Advanced TMS approaches to probe corticospinal excitability during action preparation

The motor system displays strong changes in neural activity during action preparation. In the past decades, several techniques, including transcranial magnetic stimulation (TMS), electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have allowed us to gain insights into the functional role of such preparatory activity in humans. More recently, new TMS tools have been proposed to study the mechanistic principles underlying the changes in corticospinal excitability during action preparation. The aim of the present review is to provide a comprehensive description of these advanced methods and to discuss the new knowledge they give access to, relative to other existing approaches. We start with a brief synthesis of the work that has been achieved so far using classic TMS protocols during action preparation, such as the so-called single-pulse and paired-pulse techniques. We then highlight three new approaches that recently arose in the field of action preparation, including (1) the exploitation of TMS current direction, known as directional TMS, which enables investigating different subsets of neurons in the primary motor cortex, (2) the use of paired-pulse TMS to study the suppressive influence of the cerebellum on corticospinal excitability and (3) the development of a double-coil TMS approach, which facilitates the study of bilateral changes in corticospinal excitability. The aim of the present article is twofold: we seek to provide a comprehensive description of these advanced TMS tools and to discuss their bearings for the field of action preparation with respect to more traditional TMS approaches, as well as to neuroimaging techniques such as EEG or fMRI. Finally, we point out perspectives for fundamental and clinical research that arise from the combination of these methods, widening the horizon of possibilities for the investigation of the human motor system, both in health and disease.


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Three decades of work using single-pulse and paired-pulse TMS during action 123 preparation 124 In its classic form, the single-pulse technique involves placing a coil composed of two 125 circular wings of wire (i.e., namely a "figure-of-eight" coil) on the scalp over M1, with the 126 handle oriented towards the back of the head and turned laterally to form a 45° angle with 127 respect to the midline (see Figure 1). The center of the coil is positioned over a so-called  latter tasks, a pre-cue allows subjects to prepare (part of) their response in advance of the 182 imperative signal. Importantly, recording MEPs in such RT tasks necessitates to control for 183 any background EMG activity, which may potentiate MEP amplitude. Hence, with such 184 protocols, MEPs can be recorded in muscles that are selected for the forthcoming action (e.g., 185 in the left FDI muscle before left index finger movements), as well as in muscles that are non-186 selected but are part of the potential effector repertoire (e.g., in the left FDI muscle before 187 right index finger movements). In addition, MEPs are also sometimes recorded in other, task-188 7 irrelevant muscles (e.g., in a left pinky muscle before left index finger movements), in order 189 to investigate the spatial specificity of the changes in CS excitability. One main advantage of 190 MEP measurements in this context, compared to other approaches such as EEG or fMRI, is 191 the possibility to probe changes in different muscles, thus reflecting neural activity in 192 different pools of CS cells. This is what we refer to as the high spatial resolution of TMS.

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Notably, a single TMS pulse can elicit MEPs in adjacent muscles simultaneously. This is during action preparation (Soteropoulos, 2018). Interestingly, TMS studies also revealed that this 216 early suppression concerns not only the selected muscle but also non-selected and task-irrelevant findings led to the suggestion that action preparation involves an initial suppression of the activity 220 of the motor system (a phenomenon sometimes referred to as "preparatory inhibition" or hypotheses. One idea in the field is that these changes in CS excitability reflect action selection 228 processes (i.e., "What and when to move?"; e.g., Duque et al., 2012;Duque and Ivry, 2009).

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Another hypothesis posits that these changes are related to action specification processes (i.e., 230 "How to move?"; Greenhouse et al., 2015;Hannah et al., 2018). Notably, while these hypotheses 231 are usually perceived as mutually exclusive, a potential alternative idea, which is in line with 232 integrated models of action preparation (e.g., Cisek, 2007), would be that CS excitability is shaped 233 by both action selection and specification processes, with some of them having suppressive 234 effects. Since the introduction of TMS, the field of brain stimulation has seen the emergence of more 256 sophisticated protocols, allowing one to probe, with a higher degree of specificity, different

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Hence, single-pulse TMS has allowed us to gain substantial insights as regards to how 319 preparatory processes unfold within the motor system, revealing both the temporal dynamics and    The use of directional TMS requires taking into account at least three key technical 394 issues. First, one has to be aware of the direction of the current flow within the coil itself (i.e., 395 the coil current direction). As such, the three cortical current directions mentioned earlier (i.e., 396 PA, LM and AP) will only be generated with the three coil orientations described (i.e., 45°, 397 90° and 225°, respectively) if the current within the coil flows in a clockwise direction in the 398 left wing and in an anticlockwise one in the right wing, as described in Figure 1. Yet, the 399 default coil current direction can change from one TMS device to another and is even 400 configurable on some of them. Hence, it is essential to be vigilant regarding this aspect when 401 designing a directional TMS protocol. Second, the shape of the pulse is of critical importance.

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In fact, most TMS devices allow the production of either monophasic or biphasic pulses.    Interestingly though, the authors did report a difference between changes in MEP PA and 476 MEP AP amplitudes when considering the selected and non-selected muscles. In fact, while 477 MEP AP were reduced in these muscles (as described above), the authors did not observe any How does it work? 507 As described above, ppTMS has been largely exploited to investigate CS modulatory 508 sources originating from cortical sites, including M1, prefrontal, premotor and parietal areas.

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More recently, the use of ppTMS has been extended to a key subcortical structure, namely the ascending volleys (i.e., travelling up to the cortex). The latter volleys may suppress those 552 descending from the cortex following the M1 Pulse Test (Taylor, 2006) and may thus 553 potentially reduce the amplitude of conditioned MEPs in the exact same way as CBI would do 554 (Fisher et al., 2009). An important challenge is therefore to determine a Pulse Cond intensity 555 that is sufficient to recruit Purkinje cells and probe CBI, but not too high to avoid direct    The authors were thus able to compute an MEP ratio (i.e., [conditioned / unconditioned]) and 621 probe CBI for muscles that are either selected for the forthcoming response (i.e., FDI and TA 622 before index and foot responses, respectively) or task-irrelevant (i.e., TA and FDI before 623 index and foot responses, respectively). Hence, such a protocol allows one to determine  One recent study has used double-coil TMS to probe CS excitability during action 729 preparation, and showed that MEPs obtained using this method reflect similar changes in CS 730 excitability compared to MEPs elicited using single-pulse TMS . 731 Hence, double-coil TMS can be reliably used to probe preparatory activity bilaterally. This 732 technique has two main advantages for studies in the field of action preparation.

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Firstly, it allows researchers to obtain markers of CS excitability in both hands at a near-  The level of understanding that can be reached when studying a given system or process 789 depends closely on the tools that are available to examine it and, whatever the field of study,