Cerebellar connectivity in Parkinson's disease with levodopa‐induced dyskinesia

Abstract

ObjectiveThe precise pathogenesis or neural correlates underlying levodopa‐induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID.MethodsWe enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score‐matched PD patients who had not developed LID, and 24 age‐ and sex‐matched healthy controls. We performed a comparative analysis of resting‐state functional connectivity (FC) between the motor cerebellum and whole brain between the groups.ResultsThe patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID.InterpretationIncreased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.

Cerebellar functional connectivity change is associated with motor and neuropsychological function in early stage drug-naïve patients with Parkinson’s disease

“…Previous studies showed that the M1 had FC with both the first representation and second representation although they are anatomically distant ( Bernard et al, 2012 ; Guell et al, 2018b ). In this study, we found increased intra-cerebellar FC consistent with previous studies ( Cerasa et al, 2016 ; Tuovinen et al, 2018 ; Gratton et al, 2019 ; Yoo et al, 2019 ; Kaut et al, 2020 ). Specifically, we found out that enhanced FC between all the subdivisions of the first somatomotor representation (left and right lobule III, left and right lobule IV/V) and the second somatomotor representation on the left side (left lobule VIIb/VIII) in PD patients when compared with HCs.…”

Cerebellar functional connectivity change is associated with motor and neuropsychological function in early stage drug-naïve patients with Parkinson’s disease

“…Previous studies showed that the M1 had FC with both the first representation and second representation although they are anatomically distant ( Bernard et al, 2012 ; Guell et al, 2018b ). In this study, we found increased intra-cerebellar FC consistent with previous studies ( Cerasa et al, 2016 ; Tuovinen et al, 2018 ; Gratton et al, 2019 ; Yoo et al, 2019 ; Kaut et al, 2020 ). Specifically, we found out that enhanced FC between all the subdivisions of the first somatomotor representation (left and right lobule III, left and right lobule IV/V) and the second somatomotor representation on the left side (left lobule VIIb/VIII) in PD patients when compared with HCs.…”

Multimodal Neuroimaging Reveals Distinct Characteristics of Levodopa-Induced Dyskinesias in de novo Parkinson’s Disease Patients

“…Specifically, we found stronger connectivity of the left IFG with left putamen and bilateral somatosensory cortices in dyskinetic PD patients. Consistent with our findings, a more recent study showed an increased FC of the left IFG with the motor cerebellum (lobule VIIIb) in PD patients who developed LID within 5 years compared to those who did not (Yoo HS et al, 2019). Desynchronized FC of the IFG and pre-supplementary motor area during medication “on” state in dyskinetic compared to non-dyskinetic PD patients has also been shown suggesting uncoordinated inhibitory control over motor circuits as a mechanism underlying LID (Gan et al, 2020).…”

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease

“…It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors. [44][45][46][47] This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine-related motor symptoms. 12 Rather, it is speculated that DHPs may have a beneficial effect on the extranigral system.…”

“…Contrary to expectations, we found that DHPs did not have beneficial effects on the nigrostriatal dopaminergic density at diagnosis and longitudinal motor prognosis. It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors 44‐47 . This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine‐related motor symptoms 12 .…”

Cerebellar functional connectivity change is associated with motor and neuropsychological function in early stage drug-naïve patients with Parkinson’s disease

“…Previous studies showed that the M1 had FC with both the first representation and second representation although they are anatomically distant ( Bernard et al, 2012 ; Guell et al, 2018b ). In this study, we found increased intra-cerebellar FC consistent with previous studies ( Cerasa et al, 2016 ; Tuovinen et al, 2018 ; Gratton et al, 2019 ; Yoo et al, 2019 ; Kaut et al, 2020 ). Specifically, we found out that enhanced FC between all the subdivisions of the first somatomotor representation (left and right lobule III, left and right lobule IV/V) and the second somatomotor representation on the left side (left lobule VIIb/VIII) in PD patients when compared with HCs.…”

Multimodal Neuroimaging Reveals Distinct Characteristics of Levodopa-Induced Dyskinesias in de novo Parkinson’s Disease Patients

“…Specifically, we found stronger connectivity of the left IFG with left putamen and bilateral somatosensory cortices in dyskinetic PD patients. Consistent with our findings, a more recent study showed an increased FC of the left IFG with the motor cerebellum (lobule VIIIb) in PD patients who developed LID within 5 years compared to those who did not (Yoo HS et al, 2019). Desynchronized FC of the IFG and pre-supplementary motor area during medication “on” state in dyskinetic compared to non-dyskinetic PD patients has also been shown suggesting uncoordinated inhibitory control over motor circuits as a mechanism underlying LID (Gan et al, 2020).…”

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease

“…It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors. [44][45][46][47] This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine-related motor symptoms. 12 Rather, it is speculated that DHPs may have a beneficial effect on the extranigral system.…”

“…Contrary to expectations, we found that DHPs did not have beneficial effects on the nigrostriatal dopaminergic density at diagnosis and longitudinal motor prognosis. It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors 44‐47 . This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine‐related motor symptoms 12 .…”

Cerebellar functional connectivity change is associated with motor and neuropsychological function in early stage drug-naïve patients with Parkinson’s disease

“…Previous studies showed that the M1 had FC with both the first representation and second representation although they are anatomically distant ( Bernard et al, 2012 ; Guell et al, 2018b ). In this study, we found increased intra-cerebellar FC consistent with previous studies ( Cerasa et al, 2016 ; Tuovinen et al, 2018 ; Gratton et al, 2019 ; Yoo et al, 2019 ; Kaut et al, 2020 ). Specifically, we found out that enhanced FC between all the subdivisions of the first somatomotor representation (left and right lobule III, left and right lobule IV/V) and the second somatomotor representation on the left side (left lobule VIIb/VIII) in PD patients when compared with HCs.…”

Multimodal Neuroimaging Reveals Distinct Characteristics of Levodopa-Induced Dyskinesias in de novo Parkinson’s Disease Patients

“…Specifically, we found stronger connectivity of the left IFG with left putamen and bilateral somatosensory cortices in dyskinetic PD patients. Consistent with our findings, a more recent study showed an increased FC of the left IFG with the motor cerebellum (lobule VIIIb) in PD patients who developed LID within 5 years compared to those who did not (Yoo HS et al, 2019). Desynchronized FC of the IFG and pre-supplementary motor area during medication “on” state in dyskinetic compared to non-dyskinetic PD patients has also been shown suggesting uncoordinated inhibitory control over motor circuits as a mechanism underlying LID (Gan et al, 2020).…”

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease

“…It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors. [44][45][46][47] This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine-related motor symptoms. 12 Rather, it is speculated that DHPs may have a beneficial effect on the extranigral system.…”

“…Contrary to expectations, we found that DHPs did not have beneficial effects on the nigrostriatal dopaminergic density at diagnosis and longitudinal motor prognosis. It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors 44‐47 . This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine‐related motor symptoms 12 .…”