This polysynaptic circuitry is a major contributor to the controversy surrounding the organization of the cerebellum. Because there are no monosynaptic projections between the cerebral cortex and the cerebellum, the organization of the cerebellum could not be unraveled using conventional anterograde and retrograde tracing techniques that do not cross the synapse. Foundational

questions including whether portions AUY-922 price of the cerebellum map to domains of the cortex involved in nonmotor function were left unanswered. In the absence of clear anatomical evidence that the cerebellum projects to nonmotor structures and the emphasis on motor deficits in clinical settings, early influential models of the cerebellum focused exclusively on motor function (e.g., Evarts and Thach, 1969). The past 25 years have witnessed a major revision in our understanding of the cerebellum. Discoveries beginning in the 1980s set the stage for reframing the role of the cerebellum in cognition. The initial impetus was an incisive review by the interdisciplinary team of Henrietta Leiner, Alan Leiner, and Robert Dow. Leiner et al. (1986) (see also Leiner et al., 1989 and Leiner et al., 1993) summarized extensive evidence to suggest that the human cerebellum contains regions

linked to cerebral association areas. Their review, which initially met resistance (Leiner, 2010), was based on the observation that the lateral output nucleus of the cerebellum (the dentate) is expanded in apes and CP-690550 nmr humans

ADAMTS5 relative to other species. The expansion is accounted for by preferential of the newer ventrolateral portion of the dentate and, by their estimates, occurred in parallel with expansion of prefrontal cortex. By comparing the topography of the dentatothalamic and thalamocortical projections, they deduced that the output channel from the cerebellum contains substantial projections to cerebral association areas including those within the prefrontal cortex. Foreshadowing research to appear over the next several decades, they further suggested that human neuroimaging methods could be used to confirm their hypothesis. Human neuroimaging techniques emerged in the mid-1980s as a revolutionary tool to indirectly map brain function in humans (Raichle, 1987). Early studies were conducted using positron emission tomography (PET). fMRI first appeared in the early 1990s (Kwong et al., 1992 and Ogawa et al., 1992) and became widely available within a few years. PET and fMRI both measure brain activity indirectly through the coupling of neuronal activity to increases in blood flow, often called the hemodynamic response.