Cerebellar-thalamic connectivity in schizophrenia.

The literature on alterations in brain structure and function in schizophrenia, particularly in relationship to impairments in cognitive, motor, and affective functions, has made it increasingly clear that changes in the function of a single brain region cannot explain the range of impairments seen in this illness.1–4 This realization has led to a surgence of interest in studies examining neurobiological changes in schizophrenia from the perspective of brain networks and connections among brain regions and networks, with a particular focus on neural circuits known to work together to support sensory, cognitive, and emotional processes.5 This shift in focus is consistent with long-standing hypotheses about schizophrenia as a “dysconnection” syndrome, where impairments in cognition and behavior occur because of a failure of coordinated action across multiple brain regions. As many researchers have noted,6 versions of this hypothesis were put forth as early as the work of Wernicke7 and Bleuler.8 Further, theories about abnormalities in connections among brain regions have also played a central role in more recent theories of the pathophysiology of schizophrenia. For example, one such prominent theory, put forth by Andreasen and colleagues,9 suggested that schizophrenia involves a disruption in the integration of cortical-subcortical-cerebellar circuits, a hypothesis termed “cognitive dysmetria.” Although the cognitive dysmetria hypothesis suggested the critical involvement of cerebellar, striatal, and thalamic circuits as well as cortical circuits, the majority of the work on structural and functional connectivity deficits in schizophrenia has focused on cortical and striatal dysfunction and disconnection,10–14 with the need for additional work on the thalamus. Alterations in the structure15–17 and function of the thalamus are prominent in the schizophrenia literature.2,18–21 As shown in anatomical studies of primates, the thalamus is topographically organized into parallel pathways connecting specific thalamic nuclei to different regions of cortex brain regions,22 helping to form parallel loops for various types of information processing between subcortical and cortical regions. A growing number of studies have examined deficits in thalamic connectivity in schizophrenia, with several studies finding alterations in the functional connectivity between the thalamus and regions in the prefrontal in individuals with schizophrenia,23–27 consistent with the known anatomical connectivity of the thalamus. Surprisingly few studies have examined cerebellar dysconnectivity in schizophrenia, or abnormalities in cerebellar-thalamic connections.28–31 In part this may reflect the fact that until recently, the involvement of the cerebellum in nonmotor functions was not well-appreciated, perhaps making it a potentially less attractive target for work trying to understand the neural basis of cognitive and affective, as well as motor deficits in schizophrenia. However, there is now strong evidence that the cerebellum plays important roles in nonmotor cognitive and affective functions32–37 though the precise mechanistic contributions that the cerebellum makes to these functions remains to be elucidated. Existing theories of cerebellar function suggest that it influences motor and higher cognitive functions through feed-back and feed-forward loops via the thalamus and pons, with the thalamus the obligatory relay for all efferent cerebellar projections to the cortex. In particular, it is thought that the cerebellum plays a key role in cognitive and affective control through error processing,38 with potential roles for the cerebellum in reinforcement learning39 and/or supervised learning.40,41 Further, there is also strong evidence that the cerebellum, particularly the olivo-cerebellar loop, plays a key role in timing functions.42 A substantial amount of work has found that cerebellar regions display anatomical and functional alterations in schizophrenia,43–47 and there is evidence for abnormalities in motor,48 conditioning,49–53 and timing functions54–58 Schizophrenia Bulletin Advance Access published June 3, 2014