As a group, the regions of the cerebellum functionally coupled with prefrontal cortex occupy a significant extent of the posterior hemisphere. Interestingly, the prefrontal-coupled regions of cerebellum in particular appear to have undergone significant expansion in recent hominid evolution. We also note that the network of cortical regions correlated with a particular lobule in posterior cerebellum, Crus I, is similar to the default network (Raichle et al. 2001
; Buckner et al. 2008
). Thus, the human cerebellum contains multiple regions that are correlated with distinct areas of prefrontal cortex. Functional understanding of the cerebellum should consider these distinctions.
Early anatomical work demonstrated that the dentate nucleus projects to regions of the thalamus with known connections to association areas of cerebral cortex (for a review see Leiner et al. 1986
), providing an initial hint of the neural architecture that could support cerebellar influence on these areas. However, the application of both antereograde and retrograde viral tracers in the monkey provided the most compelling evidence for this hypothesis by showing that different areas of cortex that include prefrontal areas participate in closed circuits with different regions of the cerebellum (Middleton and Strick 2000
; Kelly and Strick 2003
). Our use of fcMRI produces results consistent with the known anatomy of cerebro-cerebellar connections.
On the basis of the tracing work, we expected to find crossed laterality in our fronto-cerebellar correlation maps. Though all cortical regions were preferentially correlated with contralateral cerebellum as predicted (i.e., MOT and DLPFC), bilateral connectivity was present for all regions tested to varying degrees (i.e., ). Although connectional architecture is mostly crossed, a moderate number of projections from neocortex (20–30%) terminate—via the pons—on ipsilateral cerebellum. Similarly, the pathway from cerebellum to the thalamus is predominantly, but not wholly, crossed (Schmahmann 1996
Inspection of the raw correlation maps () suggests that the MOT seeds produce relatively few ipsilateral correlations compared with the more robust bilateral pattern seen for the 3 prefrontal seed regions. Future work on this topic can determine whether this is a meaningful functional or anatomic difference. It is also possible that the ipsilateral cerebellar correlations reflect correlations with the “frontal” site contralateral to the original neocortical seed. A neocortical seed in one hemisphere often produces robust correlations with the same region in the opposite hemisphere (Biswal et al. 1995), presumably reflecting strong interconnectivity of these regions via the corpus callosum (Johnston et al. 2008
). Therefore, ipsilateral cerebellar correlations could arise indirectly via the correlated contralateral neocortex.
As predicted, we observed intrinsic, correlated activity between MOT and the anterior cerebellar hemispheres and lobule VIIIB and between DLPFC and the posterior cerebellar hemispheres. Examining our results in more detail reveals a fractionation of the posterior cerebellum into regions that preferentially correlated with MPFC relative to DLPFC (such as Crus I) and vice versa (Crus II). Additionally, we found that placing a seed region in APFC resulted in correlated activity in dorsal lobule VI and ventral VIIB–VIIIA, defining a fourth zone (which can also be distinguished from MOT representations). The cerebellar topography resulting from motor and DLPFC seeds is consistent with established anatomical connectivity in the monkey.
We additionally provide strong evidence that there are at least 2 other circuits connecting the cerebellum to medial and anterior prefrontal cortices in humans. Studies in nonhuman primates suggest that there are some projections to the pons from dorsomedial prefrontal convexities but not from ventrolateral or orbitofrontal cortices (for a summary see Schmahmann and Pandya 1997
). Our map of cortical correlations with the posterior cerebellar hemispheres () suggests the possibility that there exist cerebro-cerebellar circuits in human prefrontal cortex that may not find a homologue in monkeys. Placing seeds in primary auditory and visual cortices did not produce correlations in the cerebellum, providing an internal control for our results.
The observation that extensive portions of the posterior cerebellum are associated with putatively “cognitive” networks is especially interesting in light of the suggestion that phylogenetic expansion of certain lateral and posterior aspects of the cerebellum and cerebellar nuclei has paralleled the expansion of the frontal cortex (Rilling and Insel 1998
; MacLeod et al. 2003
; Whiting and Barton 2003
). The ventral half of the dentate nucleus, which comprises the fiber connections to prefrontal cortex, is more developed in humans than in great apes (Middleton and Strick 1994
; Matano and Hirasaki 1997
; Matano 2001
; Dum and Strick 2003
; Akkal et al. 2007
). Further, relative to cerebellar midline (vermis), the lateral hemispheres of the cerebellum have undergone significant expansion in hominoids relative to monkeys (MacLeod et al. 2003
). The thalamus and pons, relay stations between the cerebellum and the neocortex, have also displayed correlated evolutionary development (Whiting and Barton 2003
). The preferential expansion of these particular cerebellar regions may contribute to cognitive functions particularly well developed in humans, such as language and reasoning (Leiner et al. 1991
Several caveats and open questions must be considered when interpreting functional connectivity results. A pertinent issue to the present study is to what degree functional connectivity reflects underlying structural connectivity. The observation that DLPFC and MOT seed regions produced correlated regions in the cerebellum that are predicted by the monkey tracing work suggests that fcMRI respects anatomical constraints. Additionally, our control seeds in or near striate and primary auditory cortex did not produce correlations in the cerebellum, consistent with known anatomy. However, fcMRI connectivity is inherently a more pervasive measure than anatomical connectivity because 2 regions can be correlated with one another just by virtue of the fact that they participate in a common functional network.
One implication of the possibility of indirect correlations for the present study is that other regions outside of the frontal cortex may drive the coherence patterns observed between the neocortex and the cerebellum. For example, seeding the posterior cerebellum (Crus I) produced a distributed network of correlations similar to the default network, including MPFC, the inferior parietal lobule and the posterior cingulate (). Although MPFC was identified as the neocortical region exhibiting the strongest correlations with Crus I, we cannot rule out the possibility that another region within that network, for example, the posterior cingulate, could mediate the relationship between MPFC and the cerebellum or contribute to the correlations in the cerebellum. For instance, parietal cortex has known anatomical connections with the cerebellum (Clower et al. 2001
). This may also explain why regions in inferior temporal cortex exhibit correlations with regions in the cerebellum (i.e., ) despite evidence from tracing work that few, if any, projections exist between the pons and inferior temporal cortex (Glickstein et al. 1985; Schmahmann and Pandya 1991
). Similarly, neocortical regions contralateral to a seed region may be responsible for driving the ipsilateral cerebellar response ().
Functional connectivity in other animals for which anatomical pathways are well characterized may help to resolve these questions. However, it is important to note that although the issue of pervasiveness makes the overlap of 2 correlation maps difficult to interpret, it does not undermine the interpretation of correlated networks that are clearly segregated; fcMRI remains a powerful technique for detecting divergent networks and for characterizing the topography of regions participating in them.