Human brain connectivity during single and paired pulse transcranial magnetic stimulation

Abstract

Objective

Intracortical inhibition (SICI) and facilitation (ICF) in the human motor cortex can be measured using a paired pulse transcranial magnetic stimulation (ppTMS) protocol. Recently, a technical device has been introduced, which allows recording electroencephalographic (EEG) responses to TMS of a given scalp site. The latency, amplitude and scalp topography of such responses are considered a reflection of cortico-cortical connectivity and functional state. The aim of the present study is to better characterize the neuronal circuits underlying motor cortex connectivity as well as the mechanisms regulating its balance between inhibition and facilitation by means of EEG navigated-ppTMS coregistration.

Methods

Sub-threshold and supra-threshold single and ppTMS of the left primary motor cortex were carried out during a multi-channel EEG recording on 8 healthy volunteers; the between-pulse intervals used in the paired pulse trials were 3 (for SICI) and 11 ms (for ICF). Motor evoked potentials (MEPs) from the opposite hand were simultaneously recorded.

Results

Single and ppTMS induced EEG responses characterized by a sequence of negative deflections peaking at approximately 7, 18, 44, 100 and 280 ms alternated with positive peaks at approximately 13, 30, 60 and 190 ms post-TMS. Moreover, ppTMS modulated both EEG evoked activity and MEPs. Amplitude variability of EEG responses was correlated with – and therefore might partially explain – amplitude variability of MEPs.

Interpretation

EEG-ppTMS is a promising tool to better characterize the neuronal circuits underlying cortical effective connectivity as well as the mechanisms regulating the balance between inhibition and facilitation within the human cortices and the corticospinal pathway.

Introduction

Transcranial magnetic stimulation (TMS) is a non-invasive technique that allows the investigation of the functional state of the cerebral cortex. In TMS the excitation of neurons in deep gray matter can be either direct or indirect through volleys from superficial neurons (Barker et al., 1985). Adequate stimulation of the primary motor cortex (M1) evokes indirect excitation of pyramidal neurons via local inter-neurons with higher probability than direct excitation (Amassian and Cracco, 1987). The volley along the corticospinal pathway can elicit electromyographic (EMG) responses, termed motor evoked potentials (MEPs), in the target muscles contra-lateral to the side of the stimulation (Hallett, 2000), thus providing a reliable, but indirect, measure of pyramidal tract excitability as well as its cortico-cortical and cortico-subcortical connections. Amplitudes and latencies of MEPs are parameters resulting from a combination of excitatory and inhibitory events occurring in a complex synaptic network at different neural levels along the motor pathway (Ferreri et al., 2003, Rossini and Rossi, 2007), although the relative contribution of these events is far from being fully elucidated. Paired pulse TMS techniques (ppTMS; Kujirai et al., 1993) include a well-known paradigm to test this intracortical inhibitory/facilitatory balance by means of a sub-threshold conditioning stimulus (S1) followed by a supra-threshold test stimulus (S2). The test responses are inhibited at inter-stimulus intervals (ISIs) of 1–5 ms and are facilitated at ISIs of 8–30 ms; these phenomena are referred as short intracortical inhibition (SICI) and intracortical facilitation (ICF). The effect of S1 on the size of control MEP is thought to originate at the cortical level (Shimizu et al., 1999, Orth et al., 2003). It is in fact known that a supra-threshold stimulus determines a corticospinal output leading to a MEP, while a sub-threshold stimulus only excites local, cortical inter-neurons (Di Lazzaro et al., 2002). Thus, by combining a sub-threshold pulse with a supra-threshold pulse one can assess the effects of inter-neurons on cortical output (Ziemann et al., 1998). A significant limitation for the understanding of physiological basis of SICI and ICF is that M1 excitatory/inhibitory balance has only been indirectly investigated by means of MEPs amplitude modulation (Ferreri et al., 2006). Recently, a technical device has been introduced that allows recording electroencephalographic (EEG) responses to TMS of a given scalp site with millisecond resolution. Combining TMS with EEG enables a non-invasive, finally direct, method to study cortical reactivity and connectivity (Ilmoniemi et al., 1997). A network of neuronal connections is in fact engaged when TMS-evoked activation extends from a stimulation site to other parts of the brain and the summation of synaptic potentials produces deflections in scalp EEG signals, starting a few milliseconds after stimulus and lasting about 300 ms, first in the form of rapid oscillations and then as lower-frequency waves (Ilmoniemi and Karhu, 2008). The amplitude, latency, and scalp topography of single pulse TMS-evoked EEG responses have been clearly described (Komssi et al., 2004). The characteristics of these responses are thought to depend on the stimulation intensity and functional state of the stimulated cortex as well as the overall brain. Particularly, it has been suggested that the very first part of the TMS-evoked EEG response reflects the reactivity – that is the functional state – of the stimulated cortex while its spatio-temporal distribution over the scalp reflects the spread of activation to other cortical areas via intra and inter-hemispheric cortico-cortical connections as well as to subcortical structures and spinal cord via projection fibres — that is the effective connectivity of the stimulated area (Lee et al., 2003, Komssi and Kähkönen, 2006). The EEG correlates of SICI and ICF as well as their relationships with MEPs modulation have yet to be clearly demonstrated (Daskalakis et al., 2008). In the present study our purposes were, extending previous preliminary results (Paus et al., 2001, Komssi et al., 2004) by means of EEG navigated-ppTMS coregistration, to characterize the neuronal circuits underlying human M1 connectivity, to evaluate SICI and ICF directly from the cortex using EEG and to investigate whether EEG measures of SICI and ICF are related to the same mechanisms underlying EMG measures of SICI and ICF.