The Effects of Stimulator, Waveform, and Current Direction on Intracortical Inhibition and Facilitation: A TMS Comparison Study

Background: Cortical function is dependent on the balance between excitatory and inhibitory influences. In the human motor cortex, surrogates of these interactions can be measured in vivo, non-invasively with double-pulse transcranial magnetic stimulation (TMS). To compare results from data acquired with different available setups and bring data together, it is inevitable to determine whether different TMS setups lead to comparable or differential results. Objective: We assessed and compared short intracortical inhibition (SICI) and intracortical facilitation (ICF) testing four different experimental conditions. Methods: SICI and ICF were studied with different stimulators (Magstim BiStim2 or MagVenture MagPro X100), waveforms (monophasic or biphasic), current directions (anterior-posterior or posterior-anterior) at interstimulus intervals (ISIs) of 1, 3, 10, 15 ms. Results: We were not able to detect differences for SICI and ICF, when comparing the tested conditions, except for 3 ms SICI in which the anterior-posterior current direction led to stronger modulation. Correlation analysis suggested comparability for 3 ms SICI for the Magstim monophasic posterior-anterior condition with both tested MagVenture conditions. Conclusions: 3 ms SICI data sets obtained with two different, commonly used stimulators (Magstim BiStim2 or MagVenture MagPro X100) with conventionally used stimulation parameters are largely comparable. This may allow the combination of data sets in an open science view.

Spatiotemporal stimulation strategies in neuroprostheses to improve locomotion after spinal cord injury

Jérôme Gandar

Spinal cord injury (SCI) disrupts communication within central nervous system and lead to range of neurological disorders including paralysis. Current rehabilitation strategies to restore locomotion are poorly effective in people with severe SCI. Epidural electrical stimulation (EES) showed promising results in animal models and humans to improve recovery. However, EES protocols have remained empirical, which has limited the efficacy of this paradigm. In this thesis, I report my contribution to the development of EES related software and hardware that were driven by the under- standing of the mechanisms underlying EES. These neurotechnologies showed a remarkable efficacy to reestablish locomotion in animal models of leg paralysis. EES protocols have primarily been delivered with continuous stimulations applied over the middle of the spinal cord, independently of current limb positions. However the natural activity of the spinal cord does not correspond to this limited monotone modulation. In the first part of this thesis, we developed spatiotemporal stimulation protocols that seek to reproduce the natural activity of the spinal cord during walking. Using computational models, we identified optimal electrode locations that target individual posterior roots. These simulations steered the design of spatially selective spinal implants. Control software triggered stimulation trains in real-time to engage extensor and flexor synergies according to limb positions. This spatiotemporal neuro- modulation therapy enhanced locomotor performances in rats with severe SCI. However, these spatiotemporal neuromodulation protocols were controlled via an external computer. The animal had no control over the occurrence of the stimulation. To remedy this limitation, we designed a brain-spine interface. We linked motor states decoded from leg motor cortex activity to spinal cord stimulation protocols to elicited the intended movements. We implemented this brain-spine interface in a nonhuman primate models of transient unilateral leg paralysis. All the animals immediately regained movements of the paralyzed leg. There is often a mechanical mismatch between current stiff implants and the soft neural tissues of the host. The third part of this thesis is dedicated to the design and fabrication of soft neural implants that present the same elasticity as the dura mater. These implants maintain the ability to deliver electrochemical stimulation while being stretched. Such interfaces can be applied to multiple neuroprosthetic applications, including the restoration of locomotion in paralyzed rats. In the last part of this thesis, I addressed the current limitations of spinal implant specificity. We found that EES activates the large afferent fibers within the dorsal rots and developed novel implants that take advantage of the known trajectories of the dorsal roots to increase the specificity of EES. First, we built a precise anatomical computational model of the lumbosacral roots. We then ran simulations that identi- fied multipolar electrode configurations capable of steering the current specifcally. These results drove the fabrication of soft neural implants that we inserted chronically in rat models of severe SCI. Experiments showed that multipolar EES increases the specificity of the stimulation compared to conventional protocols. All the concepts developed and validated in my thesis are already applied or are steering applications in humans with SCI.

EPFL2019

Hand perceptions induced by single pulse transcranial magnetic stimulation over the primary motor cortex

Michela Bassolino, Olaf Blanke, Matteo Franza, Andrea Serino, Giuliana Sorrentino, Matteo Vissani

Background When single pulse transcranial magnetic stimulation (TMS) is applied over the primary motor cortex (M1) with sufficient intensity, it evokes muscular contractions (motor-evoked potentials, MEPs) and muscle twitches (TMS-evoked movements). Participants may also report various hand sensations related to TMS, but the perception elicited by TMS and its relationship to MEPs and evoked movements has not been systematically studied. Objective The main aim of this work is to evaluate participants' kinesthetic and somatosensory hand perceptions elicited by single-pulse TMS over M1-hand area at different intensities of stimulation and their relation with MEPs and TMS-evoked movements. Methods We compared the number of MEPs (measured by electromyography), TMS-evoked movements (measured by an accelerometer) and participants' hand perception (measured by verbal report) elicited by TMS at different intensity of stimulation. This way, we estimated the amplitude of MEPs and the acceleration of TMS-evoked movements sufficient to trigger TMS evoked hand perceptions. Results We found that TMS-evoked hand perceptions are induced at 105% of the individual resting motor threshold, a value significantly different from the threshold inducing MEPs (about 100%) and TMS-evoked movements (about 110%). Our data indicate that only MEPs with an amplitude higher than 0.62 mV and TMS-evoked movements with acceleration higher than 0.42 m/s2 were associated with hand perceptions at threshold. Conclusions Our data reveal the main features of TMS-evoked hand perception and show that in addition to MEPs and TMS-evoked movements, this is a separate discernible response associated to single-pulse TMS over M1.

2019

TMS-induced control of bodily self-consciousness by combining non-invasive brain stimulation and immersive virtual reality

Matteo Franza

Our brain constantly receives and integrates a flow of sensory and motor information that shapes the way our body is represented. Several experimental approaches have been proposed to alter the body representation, by manipulating exteroceptive or interoceptive bodily signals. During my thesis, I studied the contribution of central, rather than peripheral, motor brain mechanisms underlying bodily self-consciousness (BSC). For this purpose, I attempted to manipulate BSC, specifically inducing embodiment for a fake hand in healthy participants, by using a novel method that combines non-invasive transcranial magnetic stimulation (TMS) with immersive virtual reality (VR). First, we managed to induce embodiment for a virtual hand utilizing the spatio-temporal coherence between an artificial TMS-induced activation of the motor system and movement-related visual feedback in VR (Study 1). I observed that embodiment for a virtual hand was induced only when the provided stimulation is supra-threshold but not when TMS is delivered sub-threshold. I argue that such TMS-induced illusory embodiment is due to neuro-visual integration between TMS-induced primary motor cortex (M1) activation and hand twitches with visual VR feedback. In a second study (Study 2), by refining the parameters of our TMS-VR protocol we investigated the different peripheral components elicited by TMS with a special focus on hand perception. Our data revealed the main features of TMS-evoked hand perceptions (in terms of threshold and evoked subjective perceptions) and show that these are discernible from MEPs and TMS-evoked movements associated with single-pulse TMS over M1. Finally, we combined the TMS-VR setup (Study 1) and our stimulation protocol (Study 2) to investigate whether the awareness of peripheral bodily stimuli is necessary to induce changes in BSC (Study 3). Our findings reveal a prominent role of conscious bodily perceptions in triggering illusory embodiment, even in the absence of peripheral stimuli. Furthermore, I have been involved in other projects investigating the plasticity of body and space representation in healthy young and elderly participants (listed in appendix 1 & 2) and the robotically controlled induction of presence hallucinations (appendix 3). The present work provides important findings and promising tools regarding the role of non-invasive brain stimulation and virtual technology in the study of BSC. In particular, I showed that it is possible to manipulate BSC by directly stimulating the M1 cortical representation of the hand inducing embodiment for a virtual hand. Furthermore, I investigated the role of the TMS-evoked hand sensations and their role in the embodiment showing that the hand ownership is mainly driven by the detection of TMS stimuli on the hand.