The Role of Cerebellum and Basal Ganglia Functional Connectivity in Altered Voluntary Movement Execution in Essential Tremor.

Substantial evidence highlights the role of the cerebellum in the pathophysiology of tremor in essential tremor (ET), although its potential involvement in altered movement execution in this condition remains unclear. This study aims to explore potential correlations between the cerebellum and basal ganglia functional connectivity and voluntary movement execution abnormalities in ET, objectively assessed with kinematic techniques. A total of 20 patients diagnosed with ET and 18 healthy subjects were enrolled in this study. Tremor and repetitive finger tapping were recorded using an optoelectronic kinematic system. All participants underwent comprehensive 3T-MRI examinations, including 3D-T1 and blood-oxygen-level dependent (BOLD) sequences during resting state. Morphometric analysis was conducted on the 3D-T1 images, while a seed-based analysis was performed to investigate the resting-state functional connectivity (rsFC) of dorsal and ventral portions of the dentate nucleus and the external and internal segments of the globus pallidus. Finally, potential correlations between rsFC alterations in patients and clinical as well as kinematic scores were assessed. Finger tapping movements were slower in ET than in healthy subjects. Compared to healthy subjects, patients with ET exhibited altered FC of both dentate and globus pallidus with cerebellar, basal ganglia, and cortical areas. Interestingly, both dentate and pallidal FC exhibited positive correlations with movement velocity in patients, differently from that we observed in healthy subjects, indicating the higher the FC, the faster the finger tapping. The findings of this study indicate the possible role of both cerebellum and basal ganglia in the pathophysiology of altered voluntary movement execution in patients with ET.

White and gray matter alterations in de novo PD patients: which matter most?

OBJECTIVES: This paper aimed to identify white matter (WM) and gray matter (GM) abnormalities in a sample of early PD patients, and their correlations with motor and non-motor symptom severity. METHODS: We enrolled 62 de novo PD patients and 31 healthy subjects. Disease severity and non-motor symptom burden were assessed by the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale, respectively. Cognitive performance was assessed using Montreal Cognitive Assessment and Frontal Assessment Battery. All subjects underwent a 3-Tesla MRI protocol. MRI analyses included tract-based spatial statistics, cortical thickness, and subcortical and cerebellar volumetry. RESULTS: In comparison to control subjects, PD patients exhibited lower fractional anisotropy and higher mean, axial, and radial diffusivity in most WM bundles, including corticospinal tracts, the internal and external capsule, the anterior and posterior thalamic radiations, the genu and body of the corpus callosum, cerebellar peduncles, and superior and inferior longitudinal and fronto-occipital fasciculi. Correlations between Montreal Cognitive Assessment scores and fractional anisotropy values in the right posterior thalamic radiation, left superior corona radiata, right inferior-fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral anterior thalamic radiations, and bilateral superior longitudinal fasciculi were found. Smaller cerebellar volumes in early PD patients in the left and right crus I were also found. No GM changes were present in subcortical or cortical regions. CONCLUSION: The combined evaluation of WM and GM in the same patient sample demonstrates that WM microstructural abnormalities precede GM structural changes in early PD patients.

Focal Dystonia: Functional Connectivity Changes in Cerebellar-Basal Ganglia-Cortical Circuit and Preserved Global Functional Architecture.

BACKGROUND AND OBJECTIVES: Neuroimaging studies suggest that changes in the cerebellar-basal ganglia-thalamo-cortical sensorimotor circuit are a pathophysiologic feature of focal dystonia. However, it remains unclear whether structural and functional alterations vary in different forms of focal dystonia. Thus, in patients with cervical dystonia (CD) and blepharospasm (BSP), we aimed to investigate structural damage and resting-state functional alterations using whole-brain and seed-based approaches to test the hypothesis of possible functional connectivity (FC) alterations in specific circuits, including the cerebellum, basal ganglia, and cerebral cortex, in the context of preserved global FC. METHODS: In this cross-sectional study, we applied a multimodal 3T MRI protocol, including 3-dimensional T1-weighted images to extract brain volumes and cortical thickness, and fMRI at rest to study FC of the dentate nucleus and globus pallidus with a seed-based approach and whole-brain FC with a graph theory approach. RESULTS: This study included 33 patients (17 with CD [14 female] age 55.7 ± 10.1 years, 16 with BSP [11 female] age 62.9 ± 8.8 years) and 16 age- and sex-matched healthy controls (HC) (7 female) 54.3 ± 14.3 years if age. Patients with CD, patients with BSP, and HC did not differ in terms of cortical or subcortical volume. Compared to HC, both patients with CD and patients with BSP had a loss of dentate FC anticorrelation with the sensorimotor cortex. Patients with CD and those with BSP showed increased pallidal FC with the cerebellum, supplementary motor area, and prefrontal cortices with respect to HC. Increased dentate FC with the cerebellum and thalamus and increased pallidal FC with the bilateral thalamus, sensorimotor and temporo-occipital cortices, and right putamen were present in patients with CD but not patients with BSP compared to HC. Measures of global FC, that is, global efficiency and small-worldness, did not differ between patients and HC. DISCUSSION: Both patients with CD and those with BSP showed altered dentate and pallidal FC with regions belonging to the integrated cerebellar-basal ganglia-thalamo-cortical sensorimotor circuit, supporting the concept that focal dystonia is a disorder of specific networks and not merely a result of basal ganglia alterations in the context of a preserved whole-brain functional architecture. Differences in functional interplay among specific brain structures may distinguish CD and BSP.

Are Neurophysiological Biomarkers Able to Discriminate Multiple Sclerosis Clinical Subtypes?

Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype.

Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis.

BACKGROUND: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability. OBJECTIVE: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS). METHODS: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I-V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach. RESULTS: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results. CONCLUSION: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.

The Functional Relevance of Diffusion Tensor Imaging in Patients with Degenerative Cervical Myelopathy.

(1) Background: In addition to conventional magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) has been investigated as a potential diagnostic and predictive tool for patients with degenerative cervical myelopathy (DCM). In this preliminary study, we evaluated the use of quantitative DTI in the clinical practice as a possible measure to correlate with upper limbs function. (2) Methods: A total of 11 patients were enrolled in this prospective observational study. Fractional anisotropy (FA) values was extracted from DTI data before and after surgery using a GE Signa 1.5 T MRI scanner. The Nine-Hole Peg Test and a digital dynamometer were used to measure dexterity and hand strength, respectively. (3) Results: We found a significant increase of FA values after surgery, in particular below the most compressed level (p = 0.044) as well as an improvement in postoperative dexterity and hand strength. Postoperative FA values moderately correlate with hand dexterity (r = 0.4272, R2 = 0.0735, p = 0.19 for the right hand; r = 0.2087, R2 = 0.2265, p = 0.53 for the left hand). (4) Conclusion: FA may be used as a marker of myelopathy and could represent a promising diagnostic value in patients affected by DCM. Surgical decompression can improve the clinical outcome of these patients, especially in terms of the control of finger-hand coordination and dexterity.

Practice-dependent motor cortex plasticity is reduced in non-disabled multiple sclerosis patients.

OBJECTIVES: Skill acquisition after motor training involves synaptic long-term potentiation (LTP) in primary motor cortex (M1). In multiple sclerosis (MS), LTP failure ensuing from neuroinflammation could contribute to worsen clinical recovery. We therefore addressed whether practice-dependent plasticity is altered in MS. METHODS: Eighteen relapsing-remitting (RR)-MS patients and eighteen healthy controls performed 600 fast abductions of index finger in 30 blocks of 20 movements. Before and after practice, transcranial magnetic stimulation (TMS) was delivered over the hot spot of the trained first dorsal interosseous muscle. Movements kinematics, measures of cortical excitability, and the input/output curves of motor evoked potentials (MEPs) were assessed. RESULTS: Kinematic variables of movement improved with practice in patients and controls to a similar extent, although patients showed lower MEPs amplitude increase after practice. Practice did not change the difference in resting motor threshold values observed between patients and controls, nor did modulate short-interval intracortical inhibition. Clinical/radiological characteristics were not associated to practice-dependent effects. CONCLUSIONS: Practice-induced reorganization of M1 is altered in non-disabled RR-MS patients, as shown by impaired MEPs modulation after motor learning. SIGNIFICANCE: These findings suggest that in RR-MS physiological mechanisms of practice-dependent plasticity are altered.

White matter rather than gray matter damage characterizes essential tremor.

OBJECTIVES: We investigated changes in gray matter (GM) and white matter (WM) in the whole brain, including both cortical and subcortical structures, and their relationship with tremor severity, psychiatric symptoms, and cognitive impairment in patients affected by essential tremor (ET). METHODS: We studied 19 ET patients and 15 healthy subjects (HS). All the subjects underwent a 3-T MRI study based on 3D-T1 and diffusion tensor images. For the GM analysis, cortical thickness was assessed by using the Computational Anatomy Tool, basal ganglia and thalamus volumes by using the FMRIB software library, and cerebellum lobular volumes by using the spatial unbiased atlas template. For the WM assessment, we performed a voxel-wise analysis by means of tract-based spatial statistics. Patients' tremor severity and psychiatric and cognitive disorders were evaluated by means of standard clinical scales. Neuroimaging data were correlated with clinical scores. RESULTS: We found significantly smaller right and left thalamic volumes in ET patients than in HS, which correlated with cognitive scores. We did not observe any significant differences either in cortical thickness or in cerebellar lobular volumes between patients and HS. WM abnormalities were detected in most hemisphere bundles, particularly in the corticospinal tract, cerebellar peduncles, and corpus callosum. The WM abnormalities significantly correlated with tremor severity, cognitive profile, and depression. CONCLUSION: Our study indicates that ET is characterized by several GM and WM changes of both infra- and supratentorial brain structures. The results may help to better understand mechanisms underlying tremor severity and psychiatric and cognitive impairment in ET. KEY POINTS: • We performed a comprehensive evaluation of gray and white matter in the same sample of patients with essential tremor using recently developed data analysis methods. • Essential tremor is characterized by widespread gray and white matter changes in both infra- and supratentorial brain structures. The results may help to better understand motor and non-motor symptoms in patients with essential tremor.