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