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Dorsomedial prefrontal cortex

The dorsomedial prefrontal cortex (dmPFC) is a subregion of the prefrontal cortex situated on the medial surface of the frontal lobe, dorsally bounded by the superior frontal gyrus and ventrally by the cingulate sulcus, with anterior limits at the dorsomedial polar sulcus and posterior boundaries near the paracingulate sulcus.^[1] It encompasses portions of Brodmann areas 8, 9, and 32, and is anatomically adjacent to the dorsal anterior cingulate cortex (dACC), forming a functional cluster that overlaps frontal and cingulate territories without strict boundaries.^[1] This region receives inputs from limbic structures such as the amygdala and hippocampus, as well as dopaminergic projections from the midbrain, enabling its integration of emotional, motivational, and cognitive signals.^[2] Functionally, the dmPFC is implicated in a range of higher-order processes, including social cognition—such as inferring mental states (theory of mind) and empathy—through connectivity with the default mode network and salience network.^[3] It supports cognitive control by monitoring conflicts and adjusting goal-directed behavior, as evidenced by its activation during error detection and decision-making under uncertainty.^[1] Additionally, the dmPFC contributes to emotion regulation and self-referential processing, modulating amygdala activity to reappraise emotional stimuli and influencing traits like rumination in affective disorders.^[2] Subdivisions within the dmPFC reveal functional segregation: rostral portions are linked to memory and social tasks, while caudal areas show hemispheric specialization in empathy and reward processing, highlighting its role in integrating personal and interpersonal cognition.^[3] Lesions or dysfunction in this area are associated with impaired social functioning and increased vulnerability to depression, underscoring its clinical significance.^[2]

Anatomy and Location

Definition and boundaries

The dorsomedial prefrontal cortex (dmPFC) is defined as the medial portion of the prefrontal cortex located on the medial surface of the frontal lobes in humans. This region encompasses parts of Brodmann areas 8, 9, 24, and 32, reflecting its position within the broader medial prefrontal cortex (mPFC).^[4]^[5] Grossly, the dmPFC lies superior to the corpus callosum and dorsal to the cingulate sulcus, forming part of the medial wall of the frontal lobe.^[1] Anatomically, the dmPFC is bounded superiorly by the superior frontal gyrus, which separates it from more dorsal frontal structures. Inferiorly, it is adjacent to the ventromedial prefrontal cortex (vmPFC), transitioning via the cingulate sulcus. Posteriorly, its boundary is marked by the anterior cingulate cortex (ACC), often overlapping with the dorsal ACC in functional studies. Anteriorly, it is limited by the dorsomedial polar sulcus, and posteriorly near the paracingulate sulcus. Laterally, the dmPFC abuts the dorsolateral prefrontal cortex (dlPFC) along the medial aspect of the superior frontal gyrus.^[1]^[5] Historically, the dmPFC has been referred to using various synonyms, including the dorsal subregion of the mPFC or areas overlapping with the dorsal anterior cingulate cortex (dACC), due to inconsistent anatomical delineations across early cytoarchitectonic maps. These naming conventions stem from foundational work by Korbinian Brodmann in 1909, who outlined the prefrontal areas without strict functional subdivisions, leading to ongoing debates about precise borders in neuroimaging.^[1]^[6]

Cytoarchitecture and subregions

The dorsomedial prefrontal cortex (dmPFC) is characterized by a six-layered neocortical cytoarchitecture typical of the prefrontal region, with variations in laminar organization across its subregions. Brodmann area 9, which forms the dorsal portions, exhibits a granular structure with a well-defined internal granular layer IV and balanced pyramidal layers III and V, reflecting its prefrontal identity.^[7] In contrast, the ventral aspects encompassing areas 24 and 32 display agranular or dysgranular features akin to the anterior cingulate cortex, marked by a reduced or indistinct layer IV, prominent layer V with large pyramidal cells, and dense packing in layer III. These differences in granularity and layer prominence contribute to the region's heterogeneous microscopic structure, with area 24 showing subdivisions such as 24a–c featuring homogeneous layers II–III and differentiated layer Va, while area 32 is distinguished by large pyramidal neurons in layer IIIc and a thinner layer IV. Subregional divisions within the human dmPFC are primarily based on these cytoarchitectonic distinctions, delineating a dorsal component (Brodmann areas 8 and 9) and a ventral component (areas 24 and 32). The dorsal subregion occupies the superior frontal gyrus and paracingulate area, with granular layering supporting its prefrontal characteristics; the ventral subregion aligns with the cingulate gyrus, exhibiting agranular traits.^[1] In rodent homologs, these correspond to the prelimbic area (dorsal/ventral dmPFC equivalent) and infralimbic area (ventral dmPFC equivalent), which share similar laminar patterns but with species-specific variations in layer thickness.^[8] At the cellular level, the dmPFC is predominantly composed of pyramidal neurons, which constitute approximately 80–85% of its neuronal population and are concentrated in layers III and V, serving as principal excitatory elements. GABAergic interneurons, comprising 15–20% of neurons, provide local inhibition and are distributed across layers II–VI, while glial cells, including astrocytes and oligodendrocytes, support neuronal function and outnumber neurons by a ratio of about 1:1 in the prefrontal cortex. Density variations exist across subregions, with higher pyramidal neuron packing in the granular dorsal areas (BA9) compared to the sparser, larger cells in the dysgranular ventral areas (BA32), and overall prefrontal pyramidal densities ranging from 20,000–30,000 cells per mm³ in layer III.^[9]^[10] The developmental origins of the dmPFC trace back to the embryonic prosencephalon, the anterior-most vesicle of the neural tube, which differentiates into the telencephalon around the fifth gestational week. Neuronal progenitors proliferate in the ventricular and subventricular zones of the telencephalon, migrating radially to form the cortical plate by weeks 8–12, with prefrontal regions emerging later than sensory areas due to prolonged neurogenesis.^[11] Maturation extends into postnatal life, with significant refinement during adolescence involving synaptic pruning, increased dendritic arborization, and myelination of axons, particularly in layers III and V, which enhances circuit efficiency and continues until early adulthood.^[12]^[13]

Neural Connectivity

Afferent inputs

The dorsomedial prefrontal cortex (dmPFC) receives a diverse array of afferent projections from limbic, cortical, and subcortical structures, enabling integration of emotional, mnemonic, sensory, and modulatory signals. These inputs primarily target specific laminar layers within dmPFC subregions such as areas 24 and 32, with terminations often concentrated in superficial (layers I-II) and deeper layers (III-VI) depending on the source. Tracing studies in non-human primates and rodents have delineated these pathways using anterograde and retrograde labeling techniques.^[14] Limbic system afferents form a core component of dmPFC input, conveying emotional and contextual information. The amygdala, particularly from the intermediate and magnocellular divisions of the basal nucleus, projects directly and ipsilaterally to dmPFC areas 24a and 32, with dense terminations in layers I, II, and VI, and sparser inputs to layers III and V; these projections support emotional signal relay without significant contralateral contributions.^[14] The hippocampus contributes via its subiculum and distal CA1 fields, sending projections through the fornix to the same dmPFC regions, predominantly targeting layer III in area 32 and multiple layers in area 25; this pathway is exclusively ipsilateral and confirmed by fornix transection experiments that abolish connectivity.^[14] Thalamic inputs, relayed primarily through the mediodorsal nucleus and midline nucleus reuniens, arrive via thalamocortical pathways to the infralimbic portion of dmPFC, forming distinct synaptic microcircuits with excitatory projection neurons and interneurons (e.g., NDNF-expressing cells in layer I), providing sensory and relay functions.^[15]^[8] Cortical afferents to dmPFC originate from association areas involved in perception and valuation. The temporal lobe, including the superior temporal sulcus and rostral temporal cortex, sends projections via the extreme capsule and superior longitudinal fasciculus, integrating social perceptual cues into dmPFC processing.^[8] The orbitofrontal cortex (OFC), especially area 11, provides dense glutamatergic inputs through the uncinate fasciculus and cingulum bundle, linking reward-related valuation signals to medial frontal regions.^[8] Additionally, the posterior cingulate cortex contributes via the cingulum bundle, facilitating default mode network integration with terminations supporting spatial and mnemonic relay.^[8] Subcortical inputs modulate dmPFC activity through loops and ascending projections. Basal ganglia afferents, primarily via striatal and pallidal relays through thalamocortical circuits, influence action selection signals, with indirect projections targeting dmPFC via the anterior limb of the internal capsule.^[8] Brainstem contributions include noradrenergic fibers from the locus coeruleus, ascending via the dorsal noradrenergic bundle to provide arousal and attention-related modulation across dmPFC layers.^[16] Most afferent pathways to dmPFC are glutamatergic, originating from pyramidal neurons in source regions and forming excitatory synapses, as evidenced by anterograde tracing with vesicular glutamate transporter labeling.^[8] These are complemented by GABAergic inhibitory modulation, particularly from local interneurons activated by thalamic and hippocampal inputs, creating balanced microcircuits that gate incoming signals.^[15] Topographical organization is evident, with medial fibers in the anterior limb of the internal capsule carrying thalamic and limbic inputs dorsally.^[8]

Efferent outputs and networks

The dorsomedial prefrontal cortex (dmPFC) sends efferent projections to several key cortical regions within the prefrontal cortex, facilitating integration of cognitive and emotional processes. These include dense connections to the ventromedial prefrontal cortex (vmPFC) via the cingulum bundle and uncinate fasciculus, supporting emotional valuation and reward processing.^[8] Projections to the dorsolateral prefrontal cortex (dlPFC) travel through the superior longitudinal fasciculus, aiding executive control and working memory maintenance.^[8] Additionally, strong links to the anterior cingulate cortex (ACC) occur primarily via the cingulum bundle, enabling conflict monitoring and error detection during decision-making.^[8] Beyond cortical targets, the dmPFC extends efferents to limbic structures, exerting top-down influence on affective and motivational systems. Glutamatergic projections to the basolateral amygdala promote negative emotional behaviors and provide regulatory control over fear and anxiety responses.^[17] Outputs to the nucleus accumbens, also glutamatergic, modulate reward-seeking and motivational drive, particularly in response to predictive cues.^[18] Connections to the hypothalamus, routed through the medial forebrain bundle, coordinate autonomic responses tied to homeostatic and stress-related functions.^[19] The dmPFC serves as a core node in the default mode network (DMN), with structural connections to the posterior cingulate cortex via the cingulum bundle and to the angular gyrus, underpinning introspection, self-referential thought, and episodic memory retrieval.^[8]^[20] It also participates in the frontoparietal network through links with the dlPFC and parietal regions, contributing to task-switching, attention allocation, and cognitive flexibility.^[3] These efferent pathways are predominantly excitatory and glutamatergic, originating from pyramidal neurons that drive downstream activity.^[17] Dopaminergic modulation from the ventral tegmental area influences dmPFC output efficacy, particularly in reward and motivation contexts, by altering excitability via D1 receptors on projection neurons.^[21]^[22]

Cognitive Functions

Self-referential processing

The dorsomedial prefrontal cortex (dmPFC) plays a central role in self-referential processing, which involves the evaluation and reflection on information pertinent to one's own identity and experiences. This region activates during tasks requiring individuals to retrieve autobiographical memories, assess personal traits, and engage in self-evaluation, distinguishing it from processing unrelated to the self.^[23]^[24] Such activation helps construct a unified sense of personal history and characteristics, integrating internal representations of the self.^[25] In autobiographical memory retrieval, the dmPFC facilitates the recall of personally experienced events by coordinating with other brain areas to reconstruct episodic details into a coherent narrative. For instance, functional neuroimaging studies have shown increased dmPFC activity when participants retrieve self-relevant memories compared to non-personal ones, underscoring its involvement in linking past events to the present self.^[23] Similarly, during self-evaluation and personal trait judgments—such as deciding whether adjectives like "honest" or "creative" apply to oneself—the dmPFC exhibits heightened engagement, supporting the formation of self-knowledge.^[24]^[26] This process is evident in meta-analyses of neuroimaging data, which consistently identify the dmPFC within cortical midline structures as a key node for self-referential judgments.^[25] Mechanistically, the dmPFC integrates past experiences through its connectivity with the hippocampus, enabling the formation of a stable self-concept by associating episodic memories with ongoing self-representations. Effective connectivity analyses during memory search reveal directed influences from the hippocampus to the dmPFC, allowing for the contextualization of personal history into a continuous self-narrative. This integration is crucial for maintaining coherence in self-perception over time. Conversely, dmPFC activity is suppressed in states like depersonalization, where individuals experience detachment from their sense of self, as indicated by hypoactivation in prefrontal regions during self-referential tasks in dissociative conditions.^[27] Similar suppression occurs during role-playing, when adopting another perspective temporarily inhibits self-focused processing to facilitate perspective-taking.^[28] Experimental evidence from functional magnetic resonance imaging (fMRI) studies demonstrates dmPFC hyperactivity specifically during self-reflection tasks relative to other-referential ones. In one seminal study, participants judging trait adjectives about themselves showed greater dmPFC activation than when judging familiar others, highlighting its preferential role in self-processing.^[26] Another fMRI investigation confirmed this pattern, with dmPFC responses scaling with the degree of self-relevance in trait evaluations, independent of emotional content.^[29] These findings, replicated across multiple paradigms, establish the dmPFC's selective involvement in introspective self-focus. The dmPFC also contributes to maintaining the sense of agency and narrative self, where individuals perceive their actions as self-initiated and construct an ongoing life story. Neuroimaging research links dmPFC activity to the experience of agency in self-generated actions, differentiating it from externally driven movements.^[30] In autobiographical reasoning, the dmPFC supports the weaving of personal events into a narrative framework, fostering a stable identity over time.^[31] This function ties into broader introspective processes within the default mode network, of which the dmPFC is a core component.^[32] The dorsomedial prefrontal cortex (dmPFC) plays a central role in social cognition, particularly in theory of mind processes that enable the inference of others' beliefs, intentions, and mental states. Neuroimaging meta-analyses have consistently identified dmPFC activation as a core component of the mentalizing network, with robust engagement across 53% of theory of mind tasks, often involving verbal materials that require meta-representations of abstract mental content.^[33] This region facilitates the integration of social information over time to form enduring inferences about others, distinguishing it from more transient goal-directed attributions.^[34] In social judgment tasks, such as forming impressions or evaluating altruism, dmPFC shows heightened activation in 93% of relevant studies, supporting the processing of abstract social traits like personality dispositions rather than concrete behavioral observations.^[33] For moral reasoning, dmPFC contributes to judgments involving intentionality and fairness, with activation observed in 30% of moral dilemma tasks, frequently co-occurring with the temporoparietal junction (TPJ) to integrate perspective-taking during empathy elicitation and fairness assessments.^[33] Causal evidence from transcranial direct current stimulation (tDCS) demonstrates that dmPFC modulation enhances explicit perspective-taking, improving the integration of allocentric viewpoints into egocentric judgments in visual perspective tasks (Level 1: F(1,17)=5.05, p=0.038; Level 2: F(1,18)=4.49, p=0.048).^[35] Lesion studies further corroborate dmPFC's necessity for social inference, revealing impairments in higher-order theory of mind and self-other integration following damage, such as reduced susceptibility to social influence and deficits in faux pas recognition.^[36]^[37] Functional connectivity analyses highlight dmPFC's interaction with the TPJ in the mentalizing network, where dmPFC processes self-referential cues as a precursor to understanding others' abstract mental states during narrative comprehension and action observation.^[38] These findings underscore dmPFC's preferential involvement in abstract social traits, with subregional segregation—such as rostroventral portions linked to the default mode network—distinguishing it from concrete behavioral decoding.^[39]

Emotion regulation

The dorsomedial prefrontal cortex (dmPFC) plays a key role in emotion regulation by exerting top-down inhibitory control over subcortical structures, particularly the amygdala, to modulate fear and anxiety responses. Functional neuroimaging studies have shown that during successful emotion regulation, increased functional connectivity between the dmPFC and amygdala facilitates the downregulation of amygdala activity, thereby reducing emotional intensity.^[40] This mechanism is evident in tasks involving cognitive reappraisal, where dmPFC activation helps reinterpret negative stimuli to lessen their affective impact, as demonstrated in meta-analyses of reappraisal paradigms that consistently engage the dmPFC alongside other prefrontal regions.^[41] Similarly, in fear extinction learning, the dmPFC contributes to the inhibition of conditioned fear responses by enhancing contextual safety signals that suppress amygdala-driven reactivity.^[42] In addition to dampening negative emotions, the dmPFC supports the enhancement of positive affect through interactions with the ventromedial prefrontal cortex (vmPFC). During upregulation of positive social emotions, such as in response to rewarding interpersonal stimuli, the dmPFC coordinates with the vmPFC to amplify affective valence, promoting sustained positive states.^[43] This connectivity is particularly pronounced in regulation strategies targeting positive emotions, where dmPFC engagement, often alongside orbitofrontal cortex activity, differs from patterns seen in negative emotion processing by emphasizing reward amplification rather than threat reduction.^[44] Evidence from functional magnetic resonance imaging (fMRI) further highlights the dmPFC's role in adaptive regulation, with successful reappraisal linked to decoupled or modulated dmPFC-amygdala interactions that predict reduced subjective distress.^[45] Conversely, dmPFC hyperactivity during rumination tasks in individuals with major depressive disorder correlates with prolonged negative affect, reflecting impaired disengagement from self-focused emotional processing.^[46] In bipolar disorder, diminished dmPFC activation during emotion regulation tasks contributes to emotional lability, underscoring its involvement in stabilizing affective fluctuations across mood states.^[47] These findings illustrate the dmPFC's differential activation profiles, with stronger recruitment for negative versus positive emotion contexts, aiding in the flexible control of affective states often triggered by social cues.^[48]

Decision making

The dorsomedial prefrontal cortex (dmPFC) plays a key role in decision making by computing subjective value, resolving conflicts between options, and supporting strategic planning, particularly in scenarios involving uncertainty or multiple attributes.^[49]^[50] In tasks requiring intertemporal choices, where individuals weigh immediate versus delayed rewards, dmPFC activity encodes the subjective value of options, integrating factors like delay discounting to guide selections.^[49] Similarly, during risky decision making, such as gambling paradigms, dmPFC activation reflects the evaluation of potential outcomes under probabilistic uncertainty, contributing to adaptive choice behavior.^[51] These functions distinguish dmPFC involvement from simpler motor selections, emphasizing its specialization for abstract, multi-attribute evaluations that require balancing diverse costs and benefits. At the process level, the dmPFC integrates costs and benefits through interactions with basal ganglia loops, where it modulates signals to weigh effort, risk, and reward in a unified net value representation.^[52] This integration facilitates conflict resolution by suppressing suboptimal responses and promoting goal-directed actions in ambiguous contexts. Additionally, the dmPFC supports observational learning by encoding the outcomes of others' actions, allowing individuals to update their own value estimates without direct experience, as seen in social foraging or imitation tasks.^[50] Electrophysiological evidence from primates underscores these roles, with single-unit recordings in the anterior cingulate cortex—a core dmPFC subregion—revealing neurons that encode subjective value during intertemporal choices, firing proportionally to the discounted reward magnitude of selected options.^[53] In monkeys performing effort-based decisions, dmPFC neurons similarly represent integrated cost-benefit signals, adapting activity to maximize net utility. Human neuroimaging complements this, showing task-invariant dmPFC patterns for subjective value across effortful and risky contexts.^[49] Causal studies using transcranial magnetic stimulation (TMS) over the dmPFC impair performance in complex, multi-attribute decisions, such as effort discounting tasks, by disrupting strategic adjustments and increasing impulsive selections, while leaving basic choices unaffected.^[54] Emotional states can briefly modulate dmPFC-driven choices, enhancing value sensitivity to affective cues in uncertain environments.^[55]

Comparative Aspects

In non-human animals

In non-human animals, the dorsomedial prefrontal cortex (dmPFC) has identifiable homologs that have been extensively studied to elucidate its roles in cognition and behavior. In rodents, the prelimbic (PL) and infralimbic (IL) cortices are considered primary homologs of the dmPFC, based on cytoarchitectonic similarities and connectivity patterns with limbic structures such as the amygdala and hippocampus. These regions are located on the medial wall of the frontal lobe, with the PL corresponding more closely to the dorsal aspects of the human dmPFC and the IL to its ventral parts. In primates, including macaques, the homologs are primarily Brodmann areas 24 and 32, which exhibit comparable laminar organization and projections to subcortical targets. Functional investigations in these animal models have revealed critical roles for dmPFC homologs in emotional regulation, social behavior, and cognitive flexibility. In rats, the IL cortex is pivotal for fear extinction, where it inhibits conditioned fear responses by modulating amygdala output during extinction learning; optogenetic activation of IL projections to the amygdala enhances extinction recall, while silencing impairs it. Similarly, the PL cortex contributes to the acquisition and expression of fear memories in conditioning paradigms, with optogenetic manipulations demonstrating bidirectional control over freezing behaviors. For social behavior, studies in macaque monkeys show that area 24 encodes social value and hierarchy, with neurons responding selectively to dominance status during gaze interactions or rank-based decisions. Cognitive flexibility is another key domain, where rodent PL inactivation disrupts reversal learning in probabilistic tasks, leading to perseverative errors as animals fail to adapt to changing reward contingencies. Methodological approaches in these models include lesion studies, electrophysiological recordings, and advanced imaging techniques to draw parallels with human dmPFC functions. Electrolytic or pharmacological lesions of the PL in rats impair set-shifting and attentional control, mirroring deficits observed in human prefrontal dysfunction. Single-unit recordings in primates reveal dmPFC homolog activity during social decision-making, with firing rates correlating to anticipated social rewards. Functional magnetic resonance imaging (fMRI) in awake rodents has further confirmed activation in PL/IL during emotional conflict resolution, providing non-invasive insights into network dynamics. These techniques collectively underscore the conserved role of dmPFC homologs across species in integrating affective and cognitive processes. Recent connectomic studies (as of 2023) using diffusion MRI confirm conserved dmPFC-limbic pathways in great apes, supporting homology claims.^[56]

Evolutionary perspectives

The dorsomedial prefrontal cortex (dmPFC) shares a conserved architecture across mammals, with its agranular subdivisions—such as areas 24, 32, and 25—emerging in early mammalian lineages to mediate limbic functions, including autonomic regulation and survival-oriented decisions like predator avoidance and resource allocation. These foundational roles, supported by connections to the mediodorsal thalamus, persisted through evolutionary divergence, providing a neural substrate for basic executive control that predates the cognitive demands of advanced sociality. In primates, the dmPFC expanded markedly, particularly its granular components like area 9, aligning with the rise of socioecological complexity in simian ancestors around 60 million years ago; this growth is attributed to selective pressures from larger group sizes and alliance formation, enhancing the integration of social cues with decision-making.^[57] Among hominids, adaptations in the dmPFC are inextricably tied to the emergence of theory of mind, the capacity to infer others' intentions, beliefs, and emotions, which likely intensified during the Pliocene-Pleistocene transition as group sizes grew and cooperative foraging became essential. Phylogenetic comparisons indicate that the human dmPFC exhibits pronounced enlargement relative to other apes, with prefrontal cortex gray matter volume averaging about 513 cm³ in modern humans compared to roughly 134 cm³ in chimpanzees, representing an extreme in the primate distribution and correlating with denser connectivity for mental state attribution.^[58] This disparity underscores how hominid-specific expansions, driven by genetic changes in regulatory genes like those influencing cortical folding, enabled nuanced social navigation beyond the capabilities of earlier primates.^[57] Evolutionary theories emphasize the dmPFC's role in fostering cooperation and group cohesion, positing that its development allowed hominids to model reciprocal altruism and enforce social norms within increasingly interdependent communities, a hypothesis supported by cross-species analyses linking prefrontal volume to grooming network complexity. Fossil endocasts provide direct evidence of this trajectory, revealing a stepwise increase in frontal lobe proportions and encephalization quotients rising from about 2.5-3.0 in Australopithecus to 3.0-4.0 in Homo erectus, which paralleled shifts toward tool use and symbolic communication.^[59] These evolutionary foundations culminate in the human dmPFC's support for abstract thinking, extending mammalian precursors in survival decisions to uniquely human faculties like hypothetical scenario simulation and ethical deliberation, thereby underpinning cultural transmission and societal complexity.^[57]

Clinical Relevance

Associated disorders

The dorsomedial prefrontal cortex (dmPFC) has been implicated in several psychiatric disorders through disruptions in its roles in self-referential processing, social cognition, and emotion regulation.^[60] In major depressive disorder (MDD), dmPFC hyperactivity during rumination contributes to persistent negative self-focused thoughts, exacerbating depressive symptoms.^[61] This is supported by evidence of increased dynamic functional connectivity variance involving the dmPFC in individuals with high trait rumination, which predicts depression severity.^[62] Structural atrophy in the medial prefrontal cortex, including the dmPFC, is observed in chronic MDD, with volumetric reductions linked to illness duration and episode recurrence.^[63] Post-mortem studies reveal reduced glial cell density and neuronal alterations in prefrontal regions in MDD, while genetic analyses show transcriptome changes in the dmPFC associated with suicidal behavior in depression.^[64]^[65] In post-traumatic stress disorder (PTSD) and anxiety disorders, dmPFC hypoactivation impairs emotion regulation, leading to persistent fear responses and difficulty extinguishing threat-related memories.^[66] Reduced functional connectivity between the dmPFC and default mode network regions contributes to these deficits, correlating with symptom severity such as hyperarousal and avoidance.^[67] Symptom correlations include heightened anxiety linked to dmPFC dysregulation during cognitive reappraisal tasks.^[66] Dysfunction in the dmPFC underlies impaired social processing in autism spectrum disorder and schizophrenia, manifesting as deficits in theory of mind and social memory.^[68] In schizophrenia, reduced dmPFC activity during recognition of social information is associated with social withdrawal and interpersonal difficulties.^[69] Similar impairments in medial prefrontal regions, including the dmPFC, contribute to atypical face processing and mental state attribution in autism.^[70] In bipolar disorder, dmPFC hypoactivity during emotion regulation tasks is a stable trait marker linked to emotional instability and mood episode relapses.^[71] This hypoactivation hinders down-regulation of negative affect, promoting affective lability across mood states.^[72] Post-mortem and genetic studies indicate neuronal density changes and gene expression alterations in prefrontal areas in bipolar disorder, supporting structural and molecular vulnerabilities.^[73]^[74] The dmPFC represents a potential therapeutic target for these disorders, with repetitive transcranial magnetic stimulation (rTMS) over the dmPFC showing preliminary efficacy in reducing depressive symptoms and improving affect regulation in neuropsychiatric conditions. A 2024 meta-analysis confirmed the efficacy of dmPFC-rTMS in treating depression and reducing cravings in various psychiatric disorders.^[75]^[76] Deep brain stimulation (DBS) targeting prefrontal networks, including pathways involving the dmPFC, has been explored for treatment-resistant mood disorders, while pharmacological interventions modulating prefrontal serotonin systems may indirectly enhance dmPFC function.^[77]^[78]

Neuroimaging findings

Neuroimaging techniques, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and positron emission tomography (PET), have elucidated the functional role and connectivity of the dorsomedial prefrontal cortex (dmPFC). fMRI studies employing mentalizing paradigms, such as inferring mental states from facial expressions or narratives, consistently activate the dmPFC as part of a network involving the temporoparietal junction and superior temporal sulcus. A meta-analysis of 107 fMRI studies confirmed a spatial gradient in the medial prefrontal cortex, with anterior dmPFC regions preferentially engaged in explicit mentalizing tasks.^[25] DTI has revealed white matter tracts, such as the arcuate fasciculus and cingulum, supporting dmPFC connectivity in mentalizing; disruptions in right frontoparietal fibers correlate with impaired social inference in lesion patients.^[79] PET imaging highlights metabolic hypofrontality in prefrontal regions during cognitive demands in psychiatric disorders, providing complementary insights into dmPFC energy utilization.^[8] In healthy individuals, the dmPFC exhibits task-evoked deactivation as a core feature of the default mode network (DMN) during externally focused attention tasks, such as working memory or visual search, which suppresses self-referential processing to enhance performance. This deactivation, modulated by fronto-parietal control networks, correlates with reduced mind-wandering and better task efficiency; for instance, stronger negative coupling between dmPFC and control regions predicts higher intelligence scores. Resting-state fMRI further demonstrates dynamic functional connectivity of the dmPFC, with variance in connections to 21 distributed regions (e.g., inferior frontal and temporal gyri) predicting trait rumination (r=0.342 in training samples, p=0.001), offering a marker for internally directed thought patterns.^[62] Pathological alterations in dmPFC neuroimaging are prominent in psychiatric disorders. In schizophrenia, fMRI reveals reduced dmPFC deactivation during working memory tasks (p=0.035), mediating cognitive deficits, while PET confirms broader prefrontal hypofrontality in dopamine release capacity.^[80] Depression is characterized by hyperconnectivity of the dmPFC, or "dorsal nexus," with the DMN, cognitive control, and affective networks (F(1,29)=57.9, p<0.0001), correlating with symptom severity (r=0.85).^[81] Longitudinal fMRI in post-traumatic stress disorder shows that heightened dmPFC activation to fearful stimuli shortly after trauma predicts persistent symptoms at three months, alongside increased gray matter volume in chronic cases.^[82]^[83] Recent advances post-2020 include repetitive transcranial magnetic stimulation (rTMS) targeting the dmPFC, which enhances functional connectivity to DMN hubs like the precuneus and posterior cingulate, associating with depression remission.^[75] Machine learning applied to fMRI data has developed classifiers identifying dmPFC hypoactivation during reward anticipation as a depression biomarker, achieving high accuracy (AUC=0.87) in distinguishing patients from controls and predicting treatment response to dopaminergic enhancement.^[84]

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Feb 12, 2016 · This network, referred to the default mode network (DMN), consists of the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC)/ ...
[21]
Glutamatergic plasticity in medial prefrontal cortex and ventral ... - NIH
The mPFC is innervated by the dopaminergic afferents from the ventral tegmental area (VTA) with the highest innervation received in the infralimbic and ...
[22]
Involvement of cortical input to the rostromedial tegmental nucleus in ...
May 23, 2023 · In the present study, we observed that RMTg-projecting dmPFC neurons are glutamatergic and predominantly express D1 dopamine receptor mRNA, ...
[23]
Cortical midline involvement in autobiographical memory - PMC
In addition, recall of externally experienced real events (self or non-self) was associated with increased activity in areas of dorsomedial prefrontal cortex ...
[24]
Medial prefrontal cortex and self-referential mental activity - PNAS
In this functional magnetic resonance imaging (fMRI) study, subjects made two judgments, one self-referential, the other not, in response to affectively normed ...Missing: dorsomedial | Show results with:dorsomedial
[25]
A Meta-Analysis of Functional Neuroimaging Studies of Self and ...
We performed a meta-analysis of 107 neuroimaging studies of self- and other-related judgments using Multilevel Kernel Density Analysis (MKDA; Kober & Wager, ...
[26]
In Search of the Emotional Self: An fMRI Study Using Positive and ...
Activation in the right dorsomedial prefrontal cortex was unique to the self-referential condition regardless of the valence of the words, although positive ...Method · Fmri Results · Discussion
[27]
Neuroimaging evidence of disturbed self-appraisal in posttraumatic ...
Aberrant DMN activation in PTSD may be linked to fractured sense of self and somatic depersonalization. •. Findings may provide new insights into targeted PTSD ...Review Article · 3. Results · 4. Discussion<|separator|>
[28]
Is self special in the dorsomedial prefrontal cortex? An fMRI study
Aug 6, 2025 · The result indicated that DMPFC was not special for the self-referential process, while there are common neural bases for evaluating the ...
[29]
Medial prefrontal activity differentiates self from close others - PMC
The present study used event-related fMRI to assess whether making trait adjective judgments about the self relative to an intimate other preferentially ...<|separator|>
[30]
Role for Left Dorsomedial Prefrontal Cortex in Self-Generated, but ...
Jun 12, 2025 · The left dorsomedial prefrontal cortex (dmPFC) is known to be associated with volition and motor function but is often overlooked in models ...
[31]
the neural basis of autobiographical reasoning - PubMed Central - NIH
These regions may play a key role in the creation of personal narratives, thereby contributing to sustaining a coherent and stable sense of self and identity.Missing: dmPFC | Show results with:dmPFC
[32]
A Neurocognitive Perspective on the Forms and Functions of ...
Jan 28, 2019 · Autobiographical memory retrieval involves constructing mental representations of personal past episodes by associating together an array of details related to ...Introduction · Theories of Autobiographical... · Distinct Neural Systems for...
[33]
Social cognition and the brain: a meta-analysis - PubMed
This meta-analysis explores the location and function of brain areas involved in social cognition, or the capacity to understand people's behavioral intentions.Missing: Spreng dmPFC
[34]
Meeting of minds: the medial frontal cortex and social cognition
We review the emerging literature that relates social cognition to the medial frontal cortex and, on the basis of anatomical and functional characteristics of ...
[35]
Causal evidence for task-specific involvement of the dorsomedial ...
The dorsomedial prefrontal cortex (dmPFC) is a key hub of the 'social brain', but little is known about specific processes supported by this region.
[36]
Dorsomedial and ventromedial prefrontal cortex lesions differentially ...
We show that the dmPFC is causally implicated in susceptibility to social influence, with distinct ventral portions of mPFC involved in temporal discounting.
[37]
Faux pas deficits in people with medial frontal lesions as related to ...
This study examined the nature of deficits in mentalizing, the ability to read the mental state of other people, as measured by a faux pas task in people ...
[38]
The Role of the Theory-of-Mind Cortical Network ... - PubMed Central
The Theory of Mind network, including the dorsomedial prefrontal cortex and right temporo-parietal junction, helps understand narrative by generating ...
[39]
Functional Segregation of the Human Dorsomedial Prefrontal Cortex
Abstract. The human dorsomedial prefrontal cortex (dmPFC) has been implicated in various complex cognitive processes, including social cognition. To unrave.
[40]
Amygdala–frontal connectivity during emotion regulation - PMC - NIH
Jul 21, 2007 · We observed that the extent of coupling between amygdala and specifically OFC and DMPFC was related to effective emotion regulation, such ...
[41]
Cognitive Reappraisal of Emotion: A Meta-Analysis of Human ...
In the present meta-analysis, we found that the implementation of reappraisal consistently activated cognitive control regions, including dmPFC, dlPFC, vlPFC, ...
[42]
The Role of the Medial Prefrontal Cortex in the Conditioning ... - PMC
It is unknown, however, if this mechanism is specific to dmPFC regulating conditioning and fear recall. ... Extinction of emotional learning: contribution of ...
[43]
Attenuation processes in positive social emotion upregulation
Feb 21, 2025 · ... dmPFC), and affect generation (e.g., vmPFC). As expected in both experiments, upregulation of positive social emotions was associated with ...
[44]
Brain activation during cognitive reappraisal depending on ... - PMC
... dmPFC and OFC in regulating positive emotions, regardless of the regulation goal. We also observed a deactivation in the operculum and posterior insula ...
[45]
Functional connectivity between the amygdala and prefrontal cortex ...
Furthermore, effective amygdala-PFC (including both dmPFC and vmPFC) connectivity predicts individual differences in successful emotion regulation [36]. However ...
[46]
Meta-analysis of brain imaging studies and implications for depression
Feb 1, 2020 · Within the DMN, rumination-related hyperactivation was predominantly observed in the core and the dmPFC subsystems. A meta-analysis of studies ...
[47]
The longitudinal trajectory of emotion regulation and associated ...
The stable DLPFC and DMPFC hypo‐activity during emotion regulation represents a neuronal trait‐marker of persistent emotion regulation difficulties in BD. Hypo‐ ...
[48]
The neural correlates of regulating positive and negative emotions ...
Similarly, during positive affect enhancement, we observed recruitment of VLPFC and DMPFC in both groups. We also observed increased activity in neural ...
[49]
https://pubmed.ncbi.nlm.nih.gov/37579997/
[50]
https://elifesciences.org/articles/44939
[51]
https://www.sciencedirect.com/science/article/pii/S1053811923004779
[52]
Evidence for independent brain and neurocranial reorganization ...
Oct 14, 2019 · Throughout hominin evolution, the brain of our ancestors underwent a 3-fold increase in size and substantial structural reorganization.
[53]
Prefrontal cortex development and its implications in mental illness
Jul 3, 2025 · Dysfunction in this system is strongly implicated in anxiety, mood, and substance use disorders, where approach and avoidance behaviors become ...
[54]
Self-Referential Processing, Rumination, and Cortical ... - Frontiers
Oct 9, 2013 · Patients with depression revealed to be hyperactive during rumination-induction in anterior and posterior cingulate cortex, as well as the ...
[55]
A dorsomedial prefrontal cortex-based dynamic functional ... - Nature
Jun 15, 2023 · This study highlights the role of the dmPFC in trait rumination and provides a dynamic functional connectivity marker for rumination.
[56]
[PDF] The Impact of Stress and Major Depressive Disorder on ... - CDASR
ABSTRACT. Volumetric reductions in the hippocampus and medial prefrontal cortex (mPFC) are among the most well-documented neural abnormalities in major ...
[57]
Prefrontal cortical abnormalities in currently depressed versus ...
Notably, post mortem studies of MDD found reduced glial cell number and density and reduced GABAergic interneuron density in these regions (Rajkowska et al., ...
[58]
Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in ...
Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental ...
[59]
Transdiagnostic alterations in neural emotion regulation circuits ...
Mar 8, 2022 · The patients showed decreased activation of the prefronto-parietal network (PCC, the dmPFC, the angular gyri and the left vlPFC) in combination ...Whole-Brain Fmri Analysis · Discussion · Seed-To-Voxel And...
[60]
Regional prefrontal resting state connectivity in PTSD - ResearchGate
Aug 10, 2025 · We hypothesized that PTSD would involve weaker positive rsFC between VMPFC, DMPFC, and other default mode network (DMN) regions, and increased ...
[61]
Neural Bases for Impaired Social Cognition in Schizophrenia ... - NIH
Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits ...
[62]
Neural correlates of recognition memory of social information in ...
Impaired social memory in patients with schizophrenia may be associated with altered DMPFC activity. A reduction of DMPFC activity may reflect less ...
[63]
Neural bases for impaired social cognition in schizophrenia and ...
We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum ...
[64]
The longitudinal trajectory of emotion regulation and associated ...
Aug 14, 2022 · Patients with bipolar disorder exhibit stable, trait-related emotion regulation difficulties associated with dorsal prefrontal hypo-activity ...
[65]
Neural network of bipolar disorder: Toward integration of ... - Nature
Apr 5, 2022 · Bipolar disorder (BD) is a complex psychiatric disorder characterized by dysfunctions in three domains including emotional processing, ...
[66]
Structural characteristics of the brain reward circuit regions in ...
Post mortem studies of patients with BD have revealed reductions in the number of glial cells and neuronal soma size as well as increases in neuronal density in ...
[67]
Post-mortem molecular profiling of three psychiatric disorders
Jul 28, 2017 · We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions.Missing: atrophy | Show results with:atrophy
[68]
A Comprehensive Review of Dorsomedial Prefrontal Cortex rTMS ...
Nov 8, 2018 · Results: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects.
[69]
Targeting Prefrontal Cortical Systems for Drug Development
The unique modulation of layer III dlPFC pyramidal cell synapses provides strategies for therapeutic targets for cognitive disorders. ... Deep brain stimulation ...
[70]
[PDF] Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin ...
Recent studies provide initial evi- dence that S-carriers show enhanced reactions within several regions of the salience network including the dmPFC (19-21);.