Investigation de l’effet du polymorphisme Val66Met du gène BDNF sur les mécanismes neurophysiologiques qui sous-tendent les apprentissages moteurs procéduraux et sensorimoteurs, de même que sur le transfert intermanuel des apprentissages

Le facteur neurotrophique dérivé du cerveau (Brain-Derived Neurotrophic Factor; BDNF), synthétisé en grande partie dans les neurones glutamatergiques en réponse à l’activité neuronale, est impliqué dans la plasticité synaptique et la croissance dendritique, en plus de jouer un rôle central dans le développement, le fonctionnement et la survie des neurones du système nerveux central. Le gène BDNF se retrouve le plus fréquemment sur sa forme Valine à Valine au codon 66 (Val66Val). Le polymorphisme à nucléotide unique Val66Met du gène BDNF, présent chez environ un tiers de la population américaine, interfère avec la recapture du BDNF par les granules de sécrétion et réduit la disponibilité du BDNF dans l’espace synaptique et les dendrites. De ce fait, le polymorphisme Val66Met est associé aux altérations de la neurotransmission excitatrice glutamatergique et inhibitrice GABA-ergique, de la synaptogénèse, ainsi qu’à des différences structurelles et fonctionnelles de plusieurs régions cérébrales comparativement aux porteurs de la variante Val66Val, par exemple au niveau de l’hippocampe. Dans le cortex moteur primaire (M1), le polymorphisme Val66Met du gène BDNF est lié à une altération de la plasticité synaptique dépendante de l’activité se répercutant entre autres dans une modulation anormale des cartes corticomotrices, de l’excitabilité corticospinale et de l’homéoplasticité synaptique. Sur le plan comportemental, les individus porteurs du polymorphisme Val66Met montrent un déficit d’apprentissage et de rétention d’habiletés visuomotrices complexes. Or, les effets potentiels du polymorphisme Val66Met sur la plasticité synaptique intracorticale impliquée dans l’apprentissage moteur et sur le transfert intermanuel de l’apprentissage, sous-tendu en grande partie par les interactions interhémisphériques, demeurent à ce jour inconnu. Dans le cadre du présent ouvrage, nous avons comparé les performances en apprentissage, en rétention et en transfert intermanuel d’habiletés motrices procédurales, par le biais de la Serial Reaction Time Task (SRTT), et en apprentissage d’habiletés sensorimotrices de base, soient la vitesse de contraction motrice, la précision de force de préhension et la dextérité manuelle fine, entre des sujets Val66Met et Val66Val droitiers, âgés de 18 à 35 ans. À l’aide de la stimulation magnétique transcrânienne, nous avons également comparé la modulation de divers mécanismes neurophysiologiques en M1 en lien avec ces phénomènes, notamment l’excitabilité corticospinale, l’inhibition intracorticale de courte latence et l’inhibition interhémisphérique. Les résultats des deux études suggèrent l’absence de différence entre les sujets Val66Val et Val66Met sur l’apprentissage de composantes sensorimotrices avec la main droite dominante et la main gauche non dominante, ainsi que sur l’apprentissage procédural d’une séquence motrice. Cependant, les résultats de l’étude 1 ont indiqué une altération du transfert intermanuel de la séquence apprise avec la main dominante vers la main non dominante non entraînée chez les sujets Val66Met, suggérant une atteinte probable des interactions interhémisphériques. De plus, les résultats de l’étude 2 ont montré une absence de modulation de l’inhibition intracorticale à courte latence en M1 bilatéral suivant la pratique sensorimotrice. Les implications potentielles de ces résultats dans l’apprentissage moteur, le transfert intermanuel et les mécanismes neurophysiologiques qui les sous-tendent sont discutées. En somme, ces résultats permettent une perspective plus précise du lien entre le polymorphisme Val66Met et ces phénomènes, en plus de suggérer des hypothèses spécifiques à étudier.Brain-derived neurotrophic factor (BDNF), which is largely synthesized in glutamatergic neurons in response to stimulation, is involved in synaptic plasticity and dendritic growth, and plays a key role in development, function, and survival of neurons in the central nervous system. The BDNF gene is most commonly found in its Valine to Valine form at codon 66 (Val66Val). The single nucleotide Val66Met polymorphism, found in approximately one third of the American population, interferes with BDNF recapture in the secretory vesicles, thus altering BDNF availability in the synaptic cleft and dendrites. Thus, the Val66Met polymorphism is associated with altered excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, synaptogenesis, and functional and structural alterations of several brain structures compared to Val66Val carriers, for instance, at the level of the hippocampus. In the primary motor cortex, the Val66Met polymorphism is linked to altered activity-dependent synaptic plasticity, which may be expressed in impaired regulation of motor cortical maps, corticospinal excitability, and synaptic homeoplasticity. At the behavioral level, Val66Met carriers display impaired learning and retention of complex visuomotor skills. However, to this day, little is known regarding the effects of the Val66Met polymorphism on intracortical plasticity mechanisms involved in motor learning, and intermanual transfer of a motor skill, which relies in part on interhemispheric interactions. In the present work, we compared learning, retention and intermanuel transfer of procedural motor skills on the Serial Reaction Time Task (SRTT), and learning of basic sensorimotor components, namely muscle contraction speed, precision grip strength, and fine manual dexterity, between Val66Val and Val66Met right-handed participants aged between 18 and 35 years old. Transcranial magnetic stimulation was used to compare the underlying neurophysiological mechanisms in M1, corticospinal excitability, short intracortical inhibition, and interhemispheric inhibition. Results of the two studies suggested the absence of difference in basic sensorimotor skill learning with the right dominant hand and the left non-dominant hand, and in procedural motor learning between Val66Val and Val66Met carriers. Further, the results in study 1 indicated an impaired intermanual transfer of procedural skills from the dominant learning hand to the non-dominant untrained hand in the Val66Met group, which likely suggests altered interhemispheric interactions. Moreover, the results in study 2 showed an absence of short-intracortical inhibition in bilateral M1 among Val66Met carriers following sensorimotor learning. Potential implications of these results in the interaction between the Val66Met polymorphism, motor learning, and the underlying neurophysiological mechanisms are discussed. In sum, these results provide a more in-depth perspective of the relationship between the Val66Met polymorphism and these processes, and specific hypotheses for future studies

Occlusion of LTP-Like Plasticity in Human Primary Motor Cortex by Action Observation

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

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MEP-rc, SICI, and IHI measures.

<p>MEP-rc (A), SICI (B), and IHI (B) measures Pre- and Post- motor training are shown for the Val66Val Vs. the Vall6Met groups in the Experiment 1. The error bars represent standard errors of the mean. Dashed lines used for comparisons show simple effects. ** p < 0.01.</p

Experiment 2.

<p>The experimental design used in experiment 2 is displayed for the Control-Right (CR) group.</p

MEP-rc, SICI and IHI measures.

<p>MEP-rc (A), SICI (B), and IHI (B) measures Pre- and Post- motor training are shown for the CR group in the Experiment 2. The error bars represent standard errors of the mean. Full lines used for comparisons represent main effects and dashed lines show simple effects. * p < 0.05; ** p < 0.01.</p

Motor performances on the rapid tapping (RT), pinch grip strength (PGS), and the grooved pegboard (GPB).

<p>The mean scores on the RT (A), the PGS (B), and the GPB (C) are presented for the CR participants in Experiment 2 on the R1 and R2 conditions with the right hand. The error bars represent standard errors of the mean. Full lines used for comparisons represent main effects. ** p < 0.01; *** p < 0.001.</p

Correlation analyses between SICI modulation in the left M1 and GPB performance.

<p>Correlations between Post- to Pre- ratio of SICI in the left M1 (abscissa) and condition 2 to condition 1 ratio of GPB performance (ordinate) are displayed for the Val66Val participants’ left (A) and right (B) hands, and for the CR group’s performance with the right hand (C). Larger SICI ratios indicate a greater decrease in SICI following motor training, and smaller GPB ratios suggest greater improvement from condition 1 to condition 2 on the motor task.</p

Motor performances on the rapid tapping (RT), pinch grip strength (PGS), and the grooved pegboard (GPB).

<p>The mean scores on the RT, the PGS, and the GPB are presented for the Val66Val and the Val66Met participants in Experiment 1 on the R1 and R2 conditions with the right hand (A, B, and C, respectively), and the L1 and L2 conditions with the left hand (D, E, and F, respectively). The error bars represent standard errors of the mean. Full lines used for comparisons represent main effects. * p < 0.05; ** p < 0.01; *** p < 0.001.</p

Action Video Game Playing Is Reflected In Enhanced Visuomotor Performance and Increased Corticospinal Excitability

<div><p>Action video game playing is associated with improved visuomotor performance; however, the underlying neural mechanisms associated with this increased performance are not well understood. Using the Serial Reaction Time Task in conjunction with Transcranial Magnetic Stimulation, we investigated if improved visuomotor performance displayed in action video game players (actionVGPs) was associated with increased corticospinal plasticity in primary motor cortex (M1) compared to non-video game players (nonVGPs). Further, we assessed if actionVGPs and nonVGPs displayed differences in procedural motor learning as measured by the SRTT. We found that at the behavioral level, both the actionVGPs and nonVGPs showed evidence of procedural learning with no significant difference between groups. However, the actionVGPs displayed higher visuomotor performance as evidenced by faster reaction times in the SRTT. This observed enhancement in visuomotor performance amongst actionVGPs was associated with increased corticospinal plasticity in M1, as measured by corticospinal excitability changes pre- and post- SRTT and corticospinal excitability at rest before motor practice. Our results show that aVGPs, who are known to have better performance on visual and motor tasks, also display increased corticospinal excitability after completing a novel visuomotor task.</p></div