Transcranial Magnetic Theta-Burst Stimulation of the Human Cerebellum Distinguishes Absolute, Duration-Based from Relative, Beat-Based Perception of Subsecond Time Intervals

The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral-cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.

The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.