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Anterior cingulate cortex
Medial surface of left cerebral hemisphere, with anterior cingulate highlighted
Medial surface of right hemisphere, with Brodmann's areas numbered
Details
Identifiers
Latincortex cingularis anterior
NeuroNames161
NeuroLex IDbirnlex_936
Anatomical terms of neuroanatomy

In human brains, the anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex that resembles a "collar" surrounding the frontal part of the corpus callosum. It consists of Brodmann areas 24, 32, and 33.

It is involved in certain higher-level functions, such as attention allocation,[1] reward anticipation, decision-making, impulse control (e.g. performance monitoring and error detection),[2] and emotion.[3][4]

Some research calls it the anterior midcingulate cortex (aMCC).

Sagittal MRI slice with highlighting indicating location of the anterior cingulate cortex.
Sagittal MRI slice with highlighting indicating location of the anterior cingulate cortex

Anatomy

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Anterior cingulate gyrus of left cerebral hemisphere, shown in red

The anterior cingulate cortex can be divided anatomically based on cognitive (dorsal), and emotional (ventral) components.[5] The dorsal part of the ACC is connected with the prefrontal cortex and parietal cortex, as well as the motor system and the frontal eye fields,[6] making it a central station for processing top-down and bottom-up stimuli and assigning appropriate control to other areas in the brain. By contrast, the ventral part of the ACC is connected with the amygdala, nucleus accumbens, hypothalamus, hippocampus, and anterior insula, and is involved in assessing the salience of emotion and motivational information. The ACC seems to be especially involved when effort is needed to carry out a task, such as in early learning and problem-solving.[7]

On a cellular level, the ACC is unique in its abundance of specialized neurons called spindle cells,[8] or von Economo neurons. These cells are a relatively recent occurrence in evolutionary terms (found only in humans and other primates, cetaceans, and elephants) and contribute to this brain region's emphasis on addressing difficult problems, as well as the pathologies related to the ACC.[9]

Tasks

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A typical task that activates the ACC involves eliciting some form of conflict within the participant that can potentially result in an error. One such task is called the Eriksen flanker task and consists of an arrow pointing to the left or right, which is flanked by two distractor arrows creating either compatible (<<<<<) or incompatible (>><>>) trials.[10] Another very common conflict-inducing stimulus that activates the ACC is the Stroop task, which involves naming the color ink of words that are either congruent (RED written in red) or incongruent (RED written in blue).[11] Conflict occurs because people's reading abilities interfere with their attempt to correctly name the word's ink color. A variation of this task is the Counting-Stroop, during which people count either neutral stimuli ('dog' presented four times) or interfering stimuli ('three' presented four times) by pressing a button. Another version of the Stroop task named the Emotional Counting Stroop is identical to the Counting Stroop test, except that it also uses segmented or repeated emotional words such as "murder" during the interference part of the task. Thus, ACC affects decision making of a task.

Functions

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Many studies attribute specific functions such as error detection, anticipation of tasks, attention,[11][12] motivation, and modulation of emotional responses to the ACC.[5][6][13]

Error detection and conflict monitoring

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The most basic form of ACC theory states that the ACC is involved with error detection.[5] Evidence has been derived from studies involving a Stroop task.[6] However, ACC is also active during correct response, and this has been shown using a letter task, whereby participants had to respond to the letter X after an A was presented and ignore all other letter combinations with some letters more competitive than others.[14] They found that for more competitive stimuli ACC activation was greater.

A similar theory poses that the ACC's primary function is the monitoring of conflict. In Eriksen flanker task, incompatible trials produce the most conflict and the most activation by the ACC. Upon detection of a conflict, the ACC then provides cues to other areas in the brain to cope with the conflicting control systems.

Evidence from electrical studies

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Evidence for ACC as having an error detection function comes from observations of error-related negativity (ERN) uniquely generated within the ACC upon error occurrences.[5][15][16][17] A distinction has been made between an ERP following incorrect responses (response ERN) and a signal after subjects receive feedback after erroneous responses (feedback ERN).

Patients with lateral prefrontal cingulate (PFC) damage show reduced ERNs.[18]

Reinforcement learning ERN theory poses that there is a mismatch between actual response execution and appropriate response execution, which results in an ERN discharge.[5][16] Furthermore, this theory predicts that, when the ACC receives conflicting input from control areas in the brain, it determines and allocates which area should be given control over the motor system. Varying levels of dopamine are believed to influence the optimization of this filter system by providing expectations about the outcomes of an event. The ERN, then, serves as a beacon to highlight the violation of an expectation.[17] Research on the occurrence of the feedback ERN shows evidence that this potential has larger amplitudes when violations of expectancy are large. In other words, if an event is not likely to happen, the feedback ERN will be larger if no error is detected. Other studies have examined whether the ERN is elicited by varying the cost of an error and the evaluation of a response.[16]

In these trials, feedback is given about whether the participant has gained or lost money after a response. Amplitudes of ERN responses with small gains and small losses were similar. No ERN was elicited for any losses as opposed to an ERN for no wins, even though both outcomes are the same. The finding in this paradigm suggests that monitoring for wins and losses is based on the relative expected gains and losses. If you get a different outcome than expected, the ERN will be larger than for expected outcomes. ERN studies have also localized specific functions of the ACC.[17]

The rostral ACC seems to be active after an error commission, indicating an error response function, whereas the dorsal ACC is active after both an error and feedback, suggesting a more evaluative function (for fMRI evidence, see also[19][20][21] ). This evaluation is emotional in nature and highlights the amount of distress associated with a certain error.[5] Summarizing the evidence found by ERN studies, it appears to be the case that ACC receives information about a stimulus, selects an appropriate response, monitors the action, and adapts behavior if there is a violation of expectancy.[17]

Social evaluation

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Activity in the dorsal anterior cingulate cortex (dACC) has been implicated in processing both the detection and appraisal of social processes, including social exclusion. When exposed to repeated personal social evaluative tasks, non-depressed women showed reduced fMRI BOLD activation in the dACC on the second exposure, while women with a history of depression exhibited enhanced BOLD activation. This differential activity may reflect enhanced rumination about social evaluation or enhanced arousal associated with repeated social evaluation.[22]

The anterior cingulate cortex gyrus is involved in effort to help others.[23]

Reward-based learning theory

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A more comprehensive and recent theory describes the ACC as a more active component and poses that it detects and monitors errors, evaluates the degree of the error, and then suggests an appropriate form of action to be implemented by the motor system. Earlier evidence from electrical studies indicate the ACC has an evaluative component, which is indeed confirmed by fMRI studies. The dorsal and rostral areas of the ACC both seem to be affected by rewards and losses associated with errors. During one study, participants received monetary rewards and losses for correct and incorrect responses, respectively.[19]

Largest activation in the dACC was shown during loss trials. This stimulus did not elicit any errors, and, thus, error detection and monitoring theories cannot fully explain why this ACC activation would occur. The dorsal part of the ACC seems to play a key role in reward-based decision-making and learning. The rostral part of the ACC, on the other hand, is believed to be involved more with affective responses to errors. In an interesting expansion of the previously described experiment, the effects of rewards and costs on ACC's activation during error commission was examined.[21] Participants performed a version of the Eriksen flanker task using a set of letters assigned to each response button instead of arrows.

Targets were flanked by either a congruent or an incongruent set of letters. Using an image of a thumb (up, down, or neutral), participants received feedback on how much money they gained or lost. The researchers found greater rostral ACC activation when participants lost money during the trials. The participants reported being frustrated when making mistakes. Because the ACC is intricately involved with error detection and affective responses, it may very well be that this area forms the basis of self-confidence. Taken together, these findings indicate that both the dorsal and rostral areas are involved in evaluating the extent of the error and optimizing subsequent responses. A study confirming this notion explored the functions of both the dorsal and rostral areas of the ACC involved using a saccade task.[20]

Participants were shown a cue that indicated whether they had to make either a pro-saccade or an anti-saccade. An anti-saccade requires suppression of a distracting cue because the target appears in the opposite location causing the conflict. Results showed differing activation for the rostral and dorsal ACC areas. Early correct anti-saccade performance was associated with rostral activation. The dorsal area, on the other hand, was activated when errors were committed, but also for correct responses.

Whenever the dorsal area was active, fewer errors were committed providing more evidence that the ACC is involved with effortful performance. The second finding showed that, during error trials, the ACC activated later than for correct responses, clearly indicating a kind of evaluative function.

Role in consciousness

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The ACC area in the brain is associated with many functions that are correlated with conscious experience. Greater ACC activation levels were present in more emotionally aware female participants when shown short 'emotional' video clips.[24] Better emotional awareness is associated with improved recognition of emotional cues or targets, which is reflected by ACC activation.

The idea of awareness being associated with the ACC is supported by some evidence, in that it seems to be the case that, when subjects' responses are not congruent with actual responses, a larger error-related negativity is produced.[17]

One study found an ERN even when subjects were not aware of their error.[17] Awareness may not be necessary to elicit an ERN, but it could influence the effect of the amplitude of the feedback ERN. Relating to the reward-based learning theory, awareness could modulate expectancy violations. Increased awareness could result in decreased violations of expectancies and decreased awareness could achieve the opposite effect. Further research is needed to completely understand the effects of awareness on ACC activation.

In The Astonishing Hypothesis, Francis Crick identifies the anterior cingulate, to be specific the anterior cingulate sulcus, as a likely candidate for the center of free will in humans. Crick bases this suggestion on scans of patients with specific lesions that seem to interfere with their sense of independent will, such as alien hand syndrome.

Role in registering pain

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The ACC registers physical pain as shown in functional MRI studies that showed an increase in signal intensity, typically in the posterior part of area 24 of the ACC, that was correlated with pain intensity. When this pain-related activation was accompanied by attention-demanding cognitive tasks (verbal fluency), the attention-demanding tasks increased signal intensity in a region of the ACC anterior and/or superior to the pain-related activation region.[25] The ACC is the cortical area that has been most frequently linked to the experience of pain.[26] It appears to be involved in the emotional reaction to pain rather than to the perception of pain itself.[27]

Evidence from social neuroscience studies have suggested that, in addition to its role in physical pain, the ACC may also be involved in monitoring painful social situations as well, such as exclusion or rejection. When participants felt socially excluded in an fMRI virtual ball throwing game in which the ball was never thrown to the participant, the ACC showed activation. Further, this activation was correlated with a self-reported measure of social distress, indicating that the ACC may be involved in the detection and monitoring of social situations which may cause social/emotional pain, rather than just physical pain.[28]

Pathology

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Studying the effects of damage to the ACC provides insights into the type of functions it serves in the intact brain. Behavior that is associated with lesions in the ACC includes: inability to detect errors, severe difficulty with resolving stimulus conflict in a Stroop task, emotional instability, inattention, and akinetic mutism.[29][5][6] There is evidence that damage to ACC is present in patients with schizophrenia, where studies have shown patients have difficulty in dealing with conflicting spatial locations in a Stroop-like task and having abnormal ERNs.[6][16] Participants with ADHD were found to have reduced activation in the dorsal area of the ACC when performing the Stroop task.[30] Together, these findings corroborate results from imaging and electrical studies about the variety of functions attributed to the ACC.

OCD

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There is strong evidence that this area may have a role in obsessive–compulsive disorder. A recent study from the University of Cambridge showed that participants with OCD had higher levels of glutamate and lower levels of GABA in the anterior cingulate cortex, compared to participants without OCD. They used magnetic resonance spectroscopy to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex and supplementary motor area of healthy volunteers and participants with OCD. Participants with OCD had significantly higher levels of glutamate and lower levels of GABA in the ACC and a higher Glu:GABA ratio in that region.[31]

Recent SDM meta-analyses of voxel-based morphometry studies comparing people with OCD and healthy controls has found people with OCD to have increased grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, while decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate cortex.[32][33] These findings contrast with those in people with other anxiety disorders, who evince decreased (rather than increased) grey matter volumes in bilateral lenticular / caudate nuclei, while also decreased grey matter volumes in bilateral dorsal medial frontal / anterior cingulate gyri.[33]

Schizophrenia spectrum disorders

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In individuals with schizophrenia spectrum disorders, the anterior cingulate cortex has been found to be smaller compared to that of control subjects.[34][35] Meta-analyses have shown that its activity is reduced during emotion processing,[36] and its functional connectivity with the striatum is diminished at rest, which has been linked to cognitive rigidity.[37]

Anxiety

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The ACC has been suggested to have possible links with social anxiety, along with the amygdala part of the brain, but this research is still in its early stages.[38] A more recent study, by the Wake Forest Baptist Medical Centre, confirms the relationship between the ACC and anxiety regulation, by revealing mindfulness practice as a meditator for anxiety precisely through the ACC.[39]

Depression

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The adjacent subcallosal cingulate gyrus has been implicated in major depression and research indicates that deep-brain stimulation of the region could act to alleviate depressive symptoms.[40] Although people with depression had smaller subgenual ACCs,[41] their ACCs were more active when adjusted for size. This correlates well with increased subgenual ACC activity during sadness in healthy people,[42] and normalization of activity after successful treatment.[43] Of note, the activity of the subgenual cingulate cortex correlates with individual differences in negative affect during the baseline resting state; in other words, the greater the subgenual activity, the greater the negative affectivity in temperament.[44]

Lead exposure

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A study of brain MRIs taken on adults that had previously participated in the Cincinnati Lead Study found that people that had higher levels of lead exposure as children had decreased brain size as adults. This effect was most pronounced in the ACC (Cecil et al., 2008)[45] and is thought to relate to the cognitive and behavioral deficits of affected individuals.

Autism

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Impairments in the development of the anterior cingulate, together with impairments in the dorsal medial-frontal cortex, may constitute a neural substrate for socio-cognitive deficits in autism, such as social orienting and joint attention.[46]

PTSD

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An increasing number of studies are investigating the role of the ACC in post-traumatic stress disorder. PTSD diagnosis and related symptoms such as skin conductance response (SCR) to "potentially startling sounds" were found to be correlated with reduced ACC volume.[47] Further, childhood trauma and executive dysfunction seem to correlate with reduced ACC connectivity to surrounding neural regions.[48] In a longitudinal study, this reduced connectivity was able to predict high-risk drinking (binge drinking at least once per week for the past 12 months) up to four years later.[48]

General risk of psychopathology

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A study on differences in brain structure of adults with high and low levels of cognitive-attentional syndrome demonstrated diminished volume of the dorsal part of the ACC in the former group, indicating relationship between cortical thickness of ACC and general risk of psychopathology.[49]

Additional images

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  • Medial surface of human cerebral cortex - gyri
    Medial surface of human cerebral cortex - gyri
  • Anterior Cingulate Cortex of monkey (Macaca mulatta).
    Anterior Cingulate Cortex of monkey (Macaca mulatta).
  • Caudal Anterior Cingulate gyrus
    Caudal Anterior Cingulate gyrus
  • Rostral Anterior Cingulate gyrus
    Rostral Anterior Cingulate gyrus

See also

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Wikimedia Commons has media related to Anterior cingulate cortex.

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Anterior cingulate cortex

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The anterior cingulate cortex (ACC) is a subdivision of the cingulate gyrus, a fold of cortical tissue located on the medial surface of the that encircles the , serving as a critical hub in the for integrating emotional, cognitive, and motor processes. It comprises Brodmann areas 24, 25, 32, and 33, and is anatomically bounded by the cingulate sulcus superiorly and the callosal sulcus inferiorly, connecting to regions such as the , , , , and motor areas to facilitate . Embryologically derived from the telencephalon around the sixth week of , the ACC matures functionally in stages, with motor and cognitive aspects developing in and social-emotional functions extending into . The ACC is functionally heterogeneous, often subdivided into the perigenual ACC (pACC), which primarily handles emotional processing and autonomic responses; the dorsal ACC (dACC), involved in cognitive control, reward-based , and conflict monitoring; and the midcingulate motor areas, which translate intentions into actions. In emotion regulation, the ACC receives inputs from the and regarding rewards and punishments, enabling the evaluation of emotional salience and guiding responses to stimuli like pleasure or pain. For instance, studies show activation in the pregenual ACC during exposure to pleasant stimuli and in supracallosal regions for unpleasant ones, underscoring its role in affective awareness. Cognitively, the ACC supports , goal-directed behavior, error detection, and by linking reward values to action outcomes, as evidenced by neuronal recordings in that encode effort and value during tasks. It also contributes to , including and , through connections with the and hippocampus, which aid in processing and relevant to interpersonal interactions. Lesions or dysfunction in the ACC, as seen in conditions like depression or , impair these functions, leading to deficits in initiation, volition, and adaptive responding. Overall, the ACC's evolutionary adaptations, such as the presence of spindle-shaped von Economo neurons found in humans, great apes, and other socially complex mammals such as cetaceans and , highlight its expanded role in complex, flexible behaviors.

Anatomy

Location and Gross Structure

The anterior cingulate cortex (ACC) is located on the medial aspect of the frontal lobe, forming the anterior portion of the cingulate gyrus that arches over the genu and body of the . It resides on the medial surface of each , superior to the and separated from it by the callosal sulcus. The cingulate sulcus runs parallel and superior to the callosal sulcus, demarcating the ACC from the . The ACC spans Brodmann areas 24 (dorsal portion), 25 (subcallosal portion), 32 (rostral portion), and 33 (subgenual portion). Its gross boundaries are defined by the cingulate sulcus superiorly and the paracingulate sulcus, when present, which parallels the cingulate sulcus dorsally and contributes to individual variability in surface morphology. The paracingulate sulcus appears in approximately 50% of individuals, more prominently on the left hemisphere, influencing the overall contour and prominence of the region. In adults, the bilateral volume of the ACC is approximately 5-7 cm³, reflecting its compact yet pivotal positioning within the . Evolutionarily, the ACC has expanded in humans relative to other primates, correlating with increased encephalization and the emergence of specialized spindle-shaped von Economo neurons in layer Vb, which are found in humans, great apes, cetaceans, and elephants, but are absent in most other primate species and linked to heightened cognitive processing demands. This expansion underscores the region's adaptation for complex integration in human brain architecture.

Subregions and Cytoarchitecture

The anterior cingulate cortex (ACC) is parcellated into distinct subregions based on cytoarchitectonic criteria, with the dorsal ACC (dACC) primarily encompassing Brodmann area 24 and the rostral/ventral ACC (rACC/vACC) including areas 25, 32, and 33. The dACC features a more differentiated laminar organization suited to cognitive demands, while the rACC/vACC shows variations that align with affective processing, such as in the subgenual zone (areas 25 and s32). These divisions arise from differences in cell packing, layer widths, and neuronal morphology along the dorsoventral axis. Cytoarchitecturally, the ACC belongs to the limbic cortex, exhibiting predominantly agranular (e.g., area 25, lacking a distinct layer IV) and dysgranular (e.g., area 32, with a rudimentary layer IV) patterns that distinguish it from isocortical regions. Layers II and III are often broad and neuron-dense in ventral portions, with layer V containing large pyramidal projection neurons critical for output signaling. In the rACC, layer Vb is particularly notable for hosting von Economo neurons (VENs), which are large, spindle-shaped bipolar cells found in humans, great apes, cetaceans, and , enabling rapid interregional communication. These VENs comprise approximately 1-2% of neurons in layer V of the ACC, with densities averaging around 56 VENs per mm³ in healthy adults. Histological variations further delineate subregions: the dACC displays denser packing and more neurofilament-rich neurons in layer Va, supporting complex processing, whereas the subgenual vACC has thinner layer III, broader layer II, and smaller neurons with shorter dendrites, adaptations linked to emotional roles. The pregenual dACC (pd24c) shows aggregates of neurons in layer Vb and broader layer II compared to its ventral counterpart (pv24c), highlighting gradient-like transitions in cellular architecture.

Connectivity

The anterior cingulate cortex (ACC) receives a variety of afferent inputs that integrate sensory, emotional, and cognitive information. Prominent inputs arise from the mediodorsal nucleus of the , which provides relays for cognitive and executive signals, particularly influencing the dorsal ACC (dACC). The sends projections conveying emotional and fear-related information, with stronger connections to the rostral ACC (rACC) and subgenual ACC (sACC). Additionally, the insula contributes interoceptive signals related to visceral sensations and pain, linking primarily to the rACC for affective processing. The medial pain pathway, responsible for the affective-motivational aspects of pain, projects primarily to the rostral/dorsal anterior cingulate cortex (rdACC), overlapping with salience network regions. Efferent outputs from the ACC project to regions involved in executive control, reward evaluation, and pain modulation. The ACC sends projections to the (PFC), facilitating cognitive control and decision-making, with dACC outputs being particularly prominent to dorsolateral PFC areas. Outputs to the (OFC) support reward processing and valuation, originating mainly from rACC subregions. For pain regulation, ACC efferents contribute to descending pathways that modulate nociceptive transmission in the dorsal horn, often via intermediate structures like the and . Key tracts underpin ACC interconnectivity. The cingulum bundle serves as a major pathway for intra-cingulate communication, linking ACC subregions with posterior cingulate areas—including the posterior cingulate cortex (PCC), a core node of the default mode network (DMN)—and facilitating exchanges with prefrontal cortices—including the medial prefrontal cortex (mPFC), another DMN node—as well as thalamic nuclei. The cingulum bundle thus provides structural connectivity bridging the ACC to DMN components, facilitating integration of affective information such as pain processing with self-referential processing. Subregional differences in connectivity reflect functional specialization. The dACC exhibits stronger links to executive networks, such as the frontoparietal , via projections to lateral PFC and supplementary motor areas. In contrast, the rACC connects more extensively to limbic structures, including the for autonomic responses and the ventral for motivation. These patterns, conserved across species, enable the ACC to bridge cognitive and emotional domains.

Functions

Cognitive Control and Monitoring

The anterior cingulate cortex (ACC), particularly its dorsal subdivision (dACC), plays a central role in cognitive control by detecting and signaling conflicts in information processing, thereby enabling adaptive adjustments in attention and executive function. According to the conflict monitoring theory, the dACC identifies mismatches between competing response options, such as when multiple stimuli evoke incompatible actions, prompting recruitment of prefrontal resources to resolve the interference. This function is evident in tasks requiring selective attention, where the dACC activation scales with the degree of response competition, facilitating top-down control to suppress irrelevant information and prioritize goal-relevant responses. A key example of this monitoring process occurs in the Stroop task, where incongruent color-word stimuli (e.g., the word "red" printed in blue ink) elicit heightened dACC activity compared to congruent trials, reflecting detection of the conflict between reading the word and naming the color. (fMRI) studies consistently show dACC hyperactivity during high-conflict trials across various paradigms, correlating with subsequent behavioral adjustments like slower response times to enhance accuracy. In the , where central targets are flanked by compatible or incompatible distractors, dACC engagement signals the need for increased , particularly on incongruent trials that demand suppression of flanker interference. Error detection represents another core aspect of ACC-mediated monitoring, manifesting as the (ERN), an component observed in (EEG) approximately 50-100 ms after an erroneous response, with a peak negativity at 200-300 ms post-error. The dACC is implicated as a primary generator of the ERN, which reflects rapid evaluation of performance discrepancies and initiates compensatory mechanisms to improve future accuracy. studies in humans with anterior cingulate damage demonstrate impaired error awareness and reduced post-error slowing, underscoring the region's necessity for online performance monitoring. The ACC also contributes to task-switching by detecting the need for cognitive set reconfiguration, as seen in paradigms requiring alternation between rules or response mappings. During switches, dACC activity predicts enhanced prefrontal engagement and behavioral adaptation, such as reduced perseveration on prior tasks. Patients with ACC lesions exhibit deficits in set-shifting, including prolonged latencies and increased errors on Wisconsin Card Sorting Test-like tasks, confirming the region's role in overcoming inertial biases toward outdated strategies.

Emotional Regulation and Social Processing

The rostral anterior cingulate cortex (rACC) is pivotal in emotion regulation, particularly through its capacity to downregulate responses during cognitive reappraisal. In reappraisal tasks, where individuals reinterpret emotionally evocative stimuli to lessen their impact, rACC activation increases and negatively correlates with activity, leading to reduced negative affect and enhanced emotional control. This top-down modulation resolves emotional conflicts by inhibiting limbic reactivity, as demonstrated in studies. In social evaluation, the anterior cingulate cortex (ACC) facilitates and the processing of . Activation in the ACC occurs when individuals observe in others, engaging the affective components of without necessarily recruiting sensory pain networks, thereby enabling vicarious emotional sharing. Likewise, during the paradigm—a virtual ball-tossing game simulating —ACC engagement correlates with self-reported distress, highlighting its role in detecting and responding to interpersonal . Dysfunction in the rACC contributes to impaired maternal bonding in postpartum depression (PPD). In PPD, increased functional connectivity involving the subgenual ACC—a subregion of the rACC—reflects aberrant hyperactivity that sustains negative rumination and blunts reward responses to infant cues, thereby disrupting attachment formation and maternal sensitivity. The ACC also underpins interpersonal conflict resolution by signaling inequity aversion in social exchanges. In the ultimatum game, where participants decide whether to accept or reject resource divisions, unfair offers provoke ACC activation, which predicts rejection behavior and underscores the region's involvement in fairness judgments and social norm enforcement.

Reward Learning and Decision-Making

The anterior cingulate cortex (ACC) plays a pivotal role in reward-based learning by implementing prediction error signaling through interactions with dopaminergic systems, which facilitate the updating of value representations for actions and outcomes. Dopaminergic neurons in the midbrain project to the ACC, conveying reward prediction errors (RPEs) that highlight discrepancies between expected and actual rewards, thereby driving associative learning and behavioral adaptation. This interaction enables the ACC to integrate sensory cues with reward history, refining internal models of environmental contingencies to optimize future choices. Seminal electrophysiological studies in primates have demonstrated that ACC neurons respond to these dopaminergic signals, encoding errors that promote learning from both rewarding and non-rewarding experiences without strictly mirroring the signed nature of midbrain dopamine responses. In processes, the ACC integrates costs and benefits, particularly in tasks where individuals must evaluate resource patches under . For instance, in patch- paradigms, ACC activity signals the relative value of continuing exploitation versus switching to , balancing immediate gains against potential future rewards. Recent human intracranial recordings have revealed that beta oscillations (12-30 Hz) in the ACC predict reward biases, with increased beta power preceding choices toward higher-value options and correlating with the magnitude of behavioral preference shifts. These oscillations also track actual reward receipt, underscoring the ACC's role in dynamically adjusting decision thresholds based on integrated cost-benefit evaluations. The ACC supports the exploration-exploitation trade-off in adaptive , particularly through loops with the that optimize behavior in uncertain environments. In tasks requiring flexibility between persistent exploitation of known rewards and exploratory sampling of alternatives, ACC-striatal circuits causally modulate the balance, enhancing during periods of low certainty to maximize long-term gains. During feedback processing, the ACC encodes signed prediction errors in probabilistic tasks, differentiating between positive and negative deviations from expectations to guide value updates. For example, in reversal learning paradigms with variable reward probabilities, ACC neurons signal positive errors (e.g., +0.5 for an unexpected gain when expecting a 50% chance) by increasing activity to reinforce successful actions, while negative errors prompt strategy adjustments. This signed encoding, observed via single-unit recordings, distinguishes the ACC from regions like the ventral , which may prioritize unsigned surprise, and contributes to precise error-driven learning without overgeneralizing to mere novelty detection.

Pain and Sensory Integration

The anterior cingulate cortex (ACC), particularly its rostral subdivision (rACC), plays a central role in processing the affective dimension of pain, encoding the unpleasantness and emotional distress associated with nociceptive stimuli rather than the sensory-discriminative aspects such as intensity or location, which are primarily handled by the insula and somatosensory cortices. Functional neuroimaging studies have demonstrated that rACC activation correlates specifically with subjective ratings of pain unpleasantness during acute noxious stimulation, supporting its involvement in the motivational and emotional evaluation of pain. This affective processing facilitates adaptive behavioral responses, such as avoidance or seeking relief, by integrating nociceptive inputs with cognitive and emotional contexts. In conditions, the ACC exhibits sustained hyperactivity that contributes to central , a state of heightened neural responsiveness amplifying . Recent studies have identified synaptic potentiation mechanisms in the ACC, including (LTP) of glutamatergic synapses, as key drivers of this hypersensitivity; for instance, 2024 research using rodent models of neuropathic and showed that LTP in ACC pyramidal neurons sustains by enhancing excitatory transmission and behavioral responses. This potentiation is mediated by calcium-permeable receptors and involves signaling pathways like ERK and CaMKIV, leading to persistent amplification of signals even after the initial injury resolves. Such changes underscore the ACC's role in the transition from acute to states, where maladaptive plasticity perpetuates emotional suffering and functional impairment. The ACC integrates diverse signals, combining visceral —such as from gastrointestinal or cardiac sources—with other aversive experiences through shared neural pathways. For example, activates ACC circuits that overlap with those processing social pain, like rejection or exclusion, enabling a unified affective response to both physical and interpersonal threats; this convergence is evident in meta-analyses showing consistent ACC engagement across these domains. These integrative functions allow the ACC to contextualize within broader emotional and social frameworks, influencing and interpersonal behaviors. Furthermore, the ACC contributes to descending pain modulation by projecting to the (PAG), a structure that gates transmission at the spinal level. These projections, primarily from the dorsal ACC, release neurotransmitters like glutamate to activate PAG neurons, thereby inhibiting ascending pain signals and dampening spinal during adaptive antinociceptive responses. In chronic pain, however, dysregulated ACC-PAG signaling can shift toward facilitation, exacerbating and fear-avoidance behaviors.

Development and Plasticity

Prenatal and Postnatal Development

The anterior cingulate cortex (ACC) originates early in human gestation as part of the limbic system's foundational structures. The cingulate cortex begins to form around the 8th week of gestation, coinciding with the initial differentiation of neuroblasts in the telencephalon. Around gestational weeks 24 to 28, the cingulate sulcus emerges as one of the primary sulci, delineating the region's gross morphology. Brodmann area 24 (BA24), the primary cytoarchitectonic subdivision of the ACC, differentiates during the second trimester, as neuronal migration and layering establish its distinct granular and dysgranular characteristics. Initial thalamocortical projections to the ACC arrive by the late second trimester, around week 26, initiating basic sensory-relay pathways that support emerging thalamo-cingulate interactions. Postnatally, the ACC exhibits rapid structural refinement, with myelination accelerating in the first two years of life to enhance signal efficiency across its connections. tracts in the cingulate region, including those linking to prefrontal and limbic areas, show substantial increases in myelin density during this period, aligning with rapid overall growth rates of up to 1% per day in early infancy. The dorsal ACC (dACC), involved in cognitive monitoring, shows enhanced error-related activation patterns by age 10, though full functional maturity continues into , as evidenced by stabilized cortical thickness. In contrast, the rostral ACC (rACC), associated with emotional processing, undergoes prolonged maturation extending into early adulthood, peaking around ages 25 to 30, with continued thinning and connectivity refinements observed through the third decade. Adolescence represents a for ACC development, characterized by changes in regional volume driven by pubertal hormones such as testosterone and that influence gray matter expansion and synaptic reorganization. This hormonal modulation heightens the ACC's vulnerability to early life stress, which can disrupt volumetric trajectories and long-term adaptability. Functional connectivity within ACC networks strengthens progressively from infancy, with postnatal refinements enabling the emergence of basic cognitive control mechanisms by age 7, as task-related activations in error monitoring and shift become more robust.

Synaptic Plasticity and Adaptability

The anterior cingulate cortex (ACC) exhibits robust , particularly through (LTP), a process critical for encoding persistent neural changes underlying behaviors such as . LTP in the ACC is primarily mediated by N-methyl-D-aspartate (NMDA) receptors, where activation leads to calcium influx and subsequent enhancement of synaptic efficacy, contributing to the strengthening of pain-related signals even after the initial stimulus subsides. This NMDA-dependent LTP involves correlated pre- and postsynaptic activity driving synaptic strengthening. Adult neurogenesis in the ACC is limited but supports hippocampal-like processes, facilitating neural adaptability in response to environmental demands. A 2023 review highlights that the ACC orchestrates through connections to subventricular and subgranular zones, promoting neuron generation that aids under stress conditions, such as chronic emotional or cognitive strain. This enhances circuit flexibility, allowing the ACC to integrate stress-induced changes into long-term adaptive responses. Experience-dependent remodeling in the ACC enables dynamic neural adaptability, exemplified by mechanisms sustaining . Recent 2024 studies demonstrate that synchronized oscillating electromagnetic fields generated in the ACC's layer 2/3 pyramidal neurons contribute to chronicity by amplifying synaptic and integrating inputs from thalamic and limbic regions, thus perpetuating aversive states through experience-driven plasticity. At the molecular level, (BDNF) upregulation in the ACC drives dendritic spine growth, supporting learning-induced structural changes. BDNF signaling enhances spine density and maturation on pyramidal neurons, promoting synaptic connectivity and plasticity in response to behavioral experiences like reward or aversive learning.

Research Methods

Neuroimaging Techniques

Neuroimaging techniques have revolutionized the study of the anterior cingulate cortex (ACC) by providing non-invasive methods to map its structure, connectivity, and functional activity . These approaches, including (fMRI), structural MRI, and diffusion tensor imaging (DTI), offer complementary insights into ACC involvement in cognitive and emotional processes, with spatial resolutions enabling subregional differentiation between dorsal (dACC) and rostral (rACC) areas. Functional MRI, particularly through blood-oxygen-level-dependent (BOLD) contrast, is a primary tool for detecting ACC activation during tasks requiring cognitive control, such as conflict monitoring. With typical spatial resolutions of 2-3 mm, fMRI localizes BOLD signals to the dACC in paradigms like the Stroop task, where incongruent stimuli elicit significant activation reflecting response conflict detection. Seminal studies demonstrate robust dACC engagement in these tasks, with BOLD responses scaling to conflict intensity and predicting subsequent behavioral adjustments. Structural MRI facilitates volumetric assessment of the ACC, quantifying gray matter integrity and revealing atrophy in neuropsychiatric conditions. In major depressive disorder, volumetric analyses show significant ACC volume reductions, particularly in the subgenual region, correlating with symptom severity and treatment response. These findings highlight structural MRI's role in identifying morphological changes that underlie ACC dysfunction. Diffusion tensor imaging (DTI) evaluates integrity connecting the ACC via tracts like the cingulum bundle, using metrics such as (FA) to assess fiber coherence. In healthy adults, higher FA values indicate robust directional connectivity between the ACC and prefrontal or temporal regions. Deviations in FA signal potential disruptions in ACC-related . Recent advances in resting-state fMRI have elucidated intrinsic functional connectivity patterns involving the ACC, linking stronger rACC-dorsolateral (dlPFC) coupling to in 2024 studies. These connectivity analyses, often using seed-based approaches, complement task-based methods by revealing baseline network dynamics associated with adaptive cognition.

Electrophysiological Approaches

(EEG) and event-related potentials () provide high temporal resolution for capturing real-time activity in the anterior cingulate cortex (ACC), particularly in relation to error processing and feedback evaluation. The (ERN), a prominent ERP component, manifests as a negative deflection peaking approximately 50 ms after an erroneous response, with typical amplitudes ranging from -5 to -10 μV, and is maximal at the frontocentral FCz , reflecting ACC involvement in performance monitoring. Similarly, the feedback-related negativity (FRN), observed around 250-300 ms post-feedback, is larger for negative outcomes and also peaks at FCz, indicating ACC sensitivity to outcome valence in decision contexts. These components offer millisecond-precision insights into conflict signals, such as those arising during cognitive control tasks. Intracranial recordings enable direct measurement of ACC neural activity with superior spatial specificity compared to scalp methods. In studies, single-unit recordings reveal that ACC neurons exhibit increased firing rates 100-200 ms prior to error commission, signaling anticipatory during tasks requiring response selection. Recent human intracranial EEG (iEEG) findings from 2024 demonstrate beta-band (12-30 Hz) desynchronization in the ACC during value-based , where reduced beta power correlates with reward prediction and choice biases, highlighting the region's role in integrating motivational signals. Magnetoencephalography (MEG) complements EEG by detecting magnetic fields from ACC dipoles, particularly during , with evoked amplitudes typically in the 50-100 fT range. MEG source modeling localizes conflict-related activity to the ACC, capturing oscillatory dynamics such as theta-band increases around 200-300 ms post-stimulus in tasks involving response competition. In animal models, optogenetic techniques have established the ACC's causal contributions to exploratory behavior in . A 2024 study using optogenetic inhibition of ACC neurons in rats during decision tasks showed impaired initiation and flexibility in exploration-exploitation trade-offs, confirming the region's necessity for adaptive behavioral adjustments under uncertainty.

Pathology

Psychiatric Disorders

In obsessive-compulsive disorder (OCD), the dorsal anterior cingulate cortex (dACC) exhibits hyperactivation during error monitoring tasks, as evidenced by (fMRI) studies showing increased blood-oxygen-level-dependent (BOLD) signals in response to conflict and errors. This hyperactivity, often quantified as elevated BOLD responses compared to healthy controls, reflects impaired cognitive control and excessive error signaling in OCD pathophysiology. Surgical interventions like cingulotomy, which target the ACC, have demonstrated symptom reduction in 35-70% of treatment-refractory cases, with Yale-Brown Obsessive Compulsive Scale scores decreasing by at least 35% in responders. In , hypoactivity in the rostral anterior cingulate cortex (rACC) correlates with , a core symptom involving diminished reward responsiveness and emotional blunting. This reduced rACC engagement during emotional processing tasks underscores its role in affective regulation deficits. A 2023 study of (DBS) targeting the subgenual ACC in 10 patients with reported response rates of 90% and remission rates of 70% over 24 weeks. Schizophrenia involves reduced connectivity between the ACC and , as measured by diffusion tensor imaging (DTI) showing reduced in affected tracts, indicating disrupted structural integrity and impaired executive function. Auditory s in schizophrenia are associated with abnormal gamma-band oscillations (40-80 Hz) involving the ACC and auditory cortices, where diminished phase synchronization correlates with hallucination severity. In anxiety disorders, decoupling between the and ACC contributes to heightened worry, with reduced functional connectivity predicting and autonomic dysregulation over time. Recent studies highlight rACC involvement in feedback learning deficits, where enhanced oscillations during bias anxious individuals toward negative outcomes.

Neurodevelopmental and Toxicological Conditions

In autism spectrum disorder (ASD), structural abnormalities in the anterior cingulate cortex (ACC) include reduced gray matter volume, which contributes to impairments in social processing and cognitive control. Compared to neurotypical individuals, those with ASD exhibit smaller ACC volumes, alongside decreased glucose metabolism in this region, potentially disrupting error monitoring and response inhibition essential for social interactions. Additionally, some studies suggest alterations in von Economo neurons (also known as spindle cells), specialized projection neurons located in layer V of the ACC and frontoinsular cortex, potentially contributing to social deficits, though findings are inconsistent. Such structural and cellular alterations in the ACC are associated with core ASD symptoms like reduced social awareness and repetitive behaviors. Post-traumatic stress disorder (PTSD), particularly when arising from early-life trauma, involves ACC hyperresponsivity to threat-related stimuli, as evidenced by functional magnetic resonance imaging (fMRI) studies showing exaggerated activation in the dorsal ACC during cognitive control of emotional responses. This hyperactivation, observed in both affected individuals and those at familial risk, may heighten vigilance to potential dangers and contribute to persistent fear responses. Furthermore, during trauma recall tasks, PTSD is characterized by hyperactivity in the ACC-amygdala circuit, with increased BOLD signals in the amygdala and dorsal ACC to trauma-associated cues, leading to enhanced emotional reactivity and memory distortions for aversive events. This circuitry imbalance underscores the ACC's role in failed fear extinction following early adverse experiences. Chronic low-level lead exposure, defined as blood lead concentrations of 5-10 μg/dL, induces neurotoxic effects on the ACC, including cortical thinning and reduced gray matter volume in frontal regions encompassing the ACC, as documented in longitudinal studies of adults with childhood exposure. These changes correlate with cognitive deficits such as impairments in executive function, , and learning, persisting into adulthood despite cessation of exposure; pre-2020 cohort studies confirm that even subclinical levels below 10 μg/dL are sufficient to cause these outcomes, with no significant mechanistic updates in recent literature. Early hypo-connectivity in the ACC, particularly with default mode and salience networks, serves as a for increased risk of across multiple disorders, including anxiety, depression, and . In children and adolescents, reduced ACC functional connectivity predicts transdiagnostic vulnerability, with studies indicating increased risk of developing issues compared to those with typical connectivity. This hypo-connectivity, often linked to early adversity, reflects impaired integration of cognitive and emotional , heightening susceptibility to environmental stressors in neurodevelopment.

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