Cerebellar Activation Deficits in Schizophrenia During an Eyeblink Conditioning Task

Abstract

The cognitive dysmetria theory of psychotic disorders posits that cerebellar circuit abnormalities give rise to difficulties coordinating motor and cognitive functions. However, brain activation during cerebellar-mediated tasks is understudied in schizophrenia. Accordingly, this study examined whether individuals with schizophrenia have diminished neural activation compared to controls in key regions of the delay eyeblink conditioning (dEBC) cerebellar circuit (eg, lobule VI) and cerebellar regions associated with cognition (eg, Crus I). Participants with schizophrenia-spectrum disorders (n = 31) and healthy controls (n = 43) underwent dEBC during functional magnetic resonance imaging (fMRI). Images were normalized using the Spatially Unbiased Infratentorial Template (SUIT) of the cerebellum and brainstem. Activation contrasts of interest were "early" and "late" stages of paired tone and air puff trials minus unpaired trials. Preliminary whole brain analyses were conducted, followed by cerebellar-specific SUIT and region of interest (ROI) analyses of lobule VI and Crus I. Correlation analyses were conducted between cerebellar activation, neuropsychological test scores, and psychotic symptom scores. In controls, the largest clusters of cerebellar activation peaked in lobule VI during early dEBC and Crus I during late dEBC. The schizophrenia group showed robust cortical activation to unpaired trials but no significant conditioning-related cerebellar activation. Crus I ROI activation during late dEBC was greater in the control than schizophrenia group. Greater Crus I activation correlated with higher working memory scores in the full sample and lower positive psychotic symptom severity in schizophrenia. Findings indicate functional cerebellar abnormalities in schizophrenia which relate to psychotic symptoms, lending direct support to the cognitive dysmetria framework.

Keywords: associative learning; cerebellum; functional magnetic resonance imaging; psychosis.

Fig. 1.

Schematic of the delay eyeblink conditioning (dEBC) paradigm. Runs had 52 trials each. Each trial in run 1 contained either a tone or an air puff. Each trial in runs 2 and 3 contained a tone, which coterminated with an air puff. T, trial; ITI, intertrial interval.

Fig. 2.

Whole brain activation in the healthy control (HC) and schizophrenia (SZ) groups during unpaired air puff and tone trials compared to fixation periods, significant at a threshold of voxel-wise P < .001 and k_E = 60 for a corrected P < .05.

Fig. 3.

Cerebellar activation in healthy controls overlaid on the SUIT flat surface map, significant at a threshold of voxel-wise P < .001 and k_E = 29 voxels for a corrected P < .05. No cerebellar activation reached significance in the schizophrenia group.

Fig. 4.

Cerebellar region of interest (ROI) analysis. Left: Images of left and right hemisphere lobule VI and Crus I ROI masks overlaid on the SUIT flat surface map. Right: Mean beta values from healthy control (HC) and schizophrenia (SZ) groups from each averaged bilateral ROI for Early Paired Trials – Unpaired Trials (Early EBC) and Late Paired Trials – Unpaired Trials (Late EBC) contrasts. Error bars represent ±1 standard error of the mean. *P < .05.

Fig. 5.

Scatter plots of bilateral lobule VI and Crus I activation in the Late Paired Trials – Unpaired Trials contrast in the healthy control (HC) and schizophrenia (SZ) groups. Top: Activation related to letter number (LN) sequencing scaled scores in the full participant sample. Bottom: Activation related to log-transformed Positive and Negative Syndrome Scale (PANSS) positive subscale scores in the schizophrenia group.