Review
Localization of function in anterior cingulate cortex: From psychosurgery to functional neuroimaging

https://doi.org/10.1016/j.neubiorev.2013.01.002Get rights and content

Abstract

Early localizationists linked anterior cingulate cortex (ACC: Brodmann's area 24 and adjacent regions) with emotional behavior, paving the way for bilateral cingulotomy psychosurgery in severe, treatment resistant, cases of obsessive–compulsive disorder, chronic pain, depression, and substance abuse. Neuropsychological follow-up of such cases demonstrated executive function impairment. Abnormal neuroimaged activity in ACC has been found in many psychiatric conditions, including obsessive–compulsive disorder, chronic pain, substance abuse, and schizophrenia. With healthy participants, increased neuroimaged activity in ACC has been linked with challenging executive function tasks, homeostatically incongruous physical states, and the encoding of the pleasant/averseness of stimuli. There is disagreement on the cortical substrate subsumed by the term ACC, the existence of functionally distinct ACC subregions (e.g., dorsal: cognitive vs. ventral: emotion), and the interpretation of functional neuroimaging studies. Synthesis of neuropsychological and functional neuroimaging studies suggests ACC contributes to behavior by modifying responses especially in reaction to challenging cognitive and physical states that require additional effortful cognitive control. This is accomplished by monitoring the emotional salience of stimuli, exerting control over the autonomic nervous system, and modulating cognitive activity.

Highlights

► Review covers neuropsychological and neuroimaging studies of anterior cingulate cortex. ► Bilateral cingulotomy changes both emotional response and executive functioning. ► ACC modulates physically and cognitively challenging events. ► ACC modulates homestatically incongruous states. ► ACC encodes the pleasant/aversiveness of stimuli.

Introduction

Broca (1861) is credited with being the first to localize a complex cognitive function to a specific region of the human cortex, thereby founding the science now known as clinical neuropsychology (Ryalls and Lecours, 1996). Over 150 years later, localization of function in the human cortex, while precisely defined for certain regions like primary sensory and motor cortices, remains uncertain for many parts of association cortex, including that lying within the frontal lobe. Frontal association cortex has three major neuroanatomical subdivisions: dorsolateral, orbitofrontal, and ventromedial (Alvarez and Emory, 2006). These all mediate executive functioning, a broadly defined subcomponent of cognitive behavior that has defied consensus dissection into its constituent processes (Lenartowicz et al., 2010, Packwood et al., 2011, Stirling and Elliott, 2008), a necessary prerequisite for localization (Luria, 1973).

Anterior cingulate cortex (ACC) is an anatomically distinct subregion of ventromedial frontal cortex consisting of the cingulate sulcus and gyrus that lie dorsal to the corpus collosum and ventral to the superior frontal gyrus. It encompasses Broadmann's area 24 and adjacent regions. It is often subdivided into anterior (variously termed rostral, ventral, and genual) and posterior (caudal, rostral, or midcingulate) subregions. It has extensive bidirectional connections with dorsolateral, orbitofrontal, primary and secondary motor, and insular regions of the cerebral cortex.

There has long been speculation concerning the behavioral function of ACC. Early localizationists linked ACC with the rhinencephalon and olfactory functions until Papez (1937) used data from neuroanatomical dissection and animal lesion studies to conclude: “the hypothalamus, the anterior thalamic nuclei, the gyrus cinguli, the hippocampus and their interconnections constitute a harmonious mechanism which may elaborate the functions of central emotion” (p. 743). This circuit now forms part of what is widely known as the limbic system whose behavioral function was elaborated by MacLean (1952) as: “a visceral brain that interprets and gives expression to its incoming information in terms of feeling” (p. 415: italics as in original). Limbic (from limbus meaning border in Latin), was originally used by Broca (1878) to describe a “lobe” on the medial and basilar surfaces of the cerebral hemispheres that formed the border around the brainstem. It is now seen as unlikely that the limbic system operates as a single unit (e.g., Devinsky et al., 1995).

As noted by Papez (1937), occlusion of any of the eight branches of the anterior cerebral artery or other naturally occurring neurological condition rarely affects ACC in isolation, restricting human lesion/behavioral change correlational analysis. An alternative source of such data comes from the practice of cingulotomy psychosurgery that has been used on a very limited basis with severely disturbed, treatment resistant, psychiatric cases for over 60 years. In advancing an understanding of brain/behavioral relationships, such cases have an advantage over naturally occurring brain injuries in that the lesions (about 1 cm in diameter and 2 cm in vertical length bilaterally: Ballantine et al., 1987) are precisely limited to ACC.

This review combines information learned from studies involving neuropsychological lesion analysis of cingulotomy patients with that from functional neuroimaging studies of psychiatric and healthy participants that have focused on ACC. The goal is to arrive at a parsimonious understanding of the contribution of ACC to behavior.

Section snippets

Emotional changes and cognitive impairment following bilateral cingulotomy psychosurgery

Pioneering research in monkeys found that stimulation of ACC produced autonomic nervous system responses and bilateral ACC lesions resulted in “increased tameness and reduction of aggressiveness, with apparent loss of the sense of danger” (Glees et al., 1950, p. 189). These findings paved the way for bilateral cingulotomy psychosurgery for which it was initially reasoned: “one would expect greatest improvement not in schizophrenics, but in those anankastic cases whose obsessions or compulsions

Functional neuroimaging of ACC in mental disorder and pain states

The success of bilateral cingulotomy psychosurgery in relieving psychiatric symptomatology in some severe cases of treatment resistant obsessive–compulsive disorder, chronic pain, depression, and substance abuse lends support to a role for ACC in the regulation of emotional behavior. Consistent with psychosurgical findings, functional neuroimaging studies comparing patient and control groups have found abnormal ACC activations in obsessive–compulsive disorder (e.g., Menzies et al., 2008),

Methodological issues

Integrating findings across studies was complicated by inconsistencies in the cortical boundaries of ACC. There is general agreement that ACC includes Brodmann's area 24, but dispute as to the outer boundaries of the cortical substrate subsumed under this term. Some investigators limit ACC to area 24 (e.g., Nemeth et al., 1988), while others include adjacent area 32 (e.g., Janer and Pardo, 1991, Killgore and Yurgelun-Todd, 2004), areas 25 and 32 (e.g., Paus, 2001), or areas 25, 32, and 33

Contributions of ACC to behavior

Neuropsychological and neuroimaging studies have implicated ACC in both emotional and cognitive functions, suggesting it is a neural relay structure where these influences impact response behavior. As to its precise function, the body of literature reviewed suggests:

  • 1.

    ACC acts at the subconscious or automatic level of information processing (e.g., Carlson et al., 2012, Killgore and Yurgelun-Todd, 2004).

  • 2.

    Few studies reported lateralization effects for ACC. When differential hemispheric activation

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