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Objective Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. Methods The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. Results Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. Interpretation Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.

Agenesis of the corpus callosum (AgCC) is a congenital malformation that can occur in isolation or in association with other neurological conditions. Although the behavioral manifestations associated with AgCC have been widely studied, the effects of complete absence of the corpus callosum (CC) on cerebral cortex anatomy are still not completely understood. In this study, cortical thickness in adults with complete AgCC was compared to a group of healthy controls. Results showed highly variable patterns of cortical thickness in AgCC individuals, with few areas showing significant and consistent alterations including primary visual cortex, primary somatosensory cortex and primary motor cortex. These results suggest relatively limited effects of AgCC on cortical morphology, which are mostly restricted to primary sensory and motor areas.

Recent studies have shown, in asymptomatic concussed athletes, metabolic disruption in the primary motor cortex (M1) and abnormal intracortical inhibition lasting for more than six months. The present study aims to assess if these neurochemical and neurophysiological alterations are persistent and linked to M1 cortical thickness.Sixteen active football players who sustained their last concussion, on average, three years prior to testing and 14 active football players who never sustained a concussion were recruited for a single session of proton magnetic resonance spectroscopy ((1)H-MRS) and transcranial magnetic stimulation (TMS). Measures of M1 and whole brain cortical thickness were acquired, and (1)H-MRS data were acquired from left M1 using a MEGA-PRESS sequence. Cortical silent period (CSP) and long-interval intracortical inhibition (LICI) were measured with TMS applied over left M1.No significant group differences were observed for metabolic concentrations, TMS measures, and cortical thickness. However, whereas GABA and glutamate levels were positively correlated in control athletes, this relationship was absent in concussed athletes.These data suggest the general absence of neurophysiologic, neurometabolic and neuroanatomical disruptions in M1 three years following the last concussive event. However, correlational analyses suggest the presence of a slight metabolic imbalance between GABA and glutamate concentrations in the primary motor cortex of concussed athletes.The present study highlights the importance of multimodal assesments of the impacts of sport concussions.

Transcranial magnetic stimulation (TMS) can provide an index of intracortical excitability/inhibition balance. However, the neurochemical substrate of these measures remains unclear. Pharmacological studies suggest the involvement of GABAA and GABAB receptors in TMS protocols aimed at measuring intracortical inhibition, but this link remains inferential. Proton magnetic resonance spectroscopy (1H-MRS) permits measurement of GABA and glutamate + glutamine (Glx) concentrations in the human brain and might help in the direct empirical assessment of the relationship between TMS inhibitory measures and neurotransmitter concentrations. In the present study, MRS-derived relative concentrations of GABA and Glx measured in the left M1 of healthy participants were correlated with TMS measures of intracortical inhibition. Glx levels were found to correlate positively with TMS-induced silent period duration, whereas no correlation was found between GABA concentration and TMS measures. The present data demonstrate that specific TMS measures of intracortical inhibition are linked to shifts in cortical Glx, rather than GABA neurotransmitter levels. Glutamate might specifically interact with GABAB receptors, where higher MRS-derived Glx concentrations seem to be linked to higher levels of receptor activity.

It is known that transcranial direct current stimulation (tDCS) can induce polarity-specific shifts in brain excitability of the primary motor cortex (M1) with anodal tDCS enhancing and cathodal tDCS reducing cortical excitability. However, less is known about its impact on specific intracortical inhibitory mechanisms, such as γ-aminobutyric acid B (GABAB)-mediated inhibition. Consequently, the aim of the present study was to assess the impact of anodal and cathodal tDCS on M1 intracortical inhibition in healthy individuals. Long-interval intracortical inhibition (LICI) and cortical silent period (CSP) duration, both presumably mediated by GABAB receptors, were assessed using transcranial magnetic stimulation immediately before and after a 20 min session of tDCS over the left M1. Anodal tDCS significantly enhanced motor evoked potential size and reduced CSP duration, whereas it had no effect on LICI. Cathodal stimulation did not significantly modulate motor evoked potential size, CSP duration or LICI. This study provides evidence that anodal tDCS, presumably by synaptic plasticity mechanisms, has a direct effect on GABAB-meditated inhibition assessed by the CSP, but not by LICI. Our results further suggest that CSP and LICI probe distinct intracortical inhibitory mechanisms as they are differentially modulated by anodal tDCS. Finally, these data may have clinical value in patients in whom a pathological increase in CSP duration is present, such as schizophrenia.

PURPOSE. The aim of the present study was to assess, in healthy individuals, the impact of M1-M1 tDCS on primary motor cortex excitability using transcranial magnetic stimulation and sensorimotor metabolite concentration using (1)H-MRS. METHODS. For both experiments, each participant received the three following interventions (20 min tDCS, 1mA): left-anodal/right-cathodal, left-cathodal/right-anodal, sham. The effects of tDCS were assessed via motor evoked potentials (experiment 1) and metabolite concentrations (experiment 2) immediately after and 12 minutes following the end of stimulation and compared to baseline measurement. RESULTS. No effect of M1-M1 tDCS on corticospinal excitability was found. Similarly, M1-M1 tDCS did not significantly modulate metabolite concentrations. High inter-subject variability was noted. Response rate analysis showed a tendency towards inhibition following left-anodal/right-cathodal tDCS in 50% of participants and increased GABA levels in 45% of participants. CONCLUSION. In line with recent studies showing important inter-subject variability following M1-supraorbital tDCS, the present data show that M1-M1 stimulation is also associated with large response variability. The absence of significant effects suggests that current measures may lack sensitivity to assess changes in M1 neurophysiology and metabolism associated with M1-M1 tDCS.

Humans have a natural tendency towards symmetrical movements, which rely on a distributed cortical network that allows for complex unimanual movements. Studies on healthy humans using rTMS have shown that disruption of this network, and particularly the dorsal premotor cortex (dPMC), can result in increased physiological mirror movements. The aim of the present set of experiments was to further investigate the role of dPMC in restricting motor output to the contralateral hand and determine whether physiological mirror movements could be decreased in healthy individuals. Physiological mirror movements were assessed before and after transcranial direct current stimulation (tDCS) over right and left dPMC in three conditions: bilateral, unilateral left and unilateral right stimulation. Mirror EMG activity was assessed immediately before, 0, 10 and 20 min after tDCS. Results show that physiological mirroring increased significantly in the hand ipsilateral to cathodal stimulation during bilateral stimulation of the dPMC, 10 and 20 min after stimulation compared to baseline. There was no significant modulation of physiological mirroring in the hand ipsilateral to anodal stimulation in the bilateral condition or following unilateral anodal or unilateral cathodal stimulation. The present data further implicate the dPMC in the control of unimanual hand movements and show that physiological mirroring can be increased but not decreased with dPMC tDCS.

We describe a patient with complete agenesis of the corpus callosum and congenital mirror movements in which primary motor cortex (M1) excitability of both hemispheres was assessed with transcranial magnetic stimulation. Voluntary contraction of the index finger was associated with bilateral electromyographic activity in the first dorsal interosseus muscle. Motor-evoked potentials of identical latencies were produced bilaterally after unilateral M1 stimulation. Measures of intracortical inhibition and facilitation were within normal limits bilaterally although a shorter contralateral silent period was found for both hemispheres. Taken together, the current data suggest a pattern of M1 excitability very similar to that found in patients with congenital mirror movements and no other motor abnormality.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of neurological and psychiatric disorders such as stroke and depression. Yet, the mechanisms underlying its ability to modulate brain excitability to improve clinical symptoms remains poorly understood 33. To help improve this understanding, proton magnetic resonance spectroscopy (1H-MRS) can be used as it allows the in vivo quantification of brain metabolites such as γ-aminobutyric acid (GABA) and glutamate in a region-specific manner 41. In fact, a recent study demonstrated that 1H-MRS is indeed a powerful means to better understand the effects of tDCS on neurotransmitter concentration 34. This article aims to describe the complete protocol for combining tDCS (NeuroConn MR compatible stimulator) with 1H-MRS at 3 T using a MEGA-PRESS sequence. We will describe the impact of a protocol that has shown great promise for the treatment of motor dysfunctions after stroke, which consists of bilateral stimulation of primary motor cortices 27,30,31. Methodological factors to consider and possible modifications to the protocol are also discussed.

Passive observation of motor actions induces cortical activity in the primary motor cortex (M1) of the onlooker, which could potentially contribute to motor learning. While recent studies report modulation of motor performance following action observation, the neurophysiological mechanism supporting these behavioral changes remains to be specifically defined. Here, we assessed whether the observation of a repetitive thumb movement – similarly to active motor practice – would inhibit subsequent long-term potentiation-like (LTP) plasticity induced by paired-associative stimulation (PAS). Before undergoing PAS, participants were asked to either 1) perform abductions of the right thumb as fast as possible; 2) passively observe someone else perform thumb abductions; or 3) passively observe a moving dot mimicking thumb movements. Motor evoked potentials (MEP) were used to assess cortical excitability before and after motor practice (or observation) and at two time points following PAS. Results show that, similarly to participants in the motor practice group, individuals observing repeated motor actions showed marked inhibition of PAS-induced LTP, while the “moving dot” group displayed the expected increase in MEP amplitude, despite differences in baseline excitability. Interestingly, LTP occlusion in the action-observation group was present even if no increase in cortical excitability or movement speed was observed following observation. These results suggest that mere observation of repeated hand actions is sufficient to induce LTP, despite the absence of motor learning.

To perform strictly unilateral movements, the brain relies on a large cortical and subcortical network. This network enables healthy adults to perform complex unimanual motor tasks without the activation of contralateral muscles. However, mirror movements (involuntary movements in ipsilateral muscles that can accompany intended movement) can be seen in healthy individuals if a task is complex or fatiguing, in childhood, and with increasing age. Lateralization of movement depends on complex interhemispheric communication between cortical (i.e., dorsal premotor cortex, supplementary motor area) and subcortical (i.e., basal ganglia) areas, probably coursing through the corpus callosum (CC). Here, we will focus on transcallosal interhemispheric inhibition (IHI), which facilitates complex unilateral movements and appears to play an important role in handedness, pathological conditions such as Parkinson’s disease, and stroke recovery.