Anterior Cingulate Cortex/medial Prefrontal Cortex Research Articles

The neural and genetic underpinnings of different developmental trajectories of Attention-Deficit/Hyperactivity Symptoms in children and adolescents

BackgroundThe trajectory of attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents, encompassing descending, stable, and ascending patterns, delineates their ADHD status as remission, persistence or late onset. However, the neural and genetic underpinnings governing the trajectory of ADHD remain inadequately elucidated.MethodsIn this study, we employed neuroimaging techniques, behavioral assessments, and genetic analyses on a cohort of 487 children aged 6–15 from the Children School Functions and Brain Development project at baseline and two follow-up tests for 1 year each (interval 1: 1.14 ± 0.32 years; interval 2: 1.14 ± 0.30 years). We applied a Latent class mixed model (LCMM) to identify the developmental trajectory of ADHD symptoms in children and adolescents, while investigating the neural correlates through gray matter volume (GMV) analysis and exploring the genetic underpinnings using polygenic risk scores (PRS).ResultsThis study identified three distinct trajectories (ascending-high, stable-low, and descending-medium) of ADHD symptoms from childhood through adolescence. Utilizing the linear mixed-effects (LME) model, we discovered that attention hub regions served as the neural basis for these three developmental trajectories. These regions encompassed the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), responsible for inhibitory control; the right inferior parietal lobule (IPL), which facilitated conscious focus on exogenous stimuli; and the bilateral middle frontal gyrus/precentral gyrus (MFG/PCG), accountable for regulating both dorsal and ventral attention networks while playing a crucial role in flexible modulation of endogenous and extrinsic attention. Furthermore, our findings revealed that individuals in the ascending-high group exhibited the highest PRS for ADHD, followed by those in the descending-medium group, with individuals in the stable-low group displaying the lowest PRS. Notably, both ascending-high and descending-medium groups had significantly higher PRS compared to the stable-low group.ConclusionsThe developmental trajectory of ADHD symptoms in the general population throughout childhood and adolescence can be reliably classified into ascending-high, stable-low, and descending-medium groups. The bilateral MFG/PCG, left ACC/mPFC, and right IPL may serve as crucial brain regions involved in attention processing, potentially determining these trajectories. Furthermore, the ascending-high pattern of ADHD symptoms exhibited the highest PRS for ADHD.

Systematic review and meta-analysis: multimodal functional and anatomical neural alterations in autism spectrum disorder

BackgroundThis meta-analysis aimed to explore the most robust findings across numerous existing resting-state functional imaging and voxel-based morphometry (VBM) studies on the functional and structural brain alterations in individuals with autism spectrum disorder (ASD).MethodsA whole-brain voxel-wise meta-analysis was conducted to compare the differences in the intrinsic functional activity and gray matter volume (GMV) between individuals with ASD and typically developing individuals (TDs) using Seed-based d Mapping software.ResultsA total of 23 functional imaging studies (786 ASD, 710 TDs) and 52 VBM studies (1728 ASD, 1747 TDs) were included. Compared with TDs, individuals with ASD displayed resting-state functional decreases in the left insula (extending to left superior temporal gyrus [STG]), bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), left angular gyrus and right inferior temporal gyrus, as well as increases in the right supplementary motor area and precuneus. For VBM meta-analysis, individuals with ASD displayed decreased GMV in the ACC/mPFC and left cerebellum, and increased GMV in the left middle temporal gyrus (extending to the left insula and STG), bilateral olfactory cortex, and right precentral gyrus. Further, individuals with ASD displayed decreased resting-state functional activity and increased GMV in the left insula after overlapping the functional and structural differences.ConclusionsThe present multimodal meta-analysis demonstrated that ASD exhibited similar alterations in both function and structure of the insula and ACC/mPFC, and functional or structural alterations in the default mode network (DMN), primary motor and sensory regions. These findings contribute to further understanding of the pathophysiology of ASD.

Functional and structural brain abnormalities in substance use disorder: A multimodal meta-analysis of neuroimaging studies.

Numerous neuroimaging studies of resting-state functional imaging and voxel-based morphometry (VBM) have revealed that patients with substance use disorder (SUD) may present brain abnormalities, but their results were inconsistent. This multimodal neuroimaging meta-analysis aimed to estimate common and specific alterations in SUD patients by combining information from all available studies of spontaneous functional activity and gray matter volume (GMV). A whole-brain meta-analysis on resting-state functional imaging and VBM studies was conducted using the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software, followed by multimodal overlapping to comprehensively investigate function and structure of the brain in SUD. In this meta-analysis, 39 independent studies with 47 datasets related to resting-state functional brain activity (1444 SUD patients; 1446 healthy controls [HCs]) were included, as well as 77 studies with 89 datasets for GMV (3457 SUD patients; 3774 HCs). Patients with SUD showed the decreased resting-state functional brain activity in the bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC). For the VBM meta-analysis, patients with SUD showed the reduced GMV in the bilateral ACC/mPFC, insula, thalamus extending to striatum, and left sensorimotor cortex. This multimodal meta-analysis exhibited that SUD shows common impairment in both function and structure in the ACC/mPFC, suggesting that the deficits in functional and structural domains could be correlated together. In addition, a few regions exhibited only structural impairment in SUD, including the insula, thalamus, striatum, and sensorimotor areas.

Voxel-Wise Brain-Wide Functional Connectivity Abnormalities in Patients with Primary Blepharospasm at Rest.

Background Primary blepharospasm (BSP) is one of the most common focal dystonia and its pathophysiological mechanism remains unclear. An unbiased method was used in patients with BSP at rest to observe voxel-wise brain-wide functional connectivity (FC) changes. Method A total of 48 subjects, including 24 untreated patients with BSP and 24 healthy controls, were recruited to undergo functional magnetic resonance imaging (fMRI). The method of global-brain FC (GFC) was adopted to analyze the resting-state fMRI data. We designed the support vector machine (SVM) method to determine whether GFC abnormalities could be utilized to distinguish the patients from the controls. Results Relative to healthy controls, patients with BSP showed significantly decreased GFC in the bilateral superior medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC) and increased GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule, right superior frontal gyrus (SFG), and left paracentral lobule/supplement motor area (SMA), which were included in the default mode network (DMN) and sensorimotor network. SVM analysis showed that increased GFC values in the right postcentral gyrus/precentral gyrus/paracentral lobule could discriminate patients from controls with optimal accuracy, specificity, and sensitivity of 83.33%, 83.33%, and 83.33%, respectively. Conclusion This study suggested that abnormal GFC in the brain areas associated with sensorimotor network and DMN might underlie the pathophysiology of BSP, which provided a new perspective to understand BSP. GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule might be utilized as a latent biomarker to differentiate patients with BSP from controls.

RELATIONSHIP BETWEEN CHOLINERGIC RECEPTOR BINDING AND ATTENTION IN COGNITIVE AGING USING POSITRON EMISSION TOMOGRAPHY AND THE STROOP

Introduction Cholinergic (Ach) neurotransmission has been associated with aspects of brain attention networks. Reductions in Ach are also thought to underlie cognitive symptoms in Alzheimer's Disease (AD). In a previous study using positron emission tomography (PET) imaging to measure nicotinic Ach receptor binding in vivo, our group found that Ach receptor binding was reduced in patients with AD relative to healthy controls. Reductions were observed in areas of the brain thought to mediate attention, including the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and insula. The Stroop is a neuropsychological measure used in research and clinical settings to assess attention and executive function. In a different study of AD patients, we found that performance on the Stroop was associated with metabolic activity in brain networks in the right hemisphere; the Stroop COLOR-WORD condition was associated with metabolic rate in the intraparietal sulcus (IPS), ACC/mPFC, and insula. In the present study, we sought to extend these findings by examining whether Ach binding was associated with performance on the Stroop prior to the onset of dementia. Methods The study included a combined group of healthy older adults or older adults with amnestic mild cognitive impairment (MCI). All participants completed the Stroop. The Stroop included three conditions: two simpler tasks requiring participants to name colors (COLOR) and read words (WORD) and a more complex task in which participants are required to name the color of ink used for a word that names a different color from the ink color (COLOR-WORD). Cholinergic (Ach) receptor binding was quantified using PET imaging, specifically 18F-2-FA PET (2FA), a radiotracer that binds to alpha4beta2 nicotinic receptor subunits. Scanning utilized a bolus plus infusion technique and measurement of nonmetabolized 2FA from plasma to calculate distribution volume (VT/fp) in PET Ach image voxels. Ach images were pre-processed using SPM12, which included motion correction, normalization to Montreal Neurological Institute (MNI) space using a co-registered T1 MRI image, and spatial smoothing of 8?mm full width at half maximum. First, a voxel-based analysis across the entire brain was used to measure the association between voxel VT/fp and performance on the Stroop COLOR-WORD test using a liberal statistical threshold (p Results Seventy-six participants were included in the sample, comprised of 43 healthy older adults and 33 patients with amnestic MCI (age: mean=73.1 (SD=7.7), MMSE: mean=28.3 (SD=2.1), 57 males and 19 females, education: mean=15.7?years (SD=2.5)). The combined group included 19 African-Americans, 48 Caucasians, 6 Hispanics, and 3?Asian/?Pacific Islanders. Performance on the COLOR task was associated with mean VT/fp in the ACC/mPFC (r=.23 p=.04), insula (r=.28, p=.02), and IPS (r=.23 p Conclusions Across the spectrum of cognitive aging, performance on the Stroop was associated with Ach binding in key brain regions involved in attention—the IPS, ACC/mPFC, and insula. These findings suggest that Ach binding, in part, mediates attentional processing. This appears true regardless of whether the task is simple, as in the COLOR and WORD conditions, or more complex, as in the COLOR-WORD condition. Thus, changes in Ach receptor binding may be an important factor in attentional deficits resulting from cognitive aging prior to onset of AD, and Ach neurotransmission could be a potential molecular target for novel pharmaceuticals to address these symptoms. This research was funded by: This work was supported by a VA Career Development grant awarded to Brandon C. Yarns, MD, MS, and VA Merit Review grants awarded to David L. Sultzer, MD, and Rebecca J. Melrose, PhD.

Increased Nucleus Accumbens Connectivity in Resting-State Patients With Drug-Naive, First-Episode Somatization Disorder.

The nucleus accumbens (NAc) plays an important role in the reward circuit, and abnormal regional activities of the reward circuit have been reported in various psychiatric disorders including somatization disorder (SD). However, few researches are designed to analyze the NAc connectivity in SD. This study was designed to explore the NAc connectivity in first-episode, drug-naive patients with SD using the bilateral NAc as seeds. Twenty-five first-episode, drug-naive patients with SD and 28 healthy controls were recruited. Functional connectivity (FC) was designed to analyze the images. LIBSVM (a library for support vector machines) was used to identify whether abnormal FC could be utilized to discriminate the patients from the controls. The patients showed significantly increased FC between the left NAc and the right gyrus rectus and left medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC), and between the right NAc and the left gyrus rectus and left MPFC/ACC compared with the controls. The patients could be separated from the controls through increased FC between the left NAc and the right gyrus rectus with a sensitivity of 88.00% and a specificity of 82.14%. The findings reveal that patients with SD have increased NAc connectivity with the frontal regions of the reward circuit. Increased left NAc-right gyrus rectus connectivity can be used as a potential marker to discriminate patients with SD from healthy controls. The study thus highlights the importance of the reward circuit in the neuropathology of SD.

High-field MRS study of GABA+ in patients with migraine: response to levetiracetam treatment.

To explore alterations in γ-aminobutyric acid (GABA) levels in response to levetiracetam (LEV) treatment in patients with migraine. Patients with migraine (N=14) were treated with LEV for 12 weeks. The levels of GABA+ in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the posterior cingulate cortex (PCC) were examined by proton magnetic resonance spectroscopy before (baseline) and after treatment. LEV showed good efficacy in the reduction of headache frequency and intensity in patients with migraine. Among the 14 patients, good-quality spectral data of GABA+ in the PCC region were obtained in 11 patients. There was a significant decrease in GABA+ levels in the PCC region after LEV treatment. ACC/mPFC GABA+ was assessed by proton magnetic resonance spectroscopy in eight patients with migraine. LEV had no significant effect on GABA+ levels in the ACC/mPFC region. The decreased GABA+ levels after LEV treatment in patients with migraine suggest that GABA is a migraine biomarker.

Increased coherence-based regional homogeneity in resting-state patients with first-episode, drug-naive somatization disorder

BackgroundAbnormal neural activity has been observed in patients with somatization disorder (SD), especially in brain regions of the default-mode network (DMN). In this study, a coherence-based regional homogeneity (Cohe-ReHo) approach was used to detect abnormal regional synchronization in patients with SD, which might be used to differentiate the patients from the controls. MethodsWe recruited 25 patients with SD and 28 healthy controls. The imaging data of the participants were analyzed using the Cohe-ReHo approach. LIBSVM (a library for support vector machines) was utilized to verify whether abnormal Cohe-ReHo values could be applied to separate patients with SD from healthy controls. ResultsCompared with healthy controls, patients with SD showed an increased Cohe-ReHo in the left medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC) (t = 5.5017, p < 0.001). No correlations were detected between the increased Cohe-ReHo values and clinical variables of the patients. The Cohe-ReHo values in the left MPFC/ACC could be applied to distinguish patients from controls with a sensitivity and a specificity of 84.00% and 85.71%, respectively. ConclusionsAn increased Cohe-ReHo was observed in the anterior DMN of the patients and could be applied as a marker to distinguish patients from healthy controls. These results highlighted the importance of the DMN in the pathophysiology of SD.

Connectivity of the precuneus-posterior cingulate cortex with the anterior cingulate cortex-medial prefrontal cortex differs consistently between control subjects and first-episode psychosis patients during a movie stimulus

BackgroundFunctional connectivity is altered in psychotic disorders. Multiple findings concentrate on the default mode network, anchored on the precuneus-posterior cingulate cortex (PC-PCC). However, the nature of the alterations varies between studies and connectivity alterations have not been studied during an ecologically valid natural stimulus. In the present study, we investigated the functional and structural connectivity of a PC-PCC region, where functioning differentiated first-episode psychosis patients from control subjects during free viewing of a movie in our earlier study. Methods14 first-episode psychosis patients and 12 control subjects were imaged with GE 3T, and 29 patients and 19 control subjects were imaged with a Siemens Skyra 3T scanner while watching scenes from the movie Alice in Wonderland. Group differences in functional connectivity were analysed for both scanners separately and results were compared to identify any overlap. Diffusion tensor measures of 26 patients and 19 control subjects were compared for the related white matter tracts, identified by deterministic tractography. ResultsFunctional connectivity was increased in patients across scanners between the midline regions of the PC-PCC and the anterior cingulate cortex-medial prefrontal cortex (ACC-mPFC). We found no group differences in any of the diffusion tensor imaging measures. ConclusionsAlready in the early stages of psychosis functional connectivity between the midline structures of the PC-PCC and the ACC-mPFC is consistently increased during naturalistic stimulus.

The effects of head-cooling on brain function during passive hyperthermia: an fMRI study

Purpose: To investigate the effect of head-cooling on resting-state spontaneous brain activity during passive hyperthermia.Methods: An environmental heat exposure was simulated on 16 healthy men under a normal control condition (NC) at 25 °C and two hot conditions at 50 °C with hyperthermia with head-cooling condition (HHC) and without hyperthermia condition (HOT) keeping the head cool, respectively. Resting-state functional MRI (fMRI) data were acquired under each condition and the values of amplitude low frequency fluctuations (ALFF) and z functional connectivity (zFC) were computed to examine regional activity and functional integration, respectively. Pearson’s correlation analysis between the ALFF value and subjective sensations scores were performed.Results: Brain regions with significant ALFF differences among the three conditions were found primarily in the right medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC), bilateral posterior cingulate cortex/precuneus (PCC/PCu), and right fusiform gyrus. Compared to the NC or HOT condition, the HHC condition exhibited significantly increased ALFF in the bilateral PCC/PCu and decreased ALFF in the right fusiform gyrus. However, ALFF of the right MPFC/ACC showed no significant difference between the NC and HHC conditions. Positive FC between the right MPFC/ACC and bilateral PCC/PCu was significantly increased in HHC condition with respect to HOT condition. Negative FC between the right fusiform gyrus and the right MPFC/ACC, bilateral PCC/PCu was observed with a decreasing trend from the HHC condition to the HOT condition. Moreover, head-cooling also improved thermal comfort during passive hyperthermia.Conclusions: Head-cooling could substantially reduce the negative effect of hyperthermia on human brain activity as well as thermal sensation.

GABA+ levels in postmenopausal women with mild-to-moderate depression: A preliminary study.

Background:It is increasingly being recognized that alterations of the GABAergic system are implicated in the pathophysiology of depression. This study aimed to explore in vivo gamma-aminobutyric acid (GABA) levels in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and posterior-cingulate cortex (PCC) of postmenopausal women with depression using magnetic resonance spectroscopy (1H-MRS).Methods:Nineteen postmenopausal women with depression and thirteen healthy controls were enrolled in the study. All subjects underwent 1H-MRS of the ACC/mPFC and PCC using the “MEGA Point Resolved Spectroscopy Sequence” (MEGA-PRESS) technique. The severity of depression was assessed by 17-item Hamilton Depression Scale (HAMD). Quantification of MRS data was performed using Gannet program. Differences of GABA+ levels from patients and controls were tested using one-way analysis of variance. Spearman correlation coefficients were used to evaluate the linear associations between GABA+ levels and HAMD scores, as well as estrogen levels.Results:Significantly lower GABA+ levels were detected in the ACC/mPFC of postmenopausal women with depression compared to healthy controls (P = 0.002). No significant correlations were found between 17-HAMD/14-HAMA and GABA+ levels, either in ACC/mPFC (P = 0.486; r = 0.170/P = 0.814; r = −0.058) or PCC (P = 0.887; r = 0.035/ P = 0.987; r = −0.004) in the patients; there is also no significant correlation between GABA+ levels and estrogen levels in patients group (ACC/mPFC: P = 0.629, r = −0.018; PCC: P = 0.861, r = 0.043).Conclusion:Significantly lower GABA+ levels were found in the ACC/mPFC of postmenopausal women with depression, suggesting that the dysfunction of the GABAergic system may also be involved in the pathogenesis of depression in postmenopausal women.

Executive Functions in Frontal Lob Syndrome: A Case Report

Prefrontal cortex in frontal lobe (FL) is the center of executive functions (EF). FL damage can lead to executive dysfunction by influencing frontal-subcortical circuits (dorsolateral, orbitofrontal, ventromedial). Damage to the dorsolateral prefrontal cortex (DLPFC) can lead to deterioration in EF, whereas damage to the orbitofrontal cortex (OFC) can lead to personality changes with the characteristic of disinhibition and irritability. In addition, damage to the anterior cingulate cortex/medial prefrontal cortex (ACC/MPFC) can result in decreased spontaneity. Neuropsychological tests are important components in the assessment of EF including goal-directed behavior, decision-making, risk assessment, making plans for the future, setting of priorities and order of our actions. Clinical conditions affecting frontal-subcortical connections outside of the FL can also lead to executive dysfunctions and frontal lobe syndrome (FLS). This case report is about an adolescent patient diagnosed as FLS. The clinical symptoms, assessment and treatment processes of this case are discussed in this report. The case is a 15-year-old boy that was admitted to our clinic with behavioral problems, which began after a car accident three years ago. Magnetic resonance imaging (MRI) of the brain indicated hyperintense signal increase in periventricular deep white matter that is associated with traumatic brain damage. Neuropsychological tests results (Stroop, Wisconsin Card Sorting Test, Serial Digit Learning Test, Line Orientation Test, Verbal Memory Processes Scale) have demonstrated impairment in cognitive flexibility, verbal fluency, setting priority, inappropriate response inhibition, sustained attention, planning, problem solving, organization skills and subcortical memory functions. We thought that cognitive and behavioral symptoms of this case were associated with the dysfunctions of frontal-subcortical circuits, independent of an obvious frontal lesion. FLS for the patients with sudden-onset behavioral and cognitive problems after head traumas should be kept in mind in differential diagnosis, even in the absence of an obvious frontal lesion.

Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency.

Background and PurposeOrnithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks—default mode and set-maintenance—between OTCD patients and healthy controls.MethodsSixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity.ResultsGroup comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG.ConclusionInternodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain.

Alterations of GABA and glutamate–glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study

Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy (1H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate–glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T 1H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.

Synchronized electrical stimulation of the rat medial forebrain bundle and perforant pathway generates an additive BOLD response in the nucleus accumbens and prefrontal cortex

To study how a synchronized activation of two independent pathways affects the fMRI response in a common targeted brain region, blood oxygen dependent (BOLD) signals were measured during electrical stimulation of the right medial forebrain bundle (MFB), the right perforant pathway (PP) and concurrent stimulation of the two fiber systems. Repetitive electrical stimulations of the MFB triggered significant positive BOLD responses in the nucleus accumbens (NAcc), septum, anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), ventral tegmental area/substantia nigra (VTA/SN), right entorhinal cortex (EC) and colliculus superior, which, in general, declined during later stimulation trains. At the same time, negative BOLD responses were observed in the striatum. Thus, the same stimulus caused region-specific hemodynamic responses. An identical electrical stimulation of the PP generated positive BOLD responses in the right dentate gyrus/hippocampus proper/subiculum (DG/HC), the right entorhinal cortex and the left entorhinal cortex, which remained almost stable during consecutive stimulation trains. Co-stimulation of the two fiber systems resulted in an additive activation pattern, i.e., the BOLD responses were stronger during the stimulation of the two pathways than during the stimulation of only one pathway. However, during the simultaneous stimulation of the two pathways, the development of the BOLD responses to consecutive trains changed. The BOLD responses in regions that were predominantly activated by MFB stimulation (i.e., NAcc, septum and ACC/mPFC) did not decline as fast as during pure MFB stimulation, thus an additive BOLD response was only observed during later trains. In contrast, in the brain regions that were predominantly activated by PP stimulation (i.e., right EC, DG/HC), co-stimulation of the MFB only resulted in an additive effect during early trains but not later trains. Consequently, the development of the BOLD responses during consecutive stimulations indicates the presence of an interaction between the two pathways in a target region, whereas the observed averaged BOLD responses do not.

Positively Biased Processing of Self-Relevant Social Feedback

Receiving social feedback such as praise or blame for one's character traits is a key component of everyday human interactions. It has been proposed that humans are positively biased when integrating social feedback into their self-concept. However, a mechanistic description of how humans process self-relevant feedback is lacking. Here, participants received feedback from peers after a real-life interaction. Participants processed feedback in a positively biased way, i.e., they changed their self-evaluations more toward desirable than toward undesirable feedback. Using functional magnetic resonance imaging we investigated two feedback components. First, the reward-related component correlated with activity in ventral striatum and in anterior cingulate cortex/medial prefrontal cortex (ACC/MPFC). Second, the comparison-related component correlated with activity in the mentalizing network, including the MPFC, the temporoparietal junction, the superior temporal sulcus, the temporal pole, and the inferior frontal gyrus. This comparison-related activity within the mentalizing system has a parsimonious interpretation, i.e., activity correlated with the differences between participants' own evaluation and feedback. Importantly, activity within the MPFC that integrated reward-related and comparison-related components predicted the self-related positive updating bias across participants offering a mechanistic account of positively biased feedback processing. Thus, theories on both reward and mentalizing are important for a better understanding of how social information is integrated into the human self-concept.