Neurophysiological Estimates of Cortical Grey and White Matters Damage in Patients With Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) whose pathogenesis involved both demyelinating events and neurodegeneration. It is on of the most frequent cause of disability in young adults. It is characterized by different clinical phenotypes: currently, the relapsing-remitting form (RR), the most common, and the progressive forms of MS (primary progressive -PP, secondary progressive -SP) are recognized. The relapsing-remitting form is characterized by the presence of acute/subacute onset of clinical events, the appearance of new lesions on magnetic resonance imaging (MRI), or the uptake of gadolinium by a new or pre-existing lesion. The progressive forms, on the other hand, present with a slow accumulation of disability from the onset (PP-MS), or following a relapsing-remitting trend (SP-MS). The clinical scale mainly used for evaluating patients with MS is the Expanded Disability Status Scale (EDSS). Currently, there are several treatments available for the control of the disease and the identification of the correct therapeutic choice can lead to an important slowdown, up to stabilization, of the clinical course of the disease. It is therefore essential, given the existence of different therapeutic strategies, to recognize early those patients who respond in a sub-optimal manner to therapy. To date, the evaluation of the effectiveness of the treatment is based on clinical and radiological data. Several studies have tried to identify new markers of disability, but none of these have entered the routine clinical use. In this context, the possible role of neurophysiology in early identify markers of inflammatory/ degenerative disease activity is outlined.

Among the neurophysiological methods potentially able to identify the inflammatory or neurodegenerative phase of the disease, the most promising results were obtained with transcranial magnetic stimulation (TMS) and electroencephalography (EEG). These methods, already widely used in the clinical setting, are characterized by being reproducible, non-invasive and low-cost. Thanks to the development of EEG systems compatible with magnetic stimulation, it is possible to study the cortical potentials evoked by TMS (TEPs). The TEPs constitute a sensitive and reproducible experimental index of intracortical excitability and allow the identification of specific alterations of different neurological conditions. The study of TEPs offers a better performance than that obtainable using the single techniques, TMS and EEG, separately.

Neurophysiological estimates of white matter integrity Several evidence have confirmed that the EEG indices of functional connectivity are influenced by the degree of myelination of the white matter. Among these indices of EEG connectivity, cortico-cortical coherence is a linear correlation index between the oscillatory signal of two cortical areas and has been shown to be a sensitive index of the myelination state of the brain in physiological conditions and in various neurological pathologies.

Distinct EEG oscillations in the different frequency bands revealed many robust relationships to behavioral, cognitive, and clinical states in several studies. Spatial-temporal oscillatory dynamic patterns recorded by EEG are important brain state-dependent measures of neocortical dynamics, including functional connectivity. Myelin is critical for sustaining oscillatory neural activity and entrainment between "generators" (e.g., cell assemblies or networks at multiple scales) in brain regions separated by substantial conduction delays. Functional connectivity as assessed by scalp EEG at large scales is believed to be strongly influenced by white matter tracts, especially the cortico-cortical projections. The standard Fourier transform-based multi-channel signal measure coherence is a squared correlation coefficient expressed as a function of frequency; it can provide robust measures of cognitive state and white matter (WM) maturation or disease. WM integrity determines propagation delays (i.e. the timing) of synaptic inputs in a determined brain network thus allowing phase synchrony of local oscillations. Relatively small changes in conduction delays can have significant effects on oscillatory coupling and phase synchrony between distant brain regions. Disruption in brain synchronization contributes to dysfunction in many neurological and psychiatric disorders. Compared to scalp EEG, high-resolution EEG (HR-EEG) methods employ computer algorithms (e.g., Laplacian or dura image) to provide estimates of brain or dural surface potentials at roughly the 2-3 cm scale. HR-EEG functional connectivity measures, like narrow band (e.g., 1 Hz) alpha and theta coherence, has been linked to cortico-cortical signal propagation via (mostly) myelinated axons. The propagation time between hemispheres is about 30 ms through myelinated callosal fibers and 150-300ms through unmyelinated fibers. An investigation of scalp-registered inter-hemispheric coherence between the left and right sensorimotor hand areas using HR-EEG revealed a superposition of both bilaterally coherent and incoherent rhythmic activities within the alpha band. Synaptic integration can be expected to be strongly influenced by the degree of myelination of intercallosal axons. Combined EEG and HR-EEG can provide complementary functional connectivity estimates that are maximally sensitive to large/global (~5-10 cm) and intermediate/local {-2-3 cm) spatial scale source regions, respectively. White matter integrity is important for cortico-cortical connections and is critical to these functional connectivity estimates, especially scalp oscillatory coupling and distant sources phase coherence.

Transcranial magnetic stimulation (TMS) is a non-invasive brain-stimulation technique. By producing high-intensity magnetic pulse, TMS induces brief electric currents that can excite or inhibit a small area of the cerebral cortex. This activating property is classically used on the primary motor cortex (M1) to produce action potentials along the cortico-spinal bundle and evoke a motor potential (MEP, motor evoked potential) in the contralateral musculature. In MS patients, EEG and TMS are widely used as diagnostic tools to prove demyelination by means of abnormal conduction time along white matter tracts, even in subjects with normal MRI scans. Furthermore, when the magnetic stimulus is delivered during voluntary muscle contraction of the stimulation target muscle, the TMS of M1 can generate a brief interruption of voluntary electromyography (EMG) activity both contralateral (CSP: contralateral silent period) and ipsilateral (the " ipsilateral silent period" -IpSP). lpSP is a measure of interhemispheric motor inhibition that has been found to be altered in patient with MS and callosal lesions.