Work suggesting that cerebellar abnormalities occur in schizophrenia has been slowly accumulating for several decades. Heath (49
) was the first to call attention to the possible role of the cerebellum. His work was followed by multiple additional studies using anatomical imaging tools such as CT and later morphometric Magnetic Resonance (mMR) that have reported abnormalities in cerebellar size in schizophrenia (50
). Picard et al (58
) recently conducted a review of the evidence for cerebellar abnormalities in schizophrenia from multiple perspectives: symptoms, neurological signs, eye movements, nondeclarative learning, and cognition. They conclude that evidence for cerebellar abnormalities is strong from some perspectives (e.g., neurological soft signs, posture, equilibrium) but that the evidence for other domains such as cognition is more heterogeneous. As they discuss, methodological issues (e.g., subjects sampled, variability in designs used to assess cognition) may explain this heterogeneity.
Neuropathology studies have provided significant evidence for cerebellar abnormalities in schizophrenia (59
). Investigators have reported a decreased linear density in Purkinje cells (60
) or a specific decrease in their size (by 8.3%) (61
). The latter finding is particularly significant, since Purkinje cells play a key role in modulating the output from the cerebellum to the cerebral cortex, because they provide input to the “deep nuclei” such as the dentate nucleus. The deep nuclei in turn provide the sole output from the cerebellum to the cerebral cortex.
Studies of schizophrenia using the tools of functional imaging from our own group have found a relatively consistent pattern of abnormalities in distributed brain regions that include the cerebellum. These results are illustrated in and . Abnormalities are seen in these studies in both the vermis and in the cerebral hemispheres in patterns that are task-related. Patients with schizophrenia have decreased blood flow in the cerebellum in a broad range of tasks that tap into diverse functional systems of the brain, including memory, attention, social cognition, and emotion (1
). Vermal abnormalities are more frequently noted in tasks that use limbic regions (e.g., studies of emotion), while more lateral neocerebellar regions are abnormal in tasks that use neocortical regions (e.g., memory encoding and retrieval). illustrates some of the cerebellar regions found to be abnormal in schizophrenia in studies conducted at our Iowa laboratory. Given the broad range of cognitive functions implicated in these functional imaging studies, they appear to be most supportive of model 3.
Figure 3 A composite representation of cerebellar regions with lower activity in patients with schizophrenia than in controls. Results for 1 - 7 are from double subtraction studies (for each group the activity of a baseline task has been subtracted before the (more ...)
Findings of cerebellar abnormalities using functional imaging or related technologies have also been observed by other groups using explicit methods to study the cerebellum. For example Muller et al used a finger tapping task for an fMR study in which subjects had to tap in time to a specific pace (66
). Volkow et al used PET to examine cerebellar metabolism in schizophrenia and observed reductions in both relative and absolute metabolic rates (67
). Daskalakis et al (68
) used transcranial magnetic stimulation to the motor cortex in a cerebellar inhibition protocol and found that patients with schizophrenia had significant cerebellar inhibition in comparison with control subjects. In addition to these more targeted studies, abnormalities in the cerebellum have also been reported in many other functional imaging studies, but have not received any explicit attention or comment [e.g., (38
)]. Overall the functional literature provides relatively strong support for cerebellar abnormalities in schizophrenia, suggesting that this may be an important future direction for further work.
Other recent studies of cerebellar dysfunction have focused on the cellular and synaptic level, using the tools of in situ
hybridization and immunoautoradiography. These neocerebellar regions contain broadly distributed relays to the cerebral neocortex. Examination of the expression of three synaptic proteins in the cerebellum—synaptophysin, Complexin I, and Complexin II—has illuminated their regional distribution in Purkinje and granule cells in the normal brain and demonstrated that synaptic pathology is present in these regions in schizophrenia (70
). Specifically, synaptophysin is decreased by 31% in granule cells, and Complexin II is decreased by 36%, while Complexin I is normal. These results suggest that the excitatory input to the Purkinje cells is diminished in schizophrenia, creating an imbalance in the Purkinje cell inhibitory input to the deep nuclei. A change in Purkinje cell tone would lead in turn to an impaired ability of the cerebellum to integrate information and send appropriate “cognitive coordination” signals to the cerebral cortex. The decreased excitatory tone in the granule cells is also consistent with the reports of decreased Purkinje cell size, since decreased input is likely to lead to a decrease in activity and ultimately size of the dendritic tree over time. These results add further confirmation to the hypothesis that schizophrenia is a disease affecting distributed neural circuits, and that the cerebellum and the CCTCC are functionally and anatomically abnormal in schizophrenia.
Despite the growing evidence for cerebellar abnormalities in schizophrenia, it is much less extensive than that for other brain regions (e.g., frontal and temporal cortex). Until relatively recently few investigators have bothered to examine the “lowly” cerebellum. In fact, the potential role of the cerebellum was missed in many early imaging studies of either healthy normals or schizophrenic patients because it was “cut off” from the field of view, and because it is also excluded from the Talairach Atlas used to define activation coordinates in functional imaging studies. At present a role for the cerebellum in schizophrenia remains somewhat controversial, although the controversy arises in part from adherence to conservative models of cerebellar function (e.g., Model 1). However, it is also controversial because of a vast literature implicating other brain regions as well. For example, Shenton (71
) conducted an exhaustive review of 193 mMR studies and found relatively consistent findings in temporal and frontal regions and a variety of subcortical regions; she considered evidence for cerebellar abnormalities to be equivocal (found in 31% of studies reviewed).
Investigators have also been actively exploring the involvement of the cerebellum in other disorders. A growing literature suggests that cerebellar abnormalities may occur in autism, a disorder that has many features in common with schizophrenia, such as impairments in cognition and social awareness. MR studies have shown that children suffering from autism have unusual growth patterns in the cerebellum early in life (72
). Furthermore, functional imaging studies have indicated that autistic children have decreased cerebellar activations during a task that requires them to focus attention (73
). In addition, cerebellar abnormalities observed with structural MR imaging have also been observed in children suffering from attention deficit hyperactivity disorder (ADHD) (74
). Therefore, cerebellar abnormalities may not be specific to schizophrenia. The common thread among these observations is that schizophrenia, autism, and schizophrenia are usually considered to be neurodevelopmental brain disorders, and their symptoms share many common features, such as impairment in attention, social interactions, and emotional regulation.
Novel Directions for Schizophrenia Research
Studying the cerebellum and its possible modes of malfunction provides a heuristic and parsimonious approach that can be used to explore the mechanisms of schizophrenia in a variety of ways. Several novel directions are promising.
One future direction involves the use of in vivo
anatomical imaging of the cerebellum in an effort to pinpoint possible abnormalities in neurodevelopmental milestones in schizophrenia. Current working hypotheses suggest that schizophrenia may be both an early and an adolescent onset neurodevelopmental disease (75
). Recent work demonstrates the value of in vivo anatomical MR imaging to study both normal cerebral development and abnormalities in schizophrenia (77
). Our knowledge of neurodevelopment in the cerebellum is more limited, but the existing evidence suggests that it is both interesting and somewhat unique. Neurogenesis continues in the cerebellum after birth and during approximately the first two years of life. In addition, based on the relatively small number of human post mortem anatomic studies of the cerebellum that are available, it appears that other neurodevelopmental processes such as myelination, dendritic proliferation, and synaptogenesis also may occur through late childhood, adolescence, and early adulthood (79
). Overall, the final phases of neurodevelopment in the cerebellum are heterochronous with much of the rest of the brain—occurring relatively later. These later phases may coincide with the time of onset of schizophrenia. The relatively fine-grained gross anatomy of the cerebellum—with its small folia and even smaller deep nuclei—are likely to demand the use of higher resolution and higher field MR approaches if this strategy is pursued.
A second approach is to design functional imaging studies in a manner that explicitly targets examination of cerebellar function in the context of the three competing models. For example, a comprehensive series of experiments could be created that move through the three models using well-established protocols. For model 1, associative learning might be studied using an eyeblink conditioning protocol. For model 2 a variety of protocols are available, such as estimating the duration of time intervals, maintaining a correct rate of finger tapping that is externally paced, continuing the rate when the external stimulus is removed and the tapping must be internally paced, or judging the length of time intervals. For model 3 a variety of well-accepted protocols are available, such as the oddball paradigm or the Sternberg working memory task. If abnormalities are found using all three models, then cerebellar dysfunction in schizophrenia is supported.
A third promising approach, exemplified by the work of Eastwood (70
), is to focus post mortem genomic and neurotransmitter studies on the cerebellum—a relatively uncharted territory. In addition to genes for synaptophysin and complexin, a variety of other candidate genes are obvious options for study. Some are logical choices because of their known role in modulating neural development and function, such as BDNF (brain derived neurotrophic factor), neuregulin, or dysbindin. Some are logical choices because of their role in neurotransmission, such as the gene for catechol-o-methyl-transferase (COMT). Such molecular work can be complemented by the use of in vivo spectroscopy methods to measure metabolic markers (e.g., n-acetyl aspartate) or neurotransmitters (i.e., GABA, glutamate) in the cerebellum. There is already some evidence for abnormalities in BDNF and GABA gene expression, as well as for developmental abnormalities in serotonin receptors (80
A fourth approach is to continue the dissection of the cognitive and symptomatic abnormalities of schizophrenia at the systems level. One goal is to improve the spatial and temporal resolution of functional imaging studies through high field MR instrumentation, event-related designs, and MEG and MRS studies. (82
). Such approaches may help identify more specific loci of cerebellar abnormality, which may guide the choice of regions of interest in molecular or metabolic studies. A second goal—perhaps more distant—is to exploit the cross-species homology of the cerebellum and to identify simple cognitive tasks (e.g., associative learning, time perception) that may model the schizophrenia endophenotype and that can be used in animal studies that will facilitate the development of animal models of schizophrenia.