We found a significant effect of movement sequencing abnormalities on the functional connectivity between the motor cortex and cerebellum during the execution of sequential motor tasks in schizophrenia. We found a significant negative correlation between the magnitudes of movement sequencing abnormalities measured using the NES scale and the level of cortico-cerebellar connectivity: the more pronounced the motor abnormality, the less similar the BOLD signal between cortical and cerebellar regions. Only patients with impaired movement sequencing abilities had lower functional connectivity than healthy controls (in contrast to patients with unimpaired movement sequencing). This means that abnormal cooperation between the cerebellum and motor cortex during a motor task manifests as an impaired ability to sequence movements in time.
Several findings support the significance of cortico-eeelrfntoa dsoncin'fr various signs and symptoms of schizophrenia. Wilson et al. found right cerebellar dysfunction in a MEG study that analyzed cortico-cerebellar functional connectivity during tactile stimulation of the fingers that resulted in synchronous activation of the postcentral cortex and cerebellum in early onset psychosis [15
]. Impaired functional connectivity between the cerebellum and the medial part of the superior frontal gyrus was observed during attentional tasks in schizophrenia [16
]. Abnormal functional connectivity between the medial prefrontal cortex and the contralateral cerebellum was also found during the Hayling Sentence Completion Test in a high-risk sample [17
], and in children and adolescents with schizophrenia during verbal working-memory tasks [18
]. There are reports of abnormal functional connectivity between the cerebellum and cortex even at rest: parameters of resting state functional connectivity between the frontal cortex and cerebellum had the biggest discriminative value from a set of several regions for classification of schizophrenia patients and healthy controls [19
]. Structural equation modeling allowed the analysis of the connectivity parameters between individual nodes of a network formed by the prefrontal cortex, thalamus, and cerebellum during an n-back working-memory task in schizophrenia: patients showed decreased cortico-cerebellar and thalamo-cerebellar functional connectivity, but increased thalamo-cortical functional connectivity [20
Impaired functional cortico-cerebellar connectivity might result from abnormalities of some node of the cortico-subcortico-cerebellar circuits. However, several lines of evidence indicate that cerebellar dysfunction might have a key role in cortico-cerebellar dysconnection' and corresponding signs and symptoms, including movement sequencing abnormalities. Transcranial magnetic stimulation (TMS) data show that cerebellar activation or inhibition has a direct impact on the functioning of the motor cortex [21
]. This finding, with the theoretical implications of the involvement of cerebellum in the pathogenesis of schizophrenia, provides further support for the validity of the regions we selected for functional connectivity analysis. Furthermore, there is evidence that sequence processing is one of the key functions of the cerebellum [12
]. There are many findings that show cerebellar abnormalities in schizophrenia. Cerebellar inhibition of the motor cortex assessed by TMS is decreased in schizophrenia [22
]. Reduction of cerebellar-dependent delay eyeblink conditioning [23
] reflects impaired cerebellar time processing in schizophrenia. Cerebellar morphological changes are present in schizophrenia [24
]; they are linked with NSS [25
], including repetitive motor acts, i.e., sequences of movements [25
]. Cerebellar abnormalities are linked to non-motor symptoms of schizophrenia, such as cognitive dysfunction [16
]. Changes in cerebellar tract integrity that correlate with cognitive dysfunction [32
] have been described in schizophrenia [33
We were not able to find any effect of movement sequencing abnormalities on the pattern or magnitude of brain activation during the modified finger-tapping task. A previous fMRI study, using a similar behavioral paradigm, found reduced activation of the pallidum and putamen [36
]. Our data show that impaired movement sequencing abilities are linked with brain connectivity, rather than with the magnitude of regional activation, which points to the original concept of NSS as a consequence of impaired cooperation between system subcomponents, and not a single localized pathology [11
]. On the other hand, the lack of group differences in brain activation patterns may also reflect an inadequate behavioral paradigm for movement sequencing examination. Although the principle behind the modified sequential finger-tapping task is similar to the NES scale sequencing tasks, the tasks are not identical and may require different effort for their execution and reflect different brain loads. Our paradigm was, however, adequate for the analysis of brain connectivity in the context of movement sequences, which was the primary focus of our study.
The impaired ability to sequence movements was the most frequent movement abnormality in schizophrenia patients: 67% of the patients had at least one mild impairment of movement sequencing as compared to a 33% incidence of sensory integration problems, and 13% of motor coordination abnormalities. The pattern and incidence of individual NSS categories are in accordance with previous findings [1
]. The relative predominance of movement sequencing abnormalities in schizophrenia might reflect its link to a proposed neurobiological substrate of the illness-brain 'dysconnection'.
Patients with marked movement sequencing impairment had more psychotic episodes than those without movement sequencing disturbances. Moreover, cortico-cerebellar functional connectivity correlated negatively with the duration of treatment. These findings may mean that there is a progressive worsening of cortico-cerebellar connectivity with a corresponding impairment of movement sequencing as a result of consecutive psychotic outbreaks. Our study was, however, a cross-sectional comparison. Therefore, we cannot exclude the possibility that patients with marked impairments of movement sequencing abnormalities had such marked impairment present from the beginning of the illness. Previous studies show that the expression of NSS at the time of the first episode of schizophrenia predicts a worse response to treatment and worse outcomes [37
]. Abnormalities of cerebellar morphology are also linked with poor outcomes [40
]. The fact that there was a still a significant effect of movement sequencing abnormalities present in the post-hoc analysis of covariance suggests that movement sequencing abnormalities and their link to cortico-cerebellar connectivity are not only the result of illness progression.
Several factors might limit our results. The most important are the effects of antipsychotics, extrapyramidal symptoms, and abuse of psychoactive substances. The severity of movement sequencing abnormalities does not correlate with antipsychotic treatment parameters, nor with the severity of extrapyramidal symptoms. Similarly, the differences in cortico-cerebellar connectivity between the two patient groups are not a result of antipsychotic treatment or extrapyramidal symptoms. This is supported by previous findings [2
]. These factors are, however, linked significantly with the other NSS cluster-movement coordination abnormalities-which may reflect different neurobiology and etiology of individual movement abnormalities in schizophrenia. Findings have shown a relationship between the severity of cerebellar impairment and co-morbid alcohol abuse in schizophrenia [41
]. In our study, however, there were no differences in co-morbid psychoactive substance abuse between the two patient groups. Finally, we assessed only the functional connectivity related to movement sequencing. But the cerebellum is involved in several other functions, including cognitive and affective ones [42
]. Based on our study, we cannot exclude the possibility that there is a functional dysconnection of different parts of the cortex and cerebellum during the cerebellar functions other than movement sequencing in SQ- patients.