Michiel F. Dirkx

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.

Parkinson’s disease is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, few studies have assessed these biological frameworks in large patient samples across disease stages. Analysing the largest imaging cohort in Parkinson’s disease to date (n = 3096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities and gene expression. We found widespread cortical and subcortical atrophy in Parkinson’s disease to be associated with advancing disease stage, longer time since diagnosis and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in Parkinson’s disease and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in Parkinson’s disease. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in Parkinson’s disease across disease stages and within individual patients are influenced by both network spread and local vulnerability.

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.

Tremor occurs in various forms across diverse neurological disorders, including Parkinson’s disease and essential tremor. While clinically heterogeneous, converging evidence suggests a shared brain network may underlie tremor across conditions. Here, we empirically define such a network using four modalities: lesion locations, atrophy patterns, EMG-fMRI, and deep brain stimulation outcomes. We show that network connectivity robustly explains clinical outcomes in independent cohorts undergoing deep brain stimulation of the subthalamic nucleus for Parkinson’s disease and the ventral intermediate nucleus for essential tremor. Maps from each cohort accounted for outcomes in the respective other, supporting a disorder-independent tremor network. A multimodal agreement map revealed consistent substrates in the primary motor cortex and motor cerebellum. To validate the network, we test its predictive power in a third, independent cohort treated with pallidal stimulation for Parkinson’s disease. Our findings define a robust, cross-condition tremor network that may guide both invasive and noninvasive neuromodulation strategies.

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.

Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson’s disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4–5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Objective: Parkinson’s disease (PD) resting tremor is thought to be initiated in the basal ganglia and amplified in the cerebello-thalamo-cortical circuit. Since stress worsens tremor, the noradrenergic system may play a role in amplifying tremor. We tested if and how propranolol, a non-selective beta-adrenergic receptor antagonist, reduces PD tremor, and whether or not this effect is specific to stressful conditions. Methods: In a cross-over, double-blind intervention study, participants with PD resting tremor received propranolol (40mg, single dose) or placebo (counter-balanced) on two different days. During both days, we assessed tremor severity (with accelerometry) and tremor-related brain activity (with functional Magnetic Resonance Imaging; fMRI), as well as heart rate and pupil diameter, while subjects performed a stressful cognitive load task that has been linked to the noradrenergic system. We tested for effects of drug (propranolol vs. placebo) and stress (cognitive load vs. rest) on tremor power and tremor-related brain activity. Results: We included 27 PD patients with clear resting tremor. Tremor power significantly increased during cognitive load vs. rest ( F (1,19)=13.8; p =.001; η _p ² =0.42) and decreased by propranolol vs. placebo ( F (1,19)=6.4; p =.02; η _p ² =0.25), but there was no interaction. We observed task-related brain activity in a stress-sensitive cognitive control network, and tremor power-related activity in the cerebello-thalamo-cortical circuit. Propranolol significantly reduced tremor-related activity in the motor cortex compared to placebo ( F (1,21)=5.3; p =.03; η _p ² =0.20), irrespective of cognitive load. Interpretation: Our findings indicate that the noradrenergic system has a general, context-independent role in amplifying PD tremor at the level of the primary motor cortex.

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.

Background: Parkinson's disease (PD) rest tremor emerges from pathological activity in the basal ganglia and cerebello‐thalamo‐cortical circuits. A well‐known clinical feature is the waxing and waning of PD tremor amplitude, but the mechanisms that drive this variability are unclear. Previous work has shown that arousal amplifies PD tremor by increasing between‐network connectivity. Furthermore, brain states in PD are biased toward integration rather than segregation, a pattern that is also associated with increased arousal.Objective: The aim was to test the hypothesis that fluctuations in integrative brain states and/or arousal drive spontaneous fluctuations in PD rest tremor.Methods: We compared the temporal relationship between cerebral integration, the ascending arousal system, and tremor, both during cognitive load and in the resting state. In 40 tremor‐dominant PD patients, we performed functional magnetic resonance imaging using concurrent tremor recordings and proxy measures of the ascending arousal system (pupil diameter, heart rate). We calculated whole‐brain dynamic functional connectivity and used graph theory to determine a scan‐by‐scan measure of cerebral integration, which we related to the onset of tremor episodes.Results: Fluctuations in cerebral integration were time locked to spontaneous changes in tremor amplitude: cerebral integration increased 13 seconds before tremor onset and predicted the amplitude of subsequent increases in tremor amplitude. During but not before tremor episodes, pupil diameter and heart rate increased and correlated with tremor amplitude.Conclusions: Integrative brain states are an important cerebral environment in which tremor‐related activity emerges, which is then amplified by the ascending arousal system. New treatments focused on attenuating enhanced cerebral integration in PD may reduce tremor. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.