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

Decreased Cerebellar Fiber Density in Cortical Myoclonic Tremor but Not in Essential Tremor

<p>Pathophysiology of tremor generation remains uncertain in 'familial cortical myoclonic tremor with epilepsy' (FCMTE) and essential tremor (ET). In both disorders, imaging and pathological studies suggest involvement of the cerebellum and its projection areas. MR diffusion tensor imaging allows estimation of white matter tissue composition, and therefore is well suited to quantify structural changes in vivo. This study aimed to compare cerebellar fiber density between FCMTE and ET patients and healthy controls. Seven FCMTE patients, eight ET patients, and five healthy controls were studied. Cerebellum was annotated based on fractional anisotropy (FA) and mean diffusivity volumes. Mean cerebellar FA values were computed as well as mean cerebellar volume. Group statistics included one-way ANOVAs and post hoc independent t tests. Mean FA of the cerebellar region for FCMTE was 0.242 (SD = 0.012), for ET 0.259 (SD = 0.0115), and for controls 0.262 (SD = 0.0146). There was a significant group effect for FA (F(2) = 4.9, p = 0.02). No difference in mean cerebellar volume was found. Post hoc independent t tests revealed significantly decreased mean FA in FCMTE patients compared to controls (t[10] = 2.5, p = 0.03) and ET patients (t[13] = 2.9, p = 0.01), while there was no difference in mean FA between ET patients and controls (t[11] <1.0). This study indicates for the first time microstructural damage of the cerebellar white matter in FCMTE in vivo. These results ascertain a role of the cerebellum in 'cortical tremor'.</p>

The Phenomenology of Primary Orthostatic Tremor

Background: The presence and prevalence of several neurological signs in patients with primary orthostatic tremor have not been systematically studied. Objectives: To assess the prevalence of clinical features of primary orthostatic tremor. Methods: Video-based assessment by four raters of standardized neurological examination of 11 patients with primary orthostatic tremor. Results: On standing, bent knees (7/11), hem sign (6/10), and a broad base of support (6/11) were the three most prevalent signs. Examination of gait revealed abnormal tandem gait (9/11) and bent knees (6/11) as the most prevalent clinical signs. In the arms, none of the patients displayed bradykinesia, ataxia, or dystonia. In the legs, ataxia was absent in all patients and bradykinesia was present in only one patient. Conclusions: Abnormal tandem gait, bent knees, hem sign, and broad base on standing are the most prevalent clinical signs in primary orthostatic tremor. We did not encounter clear extrapyramidal or unequivocal cerebellar signs

Phase-locked transcranial electrical brain stimulation for tremor suppression in dystonic tremor syndromes

Objective: To establish the causal role of the cerebellum and motor cortex in dystonic tremor syndromes, and explore the therapeutic efficacy of phase-locked transcranial alternating current stimulation (TACS). Methods: We applied phase-locked TACS over the ipsilateral cerebellum (N = 14) and contralateral motor cortex (N = 17) in dystonic tremor syndrome patients, while patients assumed a tremor-evoking posture. We measured tremor power using accelerometery during 30 s stimulation periods at 10 different phase-lags (36-degrees increments) between tremor and TACS for each target. Post-hoc, TACS-effects were related to a key clinical feature: the jerkiness (regularity) of tremor. Results: Cerebellar TACS modulated tremor amplitude in a phase-dependent manner, such that tremor amplitude was suppressed or enhanced at opposite sides of the phase-cycle. This effect was specific for patients with non-jerky (sinusoidal) tremor (n = 10), but absent in patients with jerky (irregular) tremor (n = 4). Phase-locked stimulation over the motor cortex did not modulate tremor amplitude. Conclusions: This study indicates that the cerebellum plays a causal role in the generation of (non-jerky) dystonic tremor syndrome. Our findings suggest pathophysiologic heterogeneity between patients with dystonic tremor syndrome, which mirrors clinical variability. Significance: We show tremor phenotype dependent involvement of the cerebellum in dystonic tremor syndrome. Tremor phenotype may thus guide optimal intervention targets

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27). We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power. These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome

Motor network disruption in essential tremor: a functional and effective connectivity study

Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor-signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremo

Structural changes in cerebellar outflow tracts after thalamotomy in essential tremor

This study set out to determine whether structural changes are present outside the thalamus after thalamotomy in patients with essential tremor (ET), specifically in the cerebellorubrothalamic tracts. We hypothesized that diffusion tensor imaging (DTI) would detect these changes. We collected DTI scans and analyzed differences in Fractional Anisotropy (FA) and Mean Diffusivity (MD) between the left and right superior and middle cerebellar peduncle in ET patients that have undergone unilateral, left, thalamotomy and ET patients that did not undergo thalamotomy (control group). We used classical ROI-based statistics to determine whether changes are present. We found decreased FA and increased MD values in the right superior cerebellar peduncle leading to the left, lesioned thalamus, only in the thalamotomy group. Our study suggests long-term structural changes in the cerebellorubrothalamic tract after thalamotomy. This contributes to further understanding of the biological mechanism following surgical lesions in the basal gangli