Role of hyperactive cerebellum and motor cortex in Parkinson's disease

Abstract

Previous neuroimaging studies have found hyperactivation in the cerebellum and motor cortex and hypoactivation in the basal ganglia in patients with Parkinson's disease (PD) but the relationship between the two has not been established. This study examined whether cerebellar and motor cortex hyperactivation is a compensatory mechanism for hypoactivation in the basal ganglia or is a pathophysiological response that is related to the signs of the disease. Using a BOLD contrast fMRI paradigm PD patients and healthy controls performed automatic and cognitively controlled thumb pressing movements. Regions of interest analysis quantified the BOLD activation in motor areas, and correlations between the hyperactive and hypoactive regions were performed, along with correlations between the severity of upper limb rigidity and BOLD activation. There were three main findings. First, the putamen, supplementary motor area (SMA) and pre-SMA were hypoactive in PD patients. The left and right cerebellum and the contralateral motor cortex were hyperactive in PD patients. Second, PD patients had a significant negative correlation between the BOLD activation in the ipsilateral cerebellum and the contralateral putamen. The correlation between the putamen and motor cortex was not significant. Third, the BOLD activation in the motor cortex was positively correlated with the severity of upper limb rigidity, but the BOLD activation in the cerebellum was not correlated with rigidity. Further, the activation in the motor cortex was not correlated with upper extremity bradykinesia. These findings provide new evidence supporting the hypothesis that hyperactivation in the ipsilateral cerebellum is a compensatory mechanism for the defective basal ganglia. Our findings also provide the first evidence from neuroimaging that hyperactivation in the contralateral primary motor cortex is not a compensatory response but is directly related to upper limb rigidity.

Figure 1

Behavioral performance for PD patients and healthy individuals. A) Mean IRIs for the 900 ms and 2400 ms conditions. The mean IRIs did not significantly differ between patients and controls in either 900 ms or 2400 ms conditions. B) The standard deviations of IRI for the 900 ms and 2400 ms conditions. C) The mean time period that subjects pressed the button with their thumb during 900 ms and 2400 ms conditions. The error bars represent the standard error between subjects. Similarly, there was no significant between-group difference in either condition. The standard deviation increased from 900 ms to 2400 ms condition in both patient and healthy group (p < 0.0001).

Figure 2

Within-group functional maps for healthy individuals and PD patients in 900 ms and 2400 ms conditions (p < 0.05, corrected). Images are in neurological orientation (left is left). L = left; DLPFC = dorsolateral prefrontal cortex; GPe = globus pallidus external segment; IPL = inferior parietal lobule; M1 = primary motor cortex; PMd = dorsal premotor cortex; PMv = ventral preomtor cortex; SMA = supplementary motor area; STG = superior temporal gyrus.

Figure 3

Hypoactivation in PD patients compared to healthy individuals in the left putamen, left SMA, left and right pre-SMA, right caudate, and the right DLPFC (p’s < 0.05). For each region of interest, the percent signal change in PD patients was lower than healthy individuals in both 900 and 2400 ms conditions. No group by period interaction was found.

Figure 4

Hyperactivation in PD patients compared to healthy individuals in the left and right cerebellum and the left primary motor cortex (p’s < 0.05). The image indicates that the cerebellar regions with hyperactivation in PD patients are located in the superior semi-lunar lobule and the inferior semi-lunar lobule for the right and left cerebellum respectively. There was no group by period interaction found in the left and right cerebellum and the left primary motor cortex.

Figure 5

The correlation between hyperactivation in the left primary motor cortex with rigidity and bradykinesia in PD patients. A) Regions in the left M1 where PD patients had hyperactivation. B) The percent signal change in the left M1 against the rigidity score of the right upper limb in PD patients. Each percent signal change value is the average across the 900 ms and 2400 ms conditions. The horizontal solid line represents the average percent signal change of the left M1 in healthy individuals, and the dotted lines represent the standard error. A significant linear relation was found between the percent signal change in the left M1 and the rigidity score in patients (r = 0.85, p < 0.05). The number by each symbol corresponds to the patient number in Table 1. C) The percent signal change in the left M1 against the bradykinesia score from the right upper limb in PD patients. The bradykinesia score included ratings from the finger taps, hand movements, and rapid alternating movements. The linear relation was not significant (r = 0.48, p = 0.23). The number by each symbol corresponds to the patient number in Table 1.