Jean-Charles Lamy

Paired associative stimulation induces change in presynaptic inhibition of Ia terminals in wrist flexors in humans.

Enhancements in the strength of corticospinal projections to muscles are induced in conscious humans by paired associative stimulation (PAS) to the motor cortex. Although most of the previous studies support the hypothesis that the increase of the amplitude of motor evoked potentials (MEPs) by PAS involves long-term potentiation (LTP)-like mechanism in cortical synapses, changes in spinal excitability after PAS have been reported, suggestive of parallel modifications in both cortical and spinal excitability. In a first series of experiments (experiment 1), we confirmed that both flexor carpi radialis (FCR) MEPs and FCR H reflex recruitment curves are enhanced by PAS. To elucidate the mechanism responsible for this change in the H reflex amplitude, we tested, using the same subjects, the hypothesis that enhanced H reflexes are caused by a down-regulation of the efficacy of mechanisms controlling Ia afferent discharge, including presynaptic Ia inhibition and postactivation depression. To address this question, amounts of both presynaptic Ia inhibition of FCR Ia terminals (D1 and D2 inhibitions methods; experiment 2) and postactivation depression (experiment 3) were determined before and after PAS. Results showed that PAS induces a significant decrease of presynaptic Ia inhibition of FCR terminals, which was concomitant with the facilitation of the H reflex. Postactivation depression was unaffected by PAS. It is argued that enhancement of segmental excitation by PAS relies on a selective effect of PAS on the interneurons controlling presynaptic inhibition of Ia terminals.

Does Trans-Spinal Direct Current Stimulation Alter Phrenic Motoneurons and Respiratory Neuromechanical Outputs in Humans? A Double-Blind, Sham-Controlled, Randomized, Crossover Study

Although compelling evidence has demonstrated considerable neuroplasticity in the respiratory control system, few studies have explored the possibility of altering descending projections to phrenic motoneurons (PMNs) using noninvasive stimulation protocols. The present study was designed to investigate the immediate and long-lasting effects of a single session of transcutaneous spinal direct current stimulation (tsDCS), a promising technique for modulating spinal cord functions, on descending ventilatory commands in healthy humans. Using a double-blind, controlled, randomized, crossover approach, we examined the effects of anodal, cathodal, and sham tsDCS delivered to the C3–C5 level on (1) diaphragm motor-evoked potentials (DiMEPs) elicited by transcranial magnetic stimulation and (2) spontaneous ventilation, as measured by respiratory inductance plethysmography. Both anodal and cathodal tsDCS induced a progressive increase in DiMEP amplitude during stimulation that persisted for at least 15 min after current offset. Interestingly, cathodal, but not anodal, tsDCS induced a persistent increase in tidal volume. In addition, (1) short-interval intracortical inhibition, (2) nonlinear complexity of the tidal volume signal (related to medullary ventilatory command), (3) autonomic function, and (4) compound muscle action potentials evoked by cervical magnetic stimulation were unaffected by tsDCS. This suggests that tsDCS-induced aftereffects did not occur at brainstem or cortical levels and were likely not attributable to direct polarization of cranial nerves or ventral roots. Instead, we argue that tsDCS could induce sustained changes in PMN output. Increased tidal volume after cathodal tsDCS opens up the perspective of harnessing respiratory neuroplasticity as a therapeutic tool for the management of several respiratory disorders.

Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline

DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline.

Tuning Eye-Gaze Perception by Transitory STS Inhibition

Processing eye-gaze information is a key step to human social interaction. Neuroimaging studies have shown that superior temporal sulcus (STS) is highly implicated in eye-gaze perception. In autism, a lack of preference for the eyes, as well as anatomo-functional abnormalities within the STS, has been described. To date, there are no experimental data in humans showing whether it is possible to interfere with eye-gaze processing by modulating STS neural activity. Here, we measured eye-gaze perception before and after inhibitory transcranial magnetic stimulation (TMS) applied over the posterior STS (pSTS) in young healthy volunteers. Eye-gaze processing, namely overt orienting toward the eyes, was measured using eye tracking during passive visualization of social movies. Inhibition of the right pSTS led participants to look less to the eyes of characters during visualization of social movies. Such effect was specific for the eyes and was not observed after inhibition of the left pSTS nor after placebo TMS. These results indicate for the first time that interfering with the right pSTS neural activity transitorily disrupts the behavior of orienting toward the eyes and thus indirectly gaze perception, a fundamental process for human social cognition. These results could open up new perspectives in therapeutic interventions in autism.

Mutations in the netrin-1 gene cause congenital mirror movements

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.