Stepwise Functional Connectivity of the Primary Visual Cortex
When exploring visual cortex with SFC, we find that the direct connections from the early visual seed in V1/BA17 are mostly limited to within the occipital lobe, especially to its medial and dorsal areas (). There is a gradient of a decreasing degree of connectivity from the seed region to the rest of the lobe that, interestingly, expands dorsally from V1 to V2, V3 and V7 (see and details in flat projections) and also laterally from V1 to V2 and MT+ (see and details in flat projections). A third branch of connectivity is following the ventromedial part of the occipital lobe, from V1 to V2v, V3v, V4 and V8, and posterior parahipocampus (see and details in flat projections). After the initial steps of connectivity, all visual pathways converge to a set of distinct regions in the frontal eye field, superior parietal cortex (SPC, BA1/2/5), parietal operculum (or operculum parietale, OP, BA40), anterior insula/ventral premotor cortex in frontal operculum (AI+) and dorsal anterior cingulated cortex/supplementary motor area (DACC+, BA6/24/32) cortices (). Finally, in the late steps, the connectivity of the visual cortex reaches distributed cortical regions, now known as the cortical hubs of the human functional brain (Buckner et al., 2009
; Sepulcre et al., 2010
Stepwise Functional Connectivity of the Primary Somatosensory Cortex
In the early step, somatosensory cortex displays a regional-local connectivity all along the somatomotor cortex () and, to a lesser extent, also to the LOTJ (). shows that primary somatosensory cortex has a significant and direct connectivity to the secondary somatosensory area (OP4/BA43; (Eickhoff et al., 2007
)) in the ventral and anterior part of the parietal operculum (see star symbol in inflated projection of ). With increasing steps, somatosensory cortex connects to the same constellation of regions as the visual cortex, which includes the SPC, OP, AI+, and DACC+ (). Again similarly to the visual cortex, the high-order SFC maps of the somatosensory cortex show connectivity patterns reaching the cortical hubs network.
Stepwise Functional Connectivity of the Primary Auditory Cortex
In the first step, the primary auditory cortex exhibits a dense and predominant regional-local connectivity, specifically along auditory related areas such as the perisylvian secondary auditory areas (). Although to a lesser extent, auditory cortex also exhibits direct connections to somatomotor and LOTJ (). Similarly to somatosensory cortex, initial steps in the SFC analysis reveal a significant connectivity to a secondary representation area (OP4/BA43) in the parietal operculum (see star symbol in inflated projection of ); an area slightly anterior to the one described in the somatosensory SFC analysis. In later steps, the auditory cortex connectivity reaches first other perisylvian areas such as a ventral premotor cortex and OP1 (see inflated projection of ) and then the same set of regions described in the previous two sensory modalities, SPC, OP, AI+, and DACC+ (). In the final steps, the connectivity of the auditory cortex reaches the cortical hubs network.
Multimodal Integration Network
In we used a combined approach to highlight the topological convergence of the stepwise connectivity patterns in the three major sensory modalities that were explored (). In addition to the previously mentioned regions (SPC, OP, AI+, and DACC+), we find more clearly that one area in dorsolateral prefrontal (DLPFC, BA10/46) and another area in LOTJ -in the confluence region of BA19/22/37/39, and touching the superior temporal sulcus- provide also strong nexuses of convergence from all three sensory modalities (). In other words, concrete and consistent regions emerge as a common destiny for the sensory modalities and serve as transition bridges from perception to higher-order cognitive regions such as the cortical hubs (green areas and nodes in ).
Multimodal Integration Network in the Left and Right Hemispheres
We found left/right hemisphere asymmetries in the multimodal integration network, particularly in the vicinity of the temporo-parietal junction (TPJ). The OP multimodal integration region on the right side of the brain is more extensive than the one obtained in the left hemisphere (). In the right hemisphere, the OP region merges with the superior temporal gyrus while in the left hemisphere the OP is isolated. In addition, the maps of the late steps show important left-right differences in the ventrolateral prefrontal cortex, especially in the Broca’s language area ().
TPJ has been classically described as a region affected in the spatial neglect syndrome, especially in the right hemisphere (Friedrich et al., 1998
; Ro et al., 1998
; Vallar, 1998
). Neglect syndrome is an attention disturbance in which subjects are unaware of spatial stimuli in one hemi-field. The fact that the multimodal region in the right hemisphere is larger in that particular location may account for the higher rate of neglect patients with right TPJ lesions. The characterization of multimodal integration regions strongly supports a network theory of the neglect condition. Although frequently described after focal TPJ lesions, neglect syndrome seems to be a network disease (Mesulam, 1981
; Downar et al., 2000
; He et al., 2007
). For instance, other regions such as DACC or prefrontal cortex, particular in the vicinity of BA44, have been implicated in neglect patients (Vallar, 1998
). Therefore, it is not surprising that the regions that generate neglect are included in the multimodal network described in this study. Even newly characterized regions of the multimodal network such as SPC have been associated with neglect (Mesulam, 1999
). The network framework brings new insights to bear on neglect syndrome. The disruption of connectivity axes between multimodal regions may explain problematic points of previous “TPJ-centrist” interpretations. For instance, an appropriate integration of perceptual, attentional and motor planning information seems critical for a rapid access of motor actions (Ikeda et al., 1999
). It is well known that neglect patients have motor deficit, particularly initiating movements (Corbetta and Shulman, 2002
), and an interruption of connectivity from OP, AI+ or SPC to DACC+, which include the pre/supplementary motor area, can explain this aspect of the syndrome.
Characterization of the Multimodal Integration Network
After isolating the multimodal network in the first dataset, we aimed to confirm that these regions make up a robust coherent network using the second dataset. In this section, we used SFC analysis again, but this time to characterize the main connectivity axes of the previously obtained multimodal regions.
OP () and AI+ () stepwise connectivity maps show that both regions form a strong axis of connectivity between them. For higher order steps, OP and AI+ also exhibit strong connectivity with the DACC+ and SPC regions. As expected for a SFC analysis at rest, the stepwise connectivity maps of OP and AI+ eventually reach the stable state in the cortical hubs regions, but in fewer steps than the primary sensory cortices. In summary, AI+ and OP stepwise connectivity maps show a dense core of connectivity between both regions, and in later steps reach other multimodal nodes but never significantly return to the primary cortices.
Characterization of the Multimodal Integration Network: Parietal Operculum and Anterior Insula
When analyzing the SPC region, we find that this region has strong direct coupling with the OP and then a dense connectivity to the OP-AI+ axis (). On the other hand, LOTJ’s direct connectivity spreads locally across a broad region of the temporal-parietal-occipital junction (). LOTJ also has direct coupling with the SPC and OP regions, forming a posterior brain connectivity triangle. As in SPC, LOTJ connectivity converges to the OP-AI+ axis with further steps.
The DACC+ () stepwise connectivity results show that this region is directly coupled with the OP-AI+ axis. In this sense, it seems that DACC+ is actually an important component of this connectivity core (compare with ). On the other hand, DLPFC stepwise maps display a distinctive pattern of connectivity compared to other multimodal regions (). With one step, DLPFC has connections to OP and AI+. However, the connectivity profile is more posterior in the OP region and more anterior in the AI+ region than the pattern displayed by the other multimodal regions (see star symbols in the insert of ). Although these differences are subtle, the more posterior part of the OP region and the more anterior part of the AI+ has been related with another functional network, namely the fronto-parietal control network (Yeo et al., 2011
). The intimacy by which both networks are interdigitated in the inferior parietal and insula regions suggests that some of these multimodal network nodes might be implicated in the interrelation of perceptual integration and cognitive control functions.
Finally, in order to explicitly characterize the modular relationship between the multimodal regions, we performed an average-linkage hierarchical clustering analysis of the multimodal integration network (). Briefly, we first averaged the FDR-corrected whole-brain association matrices (positive correlation coefficients) from dataset 2. Then, we extracted a 48×48 matrix containing the seed voxels of OP, AI+, SPC, LOTJ DACC+ and DLPFC regions (eight voxels per region) and performed the average-linkage hierarchical clustering analysis. The hierarchical partition shows two main network modules (cutoff criteria r>0.2), one integrated by SPC and LOTJ (), and the other by OP, AI+, DACC+ and DLPFC (). We observe that the connectivity between the two modules, a and b, is mostly through the connections of the SPC-OP axis (). On the other hand, there is also a meaningful partition within the module b (cutoff criteria r>0.4); sub-module b1 formed by OP, AI+ and part of DACC+, and sub-module b2 formed by DLPFC and part of DACC+ (). illustrates the main connectivity axes described in this study, especially highlighting the SPC-OP and OP-AI+ axes.
Modules and Connectivity Axes of the Multimodal Integration Network
Interconnectors Between Modality Pairs
To further characterize patterns of connectivity between pairs of sensory modalities, we used another novel network analytical strategy that detects bimodal brain regions. The analysis of bimodal interconnectors is significantly different from the previous SFC analysis; it specifically targets the connections between two primary regions rather than the unconstrained transitions of connectivity revealed by SFC. Yet, similar to the SFC analysis, it uses a stepwise approach to detect direct and indirect connections for all the possible pairs of sensory modalities: visual-auditory (V-A), visual-somatosensory (V-S) and auditory-somatosensory (A-S) ().
The V-A results demonstrate that the posterior middle temporal gyrus, an area anterior to the LOTJ multimodal region, is engaged in the merging of direct connections between the visual and auditory cortex (). An analogous area has been extensively reported as visual-auditory bimodal integrator using other neuroimaging techniques (Driver and Noesselt, 2008
). The V-S findings show a more distributed pattern, where SPC () and dorsal and lateral occipital () regions display strong visual and somatosensory bimodality. Additionally, a motor region known to be related in oculomotor processing shows interconnector properties between visual and somatosensory cortices (anterior part of ). Primary motor and somatosensory cortices are locally interlocked by mutual connections across the central sulcus (Pandya and Kuypers, 1969
; Jones and Powell, 1970
). Therefore, it is not surprising that oculomotor areas have a deep visual-somatosensory interconnectivity suggesting early integration of somatomotor and visual processing for oculomotor functions. Finally, OP connections, such as OP4 (BA43), are especially critical for the bimodal interconnectivity of auditory and somatosensory primary cortices (). Four regions in the upper bank of the lateral sulcus can be distinguished in humans, OP 1 to 4, which correspond to S2, PV and VS areas in monkeys (Disbrow et al., 2000
; Eickhoff et al., 2006b
; Eickhoff et al., 2006a
). Our findings in the bimodal interconectors analysis suggest that OP4 is not only a somatosensory secondary representation but also a plausible early bimodal interconnector that may influence the strong modularity described previously between the somatomotor and auditory cortex (Yeo et al., 2011
). Indeed, PV in monkeys is connected to both primary somatosensory as well as medial auditory belt areas (Disbrow et al., 2003
Finally, we find that indirect interconnectors are less specific for detecting bimodal integration. Maps of indirect interconnectors show trimodal rather than bimodal regions, although with some unique features depending on the pair of modalities. For instance, we find extensive occipital, including MT+, and FEF engagement when visual modality is being analyzed. is a diagram summarizing key bimodal integrators in the human brain.