Elsevier

NeuroImage

Volume 115, 15 July 2015, Pages 177-190
NeuroImage

Functional organization of human subgenual cortical areas: Relationship between architectonical segregation and connectional heterogeneity

https://doi.org/10.1016/j.neuroimage.2015.04.053Get rights and content

Highlights

  • Human subgenual anterior cingulate cortex comprises four distinct areas.

  • Probability maps of the structurally and functionally segregated areas are provided.

  • Areas 25, s24, s32 and 33 have different functional connectivity patterns.

  • Area s24 is associated with the processing of sadness, and s32 with that of fear.

  • Area 33 is associated with the perception of pain.

Abstract

Human subgenual anterior cingulate cortex (sACC) is involved in affective experiences and fear processing. Functional neuroimaging studies view it as a homogeneous cortical entity. However, sACC comprises several distinct cyto- and receptorarchitectonical areas: 25, s24, s32, and the ventral portion of area 33. Thus, we hypothesized that the areas may also be connectionally and functionally distinct. We performed structural post mortem and functional in vivo analyses. We computed probabilistic maps of each area based on cytoarchitectonical analysis of ten post mortem brains. Maps, publicly available via the JuBrain atlas and the Anatomy Toolbox, were used to define seed regions of task-dependent functional connectivity profiles and quantitative functional decoding. sACC areas presented distinct co-activation patterns within widespread networks encompassing cortical and subcortical regions. They shared common functional domains related to emotion, perception and cognition. A more specific analysis of these domains revealed an association of s24 with sadness, and of s32 with fear processing. Both areas were activated during taste evaluation, and co-activated with the amygdala, a key node of the affective network. s32 co-activated with areas of the executive control network, and was associated with tasks probing cognition in which stimuli did not have an emotional component. Area 33 was activated by painful stimuli, and co-activated with areas of the sensorimotor network. These results support the concept of a connectional and functional specificity of the cyto- and receptorarchitectonically defined areas within the sACC, which can no longer be seen as a structurally and functionally homogeneous brain region.

Introduction

The anterior cingulate cortex (ACC), a cytoarchitectonically heterogeneous region surrounding the genu of the corpus callosum, can be divided into subgenual (sACC) and pregenual (pACC) subregions (Palomero-Gallagher et al., 2008). While in functional imaging studies most investigators considered sACC to be synonymous with Brodmann's area 25, cyto- and receptorarchitectonical studies demonstrated that sACC also comprises areas s24 and s32, as well as the most ventral portion of area 33 (Palomero-Gallagher et al., 2008). Agranular area 25 has a relatively primitive laminar cytoarchitecture, with broad and poorly differentiated layers II–III and large and densely packed layer V neurons that intermingle with the multipolar cells of layer VI. Area s24 is also agranular, with a thin layer II, larger pyramids in layers IIIa/b than those found in IIIc, a prominent cell-dense layer Va and a neuron-sparse layer Vb. Area s32 is dysgranular, its layers Va and VI appear as a pair of distinct thin layers separated by a cell sparse layer Vb. Layer II of s32 is particularly conspicuous because it shows a subdivision into a superficial, densely packed layer IIa, and a layer IIb, with less densely packed, lancet shaped pyramids (Palomero-Gallagher et al., 2008).

In healthy human volunteers, activations within sACC occur in functional neuroimaging experiments with transient sadness induced either by recalling negative autobiographical experiences, or by sensory-affective stimulation such as “sad pictures” or mournful music (George et al., 1995, Kross et al., 2009, Smith et al., 2011). Furthermore, sACC activations were larger when participants specifically facilitated ruminative behavior during recall of negative autobiographical memories as opposed to a condition where persistence of rumination was actively inhibited (Kross et al., 2009). In turn, activation of sACC was not seen during the recall of happy memories (George et al., 1995). Information concerning the function of a specific area within sACC is only available for area 25, which has been implicated in the regulation of autonomic and endocrine functions via connections with the periaqueductal gray (An et al., 1998, Chiba et al., 2001, Freedman et al., 2000, Neafsey et al., 1993, Takagishi and Chiba, 1991).

Meta-analyses have confirmed the involvement of sACC in the processing of affective experiences associated with sadness (Phan et al., 2002, Vogt, 2005), as well as during the down-regulation of negative affective responses resulting in fear extinction (Diekhof et al., 2011). They have also revealed that sACC is activated during affective pain processing, in particular when related to noxious cutaneous stimuli (Duerden and Albanese, 2013, Vogt, 2005). Additionally, sACC is part of a network enabling the integration of cognitive control and affective processes (Cromheeke and Mueller, 2014). That is, sACC is activated when a cognitive control task is carried out in an emotion-generating context, or the emotional stimuli are relevant to the cognitive task being carried out (Cromheeke and Mueller, 2014). However, these studies did not take the parcellation of sACC into architectonically distinct areas into consideration when describing the location of activation foci. Thus, sACC conceptually remained a homogeneous brain region despite a conspicuous functional diversity and the fact that the centers of activity were frequently seen at different positions. This concept of a homogeneous region challenges the widely accepted hypothesis of structural–functional relationships at the level of cortical areas.

Therefore, a multimodal analysis taking into consideration both cellular and receptor compositions as well as the connectivity and functions is necessary to reconsider the concept of a homogeneous sACC in functional neuroimaging studies. Here we will provide a detailed comparison of previously cyto- and receptorarchitectonically characterized areas 33, 25, s24, and s32 (Palomero-Gallagher et al., 2008) with the highly variable sulcal and gyral patterns in the region of the sACC. We will generate three-dimensional (3D)-probabilistic maps of these areas in standard stereotaxic reference space, which enable quantification of their intersubject variability in position and extent. These maps will also serve as volumes of interest for an analysis of co-activation patterns and functional properties of each of the cytoarchitectonically defined areas. The results demonstrate that sACC is a brain region which consists of four distinct areas with a matching structural and functional segregation.

Section snippets

Continuous probabilistic maps and maximum probability maps

We examined the cytoarchitectonic properties of sACC in ten post mortem human brains obtained through the body donor program of the Department of Anatomy, University of Düsseldorf (Table 1). Brains were fixed for 5 months in Bodian's fixative or in 4% formaldehyde, and scanned with a T1-weighted magnetic resonance sequence (“MR-volume”; flip angle = 40°; repetition time TR = 40 ms; echo time TE = 5 ms for each image; 128 sagittal sections; spatial resolution 1 × 1 × 1.17 mm; 8 bit gray value resolution)

Cyto- and receptorarchitectonically defined borders and their relationship to macroscopical landmarks

Area 25 was located mainly on the subcallosal gyrus, and its rostral border was often found in the anterior parolfactory sulcus, which was present in 16 out of 20 hemispheres (Fig. 1). However, area 25 extended rostral to the anterior parolfactory sulcus in both hemispheres of case 5 and in the right hemisphere of cases 15 and 18. It encroached hereby onto the cingulate gyrus in case 5 and the superior rostral gyrus in cases 15 and 18. Area 25 never reached the orbitofrontal surface of the

Discussion

The present study provides an analysis of the organization of the human subgenual anterior cingulate cortex by determining the functional domains and connectivity of the cytoarchitectonically defined sACC areas 25, s24, s32, and 33 (Palomero-Gallagher et al., 2008). To this end we generated continuous and maximum probability maps, the latter of which were used as seed volumes for subsequent database-driven analysis of task-dependent functional connectivity and functional decoding. Hereby,

Acknowledgments

This study was partly supported by the Deutsche Forschungsgemeinschaft (EI 816/4-1 to S.B.E. and 3071/3-1 to S.B.E.), the National Institute of Mental Health (R01-MH074457 to S.B.E.), and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604102 (HBP).

Conflict of interest

The authors have no conflict of interest to declare.

References (105)

  • S.B. Eickhoff et al.

    Activation likelihood estimation meta-analysis revisited

    NeuroImage

    (2012)
  • A. Etkin et al.

    Emotional processing in anterior cingulate and medial prefrontal cortex

    Trends Cogn. Sci.

    (2011)
  • A.C. Evans et al.

    Brain templates and atlases

    NeuroImage

    (2012)
  • L. Fiddick

    There is more than the amygdala: potential threat assessment in the cingulate cortex

    Neurosci. Biobehav. Rev.

    (2011)
  • P. Fossati

    Neural correlates of emotion processing: from emotional to social brain

    Eur. Neuropsychopharmacol.

    (2012)
  • P.T. Fox et al.

    Distributed processing; distributed functions?

    NeuroImage

    (2012)
  • T. Frodl et al.

    Anterior cingulate cortex does not differ between patients with major depression and healthy controls, but relatively large anterior cingulate cortex predicts a good clinical course

    Psychiatry Res.

    (2008)
  • S. Geyer et al.

    Areas 3a, 3b, and 1 of human primary somatosensory cortex. 1. Microstructural organization and interindividual variability

    NeuroImage

    (1999)
  • S. Geyer et al.

    Areas 3a, 3b, and 1 of human primary somatosensory cortex. 2. Spatial normalization to standard anatomical space

    NeuroImage

    (2000)
  • R. Gittins et al.

    A quantitative morphometric study of the human anterior cingulate cortex

    Brain Res.

    (2004)
  • O. Jakobs et al.

    Across-study and within-subject functional connectivity of a right temporo-parietal junction subregion involved in stimulus-context integration

    NeuroImage

    (2012)
  • T.S. Kellermann et al.

    Task- and resting-state functional connectivity of brain regions related to affection and susceptible to concurrent cognitive demand

    NeuroImage

    (2013)
  • N. Kohn et al.

    Gender differences in the neural correlates of humor processing: implications for different processing modes

    Neuropsychologia

    (2011)
  • L. Kong et al.

    Sex differences of gray matter morphology in cortico-limbic–striatal neural system in major depressive disorder

    J. Psychiatr. Res.

    (2013)
  • E. Kross et al.

    Coping with emotions past: the neural bases of regulating affect associated with negative autobiographical memories

    Biol. Psychiatry

    (2009)
  • J.S. Labus et al.

    Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: a network analysis

    NeuroImage

    (2008)
  • A.R. Laird et al.

    Networks of task co-activations

    NeuroImage

    (2013)
  • J. Lévesque et al.

    Neural correlates of sad feelings in healthy girls

    Neuroscience

    (2003)
  • M. Liao et al.

    Lack of gender effects on gray matter volumes in adolescent generalized anxiety disorder

    J. Affect. Disord.

    (2014)
  • I.M. Linares et al.

    Neuroimaging in specific phobia disorder: a systematic review of the literature

    Rev. Bras. Psiquiatr.

    (2012)
  • M. Liotti et al.

    Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders

    Biol. Psychiatry

    (2000)
  • E. Luders et al.

    Why size matters: differences in brain volume account for apparent sex differences in callosal anatomy: the sexual dimorphism of the corpus callosum

    NeuroImage

    (2014)
  • N.V. Malykhin et al.

    Fronto-limbic volumetric changes in major depressive disorder

    J. Affect. Disord.

    (2012)
  • M.L. Mechias et al.

    A meta-analysis of instructed fear studies: implications for conscious appraisal of threat

    NeuroImage

    (2010)
  • B. Merker

    Silver staining of cell bodies by means of physical development

    J. Neurosci. Methods

    (1983)
  • G. Perlaki et al.

    Are there any gender differences in the hippocampus volume after head-size correction? A volumetric and voxel-based morphometric study

    Neurosci. Lett.

    (2014)
  • K.L. Phan et al.

    Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI

    NeuroImage

    (2002)
  • E.T. Rolls

    Functional neuroimaging of umami taste: what makes umami pleasant?

    Am. J. Clin. Nutr.

    (2009)
  • D.M. Small

    Flavor is in the brain

    Physiol. Behav.

    (2012)
  • M. Takagishi et al.

    Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat: an anterograde tracer PHA-L study

    Brain Res.

    (1991)
  • R.D. Treede et al.

    Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus

    Pain

    (2000)
  • B.A. Vogt et al.

    Cytology and functionally correlated circuits of human posterior cingulate areas

    NeuroImage

    (2006)
  • T.D. Wager et al.

    Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging

    NeuroImage

    (2003)
  • K. Amunts et al.

    Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps

    Anat. Embryol.

    (2005)
  • X. An et al.

    Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys

    J. Comp. Neurol.

    (1998)
  • A.V. Apkarian et al.

    Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals

    J. Neurosci.

    (1994)
  • T. Asami et al.

    Anterior cingulate cortex volume reduction in patients with panic disorder

    Psychiatry Clin. Neurosci.

    (2008)
  • T.E. Behrens et al.

    Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging

    Nat. Neurosci.

    (2003)
  • B.J. Blatchley et al.

    Subgenual cingulate cortex and personality in chimpanzees (Pan troglodytes)

    Cogn. Affec. Behav. Neurosci.

    (2010)
  • T. Butler et al.

    Fear-related activity in subgenual anterior cingulate differs between men and women

    NeuroReport

    (2005)
  • Cited by (89)

    View all citing articles on Scopus
    View full text