Clinical, cognitive, and psychophysical correlates of structural alterations of the cerebellum in schizophrenia: a pilot-study

Background: The cerebellum is involved in motor, affective and cognitive functions. Moreover, the cerebellum is a pivotal structure that sustains the time perception of millisecond intervals as part of the cerebello-thalamo-cortical circuit (CTCC), which includes a vast part of the brain's “timing network”. In schizophrenia (SZ), significant cerebellar structural and functional alterations were consistently reported, as well as impaired perception of millisecond intervals. The Cognitive Dysmetria model of SZ posited that thought/language disorganization: i) is a core dysfunction linked to positive symptoms of SZ and depends on ii) the alteration of CTCC activity and iii) impairment in the millisecond timing function. Aims of the study: This pilot-study aim to a) replicate literature evidence of i) structural alteration of the posterior (cognitive) cerebellum in schizophrenia, with the reduced cortical thickness (CT) and gray matter volume (GMV), ii) impaired millisecond temporal perception accuracy in SZ subjects, b) test the following hypothesis: i) timing performances correlate with the structural alterations of the cognitive cerebellar lobules (e.g. Crus I/II), ii) thought/language alterations have a strong association with the millisecond timing performances and positive symptoms (hallucinations, delusions, behavioral symptoms) in accordance with the Andreasen’s Cognitive Dysmetria model. Material and methods: Subject affected by SZ and age- and sex- matched healthy controls (HC) were included. The cerebellar CT and GMV were evaluated using the CERES (CEREbellum Segmentation) image processing protocol on 3-T Magnetic Resonance Imaging (MRI) T1-weighted anatomical images. Each patient was recruited using: i) Scale for the Assessment of Negative Symptoms (SANS), ii) Scale for the Assessment of Positive Symptoms (SAPS), iii) Scale for the Assessment of Thought, Language and Communication (TLC), iv) Positive and Negative Syndrome Scale (PANSS). A complete neurocognitive assessment was performed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). The psychophysical assessment of the temporal perception was performed using a temporal bisection task. The statistical analyses were performed using: i) Spearman nonparametric correlations, ii) FDR-corrected ordinal logistic regressions, and iii) Bayesian Network analysis (R, BGGM package). Results: We recruited 56 subjects: 28 SZ (11F; mean age ± SD: 44,5 ± 17,1) and 28 HC (13F; mean age ± SD: 43,7 ± 13,2). The SZ subjects showed: i) a significant reduction of the posterior cerebellum GMV [Crus I (p=0.017) and Crus II (p=0.01)] and CT [Crus II (p=0.017) and Lobule VI (p=0.01)], ii) impairment in the millisecond temporal accuracy (higher SD in SZ; p=0.0002), iii) a significant negative correlation between Crus II CT and SD (r= -0.53; p=0.035), high strength of association (sa) between thought/language disorganization and temporal accuracy (sa=0.66), behavioral alterations (sa=0.50), and hallucinatory symptoms (sa=0.44). Strengths and limitations: The study's main limitation is the relatively small sample size. However, the study is strengthened by the presence of a complex set of evaluations, difficult to perform in schizophrenic subjects, and using a Bayesian approach to the psychophysical task and network analysis. Conclusion: Part of the cognitive cerebellum (e.g., Crus II), despite the structural abnormalities, might compensate for the disorganization of thought, language, and communication through a vicariant activity that contribute to maintaining the CTCC/timing network function. This compensatory activity might be linked to temporal accuracy. A reduced compensatory activity of the cerebellum, linked to worsening temporal accuracy, might be linked to disorganized or hebephrenic-like forms of schizophrenia, with higher thought/language disturbances, behavioral alterations, cognitive impairments, and reduced hallucinations.