Cognitive and emotional influences in anterior cingulate cortex

Anterior cingulate cortex (ACC) is a part of the brain's limbic system. Classically, this region has been related to affect, on the basis of lesion studies in humans and in animals. In the late 1980s, neuroimaging research indicated that ACC was active in many studies of cognition. The findings from EEG studies of a focal area of negativity in scalp electrodes following an error response led to the idea that ACC might be the brain's error detection and correction device. In this article, these various findings are reviewed in relation to the idea that ACC is a part of a circuit involved in a form of attention that serves to regulate both cognitive and emotional processing. Neuroimaging studies showing that separate areas of ACC are involved in cognition and emotion are discussed and related to results showing that the error negativity is influenced by affect and motivation. In addition, the development of the emotional and cognitive roles of ACC are discussed, and how the success of this regulation in controlling responses might be correlated with cingulate size. Finally, some theories are considered about how the different subdivisions of ACC might interact with other cortical structures as a part of the circuits involved in the regulation of mental and emotional activity.     

Emotional processing in anterior cingulate and medial prefrontal cortex

Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.     

The subgenual anterior cingulate cortex in mood disorders

The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.     

Risk prediction and aversion by anterior cingulate cortex

The recently proposed error-likelihood hypothesis suggests that anterior cingulate cortex (ACC) and surrounding areas will become active in proportion to the perceived likelihood of an error. The hypothesis was originally derived from a computational model prediction. The same computational model now makes a further prediction that ACC will be sensitive not only to predicted error likelihood, but also to the predicted magnitude of the consequences, should an error occur. The product of error likelihood and predicted error consequence magnitude collectively defines the general “expected risk” of a given behavior in a manner analogous but orthogonal to subjective expected utility theory. New fMRI results from an incentive change signal task now replicate the errorlikelihood effect, validate the further predictions of the computational model, and suggest why some segments of the population may fail to show an error-likelihood effect. In particular, error-likelihood effects and expected risk effects in general indicate greater sensitivity to earlier predictors of errors and are seen in risk-averse but not risktolerant individuals. Taken together, the results are consistent with an expected risk model of ACC and suggest that ACC may generally contribute to cognitive control by recruiting brain activity to avoid risk.     

Conflict monitoring and anterior cingulate cortex: an update

One hypothesis concerning the human dorsal anterior cingulate cortex (ACC) is that it functions, in part, to signal the occurrence of conflicts in information processing, thereby triggering compensatory adjustments in cognitive control. Since this idea was first proposed, a great deal of relevant empirical evidence has accrued. This evidence has largely corroborated the conflict-monitoring hypothesis, and some very recent work has provided striking new support for the theory. At the same time, other findings have posed specific challenges, especially concerning the way the theory addresses the processing of errors. Recent research has also begun to shed light on the larger function of the ACC, suggesting some new possibilities concerning how conflict monitoring might fit into the cingulate's overall role in cognition and action.     

Reward-based contextual learning supported by anterior cingulate cortex

The anterior cingulate cortex (ACC) is commonly associated with cognitive control and decision making, but its specific function is highly debated. To explore a recent theory that the ACC learns the reward values of task contexts (Holroyd & McClure in Psychological Review, 122, 54–83, 2015; Holroyd & Yeung in Trends in Cognitive Sciences, 16, 122–128, 2012), we recorded the event-related brain potentials (ERPs) from participants as they played a novel gambling task. The participants were first required to select from among three games in one “virtual casino,” and subsequently they were required to select from among three different games in a different virtual casino; unbeknownst to them, the payoffs for the games were higher in one casino than in the other. Analysis of the reward positivity, an ERP component believed to reflect reward-related signals carried to the ACC by the midbrain dopamine system, revealed that the ACC is sensitive to differences in the reward values associated with both the casinos and the games inside the casinos, indicating that participants learned the values of the contexts in which rewards were delivered. These results highlight the importance of the ACC in learning the reward values of task contexts in order to guide action selection.     

Motivation of extended behaviors by anterior cingulate cortex

Intense research interest over the past decade has yielded diverse and often discrepant theories about the function of anterior cingulate cortex (ACC). In particular, a dichotomy has emerged between neuropsychological theories suggesting a primary role for ACC in motivating or 'energizing' behavior, and neuroimaging-inspired theories emphasizing its contribution to cognitive control and reinforcement learning. To reconcile these views, we propose that ACC supports the selection and maintenance of 'options' - extended, context-specific sequences of behavior directed toward particular goals - that are learned through a process of hierarchical reinforcement learning. This theory accounts for ACC activity in relation to learning and control while simultaneously explaining the effects of ACC damage as disrupting the motivational context supporting the production of goal-directed action sequences.     

Expectations,gains, and losses in the anterior cingulate cortex

The anterior cingulate cortex (ACC) participates in evaluating actions and outcomes. Little is known on how action-reward values are processed in ACC and if the context in which actions are performed influences this processing. In the present article, we report ACC unit activity of monkeys performing two tasks. The first task tested whether the encoding of reward values is context dependent—that is, dependent on the size of the other rewards that are available in the current block of trials. The second task tested whether unexpected events signaling a change in reward are represented. We show that the context created by a block design (i.e., the context of possible alternative rewards) influences the encoding of reward values, even if no decision or choice is required. ACC activity encodes the relative and not absolute expected reward values. Moreover, cingulate activity signals and evaluates when reward expectations are violated by unexpected stimuli, indicating reward gains or losses.     

Cognitive deficits, schizophrenia, and the anterior cingulate cortex

Cognitive deficits are thought to be responsible for some of the symptoms and dysfunction in schizophrenia. Recent research on the anterior cingulate cortex supports this assumption. More detailed and definitive evidence for this association will require identification of specific neural networks whose abnormal structure, connections or activity create the cognitive deficits in question.     

Personality predicts working-memory-related activation in the caudal anterior cingulate cortex

Behavioral studies suggest that two affective dimensions of personality are associated with working memory (WM) function. WM load is known to modulate neural activity in the caudal anterior cingulate cortex (ACC), a brain region critical for the cognitive control of behavior. On this basis, we hypothesized that neural activity in the caudal ACC during a WM task should be associated with personality: correlated negatively with behavioral approach sensitivity (BAS) and positively with behavioral inhibition sensitivity (BIS). Using functional magnetic resonance imaging, we measured brain activity in 14 participants performing a three-back WM task. Higher self-reported BAS predicted better WM performance (r = .27) and lower WM-related activation in the caudal ACC (r = -.84), suggesting personality differences in cognitive control. The data bolster approach-withdrawal (action control) theories of personality and suggest refinements to the dominant views of ACC and personality.     

Dopamine D1 receptors in the anterior cingulate cortex regulate effort-based decision making

The anterior cingulate cortex (ACC) has been implicated in encoding whether or not an action is worth performing in view of the expected benefit and the cost of performing the action. Dopamine input to the ACC may be critical for this form of effort-based decision making; however, the role of distinct ACC dopamine receptors is yet unknown. Therefore, we examined in rats the effects of an intra-ACC D1 and D2 receptor blockade on effort-based decision making tested in a T-maze cost-benefit task. In this task, subjects could either choose to climb a barrier to obtain a high reward in one arm or a low reward in the other arm without a barrier. Unlike vehicle-treated rats, rats with intra-ACC infusion of the D1 receptor antagonist SCH23390 exhibited a reduced preference for the high-cost- high-reward response option when having the choice to obtain a low reward with little effort. In contrast, in rats with intra-ACC infusion of the D2 receptor antagonist eticlopride, the preference for the high-cost-high-reward response option was not altered relative to vehicle-treated rats. These data provide the first evidence that D1 receptors in the ACC regulate effort-based decision making.     

Expectation and temperament moderate amygdala and dorsal anterior cingulate cortex responses to fear faces

A chronic tendency to avoid novelty is often the result of a temperamental bias called inhibited temperament, and is associated with increased risk for anxiety disorders. Neuroimaging studies have demonstrated that an inhibited temperament is associated with increased amygdalar blood-oxygenation-level-dependent (BOLD) response to unfamiliar faces that were not expected; however, the effects of variations in expectancy remain unknown. Using functional magnetic resonance imaging (fMRI), we studied BOLD response to infrequently encountered fear faces that were either expected or not expected in 42 adults with an inhibited or an uninhibited temperament. Individuals with an inhibited temperament had greater amygdala, but less dorsal anterior cingulate cortex (dACC), BOLD response when the stimuli were expected. In contrast, those with an uninhibited temperament had a smaller amygdala but larger dorsal anterior cingulate cortex BOLD response when expecting to see fear faces. These findings demonstrate temperament differences in expectancy effects and provide preliminary evidence for the dACC as a neural substrate mediating differences in inhibited temperament. Enhanced amygdala sensitivity coupled with weak inhibitory control from the dACC may form a neural circuit mediating behaviors characteristic of inhibited temperament and risk for anxiety disorders.     

Overcoming suppression in order to remember: Contributions from anterior cingulate and ventrolateral prefrontal cortex

The ability to remember is often compromised by competition from irrelevant memories. However, acts of selective remembering can alter the competitive relationship between memories; memories that are selected against are weakened, whereas those that are retrieved are strengthened. Whereas the weakening of selectedagainst memories is typically evidenced by subsequently poorer recall of these memories, the present study tested the hypothesis that when previously selected-against memories can subsequently be successfully retrieved, such acts of successful retrieval are associated with engagement of neurobiological mechanisms that serve to detect and overcome competition. Consistent with this hypothesis, fMRI revealed that anterior cingulate cortex and right ventrolateral prefrontal cortex are differentially engaged during successful retrieval of previously selected-against memories, and that their engagement is directly related to the magnitude of weakening that is induced by prior acts of selecting against these memories.     

Impaired reward processing by anterior cingulate cortex in children with attention deficit hyperactivity disorder

Decades of research have examined the neurocognitive mechanisms of cognitive control, but the motivational factors underlying task selection and performance remain to be elucidated. We recently proposed that anterior cingulate cortex (ACC) utilizes reward prediction error signals carried by the midbrain dopamine system to learn the value of tasks according to the principles of hierarchical reinforcement learning. According to this position, disruption of the ACC–dopamine interface can disrupt the selection and execution of extended, task-related behaviors. To investigate this issue, we recorded the event-related brain potential (ERP) from children with attention deficit hyperactivity disorder (ADHD), which is strongly associated with ACC–dopamine dysfunction, and from typically developing children while they navigated a simple “virtual T-maze” to find rewards. Depending on the condition, the feedback stimuli on each trial indicated that the children earned or failed to earn either money or points. We found that the reward positivity, an ERP component proposed to index the impact of dopamine-related reward signals on ACC, was significantly larger with money feedback than with points feedback for the children with ADHD, but not for the typically developing children. These results suggest that disruption of the ACC–dopamine interface may underlie the impairments in motivational control observed in childhood ADHD.     

On the role of the anterior cingulate cortex in phonation: A case report

A 41-year-old male patient is presented with a lesion in the anterior cingulate cortex, medial orbital cortex, and rostral striatum bilaterally and supplementary motor area on the left side. The patient first exhibited a state of akinetic mutism which lasted about 6 weeks. During this state, no volitional vocal utterances were made; there were, however, occasional groans of pain. During recovery, the mute phase was replaced by a state in which the patient could whisper but not phonate verbal utterances. About 10 weeks after the accident, phonation was restored. The speech was characterized, however, by monotonous intonation and a very low frequency of spontaneous utterances. While the frequency of spontaneous speech improved noticeably during the following months, emotional intonation remained permanently defective. A comparison of the present case with other cases from the literature as well as experimental monkey data suggest that the anterior cingulate cortex is involved in the volitional control of emotional vocal utterances.     

Electrophysiological measures reveal the role of anterior cingulate cortex in learning from unreliable feedback

Although a growing number of studies have investigated the neural mechanisms of reinforcement learning, it remains unclear how the brain responds to feedback that is unreliable. A recent theory proposes that the reward positivity (RewP) component of the event-related brain potential (ERP) and frontal midline theta (FMT) power reflect separate feedback-related processing functions of anterior cingulate cortex (ACC). In the present study, the electroencephalogram (EEG) was recorded from participants as they engaged in a time estimation task in which feedback reliability was manipulated across conditions. After each response, they received a cue that indicated that the following feedback stimulus was 100%, 75%, or 50% reliable. The results showed that participants’ time estimates adjusted linearly according to the feedback reliability. Moreover, presentation of the cue indicating 100% reliability elicited a larger RewP-like ERP component than the other cues did, and feedback presentation elicited a RewP of approximately equal amplitude for all of the three reliability conditions. By contrast, FMT power elicited by negative feedback decreased linearly from the 100% condition to 75% and 50% condition, and only FMT power predicted behavioral adjustments on the following trials. In addition, an analysis of Beta power and cross-frequency coupling (CFC) of Beta power with FMT phase suggested that Beta-FMT communication modulated motor areas for the purpose of adjusting behavior. We interpreted these findings in terms of the hierarchical reinforcement learning account of ACC, in which the RewP and FMT are proposed to reflect reward processing and control functions of ACC, respectively.     

Dorsal anterior cingulate and ventromedial prefrontal cortex have inverse roles in both foraging and economic choice

Recent research has highlighted a distinction between sequential foraging choices and traditional economic choices between simultaneously presented options. This was partly motivated by observations in Kolling, Behrens, Mars, and Rushworth, Science, 336(6077), 95–98 (2012) (hereafter, KBMR) that these choice types are subserved by different circuits, with dorsal anterior cingulate (dACC) preferentially involved in foraging and ventromedial prefrontal cortex (vmPFC) preferentially involved in economic choice. To support this account, KBMR used fMRI to scan human subjects making either a foraging choice (between exploiting a current offer or swapping for potentially better rewards) or an economic choice (between two reward-probability pairs). This study found that dACC better tracked values pertaining to foraging, whereas vmPFC better tracked values pertaining to economic choice. We recently showed that dACC’s role in these foraging choices is better described by the difficulty of choosing than by foraging value, when correcting for choice biases and testing a sufficiently broad set of foraging values (Shenhav, Straccia, Cohen, & Botvinick Nature Neuroscience, 17(9), 1249–1254, 2014). Here, we extend these findings in 3 ways. First, we replicate our original finding with a larger sample and a task modified to address remaining methodological gaps between our previous experiments and that of KBMR. Second, we show that dACC activity is best accounted for by choice difficulty alone (rather than in combination with foraging value) during both foraging and economic choices. Third, we show that patterns of vmPFC activity, inverted relative to dACC, also suggest a common function across both choice types. Overall, we conclude that both regions are similarly engaged by foraging-like and economic choice.     

Errors without conflict: implications for performance monitoring theories of anterior cingulate cortex

Recent theories of the neural basis of performance monitoring have emphasized a central role for the anterior cingulate cortex (ACC). Replicating an earlier event-related potential (ERP) study, which showed an error feedback negativity that was modeled as having an ACC generator, we used event-related fMRI to investigate whether the ACC would differentiate between correct and incorrect feedback stimuli in a time estimation task. The design controlled for response conflict and frequency and expectancy effects. Although participants in the current study adjusted their performance following error feedback, we did not observe error feedback-evoked ACC activity. In contrast, we did observe ACC activity while the same subjects performed the Stroop task, in which an area of the ACC activated during both conflict and error trials. These findings are inconsistent with previous dipole models of the error feedback negativity, and suggest the ACC may not be involved in the generation of this ERP component. These results question involvement of the ACC in the detection of errors per se when controlling for conflict.     

Feeling bad about screwing up: emotion regulation and action monitoring in the anterior cingulate cortex

This study examined neural features of emotional responses to errors. We specifically examined whether directed emotion regulation of negative emotion associated with error modulates action-monitoring functions of anterior cingulate cortex, including conflict monitoring, error processing, and error prevention. Seventeen healthy adults performed a continuous performance task during assessment by fMRI. In each block, participants were asked either to increase or decrease their negative emotional responses or to react naturally after error commission. Emotion regulation instructions were associated with modulation of rostral and dorsal anterior activity and of their effective connectivity following errors and conflict. Cingulate activity and connectivity predicted subsequent errors. These data may suggest that responses to errors are affected by emotion and that aspects of emotion and cognition are inextricably linked, even during a nominally cognitive task.