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Basolateral amygdala (BLA) neurons are engaged by emotionally salient stimuli. An area of increasing interest is how BLA dynamics relate to evolving reward-seeking behavior, especially under situations of uncertainty or ambiguity. Here, we recorded the activity of individual BLA neurons in male rats across the acquisition and extinction of conditioned reward seeking. We assessed ongoing neural dynamics in a task where long reward cue presentations preceded an unpredictable, variably time reward delivery. We found that, with training, BLA neurons discriminated the CS+ and CS- cues with sustained cue-evoked activity that correlated with behavior and terminated only after reward receipt. BLA neurons were bidirectionally modulated, with a majority showing prolonged inhibition during cued reward seeking. Strikingly, population-level analyses revealed that neurons showing cue-evoked inhibitions and those showing excitations similarly represented the CS+ and behavioral state. This sustained population code rapidly extinguished in parallel with conditioned behavior. We next assessed the contribution of the orbitofrontal cortex (OFC), a major reciprocal partner to the BLA. Inactivation of the OFC while simultaneously recording in the BLA revealed a blunting of sustained cue-evoked activity in the BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in the BLA also reduced reward seeking. Our data indicate that the BLA represents reward-seeking states via sustained, bidirectional cue-driven neural encoding. This code is regulated by cortical input and is important for the maintenance of vigilant reward-seeking behavior., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other stimuli share a continuous narrative context, fMRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes. Thirty inpatient iHUD (24 male) and 25 healthy controls (16 male) watched a drug-themed movie at baseline and at follow-up after 15 weeks. Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks during ongoing inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the region-level neuroanatomical properties of the orbitofrontal cortex (OFC), but not posteromedial cortex (PMC). Informed by a growing body of research indicating that examining the morphology of specific cortical folds (sulci) can produce unique insights into behavioral outcomes, the present study modeled the association between ERI and the morphology of sulci within OFC and PMC, which is a finer scale than previously conducted., Methods: Analyses were conducted in a transdiagnostic sample of 118 adult individuals with a broad range of psychiatric syndromes. First, we manually defined over 4,000 sulci across 236 cerebral hemispheres. Second, we implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI. Third, we tested whether effects were specific to OFC sulci, sulcal depth, and ERI (as compared to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity)., Results: The LASSO regression revealed bilateral associations of ERI with the depths of eight OFC sulci. These effects were strongest for OFC sulci, sulcal depth, and ERI in comparison to PMC sulci, sulcal gray matter thickness, and non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker., Conclusions: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology., (Copyright © 2024. Published by Elsevier Ltd.)

Background: This study aimed to evaluate a novel rTMS protocol for treatment-resistant depression (TRD), using an EEG 10-20 system guided dual-target accelerated approach of right lateral orbitofrontal cortex (lOFC) inhibition followed by left dorsolateral prefrontal cortex (dlPFC) excitation, along with comparing 20 Hz dlPFC accelerated TMS v. sham., Methods: Seventy five patients participated in this trial consisting of 20 sessions over 5 consecutive days comparing dual-site (cTBS of right lOFC followed sequentially by 20 Hz rTMS of left dlPFC), active control (sham right lOFC followed by 20 Hz rTMS of left dlPFC) and sham control (sham for both targets). Resting-state fMRI was acquired prior to and following treatment., Results: Hamilton Rating Scale for Depression (HRSD-24) scores were similarly significantly improved at 4 weeks in both the Dual and Single group relative to Sham. Planned comparisons immediately after treatment highlighted greater HRSD-24 clinical responders (Dual: 47.8% v. Single:18.2% v. Sham:4.3%, χ 2 = 13.0, p = 0.002) and in PHQ-9 scores by day 5 in the Dual relative to Sham group. We further showed that accelerated 20 Hz stimulation targeting the left dlPFC (active control) is significantly better than sham at 4 weeks. Dual stimulation decreased lOFC-subcallosal cingulate functional connectivity. Greater baseline lOFC-thalamic connectivity predicted better therapeutic response, while decreased lOFC-thalamic connectivity correlated with better response., Conclusions: Our novel accelerated dual TMS protocol shows rapid clinically relevant antidepressant efficacy which may be related to state-modulation. This study has implications for community-based accessible TMS without neuronavigation and rapid onset targeting suicidal ideation and accelerated discharge from hospital.

Background: A top-down neuronal circuit from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) appears to be critical for cognitive flexibility. However, how OFC projections to different types of neurons in the DMS control cognitive flexibility and contribute to substance seeking and use, which are relatively inflexible behaviors, remains unclear., Methods: Mice were trained on two-bottle choice and operant alcohol self-administration procedures. The cognitive flexibility of the mice was tested through a place discrimination task. Electrophysiology and in vivo optogenetics were used to test the function of neural circuits in alcohol-seeking behavior., Results: We depicted a connection from the OFC to striatal neurons and found that OFC afferents could elicit functional flexibility in striatal cholinergic interneurons (CINs). A mouse model of chronic alcohol consumption showed impaired cognitive flexibility and reduced burst-pause firing. The impairment of the OFC-DMS circuit resulted in a reduction in glutamatergic transmission in OFC-medium spiny neurons (MSNs) through a CIN-mediated pre-inhibition mechanism. Importantly, remodeling the OFC-DMS circuit by inducing LTP restored cognitive flexibility. Furthermore, CINs were responsible for the impact of remodeling of the OFC-DMS circuit on cognitive flexibility. This regulatory role of CINs preferentially facilitated the potentiation of glutamatergic transmission in D2 receptor-expressing medium spiny neurons (D2-MSNs) but not in D1-MSNs. Finally, activation of the OFC-CIN-D2-MSN circuit decreased alcohol-seeking behavior., Conclusions: Improving OFC-CIN circuit-mediated cognitive flexibility may provide a novel strategy for treating uncontrolled alcohol-seeking behavior., (Copyright © 2024. Published by Elsevier Inc.)

Childhood neglect is associated with cortical thinning, hyperactivity, and deficits in cognitive flexibility that are difficult to reverse later in life. Despite being the most prevalent form of early adversity, little is currently understood about the mechanisms responsible for these neurodevelopmental abnormalities, and no animal models have yet replicated key structural and behavioral features of childhood neglect/deprivation. To address these gaps, we have recently demonstrated that mice exposed to impoverished conditions, specifically limited bedding (LB), exhibit behavioral and structural changes that resemble those observed in adolescents who have experienced severe neglect. Here, we show that LB leads to long-term deficits in reversal learning, which can be fully reversed by briefly exposing LB pups to enrichment (toys) in their home cage from postnatal days 14 to 25. Reversal learning failed to induce normal c-fos activation in the orbitofrontal cortex (OFC) of LB mice, a deficit that was normalized by early enrichment. Additionally, LB decreased the density of parvalbumin-positive cells surrounded by perineuronal nets (PV+PNN+) and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC, deficits that were also reversed by enrichment. Degradation of PNN in the OFC of adult mice impaired reversal learning, reduced c-fos activation, and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC to levels comparable to those observed in LB mice. Collectively, our findings suggest that postnatal deprivation and enrichment impact the formation of PV+PNN+ cells in the OFC, a developmental process that is essential for cognitive flexibility in adulthood., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Reinforcement learning (RL), particularly in primates, is often driven by symbolic outcomes. However, it is usually studied with primary reinforcers. To examine the neural mechanisms underlying learning from symbolic outcomes, we trained monkeys on a task in which they learned to choose options that led to gains of tokens and avoid choosing options that led to losses of tokens. We then recorded simultaneously from the orbitofrontal cortex (OFC), ventral striatum (VS), amygdala (AMY), and mediodorsal thalamus (MDt). We found that the OFC played a dominant role in coding token outcomes and token prediction errors. The other areas contributed complementary functions, with the VS coding appetitive outcomes and the AMY coding the salience of outcomes. The MDt coded actions and relayed information about tokens between the OFC and VS. Thus, the OFC leads the processing of symbolic RL in the ventral frontostriatal circuitry., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Intermittent Explosive Disorder (IED) is characterized by repeated inability to control aggressive impulses. Although the etiology and neurobiology of impulsive anger and impulse control disorders have been reviewed, no systematic review on these aspects has been published for IED specifically. We conducted a systematic search in seven electronic databases for publications about IED, screened by two authors, and retained twenty-four studies for the review. Our findings highlight a multifactorial etiology and neurobiology of IED, emphasizing the role of the amygdala and orbitofrontal cortex in emotional regulation and impulse control, and supporting interventions that target serotonergic signaling. Research also shows that childhood trauma and adverse family environment may significantly contribute to the development of IED. Yet, genetic studies focusing on IED were largely lacking, despite many examining the genetics underlying aggression as a general trait or other related disorders. Future research using consistently defined IED as a phenotype is required to better understand the etiology and underlying mechanisms and assist in informing the development of more effective interventions for IED., Competing Interests: Declaration of Interest SVF received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Akili, Atentiv, Axsome, Genomind, Ironshore, Johnson & Johnson/Kenvue, Kanjo, KemPharm/Corium, Noven, Otsuka, Sky Therapeutics, Sandoz, Supernus, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. Dr. Faraone’s research is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement 965381; NIH/NIMH grants U01AR076092-01A1, R0MH116037, 5R01AG064955-02, 1R21MH126494-01, 1R01NS128535-01, R01MH131685-01, 1R01MH130899-01A1, Corium Pharmaceuticals, Tris Pharmaceuticals and Supernus Pharmaceutical Company. JP, SE, AU, JS, and YZJ have no disclosures to report.

Epilepsy is a common and severe neurological disorder affecting millions of people worldwide. Nowadays, antiseizure medications (ASMs) are the main treatment for most epilepsy patients, although many of them do not respond to ASMs and suffer from drug-resistant epilepsy (DRE). Alternative and novel treatment methods have been offered nowadays, showing promising results for the treatment of DRE. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method that has become increasingly popular in the last decades. This article reports a patient with frontal lobe epilepsy. We aimed to investigate whether bilateral orbitofrontal (OFC) low-frequency rTMS (LF-rTMS) is feasible and tolerable, safe, and potentially clinically effective in treating epileptic seizures. The patient’s satisfaction with rTMS therapy was self-reported to be high, as rTMS helped in reducing the frequency of the focal attacks and completely abolished the preceding feeling of fear and panic. Therefore, bilateral OFC rTMS treatment can be well tolerated in patients with frontal epilepsy although the findings of the present case report with regard to clinical efficacy warrant further investigation.

Odorous sensations are based on trigeminal and olfactory perceptions. Both trigeminal and olfactory stimuli generate overlapping as well as distinctive activations in the olfactory cortex including the piriform cortex. Orbitofrontal cortex (OFC), an integrative center for all senses, is directly activated in the presence of olfactory stimulations. In contrast, the thalamus, a very important midbrain structure, is not directly activated in the presence of odors, but rather acts as a relay for portions of olfactory information between primary olfactory cortex and higher-order processing centers. The aims of the study were (1) to examine the number of streamlines between the piriform cortex and the OFC and also between the piriform cortex and the thalamus and (2) to explore potential correlations between these streamlines and trigeminal and olfactory chemosensory perceptions. Thirty-eight healthy subjects were recruited for the study and underwent diffusion MRI using a 3T MRI scanner with 67 diffusion directions. ROIs were adapted from two studies looking into olfaction in terms of functional and structural properties of the olfactory system. The “waytotal number” was used which corresponds to number of streamlines between two regions of interests. We found the number of streamlines between the piriform cortex and the thalamus to be higher in the left hemisphere, whereas the number of streamlines between the piriform cortex and the OFC were higher in the right hemisphere. We also found streamlines between the piriform cortex and the thalamus to be positively correlated with the intensity of irritating (trigeminal) odors. On the other hand, streamlines between the piriform cortex and the OFC were correlated with the threshold scores for these trigeminal odors. This is the first studying the correlations between streamlines and olfactory scores using tractography. Results suggest that different chemosensory stimuli are processed through different networks in the chemosensory system involving the thalamus.

Adaptive reward-related decision making requires accurate prospective consideration of the specific outcome of each option and its current desirability. These mental simulations are informed by stored memories of the associative relationships that exist within an environment. In this review, I discuss recent investigations of the function of circuitry between the basolateral amygdala (BLA) and lateral (lOFC) and medial (mOFC) orbitofrontal cortex in the learning and use of associative reward memories. I draw conclusions from data collected using sophisticated behavioral approaches to diagnose the content of appetitive memory in combination with modern circuit dissection tools. I propose that, via their direct bidirectional connections, the BLA and OFC collaborate to help us encode detailed, outcome-specific, state-dependent reward memories and to use those memories to enable the predictions and inferences that support adaptive decision making. Whereas lOFC→BLA projections mediate the encoding of outcome-specific reward memories, mOFC→BLA projections regulate the ability to use these memories to inform reward pursuit decisions. BLA projections to lOFC and mOFC both contribute to using reward memories to guide decision making. The BLA→lOFC pathway mediates the ability to represent the identity of a specific predicted reward and the BLA→mOFC pathway facilitates understanding of the value of predicted events. Thus, I outline a neuronal circuit architecture for reward learning and decision making and provide new testable hypotheses as well as implications for both adaptive and maladaptive decision making.

The objective of the study was to determine if sex plays a moderating role in the relationship between executive functions and academic procrastination in 106 university students of both genders (28.3% male and 71.7% female) between the ages of 18 and 30 years (M = 19.7; SD = 2.7). The Academic Procrastination Scale and the Neuropsychological Battery of Executive Functions and Frontal Lobes (BANFE-2) were used to measure the variables. The results of the study showed that the degree of prediction of the tasks linked to the orbitomedial cortex (involves the orbitofrontal cortex [OFC] and the medial prefrontal cortex [mPFC]) on academic procrastination is significantly moderated by the sex of the university students (β3 = 0.53; p < 0.01). For men, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is -0.81. For women, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is -0.28. In addition, it was shown that sex does not play a moderating role in the relationship between the tasks linked to the dorsolateral prefrontal cortex (dlPFC) and academic procrastination (b3 = 0.12; p > 0.05). It was also determined that sex does not play a moderating role in the relationship between the tasks linked to the anterior prefrontal cortex (aPFC) and academic procrastination (b3 = 0.05; p > 0.05). It is concluded that only the executive functions associated with the orbitomedial cortex are moderated by the sex of the university students, where the impact of the tasks linked to the orbitomedial cortex on academic procrastination in men is significantly greater than in women. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) patients were usually found with the hyper-activation of the orbitofrontal cortex (OFC) and a deficit in fear extinction learning. The OFC can be subdivided into the lateral OFC (lOFC) and the medial OFC (mOFC). Previous studies have suggested that both subregions are involved in the modulation of negative emotions. However, how aberrant activation of the OFC interacts with the encoding of Pavlovian fear remains unknown. In this study, the lOFC or the mOFC was pharmacologically activated or inactivated before the fear conditioning on Day 1, followed by a context test on Day 2 and a tone test on Day 3 in male Long-Evans rats. We found that for the animals that underwent fear conditioning under aberrant activation of either the lOFC or the mOFC, they showed normal within-session fear expression. However, the acquisition/consolidation of contextual fear was impaired under mOFC activation, while the acquisition/consolidation of cued fear was impaired under either the lOFC or the mOFC activation, in that these animals showed lower freezing compared to controls during the retrieval test. On the other hand, for the animals that underwent fear conditioning under inactivation of either the lOFC or the mOFC, they showed normal within-session fear expression, as well as intact encoding of both the contextual and cued fear. Together, our results suggested that the OFC was not actively engaged in the acquisition of Pavlovian fear conditioning, but aberrant activation of the OFC impaired fear learning. [ABSTRACT FROM AUTHOR]

A good‐based model, the central neurobiological model of economic decision‐making, proposes that the orbitofrontal cortex (OFC) represents binary choice outcome, that is, the chosen good. A good is defined by a group of determinants characterizing the conditions in which the commodity is offered, including commodity type, cost, risk, time delay, and ambiguity. Previous studies have found that the OFC represents the binary choice outcome in decision‐making tasks involving commodity type, cost, risk, and delay. Real‐life decisions are often complex and involve uncertainty, rewards, and penalties; however, whether the OFC represents binary choice outcomes in a complex decision‐making situation, for example, Iowa gambling task (IGT), remains unclear. Here, we propose that the OFC represents binary choice outcome, that is, advantageous choice versus disadvantageous choice, in the IGT. We propose two hypotheses: first, the activity pattern in the human OFC represents an advantageous choice; and second, choice induces an OFC‐related functional network. Using functional magnetic resonance imaging and advanced machine‐learning tools, we found that the OFC represented an advantageous choice in the IGT. The OFC representation of advantageous choice was related to decision‐making performance. Choice modulated the functional connectivity between the OFC and the superior medial gyrus. In conclusion, the OFC represents an advantageous choice during the IGT. In the framework of a good‐based model, the results extend the role of the OFC to complex decision‐making situation when making a binary choice. [ABSTRACT FROM AUTHOR]

Conduct problems (CP) in patients with disruptive behavior disorders have been linked to impaired prefrontal processing of negative facial affect compared to controls. However, it is unknown whether associations with prefrontal activity during affective face processing hold along the CP dimension in a healthy population sample, and how subcortical processing is affected. We measured functional brain responses during negative affective face processing in 1444 healthy adolescents [M = 14.39 years (SD = 0.40), 51.5% female] from the European IMAGEN multicenter study. To determine the effects of CP, we applied a two-step approach: (a) testing matched subgroups of low versus high CP, extending into the clinical range [N = 182 per group, M = 14.44 years, (SD = 0.41), 47.3% female] using analysis of variance, and (b) considering (non)linear effects along the CP dimension in the full sample and in the high CP group using multiple regression. We observed no significant cortical or subcortical effect of CP group on brain responses to negative facial affect. In the full sample, regression analyses revealed a significant linear increase of left orbitofrontal cortex (OFC) activity with increasing CP up to the clinical range. In the high CP group, a significant inverted u-shaped effect indicated that left OFC responses decreased again in individuals with high CP. Left OFC activity during negative affective processing which is increasing with CP and decreasing in the highest CP range may reflect on the importance of frontal control mechanisms that counteract the consequences of severe CP by facilitating higher social engagement and better evaluation of social content in adolescents. [ABSTRACT FROM AUTHOR]

Obesity is the second most common cause of preventable morbidity worldwide. Resting-state functional magnetic resonance imaging (fMRI) has been used extensively to characterise altered communication between brain regions in individuals with obesity, though findings from this research have not yet been systematically evaluated within the context of prominent neurobiological frameworks. This systematic review aggregated resting-state fMRI findings in individuals with obesity and evaluated the contribution of these findings to current neurobiological models. Findings were considered in relation to a triadic model of problematic eating, outlining disrupted communication between reward, inhibitory, and homeostatic systems. We identified a pattern of consistently increased orbitofrontal and decreased insula cortex resting-state functional connectivity in individuals with obesity in comparison to healthy weight controls. BOLD signal amplitude was also increased in people with obesity across studies, predominantly confined to subcortical regions, including the hippocampus, amygdala, and putamen. We posit that altered orbitofrontal cortex connectivity may be indicative of a shift in the valuation of food-based rewards and that dysfunctional insula connectivity likely contributes to altered homeostatic signal processing. Homeostatic violation signals in obesity may be maintained despite satiety, thereby 'hijacking' the executive system and promoting further food intake. Moving forward, we provide a roadmap for more reliable resting-state and task-based functional connectivity experiments, which must be reconciled within a common framework if we are to uncover the interplay between psychological and biological factors within current theoretical frameworks. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia (SZ) is associated with the highest disability rate among serious mental disorders. Excited symptoms are the core symptoms of SZ, which appear in the early stage, followed by other stages of the disease subsequently. These symptoms are destructive and more prone to violent attacks, posing a serious economic burden to the society. Abnormal spontaneous activity in the orbitofrontal cortex had been reported to be associated with excited symptoms in patients with SZ. However, whether the abnormality appears in first-episode drug-naïve patients with SZ has still remained elusive. Methods: A total of 56 first-episode drug-naïve patients with SZ and 27 healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) and positive and negative syndrome scale (PANSS). First, differences in fractional amplitude of low-frequency fluctuations (fALFF) between first-episode drug-naïve patients with SZ and healthy controls were examined to identify cerebral regions exhibiting abnormal local spontaneous activity. Based on the fALFF results, the resting-state functional connectivity analysis was performed to determine changes in cerebral regions exhibiting abnormal local spontaneous activity. Finally, the correlation between abnormal functional connectivity and exciting symptoms was analyzed. Results: Compared with the healthy controls, first-episode drug-naïve patients with SZ showed a significant decrease in intrinsic activity in the bilateral precentral gyrus, bilateral postcentral gyrus, and the left orbitofrontal cortex. In addition, first-episode drug-naïve patients with SZ had significantly reduced functional connectivity values between the left orbitofrontal cortex and several cerebral regions, which were mainly distributed in the bilateral postcentral gyrus, the right middle frontal gyrus, bilateral paracentral lobules, the left precentral gyrus, and the right median cingulate. Further analyses showed that the functional connectivity between the left orbitofrontal cortex and the left postcentral gyrus, as well as bilateral paracentral lobules, was negatively correlated with excited symptoms in first-episode drug-naïve patients with SZ. Conclusion: Our results indicated the important role of the left orbitofrontal cortex in first-episode drug-naïve patients with SZ and suggested that the abnormal spontaneous activity of the orbitofrontal cortex may be valuable to predict the occurrence of excited symptoms. These results may provide a new direction to explore the excited symptoms of SZ. [ABSTRACT FROM AUTHOR]

Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision-making and MFC supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques (Macaca mulatta) with crossed surgical disconnection of the amygdala and either MFC (MFC Χ AMY, n = 4) or OFC (OFC Χ AMY, n = 4) to a group of unoperated controls (CON, n = 5). All monkeys were assessed for their performance on two tasks to measure the following: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest and (2) object choices based on current food value using reinforcer devaluation in a test of goal-directed decision-making. Compared with the CON group, the MFC Χ AMY group, but not the OFC Χ AMY group, showed significantly reduced food-retrieval latencies while viewing videos of conspecifics, indicating reduced social valuation and/or interest. By contrast, on the devaluation task, group OFC Χ AMY, but not group MFC Χ AMY, displayed deficits on object choices following changes in food value. These data indicate that the MFC and OFC must functionally interact with the amygdala to support normative social and nonsocial valuation, respectively. [ABSTRACT FROM AUTHOR]

Depression is a common comorbid symptom in patients with chronic insomnia disorder (CID). Previous neuroimaging studies found that the orbital frontal cortex (OFC) might be the core brain region linking insomnia and depression. Here, we used a machine learning approach to differentiate CID patients with depressive symptoms from CID patients without depressive symptoms based on OFC functional connectivity. Seventy patients with CID were recruited and subdivided into CID with high depressive symptom (CIDHD) and low depressive symptom (CID-LD) groups. The OFC functional connectivity (FC) network was constructed using the altered structure of the OFC region as a seed. A linear kernel SVM-based machine learning approach was carried out to classify the CID-HD and CID-LD groups based on OFC FC features. The predict model was further verified in a new cohort of CID group (n = 68). The classification model based on the OFC FC pattern showed a total accuracy of 76.92% (p = 0.0009). The area under the receiver operating characteristic curve of the classification model was 0.84. The OFC functional connectivity with reward network, salience network and default mode network contributed the highest weights to the prediction model. These results were further validated in an independent CID group with high and low depressive symptom (accuracy = 67.9%). These findings provide a potential biomarker for early diagnosis and intervention in CID patients comorbid with depression based on an OFC FC-based machine learning approach. [ABSTRACT FROM AUTHOR]

The PV2 (Celio 1990), a cluster of parvalbumin-positive neurons located in the ventromedial region of the distal periaqueductal gray (PAG) has not been previously described as its own entity, leading us to study its extent, connections, and gene expression. It is an oval, bilateral, elongated cluster composed of approximately 475 parvalbumin-expressing neurons in a single mouse hemisphere. In its anterior portion it impinges upon the paratrochlear nucleus (Par4) and in its distal portion it is harbored in the posterodorsal raphe nucleus (PDR). It is known to receive inputs from the orbitofrontal cortex and from the parvafox nucleus in the ventrolateral hypothalamus. Using anterograde tracing methods in parvalbumin-Cre mice, the main projections of the PV2 cluster innervate the supraoculomotor periaqueductal gray (Su3) of the PAG, the parvafox nucleus of the lateral hypothalamus, the gemini nuclei of the posterior hypothalamus, the septal regions, and the diagonal band in the forebrain, as well as various nuclei within the reticular formation in the midbrain and brainstem. Within the brainstem, projections were discrete, but involved areas implicated in autonomic control. The PV2 cluster expressed various peptides and receptors, including the receptor for Adcyap1, a peptide secreted by one of its main afferences, namely, the parvafox nucleus. The expression of GAD1 and GAD2 in the region of the PV2, the presence of Vgat-1 in a subpopulation of PV2-neurons as well as the coexistence of GAD67 immunoreactivity with parvalbumin in terminal endings indicates the inhibitory nature of a subpopulation of PV2-neurons. The PV2 cluster may be part of a feedback controlling the activity of the hypothalamic parvafox and the Su3 nuclei in the periaqueductal gray. [ABSTRACT FROM AUTHOR]

Background: Observation of real-time neural characteristics during gameplay would provide distinct evidence for discriminating the currently controversial diagnosis of internet gaming disorder (IGD), and elucidate neural mechanisms that may be involved in addiction. We aimed to provide preliminary findings on possible neural features of IGD during real-time internet gaming using functional near-infrared spectroscopy (fNIRS). Methods: Prefrontal cortical activations accompanying positive and negative in-game events were investigated. Positive events: (1) participant’s champion slays or assists in slaying an opponent without being slain. (2) the opposing team’s nexus is destroyed. Negative events: (1) participant’s champion is slain without slaying or assisting in slaying any opponent. (2) the team’s nexus is destroyed. Collected data were compared between the IGD group and control group, each with 15 participants. Results: The IGD group scored significantly higher than the CTRL group on the craving scale. Following positive events, the IGD group displayed significantly stronger activation in the DLPFC. Following negative events, the IGD group displayed significantly weaker activation in the lateral OFC. Discussion and Conclusions: Individuals scoring high on the IGD scale may crave for more internet gaming after encountering desired events during the game. Such observations are supported by the correlation between the craving scale and DLPFC activation. The IGD group may also show diminished punishment sensitivity to negative in-game experiences rendering them to continue playing the game. The present study provides preliminary evidence that IGD may demonstrate neural characteristics observed in other addictive disorders and suggests the use of fNIRS in behavioral addiction studies. [ABSTRACT FROM AUTHOR]

The Frontal Systems Behavior Scale (FrSBe) is a self-report measure that assesses difficulties with cognitive and emotional control such as apathetic behavior, lack of inhibitory control, and executive dysfunction. Previous neuroimaging studies highlight the involvement of the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex (DLPFC) in these processes. In this study, we investigated whether there was convergence across subjective and objective measures of apathy, disinhibition, and executive dysfunction. Specifically, we studied whether ACC, OFC, and DLPFC activation during a modified version of the Multi-Source Interference Task (MSIT), is associated with FrSBe apathy, disinhibition, and executive dysfunction scores, in healthy controls (HC) and individuals with Bipolar Disorder (BD), who commonly exhibit difficulties in these domains. Individuals with BD (n = 31) and HCs (n = 31) with no current or past psychiatric illness completed the FrSBe and the MSIT during fMRI scanning. We investigated task-specific changes in the ACC, DLPFC, and OFC and their correlations with FrSBe apathy, disinhibition, and executive dysfunction subscale scores, respectively. Individuals with BD and the HC group demonstrated greater ACC, DLPFC, and OFC activation during MSIT interference conditions compared with non-interference conditions. Furthermore, there was a significant negative correlation between OFC activation and disinhibition scores, which remained significant after accounting for medication load. Together, these results demonstrate the FrSBe disinhibition subscale, in particular, can be a self-report measure that converges with behavioral and neural markers of disinhibition in BD. [ABSTRACT FROM AUTHOR]

Behavioral flexibility depends on our capacity to build and leverage abstract knowledge about tasks. Recently, two separate lines of research have implicated distinct brain networks in representing abstract task information: a frontoparietal cortical network, and a network involving the medial temporal lobe (MTL), medial prefrontal, and orbitofrontal cortex (OMPFC). These observations have mostly been made in parallel, with little attempt to understand their relationship. Here, we hypothesize that abstract task representations in these networks differ primarily in format, not content. Namely, that the MTL–OMPFC network maintains task knowledge in a flexible cognitive map, while the frontoparietal network formats this knowledge as productions that facilitate action selection. We discuss novel implications and predictions for behavioral flexibility arising from this hypothesis. Recent research has identified two distinct cortical networks representing abstract task knowledge: a frontoparietal network, and a network involving the MTL and OMPFC. Here, we suggest that these networks differ in format but not content, with the MTL–OMPFC network maintaining abstract task knowledge in a cognitive map, while frontoparietal cortex uses this knowledge to build rules for action selection. This format distinction would allow the MTL–OMPFC network to form novel inferences and plan trajectories in an abstract state space, and for the frontoparietal network to rapidly apply abstract rules without referencing a more elaborate internal task model. This hypothesis makes novel predictions about the function of these networks in learning and promoting flexible behavior. [ABSTRACT FROM AUTHOR]

Areas dedicated to higher brain functions such as the orbitofrontal cortex (OFC) are thought to be unique to hominidae. The OFC is involved in social behavior, reward and punishment encoding and emotional control. Here, we focused on the putative corresponding area in the sheep to assess its homology to the OFC in humans. We used classical histology in five sheep (Ovis aries) and four chimpanzees (Pan troglodytes) as a six-layered-cortex primate, and Diffusion Tensor Imaging (DTI) in three sheep and five human brains. Nissl's staining exhibited a certain alteration in cortical lamination since no layer IV was found in the sheep. A reduction of the total cortical thickness was also evident together with a reduction of the prevalence of layer one and an increased layer two on the total thickness. Tractography of the sheep OFC, on the other hand, revealed similarities both with human tracts and those described in the literature, as well as a higher number of cortico-cortical fibers connecting the OFC with the visual areas in the right hemisphere. Our results evidenced the presence of the basic components necessary for complex abstract thought in the sheep and a pronounced laterality, often associated with greater efficiency of a certain function, suggested an evolutionary adaptation of this prey species. [ABSTRACT FROM AUTHOR]

The orbitofrontal cortex (OFC) is an important brain area for executive functions. The OFC projects to both the nucleus accumbens(NAc)andthebasolateralnucleusoftheamygdala(BLA).Thesetwopathwayssharesomesimilarbehavioralfunctions, but their anatomical and physiological properties have not been compared before. In this study, we first explored the connection of the lateral OFC (lOFC) to NAc core (NAcc) and/or BLA, especially the collateral projections (experiments 1 and 2)with rats. In experiment 1, fluorophore-conjugated retrograde tracers were locally infused into the NAcc and the BLA to sample neurons in the lOFC. Our results revealed that along the anterior-posterior axis of the lOFC, more NAcc- and/or BLA-projecting neurons were distributed toward the posterior end, but the average percentage of collateral projecting neurons at the four sampled lOFC levels remained fairly stable. In experiment 2, antidromic single units in the lOFC responsive to the NAcc and/or the BLA stimulation were identified in anesthetized rats. However, we found that collateral projections from the lOFC to NAcc and BLA were sparse. We next studied the physiological characteristics of these two pathways (experiment 3). In this experiment, orthodromic single units in the NAcc or the BLA responsive to the lOFC stimulation were located in anesthetized rats. Our results showed no difference in the evoked thresholds or the intensity-response probability curves between the two. Together, our results showed that these two pathways were similar in projecting neuron distribution and physiological characteristics. NEW & NOTEWORTHY Using the double retrograde tracing and electrophysiological approach, we reported that among the sampled NAcc- or the BLA-projecting lOFC neurons, the percentage of collateral projections were fairly stable (about 20%--25%) along the lOFC anterior-posterior axis. Furthermore, among the neurons sampled in the NAcc and the BLA, there was no difference in physiological characteristics in response to lOFC stimulation between the two pathways. [ABSTRACT FROM AUTHOR]

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Usher syndrome (USH) is a condition characterized by ciliary dysfunction leading to retinal degeneration and hearing/vestibular loss. Putative olfactory deficits in humans have been documented at the psychophysical level and remain to be proven at the neurophysiological level. Thus, we aimed to study USH olfactory impairment using functional magnetic resonance imaging. We analyzed differences in whole-brain responses between 27 USH patients and 26 healthy participants during an olfactory detection task with a bimodal odorant (n-butanol). The main research question was whether between-group differences could be identified using a conservative whole-brain approach and in a ROI-based approach in key olfactory brain regions. Results indicated higher olfactory thresholds in USH patients, thereby confirming the hypothesis of reduced olfactory acuity. Importantly, we found decreased BOLD activity for USH patients in response to odorant stimulation in the right piriform cortex, while right orbitofrontal cortex showed increased activity. We also found decreased activity in other higher-level regions in a whole brain approach. We suggest that the hyper activation in the orbitofrontal cortex possibly occurs as a compensatory mechanism after the under-recruitment of the piriform cortex. This study suggests that olfactory deficits in USH can be objectively assessed using functional neuroimaging which reveals differential patterns of activity both in low- and high-level regions of the olfactory network. Highlights: 1. Psychophysical olfactory deficits are present in Usher Syndrome, a ciliary disorder. 2. USH patients show decreased BOLD activity in the right piriform olfactory cortex; 3. USH patients show increased activity in the orbitofrontal olfactory cortex; 4. USH patients show patterns of decreased activity in high-level cortical regions; 5. Functional neuroimaging unravels USH olfactory deficits at the population level. [ABSTRACT FROM AUTHOR]

Weiwei Liu,1,&ast; Hua Shao,2,&ast; Jing Liao,1 Dalu Yang,1 Maoliang Ma,3 Jianli Yang2 1Tianjin Medical University, Tianjin, People’s Republic of China; 2Clinical Psychology Department, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Tianjin Medical University General Hospital Airport Site, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianli YangClinical Psychology Department, Tianjin Medical University General Hospital, Anshan Road #154, Heping District, Tianjin, People’s Republic of ChinaEmail adyy005@163.comPurpose: Examining whether modulation of right orbitofrontal cortex (OFC) activity by continuous theta-burst stimulation (cTBS) affects obsessive-compulsive disorder (OCD) symptoms.Patients and Methods: A total of 28 treatment-resistant OCD participants were treated with either active or sham cTBS of the OFC twice per day, for five days a week, for 2 weeks, in a double-blinded manner. Clinical response to treatment was determined using the Yale–Brown Obsessive-Compulsive Scale (Y-BOCS).Results: There were no statistically significant differences between the 2 groups after two weeks of treatment in the Yale–Brown Obsessive-Compulsive Scale score (group&ast;time interaction, F2,20=0.996, p=0.387) and other secondary outcome measures, including anxiety symptoms and responder rates. Depressive symptoms improved significantly in the active group (p=0.027), but the significant difference disappeared at 6 weeks (p=0.089).Conclusion: This is the first randomized controlled study using cTBS in the right OFC to observe the improvement of treatment-resistant OCD symptoms. It is safe to use cTBS, but 2 weeks of treatment is not enough to achieve a curative effect. Future studies are needed to explore more advanced stimulation parameters suitable for the treatment of OCD.Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2000034814.Keywords: obsessive-compulsive disorder, continuous theta-burst stimulation, orbitofrontal cortex, transcranial magnetic stimulation

Abstract Background: Migraine is a prevalent neurological disease that leads to severe headaches. Moreover, it is the commonest among the primary headaches that cause medication overuse headache (MOH). The orbitofrontal cortex (OFC) is one of the structures most associated with medication overuse. Objective: To determine microstructural changes in the OFC among migraine patients who developed MOH, through the diffusion tensor imaging (DTI) technique. Methods: Fifty-eight patients who had been diagnosed with migraine based on the Classification of Headache Disorders (ICHD-III-B) were included in the study. Patients were sub-classified into two groups, with and without MOH, based on the MOH criteria of ICHD-III-B. DTI was applied to each patient. The OFC fractional anisotropy (FA), and apparent diffusion coefficient (ADC) values of the two groups were compared. Results: The mean age of all the patients was 35.98±7.92 years (range: 18-65), and 84.5% (n=49) of them were female. The two groups, with MOH (n=25) and without (n=33), were alike in terms of age, gender, family history, migraine with or without aura and duration of illness. It was found that there was a significant difference in FA values of the left OFC between the two groups (0.32±0.01 versus 0.29±0.01; p=0.04). Conclusions: An association was found between MOH and changes to OFC microstructure. Determination of neuropathology and factors associated with medication overuse among migraine patients is crucial in terms of identifying the at-risk patient population and improving proper treatment strategies specific to these patients.

Interpersonal distance is central to communication and complex social behaviors but the neural correlates of interpersonal distance preferences are not defined. Previous studies suggest that damage to the orbitofrontal cortex (OFC) is associated with impaired interpersonal behavior. To examine whether the OFC is critical for maintaining appropriate interpersonal distance, we tested two groups of patients with OFC damage: Patients with OFC lesions and patients with behavioral variant frontotemporal dementia. These two groups were compared to healthy controls and to patients with lesions restricted to the dorsolateral prefrontal cortex. Only patients with OFC damage showed abnormal interpersonal distance preferences, which were significantly different from both controls and patients with dorsolateral prefrontal damage. The comfortable distances these patients chose with strangers were significantly closer than the other groups and resembled distances normally used with close others. These results shed light on the role of the OFC in regulating social behavior and may serve as a simple diagnostic tool for dementia or lesion patients.

Adolescence is a developmental period characterized by a greater tendency to take risks. While the adult literature has shown that sex steroids influence reward-related brain functioning and risk taking, research on the role of these hormones during puberty is limited. In this study, we examined the relation between pubertal hormones and adolescent risk taking using a probabilistic decision-making task. In this task, participants could choose on each trial to play or pass based on explicit information about the risk level and stakes involved in their decision. We administered this task to 58 11-to-13-year-old girls while functional MRI images were obtained to examine reward-related brain processes associated with their risky choices. Results showed that higher testosterone levels were associated with increased risk taking, which was mediated by increased medial orbitofrontal cortex activation. Furthermore, higher estradiol levels were associated with increased nucleus accumbens activation, which in turn related to decreased risk taking. These findings offer potential neuroendocrine mechanisms that can explain why some adolescent girls might engage in more risk taking compared to others.

Social stress can contribute to the development of substance use disorders (SUDs) and increase the likelihood of relapse. Oxytocin (OT) is a potential pharmacotherapy that may buffer the effects of social stress on arousal and reward neurocircuitry. However, more research is needed to understand how OT moderates the brain’s response to social stress in SUDs. The present study examined the effect of intransasal OT (24 IU) versus placebo (PBO) on corticolimbic functional connectivity associated with acute social stress in individuals with cocaine use disorder (CUD; n = 67) and healthy controls (HC; n = 52). Psychophysiological interaction modeling used the left and right amygdala as seed regions with the left and right orbitofrontal and anterior cingulate cortex as a priori regions of interest. Moderators of the OT response included childhood trauma history and biological sex, which were examined in independent analyses. The main finding was that OT normalized corticolimbic connectivity (left amygdala-orbitofrontal and left amygdala-anterior cingulate) as a function of childhood trauma such that connectivity was different between trauma-present and trauma-absent groups on PBO, but not between trauma groups on OT. Effects of OT on corticolimbic connectivity were not different as a function of diagnosis (CUD vs HC) or sex. However, OT reduced subjective anxiety during social stress for CUD participants who reported childhood trauma compared to PBO and normalized craving response as a function of sex in CUD. The present findings add to some prior findings of normalizing effects of OT on corticolimbic circuitry in individuals with trauma histories and provide some initial support that OT can normalize subjective anxiety and craving in CUD.

The objective of the study was to determine if sex plays a moderating role in the relationship between executive functions and academic procrastination in 106 university students of both genders (28.3% male and 71.7% female) between the ages of 18 and 30 years (M = 19.7; SD = 2.7). The Academic Procrastination Scale and the Neuropsychological Battery of Executive Functions and Frontal Lobes (BANFE-2) were used to measure the variables. The results of the study showed that the degree of prediction of the tasks linked to the orbitomedial cortex (involves the orbitofrontal cortex [OFC] and the medial prefrontal cortex [mPFC]) on academic procrastination is significantly moderated by the sex of the university students (β3 = 0.53; p < 0.01). For men, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is −0.81. For women, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is −0.28. In addition, it was shown that sex does not play a moderating role in the relationship between the tasks linked to the dorsolateral prefrontal cortex (dlPFC) and academic procrastination (β3 = 0.12; p > 0.05). It was also determined that sex does not play a moderating role in the relationship between the tasks linked to the anterior prefrontal cortex (aPFC) and academic procrastination (β3 = 0.05; p > 0.05). It is concluded that only the executive functions associated with the orbitomedial cortex are moderated by the sex of the university students, where the impact of the tasks linked to the orbitomedial cortex on academic procrastination in men is significantly greater than in women.

Humans and animals make predictions about the rewards they expect to receive in different situations. In formal models of behavior, these predictions are known as value representations, and they play two very different roles. Firstly, they drive choice: the expected values of available options are compared to one another, and the best option is selected. Secondly, they support learning: expected values are compared to rewards actually received, and future expectations are updated accordingly. Whether these different functions are mediated by different neural representations remains an open question. Here, we employ a recently developed multi-step task for rats that computationally separates learning from choosing. We investigate the role of value representations in the rodent orbitofrontal cortex, a key structure for value-based cognition. Electrophysiological recordings and optogenetic perturbations indicate that these representations do not directly drive choice. Instead, they signal expected reward information to a learning process elsewhere in the brain that updates choice mechanisms.

Abstract Background Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

The impulsive choice is characterized by the preference for a small immediate reward over a bigger delayed one. The mechanisms underlying impulsive choices are linked to the activity in the Nucleus Accumbens (NAc), the orbitofrontal cortex (OFC), and the dorsolateral striatum (DLS). While the study of functional connectivity between brain areas has been key to understanding a variety of cognitive processes, it remains unclear whether functional connectivity differentiates impulsive-control decisions. To study the functional connectivity both between and within NAc, OFC, and DLS during a delay discounting task, we concurrently recorded local field potential in NAc, OFC, and DLS in rats. We then quantified the degree of phase-amplitude coupling (PAC), coherence, and Granger Causality between oscillatory activities in animals exhibiting either a high (HI) or low (LI) tendency for impulsive choices. Our results showed a differential pattern of PAC during decision-making in OFC and NAc, but not in DLS. While theta-gamma PAC in OFC was associated with self-control decisions, a higher delta-gamma PAC in both OFC and NAc biased decisions toward impulsive choices in both HI and LI groups. Furthermore, during the reward event, Granger Causality analysis indicated a stronger NAc➔OFC gamma contribution in the HI group, while the LI group showed a higher OFC➔NAc gamma contribution. The overactivity in NAc during reward in the HI group suggests that exacerbated contribution of NAcCore can lead to an overvaluation of reward that biases the behavior toward the impulsive choice. • A higher theta-gamma PAC in lOFC biased choice behavior toward LL rewards. • A higher delta-gamma PAC in lOFC and NAcCore biased behavior toward SS rewards. • A bidirectional driven gamma synchrony was observed between lOFC and NAcCore. • HI group showed a higher alpha-gamma PAC during the Reward events. • HI rats showed a higher gamma driven from NAcCore➔OFC. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2 -deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2 -deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2 -deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility. • Link between Shank2 mutations and cognitive flexibility in ASD is unclear. • Cognitive flexibility was measured by Attentional Set Shifting Task (ASST). • ASST performance was not affected in Shank2 -deficient mice. • Positive NMDA receptor modulation by D-cycloserine improved ASST performance. • NMDAR subunit expression was not affected by genotype but by treatment (GluN2A). [ABSTRACT FROM AUTHOR]

Neurons from multiple prefrontal areas encode several key variables of social gaze interaction. To explore the causal roles of the primate prefrontal cortex in real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events. Microstimulations of the orbitofrontal cortex, but not the dorsomedial prefrontal cortex or the anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing the distance of fixations relative to a partner's eyes and in the temporal dimension by reducing the inter-looking interval and the latency to reciprocate the other's directed gaze. By contrast, on a longer timescale, microstimulations of the dorsomedial prefrontal cortex modulated inter-individual gaze dynamics relative to one's own gaze positions. These findings demonstrate that multiple regions in the primate prefrontal cortex may serve as functionally accessible nodes in controlling different aspects of dynamic social attention and suggest their potential for a therapeutic brain interface. [Display omitted] • Closed-loop microstimulation was applied contingently upon looking at the other's eyes • OFC microstimulations enhanced momentary spatial and temporal social attention • dmPFC microstimulations affected longer-term inter-individual gaze dynamics • Primate prefrontal cortex has causal nodes for controlling dynamic social attention Fan and Dal Monte et al. apply closed-loop microstimulations in prefrontal areas when monkeys interact with gaze. Stimulations of the orbitofrontal cortex enhance momentary spatial and temporal social attention, whereas stimulations of the dorsomedial prefrontal cortex modulate inter-individual gaze dynamics. These regions causally control social attention, with potential for therapeutic brain interface. [ABSTRACT FROM AUTHOR]

• The first investigation of brain structure and the associated functional circuitry in individuals with bulimia symptoms. • Abnormalities in the right dorsolateral prefrontal cortex and right orbitofrontal cortex were found in sub-threshold bulimia nervosa. • Attentional and self-referential related functional circuitry are associated with psychopathological symptoms of bulimia. • Our results could provide important insights into the pathology of BN. Disordered eating behaviors are prevalent among youngsters and highly associated with dysfunction in neurocognitive systems. We aimed to identify the potential changes in individuals with bulimia symptoms (sub-BN) to generate insights to understand developmental pathophysiology of bulimia nervosa. We investigated group differences in terms of degree centrality (DC) and gray matter volume (GMV) among 145 undergraduates with bulimia symptoms and 140 matched control undergraduates, with the secondary analysis of the whole brain connectivity in these regions of interest showing differences in static functional connectivity (FC). The sub-BN group exhibited abnormalities of the right dorsolateral prefrontal cortex and right orbitofrontal cortex in both GMV and DC, and displayed decreased FC between these regions and the precuneus. We also observed that sub-BN presented with reduced FC between the calcarine and superior temporal gyrus, middle temporal gyrus and inferior parietal gyrus. Additionally, brain-behavioral associations suggest a distinct relationship between these FCs and psychopathological symptoms in sub-BN group. Our study demonstrated that individuals with bulimia symptoms present with aberrant neural patterns that mainly involved in cognitive control and reward processing, as well as attentional and self-referential processing, which could provide important insights into the pathology of BN. [ABSTRACT FROM AUTHOR]

Negative symptoms and neurocognitive impairments in psychosis correlate with their severity. Currently, there is no satisfactory treatment. We aimed to evaluate and compare the effects of repetitive transcranial magnetic stimulation(rTMS) on negative symptoms and neurocognitive impairments in patients in first-episode of psychosis(FEP) in a randomized controlled trial(RCT). This is a single-site RCT of 85 patients with FEP. Patients were randomized to receive a 4-week course of active(n = 45) or sham rTMS(n = 40). Factor analysis was applied to a cross-sectional dataset of 744 FEP patients who completed negative symptom evaluation and neurocognitive battery tests. Two independent dimensions were generated and used for the K-means cluster analysis to produce sub-clusters. rTMS of 1-Hz was delivered to the right orbitofrontal(OFC) cortex. Two distinct dimensional factors of neurocognitive functions(factor-1) and negative symptoms(factor-2), and three clusters with distinctive features were generated. Significant improvements in factor-1 and factor-2 were observed after 4-weeks of rTMS treatment in both the active and sham rTMS groups. The repeated-measures analysis of variance revealed a significant effect of time×group(F = 5.594, p = 0.021, η 2 = 0.073) on factor-2, but no effect of t ime×group on factor-1. Only improvements in negative symptoms were significantly different between the active and sham rTMS groups(p = 0.028). Patients in cluster-3 characterized by extensive negative symptoms, showed greater improvement in the active rTMS group than in the sham rTMS group. The 1-Hz right OFC cortex rTMS is more effective in reducing negative symptoms than neurocognitive impairments. It is especially effective in patients with dominantly negative symptoms in FEP. • Dimensional factors are identified in first-episode psychosis(FEP) patients - neurocognitive functions and negative symptoms. • The 1-Hz right right orbitofrontal(OFC) cortex rTMS is more effective in reducing negative symptoms than neurocognitive impairments. • Add-on rTMS is particularly beneficial for individuals with predominantly negative symptoms in FEP. [ABSTRACT FROM AUTHOR]

Individual preferences for the flavor of different foods and fluids exert a strong influence on behavior. Most current theories posit that preferences are integrated with other state variables in the orbitofrontal cortex (OFC), which is thought to derive the relative subjective value of available options to guide choice behavior. Here, we report that instead of a single integrated valuation system in the OFC, another complementary one is centered in the ventrolateral prefrontal cortex (vlPFC) in macaques. Specifically, we found that the OFC and vlPFC preferentially represent outcome flavor and outcome probability, respectively, and that preferences are separately integrated into value representations in these areas. In addition, the vlPFC, but not the OFC, represented the probability of receiving the available outcome flavors separately, with the difference between these representations reflecting the degree of preference for each flavor. Thus, both the vlPFC and OFC exhibit dissociable but complementary representations of subjective value, both of which are necessary for decision-making. • Neurons in the vlPFC and OFC signal dissociable aspects of subjective value • vlPFC neurons preferentially represent the probability of receiving an outcome • OFC neurons preferentially represent outcome qualities (e.g., flavor) • Changes in preference differentially influence vlPFC and OFC representations Stoll and Rudebeck recorded the activity of more than 7,700 neurons across the ventral frontal cortex and amygdala in monkeys, revealing neuronal markers of multiple valuation systems, each integrating the animals' preferences in specific ways. [ABSTRACT FROM AUTHOR]

Beliefs—attitudes toward some state of the environment—guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia. [Display omitted] • Lesions to the mediodorsal thalamus (MD) in monkeys heighten belief volatility • Orbitofrontal cortex (OFC) lesions impair value learning • This is a double dissociation of belief learning between brain regions • Shared computational modeling across species implicates MD in paranoia Suthaharan et al. demonstrate a causal role of the primate mediodorsal thalamus (MD) in beliefs about environmental volatility. Applying a behavioral paradigm and a computational model, they establish that belief volatility increases in paranoid people and monkeys with lesions to the MD. This suggests a role for the MD in paranoia. [ABSTRACT FROM AUTHOR]

Cognitive flexibility refers to the ability to adapt flexibly to changing circumstances. In laboratory mice, we investigated whether cognitive flexibility is higher in pubertal mice than in adult mice, and whether this difference is related to the expression of distinct NMDA receptor subunits. Using the attentional set shifting task as a measure of cognitive flexibility, we found that cognitive flexibility was increased during puberty. This difference was more pronounced in female pubertal mice. Further, the GluN2A subunit of the NMDA receptor was more expressed during puberty than after puberty. Pharmacological blockade of GluN2A reduced the cognitive flexibility of pubertal mice to adult levels. In adult mice, the expression of GluN2A, GluN2B, and GluN2C in the orbitofrontal cortex correlated positively with performance in the attentional set shifting task, whereas in pubertal mice this was only the case for GluN2C. In conclusion, the present study confirms the observation in humans that cognitive flexibility is higher during puberty than in adulthood. Future studies should investigate whether NMDA receptor subunit-specific agonists are able to rescue deficient cognitive flexibility, and whether they have the potential to be used in human diseases with deficits in cognitive flexibility.