Sites of neocortical reorganization critical for remote spatial memory

The hippocampus is crucial for spatial memory formation, yet it does not store long-lasting memories. By combining functional brain imaging and region-specific neuronal inactivation in mice, we identified prefrontal and anterior cingulate cortices as critical for storage and retrieval of remote spatial memories [correction]. Imaging of activity-dependent genes also revealed an involvement of parietal and retrosplenial cortices during consolidation of remote memory. Long-term memory storage within some of these neocortical regions was accompanied by structural changes including synaptogenesis and laminar reorganization, concomitant with a functional disengagement of the hippocampus and posterior cingulate cortex [correction]. Thus, consolidation of spatial memory requires a time-dependent hippocampal-cortical dialogue, ultimately enabling widespread cortical networks to mediate effortful recall and use of cortically stored remote memories independently.     

Storage and executive processes in the frontal lobes

The human frontal cortex helps mediate working memory, a system that is used for temporary storage and manipulation of information and that is involved in many higher cognitive functions. Working memory includes two components: short-term storage (on the order of seconds) and executive processes that operate on the contents of storage. Recently, these two components have been investigated in functional neuroimaging studies. Studies of storage indicate that different frontal regions are activated for different kinds of information: storage for verbal materials activates Broca's area and left-hemisphere supplementary and premotor areas; storage of spatial information activates the right-hemisphere premotor cortex; and storage of object information activates other areas of the prefrontal cortex. Two of the fundamental executive processes are selective attention and task management. Both processes activate the anterior cingulate and dorsolateral prefrontal cortex.     

Anterior cingulate: single neuronal signals related to degree of reward expectancy

As monkeys perform schedules containing several trials with a visual cue indicating reward proximity, their error rates decrease as the number of remaining trials decreases, suggesting that their motivation and/or reward expectancy increases as the reward approaches. About one-third of single neurons recorded in the anterior cingulate cortex of monkeys during these reward schedules had responses that progressively changed strength with reward expectancy, an effect that disappeared when the cue was random. Alterations of this progression could be the basis for the changes from normal that are reported in anterior cingulate population activity for obsessive-compulsive disorder and drug abuse, conditions characterized by disturbances in reward expectancy.     

A role for the macaque anterior cingulate gyrus in social valuation

Complex human social interaction is disrupted when the frontal lobe is damaged in disease, and in extreme cases patients are described as having acquired sociopathy. We compared, in macaques, the effects of lesions in subdivisions of the anterior cingulate and the orbitofrontal cortices believed to be anatomically homologous to those damaged in such patients. We show that the anterior cingulate gyrus in male macaques is critical for normal patterns of social interest in other individual male or female macaques. Conversely, the orbitofrontal cortex lesion had a marked effect only on responses to mildly fear-inducing stimuli. These results suggest that damage to the anterior cingulate gyrus may be the cause of changes in social interaction seen after frontal lobe damage.     

Performance monitoring by the anterior cingulate cortex during saccade countermanding

Consensus is emerging that the medial frontal lobe of the brain is involved in monitoring performance, but precisely what is monitored remains unclear. A saccade-countermanding task affords an experimental dissociation of neural signals of error, reinforcement, and conflict. Single-unit activity was monitored in the anterior cingulate cortex of monkeys performing this task. Neurons that signaled errors were found, half of which responded to the omission of earned reinforcement. A further diversity of neurons signaled earned or unexpected reinforcement. No neurons signaled the form of conflict engendered by interruption of saccade preparation produced in this task. These results are consistent with the hypothesis that the anterior cingulate cortex monitors the consequences of actions.     

Early tagging of cortical networks is required for the formation of enduring associative memory

Although formation and stabilization of long-lasting associative memories are thought to require time-dependent coordinated hippocampal-cortical interactions, the underlying mechanisms remain unclear. Here, we present evidence that neurons in the rat cortex must undergo a "tagging process" upon encoding to ensure the progressive hippocampal-driven rewiring of cortical networks that support remote memory storage. This process was AMPA- and N-methyl-D-aspartate receptor-dependent, information-specific, and capable of modulating remote memory persistence by affecting the temporal dynamics of hippocampal-cortical interactions. Post-learning reinforcement of the tagging process via time-limited epigenetic modifications resulted in improved remote memory retrieval. Thus, early tagging of cortical networks is a crucial neurobiological process for remote memory formation whose functional properties fit the requirements imposed by the extended time scale of systems-level memory consolidation.     

Multiple representations of pain in human cerebral cortex

The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.     

Psychological and neural mechanisms of the affective dimension of pain

The affective dimension of pain is made up of feelings of unpleasantness and emotions associated with future implications, termed secondary affect. Experimental and clinical studies show serial interactions between pain sensation intensity, pain unpleasantness, and secondary affect. These pain dimensions and their interactions relate to a central network of brain structures that processes nociceptive information both in parallel and in series. Spinal pathways to limbic structures and medial thalamic nuclei provide direct inputs to brain areas involved in affect. Another source is from spinal pathways to somatosensory thalamic and cortical areas and then through a cortico-limbic pathway. The latter integrates nociceptive input with contextual information and memory to provide cognitive mediation of pain affect. Both direct and cortico-limbic pathways converge on the same anterior cingulate cortical and subcortical structures whose function may be to establish emotional valence and response priorities.     

Disinhibition of inhibitory conditioned responses following selective brain lesions in dogs

Discrete lesion of the genual portion of the anterior cingulate gyrus in three dogs produced temporary disinhibition of preoperatively trained inhibitory food conditioned responses. This disinhibition was accompanied by increase in general behavior motivated by food reinforcement. Lesion of the posterior cingulate gyrus in three other dogs did not produce such impairment.     

Dysfunction in the neural circuitry of emotion regulation--a possible prelude to violence

Emotion is normally regulated in the human brain by a complex circuit consisting of the orbital frontal cortex, amygdala, anterior cingulate cortex, and several other interconnected regions. There are both genetic and environmental contributions to the structure and function of this circuitry. We posit that impulsive aggression and violence arise as a consequence of faulty emotion regulation. Indeed, the prefrontal cortex receives a major serotonergic projection, which is dysfunctional in individuals who show impulsive violence. Individuals vulnerable to faulty regulation of negative emotion are at risk for violence and aggression. Research on the neural circuitry of emotion regulation suggests new avenues of intervention for such at-risk populations.     

Impulsive choice induced in rats by lesions of the nucleus accumbens core

Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.     

Anterior cingulate conflict monitoring and adjustments in control

Conflict monitoring by the anterior cingulate cortex (ACC) has been posited to signal a need for greater cognitive control, producing neural and behavioral adjustments. However, the very occurrence of behavioral adjustments after conflict has been questioned, along with suggestions that there is no direct evidence of ACC conflict-related activity predicting subsequent neural or behavioral adjustments in control. Using the Stroop color-naming task and controlling for repetition effects, we demonstrate that ACC conflict-related activity predicts both greater prefrontal cortex activity and adjustments in behavior, supporting a role of ACC conflict monitoring in the engagement of cognitive control.     

Cholinergic enhancement and increased selectivity of perceptual processing during working memory

Using functional magnetic resonance imaging, we investigated the mechanism by which cholinergic enhancement improves working memory. We studied the effect of the cholinesterase inhibitor physostigmine on subcomponents of this complex function. Cholinergic enhancement increased the selectivity of neural responses in extrastriate cortices during visual working memory, particularly during encoding. It also increased the participation of ventral extrastriate cortex during memory maintenance and decreased the participation of anterior prefrontal cortex. These results indicate that cholinergic enhancement improves memory performance by augmenting the selectivity of perceptual processing during encoding, thereby simplifying processing demands during memory maintenance and reducing the need for prefrontal participation.     

Alcohol consumption impairs detection of performance errors in mediofrontal cortex

The anterior cingulate cortex (ACC) is a critical component of the human mediofrontal neural circuit that monitors ongoing processing in the cognitive system for signs of erroneous outcomes. Here, we show that the consumption of alcohol in moderate doses induces a significant deterioration of the ability to detect the activation of erroneous responses as reflected in the amplitude of brain electrical activity associated with the ACC. This impairment was accompanied by failures to instigate performance adjustments after these errors. These findings offer insights into how the effects of alcohol on mediofrontal brain function may result in compromised performance.     

Stress-related noradrenergic activity prompts large-scale neural network reconfiguration

Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.     

Empathy for pain involves the affective but not sensory components of pain

Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.     

Learned predictions of error likelihood in the anterior cingulate cortex

The anterior cingulate cortex (ACC) and the related medial wall play a critical role in recruiting cognitive control. Although ACC exhibits selective error and conflict responses, it has been unclear how these develop and become context-specific. With use of a modified stop-signal task, we show from integrated computational neural modeling and neuroimaging studies that ACC learns to predict error likelihood in a given context, even for trials in which there is no error or response conflict. These results support a more general error-likelihood theory of ACC function based on reinforcement learning, of which conflict and error detection are special cases.     

Mnemonic function of the dorsolateral prefrontal cortex in conflict-induced behavioral adjustment

Our cognitive abilities in performing tasks are influenced by experienced competition/conflict between behavioral choices. To determine the role of the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in the conflict detection-resolution process, we conducted complementary lesion and single-cell recording studies in monkeys that were resolving a conflict between two rules. We observed conflict-induced behavioral adjustment that persisted after lesions within the ACC but disappeared after lesions within the DLPFC. In the DLPFC, activity was modulated in some cells by the current conflict level and in other cells by the conflict experienced in the previous trial. These results show that the DLPFC, but not the ACC, is essential for the conflict-induced behavioral adjustment and suggest that encoding and maintenance of information about experienced conflict is mediated by the DLPFC.     

Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex

Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain neuropathic pain. PKMζ could thus be a new therapeutic target for treating chronic pain.     

Placebo and opioid analgesia-- imaging a shared neuronal network

It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.