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A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the hands. In some people, a tremor is a symptom of another neurological disorder. Types Tremor is most commonly classified by clinical features and cause or origin. Some of the better-known forms of tremor, with their symptoms, include the following:

Cerebellar tremor (also known as intention tremor) is a slow, broad tremor of the extremities that occurs at the end of a purposeful movement, such as trying to press a button or touching a finger to the tip of one's nose. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from stroke, tumor, or disease such as multiple sclerosis or some inherited degenerative disorder. It can also result from c

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Summary

Cerebellar tremor (also known as intention tremor) is a slow, broad tremor of the extremities that occurs at the end of a purposeful movement, such as trying to press a button or touching a finger to the tip of one's nose. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from stroke, tumor, or disease such as multiple sclerosis or some inherited degenerative disorder. It can also result from c

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Exploring the pathological interaction between LRRK2 and alpha-synuclein

Alessandra Musso

Parkinson’s disease (PD) is the most common age-related neurodegenerative movement disorder that affects 1-2% of the general population over the age of 65 and rising to 4-5% over 80 years of age. It is estimated that 6.3 million people worldwide have Parkinson’s disease and 1.2 million in the European Union (EU) alone. As the disease progresses, patients frequently develop a mask-like facial expression, festinating gait and cognitive impairment and the final clinical symptoms are muscle rigidity, bradykinesia, resting tremor and postural instability in addition to non-motor problems that result in a marked reduction in quality of life. The motor symptoms of PD arise from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leading to a deficiency of the neurotransmitter dopamine (DA) in the striatum. While dopamine replacement therapy is initially effective in treating the motor symptoms of PD, there is no known cure or neuroprotective therapy for this debilitating disease. Although the pathology underlying the disease is well defined, it is still unclear why DAergic neurons degenerate and die. PD is generally considered as a sporadic disease of unknown etiology, however in the last two decades it has become clear that heritability plays an important role in the pathogenesis of PD. Of the different genes associated with familial disease, mutations in two genes encoding for α-synuclein and leucine-rich repeat kinase 2 (LRRK2) proteins cause autosomal dominant PD. One of the neuropathological hallmarks of idiopathic and some familial forms of PD are Lewy bodies, which are intracytoplasmic inclusions that are enriched with fibrillar α- synuclein protein. Notably, LRRK2 mutation carriers with PD predominantly develop Lewy body pathology suggesting that LRRK2 may lie upstream of α-synuclein aggregation. These observations and other in vivo studies have suggested a common pathogenic pathway with LRRK2 potentially regulating the aggregation and neuronal toxicity of α-synuclein. However, the relationship between LRRK2 and α-synuclein in the mammalian brain is presently unclear and requires further evaluation, especially within midbrain dopaminergic neurons that degenerate in PD. The aim of this thesis work was to delineate a potential pathogenic interplay between these two PD-related gene products in mediating neurodegeneration in vivo. Understanding how and where the functional pathways of LRRK2 and α-synuclein converge will provide important insight into the common mechanisms underlying neurodegeneration in PD.[...]

EPFL2014

Normalization of aberrant pretherapeutic dynamic functional connectivity of extrastriate visual system in patients who underwent thalamotomy with stereotactic radiosurgery for essential tremor: a resting-state functional MRI study

Meritxell Bach Cuadra, Thomas William Arthur Bolton, Elena Najdenovska, Jean-Philippe Thiran, Constantin Tuleasca, Dimitri Nestor Alice Van De Ville

OBJECTIVE The tremor circuitry has commonly been hypothesized to be driven by one or multiple pacemakers within the cerebello-thalamo-cortical pathway, including the cerebellum, contralateral motor thalamus, and primary motor cortex. However, previous studies, using multiple methodologies, have advocated that tremor could be influenced by changes within the right extrastriate cortex, at both the structural and functional level. The purpose of this work was to evaluate the role of the extrastriate cortex in tremor generation and further arrest after left unilateral stereotactic radiosurgery thalamotomy (SRS-T). METHODS The authors considered 12 healthy controls (HCs, group 1); 15 patients with essential tremor (ET, right-sided, drug-resistant; group 2) before left unilateral SRS-T; and the same 15 patients (group 3) 1 year after the intervention, to account for delayed effects. Blood oxygenation level-dependent functional MRI during resting state was used to characterize the dynamic interactions of the right extrastriate cortex, comparing HC subjects against patients with ET before and 1 year after SRS-T. In particular, the authors applied coactivation pattern analysis to extract recurring whole-brain spatial patterns of brain activity over time. RESULTS The authors found 3 different sets of coactivating regions within the right extrastriate cortex in HCs and patients with pretherapeutic ET, reminiscent of the "cerebello-visuo-motor," "thalamo-visuo-motor" (including the targeted thalamus), and "basal ganglia and extrastriate" networks. The occurrence of the first pattern was decreased in pretherapeutic ET compared to HCs, whereas the other two patterns showed increased occurrences. This suggests a misbalance between the more prominent cerebellar circuitry and the thalamo-visuo-motor and basal ganglia networks. Multiple rence of the thalamo-visuo-motor network, suggesting a compensatory pathophysiological trait. Clinical improvement after SRS-T was related to changes in occurrences of the basal ganglia and extrastriate cortex circuitry, which returned to HC values after the intervention, suggesting that the dynamics of the extrastriate cortex had a role in tremor generation and further arrest after the intervention. CONCLUSIONS The data in this study point to a broader implication of the visual system in tremor generation, and not only through visual feedback, given its connections to the dorsal visual stream pathway and the cerebello-thalamo-cortical circuitry, with which its dynamic balance seems to be a crucial feature for reduced tremor. Furthermore, SRS-T seems to bring abnormal pretherapeutic connectivity of the extrastriate cortex to levels comparable to those of HC subjects.

2020

Pretherapeutic resting-state fMRI profiles are associated with MR signature volumes after stereotactic radiosurgical thalamotomy for essential tremor

Meritxell Bach Cuadra, Thomas William Arthur Bolton, Elena Najdenovska, Jean-Philippe Thiran, Constantin Tuleasca, Dimitri Nestor Alice Van De Ville

OBJECTIVE Essential tremor (ET) is the most common movement disorder. Drug-resistant ET can benefit from standard stereotactic deep brain stimulation or radiofrequency thalamotomy or, alternatively, minimally invasive techniques, including stereotactic radiosurgery (SRS) and high-intensity focused ultrasound, at the level of the ventral intermediate nucleus (Vim). The aim of the present study was to evaluate potential correlations between pretherapeutic interconnectivity (IC), as depicted on resting-state functional MRI (rs-fMRI), and MR signature volume at 1 year after Vim SRS for tremor, to be able to potentially identify hypo-and hyperresponders based only on pretherapeutic neuroimaging data. METHODS Seventeen consecutive patients with ET were included, who benefitted from left unilateral SRS thalamotomy (SRS-T) between September 2014 and August 2015. Standard tremor assessment and rs-fMRI were acquired pretherapeutically and 1 year after SRS-T. A healthy control group was also included (n = 12). Group-level independent component analysis (ICA; only n = 17 for pretherapeutic rs-fMRI) was applied. The mean MR signature volume was 0.125 ml (median 0.063 ml, range 0.002-0.600 ml). The authors correlated baseline IC with 1-year MR signatures within all networks. A 2-sample t-test at the level of each component was first performed in two groups: group 1 (n = 8, volume < 0.063 ml) and group 2 (n = 9, volume >= 0.063 ml). These groups did not statistically differ by age, duration of symptoms, baseline ADL score, ADL point decrease at 1 year, time to tremor arrest, or baseline tremor score on the treated hand (TSTH; p > 0.05). An ANOVA was then performed on each component, using individual subject-level maps and continuous values of 1-year MR signatures, correlated with pretherapeutic IC. RESULTS Using 2-sample t-tests, two networks were found to be statistically significant: network 3, including the brain-stem, motor cerebellum, bilateral thalamus, and left supplementary motor area (SMA) (p(FWE) = 0.004, cluster size = 94), interconnected with the red nucleus (MNI -2, -22, -32); and network 9, including the brainstem, posterior insula, bilateral thalamus, and left SMA (p(FWE) = 0.002, cluster size = 106), interconnected with the left SMA (MNI 24, -28, 44). Higher pretherapeutic IC was associated with higher MR volumes, in a network including the anterior default-mode network and bilateral thalamus (ANOVA, p(FWE) = 0.004, cluster size = 73), interconnected with cerebellar lobule V (MNI -12, -70, -22). Moreover, in the same network, radiological hyporesponders presented with negative IC values. CONCLUSIONS These findings have clinical implications for predicting MR signature volumes after SRS-T. Here, using pretherapeutic MRI and data processing without prior hypothesis, the authors showed that pretherapeutic network inter-connectivity strength predicts 1-year MR signature volumes following SRS-T.

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