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1.  Segregation of the human medial prefrontal cortex in social cognition 
While the human medial prefrontal cortex (mPFC) is widely believed to be a key node of neural networks relevant for socio-emotional processing, its functional subspecialization is still poorly understood. We thus revisited the often assumed differentiation of the mPFC in social cognition along its ventral-dorsal axis. Our neuroinformatic analysis was based on a neuroimaging meta-analysis of perspective-taking that yielded two separate clusters in the ventral and dorsal mPFC, respectively. We determined each seed region's brain-wide interaction pattern by two complementary measures of functional connectivity: co-activation across a wide range of neuroimaging studies archived in the BrainMap database and correlated signal fluctuations during unconstrained (“resting”) cognition. Furthermore, we characterized the functions associated with these two regions using the BrainMap database. Across methods, the ventral mPFC was more strongly connected with the nucleus accumbens, hippocampus, posterior cingulate cortex, and retrosplenial cortex, while the dorsal mPFC was more strongly connected with the inferior frontal gyrus, temporo-parietal junction, and middle temporal gyrus. Further, the ventral mPFC was selectively associated with reward related tasks, while the dorsal mPFC was selectively associated with perspective-taking and episodic memory retrieval. The ventral mPFC is therefore predominantly involved in bottom-up-driven, approach/avoidance-modulating, and evaluation-related processing, whereas the dorsal mPFC is predominantly involved in top–down-driven, probabilistic-scene-informed, and metacognition-related processing in social cognition.
doi:10.3389/fnhum.2013.00232
PMCID: PMC3665907  PMID: 23755001
social cognition; medial prefrontal cortex; meta-analytic connectivity modeling; resting state connectivity; functional decoding; data-mining
2.  A Meta-Analysis of Functional Neuroimaging Studies of Self and Other Judgments Reveals a Spatial Gradient for Mentalizing in Medial Prefrontal Cortex 
Journal of cognitive neuroscience  2012;24(8):1742-1752.
The distinction between processes used to perceive and understand the self and others has received considerable attention in psychology and neuroscience. Brain findings highlight a role for various regions, in particular the medial prefrontal cortex (mPFC), in supporting judgments about both the self and others. We performed a meta-analysis of 107 neuroimaging studies of self- and other-related judgments using Multilevel Kernel Density Analysis (MKDA; Kober & Wager, 2010). We sought to determine what brain regions are reliably involved in each judgment type, and in particular, what the spatial and functional organization of mPFC is with respect to them. Relative to non-mentalizing judgments, both self and other judgments were associated with activity in mPFC, ranging from ventral to dorsal extents, as well as common activation of the left temporoparietal junction (TPJ) and posterior cingulate. A direct comparison between self and other judgments revealed that ventral mPFC (vmPFC), as well as left ventrolateral PFC and left insula, were more frequently activated by self-related judgments, whereas dorsal mPFC (dmPFC), in addition to bilateral TPJ and cuneus, were more frequently activated by other-related judgments. Logistic regression analyses revealed that ventral and dorsal mPFC lay at opposite ends of a functional gradient: the z-coordinates reported in individual studies predicted whether the study involved self- or other-related judgments, which were associated with increasingly ventral or dorsal portions of mPFC, respectively. These results argue for a distributed rather than localizationist account of mPFC organization and support an emerging view on the functional heterogeneity of mPFC.
doi:10.1162/jocn_a_00233
PMCID: PMC3806720  PMID: 22452556
3.  The default mode network and social understanding of others: what do brain connectivity studies tell us 
The Default Mode Network (DMN) has been found to be involved in various domains of cognitive and social processing. The present article will review brain connectivity results related to the DMN in the fields of social understanding of others: emotion perception, empathy, theory of mind, and morality. Most of the reviewed studies focused on healthy subjects with no neurological and psychiatric disease, but some studies on patients with autism and psychopathy will also be discussed. Common results show that the medial prefrontal cortex (MPFC) plays a key role in the social understanding of others, and the subregions of the MPFC contribute differently to this function according to their roles in different subsystems of the DMN. At the bottom, the ventral MPFC in the medial temporal lobe (MTL) subsystem and its connections with emotion regions are mainly associated with emotion engagement during social interactions. Above, the anterior MPFC (aMPFC) in the cortical midline structures (CMS) and its connections with posterior and anterior cingulate cortex contribute mostly to making self-other distinctions. At the top, the dorsal MPFC (dMPFC) in the dMPFC subsystem and its connection with the temporo-parietal junction (TPJ) are primarily related to the understanding of other's mental states. As behaviors become more complex, the related regions in frontal cortex are located higher. This reflects the transfer of information processing from automatic to cognitive processes with the increase of the complexity of social interaction. Besides the MPFC and TPJ, the connectivities of posterior cingulate cortex (PCC) also show some changes during tasks from the four social fields. These results indicate that the DMN is indispensable in the social understanding of others.
doi:10.3389/fnhum.2014.00074
PMCID: PMC3932552  PMID: 24605094
default mode network; social cognition; brain connectivity; morality; theory of mind; empathy
4.  The Neural Architecture of Music-Evoked Autobiographical Memories 
Cerebral Cortex (New York, NY)  2009;19(11):2579-2594.
The medial prefrontal cortex (MPFC) is regarded as a region of the brain that supports self-referential processes, including the integration of sensory information with self-knowledge and the retrieval of autobiographical information. I used functional magnetic resonance imaging and a novel procedure for eliciting autobiographical memories with excerpts of popular music dating to one's extended childhood to test the hypothesis that music and autobiographical memories are integrated in the MPFC. Dorsal regions of the MPFC (Brodmann area 8/9) were shown to respond parametrically to the degree of autobiographical salience experienced over the course of individual 30 s excerpts. Moreover, the dorsal MPFC also responded on a second, faster timescale corresponding to the signature movements of the musical excerpts through tonal space. These results suggest that the dorsal MPFC associates music and memories when we experience emotionally salient episodic memories that are triggered by familiar songs from our personal past. MPFC acted in concert with lateral prefrontal and posterior cortices both in terms of tonality tracking and overall responsiveness to familiar and autobiographically salient songs. These findings extend the results of previous autobiographical memory research by demonstrating the spontaneous activation of an autobiographical memory network in a naturalistic task with low retrieval demands.
doi:10.1093/cercor/bhp008
PMCID: PMC2758676  PMID: 19240137
emotion; episodic memory; fMRI; medial prefrontal cortex; tonality
5.  Development of functional and structural connectivity within the default mode network in young children 
NeuroImage  2010;52(1):290-301.
Functional and structural maturation of networks comprised of discrete regions is an important aspect of brain development. The default-mode network (DMN) is a prominent network which includes the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), medial temporal lobes (MTL), and angular gyrus (AG). Despite increasing interest in DMN function, little is known about its maturation from childhood to adulthood. Here we examine developmental changes in DMN connectivity using a multimodal imaging approach by combining resting-state fMRI, voxel-based morphometry and diffusion tensor imaging-based tractography. We found that the DMN undergoes significant developmental changes in functional and structural connectivity, but these changes are not uniform across all DMN nodes. Convergent structural and functional connectivity analyses suggest that PCC-mPFC connectivity along the cingulum bundle is the most immature link in the DMN of children. Both PCC and mPFC also showed gray matter volume differences, as well as prominent macrostructural and microstructural differences in the dorsal cingulum bundle linking these regions. Notably, structural connectivity between PCC and left MTL was either weak or non-existent in children, even though functional connectivity did not differ from that of adults. These results imply that functional connectivity in children can reach adult-like levels despite weak structural connectivity. We propose that maturation of PCC-mPFC structural connectivity plays an important role in the development of self-related and social-cognitive functions that emerge during adolescence. More generally, our study demonstrates how quantitative multimodal analysis of anatomy and connectivity allows us to better characterize the heterogeneous development and maturation of brain networks.
doi:10.1016/j.neuroimage.2010.04.009
PMCID: PMC2976600  PMID: 20385244
brain development; default mode network; DTI; functional brain connectivity; structural brain connectivity
6.  Valence-Based Age Differences in Medial Prefrontal Activity during Impression Formation 
Social neuroscience  2013;8(5):462-473.
Reports of age-related changes to medial prefrontal cortex (mPFC) activity during socio-cognitive tasks have shown both age-equivalence and under recruitment. Emotion work illustrates selective mPFC response dependent on valence, such that negative emotional images evoke increased ventral mPFC activity for younger adults, while older adults recruit ventral mPFC more for positive material. By testing whether this differential age-related response toward valenced material is also present for the social task of forming impressions, we may begin to understand inconsistencies regarding when age differences are present vs. absent in the literature. Using fMRI, participants intentionally formed impressions of positive and negative face-behavior pairs in anticipation of a memory task. Extending previous findings to a social task, valence-based reversals were present in dorsal and ventral mPFC, and posterior cingulate cortex. Younger adults elicited increased activity when forming negative impressions, while older adults had more recruitment when forming positive impressions. This suggests an age-related shift toward emphasizing positive social information may be reflected in the recruitment of regions supporting forming impressions. Overall, the results indicate an age-related shift in neural response to socio-cognitive stimuli that is valence dependent rather than a general age-related reduction in activity, in part informing prior inconsistencies within the literature.
doi:10.1080/17470919.2013.832373
PMCID: PMC3786866  PMID: 23998453
aging; medial prefrontal cortex; impression formation; valence
7.  Self-esteem Modulates Medial Prefrontal Cortical Responses to Evaluative Social Feedback 
Cerebral Cortex (New York, NY)  2010;20(12):3005-3013.
Self-esteem is a facet of personality that influences perception of social standing and modulates the salience of social acceptance and rejection. As such, self-esteem may bias neural responses to positive and negative social feedback across individuals. During functional magnetic resonance imaging scanning, participants (n = 42) engaged in a social evaluation task whereby they ostensibly received feedback from peers indicating they were liked or disliked. Results demonstrated that individuals with low self-esteem believed that they received less positive feedback from others and showed enhanced activity to positive versus negative social feedback in the ventral anterior cingulate cortex/medial prefrontal cortex (vACC/mPFC). By contrast, vACC/mPFC activity was insensitive to positive versus negative feedback in individuals with high self-esteem, and these individuals consistently overestimated the amount of positive feedback received from peers. Voxelwise analyses supported these findings; lower self-esteem predicted a linear increase in vACC/mPFC response to positive versus negative social feedback. Taken together, the present findings propose a functional role for the vACC/mPFC in representing the salience of social feedback and shaping perceptions of relative social standing.
doi:10.1093/cercor/bhq049
PMCID: PMC2978246  PMID: 20351022
anterior cingulate cortex; fMRI; medial prefrontal cortex; self-esteem; social
8.  Medial prefrontal cortex and the emergence of self-conscious emotion in adolescence 
Psychological science  2013;24(8):1554-1562.
In the present study, we examined the relationship between developmental modulation of socioaffective brain systems and adolescents’ preoccupation with social evaluation. Child, adolescent, and adult participants viewed cues indicating that a camera was alternately off, warming up, or projecting their image to a peer during the acquisition of behavioral-, autonomic-, and neural-response (functional MRI) data. Believing that a peer was actively watching them was sufficient to induce self-conscious emotion that was stronger in adolescents than in children and adults. Autonomic arousal was uniquely heightened in adolescents. These behavioral patterns were paralleled by emergent engagement of the medial prefrontal cortex (MPFC) and striatum-MPFC connectivity during adolescence, which are thought to promote adolescent-motivated social behavior. These findings demonstrate that adolescents’ self-consciousness is related to age-dependent sensitivity of brain systems critical to socioaffective processes. Further, unique interactions between the MPFC and striatum may provide a mechanism by which social-evaluation contexts influence adolescent behavior.
doi:10.1177/0956797613475633
PMCID: PMC3742683  PMID: 23804962
adolescence; embarrassment; evaluation; fMRI; medial prefrontal cortex; self-consciousness; social
9.  Differential Neural Activity during Search of Specific and General Autobiographical Memories elicited by Musical Cues 
Neuropsychologia  2011;49(9):2514-2526.
Previous neuroimaging studies that have examined autobiographical memory specificity have utilized retrieval cues associated with prior searches of the event, potentially changing the retrieval processes being investigated. In the current study, musical cues were used to naturally elicit memories from multiple levels of specificity (i.e., lifetime period, general event, and event-specific). Sixteen young adults participated in a neuroimaging study in which they retrieved autobiographical memories associated with musical cues. These musical cues led to the retrieval of highly emotional memories that had low levels of prior retrieval. Retrieval of all autobiographical memory levels was associated with activity in regions in the autobiographical memory network, specifically the ventromedial prefrontal cortex, posterior cingulate, and right medial temporal lobe. Owing to the use of music, memories from varying levels of specificity were retrieved, allowing for comparison of event memory and abstract personal knowledge, as well as comparison of specific and general event memory. Dorsolateral and dorsomedial prefrontal regions were engaged during event retrieval relative to personal knowledge retrieval, and retrieval of specific event memories was associated with increased activity in the bilateral medial temporal lobe and dorsomedial prefrontal cortex relative to retrieval of general event memories. These results suggest that the initial search processes for memories of different specificity levels preferentially engage different components of the autobiographical memory network. The potential underlying causes of these neural differences are discussed.
doi:10.1016/j.neuropsychologia.2011.04.032
PMCID: PMC3137744  PMID: 21600227
autobiographical memory; medial prefrontal cortex; medial temporal lobe; musical stimuli; memory characteristics; functional MRI
10.  Functional Neuroimaging of Self-Referential Encoding with Age 
Neuropsychologia  2010;48(1):211-219.
Aging impacts memory formation and the engagement of frontal and medial temporal regions. However, much of the research to date has focused on the encoding of neutral verbal and visual information. The present fMRI study investigated age differences in a social encoding task while participants made judgments about the self or another person. Although previous studies identified an intact self-reference effect with age, subserved by robust engagement of medial prefrontal cortex (mPFC) by both young and older adults, we identified a number of age differences. In regions including superior mPFC, inferior prefrontal cortex, and anterior and posterior cingulate cortex, young and older adults exhibited reversals in the pattern of activity for self and other conditions. Whereas young primarily evidenced subsequent forgetting effects in the self-reference condition, older adults demonstrated subsequent memory effects in the other-reference condition. These results indicate fundamental differences across the age groups in the engagement of elaborative encoding processes. We suggest that older adults may encode information about the self in a more normative manner, whereas young adults focus on encoding the unique aspects of the self and distinguishing the self from others.
doi:10.1016/j.neuropsychologia.2009.09.006
PMCID: PMC2794905  PMID: 19765600
Aging; self; long-term memory; prefrontal cortex; cognition; fMRI
11.  Differential Deactivation during Mentalizing and Classification of Autism Based on Default Mode Network Connectivity 
PLoS ONE  2012;7(11):e50064.
The default mode network (DMN) is a collection of brain areas found to be consistently deactivated during task performance. Previous neuroimaging studies of resting state have revealed reduced task-related deactivation of this network in autism. We investigated the DMN in 13 high-functioning adults with autism spectrum disorders (ASD) and 14 typically developing control participants during three fMRI studies (two language tasks and a Theory-of-Mind (ToM) task). Each study had separate blocks of fixation/resting baseline. The data from the task blocks and fixation blocks were collated to examine deactivation and functional connectivity. Deficits in the deactivation of the DMN in individuals with ASD were specific only to the ToM task, with no group differences in deactivation during the language tasks or a combined language and self-other discrimination task. During rest blocks following the ToM task, the ASD group showed less deactivation than the control group in a number of DMN regions, including medial prefrontal cortex (MPFC), anterior cingulate cortex, and posterior cingulate gyrus/precuneus. In addition, we found weaker functional connectivity of the MPFC in individuals with ASD compared to controls. Furthermore, we were able to reliably classify participants into ASD or typically developing control groups based on both the whole-brain and seed-based connectivity patterns with accuracy up to 96.3%. These findings indicate that deactivation and connectivity of the DMN were altered in individuals with ASD. In addition, these findings suggest that the deficits in DMN connectivity could be a neural signature that can be used for classifying an individual as belonging to the ASD group.
doi:10.1371/journal.pone.0050064
PMCID: PMC3501481  PMID: 23185536
12.  An Anterior-to-Posterior Shift in Midline Cortical Activity in Schizophrenia During Self-Reflection 
Biological psychiatry  2010;69(5):415-423.
Background
Deficits in social cognition, including impairments in self-awareness, contribute to the overall functional disability associated with schizophrenia. Studies in healthy subjects have shown that social cognitive functions, including self-reflection, rely on the medial prefrontal cortex (mPFC) and posterior cingulate gyrus, and these regions exhibit highly correlated activity during “resting” states. In this study, we tested the hypothesis that patients with schizophrenia show dysfunction of this network during self-reflection and that this abnormal activity is associated with changes in the strength of resting-state correlations between these regions.
Methods
Activation during self-reflection and control tasks was measured with functional magnetic resonance imaging in 19 patients with schizophrenia and 20 demographically matched control subjects. In addition, the resting-state functional connectivity of midline cortical areas showing abnormal self-reflection-related activation in schizophrenia was measured.
Results
Compared with control subjects, the schizophrenia patients demonstrated lower activation of the right ventral mPFC and greater activation of the mid/posterior cingulate gyri bilaterally during self-reflection, relative to a control task. A similar pattern was seen during overall social reflection. In addition, functional connectivity between the portion of the left mid/posterior cingulate gyrus showing abnormally elevated activity during self-reflection in schizophrenia, and the dorsal anterior cingulate gyrus was lower in the schizophrenia patients compared with control subjects.
Conclusions
Schizophrenia is associated with an anterior-to-posterior shift in introspection-related activation, as well as changes in functional connectivity, of the midline cortex. These findings provide support for the hypothesis that aberrant midline cortical function contributes to social cognitive impairment in schizophrenia.
doi:10.1016/j.biopsych.2010.10.003
PMCID: PMC3740539  PMID: 21144498
Cingulate gyrus; connectivity; fMRI; medial prefrontal cortex; schizophrenia; self
13.  Is He Being Bad? Social and Language Brain Networks during Social Judgment in Children with Autism 
PLoS ONE  2012;7(10):e47241.
Individuals with autism often violate social rules and have lower accuracy in identifying and explaining inappropriate social behavior. Twelve children with autism (AD) and thirteen children with typical development (TD) participated in this fMRI study of the neurofunctional basis of social judgment. Participants indicated in which of two pictures a boy was being bad (Social condition) or which of two pictures was outdoors (Physical condition). In the within-group Social–Physical comparison, TD children used components of mentalizing and language networks [bilateral inferior frontal gyrus (IFG), bilateral medial prefrontal cortex (mPFC), and bilateral posterior superior temporal sulcus (pSTS)], whereas AD children used a network that was primarily right IFG and bilateral pSTS, suggesting reduced use of social and language networks during this social judgment task. A direct group comparison on the Social–Physical contrast showed that the TD group had greater mPFC, bilateral IFG, and left superior temporal pole activity than the AD group. No regions were more active in the AD group than in the group with TD in this comparison. Both groups successfully performed the task, which required minimal language. The groups also performed similarly on eyetracking measures, indicating that the activation results probably reflect the use of a more basic strategy by the autism group rather than performance disparities. Even though language was unnecessary, the children with TD recruited language areas during the social task, suggesting automatic encoding of their knowledge into language; however, this was not the case for the children with autism. These findings support behavioral research indicating that, whereas children with autism may recognize socially inappropriate behavior, they have difficulty using spoken language to explain why it is inappropriate. The fMRI results indicate that AD children may not automatically use language to encode their social understanding, making expression and generalization of this knowledge more difficult.
doi:10.1371/journal.pone.0047241
PMCID: PMC3474836  PMID: 23082151
14.  A neural measure of behavioral engagement: Task-residual low frequency blood oxygenation level dependent activity in the precuneus 
NeuroImage  2009;49(2):1911-1918.
Brain imaging has provided a useful tool to examine the neural processes underlying human cognition. A critical question is whether and how task engagement influences the observed regional brain activations. Here we highlighted this issue and derived a neural measure of task engagement from the task-residual low frequency blood oxygenation level dependent (BOLD) activity in the precuneus. Using independent component analysis, we identified brain regions in the default circuit – including the precuneus and medial prefrontal cortex (mPFC) – showing greater activation during resting as compared to task-residuals in 33 individuals. Time series correlations with the posterior cingulate cortex as the seed region showed that connectivity with the precuneus was significantly stronger during resting as compared to task residuals. We hypothesized that if the task-residual BOLD activity in the precuneus reflects engagement, it should account for a certain amount of variance in task-related regional brain activation. In an additional experiment of 59 individuals performing a stop signal task, we observed that the fractional amplitude of low frequency fluctuation (fALFF) of the precuneus but not the mPFC accounted for approximately 10% of the variance in prefrontal activation related to attentional monitoring and response inhibition. Taken together, these results suggest that task-residual fALFF in the precuneus may be a potential indicator of task engagement. This measurement may serve as a useful covariate in identifying motivation-independent neural processes that underlie the pathogenesis of a psychiatric or neurological condition.
doi:10.1016/j.neuroimage.2009.09.004
PMCID: PMC2791356  PMID: 19761851
motivation; default circuit; precuneus; low frequency fluctuation; fMRI
15.  Development and neurophysiology of mentalizing. 
The mentalizing (theory of mind) system of the brain is probably in operation from ca. 18 months of age, allowing implicit attribution of intentions and other mental states. Between the ages of 4 and 6 years explicit mentalizing becomes possible, and from this age children are able to explain the misleading reasons that have given rise to a false belief. Neuroimaging studies of mentalizing have so far only been carried out in adults. They reveal a system with three components consistently activated during both implicit and explicit mentalizing tasks: medial prefrontal cortex (MPFC), temporal poles and posterior superior temporal sulcus (STS). The functions of these components can be elucidated, to some extent, from their role in other tasks used in neuroimaging studies. Thus, the MPFC region is probably the basis of the decoupling mechanism that distinguishes mental state representations from physical state representations; the STS region is probably the basis of the detection of agency, and the temporal poles might be involved in access to social knowledge in the form of scripts. The activation of these components in concert appears to be critical to mentalizing.
doi:10.1098/rstb.2002.1218
PMCID: PMC1693139  PMID: 12689373
16.  Neural Correlates of Using Distancing to Regulate Emotional Responses to Social Situations 
Neuropsychologia  2010;48(6):1813-1822.
Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one’s self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.
doi:10.1016/j.neuropsychologia.2010.03.002
PMCID: PMC2905649  PMID: 20226799
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
17.  The role of the medial prefrontal cortex in innate fear regulation in infants, juveniles, and adolescents 
In adult animals, the medial prefrontal cortex (mPFC) plays a significant role in regulating emotions and projects to the amygdala and periaqueductal gray (PAG) to modulate emotional responses. However, little is known about the development of this neural circuit and its relevance to unlearned fear in pre-adulthood. To address these issues, we examined the mPFC of 14 (infants), 26 (juveniles), and 38–42 (adolescents) day old rats, to represent different developmental and social milestones. The expression patterns of the neuronal marker FOS were used to assess neurological activity. Muscimol, a GABA agonist, was used to inactivate the prelimbic and infralimbic mPFC subdivisions (400 ng in 200 nl). Animals were exposed to either a threatening or non-threatening stimulus that was ecologically relevant and age-specific. Freezing was measured as an indicator of innate fear behavior. The data indicated that the mPFC is neither active nor responsive to innate fear in infant rats. In juveniles, the prelimbic mPFC became responsive in processing aversive sensory stimulation, but did not regulate freezing behavior. Finally, during adolescence, inactivation of the prelimbic mPFC significantly attenuated freezing, and decreased FOS expression in the ventral PAG. Surprisingly, across all ages, there were no significant differences in FOS levels in the medial and basolateral/lateral amygdala when either mPFC subdivision was inactivated. Taken together, unlearned fear has a unique developmental course with different brain areas involved in unlearned fear in the immature animal than the adult. In particular, the mPFC neural circuitry is different in young animals and progressively develops more capacities as the animal matures.
doi:10.1523/JNEUROSCI.5216-10.2011
PMCID: PMC3108443  PMID: 21451037
18.  Characterization of excitatory and inhibitory neuron activation in the mouse medial prefrontal cortex following palatable food ingestion and food driven exploratory behavior 
The medial prefrontal cortex (mPFC) is implicated in aspects of executive function, that include the modulation of attentional and memory processes involved in goal selection. Food-seeking behavior has been shown to involve activation of the mPFC, both during the execution of strategies designed to obtain food and during the consumption of food itself. As these behaviors likely require differential engagement of the prefrontal cortex, we hypothesized that the pattern of neuronal activation would also be behavior dependent. In this study we describe, for the first time, the expression of Fos in different layers and cell types of the infralimbic/dorsal peduncular and prelimbic/anterior cingulate subdivisions of mouse mPFC following both the consumption of palatable food and following exploratory activity of the animal directed at obtaining food reward. While both manipulations led to increases of Fos expression in principal excitatory neurons relative to control, food-directed exploratory activity produced a significantly greater increase in Fos expression than observed in the food intake condition. Consequently, we hypothesized that mPFC interneuron activation would also be differentially engaged by these manipulations. Interestingly, Fos expression patterns differed substantially between treatments and interneuron subtype, illustrating how the differential engagement of subsets of mPFC interneurons depends on the behavioral state. In our experiments, both vasoactive intestinal peptide- and parvalbumin-expressing neurons showed enhanced Fos expression only during the food-dependent exploratory task and not during food intake. Conversely, elevations in arcuate and paraventricular hypothalamic fos expression were only observed following food intake and not following food driven exploration. Our data suggest that select activation of these cell types may be required to support high cognitive demand states such as observed during exploration while being dispensable during the ingestion of freely available food.
doi:10.3389/fnana.2014.00060
PMCID: PMC4076747  PMID: 25071465
vasoactive intestinal peptide; parvalbumin; somatostatin; palatable food seeking and ingestion; prefrontal cortex; prelimbic; infralimbic
19.  The role of medial prefrontal cortex in early social cognition 
One major function of our brain is to enable us to behave with respect to socially relevant information. Much research on how the adult human brain processes the social world has shown that there is a network of specific brain areas, also called the social brain, preferentially involved during social cognition. Among the specific brain areas involved in the adult social brain, functional activity in prefrontal cortex (PFC), particularly the medial prefrontal cortex (mPFC), is of special importance for human social cognition and behavior. However, from a developmental perspective, it has long been thought that PFC is functionally silent during infancy (first year of life), and until recently, little was known about the role of PFC in the early development of social cognition. I shall present an emerging body of recent neuroimaging studies with infants that provide evidence that mPFC exhibits functional activation much earlier than previously thought, suggesting that the mPFC is involved in social information processing from early in life. This review will highlight work examining infant mPFC function across a range of social contexts. The reviewed findings will illustrate that the human brain is fundamentally adapted to develop within a social context.
doi:10.3389/fnhum.2013.00340
PMCID: PMC3701864  PMID: 23847509
infancy; development; prefrontal cortex; social cognition; fNIRS
20.  Increased default mode network activity in socially anxious individuals during reward processing 
Background
Social anxiety has been associated with potentiated negative affect and, more recently, with diminished positive affect. It is unclear how these alterations in negative and positive affect are represented neurally in socially anxious individuals and, further, whether they generalize to non-social stimuli. To explore this, we used a monetary incentive paradigm to explore the association between social anxiety and both the anticipation and consumption of non-social incentives. Eighty-four individuals from a longitudinal community sample underwent functional magnetic resonance imaging (fMRI) while participating in a monetary incentive delay (MID) task. The MID task consisted of alternating cues indicating the potential to win or prevent losing varying amounts of money based on the speed of the participant’s response. We examined whether self-reported levels of social anxiety, averaged across approximately 7 years of data, moderated brain activity when contrasting gain or loss cues with neutral cues during the anticipation and outcome phases of incentive processing. Whole brain analyses and analyses restricted to the ventral striatum for the anticipation phase and the medial prefrontal cortex for the outcome phase were conducted.
Results
Social anxiety did not associate with differences in hit rates or reaction times when responding to cues. Further, socially anxious individuals did not exhibit decreased ventral striatum activity during anticipation of gains or decreased MPFC activity during the outcome of gain trials, contrary to expectations based on literature indicating blunted positive affect in social anxiety. Instead, social anxiety showed positive associations with extensive regions implicated in default mode network activity (for example, precuneus, posterior cingulate cortex, and parietal lobe) during anticipation and receipt of monetary gain. Social anxiety was further linked with decreased activity in the ventral striatum during anticipation of monetary loss.
Conclusions
Socially anxious individuals may increase default mode network activity during reward processing, suggesting high self-focused attention even in relation to potentially rewarding stimuli lacking explicit social connotations. Additionally, social anxiety may relate to decreased ventral striatum reactivity when anticipating potential losses.
doi:10.1186/2045-5380-4-7
PMCID: PMC4114426  PMID: 25075275
Social anxiety; Default mode network; Reward; Punishment; Anticipation; Consumption; fMRI
21.  Functional Heterogeneity within the Default Network during Semantic Processing and Speech Production 
This fMRI study investigated the functional heterogeneity of the core nodes of the default mode network (DMN) during language processing. The core nodes of the DMN were defined as task-induced deactivations over multiple tasks in 94 healthy subjects. We used a factorial design that manipulated different tasks (semantic matching or speech production) and stimuli (familiar words and objects or unfamiliar stimuli), alternating with periods of fixation/rest. Our findings revealed several consistent effects in the DMN, namely less deactivations in the left inferior parietal lobule during semantic than perceptual matching in parallel with greater deactivations during semantic matching in anterior subdivisions of the posterior cingulate cortex (PCC) and the ventromedial prefrontal cortex (MPFC). This suggests that, when the brain is engaged in effortful semantic tasks, a part of the DMN in the left angular gyrus was less deactivated as five other nodes of the DMN were more deactivated. These five DMN areas, where deactivation was greater for semantic than perceptual matching, were further differentiated because deactivation was greater in (i) posterior ventral MPFC for speech production relative to semantic matching, (ii) posterior precuneus and PCC for perceptual processing relative to speech production, and (iii) right inferior parietal cortex for pictures of objects relative to written words during both naming and semantic decisions. Our results thus highlight that task difficulty alone cannot fully explain the functional variability in task-induced deactivations. Together these results emphasize that core nodes within the DMN are functionally heterogeneous and differentially sensitive to the type of language processing.
doi:10.3389/fpsyg.2012.00281
PMCID: PMC3417693  PMID: 22905029
functional MRI; language; semantic decisions; speech production; default network; words and objects
22.  Age-related Neural Differences in Affiliation and Isolation 
While previous aging studies have focused on particular components of social perception (e.g., theory of mind, self-referencing), little is known about age-related differences specifically for the neural basis of perception of affiliation and isolation. This study investigates age-related similarities and differences in the neural basis of affiliation and isolation. Participants viewed images of affiliation (groups engaged in social interaction), and isolation (lone individuals), as well as non-social stimuli (e.g., landscapes) while making pleasantness judgments and undergoing functional neuroimaging (BOLD fMRI). Results indicated age-related similarities in response to affiliation and isolation in recruitment of regions involved in theory of mind and self-referencing (e.g. temporal pole, medial prefrontal cortex). Yet, age-related differences also emerged in response to affiliation and isolation in regions implicated in theory of mind as well as self-referencing. Specifically, in response to isolation versus affiliation images, older adults showed greater recruitment than younger adults of the temporal pole, a region that is important for retrieval of personally-relevant memories utilized to understand others’ mental states. Furthermore, in response to images of affiliation versus isolation, older adults showed greater recruitment than younger adults of the precuneus, a region implicated in self-referencing. We suggest that age-related divergence in neural activation patterns underlying judgments of scenes depicting isolation versus affiliation may indicate that older adults’ theory of mind processes are driven by retrieval of isolation-relevant information. Moreover, older adults’ greater recruitment of the precuneus for affiliation versus isolation suggests that the positivity bias for emotional information may extend to social information involving affiliation.
doi:10.3758/s13415-012-0085-y
PMCID: PMC3342477  PMID: 22371086
Aging; Social; Neuroimaging; Self-Referencing; Theory of Mind
23.  Episodic memory and self-reference via semantic autobiographical memory: insights from an fMRI study in younger and older adults 
Self-referential processing relies mainly on the medial prefrontal cortex (MPFC) and enhances memory encoding (i.e., Self-Reference Effect, SRE) as it improves the accuracy and richness of remembering in both young and older adults. However, studies on age-related changes in the neural correlates of the SRE on the subjective (i.e., autonoetic consciousness) and the objective (i.e., source memory) qualitative features of episodic memory are lacking. In the present fMRI study, we compared the effects of a self-related (semantic autobiographical memory task) and a non self-related (general semantic memory task) encoding condition on subsequent episodic memory retrieval. We investigated encoding-related activity during each condition in two groups of 19 younger and 16 older adults. Behaviorally, the SRE improved subjective memory performance in both groups but objective memory only in young adults. At the neural level, a direct comparison between self-related and non self-related conditions revealed that SRE mainly activated the cortical midline system, especially the MPFC, in both groups. Additionally, in older adults and regardless of the condition, greater activity was found in a fronto-parietal network. Overall, correlations were noted between source memory performance and activity in the MPFC (irrespective of age) and visual areas (mediated by age). Thus, the present findings expand evidence of the role of the MPFC in self-referential processing in the context of source memory benefit in both young and older adults using incidental encoding via semantic autobiographical memory. However, our finding suggests that its role is less effective in aging.
doi:10.3389/fnbeh.2014.00449
PMCID: PMC4292587  PMID: 25628546
self-reference effect; autobiographical memory; semantic memory; source memory; autonoetic consciousness; medial prefrontal cortex; aging
24.  On the Role of the Ventromedial Prefrontal Cortex in Self-Processing: The Valuation Hypothesis 
With the development of functional neuroimaging, important progress has been made in identifying the brain regions involved in self-related processing. One of the most consistent findings has been that the ventromedial prefrontal cortex (vMPFC) is activated when people contemplate various aspects of themselves and their life, such their traits, experiences, preferences, abilities, and goals. Recent evidence suggests that this region may not support the act of self-reflection per se, but its precise function in self-processing remains unclear. In this article, I examine the hypothesis that the vMPFC may contribute to assign personal value or significance to self-related contents: stimuli and mental representations that refer or relate to the self tend to be assigned unique value or significance, and the function of the vMPFC may precisely be to evaluate or represent such significance. Although relatively few studies to date have directly tested this hypothesis, several lines of evidence converge to suggest that vMPFC activity during self-processing depends on the personal significance of self-related contents. First, increasing psychological distance from self-representations leads to decreased activation in the vMPFC. Second, the magnitude of vMPFC activation increases linearly with the personal importance attributed to self-representations. Third, the activity of the vMPFC is modulated by individual differences in the interest placed on self-reflection. Finally, the evidence shows that the vMPFC responds to outer aspects of self that have high personal value, such as possessions and close others. By assigning personal value to self-related contents, the vMPFC may play an important role in the construction, stabilization, and modification of self-representations, and ultimately in guiding our choices and decisions.
doi:10.3389/fnhum.2013.00372
PMCID: PMC3707083  PMID: 23847521
self; identity; value; significance; medial prefrontal cortex; ventromedial prefrontal cortex; fMRI
25.  Amygdala functional connectivity with medial prefrontal cortex at rest predicts the positivity effect in older adults’ memory 
Journal of cognitive neuroscience  2013;25(8):1206-1224.
As people get older, they tend to remember more positive than negative information. This age-by-valence interaction has been called ‘positivity effect.’ The current study addressed the hypotheses that baseline functional connectivity at rest is predictive of older adults’ brain activity when learning emotional information and their positivity effect in memory. Using fMRI, we examined the relationship among resting-state functional connectivity, subsequent brain activity when learning emotional faces, and individual differences in the positivity effect (the relative tendency to remember faces expressing positive versus negative emotions). Consistent with our hypothesis, older adults with a stronger positivity effect had increased functional coupling between amygdala and medial prefrontal cortex (MPFC) during rest. In contrast, younger adults did not show the association between resting connectivity and memory positivity. A similar age-by-memory positivity interaction was also found when learning emotional faces. That is, memory positivity in older adults was associated with a) enhanced MPFC activity when learning emotional faces and b) increased negative functional coupling between amygdala and MPFC when learning negative faces. In contrast, memory positivity in younger adults was related to neither enhanced MPFC activity to emotional faces, nor MPFC-amygdala connectivity to negative faces. Furthermore, stronger MPFC-amygdala connectivity during rest was predictive of subsequent greater MPFC activity when learning emotional faces. Thus, emotion-memory interaction in older adults depends not only on the task-related brain activity but also on the baseline functional connectivity.
doi:10.1162/jocn_a_00392
PMCID: PMC4104303  PMID: 23530897
aging; emotion and memory; medial prefrontal cortex; positivity effect; resting state

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