimensions appetite and weight gain.

Contains fulltext : 231830.pdf (Publisher’s version ) (Open Access) Incentives are frequently used by governments and employers to encourage cooperation. Here, we investigated the effect of centralized incentives on cooperation, firstly in a behavioral study and then replicated in a subsequent neuroimaging (fMRI) study. In both studies, participants completed a novel version of the Public Goods Game, including experimental conditions in which the administration of centralized incentives was probabilistic and incentives were either of a financial or social nature. Behavioral results showed that the prospect of potentially receiving financial and social incentives significantly increased cooperation, with financial incentives yielding the strongest effect. Neuroimaging results showed that activation in the bilateral lateral orbitofrontal cortex and precuneus increased when participants were informed that incentives would be absent versus when they were present. Furthermore, activation in the medial orbitofrontal cortex increased when participants would potentially receive a social versus a financial incentive. These results speak to the efficacy of different types of centralized incentives in increasing cooperative behavior, and they show that incentives directly impact the neural mechanisms underlying cooperation. 19 p.

The motivation to strive for and consume primary rewards such as palatable food is bound by internal satiation and devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Satiation procedures combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreased hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that – in contrast to primary reinforcers - secondary reinforcers can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.

The orbitofrontal cortex (OFC) is a critical structure in the flexible control of value-based behaviors. OFC dysfunction is typically only detected when task or environmental contingencies change, against a backdrop of apparently intact initial acquisition and behavior. While intact acquisition following OFC lesions in simple Pavlovian cue-outcome conditioning is often predicted by models of OFC function, this predicted null effect has not been thoroughly investigated. Here, we test the effects of lesions and temporary muscimol inactivation of the rodent lateral OFC on the acquisition of a simple single cue-outcome relationship. Surprisingly, pretraining lesions significantly enhanced acquisition after overtraining, whereas post-training lesions and inactivation significantly impaired acquisition. This impaired acquisition to the cue reflects a disruption of behavioral control and not learning since the cue could also act as an effective blocking stimulus in an associative blocking procedure. These findings suggest that even simple cue-outcome representations acquired in the absence of OFC function are impoverished. Therefore, while OFC function is often associated with flexible behavioral control in complex environments, it is also involved in very simple Pavlovian acquisition where complex cue-outcome relationships are irrelevant to task performance.

Humans and other primates can reverse their choice of stimuli in one trial when the rewards delivered by the stimuli change or reverse. Rapidly changing our behavior when the rewards change is important for many types of behavior, including emotional and social behavior. It is shown in a one-trial rule-based Go-NoGo deterministic visual discrimination reversal task to obtain points, that the human right lateral orbitofrontal cortex and adjoining inferior frontal gyrus is activated on reversal trials, when an expected reward is not obtained, and the non-reward allows the human to switch choices based on a rule. This reward reversal goes beyond model-free reinforcement learning. This functionality of the right lateral orbitofrontal cortex shown here in very rapid, one-trial, rule-based changes in human behavior when a reward is not received is related to the emotional and social changes that follow orbitofrontal cortex damage, and to depression in which this non-reward system is oversensitive and over-connected.

Context, the information surrounding an experience, can significantly alter the meaning and the affective responses to events. Yet the biological mechanisms through which context modulate experiences are not entirely understood. Here, we hypothesized that the µ-opioid system—extensively implicated in placebo effects, a clinical phenomenon thought to rely on contextual processing—modulates the effects of contextual information on emotional attributions in patients with depression. To test this hypothesis, 20 unmedicated patients with depression completed a randomized, double-blind, placebo-controlled, crossover study of one dose of 50 mg of naltrexone, or placebo immediately before completing two sessions of the Contextual Framing fMRI task. This task captures effects of valenced contextual cues (pleasant vs. unpleasant) on emotional attribution (the rating of subtle emotional faces: fearful, neutral, or happy). Behaviorally, we found that emotional attribution was significantly moderated by the interaction between contextual cues and subtle emotional faces, such that participants’ ratings of valenced faces (fearful and happy), compared to neutral, were more negative during unpleasant, compared to pleasant context cues. At a neural level, context-induced blood-oxygen-level-dependent responses in the ventromedial prefrontal cortex, the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the lateral orbitofrontal cortex, significantly moderated the effects of context on emotional attribution, and were blunted by naltrexone. Furthermore, the effects of naltrexone on emotional attribution were partially abolished in more severely depressed patients. Our results provide insights into the molecular alterations underlying context representation in patients with depression, providing pivotal early data for future treatment studies.

Anhedonia is a core symptom of major depressive disorder (MDD). Two subtypes of anhedonia: anticipatory anhedonia and consummatory anhedonia has been recognized in MDD patients. However, our knowledge regarding the distinction of anticipatory anhedonia and consummatory anhedonia in MDD remains limited. This study aimed to characterize the anticipatory anhedonia and consummatory anhedonia in first-episode, drug-naive MDD patients. Resting-state functional MRI and T1-structural MRI were acquired for 38 MDD patients and 65 matched healthy controls (HCs). The ALFF and cortical surface indexes were compared between MDD and HCs. Then the correlations between the ALFF and cortical surface indexes alternations and the scores of anticipatory and consummatory pleasure measured by Temporal Experience of Pleasure Scale were evaluated. The elevated ALFF of left dorsal anterior cingulate cortex (dACC) and the reduced cortical thickness (CT) of left rostral ACC and lateral orbitofrontal cortex (lOFC) were respectively correlated with anticipatory anhedonia and consummatory anhedonia in MDD patients. These findings suggested the dissociated pathophysiological basis and imaging characteristics of anticipatory anhedonia and consummatory anhedonia. The ALFF and CT values of ACC and lOFC might serve as the imaging biomarker of the subtypes of anhedonia in early onset of MDD.

Flexible decision-making is crucial for adaptive behaviour. Such behaviour in mammals largely relies on the frontal cortex, and specifically, the orbitofrontal cortex (OFC). How OFC neurons encode decision variables and instruct sensory areas to guide adaptive behaviour is a key open question. Here we developed a reversal learning task for head-fixed mice together with two-photon calcium imaging to monitor the activity of lateral OFC neuronal populations and investigated their dynamic interaction with primary somatosensory cortex (S1). Mice trained on this task learned to discriminate go/no-go tactile stimuli and adapt their behaviour upon changes in stimulus–reward contingencies (‘rule-switch’). Longitudinal imaging at cellular resolution across weeks during all behavioural phases revealed a distinct engagement of S1 and lateral OFC neurons: S1 neural activity reflected task learning-related responses, while neurons in the lateral OFC saliently and transiently responded to the rule-switch. A subset of OFC neurons conveyed a value prediction error signal via feedback projections to S1, as direct anatomical long-range projections were revealed by retrograde tracing combined with whole-brain light-sheet microscopy. Top-down signals implemented an update of sensory representations and functionally reconfigured a small subpopulation of S1 neurons that were differentially modulated by reward-history. Functional remapping of these neurons crucially depended on top-down inputs, as chemogenetic silencing of lateral OFC neurons disrupted reversal learning and impaired plastic changes in these outcome-sensitive S1 neurons. Our results reveal the presence of long-range cortical interactions between cellular ensembles in higher and lower-order brain areas specifically recruited during context-dependent learning and task-switching. Such interactions crucially implement history-dependent reward-value computations and error heuristics, which, in turn, help guide adaptive behaviour.

Highlights • Childhood assaultive trauma exposure is linked to less cortical thickness. • Cortical thickness in prefrontal regions is inversely associated with aggression. • Prefrontal thickness mediated the link between trauma exposure and aggression., Although the link between childhood maltreatment and violence perpetration in adulthood (i.e., the “cycle of violence”) is well-documented, the neural mechanisms driving these processes remain relatively unknown. The objectives of this study were to investigate whether cortical thickness in adulthood varies as a function of childhood assaultive trauma exposure and whether such neurobiological markers of early trauma relate to the perpetration of aggression across the lifespan. In a sample of 138 ethnically-diverse men and women, whole-brain analysis of the cortical mantle revealed that individuals with exposure to assaultive trauma before age 13 had less cortical thickness in two clusters that survived multiple comparison correction: a region that peaked in the left lateral orbitofrontal cortex (OFC) and a region peaking in the right pericalcarine cortex. Diminished cortical thickness in the left OFC cluster was, in turn, associated with greater physical aggression, and mediation analysis revealed that reductions in cortical thickness in this left prefrontal region partially accounted for the association between exposure to childhood assaultive trauma and lifetime perpetration of aggression in adulthood. Findings extend previous investigations into the morphological correlates of early assaultive trauma by implicating reductions in cortical thickness as a potential mechanism linking early violence exposure to violence perpetration that extends into adulthood.

Adaptive behaviour crucially depends on flexible decision-making, which in mammals relies on the frontal cortex, specifically the orbitofrontal cortex (OFC)1–9. How OFC encodes decision variables and instructs sensory areas to guide adaptive behaviour are key open questions. Here we developed a reversal learning task for head-fixed mice, monitored the activity of neurons of the lateral OFC using two-photon calcium imaging and investigated how OFC dynamically interacts with primary somatosensory cortex (S1). Mice learned to discriminate ‘go’ from ‘no-go’ tactile stimuli10,11 and adapt their behaviour upon reversal of stimulus–reward contingency (‘rule switch’). Imaging individual neurons longitudinally across all behavioural phases revealed a distinct engagement of S1 and lateral OFC, with S1 neural activity reflecting initial task learning, whereas lateral OFC neurons responded saliently and transiently to the rule switch. We identified direct long-range projections from lateral OFC to S1 that can feed this activity back to S1 as value prediction error. This top-down signal updated sensory representations in S1 by functionally remapping responses in a subpopulation of neurons that was sensitive to reward history. Functional remapping crucially depended on top-down feedback as chemogenetic silencing of lateral OFC neurons disrupted reversal learning, as well as plasticity in S1. The dynamic interaction of lateral OFC with sensory cortex thus implements computations critical for value prediction that are history dependent and error based, providing plasticity essential for flexible decision-making. Dynamic interaction of neurons in lateral orbitofrontal cortex with the sensory cortex implements value-prediction computations that are history dependent and error based, providing plasticity essential for flexible decision-making.

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 functional MRI (fMRI) paradigms. Participants in Study 1 (N = 37; M (mean) 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 the baseline and had their body mass index (BMI) and body fat (Studies 4 and 6 only) measured at the 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. The result 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.

Obsessive-compulsive disorder (OCD) is usually accompanied with hyperactivity of the orbitofrontal cortex (OFC). OCD patients have anxiety issues, and there is high comorbidity of OCD and post-traumatic stress disorder (PTSD). One of the leading factors of PTSD is the failure of fear extinction. In this study, we examined whether hyperactivity of the OFC interfered with extinction processes. The lateral OFC (lOFC) was pharmacologically activated with N-methyl- d -aspartate (NMDA) in behaving rats during encoding, consolidation, and retrieval, of Pavlovian fear extinction. We found that when we brought the lOFC on-line before extinction training or retrieval test, there was a general initial suppression of fear expression regardless behavioral history, which was followed by development of nonspecific fear response. Moreover, pre-extinction activation of the lOFC impaired the encoding of extinction demonstrated by a general up-shift of fear levels during retrieval test compared to controls. We also found that regardless of whether the lOFC was activated or not, immediate post-extinction manipulation interfered extinction consolidation in general. To conclude, activation of the lOFC altered expression of learned fear and negatively impaired extinction outcome. Our results provided a new angle to study the etiology of comorbid OCD and PTSD.

The neurobiological correlates of prosocial behavior are largely unknown. We examined brain structure and functional connectivity correlates of donating to a charity, a specific, costly, form of prosocial behavior. In 163 children, donating was measured using a promotional clip for a charity including a call for donations. Children could decide privately whether and how much they wanted to donate from money they had received earlier. Whole brain structural MRI scans were obtained to study associations between cortical thickness and donating behavior. In addition, resting state functional MRI scans were obtained to study whole brain functional connectivity and to examine functional connectivity between regions identified using structural MRI. In the lateral orbitofrontal cortex/pars orbitalis and pre-/postcentral cortex, a thicker cortex was associated with higher donations. Functional connectivity with these regions was not associated with donating behavior. These results suggest that donating behavior is not only situationally driven, but is also related brain morphology. The absence of functional connectivity correlates might imply that the associations with cortical thickness are involved in different underlying mechanisms of donating.

Some anxiety-related disorders, such as panic disorder, specific phobia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), develop because of the poor regulation and inappropriate expression of fear-related behavior at the wrong place and wrong time. In clinical settings, exposure therapy, which consists of repeated presentation of trauma-related stimuli without real threats in the therapeutic context, is commonly used to treat these disorders. However, 30-50 % of patients suffer from the recurrence of anxiety symptoms after they leave the therapeutic context. This behavioral phenomenon is called renewal. In this study, ABA Pavlovian fear renewal paradigm was used to assess the role of the aberrant orbitofrontal cortex (OFC) activation, a symptom of OCD patients, on fear regulation in laboratory settings. The rats were fear conditioned in one context (context A), extinguished to the tones in another context (context B), and then tested in either context A or B. During extinction, rats were subjected to lateral or medial OFC activation. We found that rats that underwent extinction with either lateral or medial OFC activation were unable to use the context to determine whether it was a safe or dangerous context during renewal test. Interestingly, the rats with lateral OFC activation during extinction showed generally high fear, whereas the rats with medial OFC activation during extinction showed generally low fear. In conclusion, our results suggested that aberrant activation of specifically the lateral OFC may have a negative impact during exposure therapy treatments and results in their poor regulation of fear-related behavior.

The orbitofrontal cortex (OFC) has long been implicated in the ability to use the current value of expected outcomes to guide behavior. More recently, this specific role has been conceptualized as a special case of a more general function that OFC plays in constructing a "cognitive map" of the behavioral task space by labeling the current task state and learning relationships among task states. Here, we have used single unit recording data from 2 prior studies to examine whether and how information relating different states within and across trials is represented in medial versus lateral OFC in rats. Using a hierarchical clustering analysis, we examined how neurons from each area represented information about differently valued trial types, defined by the cue-outcome pairings, versus how those same neurons represented information about similar epochs between these different trial types, such as the stimulus sample, delay, and reward consumption epochs. This analysis revealed that ensembles in the lateral OFC (lOFC) group states according to trial epoch, whereas those in the medial OFC (mOFC) organize the same states by trial type. These results suggest that the lOFC and mOFC construct cognitive maps that emphasize different features of the behavioral landscape, with lOFC tracking events based on local similarities, irrespective of their values and mOFC tracking more distal or higher order relationships relevant to value. (PsycINFO Database Record

Recent studies using surface-based morphometry of structural magnetic resonance imaging data have suggested that some changes in bipolar disorder (BP) might be neurodevelopmental in origin. We applied a novel analysis of cortical complexity based on fractal dimensions in high-resolution structural MRI scans of 18 bipolar disorder patients and 26 healthy controls. Our region-of-interest based analysis revealed increases in fractal dimensions (in patients relative to controls) in left lateral orbitofrontal cortex and right precuneus, and decreases in right caudal middle frontal, entorhinal cortex, and right pars orbitalis, and left fusiform and posterior cingulate cortices. While our analysis is preliminary, it suggests that early neurodevelopmental pathologies might contribute to bipolar disorder, possibly through genetic mechanisms.

Alcohol misuse is associated with significant energy deficits. As feeding involves multiple sensory, cognitive, and affective processes, low food intake in problem drinkers likely reflects alterations in both regional and inter-regional responses. To investigate the effects of problem drinking on feeding-related neural activities and connectivities, we examined functional magnetic resonance imaging (fMRI) data in 82 drinkers who viewed palatable food and nonfood images in alternating blocks. Drinking severity was assessed with the Alcohol Use Disorders Identification Test (AUDIT). A whole-brain multiple regression with AUDIT scores as the predictor showed a negative correlation between drinking severity and activation to food vs nonfood cues in the lateral orbitofrontal cortex (lOFC). AUDIT scores were also negatively correlated with the gray matter volume (GMV) of the lOFC and regions that responded preferentially to food stimuli, including the left middle frontal gyrus, bilateral middle insula, and occipital cortices. Connectivity strength between the lOFC and these regions was negatively modulated by drinking severity. In contrast, there was no relationship between AUDIT scores and lOFC connectivity with regions that did not show either selectivity to food images or GMV loss. A mediation analysis further suggested that alcohol misuse may have compromised lOFC's structural integrity, which in turn disrupted lOFC interactions with regions that support the processing of visual food cues. Overall, the findings provide evidence for the effects of problem drinking on the brain substrates of feeding, potentially shedding light on the neural mechanisms underlying energy deficits in at-risk drinkers.

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected sequential effects, including increased willingness to take risks following risky wins, and spatial ‘win-stay/lose-shift’ biases. Recordings from lateral orbitofrontal cortex (lOFC) revealed encoding of reward history and receipt, and optogenetic inhibition of lOFC eliminated rats’ increased preference for risk following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and the lOFC’s role in adaptive behavior promotes learning of more abstract biases (here, biases for the risky option), but not spatial ones.

The development of executive function is linked to maturation of prefrontal cortex (PFC) in childhood. Childhood obesity has been associated with changes in brain structure, particularly in PFC, as well as deficits in executive functions. We aimed to determine whether differences in cortical structure mediate the relationship between executive function and childhood obesity. We analyzed MR-derived measures of cortical thickness for 2700 children between the ages of 9 and 11 years, recruited as part of the NIH Adolescent Brain and Cognitive Development (ABCD) study. We related our findings to measures of executive function and body mass index (BMI). In our analysis, increased BMI was associated with significantly reduced mean cortical thickness, as well as specific bilateral reduced cortical thickness in prefrontal cortical regions. This relationship remained after accounting for age, sex, race, parental education, household income, birth-weight, and in-scanner motion. Increased BMI was also associated with lower executive function. Reduced thickness in the rostral medial and superior frontal cortex, the inferior frontal gyrus, and the lateral orbitofrontal cortex partially accounted for reductions in executive function. These results suggest that childhood obesity is associated with compromised executive function. This relationship may be partly explained by BMI-associated reduced cortical thickness in the PFC.