Alexandra Lackmy-Vallée

Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).

Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) are indirect and non-invasive methods used to induce excitability changes in the motor cortex via a wire coil generating a magnetic field that passes through the scalp. Today, TMS has become a key method to investigate brain functioning in humans. Moreover, because rTMS can lead to long-lasting after-effects in the brain, it is thought to be able to induce plasticity. This tool appears to be a potential therapy for neurological and psychiatric diseases. However, the physiological mechanisms underlying the effects induced by TMS and rTMS have not yet been clearly identified. The purpose of the present review is to summarize the main knowledge available for TMS and rTMS to allow for understanding their mode of action and to specify the different parameters that influence their effects. This review takes an inventory of the most-used rTMS paradigms in clinical research and exhibits the hypotheses commonly assumed to explain rTMS after-effects.

Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: an update.

Stroke is a leading cause of adult motor disability. The number of stroke survivors is increasing in industrialized countries, and despite available treatments used in rehabilitation, the recovery of motor functions after stroke is often incomplete. Studies in the 1980s showed that non-invasive brain stimulation (mainly repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]) could modulate cortical excitability and induce plasticity in healthy humans. These findings have opened the way to the therapeutic use of the 2 techniques for stroke. The mechanisms underlying the cortical effect of rTMS and tDCS differ. This paper summarizes data obtained in healthy subjects and gives a general review of the use of rTMS and tDCS in stroke patients with altered motor functions. From 1988 to 2012, approximately 1400 publications were devoted to the study of non-invasive brain stimulation in humans. However, for stroke patients with limb motor deficit, only 141 publications have been devoted to the effects of rTMS and 132 to those of tDCS. The Cochrane review devoted to the effects of rTMS found 19 randomized controlled trials involving 588 patients, and that devoted to tDCS found 18 randomized controlled trials involving 450 patients. Without doubt, rTMS and tDCS contribute to physiological and pathophysiological studies in motor control. However, despite the increasing number of studies devoted to the possible therapeutic use of non-invasive brain stimulation to improve motor recovery after stroke, further studies will be necessary to specify their use in rehabilitation.

Enhanced propriospinal excitation from hand muscles to wrist flexors during reach-to-grasp in humans

In humans, propriospinal neurons located at midcervical levels receive peripheral and corticospinal inputs and probably participate in the control of grip tasks, but their role in reaching movements, as observed in cats and primates, is still an open question. The effect of ulnar nerve stimulation on flexor carpi radialis (FCR) motor evoked potential (MEP) was tested during reaching tasks and tonic wrist flexion. Significant MEP facilitation was observed at the end of reach during reach-to-grasp but not during grasp, reach-to-point, or tonic contractions. MEP facilitation occurred at a longer interstimulus interval than expected for convergence of corticospinal and afferent volleys at motoneuron level and was not paralleled by a change in the H-reflex. These findings suggest convergence of the two volleys at propriospinal level. Ulnar-induced MEP facilitation was observed when conditioning stimuli were at 0.75 motor response threshold (MT), but not 1 MT. This favors an increased excitability of propriospinal neurons rather than depression of their feedback inhibition, as has been observed during tonic power grip tasks. It is suggested that the ulnar-induced facilitation of FCR MEP during reach may be due to descending activation of propriospinal neurons, assisting the early recruitment of large motoneurons for rapid movement. Because the feedback inhibitory control is still open, this excitation can be truncated by cutaneous inputs from the palmar side of the hand during grasp, thus assisting movement termination. It is concluded that the feedforward activation of propriospinal neurons and their feedback control may be involved in the internal model, motor planning, and online adjustments for reach-to-grasp movements in humans.

ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION OF THE MOTOR CORTEX INDUCES OPPOSITE MODULATION OF RECIPROCAL INHIBITION IN WRIST EXTENSOR AND FLEXOR

Transcranial direct current stimulation (tDCS) is used as a noninvasive tool to modulate brain excitability in humans. Recently, several studies have demonstrated that tDCS applied over the motor cortex also modulates spinal neural network excitability and therefore can be used to explore the corticospinal control acting on spinal neurons. Previously, we showed that reciprocal inhibition directed to wrist flexor motoneurons is enhanced during contralateral anodal tDCS, but it is likely that the corticospinal control acting on spinal networks controlling wrist flexors and extensors is not similar. The primary aim of the study was to explore the effects of anodal tDCS on reciprocal inhibition directed to wrist extensor motoneurons. To further examine the supraspinal control acting on the reciprocal inhibition between wrist flexors and extensors, we also explored the effects of the tDCS applied to the ipsilateral hand motor area. In healthy volunteers, we tested the effects induced by sham and anodal tDCS on reciprocal inhibition pathways innervating wrist muscles. Reciprocal inhibition directed from flexor to extensor muscles and the reverse situation, i.e., reciprocal inhibition, directed from extensors to flexors were studied in parallel with the H reflex technique. Our main finding was that contralateral anodal tDCS induces opposing effects on reciprocal inhibition: it decreases reciprocal inhibition directed from flexors to extensors, but it increases reciprocal inhibition directed from extensors to flexors. The functional result of these opposite effects on reciprocal inhibition seems to favor wrist extension excitability, suggesting an asymmetric descending control onto the interneurons that mediate reciprocal inhibition.

Subthalamic nucleus stimulation reverses spinal motoneuron activity in parkinsonian patients

Although a cardinal symptom of Parkinsonian disease, up to now, rigidity has been investigated much less than spasticity in hemiplegic patients. Many pathophysiological mechanisms may at least theoretically contribute to Parkinsonian rigidity, from altered viscoelastic muscle properties to inability of parkinsonian patients to relax. However, as demonstrated many years ago, motoneuron responses to muscle afferent volleys are involved in rigidity since afferent volleys are suppressed after dorsal root section. To our knowledge, homosynaptic depression (i.e. the fact that motoneuron responses to Ia afferent volleys exhibit a frequency-related depression) has not been studied in parkinsonian disease, despite the fact that in spastic patients, changes in homosynaptic depression are significantly correlated at wrist and ankle levels with the severity of spasticity. Thus, in the present series of experiments, we investigated in parkinsonian patients with chronic implantation of both subthalamic motor nuclei, the amount of homosynaptic depression at wrist and ankle levels on and off deep brain stimulation. Off deep brain stimulation, the frequency-related depression disappeared, the patients became rigid and the amount of homosynaptic depression was significantly correlated with the severity of rigidity. On deep brain stimulation, the frequency-related depression was restored and the rigidity suppressed, suggesting that homosynaptic depression is one of the mechanisms underlying rigidity in Parkinsons disease. Moreover, the unexpected finding that changes in the rigidity score and the amount of homosynaptic depression are time-locked to the onset of deep brain stimulation leads us to reconsider the mechanisms underlying changes in homosynaptic depression.

Non-linear input-output properties of the cortical networks mediating TMS-induced short-interval intracortical inhibition in humans.

The effects of transcranial magnetic stimulation (TMS) on post‐discharge histograms of single motor units in the first dorsal interosseous have been tested to estimate the input–output properties of cortical network‐mediating short‐interval intracortical inhibition (SICI) to pyramidal cells of the human primary motor cortex. SICI was studied using the paired pulse paradigm (2‐ms interval): test TMS intensity was varied to evoke peaks of different size in post‐discharge histograms, reflecting the corticospinal excitatory post‐synaptic potential in the relevant spinal motoneuron, and conditioning TMS intensity was constant (0.6 × the resting motor threshold). Navigated brain stimulation was used to monitor the coil position. A linear relationship was observed between test peak size and test TMS intensity, reflecting linear summation of excitatory inputs induced by TMS. SICI was estimated using the difference between conditioned (produced by the paired pulses) and test peaks (produced by the isolated test pulse). Although the conditioning intensity (activating cortical inhibitory interneurons mediating SICI) was kept constant throughout the experiments, the level of SICI changed with the test peak size, in a non‐linear fashion, suggesting that low‐threshold cortical neurons (excitatory interneurons/pyramidal cells) are less sensitive to SICI than those of higher threshold. These findings provide the first experimental evidence, under physiological conditions, for non‐linear input/output properties of a complex cortical network. Consequently, changes in the recruitment gain of cortical inhibitory interneurons can greatly modify the excitability of pyramidal cells and their response to afferent inputs.

Corticospinal and reciprocal inhibition actions on human soleus motoneuron activity during standing and walking

Reciprocal Ia inhibition constitutes a key segmental neuronal pathway for coordination of antagonist muscles. In this study, we investigated the soleus H‐reflex and reciprocal inhibition exerted from flexor group Ia afferents on soleus motoneurons during standing and walking in 15 healthy subjects following transcranial magnetic stimulation (TMS). The effects of separate TMS or deep peroneal nerve (DPN) stimulation and the effects of combined (TMS + DPN) stimuli on the soleus H‐reflex were assessed during standing and at mid‐ and late stance phases of walking. Subthreshold TMS induced short‐latency facilitation on the soleus H‐reflex that was present during standing and at midstance but not at late stance of walking. Reciprocal inhibition was increased during standing and at late stance but not at the midstance phase of walking. The effects of combined TMS and DPN stimuli on the soleus H‐reflex significantly changed between tasks, resulting in an extra facilitation of the soleus H‐reflex during standing and not during walking. Our findings indicate that corticospinal inputs and Ia inhibitory interneurons interact at the spinal level in a task‐dependent manner, and that corticospinal modulation of reciprocal Ia inhibition is stronger during standing than during walking.

Changes in spinal inhibitory networks induced by furosemide in humans.

It has been demonstrated in humans that furosemide crosses the blood–brain barrier and blocks activity in the epileptic brain. In this study, we demonstrated using non‐invasive electrophysiological techniques in healthy human subjects that furosemide, a cation‐chloride co‐transporter blocker, orally administered at doses commonly used in the clinic (40 mg), reduces the efficacy of pre‐ and postsynaptic inhibition of soleus motoneurons in the spinal cord. Furosemide can be a useful tool to detect the intrinsic functioning of inhibitory synapses and to explore if the reduced inhibitory interneuronal activity that probably contributes to spasticity also exists in humans with spinal cord injury.

Corticospinal control from M1 and PMv areas on inhibitory cervical propriospinal neurons in humans

Inhibitory propriospinal neurons with diffuse projections onto upper limb motoneurons have been revealed in humans using peripheral nerve stimulation. This system is supposed to mediate descending inhibition to motoneurons, to prevent unwilling muscle activity. However, the corticospinal control onto inhibitory propriospinal neurons has never been investigated so far in humans. We addressed the question whether inhibitory cervical propriospinal neurons receive corticospinal inputs from primary motor (M1) and ventral premotor areas (PMv) using spatial facilitation method. We have stimulated M1 or PMv using transcranial magnetic stimulation (TMS) and/or median nerve whose afferents are known to activate inhibitory propriospinal neurons. Potential input convergence was evaluated by studying the change in monosynaptic reflexes produced in wrist extensor electromyogram (EMG) after isolated and combined stimuli in 17 healthy subjects. Then, to determine whether PMv controlled propriospinal neurons directly or through PMv‐M1 interaction, we tested the connectivity between PMv and propriospinal neurons after a functional disruption of M1 produced by paired continuous theta burst stimulation (cTBS). TMS over M1 or PMv produced reflex inhibition significantly stronger on combined stimulations, compared to the algebraic sum of effects induced by isolated stimuli. The extra‐inhibition induced by PMv stimulation remained even after cTBS which depressed M1 excitability. The extra‐inhibition suggests the existence of input convergence between peripheral afferents and corticospinal inputs onto inhibitory propriospinal neurons. Our results support the existence of direct descending influence from M1 and PMv onto inhibitory propriospinal neurons in humans, possibly though direct corticospinal or via reticulospinal inputs.

P21.4 The non-linear input output properties of the cortical networks mediating transcranial magnetic stimulation induced short-interval intra-cortical inhibition in humans

Objectives: To determine if a second-scale inter-stimulus interval (ISI) of single-pulse TMS affects the amplitudes of the induced MEPs. The aim was to reduce the duration of the MEP measurements while maintaining response stability. Methods: Nine healthy subjects were studied. The left hemisphere was mapped for the cortical representation area of the dominant hand thenar muscle, and resting motor threshold (MT) was determined. MEPs were analyzed from 30 responses to navigated TMS with a stimulation intensity of 120% of the MT. The investigated ISIs were 1, 2, 3, 5 and 10 s as well as randomized ranges of 1 3 s, 3 5 s and 5 10 s. MEP amplitudes were analyzed over the stimulation trains and compared between different ISIs. Results: The mean amplitude of 10 first MEPs were lower (p < 0.05) at short ISIs when compared to those measured at long ISIs. This difference was not observed when the last 10 MEPs were compared. Also, no differences were observed between the MEPs at different ISIs, when the means of all 30 MEPs were compared. Significant increase (p < 0.05) in the MEP amplitudes (sliding mean of 10 MEPs) was observed during the stimulation train at constant ISIs of 1 to 5 s and at random ISI of 1 3 s. Conclusions: The ISI does not affect MEP amplitudes when >20 stimuli are applied. However, with short ISIs several stimuli may have to be rejected from the analysis from the beginning of the measurement. The MEPs in the beginning of the stimulation train at short ISI may be prone to voluntary muscle relaxation which could decrease the MEP size of a relaxed muscle. This has not been reported earlier in case of MEPs and likely this may not be an issue when MEPs from an active muscle are recorded.