Cerebellar Contribution to Motor and Non-motor Functions in Parkinson's Disease: A Meta-Analysis of fMRI Findings

Abstract

Background: Parkinson's disease (PD) results in both motor and non-motor symptoms. Traditionally, the underlying mechanism of PD has been linked to neurodegeneration of the basal ganglia. Yet it does not adequately account for the non-motor symptoms of the disease, suggesting that other brain regions may be involved. One such region is the cerebellum, which is known to be involved, together with the basal ganglia, in both motor and non-motor functions. Many studies have found the cerebellum to be hyperactive in PD patients, a finding that is seldom discussed in detail, and warrants further examination. The current study thus aims to examine quantitively the current literature on the cerebellar involvement in both motor and non-motor functioning in PD. Methods: A meta-analysis of functional neuroimaging literature was conducted with Seed-based D mapping. Only the studies testing functional activation in response to motor and non-motor paradigms in PD and healthy controls (HC) were included in the meta-analysis. Separate analyses were conducted by including only studies with non-motor paradigms, as well as meta-regressions with UPDRS III scores and disease duration. Results: A total of 57 studies with both motor and non-motor paradigms fulfilled our inclusion criteria and were included in the meta-analysis, which revealed hyperactivity in Crus I-II and vermal III in PD patients compared to HC. An analysis including only studies with cognitive paradigms revealed a cluster of increased activity in PD patients encompassing lobule VIIB and VIII. Another meta-analysis including the only 20 studies that employed motor paradigms did not reveal any significant group differences. However, a descriptive analysis of these studies revealed that 60% of them reported cerebellar hyperactivations in PD and included motor paradigm with significant cognitive task demands, as opposed to 40% presenting the opposite pattern and using mainly force grip tasks. The meta-regression with UPDRS III scores found a negative association between motor scores and activation in lobule VI and vermal VII-VIII. No correlation was found with disease duration. Solstrand Dahlberg et al. Cerebellar Activity in PD Discussion: The present findings suggest that one of the main cerebellar implications in PD is linked to cognitive functioning. The negative association between UPDRS scores and activation in regions implicated in motor functioning indicate that there is less involvement of these areas as the disease severity increases. In contrast, the lack of correlation with disease duration seems to indicate that the cerebellar activity may be a compensatory mechanism to the dysfunctional basal ganglia, where certain sub-regions of the cerebellum are employed to cope with motor demands. Yet future longitudinal studies are needed to fully address this possibility.

Distinct large-scale networks are associated with motor and nonmotor symptoms in Parkinson’s disease

“…Cerebellar hyperactivity and hyperconnectivity have been reported in task-based and resting-state fMRI studies of PD (Helmich et al, 2011, Wu and Hallett, 2013, Festini et al, 2015 and generally attributed to compensatory mechanisms. This functional pattern was most consistently exhibited in PD subjects scanned off dopaminergic medication and was either normalized or even reduced by medication (Festini et al, 2015;Solstrand Dahlberg et al, 2020). Moreover, different cerebellar lobules have been found to display diverse activation and connectivity characteristics in PD depending on the motor, emotional, and cognitive context (Solstrand Dahlberg et al, 2020) as we have also observed in our motor and nonmotor network data.…”

Altered Cerebellar Resting-State Functional Connectivity in Early-Stage Parkinson's Disease Patients With Cognitive Impairment

“…Additionally, a meta-analysis of task-related fMRI studies has emphasized that the cerebellum plays a significant role in the level of cognitive functioning in PD ( 16 ). Moreover, Gao et al ( 44 ) has shown that the performance of PD patients and healthy control subjects do not differ significantly when required to execute motor and cognitive dual-task paradigms.…”

“…The existence of a “motor” cerebellum including lobules V, VI, VIIb, and VIII as well as of a “cognitive” cerebellum including crus I and II supports this functional cerebellar dissociation ( 9 , 12 , 15 , 18 , 19 ). A recent meta-analysis has also reported cerebellar hyperactivations in PD patients who were administered cognitive or motor paradigms with significant cognitive task demands, hence suggesting that one of the main cerebellar implications in PD is linked to cognitive functioning ( 16 ). Finally, using structural and resting-state functional magnetic resonance imaging (rs-fMRI), O'Callaghan et al ( 20 ) revealed gray matter loss across the “motor” and “cognitive” cerebellar territories and altered cerebellar functional connectivity (FC) with the cortex in patients with PD compared to normal controls.…”

“…Traditionally, the pathophysiological mechanism underlying PD has been linked to the dysfunction of the striato-thalamo-cortical circuitry arising from the degeneration of basal ganglia (BG), the latter accounting partly for the cardinal motor symptoms of PD (7,8). Driven by the advances of anatomical and human neuroimaging studies in the past 2 decades, however, reciprocal basal ganglia-cerebellar and cerebellar-cortical parcellated networks have been identified, and the role of the cerebellum in PD has received increasing interest (9)(10)(11)(12)(13)(14)(15)(16).…”

Action and emotion perception in Parkinson’s disease: A neuroimaging meta-analysis

“…Although social deficits in PD have been related to dopamine depletion in these nuclei ( Coundouris et al, 2019 ), particularly in the putamen ( Palmeri et al, 2017 ), alterations in the functioning of other brain regions may contribute to the impairment. Among these, the cerebellum – which is known to be involved in cognitive processing beyond motor control ( Hull, 2020 , Schmahmann et al, 2019 ) - may play a critical role ( Solstrand Dahlberg et al, 2020 ). Indeed, abnormal cerebellum activity has been observed in PD patients during both cognitive (e.g., Cao et al, 2011 , Huang et al, 2007a , Huang et al, 2007b ) and social perception (e.g., Poisson et al, 2013 ) tasks, as well as during rest conditions (e.g., Zhan et al, 2018 ).…”