Thalamocortical sensorimotor circuit in multiple sclerosis: an integrated structural and electrophysiological assessment

Abstract

Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing-Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high-resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1-M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks.

Figure 1

Cortical generators of SEF M20 and M30 components. Sagittal section of primary sensory and motor areas with schematic representation of currents subtending M20 and M30 generators. Red row indicates current induced by EPSP and blue row the effect of IPSP. Black circle represent the position of the equivalent current dipole (ECD) of each component. Left: the M20 component is mainly generated by EPSP impinging on pyramidal neurons in primary somatosensory BA 3b. Right: the currents associated with the IPSPs impinging on pyramidal neurons in 3b area and the EPSPs onto BA 4 pyramidal neurons contribute in the same direction to the current, and consequently to the magnetic signal, and their sum reaches its maximum in about 10 ms from M20 latency, giving rise to M30 component. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Morf_SM1 index definition. Steps 1, 2, and 3 for the similarity index calculation (see methods section), comparing SEFs by left and right median nerve stimulation (morf_SM1). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

SEFs traces recorded from the population of patients and normal controls. Top: In each hemisphere of both groups, superimposition of all channels in the Rolandic region averaged on stimulus arrival at the contra‐lateral median nerve in the [−20, 100] ms period, 0 representing the stimulus delivery. On the y axes, the magnetic field amplitude is represented (femtoTesla, fT). The yellow boxes highlight the response time window used for Morf_S1M1 index estimate, whereas the entire response is shown for consistence with general literature. The morphology alteration, occurring generally in an uncorrelated manner in one or both hemispheres, disrupts the interhemispheric symmetry in MS patients. It is worth noting that while such an interhemispheric asymmetry comes out in patients, in healthy subjects, there is a striking interhemispheric similarity against a huge intersubject variability. Down left, right hemispheric data were omitted from a patient because of the presence of artifacts. Bottom: grand‐average across all patients (left side) and healthy controls (right side) of the maximum and minimum channel signals (normalized to peak amplitude) in each hemisphere. It is evident the lack of structured response shape of the second cortical component in MS patients, as a consequence of distortions occurring at different times in individual patients, while in healthy subjects the two earliest components are still clearly identifiable in the mean traces. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

SEF morphology alteration in patients. Top: the same structure as in Figure 3 of a representative healthy and RR‐MS patient. A clear morphology distortion is evident in the left hemisphere of the patient, whereas M20 component is clearly identifiable in both hemispheres. Middle: in each hemisphere, the position of the ECDs explaining the cerebral activation in correspondence to the M20 (white circle) and M30 (black circle) components is projected onto a suitable axial slice after volumetric head reconstruction from individual MR images. Bottom: mean and standard error of the mean of the Morf_S1M1 index in controls and patients, after transformation to fit its distribution to a Gaussian (see text).

Figure 5

Thalamus volume in MS patients and controls. Thalamic area identification in a representative normalized skull stripped (BET, http://www.fmrib.ox.ac.uk/fsl/bet2) axial section of a patient (F, 34 years, shown in fully coloured transparency; z‐coordinate = 8). The white‐dotted areas indicate the average across controls of thalamic dimension on that section. The black small area in the left frontal region is part of the manually derived mask obtained in the procedure applied for lesion identification.

Figure 6

Hypothesis behind M30 ECD distortions. See text for proposed hypothesis.