Original ArticleA study for the mechanism of sensory disorder in restless legs syndrome based on magnetoencephalography
Introduction
Restless legs syndrome also known as Willis-Ekbom's disease, has a relatively high incidence rate, but is often misdiagnosed [1]. RLS patients often have objectively painful sensations. However, apart from some mild demyelination-like lesions in the brain white matter [2], [3], [4], there have been no reported validated structural lesions in brain gray matter, indicating a brain functional disorder is the main factor in RLS. Functional brain imaging shows that some brain network deregulatory features exist in RLS patients [5], [6], [7].
From the electrophysiological perspective, RLS should be regarded as a complex sensorimotor disorder. Cortical, subcortical, spinal cord, and peripheral nerve generators are all involved in a network disorder, which results in enhanced excitability and/or decreased inhibition [8]. Studies indicate that the brain network functional hub spots are mainly located in substantia nigra Area A8 and A9, hypothalamus Area A11 and thalamus [9], [10], [11]. These areas’ abnormal functions are probably associated with iron deficiency in the central nervous system and deregulation of neural transmitter systems.
The iron deficiency in the central nervous system is the main symptom of RLS, it causes a demyelination in brain white matter, and interferes with neural transmitter systems as well as monoamine metabolism. Glutamate and GABA [12] homeostasis are all influenced by the brain's iron status [13]. Possible reasons causing the iron deficiency are the genetic susceptibility of some genes, inadequate uptake, inflammation regulation, and epigenetic mutations [14], [15], [16]. Detailed pathogenesis of RLS is complicated, and researchers could only speculate that it closely related to abnormal dopamine uptake and/or delivery systems' decline. However, there is still no model for a deeper understanding of RLS's mechanism [17], [18], [19].
Currently it is believed that a spinal cord-involved neural network disorder is the main pathogenesis of RLS. Electrophysiological research shows that spinal hyperexcitability causes the periodic leg movements (PLMs) in RLS; RLS patients always have a low pain threshold with associated lower limb pain, which suggests the presence of sensitization in the central nervous system (spinal cord or superspinal [8]); diencephalic-spinal dysfunction may result in the disinhibition of sensory inputs to the dorsal horn. Levodopa is secreted from the A11 region and participates in sensory-motor integration in the spinal cord. Supplementation with exogenous levodopa can improve sensorimotor symptoms [20]. Conversely, active or passive movement of the limbs can increase the sensory gain control of the spinal cord and filter too much redundant information to the center, in order to reduce the feeling of conflict and relieve the sensory symptoms [21].
RLS's sensory symptoms might be the core of its pathogenesis, since abnormal activity in basic sensorimotor and other related brain systems have been found [22]. Some high-level brain regions related to attention and alertness are also involved. Abnormal electrical activity in the brain probably could be used as the electrophysiological endophenotype to describe RLS's pathophysiological features [23]. To further elucidate the specific mechanism for sensorimotor disorder, high tempo-spatial resolution brain imaging tools are still required.
Current common methods to examine brain function include functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and electroencephalography (EEG). However, the temporal resolution of fMRI and PET cannot reach the required level of precision. Although the time resolution of EEG is high enough, the spatial resolution of EEG is not high enough, which means it is difficult to locate the deep source, especially in the deep part of the cortex, such as the area supporting the lower extremities.
Magnetoencephalography (MEG) is currently one of the most powerful tools for brain functional disorders research due to its millisecond temporal resolution and millimeter scale spatial resolution. MEG maps the brain activity by recording the brain's magnetic fields. MEG measures the field from the ionic currents flowing in the dendrites of neurons during synaptic transmission. Notably magnetic fields are less distorted than electric fields by the skull and scalp, which results in better spatial resolution of the MEG. MEG is non-invasive, without ionizing radiation, as opposed to PET and has high temporal resolution as opposed to fMRI [24].
Based on previous research results, we hypothesized that [1] sensorimotor integration is abnormal at the cerebral cortex level in RLS, probably due to an impairment of the inhibitory intermediate neuron network, thus resulting in increased excitability of the primary sensory and motor cortices. Cortical excitability in RLS patients can be detected by examining somatosensory evoked magnetic field intensity [2]. Increased cortical excitability can be caused by an increased excitability of neural ensembles or by a decline of inhibition between neural ensembles. There may be different levels of gating mechanisms in some important nodes during the transmission of somatosensory information in the brain network. A paired-pulse depression test was conducted to test whether there was decreased inhibition in RLS [3]. The early somatosensory induced magnetic field, to some extent reflects the response state (excitability) of the partial somatosensory stimulation in the primary somatosensory region; the subsequent somatosensory oscillation activity reflects the process of transmitting, integrating and forming output of somatosensory information in the wider range of the brain. Somatosensory oscillations in different frequency bands reflect the synchronization status of neural ensembles in different parts and ranges. Using a time-frequency analysis of somatosensory oscillation, it can be demonstrated whether RLS patients exhibit hyperexcitability in somatosensory cortex, and it can also be demonstrated whether the brain has a corresponding compensatory strategy or a secondary change in the course of further somatosensory information transmission.
In order to gain better insight into the neural mechanism of RLS's sensory symptoms, we designed the following experiment using MEG, an experiment which could also provide guidance for RLS diagnosis and therapy; for example it could be a criteria for neuromodulation by Transcranial Magnetic Stimulation (TMS).
Section snippets
Material and methods
For this study, 15 RLS patients and 15 control subjects were recruited. Clinical manifestations of all subjects were evaluated. MEG and matching MRI 3D high resolution T1 scans were performed, capturing MEG, single-pulse SEF and paired-pulse SEF data, while subjects were in a neutral (non-task) state. Statistical analysis for somatosensory cortical excitation was made, and somatosensory gating rate and time-frequency oscillation was evaluated.
Results
As shown in Fig. 3, precise source tracing for a somatosensory stimulus in the lower limbs is achieved via the Beamformer method, and the projecting sites match up with the expected classical anatomic areas. Determination of the single somatosensory stimulus intensities and the GC ratio of paired-stimuli were performed for the experimental group and the control group, respectively; there were significant inter-group differences observed:
- 1.
The evoked magnetic field intensities of the experimental
SEF intensity in RLS patients’ lower limb is significantly higher than that of the control group
It takes about 40 ms for a somatic sensory input to the lower limbs to be delivered to primitive somatosensory cerebral cortex. With the aid of the Beamformer algorithm-based MEG Processor for temporo-spatial tracing of sources, the source could be precisely projected onto the somatosensory region of the lower limbs. The SEF intensity at 40 ms likely reflects the excitability of primitive somatosensory cerebral cortex. Past studies have shown that the nerve conduction velocity, the amplitude of
Conclusion
It is currently believed that the core mechanism of RLS might be a sensorimotor integration disorder. Sensorimotor integration is defined as “the capability of the central nervous system to integrate different sources of stimuli and, at the same time, to transform such inputs into motor actions” [59]. Does sensorimotor integration disorder originate from abnormal peripheral input or defective central nervous system processing? This question is addressed by this experiment. There are
Acknowledgement
This work was supported by the gs1:Beijing Municipal Science and Technology Commission, Grant No. Z161100002616001, and The National High-Tech R&D Program of China (863 Program), Grant No. 2015AA020514.
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