Magnetic source imaging of cortical dysfunction in amyotrophic lateral sclerosis.

OBJECTIVE: The goal was to determine whether magnetic source imaging could identify a signature for cortical involvement in patients with amyotrophic lateral sclerosis (ALS), and to determine whether the method might provide insight into functional abnormalities associated with the disease process. DESIGN: Spontaneous brain activity recordings from whole-head 148-channel magnetoencephalography (MEG) were employed to look for localized dipolar sources of focal delta-theta (1-7 Hz) discharges in patients with ALS without dementia. Localized slow wave dipoles were mapped and counted by anatomic brain region, defined by MRI, and correlated against the revised ALS functional rating scale (a functional measure of ALS disability). In a substudy, defects in cortical activations mediating purposeful movement were investigated in an ALS patient with probable motor apraxia of an upper limb. RESULTS: MEG revealed localized slow wave dipole sources in 7/7 ALS patients, including two recently diagnosed patients (0/8 age-similar controls). Systematic brain mapping of dipole source generators was possible in all seven ALS patients. The slow wave bursts were being generated from frontal, temporal, and parietal cortices, but not from occipital areas. The density of slow wave dipoles in cingulate gyrus correlated with the severity of upper-extremity disability as judged by the functional ALS measure. Further magnetic source imaging in the substudy patient with unilateral limb apraxia revealed abnormal central processing of purposeful movement with absent M2 in the contralateral secondary motor areas generating slow waves. CONCLUSIONS: This exploratory study documents widespread cortical dysfunction in patients with ALS, including those with recent onset of their disease. MEG is likely to be a powerful new tool for researching the contribution of cortical dysfunction to the motor disability that characterizes the disease process.

High-resolution magnetoencephalographic functional mapping of the cortical network mediating intentional movement.

Magnetoencephalography (MEG) is a sensitive technique that can detect and map cortical electrophysiologic activations with high spatial (mm) and temporal (msecs) resolutions. We used 148-channel whole-head MEG to record the activation sequence for the somatosensory and motor cortical network during cued hand movements in a healthy 39-yr-old subject. The complex sequence and topography of cortical activations were superimposed onto the subject's brain magnetic resonance images. Frontal premotor and supplementary motor and cingulate areas activated well before the primary motor area and again repetitively from 200 msecs onward with activations alternating repeatedly between frontal and parietal areas. The network's very close functional integration of supplementary motor areas suggests how brain injury that is localized to these regions, but not to the primary motor area itself, can disrupt integrity of movement, and why preservation of functional integrity of some areas traditionally viewed as extramotor may be necessary for recovery from neurologic disability.

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis.

We used a flow cytometry assay to measure proliferation and cytokine production of self-antigen-specific T cells in individual patients during the clinical course of multiple sclerosis (MS). Myelin-associated oligodendrocytic basic protein (MOBP) was selected for proof of principles in the assay, along with myelin basic protein (MBP) to assess specific activated T cells in 10 MS patients over an 18-month period, in parallel with brain magnetic resonance imaging (MRI) scans and clinical rating scale. A positive correlation occurred between antigen-specific T cell proliferation and interferon-gamma production with clinical relapses and MRI lesion activity that was absent when the same patients were in remission.