The estimation of short intra-cortical inhibition depends on the proportion of spinal motoneurones activated by corticospinal inputs
Introduction
Numerous experimental paradigms with transcranial magnetic stimulation (TMS) have been developed to assess cortical excitability in humans (Reis et al., 2008). In the paired pulse paradigm (Kujirai et al., 1993), the first conditioning TMS pulse is adjusted to modify motor cortex excitability, and this then influences the transsynaptic response of the pyramidal cells to the second test pulse. The conditioned motor evoked potential (MEP) is compared to the test MEP evoked by single test pulse, to investigate the excitability of inhibitory and excitatory cortical pathways. Over the past two decades, this paradigm has been extensively used, but the great variability of the data strongly limits the reliability of this technique in understanding the physiology and the pathophysiology of human motor control (Orth et al., 2003).
Stimulus parameters such as the coil location, the interval between pulses, and their intensity greatly influence the results. For instance, intra-cortical inhibition is stronger when the coil is oriented to produce postero-anterior (PA) currents in the cortex (Nakamura et al., 1997, Hanajima et al., 1998), when the time interval between the two TMS pulses is ∼2 ms (short-interval intra-cortical inhibition, SICI), and when the intensity of the conditioning and test pulse are below and above the MEP threshold, respectively (Ilić et al., 2002). The threshold intensities of the conditioning pulse to activate the inhibitory and excitatory pathways are, respectively, ∼60% and 80% the MEP threshold (Ilić et al., 2002), and their ratio is rather consistent (Orth et al., 2003). Clearly MEP size and the TMS intensity are correlated (Devanne et al., 1997), but with great inter-individual variability (Wassermann, 2002), which raised the question whether the test pulse should be adjusted to a specific MEP size or as a multiple of its threshold intensity. Similar modulations in SICI have been observed when the test MEP was less than 1 mV (Roshan et al., 2003, Daskalakis et al., 2004), and when the test pulse intensity was between 100% and 130% the MEP threshold (Kang et al., 2007, Garry and Thomson, 2009), but not when the test MEP was larger or the test stimulus stronger. These parameters (PA current, conditioning and test pulses, respectively, 70–80% and 120%, or 1-mV test MEP) correspond to the paradigm used in most of the studies.
SICI is commonly evaluated with the MEP ratio, and the test MEP size is expressed in mV. However, the recording conditions strongly influence the EMG signals (De Luca, 2008), which can bias the inter- and intra-individual comparisons when using the raw EMG data. It is therefore advisable to normalise the EMG activity (Finsterer, 2001). In spinal neurophysiology, the H-reflex is normalised to the maximal motor response (Mmax), which reflects the maximal compound action muscle potential when all the motor axons to the target muscle are activated simultaneously by peripheral nerve stimulation. Normalisation to Mmax ensures that the test response size is similar in all subjects whatever the recording conditions, and that the test stimulation activates the same proportion of spinal motoneurones, limiting the influence of the non-linear input/output properties of the pool (Kernell and Hultborn, 1990), which might otherwise influence the effects of conditioning stimuli (Crone et al., 1990). While SICI may be a purely cortical phenomenon, its estimation is based on a discharge of spinal motoneurones, and the generation of a compound muscle action potential (i.e., the MEP). Moreover, the distribution of the corticospinal inputs onto the motoneurone pool is not linear (Henneman and Mendell, 1981, Bawa and Lemon, 1993, Devanne et al., 1997, Awiszus and Feistner, 1994).
We therefore addressed the question whether the recording conditions and the motoneurone recruitment can bias SICI evaluation, and contribute to the inter- and intra-subject variability. Apart from their methodological implications, the results provide further insight into the skewed distribution of corticospinal inputs at spinal level, and raise the possibility of non-linear summation at cortical level as well.
Section snippets
Methods
The experiments were carried out in 16 healthy volunteers (mean age 34.7 ± 3.5 years; 7 women; 14 right-handed) who all gave written informed consent to the experimental procedures. The study was performed according to the Code of Ethics of the World Medical Association (Declaration of Helsinki), and was approved by the Local Ethics Committees of the Pitié-Salpêtrière Hospital.
Influence of the recording technique on the MEP size
Fig. 1A and B shows the TMS-induced changes in the mean FDI EMG activity collected with the BD (A) and ZW (B) system, and the corresponding Mmax, in one subject (protocol 1). The EMG waveforms looked similar with the two systems, but the maximal MEP size and Mmax were larger with the ZW than with the BD system for the same location of the TMS-induced electric fields in the cortex (NBS system) and comparable ulnar nerve stimulation. The full recruitment curves (another subject) reveal similar
Discussion
This study has shown that normalizing the test MEP size to Mmax counteracts the influence of the recording conditions when studies are made on different subjects or repeat studies are made on the same subjects. This normalisation also revealed a U-shaped influence of the test MEP size on SICI, and it improved the coefficient of variation giving rise to a better reliability of the SICI estimation.
Conclusion
We suggest that non-linear input/output properties at spinal and cortical level interfere with the measurement of SICI, and that the Mmax normalisation would provide a more reliable measurement. We only report the findings for FDI, commonly targeted with TMS, but we suspect similar effects in other muscle groups, given the similar changes in ADM. However, in proximal muscles, spinal interneurones might also influence the results (Petersen et al., 2003). Lastly, we suggest that the motoneurone
Acknowledgements
This work was also supported by Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM, and IRME.
References (34)
- et al.
Trial-to-trial variability of corticospinal volleys in human subjects
Electroencephalogr Clin Neurophysiol
(1995) - et al.
The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs
Prog Neurobiol
(1992) EMG-interference pattern analysis
J Electromyogr Kinesiol
(2001)- et al.
Synaptic effects on recruitment gain: a mechanism of importance for the input–output relations of motoneuron pools?
Brain Res
(1990) - et al.
The variability of intracortical inhibition and facilitation
Clin Neurophysiol
(2003) Variation in the response to transcranial magnetic brain stimulation in the general population
Clin Neurophysiol
(2002)- et al.
Physiological basis of motor effects of a transient stimulus to cerebral cortex
Neurosurgery
(1987) - et al.
Correlations between size parameters and the amplitude of the excitatory postsynaptic potential evoked by magnetic brain stimulation in human hand muscle motoneurons
Exp Brain Res
(1994) - et al.
Recruitment of motor units in response to transcranial magnetic stimulation in man
J Physiol
(1993) - et al.
The influence of single monkey cortico-motoneuronal cells at different levels of activity in target muscles
J Physiol
(1994)
Sensitivity of monosynaptic test reflexes to facilitation and inhibition as a function of the test reflex size: a study in man and the cat
Exp Brain Res
Exploring the connectivity between the cerebellum and motor cortex in humans
J Physiol
Input–output properties and gain changes in the human corticospinal pathway
Exp Brain Res
Comparison of descending volleys evoked by monophasic and biphasic magnetic stimulation of the motor cortex in conscious humans
Exp Brain Res
The Oxford dictionary of statistical terms
The effect of test TMS intensity on short-interval intracortical inhibition in different excitability states
Exp Brain Res
Cited by (36)
Corticospinal properties are associated with sensorimotor performance in action video game players
2021, NeuroImageCitation Excerpt :Control and Player had different test MEP size during the SICI experiment. This difference in MEP size could have influenced SICI and partly explained why Player have stronger MEP inhibition (Lackmy and Marchand-Pauvert, 2010. However, in the present study, the absence of difference between groups in SICI induced with conditioned TMS at 70% RMT indicates that the difference observed with 60% and 80% RMT are most probably not driven entirely by the test MEP difference, but also by group differences at neural level.
Peripheral stimulation affects subthreshold Triple Stimulation Technique
2021, Journal of Neuroscience MethodsInterneuronal networks mediate cortical inhibition and facilitation
2020, Clinical NeurophysiologyA comparison of two methods for estimating 50% of the maximal motor evoked potential
2015, Clinical NeurophysiologyAge-related differences in short- and long-interval intracortical inhibition in a human hand muscle
2014, Brain StimulationCitation Excerpt :Previous studies examining changes with advancing age have therefore matched one of these variables between age groups [14,18]. Furthermore, recent research suggests that the magnitude of intracortical inhibition in young subjects also depends on the proportion of the test alone MEP relative to the maximum muscle response (Mmax; [19]). These findings suggest that comparisons of intracortical inhibition between young and older subjects, which typically exhibit different Mmax characteristics [20], may confound the estimate of SICI and LICI between subject groups.