The dorsomedial prefrontal cortex prioritizes social learning during rest.

Sociality is a defining feature of the human experience: We rely on others to ensure survival and cooperate in complex social networks to thrive. Are there brain mechanisms that help ensure we quickly learn about our social world to optimally navigate it? We tested whether portions of the brain's default network engage "by default" to quickly prioritize social learning during the memory consolidation process. To test this possibility, participants underwent functional MRI (fMRI) while viewing scenes from the documentary film, Samsara. This film shows footage of real people and places from around the world. We normed the footage to select scenes that differed along the dimension of sociality, while matched on valence, arousal, interestingness, and familiarity. During fMRI, participants watched the "social" and "nonsocial" scenes, completed a rest scan, and a surprise recognition memory test. Participants showed superior social (vs. nonsocial) memory performance, and the social memory advantage was associated with neural pattern reinstatement during rest in the dorsomedial prefrontal cortex (DMPFC), a key node of the default network. Moreover, it was during early rest that DMPFC social pattern reinstatement was greatest and predicted subsequent social memory performance most strongly, consistent with the "prioritization" account. Results simultaneously update 1) theories of memory consolidation, which have not addressed how social information may be prioritized in the learning process, and 2) understanding of default network function, which remains to be fully characterized. More broadly, the results underscore the inherent human drive to understand our vastly social world.

Belief Updating during Social Interactions: Neural Dynamics and Causal Role of Dorsomedial Prefrontal Cortex.

In competitive interactions, humans have to flexibly update their beliefs about another person's intentions in order to adjust their own choice strategy, such as when believing that the other may exploit their cooperativeness. Here we investigate both the neural dynamics and the causal neural substrate of belief updating processes in humans. We used an adapted prisoner's dilemma game in which participants explicitly predicted the coplayer's actions, which allowed us to quantify the prediction error between expected and actual behavior. First, in an EEG experiment, we found a stronger medial frontal negativity (MFN) for negative than positive prediction errors, suggesting that this medial frontal ERP component may encode unexpected defection of the coplayer. The MFN also predicted subsequent belief updating after negative prediction errors. In a second experiment, we used transcranial magnetic stimulation (TMS) to investigate whether the dorsomedial prefrontal cortex (dmPFC) causally implements belief updating after unexpected outcomes. Our results show that dmPFC TMS impaired belief updating and strategic behavioral adjustments after negative prediction errors. Taken together, our findings reveal the time course of the use of prediction errors in social decisions and suggest that the dmPFC plays a crucial role in updating mental representations of others' intentions.

Empathy incites a stable prosocial decision bias.

Empathy toward suffering individuals serves as potent driver for prosocial behavior. However, it remains unclear whether prosociality induced by empathy for another person's pain persists once that person's suffering diminishes. To test this, participants underwent functional magnetic resonance imaging while performing a binary social decision task that involved allocation of points to themselves and another person. In block one, participants completed the task after witnessing frequent painful stimulation of the other person, and in block two, after observing low frequency of painful stimulation. Drift-diffusion modeling revealed an increased initial bias toward making prosocial decisions in the first block compared with baseline that persisted in the second block. These results were replicated in an independent behavioral study. An additional control study showed that this effect may be specific to empathy as stability was not evident when prosocial decisions were driven by a social norm such as reciprocity. Increased neural activation in dorsomedial prefrontal cortex was linked to empathic concern after witnessing frequent pain and to a general prosocial decision bias after witnessing rare pain. Altogether, our findings show that empathy for pain elicits a stable inclination toward making prosocial decisions even as their suffering diminishes.

Debates on the dorsomedial prefrontal/dorsal anterior cingulate cortex: insights for future research.

The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) is a brain area subject to many theories and debates over its function(s). Even its precise anatomical borders are subject to much controversy. In the past decades, the dmPFC/dACC has been associated with more than 15 different cognitive processes, which sometimes appear quite unrelated (e.g. body perception, cognitive conflict). As a result, understanding what the dmPFC/dACC does has become a real challenge for many neuroscientists. Several theories of this brain area's function(s) have been developed, leading to successive and competitive publications bearing different models, which sometimes contradict each other. During the last two decades, the lively scientific exchanges around the dmPFC/dACC have promoted fruitful research in cognitive neuroscience. In this review, we provide an overview of the anatomy of the dmPFC/dACC, summarize the state of the art of functions that have been associated with this brain area and present the main theories aiming at explaining the dmPFC/dACC function(s). We explore the commonalities and the arguments between the different theories. Finally, we explain what can be learned from these debates for future investigations of the dmPFC/dACC and other brain regions' functions.

Evaluating Back-to-Back and Day-to-Day Reproducibility of Cortical GABA+ Measurements Using Proton Magnetic Resonance Spectroscopy (1H MRS).

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy (1H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson's r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC.

Theory of Mind Following the Violation of Strong and Weak Prior Beliefs.

Recent work in psychology and neuroscience has revealed differences in impression updating across social distance and group membership. Observers tend to maintain prior impressions of close (vs. distant) and ingroup (vs. outgroup) others in light of new information, and this belief maintenance is at times accompanied by increased activity in Theory of Mind regions. It remains an open question whether differences in the strength of prior beliefs, in a context absent social motivation, contribute to neural differences during belief updating. We devised a functional magnetic resonance imaging study to isolate the impact of experimentally induced prior beliefs on mentalizing activity. Participants learned about targets who performed 2 or 4 same-valenced behaviors (leading to the formation of weak or strong priors), before performing 2 counter-valenced behaviors. We found a greater change in activity in dorsomedial prefrontal cortex (DMPFC) and right temporo-parietal junction following the violation of strong versus weak priors, and a greater change in activity in DMPFC and left temporo-parietal junction following the violation of positive versus negative priors. These results indicate that differences in neural responses to unexpected behaviors from close versus distant others, and ingroup versus outgroup members, may be driven in part by differences in the strength of prior beliefs.

Private but not social information validity modulates social conformity bias.

It is well established that human behaviors are susceptible to others' opinions. However, optimal decision theory mandates choices be made upon the estimated validities of different information sources and little is known about whether and how people could wean themselves off social conformity bias, especially when the social signals are uninformative. Here, we asked subjects to participate in a probabilistic urn guessing task based on their private information as well as observed choices from their partners. Specifically, we manipulated the information validity of these two sources such that only the private evidence was informative. Across trials, social conformity declined, manifested by the increased influence of the private evidence but steady effect of social information. Correspondingly, we found dorsomedial prefrontal cortex (dmPFC) was involved in detecting the conflict of private and social information and conforming to social signal whereas striatum was responsible for selectively updating the influence of private (but not social) evidence contingent on its inferred validity. Furthermore, functional coupling between striatum and dmPFC predicted the resistance toward the influence of social information. Together, these results may provide a mechanistic account of how the conformity bias toward uninformative social information can be remedied.

A Comprehensive Review of Dorsomedial Prefrontal Cortex rTMS Utilizing a Double Cone Coil.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has become increasingly popular during the last decades mainly driven by the antidepressant effects of dorsolateral prefrontal cortex stimulation with "butterfly" coils. Only recently, alternative targets such as the dorsomedial prefrontal cortex (dmPFC) have been brought into focus and innovative coil designs such as the angled geometry of the double cone coil (DCC) have raised hope to reach even deeper located targets. OBJECTIVE: To provide a systematic and comprehensive review on the application of rTMS stimulation of the dmPFC using the DCC in neuropathological and healthy samples. METHODS: We systematically searched the MEDLINE® database (http://www.ncbi.nlm.nih.gov/pubmed/). Due to the heterogeneous naming of DCC stimulation over the dmPFC a variety of search terms was applied resulting in a numeral quantity of 340 hits. RESULTS: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects. Clinical results are encouraging, but have to be considered as preliminary as data from sham-controlled clinical trials and knowledge about the neurobiological underpinnings are still scarce. CONCLUSION: DCC stimulation over the dmPFC represents a promising approach in the fast evolving noninvasive brain stimulation techniques aiming at the functional modulation of brain areas vitally involved in affect, sensory autonomic, cognitive, and salience regulation. This may hold potential for both neuroscientific research and clinical applications in the treatment of psychiatric disorders.

Altered brain activation and connectivity during anticipation of uncertain threat in trait anxiety.

In the research field of anxiety, previous studies generally focus on emotional responses following threat. A recent model of anxiety proposes that altered anticipation prior to uncertain threat is related with the development of anxiety. Behavioral findings have built the relationship between anxiety and distinct anticipatory processes including attention, estimation of threat, and emotional responses. However, few studies have characterized the brain organization underlying anticipation of uncertain threat and its role in anxiety. In the present study, we used an emotional anticipation paradigm with functional magnetic resonance imaging (fMRI) to examine the aforementioned topics by employing brain activation and general psychophysiological interactions (gPPI) analysis. In the activation analysis, we found that high trait anxious individuals showed significantly increased activation in the thalamus, middle temporal gyrus (MTG), and dorsomedial prefrontal cortex (dmPFC), as well as decreased activation in the precuneus, during anticipation of uncertain threat compared to the certain condition. In the gPPI analysis, the key regions including the amygdala, dmPFC, and precuneus showed altered connections with distributed brain areas including the ventromedial prefrontal cortex (vmPFC), dorsolateral prefrontal cortex (dlPFC), inferior parietal sulcus (IPS), insula, para-hippocampus gyrus (PHA), thalamus, and MTG involved in anticipation of uncertain threat in anxious individuals. Taken together, our findings indicate that during the anticipation of uncertain threat, anxious individuals showed altered activations and functional connectivity in widely distributed brain areas, which may be critical for abnormal perception, estimation, and emotion reactions during the anticipation of uncertain threat.

Dorsomedial prefrontal cortex 5-HT6 receptors regulate anxiety-like behavior.

The dorsomedial prefrontal cortex (dmPFC) plays a very important role in decision-related and anxiety-related information processing. It has enriched 5-HT6 receptors; however, the precise role of dmPFC 5-HT6 receptors in anxiety remains to be fully investigated. In this study, we injected dmPFC with the 5-HT6 receptor agonist EMD 386088 and antagonist SB 271046 using stereotactic technology. 5-HT6 receptor activation in mice increased time spent in the center area on the open-field test, increased exploration of the open arms on the elevated plus maze test, and increased ratio on the social interaction test. 5-HT6 receptor inactivation induced the opposite effects. In brain slices, EMD 386088 decreased both spontaneous inhibitory postsynaptic currents (sIPSC) and spontaneous excitatory postsynaptic currents (sEPSC), while SB 271046 only increased sEPSC. These effects of EMD 386088 and SB 271046 could be reversed by the GABAA receptor antagonist bicuculline (BMI) and positive allosteric modulator clonazepam (CLZ), respectively. Our results suggest that neurotransmission in the dmPFC by 5-HT6 receptor activation and inhibition may play an important role in anxiety-like behavior, and may provide new insight into the pathological mechanism and potential target of anxiety disorders.

Solving the prefrontal conundrum of high-order anxiety: conciliating HOTEC and hypofrontality. A theoretical review.

INTRODUCTION: According to the High-order Theory of Emotional Consciousness (HOTEC), every emotional process is a conscious and high-order state of mind carried out by the General Networks of Cognition (GNC), which consists mainly of prefrontal mechanisms. This means that anxiety is also an emotional state of mind carried out by the GNC (positive correlation). However, numerous studies have suggested what is commonly called "hypofrontality" during states of anxiety (negative correlation), which seems to give rise to a theoretical and empirical contraction. METHODS: I present a theoretical review to address the following issue: how to advocate a HOTEC view of anxiety in the face of a growing paradigm of hypofrontality during states of anxiety? RESULTS: Here I propose that dmPFC, the dACC, and the anterior insula are GNC areas positively correlated with anxiety, which, along with the prefrontal areas responsible for regulating the activation of survival circuits and driving the attention to adaptive ways to overcome potential threats, form an interconnective model of anticipatory and regulatory mechanisms related to learned threats based on autobiographical memories. CONCLUSIONS: Through this model, I propose that HOTEC is still a valid way to approach and understand both healthy and unhealthy anxious states of mind.

Neural correlates of the self-concept in adolescence-A focus on the significance of friends.

The formation of a coherent and unified self-concept represents a key developmental stage during adolescence. Imaging studies on self-referential processing in adolescents are rare, and it is not clear whether neural structures involved in self-reflection are also involved in reflections of familiar others. In the current study, 41 adolescents were asked to make judgments about trait adjectives during functional magnetic resonance imaging (fMRI): they had to indicate whether the word describes themselves, their friends, their teachers or politicians. Findings indicate a greater overlap in neural networks for responses to self- and friend-related judgments compared to teachers and politicians. In particular, classic self-reference structures such as the ventromedial prefrontal cortex and medial posterior parietal cortex also exhibited higher activation to judgments about friends. In contrast, brain responses towards judgments of teachers (familiar others) compared to politicians (unfamiliar others) did not significantly differ. Results support behavioral findings of a greater relevance of friends for the development of a self-concept during adolescence and indicate underlying functional brain processes. Hum Brain Mapp 38:987-996, 2017. © 2016 Wiley Periodicals, Inc.

Mechanisms of Action of TMS in the Treatment of Depression.

Transcranial magnetic stimulation (TMS) is entering increasingly widespread use in treating depression. The most common stimulation target, in the dorsolateral prefrontal cortex (DLPFC), emerged from early neuroimaging studies in depression. Recently, more rigorous casual methods have revealed whole-brain target networks and anti-networks based on the effects of focal brain lesions and focal brain stimulation on depression symptoms. Symptom improvement during therapeutic DLPFC-TMS appears to involve directional changes in signaling between the DLPFC, subgenual and dorsal anterior cingulate cortex, and salience-network regions. However, different networks may be involved in the therapeutic mechanisms for other TMS targets in depression, such as dorsomedial prefrontal cortex or orbitofrontal cortex. The durability of therapeutic effects for TMS involves synaptic neuroplasticity, and specifically may depend upon dopamine acting at the D1 receptor family, as well as NMDA-receptor-dependent synaptic plasticity mechanisms. Although TMS protocols are classically considered 'excitatory' or 'inhibitory', the actual effects in individuals appear quite variable, and might be better understood at the level of populations of synapses rather than individual synapses. Synaptic meta-plasticity may provide a built-in protective mechanism to avoid runaway facilitation or inhibition during treatment, and may account for the relatively small number of patients who worsen rather than improve with TMS. From an ethological perspective, the antidepressant effects of TMS may involve promoting a whole-brain attractor state associated with foraging/hunting behaviors, centered on the rostrolateral periaqueductal gray and salience network, and suppressing an attractor state associated with passive threat defense, centered on the ventrolateral periaqueductal gray and default-mode network.

Outcome dependency alters the neural substrates of impression formation.

How do people maintain consistent impressions of other people when other people are often inconsistent? The present research addresses this question by combining recent neuroscientific insights with ecologically meaningful behavioral methods. Participants formed impressions of real people whom they met in a personally involving situation. fMRI and supporting behavioral data revealed that outcome dependency (i.e., depending on another person for a desired outcome) alters previously identified neural dynamics of impression formation. Consistent with past research, a functional localizer identified a region of dorsomedial PFC previously linked to social impression formation. In the main task, this ROI revealed the predicted patterns of activity across outcome dependency conditions: greater BOLD response when information confirmed (vs. violated) social expectations if participants were outcome-independent, and the reverse pattern if participants were outcome-dependent. We suggest that, although social perceivers often discount expectancy-disconfirming information as noise, being dependent on another person for a desired outcome focuses impression-formation processing on the most diagnostic information, rather than on the most tractable information.

Brain areas involved in the control of speed during a motor sequence of the foot: real movement versus mental imagery.

We investigated the cerebral networks involved in execution and mental imagery of sequential movements of the left foot, both performed at slow and fast speed. Twelve volunteers were scanned with a 3T MRI during execution and imagination of a sequence of ankle movements. Overt movement execution and motor imagery shared a common network including the premotor, parietal and cingulate cortices, the striatum and the cerebellum. Motor imagery recruited specifically the prefrontal cortex, whereas motor execution recruited specifically the sensorimotor cortex. We also found that slow movements specifically recruited frontopolar and right dorsomedian prefrontal areas bilaterally, during both execution and mental imagery, whereas fast movements strongly activated the sensorimotor cerebral cortex. Finally, we noted that anterior vermis, lobules VI/VII and VIII of the cerebellum were specifically activated during fast movements, both in imagination and execution. We show that the selection of the neural networks underlying voluntary movement of the foot is depending on the speed strategy and is sensitive to execution versus imagery. Moreover, to the light of surprising recent findings in monkeys showing that the vermis should no longer be considered as entirely isolated from the cerebral cortex (Coffman et al., 2011 [2]), we suggest that the anterior vermis contributes to computational aspects of fast commands, whereas more lateral cerebellar superior lobe and lobule VIII would regulate patterning and sequencing of submovements in conjunction with movement rate. We also suggest that execution of overt slow movements, which strongly involves prefrontal executive cortex as during motor mental imagery, is associated with conscious mental representation of the ongoing movements.

Effects of prefrontal theta burst stimulation on neuronal activity and subsequent eating behavior: an interleaved rTMS and fNIRS study.

The dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) are both important nodes for self-control and decision-making but through separable processes (cognitive control vs evaluative processing). This study aimed to examine the effects of excitatory brain stimulation [intermittent theta burst stimulation (iTBS)] targeting the dlPFC and dmPFC on eating behavior. iTBS was hypothesized to decrease consumption of appetitive snack foods, via enhanced interference control for dlPFC stimulation and reduced delay discounting (DD) for dmPFC stimulation. Using a single-blinded, between-subjects design, participants (N = 43) were randomly assigned to one of three conditions: (i) iTBS targeting the left dlPFC, (ii) iTBS targeting bilateral dmPFC or (iii) sham. Participants then completed two cognitive tasks (DD and Flanker), followed by a bogus taste test. Functional near-infrared spectroscopy imaging revealed that increases in the medial prefrontal cortex activity were evident in the dmPFC stimulation group during the DD task; likewise, a neural efficiency effect was observed in the dlPFC stimulation group during the Flanker. Gender significantly moderated during the taste test, with females in the dmPFC showing paradoxical increases in food consumption compared to sham. Findings suggest that amplification of evaluative processing may facilitate eating indulgence when preponderant social cues are permissive and food is appetitive.

Blame and Praise cross-culturally: An fMRI investigation into causal attribution and moral judgment.

People from independent cultures are more likely to causally explain others' behaviors by their disposition [vs. situation] compared to those from interdependent cultures. However, few studies have directly examined how these differences in attribution shape individuals' moral judgment, nor the underlying neural mechanisms of this process. Aiming to address these questions, in the scanner, participants rated the blameworthiness or praiseworthiness of protagonists who did either a negative or positive behavior, respectively. These behaviors were pretested and found to be perceived as dispositionally or situationally caused to different extents on average. Regardless of their self-construal, participants showed enhanced dorsomedial prefrontal cortex (dmPFC) activity in response to the behaviors that were evaluated as more situationally caused on average. Importantly, relatively independent participants reduced their blame for the behaviors that they showed greater dmPFC activity to. Relatively interdependent participants reduced blame for the behaviors that they themselves inferred more situational causes for, but dmPFC activity did not explain their blame. These findings suggest that while dmPFC might support relatively independent participants' effortful consideration of situational contributors to a behavior to make moral judgments, relatively interdependent participants might engage in this process automatically and relied less on dmPFC recruitment.

How social information impacts action in rodents and humans: the role of the prefrontal cortex and its connections.

Day-to-day choices often involve social information and can be influenced by prior social experience. When making a decision in a social context, a subject might need to: 1) recognize the other individual or individuals, 2) infer their intentions and emotions, and 3) weigh the values of all outcomes, social and non-social, prior to selecting an action. These elements of social information processing all rely, to some extent, on the medial prefrontal cortex (mPFC). Patients with neuropsychiatric disorders often have disruptions in prefrontal cortical function, likely contributing to deficits in social reasoning and decision making. To better understand these deficits, researchers have turned to rodents, which have revealed prefrontal cortical mechanisms for contending with the complex information processing demands inherent to making decisions in social contexts. Here, we first review literature regarding social decision making, and the information processing underlying it, in humans and patient populations. We then turn to research in rodents, discussing current procedures for studying social decision making, and underlying neural correlates.

Mentalizing in an economic games context is associated with enhanced activation and connectivity in the left temporoparietal junction.

Prior studies in Social Neuroeconomics have consistently reported activation in social cognition regions during interactive economic games, suggesting mentalizing during economic choice. Such mentalizing occurs during active participation in the game, as well as during passive observation of others' interactions. We designed a novel version of the classic false-belief task (FBT) in which participants read vignettes about interactions between agents in the ultimatum and trust games and were subsequently asked to infer the agents' beliefs. We compared activation patterns during the economic games FBT to those during the classic FBT using conjunction analyses. We find significant overlap in the left temporoparietal junction (TPJ) and dorsal medial prefrontal cortex, as well as the temporal pole (TP) during two task phases: belief formation and belief inference. Moreover, generalized Psychophysiological Interaction (gPPI) analyses show that during belief formation, the right TPJ is a target of both the left TPJ and the right TP seed regions, whereas during belief inferences all seed regions show interconnectivity with each other. These results indicate that across different task types and phases, mentalizing is associated with activation and connectivity across central nodes of the social cognition network. Importantly, this is the case for both the novel economic games and the classic FBTs.

Regional gray matter volume mediates the relationship between neuroticism and depressed emotion.

The underlying psychological mechanism of the effect of neuroticism on depressed emotion has been widely studied. However, the neural mechanism of this relationship remains unclear. Therefore, the present study aimed to apply voxel-based morphometry (VBM) to explore the neural mechanism of the relationship between depressed emotion and neuroticism in healthy and young participants through longitudinal tracking research. The behavioral results showed that neuroticism was positively related to depressed emotion at T1 and T2 (6 months later). The VBM analysis revealed that neuroticism positively associated with the gray matter volume (GMV) in the dorsal medial prefrontal cortex (dmPFC). Mediation analysis was conducted to investigate the neural basis of the association between depressed emotion and neuroticism. The mediation result revealed that GMV of the dmPFC partially mediates the relationship between neuroticism and depressed emotion at T1 but not T2. Together, these findings suggest that the gray matter volume of dmPFC could may affect the relationship between depressed emotion and neuroticism.