Orbitofrontal Cortex Function Research Articles

Optogenetic inhibition of the orbitofrontal cortex disrupts inhibitory control during stop-change performance in male rats.

Historically, the orbitofrontal cortex (OFC) has been implicated in a variety of behaviors ranging from reversal learning and inhibitory control to more complex representations of reward value and task space. While modern interpretations of the OFC's function have focused on a role in outcome evaluation, these cognitive processes often require an organism to inhibit a maladaptive response or strategy. Single unit recordings from the OFC in rats performing a stop-change task show that the OFC responds strongly to STOP trials. To investigate the role that the OFC plays in stop-change performance we expressed halorhodopsin (eNpHR3.0) in excitatory neurons in the OFC and tested rats on the stop-change task. Previous work suggests that the OFC differentiates between STOP trials based on trial sequence (i.e., gS trials: STOP trials preceded by a GO versus sS trials: STOP trials preceded by a STOP). We found that yellow light activation of the eNpHR3.0 expressing neurons significantly decreased accuracy only on STOP trials that followed GO trials (gS trials). Further, optogenetic inhibition of OFC speeded reaction times on error trials. This suggests that the OFC plays a role in inhibitory control processes, and that this role needs to be accounted for in modern interpretations of OFC function.Significance Statement The orbitofrontal cortex (OFC) is a highly interconnected brain region thought to be essential for healthy cognitive function. Historically, research has implicated the OFC in the inhibition of inappropriate actions, however, more recent work has focused on its role in guiding value-based decision making. Using a modified version of a canonical inhibitory control task in combination with optogenetics, we show that while important for value-based decision making, disruption of excitatory neurons in the OFC impairs inhibitory control processes as well. This highlights the need for theoretical accounts of OFC function to accommodate its role in both types of cognitive processes.

Impairments in expression of devaluation in a Pavlovian goal-tracking task, but not a free operant devaluation task, after fentanyl exposure in female rats

In laboratory animals, there are numerous demonstrations that past exposure to drugs of abuse can lead to devaluation impairments weeks after the final drug exposure, with the majority of these demonstrations examining effects of exposure to psychostimulants. There has been minimal investigation into whether prior exposure to opiates can lead to devaluation impairments. Here, we first trained female rats that two separate cuelights predicted two different foods and measured Pavlovian goal-tracking responses (Experiment 1) or trained female rats to press two levers to earn two different foods and measured this operant response (Experiment 2). In both experiments, we subsequently gave the rats injections of fentanyl twice daily for 6 days, and then tested rats for conditioned responses after satiation on one of the foods 48-h after the final injection. We found that rats were impaired in the expression of devaluation in the Pavlovian task after fentanyl exposure, but were unimpaired in the expression of devaluation in the operant task. The pattern of results is most consistent with an impairment in lateral orbitofrontal cortex function, but additional research is needed to determine the neurobiological cause of this pattern of results.

The orbitofrontal cortex: A goal-directed cognitive map framework for social and non-social behaviors

The orbitofrontal cortex (OFC) is regarded as one of the core brain areas in a variety of value-based behaviors. Over the past two decades, tremendous knowledge about the OFC function was gained from studying the behaviors of single subjects. As a result, our previous understanding of the OFC’s function of encoding decision variables, such as the value and identity of choices, has evolved to the idea that the OFC encodes a more complex representation of the task space as a cognitive map. Accumulating evidence also indicates that the OFC importantly contributes to behaviors in social contexts, especially those involved in cooperative interactions. However, it remains elusive how exactly OFC neurons contribute to social functions and how non-social and social behaviors are related to one another in the computations performed by OFC neurons. In this review, we aim to provide an integrated view of the OFC function across both social and non-social behavioral contexts. We propose that seemingly complex functions of the OFC may be explained by its role in providing a goal-directed cognitive map to guide a wide array of adaptive reward-based behaviors in both social and non-social domains.

The role of the orbitofrontal cortex in exercise addiction and exercise motivation: A brain imaging study based on multimodal magnetic resonance imaging

BackgroundExcessive exercise may also lead to exercise addiction (EXA), which is harmful to people's physical and mental health. Behavioral and neuroimaging studies have demonstrated that addictive disorders are essentially motivational problems. However, little is known about the neuropsychological mechanism of EXA and the effects of motivation on EXA. MethodsWe investigated 130 regularly exercised participants with EXA symptoms to explore the neurobiological basis of EXA and its association with motivation. The correlation between EXA and gray matter volume (GMV) was evaluated by whole-brain regression analysis based on voxel-based morphometry. Then, regional brain function was extracted and the relationship between brain structure-function-EXA was analyzed. Finally, mediation analysis was performed to further detect the relationship between the brain, motivation, and EXA. ResultsWhole-brain correlation analyses showed that the GMV of the right orbitofrontal cortex (OFC) was negatively correlated with EXA. The function of the right OFC played an indirect role in EXA and affected EXA via the GMV of the OFC. Importantly, the GMV of the right OFC played a mediating role in the relationship between ability motivation and EXA. These results remain significant even when adjusting for sex, age, body mass index, family socioeconomic status, general intelligence, total intracranial volume, and head motion. LimitationThe results should be interpreted carefully because only the people with EXA symptoms were included. ConclusionThis study provided evidence for the underlying neuropsychological mechanism of the important role of the right OFC in EXA and revealed that there may be a decrease in executive control function in EXA.

Emotion-based behavioral inhibition and self-repairing memristive circuit

In this paper, an emotion-based behavioral inhibition and self-repairing memristive circuit is proposed, which can emulate the repair process of the amygdala in the limbic system. The circuit is mainly composed of recognition and retention module, damage detection module, repair compensation module and output module. The recognition and retention module mainly includes emotion recognition module and retention module, which realize the emotion recognition function of amygdala and orbitofrontal cortex. The damage detection module can determine whether the amygdala is damaged. If the amygdala is damaged, the repair compensation module repairs the amygdala, so that the amygdala can produce behavioral inhibition when it recognizes fear. The realization of emotion-based behavioral inhibition and self-repairing memristive circuit provides a reference for the further development of memristive affective bionic circuits.

Effects of cannabinoid exposure on short-term memory and medial orbitofrontal cortex function and chemistry in adolescent female rhesus macaques.

AimThere is increasing concern that cannabinoid exposure during adolescence may disturb brain maturation and produce long-term cognitive deficits. However, studies in human subjects have provided limited evidence for such causality. The present study utilized behavioral and neuroimaging endpoints in female non-human primates to examine the effects of acute and chronic exposure during adolescence to the cannabinoid receptor full agonist, AM2389, on cognitive processing and brain function and chemistry.Materials and methodsAdolescent female rhesus macaques were trained on a titrating-delay matching-to-sample (TDMTS) touchscreen task that assays working memory. TDMTS performance was assessed before and during chronic exposure to AM2389, following antagonist (rimonabant) administration, and after discontinuation of the chronic regimen. Resting-state fMRI connectivity and magnetic resonance spectroscopy data were acquired prior to drug treatment, during chronic exposure, and following its discontinuation. Voxels were placed in the medial orbitofrontal cortex (mOFC), a region involved in memory processing that undergoes maturation during adolescence.ResultsTDMTS performance was dose-dependently disrupted by acute AM2389; however, chronic treatment resulted in tolerance to these effects. TDMTS performance also was disrupted by discontinuation of the chronic regimen but surprisingly, not by rimonabant administration during chronic AM2389 treatment. mOFC N-acetylaspartate/creatine ratio decreased after acute and chronic administration but returned to baseline values following discontinuation of chronic treatment. Finally, intra-network functional connectivity (mOFC) increased during the chronic regimen and returned to baseline values following its discontinuation.ConclusionNeural effects of a cannabinergic drug may persist during chronic exposure, notwithstanding the development of tolerance to behavioral effects. However, such effects dissipate upon discontinuation, reflecting the restorative capacity of affected brain processes.

Heart rate variability (HRV) changes and cortical volume changes in a randomized trial of five weeks of daily HRV biofeedback in younger and older adults

Previous studies indicate that the structure and function of medial prefrontal cortex (PFC) and lateral orbitofrontal cortex (OFC) are associated with heart rate variability (HRV). Typically, this association is assumed to reflect the PFC's role in controlling HRV and emotion regulation, with better prefrontal structural integrity supporting greater HRV and better emotion regulation. However, as a control system, the PFC must monitor and respond to heart rate oscillatory activity. Thus, engaging in regulatory feedback during heart rate oscillatory activity may over time help shape PFC structure, as relevant circuits and connections are modified. In the current study with younger and older adults, we tested whether 5 weeks of daily sessions of biofeedback to increase heart rate oscillations (Osc+ condition) vs. to decrease heart rate oscillations (Osc− condition) affected cortical volume in left OFC and right OFC, two regions particularly associated with HRV in prior studies. The left OFC showed significant differences in volume change across conditions, with Osc+ increasing volume relative to Osc−. The volume changes in left OFC were significantly correlated with changes in mood disturbance. In addition, resting low frequency HRV increased more in the Osc+ than in the Osc− condition. These findings indicate that daily biofeedback sessions regulating heart rate oscillatory activity can shape both resting HRV and the brain circuits that help control HRV and regulate emotion.

Neuroanatomical Correlates of Emotion-Related Impulsivity

BackgroundEmotion-related impulsivity (ERI) refers to chronically poor self-control during periods of strong emotion. ERI robustly predicts psychiatric disorders and related problems, yet its neuroanatomical correlates are largely unknown. We tested whether local brain morphometry in targeted brain regions that integrate emotion and control could explain ERI severity. MethodsOne hundred twenty-two adults (ages 18–55 years) with internalizing or externalizing psychopathology completed a structural magnetic resonance imaging (MRI) scan, the Three-Factor Impulsivity Index, and the Structured Clinical Interview for DSM-5. The Three-Factor Impulsivity Index measures two types of ERI and a third type of impulsivity not linked to emotion. Cortical reconstruction yielded cortical thickness and local gyrification measurements. We evaluated whether morphometry in the orbitofrontal cortex (OFC), insula, amygdala, and nucleus accumbens was associated with ERI severity. Hypotheses and analyses were preregistered. ResultsLower cortical gyrification in the right lateral OFC was associated with high ERI severity in a full, preregistered model. Separate examinations of local gyrification and cortical thickness also showed a positive association between gyrification in the left lateral OFC and ERI. An integrated measure of hemispheric imbalance in lateral OFC gyrification (right < left) correlated with ERI severity. These findings were specific to ERI and did not appear with non–emotion-related impulsivity. ConclusionsLocal gyrification in the lateral OFC is associated with ERI severity. The current findings fit with existing theories of OFC function, strengthen the connections between the transdiagnostic literature in psychiatry and neuroscience, and may guide future treatment development.

Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation.

Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.

Modulation of Ventromedial Orbitofrontal Cortical Glutamatergic Activity Affects the Explore/Exploit Trade-Off and Influences Reward-Related Decision-Making

Cognitive flexibility and the balance between exploration and exploitation are essential for reward-related decision-making. The orbitofrontal cortex (OFC) is pivotal to these processes. Since impairments in OFC function and glutamatergic abnormalities are evident in several psychiatric disorders, we investigated how ventromedial OFC (vmOFC) glutamate neuron activity modulation affects reward-related decision-making,

Taking stock of value in the orbitofrontal cortex.

People with damage to the orbitofrontal cortex (OFC) have specific problems making decisions, whereas their other cognitive functions are spared. Neurophysiological studies have shown that OFC neurons fire in proportion to the value of anticipated outcomes. Thus, a central role of the OFC is to guide optimal decision-making by signalling values associated with different choices. Until recently, this view of OFC function dominated the field. New data, however, suggest that the OFC may have a much broader role in cognition by representing cognitive maps that can be used to guide behaviour and that value is just one of many variables that are important for behavioural control. In this Review, we critically evaluate these two alternative accounts of OFC function and examine how they might be reconciled.

Disassociated and concurrent structural and functional abnormalities in the drug-naïve first-episode early onset schizophrenia

Schizophrenia which is an abnormally developmental disease has been widely reported to show abnormal brain structure and function. Enhanced functional integration is a predominant neural marker for brain mature. Abnormal development of structure and functional integration may be a biomarker for early diagnosis of schizophrenia. Fifty-five patients with early onset schizophrenia (EOS) and 79 healthy controls were enrolled in this study. Voxel-based morphometry (VBM) and functional connectivity density (FCD) were performed to explore gray matter volume (GMV) lesion, abnormal functional integration, and concurrent structural and functional abnormalities in the brain. Furthermore, the relationships between abnormalities structural and function and clinical characteristics were evaluated in EOS. Compared with healthy controls, EOS showed significantly decreased GMV in the bilateral OFC, frontal, temporal, occipital, parietal and limbic system. EOS also showed decreased FCD in precuneus and increased FCD in cerebellum. Moreover, we found concurrent changes of structure and function in left lateral orbitofrontal cortex (lOFC). Finally, correlation analyses did not find significant correlation between abnormal neural measurements and clinical characteristic in EOS. The results reveal disassociated and bound structural and functional abnormalities patterns in EOS suggesting structural and functional measurements play different roles in delineating the abnormal patterns of EOS. The concurrent structural and functional changes in lOFC may be a biomarker for early diagnosis of schizophrenia. Our findings will deepen our understanding of the pathophysiological mechanisms in EOS.

Altered spontaneous neural activity in frontal and visual regions in patients with acrophobia

BackgroundAcrophobia is a prevalent type of specific phobia, which frequently leads to functional impairments and occupational limitations. However, the neural pathology of acrophobia is still largely unknown. Methods26 acrophobic patients and 30 healthy controls were enrolled in this study. All participants underwent a resting-state fMRI scan. Severity of symptoms was evaluated using self-report and behavioral measures. The regional homogeneity (ReHo) and seed-based functional connectivity (FC) were then examined. ResultsCompared to controls, acrophobic patients demonstrated higher ReHo in the right fusiform gyrus and lower ReHo in the bilateral superior frontal gyrus. Lower FC of right fusiform gyrus-bilateral caudate, right fusiform gyrus-right parahippocampal gyrus, and left medial superior frontal gyrus-left cuneus was also found in the acrophobia group. Additionally, there were negative correlations between behavior avoidance scores and FC of right fusiform gyrus- right parahippocampal gyrus (r = -0.42, p = 0.04) and between scores of the 7-item generalized anxiety disorder scale and FC of left medial superior frontal gyrus- left cuneus (r = -0.40, p = 0.049) in the acrophobia group. LimitationsOwing to the cross-sectional design, it was unclear whether the functional abnormalities found in the acrophobic patients were related to state or trait effects. ConclusionsPreliminary results indicated that acrophobic patients revealed abnormal brain function in orbitofrontal cortex, medial prefrontal cortex, and visual regions. These abnormalities may be helpful in understanding the possible neurobiological mechanism of acrophobia and may serve as potential intervention and prevention targets.

Relationship between psychopathic traits and performance on the Mini Social Cognition and Emotional Assessment in incarcerated males.

Psychopathy is a constellation of personality traits such as callousness, manipulativeness, and impulsivity, and these traits often co-occur with antisocial behavior. Researchers and clinicians have posited that these traits may be associated with impairments in orbitofrontal cortex functioning, but researchers have rarely assessed this using clinical neuropsychological assessments. In a sample of 87 male inmates in a county jail, this study examined the relationship between psychopathic traits and performance on the Mini Social Cognition and Emotional Assessment (Mini-SEA), an assessment of orbitofrontal cortex functioning. Psychopathy scores (total or factor) were not correlated with Mini-SEA performance. Potential reasons for our null findings and study limitations are discussed. PRACTITIONER POINTS: Psychopathic traits were not associated with performance on a neuropsychological measure assessing orbitofrontal cortex functioning. Deficits in OFC functioning observed in psychopathy may be different in nature, or less severe, than those observed in patients with frontotemporal dementia, who perform poorly on this measure.

Differential Effects of the Inactivation of Anterior and Posterior Orbitofrontal Cortex on Affective Responses to Proximal and Distal Threat, and Reward Anticipation in the Common Marmoset.

Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in affective disorders that manifest anxiety-related symptoms. However, research into the functions of primate OFC has predominantly focused on reward-oriented rather than threat-oriented responses. To redress this imbalance, the present study performed a comprehensive analysis of the independent role of 2 distinct subregions of the central OFC (anterior area 11; aOFC and posterior area 13; pOFC) in the processing of distal and proximal threat. Temporary inactivation of both aOFC and pOFC heightened responses to distal threat in the form of an unknown human, but not to proximal threat assessed in a discriminative Pavlovian conditioning task. Inactivation of the aOFC, however, did unexpectedly blunt conditioned threat responses, although the effect was not valence-specific, as conditioned appetitive responses were similarly blunted and appeared restricted to a discriminative version of the task (when both CS− and CS+ are present within a session). Inactivation of the pOFC did not affect conditioned responses to either proximal threat or reward and basal cardiovascular activity was unaffected by manipulations of activity in either subregion. The results highlight the contribution of aOFC and pOFC to regulation of responses to more distal uncertain but not proximal, certain threat and reveal their opposing contribution to that of the immediately adjacent medial OFC, area 14.

Investigating morphological changes in the brain in relation to etiology and duration of olfactory dysfunction with voxel-based morphometry

Olfactory loss (OL) affects up to 20% of the general population and is related to changes in olfaction-related brain regions. This study investigated the effect of etiology and duration of OL on gray matter volume (GMV) of these regions in 257 patients. Voxel-based morphometry was applied to measure GMV in brain regions of interest to test the effects of etiology and duration on regional GMV and the relation between olfactory function and regional GMV. Etiology of OL had a significant effect on GMV in clusters representing the gyrus rectus and orbitofrontal cortex (OFC), bilaterally. Patients with congenital anosmia had reduced GMV in the gyrus rectus and an increased OFC volume compared to patients with acquired OL. There was a significant association between volume of the left OFC and olfactory function. This implies that changes in GMV in patients with acquired OL are mainly reflected in the OFC and depend on olfactory function. Morphology of olfactory areas in the brain therefore seems to relate to olfactory function and the subsequent degree of exposure to olfactory input in patients with acquired OL. Differences in GMV in congenital anosmia are most likely due to the fact that patients were never able to smell.

Effects of Withdrawal from Cocaine Self-Administration on Rat Orbitofrontal Cortex Parvalbumin Neurons Expressing Cre recombinase: Sex-Dependent Changes in Neuronal Function and Unaltered Serotonin Signaling.

The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT1A and 5-HT2A receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking interneurons (OFCPV), whose function is essential to normal OFC-mediated behavior. Here, 5-HT function in naive rats and those withdrawn from CSA were evaluated using a novel rat transgenic line in which the rat parvalbumin promoter drives Cre-recombinase expression to permit identification of OFCPV cells by fluorescent reporter protein expression. We find that whereas CSA altered basal synaptic and membrane properties of the OFCPV neurons in a sex-dependent manner, the effects of 5-HT on these cells were unchanged by CSA. These data suggest that the behavioral effects of dysregulated OFC 5-HT function caused by cocaine experience are primarily mediated by changes in 5-HT signaling at PyNs, and not at OFCPV neurons.

The rodent lateral orbitofrontal cortex as an arbitrator selecting between model-based and model-free learning systems.

Our understanding of orbitofrontal cortex (OFC) function has progressed remarkably over the past decades in part due to theoretical advances in associative and reinforcement learning theories. These theoretical accounts of OFC function have implicated the region in progressively more psychologically refined processes from the value and sensory-specific properties of expected outcomes to the representation and inference over latent state representations in cognitive maps of task space. While these accounts have been successful at modeling many of the effects of causal manipulation of OFC function in both rodents and primates, recent findings suggest that further refinement of our current models are still required. Here, we briefly review how our understanding of OFC function has developed to understand two cardinal deficits following OFC dysfunction: Reversal learning and outcome devaluation. We then consider recent findings that OFC dysfunction also significantly affects initial acquisition learning, often assumed to be intact. To account for these findings, we consider a possible role for the OFC in the arbitration and exploration between model-free (MF) and model-based (MB) learning systems, offline updating of MB representations. While the function of the OFC as a whole is still likely to be integral to the formation and use of a cognitive map of task space, these refinements suggest a way in which distinct orbital subregions, such as the rodent lateral OFC, might contribute to this overall function. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The orbitofrontal cartographer.

Theories of orbitofrontal cortex (OFC) function have evolved substantially over the last few decades. There is now a general consensus that the OFC is important for predicting aspects of future events and for using these predictions to guide behavior. Yet the precise content of these predictions and the degree to which OFC contributes to agency contingent upon them has become contentious, with several plausible theories advocating different answers to these questions. In this review we will focus on three of these ideas-the economic value, credit assignment, and cognitive map hypotheses-describing both their successes and failures. We will propose that these failures hint at a more nuanced and perhaps unique role for the OFC, particularly the lateral subdivision, in supporting the proposed functions when an underlying model or map of the causal structures in the environment must be constructed or updated. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The orbitofrontal cortex in temporal cognition.

One of the most important factors in decision-making is estimating the value of available options. Subregions of the prefrontal cortex, including the orbitofrontal cortex (OFC), have been deemed essential for this process. Value computations require a complex integration across numerous dimensions, including, reward magnitude, effort, internal state, and time. The importance of the temporal dimension is well illustrated by temporal discounting tasks, in which subjects select between smaller-sooner versus larger-later rewards. The specific role of OFC in telling time and integrating temporal information into decision-making remains unclear. Based on the current literature, in this review we reevaluate current theories of OFC function, accounting for the influence of time. Incorporating temporal information into value estimation and decision-making requires distinct, yet interrelated, forms of temporal information including the ability to tell time, represent time, create temporal expectations, and the ability to use this information for optimal decision-making in a wide range of tasks, including temporal discounting and wagering. We use the term "temporal cognition" to refer to the integrated use of these different aspects of temporal information. We suggest that the OFC may be a critical site for the integration of reward magnitude and delay, and thus important for temporal cognition. (PsycInfo Database Record (c) 2021 APA, all rights reserved).