Re: 소뇌 문제관련 파킨슨 tremer, 심부자극기 이해를 위해..2022 nature

[문형철]

1. nature  
2. npj parkinson's disease  
3. review articles  
4. article

• Review Article
• Open access
• Published: 24 June 2022

A review on pathology, mechanism, and therapy for cerebellum and tremor in Parkinson’s disease

• Yuke Zhong, 

Abstract

Tremor is one of the core symptoms of Parkinson’s disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

떨림은 파킨슨병(PD)의 핵심 증상 중 하나이지만 그 메커니즘은 잘 알려져 있지 않습니다. 

소뇌는 

파킨슨병 관련 연구에서 점점 더 많은 관심을 받고 있으며 

파킨슨병의 떨림에 중요한 역할을 하는 것으로 보고되고 있습니다. 

소뇌는 

소뇌-시상-피질 회로를 통해 

진전 진폭의 조절에 관여할 수 있습니다. 

cerebello-thalamo-cortical circuits.

시상 복측 중간핵으로의 소뇌 흥분성 돌기는 

도파민/비도파민계 이상, 백질 손상, 심부핵 손상 등 

PD 관련 변화로 인해 강화될 수 있으며, 

이는 tremer의 조절 장애 및 저항에 기여할 수 있습니다. 

The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. 

Ventral intermediate thalamic stimulation is effective in treating essential tremor and tremor-dominant Parkinson’s disease, but its precise mechanism of action is unclear. Milosevic  et al.  show that thalamic inhibition of neuronal firing is necessary for tremor reduction, suggesting that the thalamus acts as a filter for uncoupling central and peripheral tremor networks.

이 리뷰에서는 

본태성 진전증에서 

소뇌의 병리적, 구조적, 기능적 변화를 요약하고 

본태성 진전증에서 소뇌의 역할을 논의하여 

본태성 진전증의 소뇌 관련 메커니즘에 대한 개요를 제공하는 것을 목표로 했습니다.

Similar content being viewed by others

Linking the cerebellum to Parkinson disease: an update

Article 26 September 2023

Cerebro-cerebellar motor networks in clinical subtypes of Parkinson’s disease

Article Open access06 September 2022

Essential tremor pathology: neurodegeneration and reorganization of neuronal connections

Article 20 January 2020

Introduction

Tremor, defined as an involuntary, rhythmic, and oscillatory movement of a body part, is one of the cardinal symptoms of Parkinson’s disease (PD)1,2. Traditional taxonomy of PD introduced several subtypes, including tremor-dominant PD and non-tremor-dominant PD (including postural instability and gait disability-dominant PD, akinesia/rigidity-dominant PD)3. Recent studies demonstrated there might be different biological bases for different subtypes of PD4. Tremor-dominant PD patients tend to have lower proportion of death and disability, slower progression of the disease, better cognitive function, lower burden of nonmotor symptoms, and longer survival time3,4. Thus, tremor-dominant PD is considered a benign subtype of PD5. However, among all the motor symptoms of PD, the mechanism of tremor is still poorly understood6, and its responsiveness to levodopa varies5,7.

The role of the cerebellum in the mechanism of tremor in PD has been increasingly focused8. The cerebellar output has been verified to modulate tremor-related activity, which arises from globus pallidum and propagates to cerebello-thalamo-cortical (CTC) circuits9. Moreover, tremor-related cerebellar activity differs between PD patients with dopamine-responsive tremor and dopamine-resistant tremor5, indicating a role of the cerebellum in the responsiveness of tremor to dopamine in PD.

We reviewed the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

소개

떨림은

신체 부위의

불수의적이고 리드미컬한 진동 운동으로 정의되며,

파킨슨병(PD)의 주요 증상 중하나입니다1,2.

involuntary, rhythmic, and oscillatory movement 

기존의 PD 분류법에서는

떨림 우세형 PD와

비떨림 우세형 PD(자세 불안정 및 보행 장애 우세형 PD,

운동 이상증/경직 우세형 PD 포함)3을 포함한

여러 가지 하위 유형을 도입했습니다.

특발성 파킨슨병 환자 334명에서 정신 상태의 악화는 서동증, 자세 불안정성, 보행 장애의 중증도와 유사하게 나타났습니다. 떨림은 다른 주요 징후와는 상대적으로 독립적이었으며 정신 상태의 상대적 보존, 발병 연령의 조기, 파킨슨병의 가족력, 더 유리한 예후와 관련이 있었습니다. 파킨슨병의 하위 그룹은 자세 불안정성과 보행 장애가 있는 그룹과 떨림이 주된 특징인 그룹으로 나뉘는 것으로 보입니다.

최근 연구에 따르면

파킨슨병의 아형에 따라

생물학적 기반이 다를 수 있다는 사실이 밝혀졌습니다4.

진전 우세형 파킨슨병 환자는

사망 및 장애 비율이 낮고,

질병의 진행이 느리며,

인지 기능이 개선되고,

비운동 증상 부담이 적으며,

생존 기간이 길어지는 경향이 있습니다3,4.

따라서

진전 우세형 PD는 PD5의 양성 아형으로 간주됩니다.

그러나

PD의 모든 운동 증상 중에서 떨림의 메커니즘은

아직 잘 알려져 있지 않으며6,

레보도파에 대한 반응도 다양합니다5,7.

본태성 떨림의 메커니즘에서

소뇌의 역할에 대한 관심이 점점 더 집중되고 있습니다8.

소뇌 출력은

떨림 관련 활동을 조절하는 것으로 확인되었으며,

이는 구상체 globus pallidum 에서 발생하여

소뇌-탈라모-피질(CTC) 회로로 전파되는 것으로 확인되었습니다9.

또한,

떨림 관련 소뇌 활동은

도파민 반응성 떨림과

도파민 저항성 떨림을 가진 PD 환자 간에 차이가 있으며5,

이는 PD에서 떨림이 도파민에 반응하는 데

소뇌의 역할이 있음을 나타냅니다.

우리는 PD에서 소뇌의 병리학적, 구조적, 기능적 변화를 검토하고 PD 관련 떨림에서 소뇌의 역할에 대해 논의하여 PD에서 떨림의 소뇌 관련 메커니즘에 대한 개요를 제공하고자했습니다.

Pathological changes in the cerebellum in PD

PD is characterized by Lewy body pathology formed by α-synuclein, while cerebellum was thought to be unaffected by Lewy bodies previously8,10. However, recent studies discovered α-synuclein-related pathological changes in the cerebellum in PD patients, which may be associated with tremor symptoms. In PD patients, α-synuclein-formed Lewy bodies, which were speculated to originate in the pre-cerebellar brainstem and spread in a prion-like manner, were identified in the cerebellum11. Lewy bodies were found mainly in the cerebellar nuclei and adjacent white matters, while cerebellar lobules were only affected mildly11. Histologically, in the cerebellum of PD patients, Lewy bodies were found in Bergmann glia in the molecular layer and Purkinje cell axons12,13.

PD에서 소뇌의 병리학적인 변화

PD는 α-시누클레인에 의해 형성되는 루이체 병리가 특징이며,

소뇌는 이전에는 루이체의 영향을 받지 않는 것으로 여겨졌습니다8,10.

그러나

최근 연구에서

떨림 증상과 관련이 있을 수 있는 소뇌의

α-시누클레인 관련 병리적 변화가

PD 환자의 소뇌에서 발견되었습니다.

PD 환자에서

소뇌 전뇌간에서 시작되어

프리온과 유사한 방식으로 퍼지는 것으로 추정되는

α-시누클레인 형태의 루이체가 소뇌에서 확인되었습니다11.

루이소체가 있는 파킨슨병 또는 치매 환자의 뇌는 소뇌 전뇌간 구조에 알파-시누클레인이 응집된 것으로 나타났습니다. 또한 환자들은 안정 시 떨림, 불안정한 걸음걸이, 균형 감각 장애를 보이는데, 이는 소뇌 기능 장애와 관련이 있을 수 있습니다. 따라서 우리는 알파-시누클레인 병증 환자 12명의 소뇌에서 신경 병리학적인 변화를 검사했습니다. 소뇌 핵과 주변 백질은 수많은 응집체를 보였지만 소엽은 경미한 영향을 받았습니다. 소뇌 응집 병리는 영향을받은 소뇌 구조에서 비롯된 프리온 유사 확산을 시사 할 수 있으며, 루이체 치매와 파킨슨 병 환자 간의 높은 동질성은 두 질병이 동일한 신경 병리학 적 스펙트럼에 속할 가능성이 있음을 보여줍니다

루이체는

주로 소뇌 핵과 인접한 백질에서 발견되었으며

소뇌 소엽은 경미한 영향을 받았습니다11.

Histologically, in the cerebellum of PD patients, Lewy bodies were found in Bergmann glia in the molecular layer and Purkinje cell axons

조직학적으로,

PD 환자의 소뇌에서 루이체는

분자층의 베르그만 신경교와 푸르킨예 세포 축삭에서 발견되었습니다12,13.

PD patients have longer climbing fiber length, more climbing fibers extending into the molecular layer, more climbing fiber-Purkinje cell synapses, and increased percentage of climbing fiber-Purkinje cell synapses on the thin Purkinje cell dendritic branchlets compared with healthy controls, accompanied by torpedoes/swelling of Purkinje cell axons14,15. Based on cluster analysis, these pathological changes may form a pattern that predicts the presence of resting tremor, PD patients with lower climbing-fiber synaptic density and a higher Purkinje cell count tend to have rest tremor15.

Moreover, iron accumulation has been identified in the deep nuclei of the cerebellum in PD. Using quantitative susceptibility mapping (QSM), iron content in dentate nuclei was found elevated in tremor-dominant PD patients compared with healthy controls and akinesia/rigidity-dominant PD patients, and was proven positively correlated to tremor severity despite subtypes of PD16,17,18. Because iron accumulation may indicate ferroptosis, a nonapoptotic cell death pathway, increased iron content in dentate nuclei suggests a role of dentate nuclei and cerebellum in the pathophysiological mechanism of tremor in PD16,17,18,19. Notably, ferroptosis may also promote α-synuclein aggregation16,17,18.

PD 환자는 건강한 대조군에 비해 등반 섬유 길이가 길고, 분자층으로 확장되는 등반 섬유가 많으며, 등반 섬유-푸르킨예 세포 시냅스가 많고, 얇은 푸르킨예 세포 수상돌기 가지에서 등반 섬유-푸르킨예 세포 시냅스의 비율이 증가하며, 어뢰/푸르킨예 세포 축삭의 부종14,15이 동반됩니다.

군집 분석에 따르면

이러한 병리학적인 변화는

안정 시 진전의 존재를 예측하는 패턴을 형성할 수 있으며,

등반 섬유 시냅스 밀도가 낮고 푸르킨예 세포 수가 높은 PD 환자는

안정 시 진전이 있는 경향이 있습니다15.

또한,

PD의 소뇌 심부핵에서

철분 축적이 확인되었습니다.

정량적 감수성 매핑(QSM)을 사용하여

건강한 대조군 및 운동성/경직성 PD 환자에 비해 떨림 우세 PD 환자에서

치상핵 dentate nuclei 의 철 함량이 높은 것으로 나타났으며,

PD의 하위 유형에 관계없이 떨림 중증도와 양의 상관관계가 있는 것으로 입증되었습니다16,17,18.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188502/

철분은 파킨슨병 및 관련 질환에서 오랜 역사를 가지고 있습니다. 이 필수 미량 영양소는 정상적인 뇌 기능에 매우 중요하지만 비정상적인 뇌 철분 축적은 한 세기 동안 추체외로 질환과 연관되어 왔습니다. 철분이 왜, 어떻게, 언제 신경세포의 죽음에 관여하는지는 아직까지 정확히 밝혀지지 않은 연구 주제입니다. 이 글에서는 20세기 초의 첫 관찰부터 추체외로 철을 새로운 치료 표적 및 진단 지표로 간주하는 최근의 노력에 이르기까지 운동 장애에서 철의 역사를 살펴봅니다.

철분 축적은

세포 사멸이 아닌 세포 사멸 경로인 페로옵토시스를 나타낼 수 있으므로,

치상핵의 철분 함량 증가는 PD16,17,18,19에서

진전의 병리 생리학적 메커니즘에서

치상핵과 소뇌의 역할을 시사합니다.

특히

페로렙토시스는

α-시누클레인 응집을 촉진할 수도 있습니다16,17,18.

Interestingly, both α-synucleinopathies and iron accumulation affect dentate nuclei, which act as the only output nuclei of the cerebellum, indicating a role of the cerebellum in tremor. White matter changes in the cerebellum, especially Purkinje cells and related climbing fiber changes, presented a clinical manifestation-related pattern, suggesting a role of cerebellar network damage in the tremor of PD. Therefore, in PD patients, damage exists in both deep nuclei and white matters of the cerebellum. These pathological changes outline a comprehensive impairment pattern of the cerebellum.

흥미롭게도

α-시누클레인 병증과 철 축적은

모두 소뇌의 유일한 출력 핵으로 작용하는

치상핵에 영향을 미치며,

이는 떨림에서 소뇌의 역할을 나타냅니다.

소뇌의 백질 변화,

특히 푸르킨예 세포 및 관련 등반 섬유 변화는

임상 증상 관련 패턴을 나타내어

PD의 떨림에서 소뇌 네트워크 손상의 역할을 시사합니다.

따라서

PD 환자에서는

소뇌의 심부핵과 백질 모두에 손상이 존재합니다.

이러한

병리학적인 변화는

소뇌의 포괄적인 손상 패턴을 설명합니다.

Tremor-related structural and functional changes in the cerebellum in PDStructural change

In previous studies, several tremor-related structural changes have been identified in the cerebellum of PD. When compared with PD patients without rest tremor, PD patients with rest tremor presented decreased gray matter volume mainly in quadrangular lobe and declive20, and tremor-dominant PD patients had decreased gray matter volume in left cerebellar lobule VIIIa compared with akinesia/rigidity-dominant PD patients21. Besides, larger volume of cerebellar lobule IV is associated with severer resting tremor in all PD patients22. These findings suggest a possible relation between these cerebellar regions and tremor in PD.

떨림과 관련된 소뇌의 구조적 및 기능적 변화파킨슨병의 소뇌 구조적 변화
이전 연구에서 본태성 진전 환자의 소뇌에서 몇 가지 진전 관련 구조적 변화가 확인되었습니다. 안정 시 진전이 없는 PD 환자와 비교했을 때, 안정 시 진전이 있는 PD 환자는 주로 사변엽과 소뇌에서 회백질 용적이 감소했으며20, 진전 우세 PD 환자는 운동성/경직 우세 PD 환자에 비해 좌측 소뇌엽 VIIIa의 회백질 용적이 감소한 것으로 나타났습니다21. 또한, 소뇌 소엽 IV의 부피가 클수록 모든 PD 환자에서 더 심한 안정 시 진전과 관련이 있습니다22. 이러한 연구 결과는 이러한 소뇌 영역과 본태성 진전 사이의 연관성을 시사합니다.

Additionally, tremor-dominant PD patients also present decreased gray matter volume in left cerebellar lobule VI, VIIb,VIIIb, and vermal cerebellar lobules VI and VIIIa compared with healthy controls, but such decrease in gray matter volume in these cerebellar regions was not correlated with tremor severity21. It has also been reported that no significant difference in gray matter volume and white matter volume exists between PD patients with tremor and healthy controls23. The relation of volume changes in these cerebellar regions with tremor needs to be further illustrated.

The findings above present controversial relation between tremor and cerebellar gray matter volume changes in PD. Notably, the atrophy of a lobule may cause the neighboring lobule to be volumetrically larger or vice versa. Therefore, volumetric analysis of cerebellar regions separately may be insufficient for outlining the tremor-related volumetric change of cerebellum in PD. A comprehensive pattern of volumetric change of cerebellum may be helpful for a better understanding of the role of the cerebellum in tremor in PD.

또한 진전이 우세한 PD 환자는 건강한 대조군에 비해 좌측 소뇌 소엽 VI, VIIb, VIIIb, 배 소뇌 소엽 VI 및 VIIIa의 회백질 용적이 감소하지만 이러한 소뇌 영역의 회백질 용적 감소는 진전 정도와 상관관계가 없었습니다21. 또한 떨림이 있는 파킨슨병 환자와 건강한 대조군 간에 회백질 부피와 백질 부피에 유의미한 차이가 없는 것으로 보고되었습니다23. 이러한 소뇌 영역의 부피 변화와 떨림의 관계는 더 자세히 설명할 필요가 있습니다.

위의 연구 결과는 본태성 떨림과 소뇌 회백질 용적 변화 사이의 논란의 여지가 있는 관계를 제시합니다. 특히 소엽의 위축으로 인해 인접한 소엽의 부피가 커지거나 그 반대의 경우도 발생할 수 있습니다. 따라서 소뇌 영역의 체적 분석만으로는 PD에서 소뇌의 떨림 관련 체적 변화를 설명하기에 불충분할 수 있습니다. 소뇌의 체적 변화에 대한 포괄적인 패턴은 본태성 떨림에서 소뇌의 역할을 더 잘 이해하는 데 도움이 될 수 있습니다.

More importantly, although possible relevance exists between volumetric changes and tremor in PD, whether the volumetric change is a causal factor, consequence, or concomitant phenomenon of tremor is unclear. Therefore, in the future, histological research may be necessary for further illustration of the relation between cerebellar change and tremor in PD.

Although there is limited Diffusion tensor imaging (DTI) studies investigating the role of the cerebellum in tremor in PD, a DTI study demonstrated white matter abnormality within multiple tracts including middle cerebellar peduncle and superior cerebellar peduncle compared with healthy controls and non-tremor-dominant PD patients24. This study adds a probability of the involvement of the cerebellar white matters in the tremor mechanism in PD. However, another study found no cerebellar white matter change between tremor-dominant PD patients and non-tremor-dominant PD patients25,26 (Table 1). Further DTI study investigating the role of the cerebellar white matter changes in the tremor of PD is needed.

더 중요한 것은 PD에서 체적 변화와 진전 사이에 가능한 관련성이 존재하지만, 체적 변화가 진전의 원인인지, 결과인지 또는 수반되는 현상인지는 불분명하다는 것입니다. 따라서 향후 PD에서 소뇌 변화와 진전 사이의 관계를 더 명확히 설명하기 위해서는 조직학적 연구가 필요할 수 있습니다.

본태성 떨림에서 소뇌의 역할을 조사한 확산텐서영상(DTI) 연구는 제한적이지만, 한 DTI 연구에서는 건강한 대조군 및 떨림이 우세하지 않은 PD 환자에 비해 중소뇌소체와 상소뇌소체를 포함한 여러 관로 내에서 백질 이상이 있는 것으로 나타났습니다24. 이 연구는 본태성 진전 메커니즘에 소뇌 백질이 관여할 가능성을 높여줍니다. 그러나 다른 연구에서는 진전 우세형 PD 환자와 비진전 우세형 PD 환자 간에 소뇌 백질 변화가 없는 것으로 나타났습니다25,26 (표 1). 본태성 떨림에서 소뇌 백질 변화의 역할을 조사하는 추가 DTI 연구가 필요합니다.

Functional change

Studies found functional changes in the cerebellum in tremor-dominant PD patients. PD patients presented a tremor-related metabolic pattern in 18F-deoxyglucose positron emission tomography (FDG-PET), glucose metabolism in their dentate nuclei and anterior cerebellar lobule (IV and V) was increased in resting state. This increase in glucose metabolism was positively correlated with tremor amplitude and could be suppressed by both VIM and subthalamic nucleus (STN) deep brain stimulation (DBS)27.

In resting-state functional MRI (fMRI), tremor-dominant PD patients showed decreased voxel-mirrored homotopic connectivity (VMHC) in the cerebellar posterior lobe. Moreover, VMHC in the cerebellar posterior lobe was reported negatively correlated with tremor severity in PD patients, while the amplitude of low-frequency fluctuations (ALFF) in this region was reported positively correlated with tremor severity28,29. Besides, increased local synchronization of activity in cerebellar crus I and cerebellar lobule VI and decreased local synchronization of activity in cerebellar vermis III, cerebellar lobule IV, and cerebellar lobule V in resting-state was also found in tremor-dominant PD patients. However, no correlation between local synchronization of activity in those regions and clinical manifestations was identified30. fMRI studies also found changes in functional connectivity between different cerebellar regions. Functional connectivity between cerebellar cortex and dentate nuclei in tremor-dominant PD patients is increased when compared with non-tremor-dominant PD patients31. Interestingly, among these functional connectivities, the functional connectivity between dentate nuclei and the cerebellar posterior lobe is positively correlated with tremor severity, while the connectivity between the anterior cerebellar lobules and dentate nuclei presents no correlation with clinical manifestations31. Additionally, tremor-dominant PD patients presented decreased connectivity between bilateral cerebellar hemispheres compared with healthy controls32.

Functional connectivity between the cerebellum and other structures was also altered. Functional connectivity in tremor-dominant PD patients between cerebellar lobule VI and basal ganglia, between the cerebellum and supplementary motor areas/insula, were found to be increased compared with healthy controls32. Connectivity between bilateral dentate nuclei and prefrontal cortex in tremor-dominant PD patients was decreased compared with healthy controls and non-tremor-dominant PD patients31. Furthermore, connectivity between these regions was negatively correlated with tremor severity, while connectivity between a region comprising cerebellar lobules V, VI, VII, and VIII, and supplementary motor areas was positively correlated with tremor severity in all PD patients31,32 (Table 2).

According to these previous reports, it seems that dentate nuclei plays a key role in cerebellum-related tremor regulation in tremor-dominant PD patients. It is possible that the activation of dentate nuclei or increase of dentate nuclei-cerebellar cortex interaction may enhance tremor, while the prefrontal cortex may suppress tremor via regulating the activity of dentate nuclei. These findings suggest that direct or indirect intervention on dentate nuclei may be a potential target of alleviating tremor in PD. As dentate nuclei lies deep in the cerebellum, it is inconvenient for intervention therapy such as DBS. However, the prefrontal cortex may be a potential target to regulate dentate nuclei more accessibly. Moreover, cerebellar lobules may be involved in the mechanism of tremor in PD via its influence on dentate nuclei activity. The interaction between the bilateral cerebellar hemisphere, cerebellar lobules, and dentate nuclei may also play a role in tremor activity, but the definite mechanism requires further study.

The role of the cerebellum in tremor in PDCerebellum may participate in tremor mechanism via cerebello-thalamo-cortical circuit

The basic of recent research on rest tremor and its responsiveness to dopaminergic treatment is the “dimmer switch model”, which is described in a systematic/circuit-level, and this model is also a foundation for the role of the cerebellum in tremor in PD1. This model focus on activity within two important tremor-related circuits, the basal ganglia circuits and the cerebello-thalamo-cortical circuits, and the interaction between these two important circuits. According to the “dimmer-switch model”, transient tremor-related activity first arises in the basal ganglia and, more precisely, internal pallidal globus (GPi), possibly as a consequence of pathological activity due to dopamine depletion in striato-pallidal circuit1,9,33. This tremor-related activity propagates to cerebello-thalamo-cortical (CTC) circuits via the connection between GPi and motor cortex5,9,33,34,35. Then, tremor-related activity may propagate to the thalamus and cerebellum via cortico-thalamic and cortico-cerebellar connectivity, within the CTC circuits9,36,37. And tremor-related activity may continue to exist in the CTC circuits and thus maintain the tremor until another signal that interacts with tremor-related firing in the CTC circuits is generated1.

Moreover, cortico-thalamic excitatory projections from the motor cortex to VIM may lead to low-frequency oscillations within the thalamocortical network37. On the other hand, the cerebellum influences the thalamus via glutamatergic excitatory projections from cerebellar deep nuclei to VIM38,39,40,41.

Conclusionally, tremor-related activity origins at GPi and propagates to the motor cortex, where the CTC circuit is activated. Activation of CTC circuits forms cortex-thalamus oscillations, which act as the base of tremor in PD, while the cerebellum modulates tremor amplitude by modulating the activity of VIM in the thalamus. Moreover, the modulation of the cerebellum on VIM is regulated by the motor cortex9,33 (Fig. 1).

기능적 변화

연구에 따르면

떨림이 우세한 본태성 PD 환자에서

소뇌의 기능적 변화가 발견되었습니다.

PD 환자는

18F- 데옥시글루코스 양전자방출단층촬영(FDG-PET)에서

떨림 관련 대사 패턴을 보였으며,

휴식 상태에서 상아핵과 전소뇌소엽(IV 및 V)의 포도당 대사가 증가했습니다.

이러한

포도당 대사의 증가는

진전 진폭과 양의 상관관계가 있으며,

VIM과 시상하핵(STN) 심부 뇌자극(DBS)27에 의해 억제될 수 있습니다.

안정 상태 기능적 MRI(fMRI)에서 떨림 우세형 PD 환자는 소뇌 후엽의 복셀 미러링 동형 연결성(VMHC)이 감소한 것으로 나타났습니다. 또한 소뇌 후엽의 VMHC는 PD 환자의 진전 중증도와 음의 상관관계가 있는 반면, 이 영역의 저주파 변동 진폭(ALFF)은 진전 중증도와 양의 상관관계가 있는 것으로 보고되었습니다28,29. 또한, 휴식 상태에서 소뇌 소체 I과 소뇌 소엽 VI의 국소적 활동 동기화 증가와 소뇌 소체 III, 소뇌 소엽 IV, 소뇌 소엽 V의 국소적 활동 동기화 감소도 진전 우세형 PD 환자에서 발견되었습니다. 그러나 해당 영역의 국소적 활동 동기화와 임상 증상 간의 상관관계는 확인되지 않았습니다30. fMRI 연구에서는 다른 소뇌 영역 간의 기능적 연결성 변화도 발견되었습니다. 진전이 우세한 PD 환자에서 소뇌 피질과 치상핵 사이의 기능적 연결성은 진전이 우세하지 않은 PD 환자에 비해 증가합니다31. 흥미롭게도 이러한 기능적 연결성 중 상아핵과 소뇌 후엽 사이의 기능적 연결성은 진전 중증도와 양의 상관관계가 있는 반면, 전소뇌엽과 상아핵 사이의 연결성은 임상 증상과 상관관계가 없는 것으로 나타났습니다31. 또한 진전 우세형 PD 환자는 건강한 대조군에 비해 양측 소뇌 반구 간의 연결성이 감소한 것으로 나타났습니다32.

소뇌와 다른 구조 사이의 기능적 연결성 또한 변경되었습니다. 진전 우세 PD 환자에서 소뇌 소엽과 기저핵, 소뇌와 보조 운동 영역/섬 사이의 기능적 연결성이 건강한 대조군에 비해 증가한 것으로 나타났습니다32. 진전 우세 PD 환자의 양측 치상핵과 전전두피질 사이의 연결성은 건강한 대조군 및 비진전 우세 PD 환자에 비해 감소한 것으로 나타났습니다31. 또한, 이러한 영역 간의 연결성은 진전 중증도와 음의 상관관계가 있는 반면, 소뇌 소엽 V, VI, VII, VIII로 구성된 영역과 보조 운동 영역 간의 연결성은 모든 PD 환자에서 진전 중증도와 양의 상관관계가 있었습니다31,32 (표 2).

이러한 이전 보고에 따르면, 본태성 PD 환자에서 치상핵은 소뇌 관련 진전 조절에 중요한 역할을 하는 것으로 보입니다. 상아핵의 활성화 또는 상아핵-소뇌 피질 상호 작용의 증가는 진전을 강화할 수 있고, 전전두엽 피질은 상아핵의 활동을 조절하여 진전을 억제할 수 있습니다. 이러한 연구 결과는 상아핵에 대한 직간접적인 개입이 본태성 진전증 완화의 잠재적 표적이 될 수 있음을 시사합니다. 상아핵은 소뇌의 깊은 곳에 위치하기 때문에 DBS와 같은 중재 요법에는 불편합니다. 그러나 전전두엽 피질은 치아핵을 더 쉽게 조절할 수 있는 잠재적 표적이 될 수 있습니다. 또한 소뇌 소엽은 상아핵 활동에 영향을 미침으로써 PD의 떨림 메커니즘에 관여할 수 있습니다. 양측 소뇌 반구, 소뇌 소엽 및 상아핵 사이의 상호 작용도 진전 활동에 중요한 역할을 할 수 있지만 명확한 메커니즘은 추가 연구가 필요합니다.

본태성 진전에서 소뇌의 역할소뇌는 소뇌-탈라모-피질 회로를 통해 진전 메커니즘에 관여할 수 있습니다.

휴식 진전과 도파민 치료에 대한 반응성에 대한 최근 연구의 기본은 체계적/회로 수준에서 설명되는 “디머 스위치 모델”이며, 이 모델은 PD1에서 진전에서 소뇌의 역할에 대한 기초이기도 합니다. 이 모델은 두 가지 중요한 떨림 관련 회로인 기저핵 회로와 소뇌-탈라모-피질 회로 내의 활동과 이 두 가지 중요한 회로 간의 상호 작용에 초점을 맞추고 있습니다. “디머 스위치 모델”에 따르면, 일시적인 떨림 관련 활동은 선조체-팔라모 회로1,9,33의 도파민 고갈로 인한 병리적 활동의 결과로 기저핵과 더 정확하게는 내부 팔라모 구상체(GPi)에서 먼저 발생한다고 합니다. 이러한 떨림 관련 활동은 GPi와 운동 피질 사이의 연결을 통해 소뇌-탈라모-피질(CTC) 회로로 전파됩니다5,9,33,34,35. 그런 다음 떨림 관련 활동은 CTC 회로 내에서 코르티코-시상체 및 코르티코-소뇌 연결을 통해 시상과 소뇌로 전파될 수 있습니다9,36,37. 그리고 떨림 관련 활동은 CTC 회로에 계속 존재할 수 있으므로 CTC 회로에서 떨림 관련 발화와 상호 작용하는 다른 신호가 생성될 때까지 떨림이 유지될 수 있습니다1.
또한, 운동 피질에서 VIM으로의 코르티코-시상 흥분성 돌출은 시상 피질 네트워크 내에서 저주파 진동을 유발할 수 있습니다37. 반면에 소뇌는 소뇌 심부핵에서 VIM으로의 글루탐산 흥분성 돌기를 통해 시상피질에 영향을 미칩니다38,39,40,41.

결론적으로, 떨림 관련 활동은 GPi에서 시작하여 운동 피질로 전파되어 CTC 회로가 활성화됩니다. CTC 회로의 활성화는 피질-시상체 진동을 형성하여 PD에서 진전의 기저로 작용하고, 소뇌는 시상에서 VIM의 활동을 조절하여 진전 진폭을 조절합니다. 또한, VIM에 대한 소뇌의 조절은 운동 피질9,33에 의해 조절됩니다(그림 1).

Fig. 1: Dimmer switch model of tremor in Parkinson’s disease (PD).

Tremor-related activity originates at internal pallidal globus (GPi), which propagate to cortex. Cortex and ventral intermediate nucleus of thalamus (VIM) form a circuit, which is possible the base of tremor-related oscillation. Cerebellum also projects to VIM, this projection possibly modulate amplitude of tremor, while cerebellum was modulated by cerebral cortex. COR cortex, CER cerebellum. Orange arrows indicate projections within cerebello-thalamo-cortical circuit, blue arrow indicates projection from GPi to cortex.

Before the “dimmer-switch model” was proposed, some previous studies focus on single oscillator (or pacemaker) in tremor mechanism, and localized tremor pacemaker in the basal ganglia or the thalamus according to the ability to oscillate at the same or double frequency of tremor in PD1. However, studies found multiple nodes, such as VIM, subthalamic nucleus, and pallidum might serve as a pacemaker, while the modulation of tremor frequency and tremor amplitude seemed independent9. Therefore, the “dimmer-switch model” was proposed for a better explanation of the mechanism of tremor in PD.

The “dimmer-switch model” attributes different contributions to different networks (or network nodes), and provide us with a comprehensive view of the tremor mechanism in PD. However, due to the spatial resolution limit of the methods used in current studies, some small nucleus that has been recognized to play a role in tremor mechanism, such as the subthalamic nucleus, is not involved in this model. The absence of these small but important nuclei can make the model incomplete and may lead to errors, especially when speculating the pathways in which tremor-related activity propagates through the brain using dynamic causal modeling (DCM) approaches that require a priori model1,9,34. Therefore, it is necessary to be cautious when making anatomical-level speculations on activity propagating pathways based on the “dimmer-switch model”.

In the dimmer switch model, the cerebellum may act as a modulator of tremor-related activity in PD mainly based on the following evidence: (1) there is bidirectional connectivity between the motor cortex and thalamus, forming a circuit that could maintain the tremor-related oscillation independently; (2) cerebellum participates in tremor-related circuit with a unidirectional manner, more specifically cortico→cerebello→thalamic connectivity9; (3) cerebellar stimulation could not reset tremor1 (Fig. 1).

Additionally, previous studies found that the cerebellum may be involved in processing tremor-related afferents from periphery42, while the cortex drives limb tremor43, and VIM is involved in both processing tremor-related afferents and driving of limb tremor44. Therefore, the cerebellum may be a key structure in the feedback of tremor. Thus, impaired cerebellar function due to PD may contribute to the tremor mechanism in PD via modulating tremor amplitude and feedback of peripheral tremor-related afferents.

Moreover, recent studies found there were bidirectional anatomical connectivities between the cerebellum and basal ganglia, that was: (1) cerebellum nuclei (dentate nuclei) → thalamus → striatum (2) subthalamic nuclei→ pontine nuclei→ cerebellum cortex45,46,47, but whether this bidirectional connectivity has a role in the mechanism of tremor in PD requires further investigation.

Neurotransmitters, cerebellum, and tremor in PD

Dopaminergic dysfunction is traditionally regarded as the cause of PD48. More specifically, there may be a pallidal and thalamic dopamine depletion in PD patients, subsequent to dopaminergic degeneration in substantia nigra, ventral tegmental area, and mesencephalic retrorubral area1,49. According to the “dimmer switch model”, dopamine depletion in pallidum may be the trigger of tremor-related activity in PD33. Dopamine depletion may also cause thalamic excitation, which contributes to tremor-related circuit activity34. Additionally, although the cerebellum is traditionally regarded as a non-dopaminergic brain area, recent studies demonstrated dopaminergic neurotransmission in the cerebellum50. These projections may arise from basal ganglia based on the anatomical connectivity between the cerebellum and basal ganglia45,46,47 and may be influenced by PD-related pathology in the cerebellum50. Unfortunately, few studies directly investigated the relevance of the cerebellar dopaminergic system to tremor in PD.

Although dopaminergic dysfunction may contribute to tremor, it seems not the unique cause of tremor in PD. Levodopa treatment presents various effects on tremor in PD patients. In some PD patients, levodopa may present a poor effect on tremor, even though their other symptoms, including bradykinesia and rigidity, are alleviated5,7,51,52. This phenomenon persists even at a high dose of levodopa treatment5,7, and this tremor is known as dopamine-resistant tremor, which we discussed in the section “Dopamine-resistant Parkinson’s tremor and its relation with cerebellum” below.

Serotonergic neurons in raphe nuclei act as the main source of serotonin in the brain, they gradually degenerate in PD patients as PD pathology progresses53,54,55, leading to serotonin depletion in structures that receive serotonergic projections, such as cortex, thalamus, and basal ganglia56,57,58,59.

Serotonin system damage plays an important role in the mechanism of tremor in PD. Polymorphism of the SLC6A4 gene encoding the serotonin reuptake transporter is associated with rest tremor in PD60. The serotonin-transporter availability in raphe nuclei is decreased in both early stage and advanced tremor-dominant PD patients compared with akinetic-rigidity-dominant PD patients. Moreover, this availability was negatively correlated with tremor severity in all subtypes of PD patients57,61. Importantly, serotonergic system degeneration contributes more to tremor than striatal dopaminergic degeneration, and its severity is negatively correlated with responsiveness to levodopa61.

Serotonergic neurons influence the cerebellum directly by projection to cerebellar cortex62,63,64,65 and indirectly via multiple structures45,46,47. Serotonergic neurons in raphe nuclei project to basal ganglia66, which connects with the cerebellum bidirectionally45,46,47. Besides, serotonergic neurons also project to structures such as the cortex, several brainstem nuclei, and spinal cord that may influence cerebellar activity59,67. Thus, serotonergic system impairment may result in abnormal input into the cerebellum and, consequently, affect tremor-related circuits1.

Although a few single photon emission computed tomography (SPECT) studies investigate the state and role of the serotoninergic system in the tremor of PD57,61, they did not investigate the role of the serotoninergic system in the cerebellum, possibly due to that 123I-FP-CIT in SPECT could act as a tracer for serotonin only in serotonin-transporter-rich region such as raphe nuclei, and cerebellum may not meet the requirement68. Besides, in PET and SPECT studies, the cerebellum is traditionally considered as a region with mainly nonspecific binding and is usually used as a reference region for calculating binding ratio68,69,70. Thus, the status and role of the serotonergic system in the cerebellum in PD may be ignored. Radioligand that could selectively reflect serotonin distribution may help investigate the role of the cerebellar serotonergic system in PD tremor.

Locus coeruleus is affected in the early stage of PD pathology spread, which leads to noradrenergic content loss of up to 70% in the brain71,72,73,74,75,76, resulting in decreased noradrenergic projection to cerebellum77, thalamus78, and motor cortex78 in PD. In other words, all structures involved in CTC circuits suffer the loss of noradrenergic input in PD.

Interestingly, tremor-dominant PD patients present less neuronal loss in locus coeruleus79, which may indicate a relatively preserved noradrenergic system. Consistently, activating the noradrenergic system (by acute cognitive stress72) in human could enhance the activity of the CTC circuit, exacerbate tremor, and suppress the effect of levodopa on tremor in PD patients72,80. Activation of the noradrenergic system stimulates both the bottom-up arousal and top-down cognitive control networks, enhances the thalamic activity and CTC circuit activity80. On the other hand, inactivating the noradrenergic system by sleep, β-blockers, or placebo, may ameliorate tremor in PD patients81,82,83,84,85. These findings support that the noradrenergic system exacerbates tremor in PD.

Interestingly, noradrenergic neurons in locus coeruleus project directly to cerebellum71,72,86,87,88,89,90,91,92,93,94, and may indirectly influence the cerebellum by affecting the thalamus and cortex. It is possible that the direct and indirect effect of noradrenergic system on the cerebellum may influence its modulation on tremor amplitude in PD1. Notably, current studies focused on the short-time effect of noradrenergic system change in PD. However, the noradrenergic system is persistently preserved in tremor-dominant PD patients compared with non-tremor dominant PD patients79, suggesting a potential background of the continuous noradrenergic system activation, which may lead to a different cerebellar activity status in tremor-dominant PD patients from in non-tremor dominant PD patients. It is a pity that, to our knowledge, there is an absence of direct measurements of noradrenergic activity in vivo, making it difficult to investigate the relation between cerebellar noradrenergic status and tremor in PD patients. Further study is needed to illustrate the role of the noradrenergic system in cerebellum-related tremor activity.

Abnormal output of cerebellum may contribute to tremor in PD, possibly via CTC circuit

Cerebellum itself has a complex information processing system. The Glutamatergic granule cell in the cerebellum receives multiple inputs, including dopaminergic input from mesencephalon, serotonergic input from raphe nuclei, and noradrenergic input from locus coeruleus, while all these structures are affected in PD95,96,97 (Fig. 2). For cerebellar projection, GABAergic Purkinje cells form a network in the cerebellum and integrate input from parallel fibers (from granule cell in the cerebellum) and climbing fibers (from inferior olive nuclei), and connect with dentate nuclei76,95,96, which project to thalamus and other structures8,45,46,47,98,99. This integrating process could also be damaged by PD-induced Purkinje cell loss, axonal/white matter abnormality, and altered fiber character11,12,13,14,15. Moreover, iron accumulation in dentate nuclei in PD patients may also indicate damage of cerebellar output16,17,18,19, more specifically, the output from cerebellar dentate nuclei to the thalamus via its excitatory glutamatergic projection on VIM8,45,46,47,98,99. Therefore, the external input into the cerebellum, the integrating process in the cerebellum, and the output nuclei are all damaged in PD.

Fig. 2: Neurotransmitters modulate tremor activity in Parkinson’s disease (PD) via influencing cerebellar output.

Various neurotransmitters including dopamine (DA), serotonin (5HT), and noradrenaline (NA), affect the cerebellar cortex (CER-COR), which modulate the output activity of dentate nuclei (DN). DN project to ventral intermediate nucleus of the thalamus (VIM) and modulate tremor activity. Orange arrows indicate projections between CER-COR, DN, and VIM. The Blue arrows indicate cerebellar output to other brain regions. Black arrows indicate the effect of neurotransmitters.

Full size image

VIM receives glutamatergic projections from cortex and cerebellum, and GABAnergic self-inhibitory projection98, and it may be a key modulator of tremor in PD patients, according to recent studies reporting the following findings: (1) high-frequency DBS stimulation on VIM may induce synaptic fatigue at excitatory glutamatergic synapses after a transient excitation of these synapses, thereby suppresses tremor in PD patients8,98; (2) low-frequency DBS stimulation on VIM that can excite glutamatergic synapses while allowing glutamatergic synaptic vesicle to be replenished worsens tremor in PD patients98; (3) excitation of VIM induced by cognitive load was reported to exacerbate tremor in PD patients80 (Fig. 3).

Fig. 3: Ventral intermediate nucleus of the thalamus (VIM) plays a central role in tremor activity and may be a target of tremor interference.

Acute cognitive stress, deep brain stimulation (DBS), and dopamine could influence VIM and thus regulate tremor. DBS with different frequency present a different effect on tremor activity. Orange arrows indicate excitatory effect, blue arrows indicate inhibitory effect.

Full size image

Notably, excitatory glutamatergic synapses on VIM are from the cerebellum, at least partially5,98, indicating an important role of the cerebellum in the modulation of tremor in PD patients, possibly by its glutamatergic projection. Consistently, levodopa-resistant tremor-dominant PD patients present relatively higher activity in the cerebellum, including dentate nuclei, lobule IV, lobule V, vermis IX, and interposed nuclei5. Therefore, the cerebellum may also play an important role in the modulation of tremor in PD via regulating the activity of VIM by its glutamatergic projection. Thus, suppressing cerebellar glutamatergic projection to VIM may be a potential strategy for treating PD tremor.

Additionally, it has been demonstrated in essential tremor that GABAergic projection abruption15,100,101,102,103,104, as well as its possible influence on deep nuclei105,106, may lead to disinhibition of dentate nuclei, which may serve as the pacemaker and drive the CTC circuit to generate tremor15,99. Therefore, it is also possible in PD that abnormal output of dentate nuclei may contribute to disinhibition of the CTC circuit and lead to tremor, but direct evidence is required for this hypothesis.

Conclusionally, in PD, altered input from the dopaminergic, serotonergic and noradrenergic system into the cerebellum, damage of cerebellar integrating process, and dentate nuclei damage may alter cerebellar (excitatory) output at three different levels, and thereby, may possibly influence the modulation of tremor via affecting VIM and then CTC circuit, as indicated by the “dimmer switch model”1.

Cerebellum-related mechanism of therapy for tremor in PD

As the most commonly used drug therapy for PD, levodopa could ameliorate tremor in PD patients by suppressing tremor-onset-related activity in GPi and inhibiting tremor-amplitude-related activity in VIM (where D2 receptor was identified recently)34. The latter mechanism possibly decreases/normalizes functional coupling between the thalamus and motor cortical areas5,107. The mechanism of VIM inhibiting exists in both dopamine-responsive and dopamine-resistant PD patients, but is more prominent in dopamine-responsive PD patients5,34.

Interestingly, levodopa suppresses tremor in PD via inhibiting tremor-amplitude-related activity in VIM, supporting VIM as a key target of levodopa treatment in suppressing tremor in PD5,34,98,107. Thereby, abnormally enhanced glutamatergic projection from the cerebellum on VIM may decrease the susceptibility of VIM to dopamine, and thus, results in levodopa resistance5,34. Therefore, if further investigated, the cerebellum may be a promising alternative therapeutic target in PD patients with dopamine-resistant tremor.

Dopamine agonists (such as pramipexole)85,108,109,110, monoamine oxidase B (MAOB) inhibitors (such as selegiline, rasagiline)111,112,113, and catechol-O-methyltransferase (COMT) inhibitors (such as entacapone, tolcapone)85,114 were also reported to alleviate tremor via different mechanisms. It is easy to understand that COMT inhibitors alleviate tremor by promoting the effect of levodopa85,114. Pramipexole has been reported to be effective in some tremor resistant to antiparkinsonian drugs other than pramipexole110. However, the effect of pramipexole on tremor-related circuits and cerebellum is unclear. Similarly, the effect of MAOB inhibitors on tremor-related circuits and cerebellum is also unclear, and further investigations are needed.

Additionally, as classical anti-tremor drugs, anticholinergic drugs, including benzhexol, could alleviate tremor by modulating the balance between the dopaminergic and cholinergic systems. However, the specific mechanism and its effect on tremor-related circuits and cerebellum are also poorly understood115,116,117.

Notably, dopamine receptors and choline receptors are expressed in the cerebellum, although at relatively low level50,118, it is possible that these drugs (except levodopa) may modulate cerebellar activity and thus, alleviate tremor via CTC circuits. However, no existing direct evidence support this hypothesis; further study is needed.

In addition to drug therapy, non-pharmacological treatment is another approach to alleviate tremor, particularly dopamine-resistant tremor, in PD119. Thalamotomy is historically an invasive method of relieving drug-resistant tremor in PD120,121. The mechanism may be direct damage to the VIM, which plays an essential role in the tremor mechanism120. However, thalamotomy is irreversible and uncontrollable, and may bring complications such as paresthesia and gait disturbance122. Even with modification of surgical approach, complications related to surgery itself may occur122,123.

DBS is the preferred method for relieving PD tremor compared to thalamotomy currently122. VIM-DBS effectively alleviates both dopamine-responsive and dopamine-resistant tremor, but has limited effect on other parkinsonian symptoms such as rigidity and bradykinesia124. This puts VIM at a disadvantage compared with other targets for DBS, such as the subthalamic nucleus, which could alleviate multiple symptoms and possibly slow the progression of PD125. Anyway, the effectiveness of VIM-DBS provides us with better insight into the tremor mechanism in PD. VIM-DBS was reported to ameliorate tremor by inhibiting neuronal firing in the VIM, and this inhibition occurs after transient neuronal firing in the VIM, which leads to transient worsening of tremor, and finally lead to fatigue of VIM excitatory afferents, and inhibition of VIM activity98. Indeed, VIM is nucleus that receives glutamatergic excitatory afferents from the cerebellum38,39. Thus, VIM-DBS may alleviate tremor by modulating cerebellum-regulated VIM activity, and thus may change the activity in the CTC circuit. However, the specific mechanism that VIM-DBS ameliorate tremor in PD is still unclear and needs further research.

Dopamine-resistant Parkinson’s tremor and its relation with cerebellum

The effect of dopamine on tremor in PD is variable between individuals. Zach, et al. Categorized PD patients into three clusters (the dopamine-responsive, intermediate, and dopamine-resistant rest tremor) based on the change of tremor amplitude and the change of tremor power after levodopa challenge7. The PD patients with dopamine-responsive rest tremor (PD-RP) display a higher disease severity, longer disease duration, and a higher frequency of accompanying dyskinesia when compared with PD patients with intermediate and dopamine-resistant rest tremor7. As mentioned above, VIM inhibition is an essential mechanism for dopamine to alleviate tremor34, this inhibition is more significant in PD-RP when compared with dopamine-resistant rest tremor (PD-RS)5,34. Furthermore, several brain regions in the cortex, thalamus, and cerebellum present different tremor-related activity between PR-RS and PR-RP5. Besides, although not statistically significant, the score for rest tremor severity is lower in PD-RS when compared with PD-RP5,7. These studies indicate that there may be a different mechanism underlying the two/three phenotypes as they represent different clinical and pathophysiological characters.

A possible explanation for the above differences in responsiveness of tremor to dopamine between PD-RS and PD-RP may be as follows: Because different brain regions may be affected as the PD pathology progresses11,53,54,55,56,73,74,75,76,77,78. At different disease stages, brain regions responsible for tremor may be affected by PD pathology to different degrees. In other words, many brain regions may participate in tremor mechanisms, but at a certain disease stage, one of these regions may account most for tremor, which may result in altered responsiveness of rest tremor to dopamine as the disease progresses7. As the cerebellum is mainly affected by various non-dopaminergic neurotransmitters rather than dopaminergic neurotransmitters5, resistance to dopamine may occur when the cerebellum accounts most for tremor at a certain disease stage. This speculation is supported by the study of Dirkx, et al., which found increased tremor-related activity in cerebellar lobules IV/V/IX and nuclei5.

Further longitudinal researches on the change of tremor-related activity in different brain regions (e.g., cerebellum, thalamus, and cortex), tremor responsiveness to dopamine, and tremor-related activity-dopamine responsiveness relationships as disease progressing are needed for a better understanding of the mechanisms of dopamine-resistant rest tremor and the role of the cerebellum in it.

In conclusion, the cerebellum is affected by α-synuclein-formed Lewy bodies and by iron accumulation in PD, which may induce tremor-related white matter alteration and tremor-specific structural and functional changes in the cerebellum. This damage in the cerebellum, together with damage of other structures, including mesencephalon, raphe nuclei, and locus coeruleus, may alter cerebellar (excitatory) output at three different levels (the input, the integrating process, and the output nuclei). The altered output of the cerebellum to VIM could excite the CTC circuit and enhance the tremor amplitude in PD. The dysregulation of cerebellum-modulated VIM activity may also decrease the susceptibility of VIM to levodopa, thus leading to dopamine-resistant tremor. Currently, few studies investigated the role of the cerebellum in PD-related tremor and its therapy, but still indicated an important role of the cerebellum in the mechanism of PD-related tremor. If further researched, the cerebellum may be a promising target of understanding and treatment of tremor in PD.

Table 1 Structural imaging studies reporting on tremor and cerebellum in Parkinson’s disease.

Full size table

Table 2 Functional imaging studies reporting on tremor and cerebellum in Parkinson’s disease.

Full size table

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
10.  
11.  
12.  
13.