Clinical Neuroscience
Effect of individual anatomy on resting motor threshold – Computed electric field as a measure of cortical excitability

https://doi.org/10.1016/j.jneumeth.2011.10.004Get rights and content

Abstract

Introduction

Transcranial magnetic stimulation (TMS) is used for assessing the excitability of cortical neurons and corticospinal pathways by determining the subject-specific motor threshold (MT). However, the MT is dependent on the TMS instrumentation and exhibits large variation. We hypothesized that between-subject differences in scalp-to-cortex distance could account for the variation in the MT. Computational electric field (EF) estimation could theoretically be applied to reduce the effect of anatomical differences, since it provides a more direct measure of corticospinal excitability.

Methods

The resting MT of the thenar musculature of 50 healthy subjects (24 male and 26 female, 22–69 years) was determined bilaterally at the primary motor cortex with MRI-navigated TMS using monophasic and biphasic stimulation. The TMS-induced maximum EF was computed at a depth of 25 mm from the scalp (EF25 mm) and at the individual depth of the motor cortex (EFcortex) determined from MRI-scans.

Results

All excitability parameters (MT, EF25 mm and EFcortex) correlated significantly with each other (p < 0.001). EFcortex at MT intensity was 95 ± 20 V/m for biphasic and 120 ± 24 V/m for monophasic stimulation. The MT did not correlate with the anatomical scalp-to-cortex distance, whereas the coil-to-cortex distance was found to correlate positively with the MT and negatively with EFcortex (p < 0.05).

Discussion

In healthy subjects, the scalp-to-cortex distance is not a significant determinant of the MT, and thus the use of EFcortex does not offer substantial advantages. However, it provides a purposeful and promising tool for studying non-motor cortical areas or patient groups with possible disease-related anatomical alterations.

Highlights

► The motor threshold (MT) in transcranial magnetic stimulation (TMS) exhibits large variation between subjects possibly due to anatomical differences. ► Individual coil-to-cortex distance was measured and the TMS-induced electric field modelled at the cortex. ► Individual anatomy did not affect the MT in healthy subjects. ► Cortical electric field can be used as measure of motor excitability.

Introduction

Transcranial magnetic stimulation (TMS) is a non-invasive method for studying the function of cortical neurons and corticospinal pathways (Barker et al., 1985). In TMS, a rapidly modulated electric current is directed in a stimulation coil, which induces a magnetic field that penetrates the skull and the soft tissues of the head in a painless manner. Concurrently, an electric field is induced in the cortical neurons which, when sufficient in strength, results in the generation of an action potential. When the stimulus is targeted to the primary motor cortex (M1), it produces a motor evoked potential (MEP) in the peripheral muscle corresponding to the stimulated cortical representation area (Fatemi-Ardekani, 2008, Terao and Ugawa, 2002). TMS can be used for studying various aspects of corticospinal excitability, with motor excitability being the most widely used, since MEPs are suitable for objective monitoring by electromyography (EMG) (Caramia et al., 1989, Rossini et al., 1991). The level of individual corticospinal excitability is commonly determined by the motor threshold (MT). In a relaxed muscle, the MT is often defined as the lowest stimulation intensity that produces MEPs over 50 μV in amplitude in 50% of trials (Rossini et al., 1994). The determination of the individual MT is a fundamental procedure in most TMS-studies, since it provides a baseline parameter of excitability, to which other TMS measurements are proportioned. As the MT is traditionally reported as a percentage of maximum stimulator output (%-MSO), it is dependent on the applied instrumentation, which complicates direct comparison with results obtained with different stimulator types. Furthermore, the MT displays extensive variability, both between and within subjects (Danner et al., 2008, Kimiskidis et al., 2004, Koski et al., 2005, Mills and Nithi, 1997, Säisänen et al., 2008, Wassermann, 2002). However, it has not been extensively characterized to which extent the variation of the MT derives from methodological and anatomical factors as opposed to physiological variation of cortical excitability.

As the strength of the TMS-generated magnetic field decreases in proportion to the distance from the stimulation coil, the electric field induced in the cortex depends on the distance between the coil and the cortex (Ruohonen and Ilmoniemi, 1999) (Fig. 1). Therefore, the individual scalp-to-cortex distance can be considered as an important anatomical determinant of the clinical effect of TMS. Since scalp-to-cortex distance is the major contributor to the distance between the stimulation coil and the eloquent cortex, it will partially define the stimulus intensity required for the generation of MEPs, and consequently be reflected in the MT estimates (Herbsman et al., 2009, Kozel et al., 2000, McConnell et al., 2001, Stokes et al., 2005, Stokes et al., 2007). Accordingly, the between-subject variation of the MT has been reported to be greater than the within-subject variation (Danner et al., 2008, Kimiskidis et al., 2004, Koski et al., 2005, Mills and Nithi, 1997, Säisänen et al., 2008, Wassermann, 2002). In addition to the anatomical variation, inaccurate positioning of the stimulation coil may affect the properties of the induced electric field in the brain, since changes in the location, orientation or tilting of the coil on the scalp may be responsible for significant changes in the distance between the coil and the targeted cortical area (Conforto et al., 2004, Knecht et al., 2005, Maccabee et al., 1993, Mills et al., 1992).

It is crucially important to be aware of and account for the methodological and anatomical factors contributing to the variation of the MT in order to reliably evaluate the physiological variation of cortical excitability. Therefore the present study was designed to minimize the variation caused by coil positioning by using navigated TMS which can be utilized to stabilize the coil position, orientation and tilting throughout the stimulation procedure (Hannula et al., 2005, Julkunen et al., 2009). The TMS-induced electric field in the brain can be estimated computationally by using a navigation system. The location of the maximum electric field strength is assumed to be at the centre of the area where cortical motor neurons are activated and thus regarded as the target of the stimulation (Ruohonen and Karhu, 2010). We aimed to reduce the between-subject variation of the MT by utilizing an electric field estimate in the motor cortex computed at stimulation intensity corresponding to the MT. Hypothetically, the electric field estimate should be independent of subject anatomy and the instrumentation used, and consequently, it should reduce the anatomical and methodological variation in cortical excitability measurements.

Section snippets

Subjects

Fifty-five volunteers participated in the study. The data was gathered from our previous study conducted with a population with a wider age-range (Säisänen et al., 2008). Five subjects were excluded from the 55 subjects, as sufficiently high stimulation intensity for MT determination could not be achieved with monophasic stimulation. Thus, the final study population consisted of fifty subjects (24 male and 26 female, age 44 ± 14 years, range 22–69 years). The subjects had no neurological

Results

All parameters of corticospinal excitability (MT, EF25 mm and EFcortex) correlated significantly with each other (p < 0.001). There was a significant correlation between the hemispheres (p < 0.001) with no interhemispheric differences being observed. All the parameters exhibited also similar variations, with coefficients of variation ranging from 18% to 22% (Table 1). In the 5 subjects who were excluded from the analyses due to indeterminable MT with monophasic stimulation on either or both

Discussion

The maximum computational electric field on the cortex is a purposeful measure of motor excitability, as it is a direct estimate of the stimulation intensity required to produce activation in cortical neurons. Ideally, it should be independent of individual anatomy and would permit a comparison of results from different studies conducted with different stimulation systems. In the current study, EFcortex exhibited remarkable concordance with the traditional, instrumentation-dependent MT as well

Financial disclosures

Petro Julkunen and Laura Säisänen have received consulting fees, unrelated to this study, from Nexstim Ltd., manufacturer of navigated TMS systems.

Acknowledgements

Nils Danner has received funding for the study from The Cultural Foundation of Northern Savo, The Epilepsy Research Foundation, The Emil Aaltonen Foundation and The Finnish Medical Society Duodecim.

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