Unilateral pallidotomy has gained popularity in treating the motor symptoms of Parkinson's disease. We present the results of a 2-year post-pallidotomy follow-up study. Using the Unified Parkinson's Disease... more
Unilateral pallidotomy has gained popularity in treating the motor symptoms of Parkinson's disease. We present the results of a 2-year post-pallidotomy follow-up study. Using the Unified Parkinson's Disease Rating Scale (UPDRS), the Goetz dyskinesia scale and the Purdue Pegboard Test (PPBT), we evaluated 20 patients at regular intervals both off and on medications for 2 years post-pallidotomy. There were no significant changes in the dosages of antiparkinsonian medications from 3 months pre-pallidotomy to 2 years post-pallidotomy. On the side contralateral to the operation, the improvements were preserved in 'on'-state dyskinesia (83% reduction from pre-pallidotomy to 2 years post-pallidotomy, P < 0.001) and 'off'-state tremor (90% reduction from pre-pallidotomy to 2 years post-pallidotomy, P = 0.005). There were no statistically significant differences between pre-pallidotomy scores and those at 2 years post-pallidotomy in ipsilateral dyskinesia, axial dyskinesia, 'off'- or 'on'-state PPBT, 'off'-state Activities of Daily Living (ADL) and 'off'-state gait and postural stability. After 2 years, the 'on'-state ADL scores worsened by 75%, compared with pre-pallidotomy (P = 0.005). We conclude that 2 years after pallidotomy, the improvements in dyskinesia and tremor on the side contralateral to pallidotomy are preserved, while the initial improvements in most other deficits disappear, either because of progression of pathology or loss of the early efficacy achieved by surgery.
This paper presents a two stage algorithm for real-time estimation of instantaneous tremor parameters from gyroscope recordings. Gyroscopes possess the advantage of providing directly joint rotational speed, overcoming the limitations of... more
This paper presents a two stage algorithm for real-time estimation of instantaneous tremor parameters from gyroscope recordings. Gyroscopes possess the advantage of providing directly joint rotational speed, overcoming the limitations of traditional tremor recording based on accelerometers. The proposed algorithm first extracts tremor patterns from raw angular data, and afterwards estimates its instantaneous amplitude and frequency. Real-time separation of voluntary and tremorous motion relies on their different frequency contents, whereas tremor modelling is based on an adaptive LMS algorithm and a Kalman filter. Tremor parameters will be employed to drive a neuroprosthesis for tremor suppression based on biomechanical loading.
Tremor constitutes the most common movement disorder; in fact 14.5% of population between 50 to 89 years old suffers from it. Moreover, 65% of patients with upper limb tremor report disability when performing their activities of daily... more
Tremor constitutes the most common movement disorder; in fact 14.5% of population between 50 to 89 years old suffers from it. Moreover, 65% of patients with upper limb tremor report disability when performing their activities of daily living (ADL). Unfortunately, 25% of patients do not respond to drugs or neurosurgery. In this regard, TREMOR project proposes functional compensation of upper limb tremors with a soft wearable robot that applies biomechanical loads through functional electrical stimulation (FES) of muscles. This wearable robot is driven by a Brain Neural Computer Interface (BNCI). This paper presents a multimodal BCI to assess generation, transmission and execution of both volitional and tremorous movements based on electroencephalography (EEG), electromyography (EMG) and inertial sensors (IMUs). These signals are combined to obtain: 1) the intention to perform a voluntary movement from cortical activity (EEG), 2) tremor onset, and an estimation of tremor frequency fro...
Two main findings emerged from our study. First, AED users exhibited a higher propensity of switch-back to branded drugs compared to patients treated with other chronic-disease drugs. Secondly, the use of generic lamotrigine was... more
Two main findings emerged from our study. First, AED users exhibited a higher propensity of switch-back to branded drugs compared to patients treated with other chronic-disease drugs. Secondly, the use of generic lamotrigine was associated with increased physician ...
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise... more
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1).
A double-blind sham-controlled study demonstrated that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) provided relief of motor symptoms in patients with... more
A double-blind sham-controlled study demonstrated that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) provided relief of motor symptoms in patients with Parkinson's disease (PD). However, it remains to be determined which parkinsonian symptoms were improved by this treatment. Subanalysis of Unified Parkinson Disease Rating Scale revealed that rTMS over SMA significantly improved bradykinesia in PD. Results support the hypothesis that neuronal activity of SMA was profoundly associated with hypokinetic symptoms in PD.
Tremor in Parkinson's disease... more
Tremor in Parkinson's disease (PD) is generated by an oscillatory neuronal network consisting of cortex, basal ganglia and thalamus. The subthalamic nucleus (STN) which is part of the basal ganglia is of particular interest, since deep brain stimulation of the STN is an effective treatment for PD including Parkinsonian tremor. It is controversial if and how the STN contributes to tremor generation. In this study, we analyze neuronal STN activity in seven patients with Parkinsonian rest tremor who underwent stereotactic surgery for deep brain stimulation. Surface EMG was recorded from the wrist flexors and extensors. Simultaneously, neuronal spike activity was registered in different depths of the STN using an array of five microelectrodes. After spike-sorting, spectral coherence was analyzed between spike activity of STN neurons and tremor activity. Significant coherence at the tremor frequency was detected between EMG and neuronal STN activity in 76 out of 145 neurons (52.4%). In contrast, coherence in the beta band occurred only in 10 out of 145 neurons (6.9%). Tremor-coherent STN activity was widely distributed over the STN being more frequent in its dorsal parts (70.8-88.9%) than in its ventral parts (25.0-48.0%). Our results suggest that synchronous neuronal STN activity at the tremor frequency contributes to the pathogenesis of Parkinsonian tremor. The wide-spread spatial distribution of tremor-coherent spike activity argues for the recruitment of an extended network of subthalamic neurons for tremor generation.
The objective of the study was to investigate the interplay between involuntary tremulous activities and task performance under volitional control for patients with Parkinson's disease (PD) during position tracking. A volunteer sample... more
The objective of the study was to investigate the interplay between involuntary tremulous activities and task performance under volitional control for patients with Parkinson's disease (PD) during position tracking. A volunteer sample of nine untreated patients and nine age-matched healthy subjects participated in this study. They performed a sinusoidal tracking maneuver with a shoulder and a static pointing task; meanwhile, a position trace of the index and accelerometer data in the upper limb were recorded to characterize tracking performance and postural-kinetic tremors. In reference to postural tremor, the kinetic tremor of control subjects during tracking was considerably modulated, leading to a lower regularity and greater spectral deviation. In contrast, patients with PD demonstrated greater postural and kinetic tremors than control subjects, and tremulous movements of the patients were comparatively task-invariant. The prominent coherence peak, which occurred at 8-12 Hz ...
The time- and frequency-dependent patterns of standing balance centre of pressure (COP) and finger postural/resting tremor of 12 older individuals and eight age-matched Parkinsonian (PD) participants (on/off medication) were investigated.... more
The time- and frequency-dependent patterns of standing balance centre of pressure (COP) and finger postural/resting tremor of 12 older individuals and eight age-matched Parkinsonian (PD) participants (on/off medication) were investigated. Tremor and COP data were analysed using measures of signal amplitude (RMS), time-dependent structure (approximate entropy, ApEn), time-frequency analysis and synchrony (Cross ApEn). Results showed that the PD individuals had significantly greater tremor amplitude and COP excursions in comparison to controls. Differences in the time-dependent structure were also observed between groups. In comparison to the elderly, the resting/postural tremor output of the PD subjects was more regular (lower ApEn). However, for the postural measures, a reciprocal pattern was observed with the COP being more complex (higher ApEn). All group differences were magnified when the PD individuals were off their medication. There was also greater synchrony between tremor and postural sway for the PD individuals, indicating a high degree of association between these motor outputs. These results are consistent with the view that the neural signal driving the enhanced limb tremor in PD is propagated throughout the motor system, consequently emerging within the postural sway dynamics. This commonality of motor output may be a contributing factor in the differential pattern in the dynamics of effector signal structure in PD as a function of task.
The major motor disturbances in Parkinson's disease are thought to be caused by overactivity of the internal segment of the globus pallidus (GPi), in large part due to excessive drive from the subthalamic nucleus. The excessive... more
The major motor disturbances in Parkinson's disease are thought to be caused by overactivity of the internal segment of the globus pallidus (GPi), in large part due to excessive drive from the subthalamic nucleus. The excessive inhibitory activity of GPi is thought to "brake' the motor thalamus and the cortical motor system to produce the slowness, rigidity, and poverty of movement characteristic of parkinsonian states. To test the hypothesis that direct reduction of Gpi activity can improve motor function, we studied the effect of GPi pallidotomy in 14 patients. The location of the GPi nucleus was confirmed by microelectrode recording before lesion creation. Standardised videotape recordings before and after operation were randomised and scored by a "blinded' evaluator. 6 months after surgery, total motor score in the "off" state had improved by 30% and the total akinesia score by 33%. The gait score in the "off" state improved by 15% and a composite postural instability and gait score by 23%. After surgery there was almost total elimination of drug-induced involuntary movements (dyskinesias), with a 92% reduction on the side contralateral to the pallidotomy. No patient had visual or corticospinal complications. In these patients GPi pallidotomy enhanced motor performance, reduced akinesia, improved gait, and eliminated the neural elements responsible for levodopa-induced dyskinesias.
The study developed a novel multi-scale model for simulating the surface electromyogram (EMG) of an antagonistic pair of muscles during pathological tremor. By combining and expanding mathematical descriptions from motor units to limb... more
The study developed a novel multi-scale model for simulating the surface electromyogram (EMG) of an antagonistic pair of muscles during pathological tremor. By combining and expanding mathematical descriptions from motor units to limb kinematics, the model constitutes the first attempt to simulate the surface EMG and the individual motor unit activity under the influence of descending voluntary command, oscillatory noise in the descending signal, and afferent feedback when controlling a freely moving limb to achieve a predefined angular trajectory. The oscillatory noise was adjusted to simulate various types of pathological tremor. The simulations replicated previously reported experimental results for the power spectral density of the surface EMG, the angular velocity of the limb, and single motor unit activity. The model provides a powerful tool for extracting information about how the surface EMG can be used to describe tremor in various conditions, including different tremor frequencies and intensities, that cannot be achieved solely with experimental approaches.
Hereditary hyperekplexia is caused by disinhibition of motoneurons resulting from mutations in the ionotropic receptor for the inhibitory neurotransmitter glycine (GlyR). To study the pathomechanisms involved in vivo, we generated and... more
Hereditary hyperekplexia is caused by disinhibition of motoneurons resulting from mutations in the ionotropic receptor for the inhibitory neurotransmitter glycine (GlyR). To study the pathomechanisms involved in vivo, we generated and analyzed transgenic mice expressing the hyperekplexia-specific dominant mutant human GlyR alpha1 subunit 271Q. Tg271Q transgenic mice, in contrast to transgenic animals expressing a wild-type human alpha1 subunit (tg271R), display a dramatic phenotype similar to spontaneous and engineered mouse mutations expressing reduced levels of GlyR. Electrophysiological analysis in the ventral horn of the spinal cord of tg271Q mice revealed a diminished GlyR transmission. Intriguingly, an even larger reduction was found for GABA(A)-receptor-mediated inhibitory transmission, indicating that the expression of this disease gene not only affects the glycinergic system but also leads to a drastic downregulation of the entire postsynaptic inhibition. Therefore, the tra...
The following study included 5 Wilson's disease (WD) patients showing a right-sided postural forearm tremor (4-6 Hz) and addressed the question of whether the primary motor cortex (M1) is involved in tremor generation. Using a... more
The following study included 5 Wilson's disease (WD) patients showing a right-sided postural forearm tremor (4-6 Hz) and addressed the question of whether the primary motor cortex (M1) is involved in tremor generation. Using a 122-channel whole-head neuromagnetometer and surface electromyogram (EMG), we investigated cerebromuscular coupling. Postural tremor was observed in a sustained 45-degree posture of the right-sided forearm. Data were analyzed using dynamic imaging of coherent sources (DICS), revealing cerebromuscular coupling between EMG and cerebral activity. Coherent sources were superimposed on individual high-resolution T1-weighted magnetic resonance images (MRI). Phase lags between EMG and cerebral areas showing strongest coherence were determined by means of a Hilbert transform of both signals. In all patients, postural tremor was associated with strong coherence between tremor EMG and activity in contralateral primary sensorimotor cortex (S1/M1) at tremor or double...