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Several cortical structures are involved in theory of mind (ToM), including the dorsolateral prefrontal cortex (dlPFC), the ventromedial prefrontal cortex (vmPFC), and the right temporo- parietal junction (rTPJ). We investigated the role of these regions in mind reading with respect to the valence of mental states. Sixty-five healthy adult participants were recruited and received transcranial direct current stimulation (tDCS) (1.5 mA, 20 min) with one week interval in three separate studies. The stimulation conditions were anodal tDCS over the dlPFC coupled with cathodal tDCS over the vmPFC, reversed stimulation conditions, and sham in the first study, and anodal tDCS over the vmPFC, or dlPFC, and sham stimulation, with an extracranial return electrode in the second and third study. During stimulation, participants underwent the reading mind from eyes/voice tests (RMET or RMVT) in each stimulation condition. Anodal left dlPFC/cathodal right vmPFC stimulation increased the accuracy of negative mental state attributions, anodal rTPJ decreased the accuracy of negative and neutral mental state attributions, and decreased the reaction time of positive mental state attributions. Our results imply that the neural correlates of ToM are valence-sensitive.

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INTRODUCTION: Emotion recognition, the ability to interpret the emotional state of individuals by looking at their facial expressions, is essential for healthy social interactions and communication. There is limited research on the effects of tDCS on emotion recognition in the literature. This study aimed to investigate the effects of anodal stimulation of the ventromedial prefrontal cortex (vmPFC), a key region for emotion recognition from facial expressions, on emotion recognition and brain oscillations. METHOD: A single-blind randomized-controlled study was conducted with 54 healthy participants. Before and after brain stimulation emotion recognition tasks were administered and resting-state EEG were recorded. The changes in task performances and brain oscillations were analyzed using repeated-measures two-way ANOVA analysis. RESULTS: There was no significant difference in the emotion recognition tasks between groups in pre-post measurements. The changes in delta, theta, alpha, beta and gamma frequency bands in the frontal, temporal, and posterio-occipital regions, which were determined as regions of interest in resting state EEG data before and after tDCS, were compared between groups. The results showed that there was a significant difference between groups only in delta frequency before and after tDCS in the frontal and temporal regions. While an increase in delta activity was observed in the experimental group in the frontal and temporal regions, a decrease was observed in the control group. CONCLUSIONS: The tDCS may not have improved emotion recognition because it may not have had the desired effect on the vmPFC, which is in the lower part of the prefrontal lobe. The changes in EEG frequencies observed section tDCS may be similar to those seen in some pathological processes, which could explain the lack of improvement in emotion recognition. Future studies to be carried out for better understand this effect are important.

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Individuals with attention deficit-hyperactivity disorder (ADHD) struggle with the interaction of attention and emotion. The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are assumed to be involved in this interaction. In the present study, we aimed to explore the effect of stimulation applied over the dlPFC and vmPFC on attention bias in individuals with ADHD. Twenty-three children with ADHD performed the emotional Stroop and dot probe tasks during transcranial direct current stimulation (tDCS) in 3 conditions: anodal dlPFC (F3)/cathodal vmPFC (Fp2), anodal vmPFC (Fp2)/cathodal dlPFC (F3), and sham stimulation. Findings suggest reduction of attention bias in both real conditions based on emotional Stroop task and not dot probe task. These results were independent of emotional states. The dlPFC and vmPFC are involved in attention bias in ADHD. tDCS can be used for attention bias modification in children with ADHD.

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Children with attention deficit-hyperactivity disorder (ADHD) have impaired hot and cold executive functions, which is thought to be related to impaired ventromedial and dorsolateral prefrontal cortex (vmPFC and dlPFC) functions. The present study aimed to assess the impact concurrent stimulation of dlPFC and vmPFC through transcranial random noise stimulation (tRNS), a non-invasive brain stimulation tool which enhances cortical excitability via application of alternating sinusoidal currents with random frequencies and amplitudes over the respective target regions on hot and cold executive functions. Eighteen children with ADHD received real and sham tRNS over the left dlPFC and the right vmPFC in two sessions with one week interval. The participants performed Circle Tracing, Go/No-Go, Wisconsin Card Sorting, and Balloon Analogue Risk Tasks during stimulation in each session. The results showed improved ongoing inhibition, prepotent inhibition, working memory, and decision making, but not set-shifting performance, during real, as compared to sham stimulation. This indicates that simultaneous stimulation of the dlPFC and the vmPFC improves hot and cold executive functions in children with ADHD.

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BACKGROUND: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as a mechanism for PTSD development, but studies on potential sex differences in this neurobiological mechanism and how it relates to PTSD severity and progression are relatively rare. Here, we examined sex differences in neural activation during response inhibition and PTSD following recent trauma. METHODS: Participants (n = 205, 138 female sex assigned at birth) were recruited from emergency departments within 72 hours of a traumatic event. PTSD symptoms were assessed 2 weeks and 6 months posttrauma. A Go/NoGo task was performed 2 weeks posttrauma in a 3T magnetic resonance imaging scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex, right inferior frontal gyrus, and bilateral hippocampus. General linear models were used to examine the interaction effect of sex on the relationship between our regions of interest and the whole brain, PTSD symptoms at 6 months, and symptom progression between 2 weeks and 6 months. RESULTS: Lower response inhibition-related ventromedial prefrontal cortex activation 2 weeks posttrauma predicted more PTSD symptoms at 6 months in females but not in males, while greater response inhibition-related right inferior frontal gyrus activation predicted lower PTSD symptom progression in males but not females. Whole-brain interaction effects were observed in the medial temporal gyrus and left precentral gyrus. CONCLUSIONS: There are sex differences in the relationship between inhibition-related brain activation and PTSD symptom severity and progression. These findings suggest that sex differences should be assessed in future PTSD studies and reveal potential targets for sex-specific interventions.

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BACKGROUND: The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are key brain regions involved in risky decision making, affected in individuals with attention deficit hyperactivity disorder (ADHD). This study aims to examine how entrainment of these areas impacts the process and outcome of risky decision making in children with ADHD. METHODS: Eighteen children with ADHD performed the balloon analogue risk-taking task (BART) during five different sessions of tACS (1.5 mA, 6 Hz), separated by one-week intervals, via (1) two channels with synchronized stimulation over the left dlPFC and right vmPFC, (2) the same electrode placement with anti-phase stimulation, (3) stimulation over the left dlPFC only, (4) stimulation over right vmPFC only, and (5) sham stimulation. Four-parameter and constant-sensitivity models were used to model the data. RESULTS: The study showed that synchronized stimulation was associated with a reduction in positive prior belief, risk propensity, and deterministic selection. Desynchronized stimulation was associated with accelerated learning from initial selections. Isolated stimulation of the dlPFC leads to riskier decision enhanced learning updates and risk propensity, whereas isolated stimulation of the vmPFC facilitated faster learning and increased probabilistic selection. CONCLUSION: The results highlight the important roles of the dlPFC and vmPFC and their communication in decision making, showcasing their impact on various aspects of the decision-making process. The findings provide valuable insights into the complex interplay between cognitive and emotional factors in shaping our choices.

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BACKGROUND AND AIMS: Mind wandering refers to spontaneously occurring, often disruptive thoughts during an ongoing task or resting state. The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are two main cortical areas which are involved in this process. This study aimed to explore the interaction of these areas during mind wandering by enhancing specific oscillatory activity of these areas via transcranial alternating current stimulation (tACS) in the theta frequency range. MATERIAL AND METHODS: Eighteen healthy adults participated in a randomized, single-blinded, crossover study. tACS (1.5 mA, 6 Hz) was applied in five sessions with one week interval via (1) two channels with synchronized stimulation over the left dlPFC and right vmPFC, (2) the same electrode placement with anti-phase stimulation, (3) stimulation over the left dlPFC only, (4) stimulation over right vmPFC only, and (5) sham stimulation. The return electrodes were placed over the contralateral shoulder in all conditions. The sustained attention to response task (SART) with embedded probes about task-unrelated-thoughts and awareness of these thoughts was performed during intervention. RESULTS: Stimulation did not alter SART performance. Right vmPFC stimulation decreased mind wandering and increased awareness of mind wandering. Left dlPFC stimulation and desynchronized stimulation over the dlPFC and vmPFC increased mind wandering compared to the sham stimulation condition. Synchronized stimulation had no effect on mind wandering, but increased awareness of mind wandering. CONCLUSION: The results suggest that regional entrainment of the vmPFC decreases mind wandering and increases awareness of mind wandering, whereas regional entrainment of the dlPFC increases mind wandering, but decreases awareness. Under desynchronized stimulation of both areas, the propensity of mind wandering was increased, whereas synchronized stimulation increased the awareness of mind wandering. These results suggest a role of the dlPFC in initiation of mind wandering, whereas the vmPFC downregulates mind wandering, and might exert this function by counteracting respective dlPFC effects via theta oscillations.

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BACKGROUND: Preclinical findings suggest that transcranial infrared laser stimulation (TILS) improves fear extinction learning and cognitive function by enhancing prefrontal cortex (PFC) oxygen metabolism. These findings prompted our investigation of treating pathological fear using this non-invasive stimulation approach either alone to the dorsolateral PFC (dlPFC), or to the ventromedial PFC (vmPFC) in combination with exposure therapy. METHODS: Volunteers with pathological fear of either enclosed spaces, contamination, public speaking, or anxiety-related bodily sensations were recruited for this randomized, single-blind, sham-controlled trial with four arms: (a) Exposure + TILS_vmPFC (n = 29), (b) Exposure + sham TILS_vmPFC (n = 29), (c) TILS_dlPFC alone (n = 26), or (d) Sham TILS _dlPFC alone (n = 28). Post-treatment assessments occurred immediately following treatment. Follow-up assessments occurred 2 weeks after treatment. RESULTS: A total of 112 participants were randomized [age range: 18-63 years; 96 females (85.71%)]. Significant interactions of Group × Time and Group × Context indicated differential treatment effects on retention (i.e. between time-points, averaged across contexts) and on generalization (i.e. between contexts, averaged across time-points), respectively. Among the monotherapies, TILS_dlPFC outperformed SHAM_dlPFC in the initial context, b = -13.44, 95% CI (-25.73 to -1.15), p = 0.03. Among the combined treatments, differences between EX + TILS_vmPFC and EX + SHAM_vmPFC were non-significant across all contrasts. CONCLUSIONS: TILS to the dlPFC, one of the PFC regions implicated in emotion regulation, resulted in a context-specific benefit as a monotherapy for reducing fear. Contrary to prediction, TILS to the vmPFC, a region implicated in fear extinction memory consolidation, did not enhance exposure therapy outcome.

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OBJECTIVE: Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response. METHODS: Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated). RESULTS: ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group. CONCLUSIONS: The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

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The human orbitofrontal cortex, ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex are involved in reward processing and thereby in emotion but are also implicated in episodic memory. To understand these regions better, the effective connectivity between 360 cortical regions and 24 subcortical regions was measured in 172 humans from the Human Connectome Project and complemented with functional connectivity and diffusion tractography. The orbitofrontal cortex has effective connectivity from gustatory, olfactory, and temporal visual, auditory, and pole cortical areas. The orbitofrontal cortex has connectivity to the pregenual anterior and posterior cingulate cortex and hippocampal system and provides for rewards to be used in memory and navigation to goals. The orbitofrontal and pregenual anterior cortex have connectivity to the supracallosal anterior cingulate cortex, which projects to midcingulate and other premotor cortical areas and provides for action-outcome learning including limb withdrawal or flight or fight to aversive and nonreward stimuli. The lateral orbitofrontal cortex has outputs to language systems in the inferior frontal gyrus. The medial orbitofrontal cortex connects to the nucleus basalis of Meynert and the pregenual cingulate to the septum, and damage to these cortical regions may contribute to memory impairments by disrupting cholinergic influences on the neocortex and hippocampus.

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BACKGROUND: Individuals with major depressive disorder (MDD) have deficits in emotion regulation, which plays a putative role in psychopathology. The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are assumed to be involved in respective processes. In the present study, we aimed to explore the effect of stimulation over the dlPFC and vmPFC on emotion regulation in female with MDD. MATERIAL AND METHODS: Twenty women with MDD performed the Emotional Stroop, Emotional Go/No-Go, and Emotional 1-Back tasks during transcranial direct current stimulation (tDCS) in three separate sessions with the following electrode montages: anodal dlPFC (F3)/cathodal vmPFC (Fp2), anodal vmPFC (Fp2)/cathodal dlPFC (F3), and sham stimulation. RESULTS: Independent of the valence of the respective stimuli, accuracy and speed of interference control, accuracy of pre-potent inhibition, and accuracy, but not speed, of working memory performance improved during anodal left dlPFC/cathodal right vmPFC stimulation. Independent of stimulation conditions, interference control was reduced for sad faces, as compared to happy and neutral faces, and working memory performance was faster for happy than for neutral and sad faces. For the impact of stimulation on specific emotional qualities, anodal left dlPFC/cathodal right vmPFC, compared to sham stimulation, led to improved interference control of sad and neutral faces in the emotional Stroop task, as shown by faster reaction times. Furthermore, in that task accuracy with respect to neutral and happy face conditions was higher during both real stimulation conditions, as compared to sham stimulation. CONCLUSION: The dlPFC is involved in emotion regulation in MDD. Emotional valence is moreover relevant for the effect of stimulation over this area on interference control in MDD.

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Stimuli in reality rarely co-occur with primary reward or punishment to allow direct associative learning of value. Instead, value is thought to be inferred through complex higher-order associations. Rodent research has demonstrated that the formation and maintenance of first-order and higher-order associations are supported by distinct neural substrates. In this study, we explored whether this pattern of findings held true for humans. Participants underwent first-order and subsequent higher-order conditioning using an aversive burst of white noise or neutral tone as the unconditioned stimuli. Four distinct tones, initially neutral, served as first-order and higher-order conditioned stimuli. Autonomic and neural responses were indexed by pupillometry and evoked response potentials (ERPs) respectively. Conditioned aversive values of first-order and higher-order stimuli led to increased autonomic responses, as indexed by pupil dilation. Distinct temporo-spatial auditory evoked response potentials were elicited by first-order and high-order conditioned stimuli. Conditioned first-order responses peaked around 260 ms and source estimation suggested a primary medial prefrontal and amygdala source. Conversely, conditioned higher-order responses peaked around 120 ms with an estimated source in the medial temporal lobe. Interestingly, pupillometry responses to first-order conditioned stimuli were diminished after higher order training, possibly signifying concomitant incidental extinction, while responses to higher-order stimuli remained. This suggests that once formed, higher order associations are at least partially independent of first order conditioned representations. This experiment demonstrates that first-order and higher-order conditioned associations have distinct neural signatures, and like rodents, the medial temporal lobe may be specifically involved with higher-order conditioning.

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Traumatic stress is associated with risk of psychiatric and physical illnesses. However, the differential and separable effects of past versus recent traumas on maladaptive coping and neural responses are not known. We conducted two studies to assess separate and combined effects of cumulative recent and past trauma on health outcomes (study 1) and on neural responses to acute stress exposure in a subsample of individuals (study 2). Study 1 assessed a large cohort of 677 community adults cross-sectionally, and findings indicated that both high recent (within the last 12 months) and past trauma (prior to the last twelve months) were associated with more physical and psychological symptoms, including increased depression (all p's < .05). However, recent trauma alone was associated with higher problematic alcohol use, a greater maximum number of alcohol drinks consumed, greater emotional eating scores, higher state and trait anxiety scores, and poorer lifestyle habits (all p's < .05). Past trauma alone was associated with higher BMI, decreased social support, and a lower average cortisol relative to ACTH ratio (all p's < .02). Study 2 involving a functional brain scan on a subsample (N = 75) indicated greater recent trauma was associated with a hyperactive response in the ventromedial prefrontal cortex (VmPFC) to neutral-relaxed exposure, but blunted VmPFC response to acute stress exposure (p < .05: whole brain corrected-WBC). By contrast, high past trauma was associated with a hyper-sensitized neural response to stress in the cortico-limbic-striatal regions (p < .05, WBC) critical for reward and emotion processing. Together, these findings suggest differential neurobehavioral and health effects of cumulative past versus recent trauma exposure.

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Background: Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. Objective: To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). Methods: 36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Results: Relaxation was differentially linked to heart rate in both groups (t = 2.20, p = 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants (t = 1.99, p = 0.045) although this link differed weakly between groups (t = 1.62, p = 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS (t = -5.55, pfamily-wise-error(FWE)corrected = 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) (t = -4.89, pFWE = 0.039). Conclusion: PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS.

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BACKGROUND: Recent studies show that changes in one of the brain areas related to empathic abilities (i.e. the ventromedial prefrontal cortex (vmPFC)) plays an important role in violent behavior in abusers of alcohol and cocaine. According to the models of James Blair, empathy is a potential inhibitor of violent behavior. Individuals with less empathic abilities may be less susceptible and motivated to inhibit violent behavior, which causes a higher risk of violence. Recent neuroscientific research shows that modulating (stimulation or inhibition) certain brain areas could be a promising new intervention for substance abuse and to reduce violent behavior, such as the neurostimulation technique transcranial direct current stimulation (tDCS). This study aims to investigate tDCS as an intervention to increase empathic abilities and reduce violent behavior in forensic substance use offenders. METHODS/DESIGN: A total sample of 50 male forensic substance abuse patients (25 active and 25 sham stimulation) will be tested in a double-blind placebo-controlled study, from which half of the patients will receive an active stimulation plus treatment as usual (TAU) and the other half will receive sham stimulation (placebo) plus TAU. The patients in the active condition will receive multichannel tDCS targeting the bilateral vmPFC two times a day for 20 min for five consecutive days. Before and after the stimulation period, the patients will complete self-report measurements, perform the Point Subtraction Aggression Paradigm (PSAP) and a passive viewing empathy task. Resting state electroencephalography (rsEEG) will be performed before and after the treatment period. A follow up will be conducted after 6 months. The primary outcome is to investigate multichannel tDCS as a new intervention to increase empathic abilities and reduce violent behavior in offenders with substance abuse problems. In addition, we will determine whether electrophysiological responses in the brain are affected by the tDCS intervention. Finally, the effects of tDCS on reducing craving will be investigated. DISCUSSION: This study is one of the first studies using multichannel tDCS targeting the vmPFC in a forensic sample. This study will explore the opportunities to introduce a new intervention to improve empathic abilities and reduce violence in forensic substance use offenders. Specifically, this study may give insight into how to implement the tDCS intervention in the setting of daily clinical practice in this complex, multiple-problem target group and with that contribute to reduction of recidivism. TRIAL REGISTRATION: Dutch Trial Register, NTR7701. Registered on 12 January 2019. Prospectively registered before the recruitment phase. https://www.trialregister.nl/trial/7459. Recruitment started on the 1st of February 2019 and will be finished approximately in the winter of 2019. Protocol version 1. 22 May 2019.

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Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

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Despite growing interest in underlying cognitive mechanisms of self-esteem, its neurocognitive correlates are not fully-understood. Attention bias to self-related stimuli is an example of self-referential processing (SRP) and its association with self-esteem is not well-studied. Moreover, previous studies showed that the medial prefrontal regions are involved in SRP which might suggest its involvement in self-esteem too. We investigated attentional bias to self-related stimuli and its association with the level of self-esteem in the first study (N = 30). In the second study (N = 15), we modulated activity of the ventromedial prefrontal cortex (VMPFC), as one of the medial prefrontal regions, using transcranial direct current stimulation (tDCS) to see how it affects different domains of self-esteem. Results showed that individuals with a higher level of self-esteem have more attentional bias to their own facial pictures (compared to other-facial pictures) and self-related words (compared to self-unrelated words) suggesting an impact of self-esteem on attentional and perceptual processes. Additionally, modulating activity of the VMPFC with 2 mA anodal and cathodal tDCS was associated with significantly higher ratings of global and total self-esteem but not other self-esteem domains. Our findings provide supporting evidence of neurocognitive correlates of self-esteem indicating a biasing influence of self-esteem on attention toward "self" and suggesting self-esteem as a function of SRP at behavioural and neural levels.

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Using contextual information to predict aversive events is a critical ability that protects from generalizing fear responses to safe contexts. Animal models have demonstrated the importance of spatial context representations within the hippocampal formation in contextualization of fear learning. The ventromedial prefrontal cortex (vmPFC) is known to play an important role in safety learning, possibly also through the incorporation of context information. However, if contextual representations are related to context-dependent expression of fear memory in humans remains unclear. Twenty-one healthy participants underwent functional MRI combined with a cue-context conditioning paradigm within a self-navigated virtual reality environment. The environment included two buildings (Threat and Safe context), which had distinct features outside but were identical inside. Within each context, participants saw two cues (CS+, CS-). The CS+ was consistently (100% reinforcement rate) paired with an electric shock in the Threat context, but never in the Safe context. The CS- was never paired with a shock. We found robust differential skin conductance responses (SCRs; CS+ â€‹> â€‹CS-) in the Threat context, but also within the Safe context, indicating fear generalization. Within the Safe context, vmPFC responses to the CS+ were larger than those in the Threat context. We furthermore found environment-specific representations for the two contexts in the training paradigm (i.e., before conditioning took place) in the hippocampus to be related to fear expression and generalization. Namely, participants with a weak context representation (z-score < 1.65) showed stronger fear generalization compared to participants with a strong context representation (z-score > 1.65). Thus, a weak neural representation strength of spatial context may explain overgeneralization of memory to safe contexts. In addition, our findings demonstrate that context-dependent regulation of fear expression engages ventromedial prefrontal pathways suggesting this involves a similar mechanism that is known to be involved in retrieval of extinction memory.

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Previous studies demonstrate that drug addiction can share the neural circuits in the brain with normal learning and memory. Re-exposure to drug-associated contexts, one way to retrieve the drug-associated memory, can trigger strong psychic craving and even relapse in addicts after prolonged abstinence. The ventromedial prefrontal cortex (vmPFC) has been shown to be involved in time-dependent reinstatement of drug self-administration. This work is designed to investigate the role of AMPA receptor (AMPAR) in the vmPFC in the recent and remote retrieval of morphine-associated memory. Rats were re-exposed to the morphine-paired context 1 day (recent) and 3 weeks (remote) after morphine conditioned place preference (CPP) training. Results showed that membrane expression of GluA1 and GluA2 in the vmPFC was decreased following the recent retrieval, while the membrane expression of GluA1 and GluA2 in the vmPFC was increased following the remote retrieval of morphine-associated memory. Furthermore, the microinfusion of Tat-GluA2-3Y, a GluA2 endocytosis inhibitor, into the vmPFC impaired the recent retrieval of morphine-associated memory. The microinfusion of AMPAR antagonist NBQX into the vmPFC prevented the remote retrieval of morphine-associated memory. Taking together, the present study proved that AMPAR in the vmPFC played different roles in the recent and remote retrieval of morphine-associated memory.

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