Although inhibitory cortical interneurons play a critical role in regulating brain excitability and function, the effects of stroke on these neurons is poorly understood. In particular, interneurons expressing vasoactive intestinal peptide (VIP) specialize in inhibiting other classes of inhibitory neurons, and thus serve to modulate cortical sensory processing. To understand how stroke affects this circuit, we imaged VIP neuron responses (using GCaMP6s) to low and high intensity forepaw stimulation, both before and after focal stroke in somatosensory cortex. Our data show that the fraction of forelimb responsive VIP interneurons and their response fidelity (defined as a cell’s number of responsive trials out of eight trials at a certain imaging week) was significantly reduced in the first week after stroke, especially when lower intensity forepaw stimulation was employed. The loss of responsiveness was most evident in highly active VIP neurons (defined by their level of responsiveness before stroke), whereas less active neurons were minimally affected. Of note, a small fraction of VIP neurons that were minimally active before stroke, became responsive afterwards suggesting that stroke may unmask sensory responses in some neurons. Although VIP responses to forepaw stimulation generally improved from 2-5 weeks recovery, the variance in response fidelity after stroke was comparatively high and therefore less predictable than that observed before stroke. Lastly, stroke related changes in response properties were restricted to within 400μm of the infarct border. These findings reveal the dynamic and resilient nature of VIP neurons and suggest that a sub-population of these cells are more apt to lose sensory responsiveness during the initial phase of stroke, whereas some minimally responsive cells are progressively recruited into the forelimb sensory circuit. Furthermore, stroke appears to disrupt the predictability of sensory-evoked responses in these cortical interneurons which could have important consequences for sensory perception. / Graduate / 2021-01-13

When it comes to perception, one of the most remarkable characteristics of the brain is its omnipresent variability: Even to identical sensory stimuli, no neural response is the same. It has been hypothesized that this response variability is induced by fluctuations of the brain’s instantaneous state, yet the underlying dynamics that link such neural states with stimulus-related processes remain poorly understood. Specifically, fluctuations of excitability in sensory regions of the cortex may shape the brain’s response to external stimuli and hence the perception thereof. The current work aimed at characterizing the modulatory role and spatiotemporal organization of cortical excitability in a series of three somatosensory stimulation paradigms in humans, employing electroencephalography (EEG) to examine the interplay between pre-stimulus oscillatory state and short-latency somatosensory evoked potentials, as well as their association with the consciously accessible stimulus percept. Excitability dynamics of the primary somatosensory cortex were found to be (i) temporally structured in a special way (long-range temporal dependencies in line with the concept of criticality), (ii) linked to the behaviorally perceived stimulus intensity already through initial cortical responses, and (iii) organized with spatially confined, somatotopic patterns. Taken together, these findings suggest that fluctuations of cortical excitability reflect the maintenance of a sensitive tradeoff between robustness and flexibility of neural responses to sensory stimuli, enabling the brain to adaptively change the neural encoding of even low-level stimulus features, such as the stimulus’ intensity. Importantly, however, moment-to-moment neural response variability appears not to occur “at random”, that is, in a stochastically independent manner, but to be organized according to specific principles – both in the temporal and spatial domain.

Muscle fatigue is an intrinsic myoprotective process that prevents damaging ATP depletion during intense or prolonged exercise by limiting ATP demand when ATP production becomes insufficient. One mechanism of fatigue involves a reduction in membrane excitability with the opening of ATP-sensitive K+ (KATP) and ClC-1 Cl- channels, resulting in submaximal sarcoplasmic reticulum Ca2+ release and reduced force generation, but the intracellular signalling pathways for this process is unknown. As a first step toward understanding this process, the objective of this study was to test the hypothesis that adenosine receptors (ARs) and AMPK trigger fatigue when a metabolic stress occurs during muscular activity. Compared to control conditions, a pan-activation of ARs with 10 µM adenosine and NECA initially reduced the fatigue rate during the first 60 s of a 3 min fatigue bout triggered with 1 tetanic contraction every s. An activation of the A1 adenosine receptor (A1R) with 10 and 20 µM ENBA resulted in faster rate of fatigue; an effect blocked by 5 µM DPCPX, an A1R antagonist. At 10 and 20 µM, adenosine, NECA, and ENBA activated AMPK via an increased in T172 phosphorylation. At 10 µM, MK8722, an AMPK agonist, initially caused a reduction in fatigue rate during the first 60 s followed by an increased fatigue rate during the last 2 min of the fatigue bout. Co-activation of ARs and AMPK did not give rise to either an additive or synergistic effect. FDB from AMPK α1-/- and α2-/- mice had faster fatigue rate and greater increased in unstimulated force compared to FDB from AMPK α1+/+ and α2+/+ mice. It is suggested that ARs and AMPK play a role in the mechanism of fatigue when a metabolic stress develops during muscle activity.

No description available.

No description available.

MicroRNAs (miRNAs) are short, non-coding RNA sequences that are generated from longer primary transcripts (pri-miRNA). These pri-miRNAs are processed by the endonuclease Drosha into a hairpin secondary structure (pre-miRNA), exported from the nucleus and cleaved by the enzyme Dicer to form a duplex RNA molecule. This miRNA:miRNA* duplex is subsequently further processed to form a single-stranded, mature miRNA. miRNAs have been extensively characterized and are known to play important roles in various physiologic and pathologic pathways. One hallmark of miRNAs function is their ability to modulate the downstream activities of protein-coding genes, as well as various other aspects of gene expression, by acting as post-transcriptional repressors of their messengerRNA (mRNA) targets. miR-184 is a highly conserved miRNA gene expressed in the Drosophila nervous system throughout development; and has been shown to target key regulators of differentiation, proliferation and apoptosis. Here we identify a novel role for miR-184 in regulating the development and maintenance of the Drosophila melanogaster post-embryonic nervous system. We present evidence which suggest miR-184 targets (i) paralytic (para), a voltage-gated sodium channel, shown to control neuronal excitability; and (ii) tramtrack69 (ttk69), a transcription factor known to regulate glial cell number and fate determination during embryonic development. In the absence of miR-184, homozygous loss-of-function mutant adult flies demonstrate hyperactive episodes in response to mechanical shock, indicative of increased susceptibility to seizures. Homozygous loss-of-function mutants also exhibit shortened lifespan, as well as reduced group longevity. Additionally, miR-184 deficient mutant larvae exhibit abnormal development of glia and glial progenitors; while expression of miR-184 exclusively in glia - reversed polarity- (repo) expressing cells - up-regulates development of glial cells. Phenotypes of the adult loss-of-function mutant are suppressed by genetic loss of para function; while larval phenotypes are rescued by reducing the genetic dosage of ttk69. These data imply that miR-184 functions to control post-embryonic gliogenesis, as well as in maintaining neuronal excitability and integrity of the Drosophila aging brain. / Biology

We study stochastic heat equations of the forms $[\partial_t u-\sL u]\d t\d x=\lambda\int_\R\sigma(u,h)\tilde{N}(\d t,\d x,\d h),$ and $[\partial_t u-\sL u]\d t\d x=\lambda\int_{\R^d}\sigma(u,h)N(\d t,\d x,\d h)$. Here, $u(0,x)=u_0(x)$ is a non-random initial function, $N$ a Poisson random measure with its intensity $\d t\d x\nu(\d h)$ and $\nu(\d h)$ a L\'vy measure; $\tilde$ is the compensated Poisson random measure and $\sL$ a generator of a L\'{e}vy process. The function $\sigma:\R\rightarrow\R$ is Lipschitz continuous and $\lambda>0$ the noise level. The above discontinuous noise driven equations are not always easy to handle. They are discontinuous analogues of the equation introduced in \cite{Foondun} and also more general than those considered in \cite{Saint}. We do not only compare the growth moments of the two equations with each other but also compare them with growth moments of the class of equations studied in \cite{Foondun}. Some of our results are significant generalisations of those given in \cite{Saint} while the rest are completely new. Second and first growth moments properties and estimates were obtained under some linear growth conditions on $\sigma$. We also consider $\sL:=-(-\Delta)^{\alpha/2}$, the generator of $\alpha$-stable processes and use some explicit bounds on its corresponding fractional heat kernel to obtain more precise results. We also show that when the solutions satisfy some non-linear growth conditions on $\sigma$, the solutions cease to exist for both compensated and non-compensated noise terms for different conditions on the initial function $u_0(x)$. We consider also fractional heat equations of the form $ \partial_t u(t,x)=-(-\Delta)^{\alpha/2}u(t,x)+\lambda\sigma(u(t,x)\dot{F}(t,x),\,\, \text{for}\,\, x\in\R^d,\,t>0,\,\alpha\in(1,2),$ where $\dot{F}$ denotes the Gaussian coloured noise. Under suitable assumptions, we show that the second moment $\E|u(t,x)|^2$ of the solution grows exponentially with time. In particular we give an affirmative answer to the open problem posed in \cite{Conus3}: given $u_0$ a positive function on a set of positive measure, does $\sup_{x\in\R^d}\E|u(t,x)|^2$ grow exponentially with time? Consequently we give the precise growth rate with respect to the parameter $\lambda$.

This thesis describes a series of experiments in human observers using neurophysiological and behavioural approaches to investigate the effects of varying haptic stimuli, attentional demand and age on motor control and perception during haptic sensing (i.e., using the hand to seek sensory information by touch). In Experiments I-IV, transcranial magnetic stimulation (TMS) was used to explore changes in corticomotor excitability when participants were actively engaged in haptic sensing tasks. These studies showed that corticospinal excitability, as reflected in motor evoked potential (MEP) amplitude, was greatly enhanced when participants were engaged in different forms of haptic sensing. Interestingly, this extra corticomotor facilitation was absent when participants performed finger movements without haptic sensing or when attention was diverted away from haptic input by a concurrent cognitive task (Exp I). This provided strong evidence that the observed corticomotor facilitation was likely central in origin and related to haptic attention. Neuroimaging has shown activation of the parieto-frontal network likely subserves this aspect of haptic perception. Further, this haptic-specific corticomotor facilitation was finely modulated depending on whether participants focused attention on identifying material (texture) as opposed to geometric properties of scanned surfaces (Exp II). With regards to aging effects, haptic-related corticomotor facilitation was associated with higher recognition accuracy in seniors (Exp III). In line with this, seniors exhibited similar levels of haptic-related corticomotor facilitation to young adults when task demands were adjusted for age (Exp IV). Interestingly, both young and senior adults also showed substantial corticomotor facilitation in the ‘resting’ hand when the ipsilateral hand was engaged in haptic sensing (Exp IV). Simply touching the stimulus without being required to identify its properties (no attentional task demands) produced no extra corticomotor facilitation in either hand or age group, attesting again to the specificity of the effects with regards to haptic attention. In Experiments V-VI, the ability to recognise 2-D letters by touch was investigated using kinematic and psychophysical measures. In Experiment V, we characterized how age affected contact forces deployed at the fingertip. This investigation showed that older adults exhibited lower normal force and increased letter-to-letter variability in normal force when compared to young adults. This difference in contact force likely contributed to longer contact times and lower recognition accuracy in older adults, suggesting a central contribution to age-related declines in haptic perception. Consistent with this interpretation, Experiment VI showed that haptic letter recognition in older adults was characterized not only by lower recognition accuracy but also by substantial increases in response times and specific patterns of confusion between letters. All in all, these investigations highlight the critical interaction of central factors such as attentional demand with aging effects on motor and perceptual aspects of haptic sensing. Of particular significance is the clear demonstration that corticomotor excitability is greatly enhanced when a haptic sensing component (i.e., attending to specific haptic features) is added to simple finger movements performed at minimal voluntary effort levels (typically <15 % of the maximal effort). These observations underline the therapeutic potential of active sensory training strategies based on haptic sensing tasks for the re-education of motor and perceptual deficits in hand function (e.g., subsequent to a stroke). The importance of adjusting attentional demands and stimuli is highlighted, particularly with regards to special considerations in the aging population.

No description available.

Notre travail a porté : 1) sur l'étude des modifications d'excitabilité corticale au cours du traitement des poussées de sclérose en plaques (SEP) et de l'évolution naturelle des formes progressives de SEP ; 2) sur la caractérisation du tremblement d'action, fréquemment observé dans le cadre de cette maladie et qui constitue une importante source de handicap. Ceci a conduit à la réalisation de 5 études. La première étude a démontré que l'amélioration rapide des performances motrices observées à la suite du traitement de poussées de SEP par une corticothérapie administrée en flash quotidien sur plusieurs jours, s'accompagnait de modifications significatives d'excitabilité corticale étudiée par stimulation magnétique transcrânienne. Ces modifications portaient sur la balance d'influences GABAergiques et glutamatergiques au sein du cortex moteur. Cette augmentation d'excitabilité survient bien avant toute possibilité de remyélinisation ou de régénérescence axonale et constitue donc une amélioration fonctionnelle induite par le traitement. Dans la deuxième étude, différents paramètres d'excitabilité corticale ont été suivis sur un an chez des patients présentant une forme progressive de SEP, traitée ou non traitée. Cette étude a mis en évidence une diminution de l'inhibition intracorticale et une augmentation du seuil moteur au repos chez les patients non traités, accompagnant une augmentation des scores cliniques de handicap. En revanche, les patients traités restaient stables, aussi bien sur le plan neurophysiologique que clinique. Ces résultats montrent que l'évolution de la SEP progressive est associée à une altération globale et évolutive de l'excitabilité du cortex moteur, portant aussi bien sur les neurones pyramidaux que sur les circuits de contrôle inhibiteur, probablement liée à l'aggravation de la perte neuronale au fil du temps. Nos résultats montrent également que différents types de traitement immunomodulateur peuvent arrêter ce cours évolutif. Dans une troisième étude, nous avons caractérisé l'existence d'un tremblement chez 32 patients atteints de SEP au moyen d'enregistrements électromyographiques et accélérométriques réalisés au membre supérieur. Ces enregistrements n'ont permis de confirmer l'existence d'un véritable tremblement que chez un seul patient. L'étude neurophysiologique concomitante de circuits de contrôle cérébelleux et protubérantiels a permis de montrer que la plupart des aspects cliniques de tremblement dans la SEP ne révélait en fait qu'un pseudo-tremblement lié en grande partie à des dysfonctions cérébelleuses. Nos deux dernières études ont permis de préciser ce résultat, au moyen d'une analyse du signal électromyographique et accélérométrique par décomposition modale empirique associée à une transformée de Hilbert-Huang. Cette méthode d'analyse apparaît valide et performante pour caractériser les tremblements et pseudo-tremblements survenant dans la SEP et les distinguer d'autres types de tremblement, comme le tremblement essentiel. / Our work focused on: 1) the study of cortical excitability changes in the treatment of multiple sclerosis (MS) relapses and the natural history of progressive forms of MS; 2) the characterization of action tremor, which is frequently observed in the course of the disease and is a major source of disability. This has led to the realization of five studies. The first study demonstrated that a rapid improvement in motor performance can be observed following treatment of MS relapses by intravenous corticosteroids administered daily over several days, accompanied by significant changes in cortical excitability parameters studied by transcranial magnetic stimulation techniques. These changes focused on the balance between GABAergic and glutamatergic influences in the motor cortex. An increase in cortical excitability occurs well before any possibility of remyelination or axonal regeneration, demonstrating a functional improvement induced by the treatment. In the second study, different parameters of cortical excitability were followed over one year in patients with progressive MS, treated or untreated. This study showed a decrease of intracortical inhibition and increased motor threshold at rest in untreated patients, accompanying a worsening of clinical disability scores. In contrast, treated patients remained stable, both on clinical and neurophysiological parameters. These results show that the evolution of progressive MS is associated with a global and progressive impairment of motor cortex excitability, concerning both pyramidal neurons on inhibitory control circuits, probably due to the progression of cortical neuronal loss over time. Our results also showed that different types of immunomodulatory therapy can stop this evolutionary course. In a third study, we characterized the existence of action tremor in 32 MS patients using electromyographic and accelerometer recordings in the upper limb. These recordings confirmed the existence of a real tremor in only one patient. Concomitant neurophysiological study of cerebellar and pontine circuits of control showed that most of the clinical aspects of tremor in MS in fact revealed a pseudo-tremor largely due to cerebellar dysfunctions. Our last two studies have clarified this result by means of an analysis of the electromyographic and accelerometer signal using empirical mode decomposition associated with Hilbert-Huang transform. This method of analysis appears valid and effective to characterize tremor or pseudo-tremor occurring in MS patients and to distinguish them from other types of tremor, such as essential tremor.