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Purpose: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI)., Methods: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed., Results: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR., Conclusion: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC)., Methods: Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNR LC ) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume., Results: Significant difference of CNR LC was found between ET and HC groups. The CNR LC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNR LC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNR LC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNR LC and TETRAS scores., Conclusion: The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The precise associations between dysphagia and palatal tremor (PT) remain unknown. We aimed to identify the association between PT and dysphagia among patients with midbrain/pontine stroke, compare the characteristics of dysphagia between patients with PT (PT + dysphagia) and without PT (PT- dysphagia), and verify neuroanatomical predictors of PT + dysphagia in this patient population. This retrospective observational study enrolled 40 patients (34 males, 6 females; mean age: 95% confidence interval [CI], 56.6 ± 14.6 years) with first-ever midbrain or pontine stroke exhibiting brain stem lesions admitted to the stroke unit of a single rehabilitation hospital between January 2010 and April 2020. Main outcome measures included dysphagia and aspiration rates and videofluoroscopic swallowing study findings. Lesion localization was stratified according to established vascular territories. Associations between PT and dysphagia and lesion location according to PT and dysphagia were analyzed. Dysphagia and aspiration rates were greater among patients with PT than among those without PT (95% CI, p = 0.030 and p = 0.017, respectively). The proportion of patients exhibiting oral stage impairment (95% CI, p = 0.007) was greater in the PT + dysphagia group than in the PT- dysphagia group. The posterolateral portion of the midbrain and pons (95% CI, p = 0.001 and p < 0.001, respectively) were the lesions more often involved in the PT + dysphagia group. Patients with PT following midbrain/pontine stroke more frequently present with dysphagia than those without PT. Thus, they should be carefully examined for PT and delayed dysphagia, including oral stage impairment, if initial brain images show posterolateral midbrain and pons lesions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.

Holmes's tremor (HT) is assumed to be the result of coexistence of nigrostriatal dopaminergic system impairment and the lesion of cerebello-thalamic pathways. It was suggested that dopaminergic deficiency is responsible for rest tremor, and lack of compensatory cerebellar function leads to spill of tremor into voluntary movements. Cases of HT with and without abnormalities of the presynaptic part of dopaminergic nigrostriatal were published and these findings raised the question of possibility of the postsynaptic lesion. Three patients with HT diagnosed according to criteria of Consensus Statement on Tremor were studied. In all of them SPECT imaging with ligands of presynaptic (I 123-FP CIT-DaTSCAN) and postsynaptic (I 123-iodobenzamide-IBZM) nigrostriatal dopaminergic neurons was performed. Indices of uptake in caudate and putamen normalized to nonspecific uptake in occipital cortex and indices of asymmetry for each whole striatum as well as for putamen and caudate separately were calculated. SPECT studies did not reveal asymmetry of DaTSCAN and IBZM binding in striatum in all studied subjects. The current clinical diagnostic criteria of HT are presumably insufficiently specific and when using them we identify patients both with and without the involvement of dopaminergic system. These two groups may represent tremor disorders of similar phenomenology but of different pathomechanism.

In this work, we investigated motor network structure in patients affected by essential tremor (ET) with or without resting tremor, using probabilistic tractography of the cerebello-thalamo-basal ganglia-cortical loop. Twenty-five patients with ET, twenty-two patients with ET associated with resting tremor (rET), and twenty-five age- and sex-matched healthy controls were included in the study. All participants underwent whole-brain 3D T1-weighted and diffusion-weighted MRI, and DAT-SPECT. Probabilistic tractography was performed on diffusion data in network mode, reconstructing connections between the different structures of the cerebello-thalamo-basal ganglia-cortical loop. All patients with ET, regardless of the presence of resting tremor, had normal DAT-SPECT, but showed significantly decreased connectivity in the cerebello-thalamo-precentral cortex network bilaterally, compared to healthy controls. In addition, patients with rET showed reduced connectivity in a pathway connecting globus pallidus, caudate, and supplementary motor area, compared to ET and controls. This latter circuit was significantly damaged in the hemisphere contralateral to the side clinically most affected by resting tremor. These findings provide insights upon structural changes underlying the different clinical presentations of ET. Our study demonstrates that ET and rET share common alterations in the cerebello-thalamo-precentral cortex circuit, while rET patients are characterized by specific damage to additional structures of motor network, such as globus pallidus, caudate nucleus, and supplementary motor area. Our findings suggest that ET and rET are different subtypes of the same neurodegenerative disorder.

Introduction: To explore the neuroanatomical correlates of primary writing tremor (PWT) and the role of cerebellum, using advanced structural neuroimaging. Till date, there are no studies exploring the gray and white matter changes using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) in PWT., Methods: Ten male patients with PWT were evaluated clinically and with magnetic resonance imaging. VBM and DTI images of patients were compared with that of 10 healthy male subjects. Spatially unbiased infra-tentorial template (SUIT) analysis was done to investigate the alterations of cerebellar gray matter. Region-of-interest analysis was performed on regions observed to be significantly different on DTI analysis., Results: The mean duration of illness and mean age of the patients were 3.5 ± 1.9 and 51.7 ± 8.6 years, respectively. On VBM analysis, the cluster of gray matter atrophy was found in bilateral cerebellar areas of culmen and left declive, right superior and medial frontal gyrus, bilateral middle frontal gyrus, bilateral anterior cingulate gyrus, and bilateral parahippocampal gyrus. DTI showed significantly reduced fractional anisotrophy of the anterior thalamic radiation, cingulum, and inferior fronto-occipital fasciculus in PWT patients compared to controls. The axial diffusivity, mean diffusivity, and radial diffusivity maps did not reveal any significant differences. On SUIT analysis, significant atrophy was found in right uvula and semilunar lobule in patients with PWT compared to controls., Conclusions: Our study found that patients with PWT had predominant gray matter atrophy in parts of cerebellum and frontal lobe along with white matter changes of the cingulum and frontal lobe connections.

Parkinson's disease (PD) can be classified into the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype, which present with different clinical courses and prognoses. However, the symptom-specific intrinsic neural mechanisms underlying the subtypes of PD still remain elusive. In the current study, we utilized resting-state fMRI (rs-fMRI) combined with the regional homogeneity (ReHo) method to investigate the modulations of neural activity in 13 patients with predominantly PIGD (p-PIGD) and 15 patients with predominantly TD (p-TD) in the resting state. Compared with healthy controls, the p-PIGD and the p-TD groups both displayed ReHo changes in the default mode network (DMN). By contrast, the p-TD group exhibited more ReHo alterations in the cerebellum involved in the cerebello-thalamo-cortical (CTC) loops, whilst the p-PIGD group in extensive cortical and sub-cortical areas, including the frontal, parietal, occipital, temporal, limbic lobes, basal ganglia and thalamus, which are involved in the striatal-thalamo-cortical (STC) loops. Direct comparison between the two groups showed significant ReHo alterations in the primary visual cortex. Our findings underscore the differential involvement of the STC and CTC circuits underlying the two subtypes of PD. Moreover, relatively widespread neural activity abnormality, especially in the motor-related regions as well as the visual network, is apparently a characteristic feature of PIGD symptoms. This study could shed light on the underlying pathophysiology and clinical heterogeneity of PD presentation.

Our aim was to address three characteristics of task-specific tremor in musicians (TSTM): First, we quantified muscular activity of flexor and extensor muscles, of coactivation as well as tremor acceleration. Second, we compared muscular activity between task-dependent and position-dependent tremor. Third, we investigated, whether there is an overflow of muscular activity to muscles adjacent to the affected muscles in TSTM. Tremor acceleration and muscular activity were measured in the affected muscles and the muscles adjacent to the affected muscles in 22 patients aged 51.5 ± 11.4 years with a task-specific tremor. We assessed power of muscular oscillatory activity and calculated the coherence between EMG activity of affected muscles and tremor acceleration as well as between adjacent muscles and tremor acceleration. This was done for task-dependent and position-dependent tremor. We found the highest power and coherence of muscular oscillatory activity in the frequency range of 3-8 Hz for affected and adjacent muscles. No difference was found between task-dependent and position-dependent tremor in neither power nor coherence measures. Our results generalize previous results of a relation between coactivation and tremor among a variety of musicians. Furthermore, we found coherence of adjacent muscles and TSTM. This indicates that overflow exists in TSTM and suggests an association of TST with dystonia.

Focal lesions of brainstem, thalamus, and subcortical white matter may cause movement disorders that are clinically indistinguishable from cerebellar symptoms. It is suspected that ataxia in these cases is due to damage of efferent or afferent pathways of the cerebellum. However, the precise anatomical correlate often remains undefined. We used deterministic diffusion tensor magnetic resonance imaging (DTI) tractography to study the anatomical relationship between lesions causing ataxia and efferent cerebellar pathways. Study subjects were six male patients with focal lesions of different etiology (demyelination, hemorrhage, ischemia, neoplasm) outside the cerebellum. Five patients had cerebellar-like ataxia with prominent contralateral upper limb involvement. One patient with an almost midline mesencephalic lesion had a symmetrical ataxic syndrome. We used 3T MRI (Intera, Philips Medical Systems, Best, Netherlands) and DTI tractography (32 directions, StealthViz DTI, Medtronic Navigation, Louisville, USA) to delineate the dentato-rubro-thalamo-cortical tract (DRT). In all patients, tractography demonstrated focal lesions affecting the DRT in different locations. We conclude that in vivo mapping of cerebral pathways using DTI tractography in patients with focal extracerebellar brain lesions may provide direct evidence of circumscribed damage to the DRT, causing unilateral cerebellar-like ataxia. Also, a unilateral mesencephalic lesion at the level of the crossing of the DRT may cause bilateral ataxia.

Coherences between coactivation of wrist antagonist muscles and movement fluctuation were assessed in four violinists with a task-specific tremor and four age-matched healthy violinists using electromyography and accelerometer. We found coherence between individual muscular activation and tremor only in patients at a frequency range of 3-8 Hz. The finding corroborates the notion that primary bowing tremor emerges mainly due to central neurogenic contributions via motor-unit synchronization. Furthermore, the coherence between the muscular coactivation and tremor suggests a relation of the tremor to dystonia.

Background: Rest tremor is a hallmark of Parkinson's disease (PD), but its pathogenesis remains incompletely understood. Nigro-striatal dopamine deficiency correlates best with bradykinesia, but not with tremor. Oscillating neurons in one or multiple localizations within the basal gangliathalamo-cortical loop may cause rest tremor, and an active contribution of the cerebellum and the cerebello-thalamo-cortical projections has been postulated., Objective: To compare the pattern of grey matter volume in PD patients with and without tremor to identify structural correlates of rest tremor., Methods: Voxel-based morphometry (VBM) of a high-resolution 3 Tesla, T1-weighted MR images, pre-processed according to an optimized protocol using SPM2, was performed in 24 patients with mild to moderate PD comparing local grey matter volume in patients with (n = 14) and without rest tremor (n = 10)., Results: Grey matter volume is decreased in the right quadrangular lobe and declive of the cerebellum in PD with tremor compared to those without (PFDR < 0.05)., Conclusions: These results demonstrate for the first time morphological changes in the cerebellum in PD patients with rest tremor and highlight the involvement of the cerebellum and cerebello- thalamo-cortical circuit in the pathogenesis of parkinsonian rest tremor.

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson's disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [(123)I]beta-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD(T)) and without tremor (PD(WT)) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [(123)I]beta-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD(T) than in the PD(WT) subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [(123)I]beta-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset.

Tremor in multiple sclerosis is considered to be a persistent and progressive sign. We describe five patients with multiple sclerosis in whom upper limb tremor severity gradually decreased over a period of several years after deep brain stimulation. In every case this attenuation of tremor was accompanied by increasing pyramidal weakness in the relevant upper limb. In two patients this attenuation of tremor remained after stimulation was permanently switched off. In one other patient, where upper limb strength remained normal, tremor severity gradually worsened in spite of continuing stimulation. There was a highly significant difference (p = 0.0007) between the changes in intention tremor severities when the arms with increasing pyramidal weakness (n = 9) were compared to those in which normal strength was retained throughout follow-up period (n = 3); intention tremor decreased in the former and increased in the latter by means of -3.66 and +4.0 points of a 0-10 tremor scale respectively. There was also a significant correlation (0.699; p = 0.0359) between decreasing upper limb strength and decreasing intention tremor severity for the upper limbs of patients that had undergone contralateral DBS.

Objectives: Previous studies suggest that the nigrostriatal dopaminergic transmission is impaired in patients with primary orthostatic tremor., Methods: We used transcranial sonography (TCS) to examine the morphology of the substantia nigra (SN) in four patients with primary orthostatic tremor (OT)., Results: TCS revealed an SN echogenicity in all patients, in three patients unilaterally, in one patient bilaterally., Conclusions: Our data suggest nigrostriatal dopaminergic deficits in OT patients. The exact impact of these dopaminergic deficits on OT generation is unclear.

Recent evidence points to involvement of central nervous system oscillators in Parkinson's disease (PD) rest tremor. It remains unknown whether one or multiple oscillators cause tremor in multiple limbs. Based on the prediction that multiple oscillators would cause low coherence even with similar average frequency, we studied 22 PD patients using accelerometers on multiple limbs. Records were digitized and spectral analysis was performed. Peak frequencies in the arms, legs, and chin were similar, indicating that biomechanical factors did not determine the frequency. Coherence between different axes of individual accelerometers and between different segments of the same limb was high. However, coherence between tremor in different limbs was low. There was no consistent pattern across patients of ipsi- vs. contralateral predominance of coherence. These data suggest that tremor in PD is generated by multiple oscillatory circuits, which operate on similar frequencies.