We performed simultaneous acquisition of EEG-fMRI in seven patients with Unverricht-Lundborg disease (ULD) and in six healthy controls using self-paced finger extension as a motor task. The event-related desynchronization/synchronization (ERD/ERS) analysis showed a greater and more diffuse alpha desynchronization in central regions and a strongly reduced post-movement beta-ERS in patients compared with controls, suggesting a significant dysfunction of the mechanisms regulating active movement and movement end. The event-related hemodynamic response obtained from fMRI showed delayed BOLD peak latency in the contralateral primary motor area suggesting a less efficient activity of the neuronal populations driving fine movements, which are specifically impaired in ULD.
The analysis of the EEG recorded during motor performance (self-paced movement) provides information about the movement-related changes in oscillatory cortical activity. In normal subjects, an amplitude attenuation of specific frequency components (event-related desynchronization, ERD) in the
In Unverricht-Lundborg disease (ULD) patients, voluntary movements are selectively impaired by the presence of action myoclonus [
We simultaneously acquired EEG and fMRI in order to study the spatiotemporal pattern of ERD/ERS resulting from self-paced extension of the index finger in ULD patients and to explore the correlation with hemodynamic changes.
We enrolled 7 right-handed patients (mean age: 29.1
Patient data.
Subject, Age [yrs], Sex | Disease duration [yrs] | AED | Simplified myoclonus rating |
---|---|---|---|
1, 22, f | 12 | VPA, TPM, CLZ | 2 |
2, 26, f | 16 | VPA, CZP | 2 |
3, 36, m | 22 | VPA, LVT, PB | 2 |
4, 25, m | 14 | VPA, CZP, piracetam | 3 |
5, 49, m | 34 | VPA, TPM | 2 |
6, 22, f | 11 | VPA, LVT, TPM | 2 |
7, 24, f | 12 | VPA | 3 |
AED: antiepileptic drugs; VPA: valproate; TPM: topiramate; CLZ: clobazam; CZP: clonazepam LVT: levetiracetam; PB: phenobarbital. Simplified myoclonous rating [
Inside the bore of the scanner, subjects laid supine with their arms relaxed; their head was stabilized with adjustable padded restraints on both sides. They were instructed to remain as still as possible throughout the experiment, to keep their eyes open and avoid blinking during the task. Subjects were asked to perform brisk (i.e., lasting less than one second) self-paced extensions of the right index, with a time interval between the end of a movement and the onset of the following one of about 10 seconds. Each subject was trained for several minutes before the experiment. The movement was monitored by electromyography (EMG) and visual observation.
EEG was acquired using an MR compatible EEG amplifier (SD MRI 32, Micromed, Treviso, Italy) and a cap providing 30
Imaging was performed on a 1.5 T MR scanner (Magnetom Avanto, Siemens AG, Erlangen, Germany). Functional images were acquired with an axial gradient-echo echo-planar sequence (21 slices, TR = 2000 ms, TE = 50 ms,
The scanner provided a trigger signal corresponding to the excitation of the first slice of each volume, which was recorded by the EEG system enabling real-time artefact removal, making possible to monitor the EEG signal as well as task performance through EMG.
The imaging gradient artefact and the ballistocardiogram were digitally removed from the EEG using an adaptive filter [
Movement onset was determined by the beginning of the burst of EMG activity. EEG data were epoched four seconds before and three seconds after movement onset. Epochs with artefacts, incomplete muscle relaxation between movements, and intertrial interval shorter than 8 seconds were excluded from the analysis. A reference period at rest, from 3500 to 2500 ms before movement onset, was considered. Each trial was digitally band-pass filtered from 1 Hz below to 1 Hz above the individual frequencies of the most movement-sensitive power peaks in
The statistical significance of the differences between the mean power observed during the reference period and that measured during the subsequent 125-milisecond intervals was expressed as a probability value using Wilcoxon’s signed rank test. The power changes were considered significant when the
The fMRI data were analyzed by means of the SPM5 software (Wellcome Neuroimaging Dept., Institute of Neurology, London, UK). Preprocessing included three-dimensional motion correction, slice-timing correction, Gaussian smoothing, and normalization into MNI (Montreal Neurological Institute) space. First-level analysis was performed by general linear model (GLM), using the event function from EMG, convolved with the canonical hemodynamic response function, as regressor. Three-dimensional regions of interest (ROIs) were manually drawn for each subject by an experienced operator on the contralateral and ipsilateral primary motor areas as well as on the contralateral supplementary motor area. The average signal time-course was obtained, and the amplitude and latency of the peak of the fitted hemodynamic response were measured.
For statistical analysis, the Mann-Whitney
All subjects performed the motor task well: the mean movement duration was on average longer in the patients group (535.8
In all subjects
Statistical analysis of ERD/ERS values assessed in subsequent epochs.
Alpha ERD | F4 | C4 | P4 | F3 | C3 | P3 | Fz | Cz | Pz |
---|---|---|---|---|---|---|---|---|---|
— | 0.015 | — | — | — | — | — | 0.032 | ||
— | 0.010 | — | — | — | 0.042 | — | — | ||
— | 0.003 | — | — | — | — | — | 0.003 | ||
0.045 | 0.010 | — | — | 0.015 | 0.004 | 0.007 | 0.003 | 0.032 | |
— | — | — | — | — | — | — | 0.007 | ||
Beta ERD/ER | F4 | C4 | P4 | F3 | C3 | P3 | Fz | Cz | Pz |
0.032 | 0.007 | 0.032 | 0.015 | ||||||
0.032 | 0.022 | 0.012 | 0.010 |
Results of
Color maps showing the grand average of
The expected postmovement
Color maps showing the grand average of
The peak amplitude of the hemodynamic response was comparable in controls and patients in the contralateral (0.56
Time-courses of the hemodynamic response for controls (blue) and patients (red).
The changes found in ERD/ERS pattern of ULD subjects suggest an increased activation of motor cortex during movement planning and a significant reduction of post-excitatory inhibition. These data overlap those obtained in our previous study [
Differently from ERD/ERS, fMRI did not highlight any clear difference in the amplitude of cortical activation in ULD patient with respect to controls. The hemodynamic response analysis allowed detecting subtle but significant effects on the time course of activation that showed a delayed peak in ULD patients. This finding, together with the slightly longer duration of individual movements in patients with respect to controls, may agree with a less efficient performance of the motor cortex in this disorder, characterized by a prominent motor dysfunction resulting in action activated myoclonic jerks. Based on the present data, the ERD/ERS changes detectable on EEG appear to be more reliable with respect to fMRI in detecting the cortical dysfunction characterizing ULD patients, being able to detect and quantify the functional changes of the neuronal pools impaired by the disease. A final conclusion cannot however be reached because of the small number of observation that limited the statistical power; moreover, further analyses exploring the functional connectivity during motor performance may allow to better detect subtle changes in the BOLD signals [
The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant agreement no. HEALTH-F5-2008-201076.