ReviewMidcingulate cortex: Structure, connections, homologies, functions and diseases
Introduction
The history of the human midcingulate cortex (MCC) extends back to the beginning of the 20th century but went unnoticed because Brodmann (1909) failed to recognize its presence. Smith (1907) first showed MCC and demonstrated its anterior and posterior divisions (aMCC, pMCC; see Vogt et al., 2003, for his figure). While the Vogts (1919) provided a map of cingulate cortex based on myeloarchitecture that was somewhat complex, it also showed subregions that could be related to aMCC and pMCC (Fig. 1A). While we identified caudal components of area 24 referred to as area 24′ and recognized then current imaging studies that differentiated these areas (Vogt et al., 1995), we continued for a few years to treat area 24′ as part of anterior cingulate cortex (ACC; Devinsky et al., 1995, Vogt et al., 2003). However, the evidence that area 24′ is fundamentally different from area 24 became so great that the MCC was introduced as a unique cingulate region in its own right to explain key cytoarchitectural differences with ACC and posterior cingulate cortex (PCC; Vogt, 2005) and their extensive functional differences (Vogt, 2009b; Fig. 1B).
The growing interest in MCC as a separate functional unit suggests a realization that MCC has unique contributions to brain function and is not a division of ACC. Indeed, the number of citations in Science Citation Index for “midcingulate” and “mid-cingulate” has been growing significantly over the past 20 years as shown in Fig. 2. The spike in citations starting in 2010 immediately followed publication of Cingulate Neurobiology and Disease in 2009 (Oxford University Press) which focuses primarily on primate cingulate organization, functions and diseases including those of MCC. The past five years has generated a diverse and thought provoking body of literature that leads to new insights into the functions and diseases of MCC. This is the first review of MCC and considers its key anatomical, connectional, and functional characteristics. Developing experimental animal models of human diseases requires a clear understanding of the comparative organization of MCC and it is now possible to link the distribution and characteristics of MCC in five species including humans. Finally, a critical part of validating MCC as a unique entity is demonstrating that human diseases have a differential impact on its structure and function as shown in the last section.
Section snippets
MCC≠ACC & dACC≠ACC
In spite of the past 20 years of detailed cytoarchitectural and immunohistochemical studies, many functional imaging studies report involvement of Brodmann areas for which there is no MCC equivalent. The use of Brodmann area 24 is inaccurate when activity is located only in MCC as his area 24 extends substantially more rostral and ventral to include subgenual ACC (sACC). Indeed, no functional imaging study has ever activated his entire ACC, thus demonstrating that it is not a single entity. The
Regions/subregions are models of cortical function; not labels
The extent to which the four-region model of cingulate cortex including ACC, MCC, PCC, and retrosplenial cortex (RSC) has value is determined by its ability to predict relationships that are not apparent with other models. Defining cingulate regions and subregions is not simply a matter of taxonomy or even cytoarchitecture. Such designations are not just labels for descriptive structural and functional studies. Their use here represents cortical models that have predictive value; an example of
The midcingulate dichotomy
The MCC is not uniform as it has aMCC and pMCC (Smith, 1907, Vogt and Vogt, 1919, Vogt, 2009b). It is to be expected that these divisions have differential connections and they have been identified in monkey and human. Indeed, amygdala and parietal afferents in the monkey differentiate them and this was one of the criteria for their dissociation (Vogt, 2009a). Before proceeding further, the terminology for various parts of MCC in primates is provided in Fig. 3 for reference throughout this
Comparative organization of MCC
The use of experimental animals to evaluate cingulate functions and devise animal models of human diseases requires comparative analyses of the content of cingulate cortex in each species in relation to the human. The very substantial differences in daMCC between monkey and human species are of particular importance to cognitive research and area 32′ functions cannot be studied in monkeys where it likely does not exist. Further, the pain literature often reports that medial prefrontal cortex is
Cingulate premotor area architecture, circuitry and imaging
One of the key features of MCC is its role in skeletomotor functions in contrast to ACC where emotion and autonomic regulation are predominant. In 1973, Talairach et al. (1973) reported that electrical stimulation of MCC evoked movements such as lip puckering, finger kneading, and bilateral limb movements; not movement in single muscle groups. These coordinated movements reflect behaviors that are valenced and context dependent. For example, lip puckering is not a routine movement but rather
aMCC & vaMCC: nociception, itch, fear, pain catastrophizing
Activity generated by acute nociceptive stimuli recorded with fMRI is located mainly in MCC as shown in Fig. 11A. While not overtly painful, itch evoked with cowhage spicules also activates aMCC (Fig. 10B; red–orange). In contrast, active scratching of such an itch activates pMCC enhancing the view that reflexive motor activity is mediated by this subregion and demonstrating a functional dissociation between aMCC and pMCC. Interestingly, both active and passive scratching of an itch inactivates
daMCC: components of the feedback-mediated decision making model
The pACC and aMCC are involved in different functions and reciprocal inhibition can enhance the unique functions of each subregion as noted later. Bush et al. (1998) and Whalen et al. (1998) performed two Stroop interference tasks that involved different sources of interference, one cognitive and one affective, in the same subjects during the same scanning session. Stroop testing requires the subject to overcome reflexive responses to execute a button press. In the counting Stroop word stimuli
pMCC: parietal input, rapid motor responses, body orientation, nociception
A primary role of pMCC in brain function is reflexive orientation of the body in space to sensory stimuli including noxious ones. It contrasts significantly from activity in aMCC where working memory requires longer times to modulate cognitive/motor functions. This view is supported by the fact that pMCC has almost no evoked emotion activity (Vogt, 2005), neuronal discharges in the cCPMA have short latency, pre-movement responses (above), and electrical stimulation of muscles evoke potentials
Diseases of midcingulate cortex and drug responses
The vulnerability of MCC in human disease both confirms the unique organization of MCC and provides a basis for developing animal models. This is not to say that MCC is the only region involved in a particular disease, only that it is prominent among multiple players and is often linked to specific symptoms and functional impairments shown with behavioral testing.
Not surprisingly, since aMCC is highly responsive to acute noxious stimuli, studies of chronic pain show a vulnerability of MCC and
Perspectives on midcingulate cortex and future challenges
Anatomical organization sets the table for functional studies as it is a stable perspective on functional units of cortex. The cytoarchitectural borders of aMCC and pMCC have proven to be of substantial value in assessing functional imaging findings as the past two decades has produced a plethora of observations to show that the eight-subregion model of cingulate cortex is robust and has predictive value. Clinical imaging studies including those of drug activity, are finding this model more and
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