This paper provides a systematic mapping of the resting-state functional connectivity of PMC using a true voxelwise method. We used a ROI-based parcellation as previously employed by Margulies et al. [20] to confirm our results. Previous efforts to provide a comprehensive examination of functional connectivity in PMC using task-based approaches have required the synthesis of findings across multiple studies via meta-analysis [28], [29]. We hypothesized that the application of correlational analyses to resting-state fMRI data in a single study can enable the characterization of task-independent patterns of functional connectivity with more subtle regional differentiations. Therefore, we conducted an unbiased study to examine both cortical and subcortical functional correlations of all cytoarchitectonic areas within the PMC, using (i) a fuzzy clustering approach, clusterizing in a voxelwise fashion all the PMC parenchyma and (ii) a ROI-based parcellation approach involving the creation of 10 equispaced ROIs along four parallel curves aligned with the corpus callosum in each hemisphere.

Intrinsic and shared correlations among PMC components

Our findings indicate that distinct cytoarchitectonic areas in the PMC are functionally correlated with each other, and the local intercorrelations are stronger between immediately adjacent areas than areas further apart. Interestingly, these results reflect previously obtained connectivity data from the macaque brain, which is the closest approximation to the human brain in conventional anatomical tracing experiments [18], [19]. For instance, almost all PMC areas (BA 7m, B23 and BA 29, located within the precuneus, posterior cingulate cortex and retrosplenial cortex) showed both positive and negative correlations with BA 31, which is an architectonically transitional area between BA7m and BA23. Moreover, according to voxel distance calculations, ROI located within the same cytoarchitectonic boundaries tended to be more strongly correlated.

Our results suggest a progressive shift in PMC functional connectivity from anterior to posterior and from dorsal to ventral ROIs. That is, dorsal posterior portions of PMC (i.e. the dorsal posterior part of BA 7 and 31 - ROIs 5 and 6) were shown to be part of a fronto-parietal network implicated in the visuo-spatial guidance of movements, whereas dorsal anterior portions of PMC (dorsal anterior part of BA 23 - ROI 1) were interlinked with areas involved in attentional control. The ventral anterior PMC (BA 30 and the ventral part of BAs 23 and 31 - ROIs 2–4, 7, 9) selectively correlated with a network showing considerable overlap with the DMN (TNN), the exact function of which has not been elucidated, although a central role for self processing and self awareness has been suggested [2]. Finally, the ventral posterior PMC (ventral part of BA 7 - ROIs 8 and 10) was shown to be functionally connected with a visual network.

The convergence of anatomical interconnectivity and functional intercorrelation maps provides strong evidence for the identification of a functional unit in baseline resting state activity [66]. This hypothesis is consistent with the considerable overlap between the shared connectivity pattern of PMC areas and the TNN (DMN). It has been shown that in the primate brain all PMC components are interconnected with the anterior cingulate gyrus, the mid-dorsolateral prefrontal cortex (area 46 and, to lesser extent, area 9), the lateral parietal cortex, and the TPO [19]. In addition to these regions, we found that the PMC has extensive functional correlations with other bilateral cortical areas within the frontal lobe, such as the VMPFC and the motor/supplementary motor cortex. These minor differences compared to primate data could be merely due to methodological differences between studies. Alternatively, they can be related to inter-species differences, with a more prominent role for fronto-parietal connections in Homo Sapiens. Moreover, functional connectivity studies disclose not only direct (anatomical) connections, but additional connectivity patterns which are mediated by other brain structures.

Beyond this shared connectivity pattern, our results showed progressive shifts in PMC functional connectivity from anterior/rostral to posterior/caudal and from dorsal to ventral ROIs. These findings suggest functional heterogeneity within the PMC (cfr. [20]). For example, although ROI 5 and 6 belong to the same sensorimotor cluster, the superior part of the precuneus (BA 7m) is characterized by its selective correlation pattern with the lateral parietal cortex, intraparietal sulcus (BA 5,7), inferior parietal lobule (BA 40), temporal neocortex (BA 20,21,22,37,38), visual cortex (BA 17,18,19), cerebellum and amygdala. The connectivity study by Parvizi et al. [19] showed a similar pattern of connections with frontal and cingulate structures involved in execution or planning of actions. In addition, the more rostral portion of BA 7m shows a broad pattern of connections with the motor and premotor cortex, the cerebellum, the visual system, and the insula. These findings are consistent with converging evidence suggesting that the anterior portion of the precuneus subserves visuo-spatial coordination skills required for reaching and grasping behaviors [2]. Specifically, the integration of mental imagery with sensorimotor and cerebellar information is thought to provide visual guidance to hand movements in conjunction with the superior parietal lobule [2], [67], [68], [69], [70]. Moreover, the results of our functional correlation analysis support the existence of a topographically-specific organization in the reciprocal parieto-frontal connections first proposed by Cavada and Goldman-Rakic [68] and subsequently confirmed by Leichnetz [18], such that the precuneus has important cortico-cortical connections with the rostral-most dorsal premotor cortex (BA 6, frontal eye field). Of note, experimental studies of electrical stimulation of BA 7m have resulted in saccade-like eye movements, thus suggesting the existence of another oculomotor center within the precuneus, a “medial parietal eye field” [71]. Cavanna and Trimble [2] have proposed that visuo-spatial information processing and spatially guided behavioural tasks primarily activate lateral parietal areas, with the areas of (co)activation spreading into other parts of the parietal cortex and thus extending into the anterior precuneus. This functional specialization within BA 7m could also reflect underlying cytoarchitectonical differences. Based on gradual rostrocaudal architectonic changes within area 7, Brodmann [72] described two main subdivisions, which he named 7a and 7b. A few years later Von Economo and Koskinas [73] described a virtually identical location for their area PE, which was subdivided into the anterior area PEm, with a more pronounced magnocellular appearance, and the relatively smaller-celled posterior area PEp. Topographical comparisons have suggested that PEm and PEp are probably equivalent to Brodmann's subdivisions 7a and 7b [1].

Both the anterior portion of the precuneus (BA 31) and the posterior cingulate cortex (BA 23) are characterized by a rostro-caudal gradient in functional connections. The dorsal portion seems to be functionally associated with the TPN, whereas the ventral portion, along with the retrosplenial cortex (BA 29 and BA 30), is selectively interlinked with the TNN. As reported by Fox at al. [5], [74], the TPN includes pre-supplementary motor area, IPS, FEF, right insular cortex and DLPFC and activates during performance of externally directed cognitively demanding tasks. On the other hand, the TNN includes medial prefrontal cortex, posterior cingulate/precuneus, and angular gyrus, and activates during self-reflective tasks.

A review of the literature in terms of PCC duality suggests that the dorsal anterior portion plays a role within the TPN in orienting the body in space via the cingulate motor areas, whereas the ventral portion interacts with subgenual cortex and other components of the TNN to process self-relevant emotional and non-emotional information and objects and self-reflection [75]. Moreover, the TNN shows considerable overlap with the DMN, thus supporting the hypothesis that the ventral anterior PMC might contribute to resting-state functions such as episodic memory retrieval and reflective awareness. Our results confirm previous findings from both functional connectivity studies in humans [2] and tracing experiments in primates [19] showing selective interconnectivity between the PCC and the parahippocampal formation in subserving episodic memory retrieval. On the other hand, the functional significance of the specific connectivity pattern between the PMC and the claustrum, a neuronal structure which is interconnected with almost all cortical regions, is still unclear [66], [76], [77].

In our study, the retrosplenial cortex (BA 29 and BA 30) was characterized by selective functional correlations with the medial aspect of the temporal lobe and a number of subcortical structures, including the amygdala, the left nucleus accumbens, the left claustrum, and the caudate (left: positive correlation; right: negative correlation), and the dorsomedial thalamus (both positive and negative correlations). Again, these results replicate with fair accuracy the connectivity patterns observed in the primate brain [19]. This functional pattern is also consistent with the known cytoarchitectonical similarities between the retrosplenial allocortex and limbic structures [75]. In addition to its putative contribution to emotional processing networks [78], the retrosplenial cortex is the main source of visuo-spatial information to the mTL memory system. The strong connections with the parahippocampal cortex are of particular importance because they are thought to be related with co-activation of the two regions during spatial navigation tasks. Recent findings indicate that the parahippocampal cortex and retrosplenial cortex have distinct and complementary roles in spatial cognition, with the parahippocampal cortex more concerned with representation of the local visual scene and RSC more concerned with situating the scene within the broader spatial environment [79]. Moreover, it has recently been proposed that the retrosplenial cortex works together with the parieto-occipital sulcus allowing the integration between allocentric environmental representations provided by the hippocampus and mTL and parietal egocentric representations [80].

The emerging picture suggests that the ventral anterior portion of the PMC plays a pivotal role within the DMN in self-referential processing (including self-awareness and autobiographical/episodic memory retrieval) along with the TNN areas which are active during the conscious resting state. The retrosplenial cortex could contribute to this “default” processing by contributing to emotional salience attribution in conjunction with its limbic connections. It might also take part in visuo-spatial attention shifting, along the anterior portion of the PMC, which is an integral part of the TPN.