Elsevier

NeuroImage

Volume 29, Issue 2, 15 January 2006, Pages 452-466
NeuroImage

Cytology and functionally correlated circuits of human posterior cingulate areas

https://doi.org/10.1016/j.neuroimage.2005.07.048Get rights and content

Abstract

Human posterior cingulate cortex (PCC) and retrosplenial cortex (RSC) form the posterior cingulate gyrus, however, monkey connection and human imaging studies suggest that PCC area 23 is not uniform and atlases mislocate RSC. We histologically assessed these regions in 6 postmortem cases, plotted a flat map, and characterized differences in dorsal (d) and ventral (v) area 23. Subsequently, functional connectivity of histologically guided regions of interest (ROI) were assessed in 163 [18F]fluorodeoxyglucose human cases with PET. Compared to area d23, area v23 had a higher density and larger pyramids in layers II, IIIc, and Vb and more intermediate neurofilament-expressing neurons in layer Va. Coregisrtration of each case to standard coordinates showed that the ventral branch of the splenial sulci coincided with the border between d/v PCC at −5.4 ± 0.17 cm from the vertical plane and +1.97 ± 0.08 cm from the bi-commissural line. Correlation analysis of glucose metabolism using histologically guided ROIs suggested important circuit differences including dorsal and ventral visual stream inputs, interactions between the vPCC and subgenual cingulate cortex, and preferential relations between dPCC and the cingulate motor region. The RSC, in contrast, had restricted correlated activity with pericallosal cortex and thalamus. Visual information may be processed with an orbitofrontal link for synthesis of signals to drive premotor activity through dPCC. Review of the literature in terms of a PCC duality suggests that interactions of dPCC, including area 23d, orient the body in space via the cingulate motor areas, while vPCC interacts with subgenual cortex to process self-relevant emotional and non-emotional information and objects and self-reflection.

Introduction

The primate posterior cingulate gyrus is comprised of ventral bank retrosplenial areas 29 and 30 (RSC) and posterior cingulate areas 23 and 31 (PCC) including an extension into the cingulate sulcus. According to stroke and functional imaging in humans and single neuron electrophysiology in monkey, this region plays a role in memory access and visuospatial orientation. Strokes in right hemisphere RSC/PCC can produce topographic disorientation (Takahashi et al., 1997) as did a splenial glioma (Bottini et al., 1990), while those in the left hemisphere and tumors pressing preferentially on the left RSC produced severe anterograde and retrograde memory impairments including that for verbal and visual information (Valenstein et al., 1987, Rudge and Warrington, 1991). Functional imaging has shown that this region is part of a network that mediates topokinetic (spatial) navigation and memory (Ghaem et al., 1997, Maguire et al., 1997, Berthoz, 1997, Berthoz, 1999). Alert monkey studies by Olson et al., 1993, Olson et al., 1996 showed that neurons in the dorsal PCC were active while assessing large visual field patterns and activity was tightly linked to the position of the eye in the orbit and the direction and amplitude of saccadic eye movements. Finally, lesions of the anterior thalamic nuclei, which project to RSC, disrupt object-in-place memory in monkeys, although cingulate gyrus ablations did not (Parker and Gaffan, 1997). Taken together, it appears that RSC and its thalamic afferents have a role in accessing long-term memories including those associated with spatial orientation, while PCC is involved in topokinesis and related memories.

Functional imaging studies frequently activate PCC during facial and word recognition tasks which might conflict to some extent with the above noted conclusion relating to visuospatial orientation. An evaluation of the extent to which different cingulate subregions are activated by emotional words and faces showed that anterior and midcingulate cortices were activated only by stimuli expressing emotion, while vPCC was activated by both emotion-expressing and non-emotional stimuli (Vogt et al., 2003). For example, happiness generated by personally relevant memory and facial expressions activates vPCC (George et al., 1996, Phillips et al., 1998, Damasio et al., 2000); however, non-emotional conditions also activate this region (Fink et al., 1996, Maguire and Mummery, 1999, Shah et al., 2001, Bernstein et al., 2002). Furthermore, studies of self-reflection and self-imagery activate the vPCC (Kircher et al., 2001, Kircher et al., 2002, Johnson et al., 2002, Phan et al., 2004, Sugiura et al., 2005), and this may be pivotal to understanding the overall information processing functions of this region. Thus, the role of this region in topokinesis may be related to the egocentric orientation of the body in relation to external landmarks as well as faces and words with particular and personal meanings.

One intriguing aspect of functional imaging findings discussed above is that words, faces, and self-reflection activate the vPCC including the caudomedial subregion (Vogt et al., 2003). The caudomedial subregion is located on the ventral bank of the cingulate gyrus (Vogt et al., 2001, Vogt et al., 2004) and has direct projections to subgenual ACC, connections that dorsal PCC and posterior MCC do not have (Vogt and Pandya, 1987). Furthermore, Shibata and Yukie (2003) reported that the dorsal and ventral parts of PCC have unique thalamic connections with the dPCC receiving inputs from the central latocellular, mediodorsal, and ventral anterior and ventral lateral nuclei that do not project to the vPCC. The structural duality of PCC has also been reported in monkey brain (Vogt et al., 2005). Thus, anatomical and functional studies suggest that PCC is heterogeneous and its subdivisions interact differently with ACC.

The cytology and circuitry observations in monkey led us to formulate three hypotheses. First, the human dPCC and vPCC have qualitatively unique cytological organizations when viewed with antibodies that label proteins in neuronal somata and proximal dendrites. Second, these two areas should have substantially different connections. To test this hypothesis, the border between each division could be identified, and the subareas were used as independent regions of interest to seed correlation analyses in resting glucose metabolism for an assessment of their functional connectivity with [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Based on the thalamocortical and corticocortical connections in monkey, we predicted that correlated activity would differ in both cortex and thalamus, and these expectations could be evaluated with well-known monkey connections such as those between anterior cingulate cortex (ACC; Vogt and Pandya, 1987) and vPCC. Finally, RSC has thalamic inputs that arise mainly from the anterior thalamic nuclei and differ substantially from those in PCC (Vogt et al., 1987), and RSC is heavily connected with adjacent area 23 (Vogt and Pandya, 1987). We predicted a heavy thalamic engagement with seeding limited to RSC and heavy correlations with PCC. A final goal of this work was to evaluate the extent to which differences in circuitry uncovered by the correlation analysis provide a basis for evaluating the mechanisms of their differential functions. Since the literature has not been assessed from the perspective of two divisions of PCC, a consideration of the functions of each subdivision was undertaken.

The results confirmed the first hypothesis by showing a structural dichotomy in the human PCC similar to that in monkey. The differential visual inputs to d/vPCC were not predicted, although they are compatible with the current assessment of the functional imaging literature. Demonstrations of interactions of vPCC with ACC and those of dPCC with premotor, dorsal visual, and orbitofrontal regions all conform to well-established connections in monkey brain. Interestingly, however, in spite of the heavy connections between RSC and PCC, the correlated voxels were limited to the ventral part of the cingulate gyrus and thalamus. These findings lead to new perspectives on the structure, connections, and functions of PCC in terms of functional units rather than a homogeneous posterior cingulate region with a single organization and function.

Section snippets

Histological preparations

Six brains were used that had complete cingulate gyrus staining (below), and the characteristics of each case have been reported (Vogt et al., 2003). There were 4 males and 2 females, ages of 52 ± 2.7 years, brain weights of 1279 ± 67 g, postmortem intervals of 10.8 ± 2.5 h and causes of death as follows: carcinoma (3); pneumonia (1), midbrain stroke (1), congestive heart failure (1). All brains were obtained from the Office of the Chief Medical Examiner in cooperation with the Chief of

Cytological analysis

Fig. 1 orients the medial surface photograph and flat map formats of the posterior cingulate gyrus and sections cut in the coronal plane (i.e., vertical arrow in panel A). The sulci are also labeled and include a ventral branch (vb; asterisk) of the splenial sulci (spls). This branch is named because it approximates the level of transition between dorsal and ventral divisions of PCC, and it is present in most brains. Ono et al. (1990) reported that 84% left and 88% right hemispheres have this

Discussion

The dorsal PCC includes areas 23d, d23a/b/c, and adjacent area 31, while ventral PCC includes areas v23a/b and caudal area 31. The cytological analysis shows that area v23 has a more neuron dense layer IV, more neurofilament-expressing layer Va neurons, a dense layer IIIc, and a more dense layer Vb than does area d23. Neither division can be confused with area 31 which has a greater proportion of large layer IIIc pyramids relative to those in layer Va. The dichotomy of PCC based on neuronal

Acknowledgments

This work was supported by the National Institutes of Health (NINDS grant #044222; BAV) and the Fonds National de Recherche Scientifique (SL). We thank Pierre Maquet, Eric Salmon, Gaëtan Garraux and André Luxen (Cyclotron Research Centre, Liège); Roland Hustinx (Department of Nuclear Medicine, University Hospital Sart Tilman, Liège); Serge Goldman, Xavier De Tiège, and Patrick Van Bogaert (PET/Biomedical Cyclotron Unit, Erasmus University Hospital, Brussels); and Koen Van Laere (Department of

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