Redundancy Among Parameters Describing the Input-Output Relation of Motor Evoked Potentials in Healthy Subjects and Stroke Patients

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Redundancy Among Parameters Describing the Input-Output Relation of Motor Evoked Potentials in Healthy Subjects and Stroke Patients

Claire Kemlin¹, Eric Moulton¹, Sara Leder², Marion Houot³, Sabine Meunier¹, Charlotte Rosso^1,2† and Jean-Charles Lamy^1*†

• ¹Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France
• ²APHP, Urgences Cérébro-Vasculaires, Hôpital de la Pitié Salpêtrière, Paris, France
• ³AP-HP, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Centre of excellence of neurodegenerative disease (CoEN), Institute of Memory and Alzheimer's Disease (IM2A), ICM, CIC Neurosciences, Paris, France

Background: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability through Motor Evoked Potential (MEP) amplitude measurements. The input-output (I/O) curve is a sigmoid-shaped relation between the MEP amplitude at incremented TMS intensities. The aim of this study was to examine the relationships between seven parameters derived from the sigmoid function.

Methods: Principal Component Analysis and Spearman's rank correlation matrices were used to determine if the seven I/O curve parameters capture similar or, conversely, different aspects of the corticospinal excitability in 24 healthy subjects and 40 stroke survivors with a hand motor impairment.

Results: Maximum amplitude (MEP_max), peak slope, area under the I/O curve (AUC), and MEP amplitude recorded at 140% of the resting motor threshold showed strong linear relationships with each other (ρ > 0.72, p < 0.001). Results were found to be similar in healthy subjects and in both hemispheres of stroke patients. Our results did not support an added benefit of sampling entire I/O curves in both healthy subjects and stroke patients, with the exception of S₅₀, the stimulus intensity needed to obtain half of MEP_max amplitude.

Conclusions: This demonstrates that MEP elicited at a single stimulus intensity allows to capture the same characteristics of the corticospinal excitability as measured by the AUC, MEP_max and the peak slope, which may be of interest in both clinical and research settings. However, it is still necessary to plot I/O curves if an effect or a difference is expected at S₅₀.

Introduction

Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability in both healthy subjects and in a broad range of neuropsychiatric conditions. A common approach from basic research to pivotal clinical trials is to compare recruitment curves of TMS-induced motor evoked potentials (MEPs) between groups of subjects or before and after different types of interventions aimed at promoting brain plasticity (i.e., pharmacotherapy or non-invasive brain stimulation).

The input-output (I/O) relation in the corticospinal pathway is assessed by plotting MEP amplitude vs. stimulus intensity and fitting the data with the following sigmoid function equation (1–4): MEP(s)=MEPmax/(1+expm(S50−s))

, where MEP(s) is the MEP amplitude at the stimulation intensity s, MEP_max is the maximum MEP amplitude, S₅₀ is the stimulus intensity needed to obtain 50% of MEP_max amplitude, and m is the slope parameter of the sigmoid function, i.e., the global slope of the function (Figure 1). Three additional parameters can be derived from the I/O curve: (1) the peak slope (PS), i.e., the instantaneous slope of the ascending limb of the curve at S₅₀, which reflects the recruitment gain of motoneurons and is given by the formula: PS = m x MEP_max/4, (2) the x-intercept (X_int) of the tangent at S₅₀, and (3) the area under the I/O curve (AUC) usually calculated using the trapezoidal area method (5).

FIGURE 1

Figure 1. Electrophysiological parameters extracted from an example of an input output curve (I/O curve) fitted by a sigmoid function. Are shown the following variables: X_int: X intercept, IO140: Motor Evoked Potential amplitude recorded at 140% rMT, PS, peak slope; AUC, area under the I/O curve in gray; S₅₀, stimulus intensity needed to obtain 50% of the maximum response; MEP_max, maximum value of the sigmoid function.

To date, the inter-dependency between all these parameters are not fully understood. Indeed, although the PS depends on both m parameter and MEP_max, it does not mean these three parameters are correlated together. Same for X_int, which depends on m parameter and S₅₀. The question arises whether these variables capture similar or, conversely, different aspects of the corticospinal excitability and if so, how each of them relates to one other. To clarify the interdependency between these parameters, we estimated I/O curves from the dominant hemisphere of healthy volunteers and performed Principal Component Analyses (PCA) in addition to correlation matrices to summarize the most important linear relationships between variables. PCA is a tool capable of summarizing the most important linear relationships between variables and computing synthetic variables from the original variables named principal components (PCs). PCA provides a visual and geometric representation of the correlation matrix (6, 7). In a second step, to test whether our results could be extrapolated to patients suffering from neurological conditions, we performed the same analyses on data collected in both the affected and unaffected hemispheres of stroke patients given that this population represents the most frequent brain damaged disease worldwide. Indeed, the sigmoid function has been previously shown to be a reliable method to plot IO curve in stroke patients (4).

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