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Midcingulate cortex (MCC) has risen in prominence as human imaging identifies unique structural and
functional activity therein and this is the first review of its structure, connections, functions and disease
vulnerabilities. The MCC has two divisions (anterior, aMCC and posterior, pMCC) that represent
functional units and the cytoarchitecture, connections and neurocytology of each is shown with
immunohistochemistry and receptor binding. The MCC is not a division of anterior cingulate cortex (ACC)
and the “dorsal ACC” designation is a misnomer as it incorrectly implies that MCC is a division of ACC.
Interpretation of findings among species and developing models of human diseases requires detailed
comparative studies which is shown here forfive species with flat maps and immunohistochemistry
(human, monkey, rabbit, rat, mouse). The largest neurons in human cingulate cortex are in layer Vb of
area 24 d in pMCC which project to the spinal cord. This area is part of the caudal cingulate premotor area
which is involved in multisensory orientation of the head and body in space and neuron responses are
tuned for the force and direction of movement. In contrast, the rostral cingulate premotor area in aMCC is
involved in action-reinforcement associations and selection based on the amount of reward or aversive
properties of a potential movement. The aMCC is activated by nociceptive information from the midline,
mediodorsal and intralaminar thalamic nuclei which evoke fear and mediates nocifensive behaviors. This
subregion also has high dopaminergic afferents and high dopamine-1 receptor binding and is engaged in
reward processes. Opposing pain/avoidance and reward/approach functions are selected by assessment
of potential outcomes and error detection according to feedback-mediated, decision making. Parietal
afferents differentially terminate in MCC and provide for multisensory control in an eye- and headcentric
manner. Finally, MCC vulnerability in human disease confirms the unique organization of MCC
and supports the predictive validity of the MCC dichotomy. Vulnerability of aMCC is shown in chronic
pain, obsessive-compulsive disorder with checking symptoms and attention-deficit/hyperactivity
disorder and methylphenidate and pain medications selectively impact aMCC. In contrast, pMCC
vulnerabilities are for progressive supranuclear palsy, unipolar depression and posttraumatic stress
disorder. Thus, there is an emerging picture of the organization, functions and diseases of MCC. Future
work will take this type of modular analysis to individual areas of which there are at least 10 in MCC.
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