The cortical motor threshold reflects microstructural properties of cerebral white matter
Introduction
Transcranial magnetic stimulation (TMS) and diffusion-weighted magnetic resonance imaging (DWI) have been used extensively to study the corticospinal motor system in humans. While DWI provides information about the structure of neuronal pathways, TMS of the primary motor hand area (M1Hand) is a well-established tool to assess the function of the human motor system. The excitability and conduction of the corticospinal projections can be studied by recording the motor-evoked potential (MEP) from the contralateral hand muscles (Pascual-Leone et al., 2002). The efficiency of TMS to excite corticospinal neurons is reflected by the motor threshold (MT). The MT is defined as the lowest stimulus intensity at which single-pulse TMS to M1Hand elicits a motor response of a defined size in a contralateral target muscle (Rossini et al., 1999). At intensities around MT, a monophasic TMS pulse mainly excites corticospinal output neurons in M1Hand trans-synaptically by inducing action potentials in cortico-cortical axons that provide excitatory inputs to the corticospinal neurons (Amassian et al., 1987, Shimazu et al., 2004). The TMS-induced trans-synaptic excitation elicits high-frequency repetitive discharges in the corticospinal output neurons (Di Lazzaro et al., 2004). The orthodromic propagation of these excitatory postsynaptic potentials along the corticospinal tract can be recorded as multiple descending volleys in the corticospinal tract and elicit action potentials in the spinal motoneurons (Di Lazzaro et al., 2004). These peripheral action potentials spread to the target muscle and produce a motor response. Because corticospinal output neurons are preponderantly excited trans-synaptically by TMS, the MT is determined by the excitability of those cortico-cortical neuronal structures that are directly activated by TMS and project onto the corticospinal output neurons (Ziemann, 2004). In accordance with this view, sodium and calcium channel blockers that reduce axon excitability elevate the MT (Ziemann et al., 1996, Chen et al., 1997).
DWI provides information about the structure of white matter by mapping the diffusion characteristics of water in each voxel (Basser et al., 1994). DWI can be used to measure regional fractional anisotropy (FA) of diffusion. The regional FA value indicates how much the direction of water diffusion in a given voxel is influenced by local barriers such as myelin sheaths or microtubules in the axons (Beaulieu, 2002). Regional FA is sensitive to microstructural properties of the neuronal tissue, including the density of axon bundles and the extent of myelination (Boussaoud, 2001, Beaulieu, 2002).
Mapping the regional distribution of FA in white matter has been successfully used to study structure–function relationships in the human brain. In healthy individuals, regional FA values of the white matter correlate with specific cognitive functions (Klingberg et al., 2000, Tuch et al., 2005, Wolbers et al., 2006). In these studies, the individual performance level showed a positive correlation with regional FA in distinct subcortical fibre tracts. Mirroring the findings in healthy subjects, patients with amyotrophic lateral sclerosis showed distinct regional reductions in FA within central motor pathways that correlated with motor impairment (Sommer et al., 2002, Sach et al., 2004, Valsasina et al., 2007, Sage et al., 2007).
In the present study, we measured regional FA with DWI to test whether the MT predicts inter-individual differences in white matter structure. We used this approach to examine the relation between structure and function in healthy human brain. Rather than using a behavioural measure, we chose the MT of M1Hand as a behaviour-independent marker of regional cortical excitability. Our choice was based on two considerations: First, the MT is of great practical relevance to TMS because it is widely used to estimate the sensitivity of primary and secondary motor areas to TMS (Stewart et al., 2001, Munchau et al., 2002, Rizzo et al., 2004, Koch et al., 2006, Koch et al., 2007). Second, the MT reflects intrinsic axonal aspects of cortical excitability because it is modified by drugs that alter membrane excitability but not by drugs that influence synaptic neurotransmission (Ziemann et al., 1996). In addition to TMS measurements of the cortical MT, we mapped regional FA with DWI to test whether the MT predicts inter-individual differences in white matter structure. We reasoned that the MT should be influenced by the diameter, coherence and density of cortico-cortical axons that connect the stimulated M1 with other cortical areas. Given the trans-synaptic route of TMS-induced corticospinal excitation, we hypothesized that the level of regional excitability as indexed by the MT should be associated with higher FA values in white matter underlying M1Hand. Previous studies demonstrated a correlation between handedness and white matter structure below the precentral gyrus but not the posterior part of the internal capsule (Buchel et al., 2004, Westerhausen et al., 2007). Therefore, a second aim of this study was to examine whether the individual expression of handedness has an impact on the correlation between MT and white matter properties.
Section snippets
Participants
Twenty-three healthy volunteers (11 females), aged from 23 to 55 years (mean age, 32.4 years), participated in the study. All participants were studied with TMS and structural MRI after giving written informed consent. The experimental procedures had been approved by the local Ethics Committee and were performed according to the ethical standards laid down in the Declaration of Helsinki.
To examine the influence of handedness on the relationship between MT and FA, we included individuals with a
Cortical motor threshold
Fig. 1 illustrates the results of MT measurements. Resting MTs were consistently higher than active MTs (F(1, 20) = 594.4, p < 0.001). The MTs of the right M1Hand were higher than the MT of the left M1Hand (F(1, 20) = 51.6, p < 0.001). The factors HEMISPHERE and ACTIVITY LEVEL also showed a significant interaction (F(2,20) =4.76, p = 0.041), reflecting a stronger left-to-right difference in MTs when MTs were assessed at rest compared to measurements during tonic contraction. There was no main effect of
Discussion
In healthy human adults, individual differences in cortical MT, a physiological measure of trans-synaptic excitability of corticospinal neurons in M1Hand, were associated with widespread variations in regional FA values, a microstructural marker of white matter. The lower the MT the higher was regional FA, indicating that FA of cerebral white matter increased with motor cortex excitability. Extending previous studies that reported positive correlations between regional FA in the white matter
Acknowledgments
We would like to thank Thilo van Eimeren and Boris Schlaak for help with data acquisition and Thomas Wolbers and Volkmar Glauche for valuable advice with analyses of DWI data. This work was supported by the BMBF (grants 01 GO 0510, 0511 and 0513 to H.R.S. and C.B.) and the Volkswagenstiftung (grants I/79-932 and I /78-553 to A.M. and H.R.S.).
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Both authors contributed equally to this work.