The Best Laid Plans: Computational Principles of Anterior Cingulate Cortex.

Cingulotomy is therapeutic in OCD, but what are the possible mechanisms? Computer models that formalize cortical OCD abnormalities and anterior cingulate cortex (ACC) function can help answer this. At the neural dynamics level, cortical dynamics in OCD have been modeled using attractor networks, where activity patterns resistant to change denote the inability to switch to new patterns, which can reflect inflexible thinking patterns or behaviors. From that perspective, cingulotomy might reduce the influence of difficult-to-escape ACC attractor dynamics on other cortical areas. At the functional level, computer formulations based on model-free reinforcement learning (RL) have been used to describe the multitude of phenomena ACC is involved in, such as tracking the timing of expected outcomes and estimating the cost of exerting cognitive control and effort. Different elements of model-free RL models of ACC could be affected by the inflexible cortical dynamics, making it challenging to update their values. An agent can also use a world model, a representation of how the states of the world change, to plan its actions, through model-based RL. OCD has been hypothesized to be driven by reduced certainty of how the brain’s world model describes changes. Cingulotomy might improve such uncertainties about the world and one’s actions, making it possible to trust the outcomes of these actions more and thus reduce the urge to collect more sensory information in the form of compulsions. Connecting the neural dynamics models with the functional formulations can provide new ways of understanding the role of ACC in OCD, with potential therapeutic insights.

Anterior cingulate cortex (ACC) is known to participate in numerous brain functions, such as memory storage, emotion, attention, as well as perception of acute and chronic pain. ACC-dependent brain functions often rely on ACC processing of various forms of environmental information. To understand the neural basis of ACC functions, previous studies have investigated ACC responses to environmental stimulation, particularly complex sensory stimuli as well as award and aversive stimuli, but this issue remains to be further clarified. Here, by performing whole-cell recording in vivo in anaesthetized adult rats, we examined membrane-potential (MP) responses of layer II/III ACC neurons that were evoked by a brief flash of visual stimulation and pain-related electrical stimulation delivered to hind paws. We found that ~54 and ~81 % ACC neurons exhibited excitatory MP responses, subthreshold or suprathreshold, to the visual stimulus and the electrical stimulus, respectively, with no cell showing inhibitory MP responses. We further found that the visually evoked ACC response could be greatly diminished by local lidocaine infusion in the visual thalamus, and only their temporal patterns but not amplitudes could be changed by large-scale visual cortical lesions. Our in vivo whole-cell recording data characterized in ACC neurons a visually evoked response, which was largely dependent on the visual thalamus but not visual cortex, as well as a noxious electrical stimulus-evoked response. These findings may provide potential mechanisms that are used for ACC functions on the basis of sensory information processing.

A novel method of recording neural activity from the rodent medial prefrontal cortex reveals that the medial prefrontal cortex is composed of functionally distinct subregions that process economic decision information differentially along a dorso-ventral gradient.

Topiramate, an approved antiepileptic drug, was found effective in treating aggressive symptoms in humans and rodents. However, the effects and mechanisms of Topiramate on aggressive behavior are still unclear. Our previous study indicated that intraperitoneal administration of Topiramate successfully decreased aggression and reinforced sociability in socially aggressive mice, and increased cFos-expressing neurons in the anterior cingulate cortex (ACC). In addition to its pharmacological properties, previous studies have approved the neuroprotective effects of Topiramate. These suggest a potential effect of Topiramate on ACC's structure and function. In the present study, we first investigated the structural characteristics of ACC in the social isolation-induced aggression paradigm. The results showed that hyper-aggressive behavior in socially aggressive mice was associated with several structural alterations in ACC: increased neuron death combined with decreased neuron density, increased damaged neuronal morphology and increased neuroinflammation markers. Based on these observations, we next investigated the potential neuroprotective effect of Topiramate against structural alterations of ACC observed in socially aggressive mice. Results indicated that intraperitoneal administration of Topiramate (30mg/kg) decreased aggression and enhanced sociability without affecting locomotor activity. Interestingly, the anti-aggressive effect of Topiramate was associated with decreased neuronal death, ameliorated damaged neuronal morphology, and decreased reactive microglia markers in ACC. Our results provide insights into the structural alterations of ACC in aggressive socially aggressive mice. Moreover, the present study suggested that the anti-aggressive effect of Topiramate could be related to its neuroprotective effects against the structural alterations of ACC.

Hoarding disorder (HD), previously considered a subtype of obsessive-compulsive disorder (OCD), has been proposed as a unique diagnostic entity in DSM-5. Current models of HD emphasize problems of decision-making, attachment to possessions, and poor insight, whereas previous neuroimaging studies have suggested abnormalities in frontal brain regions. To examine the neural mechanisms of impaired decision making in HD in patients with well-defined primary HD compared with patients with OCD and healthy control subjects (HCs). We compared neural activity among patients with HD, patients with OCD, and HCs during decisions to keep or discard personal possessions and control possessions from November 9, 2006, to August 13, 2010. Private, not-for-profit hospital. A total of 107 adults (43 with HD, 31 with OCD, and 33 HCs). Neural activity as measured by functional magnetic resonance imaging in which actual real-time and binding decisions had to be made about whether to keep or discard possessions. Compared with participants with OCD and HC, participants with HD exhibited abnormal activity in the anterior cingulate cortex and insula that was stimulus dependent. Specifically, when deciding about items that did not belong to them, patients with HD showed relatively lower activity in these brain regions. However, when deciding about items that belonged to them, these regions showed excessive functional magnetic resonance imaging signals compared with the other 2 groups. These differences in neural function correlated significantly with hoarding severity and self-ratings of indecisiveness and "not just right" feelings among patients with HD and were unattributable to OCD or depressive symptoms. Findings suggest a biphasic abnormality in anterior cingulate cortex and insula function in patients with HD related to problems in identifying the emotional significance of a stimulus, generating appropriate emotional response, or regulating affective state during decision making.

Threat-related stimuli are strong competitors for attention, particularly in anxious individuals. We used functional magnetic resonance imaging (fMRI) with healthy human volunteers to study how the processing of threat-related distractors is controlled and whether this alters as anxiety levels increase. Our work builds upon prior analyses of the cognitive control functions of lateral prefrontal cortex (lateral PFC) and anterior cingulate cortex (ACC). We found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli. Participants with higher anxiety levels showed both less rostral ACC activity overall and reduced recruitment of lateral PFC as expectancy of threat-related distractors was established. This supports the proposal that anxiety is associated with reduced top-down control over threat-related distractors. Our results suggest distinct roles for rostral ACC and lateral PFC in governing the processing of task-irrelevant, threat-related stimuli, and indicate reduced recruitment of this circuitry in anxiety.

Chapter 16 - Correlates of Object Exploration and Recognition Memory in Mouse Anterior Cingulate Cortex

A computational model of risk, conflict, and individual difference effects in the anterior cingulate cortex

The cingulate gyrus is a major part of the "anatomical limbic system" and, according to classic accounts, is involved in emotion. This view is oversimplified in light of recent clinical and experimental findings that cingulate cortex participates not only in emotion but also in sensory, motor, and cognitive processes. Anterior cingulate cortex, consisting of areas 25 and 24, has been implicated in visceromotor, skeletomotor, and endocrine outflow. These processes include responses to painful stimuli, maternal behavior, vocalization, and attention to action. Since all of these activities have an affective component, it is likely that connections with the amygdala are critical for them. In contrast, posterior cingulate cortex, consisting of areas 29, 30, 23, and 31, contains neurons that monitor eye movements and respond to sensory stimuli. Ablation studies suggest that this region is involved in spatial orientation and memory. It is likely that connections between posterior cingulate and parahippocampal cortices contribute to these processes. We conclude that there is a fundamental dichotomy between the functions of anterior and posterior cingulate cortices. The anterior cortex subserves primarily executive functions related to the emotional control of visceral, skeletal, and endocrine outflow. The posterior cortex subserves evaluative functions such as monitoring sensory events and the organism's own behavior in the service of spatial orientation and memory.

The neural mechanisms of reward-guided behavior have been researched extensively but how rewards affect the neural processes underlying the production of hierarchically-organized sequential behaviors remains unclear. In particular, anterior cingulate cortex (ACC) is said to motivate the successful completion of hierarchically-organized tasks by grouping together low-level actions according to superordinate goals, which are encoded across ACC neural ensembles as distributed, multivariate representations (Holroyd & Verguts, 2021; Holroyd & Yeung, 2012). Here we applied model-based representational similarity analysis (RSA) to investigate how rewards modulate these representations. We adapted an existing recurrent neural network (RNN) model of ACC activity (Colin et al., 2024) to predict the effect of rewards on ACC representations in a hierarchical sequence production task, and then recorded the fMRI-BOLD response from participants engaged in this task. As predicted, searchlight RSA revealed a cluster of MRI activity in ACC showing the highest second-order similarity with the model representation, relative to the whole-brain distribution. Closer examination revealed that ACC discriminates between rewarded vs non-rewarded sequences mainly on the first step of each trial, consistent with evidence that ACC encodes a reward prediction error at the onset of hierarchically organized action sequences. Moreover, reward-related multivariate ACC activity positively correlated with task performance, with more distinct ACC activity patterns predicting higher accuracy and faster response times. These findings were unique to ACC as other brain areas exhibited different task-related effects. We conclude that ACC monitors reward contingencies to motivate control over hierarchically-organized, goal-directed behaviors.

Cognitive functioning after medial frontal lobe damage including the anterior cingulate cortex: A preliminary investigation

Afferent connections of the dorsal, perigenual, and subgenual anterior cingulate cortices of the monkey: Amygdalar inputs and intrinsic connections

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters. Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance. The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters. Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.

Synaptic mechanisms and neuronal oscillations have been proposed to be responsible for neuropathic pain formation. Many studies have also highlighted the important role of electrical synapses in synaptic plasticity and in neuronal oscillations. Thus, electrical synapses may contribute to neuropathic pain generation. However, previous studies have primarily focused on the role of chemical synapses, while ignoring the role of electrical synapses, in neuropathic pain generation. The authors adopted microinjection, RNA interference techniques, and behavioral tests to verify the link between connexin 36 (Cx36) and neuropathic pain. They also studied the selective Cx36 blocker mefloquine in rat chronic constriction injury and spared nerve injury model of neuropathic pain. Electrophysiologic recordings were used to further confirm the behavioral data. The authors found that Cx36, which constitutes the neuron-neuron electrical synapses, was up-regulated in the anterior cingulate cortex after nerve injury (n = 5). Meanwhile, Cx36-mediated neuronal oscillations in the gamma frequency range (30 to 80 Hz) (n = 7 to 8) and the neuronal synaptic transmission (n = 13 to 19) were also enhanced. Neuropathic pain was relieved by disrupting Cx36 function or expression in the anterior cingulate cortex. They also found that mefloquine, which are clinically used for treating malaria, affected gamma oscillations and synaptic plasticity, leading to a sustained pain relief in chronic constriction injury and spared nerve injury models (n = 7 to 12). The electrical synapses blocker mefloquine could affect gamma oscillations and synaptic plasticity in the anterior cingulate cortex and relieve neuropathic pain. Cx36 may be a new therapeutic target for treating chronic pain.

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 incentivechange signal task now replicate the error-likelihood 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 risk-tolerant 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.