Kevin R. E. van Den Berg

Resting tremor in Parkinson’s disease is characterized by considerable variability: tremor affects some patients but not others, and its amplitude typically fluctuates. Previous research focused primarily on identifying mechanisms that produce tremor, showing an important role for the basal ganglia and cerebello-thalamo-cortical circuit. What has been relatively ignored are mechanisms involved in suppressing tremor. For instance, patients can reduce their tremor by making voluntary movements or by exerting conscious effort. Here, we aimed to distinguish between brain mechanisms that contribute positively or negatively to spontaneous fluctuations in Parkinson’s tremor. We leveraged a large sample of 119 tremulous Parkinson patients with concurrent accelerometry-fMRI. Frame-by-frame fluctuations in accelerometry-derived tremor power, measured per patient, were used to localize tremor-related brain activations and deactivations at a group level. Amplitude-related coupling between tremor-positive and tremor-negative brain networks was examined further using physio-physiological interaction analyses. Lastly, whole-brain multiple regression analyses were used to test the association between tremor-related activity and clinically assessed tremor severity. Tremor-related activations were found in a lateralized network consisting of contralateral (to tremor) sensorimotor cortex, ventrolateral thalamus, posterior putamen, and cerebellum (ipsilateral lobule V, vermis, and bilateral Crus I/II); activity in this network correlated positively with tremor severity. Tremor-related deactivations encompassed a bilateral “anti-tremor” network, including dorsal premotor cortex, pre-supplementary motor area, somatosensory cortex, posterior parietal cortex, and insula; activity in this network correlated negatively with tremor severity. During low versus high tremor episodes, functional connectivity between the anti-tremor and tremor-positive networks increased. This suggests that the anti-tremor network makes a relevant contribution to modulating tremor amplitude by connecting to the cerebello-thalamo-cortical circuit in a tremor-dependent manner. We conclude that spontaneous fluctuations in Parkinson’s tremor amplitude are associated with interactions between a tremor-producing cerebello-thalamo-cortical circuit and a novel antagonistic anti-tremor network. Future intervention studies may investigate whether strengthening of the anti-tremor network leads to a reduction in tremor, as a potential basis for new therapies.

Background: Tremor is one of the cardinal motor symptoms of Parkinson's disease (PD). Its severity can be quantified with clinical rating scales and neurophysiology. The pathophysiology of PD tremor involves activity in the cerebello‐thalamo‐cortical circuit (CTC), which can be quantified with concurrent accelerometry‐functional magnetic resonance imaging (fMRI). This opens possibilities for fMRI‐informed precision medicine, but it remains unclear if tremor‐related fMRI activity is a reliable biomarker at the individual level. Objectives: To assess the test–retest reliability of three PD tremor outcome measures: clinical rating scales, accelerometry, and combined accelerometry‐fMRI. Methods: We studied 26 tremor‐dominant PD patients OFF medication on two separate days (2‐month interval). On each day, tremor was characterized with clinical rating scales (Fahn–Tolosa–Marin Tremor Rating Scale), accelerometry, and concurrent accelerometry‐fMRI. Reliability was assessed using Spearman correlations and intraclass correlation coefficients. Results: Clinical and neurophysiological tremor parameters were reliable across sessions. Resting tremor‐related fMRI activity was observed within the CTC across both sessions. The amplitude of tremor‐related activity in motor cortex and cerebellum had a significant, but moderate, between‐session reliability. Furthermore, the activity‐by‐voxel distribution of tremor‐related activity within motor cortex and cerebellum showed a significant between‐session correlation in at least two‐thirds of patients, and intra‐individual variability was significantly lower than inter‐individual variability. Conclusions: Both the amplitude and location of resting tremor‐related activity in motor cortex and cerebellum, derived from concurrent accelerometry‐fMRI, are replicable between sessions. This suggests that accelerometry‐fMRI may be used as an individual biomarker for tremor pathophysiology, to guide intervention studies and assess target engagement of new anti‐tremor therapies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: The various symptoms of Parkinson's disease (PD) may change differently over time as the disease progresses. Tremor usually manifests early in the disease, but unlike other motor symptoms, its severity may diminish over time. The cerebral mechanisms underlying these symptom‐specific longitudinal trajectories are unclear. Previous magnetic resonance imaging (MRI) studies have shown structural changes in brain regions associated with PD tremor, suggesting that structural changes over time may define clinical trajectories.Objectives: The aims were to investigate the longitudinal trajectory of PD tremor in relation to bradykinesia and rigidity, and assess whether tremor progression is related to structural changes in tremor‐related areas.Methods: We used data from the Personalized Parkinson Project: a two‐year longitudinal study involving 520 PD patients and 60 healthy controls, who were measured twice clinically and with MRI. Mixed‐effects models were used to compare tremor, bradykinesia, and rigidity progression; investigate gray matter changes in tremor‐related regions (cerebello‐thalamo‐cortical circuit and pallidum); and calculate associations between symptom severity and brain structure. Associations across the whole brain were included to assess anatomical specificity.Results: Bradykinesia and rigidity worsened over 2 years, whereas tremor behaved differently: resting tremor severity remained stable, whereas postural and kinetic tremor severity decreased. Attenuation of postural and kinetic tremor was associated with, but not restricted to, atrophy in tremor‐related areas. Opposite relationships were observed for bradykinesia and rigidity.Conclusions: Action tremor (postural and kinetic) is an early symptom of PD, which reduces with disease progression. Longitudinal brain atrophy correlates with tremor and other motor symptoms in opposite ways. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction: Tremor is the most common movement disorder. Although clinical examination plays a significant role in evaluating patients with tremor, laboratory tests are useful to classify tremors according to the recent two-axis approach proposed by the International Parkinson and Movement Disorders Society. Methods: In the present review, we will discuss the usefulness and applicability of the various diagnostic methods in classifying and diagnosing tremors. We will evaluate a number of techniques, including laboratory and genetic tests, neurophysiology, and neuroimaging. The role of newly introduced innovative tremor assessment methods will also be discussed. Results: Neurophysiology plays a crucial role in tremor definition and classification, and it can be useful for the identification of specific tremor syndromes. Laboratory and genetic tests and neuroimaging may be of paramount importance in identifying specific etiologies. Highly promising innovative technologies are being developed for both clinical and research purposes. Conclusions: Overall, laboratory investigations may support clinicians in the diagnostic process of tremor. Also, combining data from different techniques can help improve understanding of the pathophysiological bases underlying tremors and guide therapeutic management.

Neuroimaging research has played a key role in identifying which cerebral changes are associated with tremor. Here we will focus on the cerebellum, which may drive tremor oscillations, process tremor-related afferents, modulate activity in remote brain regions, or a combination. On the 6^th of October 2021, we conducted a PubMed search to select articles providing neuroimaging evidence for cerebellar involvement in essential tremor (ET), Parkinson’s disease (PD) tremor, and dystonic tremor (DT). In ET, tremor-related activity is found in motor areas of the bilateral cerebellum, and altered functional connectivity within and outside the cerebellum correlates with tremor severity. Furthermore, ET is associated with cerebellar atrophy, but also with compensatory structural changes outside the cerebellum (e.g. supplementary motor area). In PD, tremor-related cerebellar activity and increased cerebello-thalamic coupling has been found. Emerging evidence suggests that the cerebellum plays a key role in dopamine-resistant rest tremor and in postural tremor. Cerebellar structural alterations have been identified in PD, but only some relate to tremor. DT is associated with more widespread cerebral networks than other tremor types. In ET, the cerebellum likely acts as an oscillator, potentially due to loss of inhibitory mechanisms. In contrast, in PD the cerebellum may be a modulator, which contributes to tremor oscillations by influencing the thalamo-cortical system. The precise role of the cerebellum in DT remains unclear. We recommend that future research measures tremor-related activity directly by combining electrophysiology with neuroimaging, while brain stimulation techniques may be used to establish causality. This review of neuroimaging studies has provided convincing evidence that the cerebellum plays a key role in the pathophysiology of ET, PD tremor, and dystonic tremor syndromes. This contribution may consist of driving tremor oscillations, processing tremor-related afferents, modulating activity in remote brain regions, or all the above.