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.

Clinical and kinematic characterization of parkinsonian soft signs in essential tremor.

BACKGROUND: Subtle parkinsonian signs, i.e., rest tremor and bradykinesia, are considered soft signs for defining essential tremor (ET) plus. OBJECTIVES: Our study aimed to further characterize subtle parkinsonian signs in a relatively large sample of ET patients from a clinical and neurophysiological perspective. METHODS: We employed clinical scales and kinematic techniques to assess a sample of 82 ET patients. Eighty healthy controls matched for gender and age were also included. The primary focus of our study was to conduct a comparative analysis of ET patients (without any soft signs) and ET-plus patients with rest tremor and/or bradykinesia. Additionally, we investigated the asymmetry and side concordance of these soft signs. RESULTS: In ET-plus patients with parkinsonian soft signs (56.10% of the sample), rest tremor was clinically observed in 41.30% of cases, bradykinesia in 30.43%, and rest tremor plus bradykinesia in 28.26%. Patients with rest tremor had more severe and widespread action tremor than other patients. Furthermore, we observed a positive correlation between the amplitude of action and rest tremor. Most ET-plus patients had an asymmetry of rest tremor and bradykinesia. There was no side concordance between these soft signs, as confirmed through both clinical examination and kinematic evaluation. CONCLUSIONS: Rest tremor and bradykinesia are frequently observed in ET and are often asymmetric but not concordant. Our findings provide a better insight into the phenomenology of ET and suggest that the parkinsonian soft signs (rest tremor and bradykinesia) in ET-plus may originate from distinct pathophysiological mechanisms.

Interhemispheric imbalance and bradykinesia features in Parkinson's disease.

In patients with Parkinson's disease, the connectivity between the two primary motor cortices may be altered. However, the correlation between asymmetries of abnormal interhemispheric connections and bradykinesia features has not been investigated. Furthermore, the potential effects of dopaminergic medications on this issue remain largely unclear. The aim of the present study is to investigate the interhemispheric connections in Parkinson's disease by transcranial magnetic stimulation and explore the potential relationship between interhemispheric inhibition and bradykinesia feature asymmetry in patients. Additionally, we examined the impact of dopaminergic therapy on neurophysiological and motor characteristics. Short- and long-latency interhemispheric inhibition was measured in 18 Parkinson's disease patients and 18 healthy controls, bilaterally. We also assessed the corticospinal and intracortical excitability of both primary motor cortices. We conducted an objective analysis of finger-tapping from both hands. Correlation analyses were performed to explore potential relationships among clinical, transcranial magnetic stimulation and kinematic data in patients. We found that short- and long-latency interhemispheric inhibition was reduced (less inhibition) from both hemispheres in patients than controls. Compared to controls, finger-tapping movements in patients were slower, more irregular, of smaller amplitudes and characterized by a progressive amplitude reduction during movement repetition (sequence effect). Among Parkinson's disease patients, the degree of short-latency interhemispheric inhibition imbalance towards the less affected primary motor cortex correlated with the global clinical motor scores, as well as with the sequence effect on the most affected hand. The greater the interhemispheric inhibition imbalance towards the less affected hemisphere (i.e. less inhibition from the less to the most affected primary motor cortex than that measured from the most to the less affected primary motor cortex), the more severe the bradykinesia in patients. In conclusion, the inhibitory connections between the two primary motor cortices in Parkinson's disease are reduced. The interhemispheric disinhibition of the primary motor cortex may have a role in the pathophysiology of specific bradykinesia features in patients, i.e. the sequence effect.

Theta-tACS modulates cerebellar-related motor functions and cerebellar-cortical connectivity.

OBJECTIVE: To evaluate the effects of cerebellar transcranial alternating current stimulation (tACS) delivered at cerebellar-resonant frequencies, i.e., theta (θ) and gamma (γ), on upper limb motor performance and cerebellum-primary motor cortex (M1) connectivity, as assessed by cerebellar-brain inhibition (CBI), in healthy subjects. METHODS: Participants underwent cerebellar-tACS while performing three cerebellar-dependent motor tasks: (i) rhythmic finger-tapping, (ii) arm reaching-to-grasp ('grasping') and (iii) arm reaching-to-point ('pointing') an object. Also, we evaluated possible changes in CBI during cerebellar-tACS. RESULTS: θ-tACS decreased movement regularity during the tapping task and increased the duration of the pointing task compared to sham- and γ-tACS. Additionally, θ-tACS increased the CBI effectiveness (greater inhibition). The effect of θ-tACS on movement rhythm correlated with CBI changes and less tapping regularity corresponded to greater CBI. CONCLUSIONS: Cerebellar-tACS delivered at the θ frequency modulates cerebellar-related motor behavior and this effect is, at least in part, mediated by changes in the cerebellar inhibitory output onto M1. The effects of θ-tACS may be due to the modulation of cerebellar neurons that resonate to the θ rhythm. SIGNIFICANCE: These findings contribute to a better understanding of the physiological mechanisms of motor control and provide new evidence on cerebellar non-invasive brain stimulation.

Objective assessment of the effects of opicapone in Parkinson's disease through kinematic analysis.

BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

Facial emotion expressivity in patients with Parkinson's and Alzheimer's disease.

Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders with some overlapping clinical features. Hypomimia (reduced facial expressivity) is a prominent sign of PD and it is also present in AD. However, no study has experimentally assessed hypomimia in AD and compared facial expressivity between PD and AD patients. We compared facial emotion expressivity in patients with PD, AD, and healthy controls (HCs). Twenty-four PD patients, 24 AD patients and 24 HCs were videotaped during neutral facial expressions and while posing six facial emotions (anger, surprise, disgust, fear, happiness, and sadness). Fifteen raters were asked to evaluate the videos using MDS-UPDRS-III (item 3.2) and to identify the corresponding emotion from a seven-forced-choice response format. We measured the percentage of accuracy, the reaction time (RT), and the confidence level (CL) in the perceived accuracy of the raters' responses. We found the highest MDS-UPDRS 3.2 scores in PD, and higher in AD than HCs. When evaluating the posed expression captures, raters identified a lower percentage of correct answers in the PD and AD groups than HCs. There was no difference in raters' response accuracy between the PD and AD. No difference was observed in RT and CL data between groups. Hypomimia in patients correlated positively with the global MDS-UPDRS-III and negatively with Mini Mental State Examination scores. PD and AD patients have a similar pattern of reduced facial emotion expressivity compared to controls. These findings hold potential pathophysiological and clinical implications.

Subtle changes in central dopaminergic tone underlie bradykinesia in essential tremor.

INTRODUCTION: In this research, our primary objective was to explore the correlation between basal ganglia dopaminergic neurotransmission, assessed using 123I-FP-CIT (DAT-SPECT), and finger movements abnormalities in patients with essential tremor (ET) and Parkinson's disease (PD). METHODS: We enrolled 16 patients with ET, 17 with PD, and 18 healthy controls (HC). Each participant underwent comprehensive clinical evaluations, kinematic assessments of finger tapping. ET and PD patients underwent DAT-SPECT imaging. The DAT-SPECT scans were subjected to both visual and semi-quantitative analysis using DaTQUANT®. We then investigated the correlations between the clinical, kinematic, and DAT-SPECT data, in patients. RESULTS: Our findings confirm that individuals with ET exhibited slower finger tapping than HC. Visual evaluation of radiotracer uptake in both striata demonstrated normal levels within the ET patient cohort, while PD patients displayed reduced uptake. However, there was notable heterogeneity in the quantification of uptake within the striata among ET patients. Additionally, we found a correlation between the amount of radiotracer uptake in the striatum and movement velocity during finger tapping in patients. Specifically, lower radioligand uptake corresponded to decreased movement velocity (ET: coef. = 0.53, p-adj = 0.03; PD: coef. = 0.59, p-adj = 0.01). CONCLUSION: The study's findings suggest a potential link between subtle changes in central dopaminergic tone and altered voluntary movement execution, in ET. These results provide further insights into the pathophysiology of ET. However, longitudinal studies are essential to determine whether the slight reduction in dopaminergic tone observed in ET patients represents a distinct subtype of the disease or could serve as a predictor for the clinical progression into PD.

Short-term plasticity of the motor cortex compensates for bradykinesia in Parkinson's disease.

Patients with Parkinson's disease (PD) show impaired short-term potentiation (STP) mechanisms in the primary motor cortex (M1). However, the role played by this neurophysiological abnormality in bradykinesia pathophysiology is unknown. In this study, we used a multimodal neuromodulation approach to test whether defective STP contributes to bradykinesia. We evaluated STP by measuring motor-evoked potential facilitation during 5 Hz-repetitive transcranial magnetic stimulation (rTMS) and assessed repetitive finger tapping movements through kinematic techniques. Also, we used transcranial alternating current stimulation (tACS) to drive M1 oscillations and experimentally modulate bradykinesia. STP was assessed during tACS delivered at beta (ß) and gamma (γ) frequency, and during sham-tACS. Data were compared to those recorded in a group of healthy subjects. In PD, we found that STP was impaired during sham- and γ-tACS, while it was restored during ß-tACS. Importantly, the degree of STP impairment was associated with the severity of movement slowness and amplitude reduction. Moreover, ß-tACS-related improvements in STP were linked to changes in movement slowness and intracortical GABA-A-ergic inhibition during stimulation, as assessed by short-interval intracortical inhibition (SICI). Patients with prominent STP amelioration had greater SICI reduction (cortical disinhibition) and less slowness worsening during ß-tACS. Dopaminergic medications did not modify ß-tACS effects. These data demonstrate that abnormal STP processes are involved in bradykinesia pathophysiology and return to normal levels when ß oscillations increase. STP changes are likely mediated by modifications in GABA-A-ergic intracortical circuits and may represent a compensatory mechanism against ß-induced bradykinesia in PD.

Relationship between the interlimb transfer of a visuomotor learning task and interhemispheric inhibition in healthy humans.

The "interlimb transfer" phenomenon consists of improved performance of the trained and untrained contralateral limbs after unilateral motor practice. We here assessed whether a visuomotor learning task can be transferred from one hemisphere to the other, whether this occurs symmetrically, and the cortical neurophysiological correlates of this phenomenon, focusing on interhemispheric connectivity measures. We enrolled 33 healthy subjects (age range: 24-73 years). Participants underwent two randomized sessions, which investigated the transfer from the dominant to the nondominant hand and vice versa. Measures of cortical and intracortical excitability and interhemispheric inhibition were assessed through transcranial magnetic stimulation before and after a visuomotor task. The execution of the visuomotor task led to an improvement in motor performance with the dominant and nondominant hands and induced a decrease in intracortical inhibition in the trained hemisphere. Participants were also able to transfer the visuomotor learned skill. The interlimb transfer, however, only occurred from the dominant to the nondominant hand and positively correlated with individual learning-related changes in interhemispheric inhibition. We here demonstrated that the "interlimb transfer" of a visuomotor task occurs asymmetrically and relates to the modulation of specific inhibitory interhemispheric connections. The study results have pathophysiological, clinical, and neuro-rehabilitative implications.

Tremor and Movement Slowness Are Two Unrelated Adverse Effects Induced by Valproate Intake.

Background: To date, only a few clinical and neurophysiological studies have assessed the features of valproate-induced tremor (VIT), and whether valproate (VPA) affects voluntary movements is underinvestigated. Objective: To better characterize the clinical and neurophysiological features of VIT in patients with epilepsy and the effect of VPA on the execution of voluntary movement. Methods: We tested 29 patients with VIT (13 taking VPA alone and 16 taking VPA plus other antiepileptics). Patients underwent a neurological examination, video recordings and kinematic assessments of postural, kinetic, and resting upper limb tremor using a motion analysis system. Movement execution was tested by kinematic assessment of finger tapping. Data of patients with VIT were compared with those of 13 patients with epilepsy taking VPA but without tremor, 13 patients with epilepsy who were not on VPA treatment, 20 patients with Parkinson's disease (PD), and 20 healthy controls (HCs). Results: Clinical and kinematic evaluations showed that tremor in patients taking VPA alone was less severe than tremor in patients taking VPA plus other antiepileptics. All patients taking VPA, regardless of the presence of tremor, performed slower finger tapping compared with HCs, similar to what was observed in PD, although with no sequence effect. Patients with epilepsy without VPA showed a normal motor performance. Conclusions: Tremor and movement slowness are motor signs induced by VPA. VIT severity is exacerbated when VPA is taken in combination with other antiepileptics. VPA-induced slowness occurs regardless of tremor, may precede tremor development, and is not attributed to epilepsy.

Validating a Portable Device for Blinking Analyses through Laboratory Neurophysiological Techniques.

Blinking analysis contributes to the understanding of physiological mechanisms in healthy subjects as well as the pathophysiological mechanisms of neurological diseases. To date, blinking is assessed by various neurophysiological techniques, including electromyographic (EMG) recordings and optoelectronic motion analysis. We recorded eye-blink kinematics with a new portable device, the EyeStat (Generation 3, blinktbi, Inc., Charleston, SC, USA), and compared the measurements with data obtained using traditional laboratory-based techniques. Sixteen healthy adults underwent voluntary, spontaneous, and reflex blinking recordings using the EyeStat device and the SMART motion analysis system (BTS, Milan, Italy). During the blinking recordings, the EMG activity was recorded from the orbicularis oculi muscles using surface electrodes. The blinking data were analyzed through dedicated software and evaluated with repeated-measure analyses of variance. The Pearson's product-moment correlation coefficient served to assess possible associations between the EyeStat device, the SMART motion system, and the EMG data. We found that the EMG data collected during the EyeStat and SMART system recordings did not differ. The blinking data recorded with the EyeStat showed a linear relationship with the results obtained with the SMART system (r ranging from 0.85 to 0.57; p ranging from <0.001 to 0.02). These results demonstrate a high accuracy and reliability of a blinking analysis through this portable device, compared with standard techniques. EyeStat may make it easier to record blinking in research activities and in daily clinical practice, thus allowing large-scale studies in healthy subjects and patients with neurological diseases in an outpatient clinic setting.

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders.

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

Driving motor cortex oscillations modulates bradykinesia in Parkinson's disease.

In patients with Parkinson's disease, beta (ß) and gamma (γ) oscillations are altered in the basal ganglia, and this abnormality contributes to the pathophysiology of bradykinesia. However, it is unclear whether ß and γ rhythms at the primary motor cortex (M1) level influence bradykinesia. Transcranial alternating current stimulation (tACS) can modulate cortical rhythms by entraining endogenous oscillations. We tested whether ß- and γ-tACS on M1 modulate bradykinesia in patients with Parkinson's disease by analysing the kinematic features of repetitive finger tapping, including movement amplitude, velocity and sequence effect, recorded during ß-, γ- and sham tACS. We also verified whether possible tACS-induced bradykinesia changes depended on modifications in specific M1 circuits, as assessed by short-interval intracortical inhibition and short-latency afferent inhibition. Patients were studied OFF and ON dopaminergic therapy. Results were compared to those obtained in a group of healthy subjects. In patients, movement velocity significantly worsened during ß-tACS and movement amplitude improved during γ-tACS, while the sequence effect did not change. In addition, short-latency afferent inhibition decreased (reduced inhibition) during ß-tACS and short-interval intracortical inhibition decreased during both γ- and ß-tACS in Parkinson's disease. The effects of tACS were comparable between OFF and ON sessions. In patients OFF therapy, the degree of short-interval intracortical inhibition modulation during ß- and γ-tACS correlated with movement velocity and amplitude changes. Moreover, there was a positive correlation between the effect of γ-tACS on movement amplitude and motor symptoms severity. Our results show that cortical ß and γ oscillations are relevant in the pathophysiology of bradykinesia in Parkinson's disease and that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia. In conclusion, abnormal oscillations at the M1 level of the basal ganglia-thalamo-cortical network play a relevant role in the pathophysiology of bradykinesia in Parkinson's disease.

Bradykinesia in motoneuron diseases.

OBJECTIVE: Only few studies investigated voluntary movement abnormalities in patients with motoneuron diseases (MNDs) or their neurophysiological correlates. We aimed to kinematically assess finger tapping abnormalities in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), as compared to healthy controls (HCs), and their relationship with motoneuron involvement. METHODS: Fourteen ALS and 5 PLS patients were enrolled. Finger tapping was assessed by a motion analysis system. Patients underwent a central motor conduction time assessment, a motor nerve conduction study, and needle electromyography. Data were compared to those of 79 HCs using non-parametric tests. Possible relationships between clinical, kinematic, and neurophysiological data were assessed in patients. RESULTS: As a major finding, ALS and PLS patients performed finger tapping slower than HCs. In both conditions, movement slowness correlated with muscle strength. In ALS, movement slowness also correlated with the amplitude of the compound muscle action potential recorded from the muscles involved in the task and with denervation activity. No correlations were found between slowness, measures of upper motoneuron involvement, and other clinical and neurophysiological data. CONCLUSIONS: This study provides novel information on voluntary movement abnormalities in MNDs. SIGNIFICANCE: The results highlight the pathophysiological role of motoneurons in generating movement slowness.

Effects of Transcranial Ultrasound Stimulation on Trigeminal Blink Reflex Excitability.

Recent evidence indicates that transcranial ultrasound stimulation (TUS) modulates sensorimotor cortex excitability. However, no study has assessed possible TUS effects on the excitability of deeper brain areas, such as the brainstem. In this study, we investigated whether TUS delivered on the substantia nigra, superior colliculus, and nucleus raphe magnus modulates the excitability of trigeminal blink reflex, a reliable neurophysiological technique to assess brainstem functions in humans. The recovery cycle of the trigeminal blink reflex (interstimulus intervals of 250 and 500 ms) was tested before (T0), and 3 (T1) and 30 min (T2) after TUS. The effects of substantia nigra-TUS, superior colliculus-TUS, nucleus raphe magnus-TUS and sham-TUS were assessed in separate and randomized sessions. In the superior colliculus-TUS session, the conditioned R2 area increased at T1 compared with T0, while T2 and T0 values did not differ. Results were independent of the interstimulus intervals tested and were not related to trigeminal blink reflex baseline (T0) excitability. Conversely, the conditioned R2 area was comparable at T0, T1, and T2 in the nucleus raphe magnus-TUS and substantia nigra-TUS sessions. Our findings demonstrate that the excitability of brainstem circuits, as evaluated by testing the recovery cycle of the trigeminal blink reflex, can be increased by TUS. This result may reflect the modulation of inhibitory interneurons within the superior colliculus.