Tremor pathophysiology:lessons from neuroimaging

Contains fulltext : 226036.pdf (Publisher’s version ) (Closed access)PURPOSE OF REVIEW: We discuss the latest neuroimaging studies investigating the pathophysiology of Parkinson's tremor, essential tremor, dystonic tremor and Holmes tremor. RECENT FINDINGS: Parkinson's tremor is associated with increased activity in the cerebello-thalamo-cortical circuit, with interindividual differences depending on the clinical dopamine response of the tremor. Although dopamine-resistant Parkinson's tremor arises from a larger contribution of the (dopamine-insensitive) cerebellum, dopamine-responsive tremor may be explained by thalamic dopamine depletion. In essential tremor, deep brain stimulation normalizes cerebellar overactivity, which fits with the cerebellar oscillator hypothesis. On the other hand, disconnection of the dentate nucleus and abnormal white matter microstructural integrity support a decoupling of the cerebellum in essential tremor. In dystonic tremor, there is evidence for involvement of both cerebellum and basal ganglia, although this may depend on the clinical phenotype. Finally, in Holmes tremor, different causal lesions map to a common network consisting of the red nucleus, internal globus pallidus, thalamus, cerebellum and pontomedullary junction. SUMMARY: The pathophysiology of all investigated tremors involves the cerebello-thalamo-cortical pathway, and clinical and pathophysiological features overlap among tremor disorders. We draw the outlines of a hypothetical pathophysiological axis, which may be used besides clinical features and cause in future tremor classifications

Systematic clinical approach for diagnosing upper limb tremor

Tremor is the most common movement disorder worldwide, but diagnosis is challenging. In 2018, the task force on tremor of the International Parkinson and Movement Disorder Society published a consensus statement that proposes a tremor classification along two independent axes: a clinical tremor syndrome and its underlying aetiology. In line with this statement, we here propose a stepwise diagnostic approach that leads to the correct clinical and aetiological classification of upper limb tremor. We also describe the typical clinical signs of each clinical tremor syndrome. A key feature of our algorithm is the distinction between isolated and combined tremor syndromes, in which tremor is accompanied by bradykinesia, cerebellar signs, dystonia, peripheral neuropathy or brainstem signs. This distinction subsequently informs the selection of appropriate diagnostic tests, such as neurophysiology, laboratory testing, structural and dopaminergic imaging and genetic testing. We highlight treatable metabolic causes of tremor, as well as drugs and toxins that can provoke tremor. The stepwise approach facilitates appropriate diagnostic testing and avoids unnecessary investigations. We expect that the approach offered in this article will reduce diagnostic uncertainty and increase the diagnostic yield in patients with tremor

The clinical and electrophysiological investigation of tremor

The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review

Visuomotor processing is altered after peripheral nerve damage in neuralgic amyotrophy

Neuralgic amyotrophy is a common peripheral nerve disorder caused by autoimmune inflammation of the brachial plexus, clinically characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Despite recovery of the peripheral nerves, patients often have residual motor dysfunction of the upper extremity, leading to persistent pain related to altered biomechanics of the shoulder region. Building on clinical signs that suggest a role for cerebral mechanisms in these residual complaints, here we show and characterize cerebral alterations following neuralgic amyotrophy. Neuralgic amyotrophy patients often develop alternative motor strategies, which suggests that (mal)adaptations may occur in somatomotor and/or visuomotor brain areas. Here, we tested where changes in cerebral sensorimotor representations occur in neuralgic amyotrophy, while controlling for altered motor execution due to peripheral neuropathy. We additionally explore the relation between potential cerebral alterations in neuralgic amyotrophy and clinical symptoms. During functional MRI scanning, 39 neuralgic amyotrophy patients with persistent, lateralized symptoms in the right upper extremity and 23 matched healthy participants solved a hand laterality judgement task that can activate sensorimotor representations of the upper extremity, across somatomotor and visuomotor brain areas. Behavioural and cerebral responses confirmed the involvement of embodied, sensorimotor processes across groups. Compared with healthy participants, neuralgic amyotrophy patients were slower in hand laterality judgement and had decreased cerebral activity specific to their affected limb in two higher-order visual brain regions: the right extrastriate cortex and the parieto-occipital sulcus. Exploratory analyses revealed that across patients, extrastriate activity specific to the affected limb decreased as persistent pain increased, and affected limb-related parieto-occipital activity decreased as imagery performance of the affected limb became slower. These findings suggest that maladaptive cerebral plasticity in visuomotor areas involved in sensorimotor integration plays a role in residual motor dysfunction and subsequent persistent pain in neuralgic amyotrophy. Rehabilitation interventions that apply visuomotor strategies to improve sensorimotor integration may help to treat neuralgic amyotrophy patients

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

peer reviewed[en] BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions

Connecting tremors - A circuits perspective

Purpose of reviewTremor is one of the most prevalent movement disorders in clinical practice. Here, we review new insights in the pathophysiology of tremor. We focus on the three most common tremor disorders: essential tremor (ET), dystonic tremor syndrome (DTS), and Parkinson's disease (PD) tremor.Recent findingsConverging evidence suggests that ET, DTS, and PD tremor are all associated with (partly) overlapping cerebral networks involving the basal ganglia and cerebello-thalamo-cortical circuit. Recent studies have assessed the role of these networks in tremor by measuring tremor-related activity and connectivity with electrophysiology and neuroimaging, and by perturbing network components using invasive and noninvasive brain stimulation. The cerebellum plays a more dominant and causal role in action tremors than in rest tremor, as exemplified by recent findings in ET, DTS, and re-emergent tremor in PD. Furthermore, the role of the cerebellum in DTS is related to clinical differences between patients, for example, whether or not the tremor occurs in a dystonic limb, and whether the tremor is jerky or sinusoidal.SummaryInsight into the pathophysiological mechanisms of tremor may provide a more direct window into mechanism-based treatment options than either the etiology or the clinical phenotype of a tremor syndrome

The cerebral tremor circuit in a patient with Holmes tremor

The cerebral network associated with Holmes tremor has never been determined directly. A previous study reported a brain network that is functionally connected, in healthy individuals, to different lesions that cause Holmes tremor (lesion connectome). We report a 71-year-old man with severe left-sided tremor caused by a microbleed near the right red nucleus. Using accelerometry-fMRI, we show tremor-related activity in contralateral sensorimotor cortex and cerebellar vermis. This network was distinct from, but functionally coupled to, the Holmes lesion connectome. We propose that Holmes tremor involves three distinct cerebral mechanisms: a structural lesion, an intermediate lesion connectome, and symptom-related activity