Tremor is a neurological movement disorders characterized by involuntary shaking of one or more body parts, often in rhythmic and oscillatory pattern. Tremor can be a disease entity of its own or may be part of a movement disorder such as Parkinson’s disease. In the Systems Neurology group, we focus on the underlying mechanisms of tremor from a pathophysiological point of view. To this end, we utilize electrophysiological, neuroimaging, and brain stimulation techniques as well as clinical data from patients. Our ultimate goal is to improve the treatment of this disabling symptom.

Gaining Insights in Parkinsonian Tremor Pathophysiology

Our aim is to understand the pathophysiology of tremor in Parkinson’s disease from a system-level perspective. That is, which cerebral regions are involved in tremor and how do these regions interact? To this end, we employ various measures including fMRI, electrophysiology, and computational modelling. Using these methods, we find that spontaneous initiations of tremor episodes co-occur with increased basal ganglia activity and that ongoing fluctuations in tremor amplitude cofluctuates with activity in the cerebello-thalamo-cortical (CTC) circuit. This has formed the basis for the dimmer-switch model, where the basal ganglia acts as the ‘light switch’ that turns on the tremor and the CTC-circuit acts as a ‘light dimmer’ which modulates its amplitude.

This cerebral tremor network yielded a starting point as to understand how dopaminergic medication is able to reduce tremor-related activity, why the response to dopaminergic medication differs between patients, and how stress amplifies tremor-related activity. We find that dopamine directly acts on the thalamus and that dopamine-resistant tremor is related to increased cerebellar activity, which may unfavorably increase thalamic tremor-related activity. Focusing on the observation that tremor is amplified during cognitive stress, we found that the arousal system increases tremor through direct stimulation of thalamic activity and indirectly by recruiting a cognitive control network.

In future studies, we will not only aim to expand our knowledge of pathophysiological mechanisms, but also aim to bridge the gap between basic and clinical sciences. For example, how can we use pathophysiological parameters to predict clinical phenotypes from a diagnostic or treatment-oriented perspective?

Tremor Progression and Cerebellar Mechanisms

Much remains unknown of the cerebral mechanisms underlying tremor progression. Large multi-centre international studies have shown cross-sectional changes in cortical, thalamic, and cerebellar areas, which may overlap with tremor-related regions and could therefore interact with the central tremor oscillator. Such changes may explain longitudinal increases or decreases in tremor severity. Currently, we are investigating longitudinal changes in clinical tremor severity and its subtypes: resting, postural, and kinetic tremor. Our aim is to explain if and how structural changes in the CTC-circuit explain large inter-individual changes in clinical tremor progression within a well-defined longitudinal Parkinson’s disease cohort. To this end, we will use data from the Personalized Parkinson Project, or in Dutch: Parkinson Op Maat.

Secondly, we are interested in the cerebellar mechanisms underlying Parkinsonian tremor. Specifically, we are interested in the differential cerebellar contributions in resting and re-emergent tremor. Re-emergent tremor is a common subtype of postural tremor in Parkinson’s disease, which occurs ~2 seconds after stable posturing of the limbs against gravity. This subtype is more debilitating than resting tremor as it directly interferes with daily activities and often does not react well to dopaminergic medication. Using transcranial magnetic stimulation, we showed that the cerebellum was able to reset tremor-rhythm significantly more in re-emergent tremor than resting tremor. In future studies, we will localize the cerebral re-emergent network using combined accelerometry and fMRI. In addition, we will use novel dual-site transcranial alternating current stimulation with the aim to desynchronize and reduce ongoing re-emergent tremor.

Link to published articles:

van den Berg, K. R. E., & Helmich, R. C. (2021). The Role of the Cerebellum in Tremor – Evidence from Neuroimaging. Tremor and other hyperkinetic movements (New York, N.Y.)11, 49.

Helmich, R. C., Van den Berg, K. R. E., Panyakaew, P., Cho, H. J., Osterholt, T., McGurrin, P., Shamim, E. A., Popa, T., Haubenberger, D., & Hallett, M. (2021). Cerebello-Cortical Control of Tremor Rhythm and Amplitude in Parkinson’s Disease. Movement disorders : official journal of the Movement Disorder Society36(7), 1727–1729.

BAT study

Tremor occurs in up to 55% of dystonia patients. This combination is known as dystonic tremor syndrome (DTS). Treatment for DTS is often unsatisfactory: drugs have low efficacies and side effects and brain surgery is invasive. Botulinum toxin (BoNT) injections are a promising therapeutic option for tremors, but their efficacy varies largely between patients. This highlights the need for personalised treatment in DTS. In our multicentre BAT study, we will follow 72 DTS patients who start 12-weekly BoNT treatment for 40 weeks. Our primary aim is to predict the treatment success of BoNT based on patients’ clinical diagnosis and clinical, electrophysiological and ultrasonographic characteristics. Secondly, we will study the differences between the two clinical manifestations of DTS: dystonic tremor and tremor associated with dystonia. This will give more insight into the underlying pathophysiologies and thereby potential applicability of therapeutic options. Thirdly, we will also explore the validity of ultrasound for muscle selection before BoNT injections, as muscle ultrasound captures muscle movements and discriminates between anatomically overlapping muscles. To summarise our BAT study: we strive towards a more personalised treatment for DTS patients.

Daily-life tremor severity and its relation to stress in Parkinson’s Disease

Adequate assessment of tremor severity and its context-dependency is necessary for elucidating the individual tremor pathophysiology, and for quantifying treatment effect in clinical trials. Currently, tremor severity is estimated based on physical examinations during routine clinical visits. However, these assessments are subjective and fail to capture the daily fluctuations and context-dependency of tremor. These limitations could be overcome by using wearable sensors that objectively measure tremor severity in daily life. In the Personalized Parkinson Project (or in Dutch: Parkinson Op Maat studie) around 500 people were continuously monitored with the Verily Study Watch. By analyzing the gyroscope and photoplethysmography signals from the watch, we will quantify individual daily-life tremor severity and its relation to stress-related heart rate parameters. Furthermore, we will investigate whether distinct subgroups regarding the stress-sensitivity of tremor can be identified and whether these subgroups differ in their tremor brain network properties measured with fMRI. Ultimately, this may aid in the development of more personalized treatment for tremor in Parkinson’s disease.