<p> Animal studies have shown that the tonotopic organization of the auditory cortex is not statically fixed, but can be remodeled by experience. The purpose of this study was to investigate whether or not frequency discrimination training can induce changes in the cortical representation of a selected frequency in humans. Six human subjects were trained for approximately 3 weeks to detect a change in pitch between two tones (40Hz amplitude modulated) using a standard frequency of 2040 Hz. Each subject was tested on his/her discriminative ability before and after training using three different standards (2040Hz, 1840Hz, and 2240Hz). EEG data were recorded both before and after training and changes in transient and steady-state responses were investigated. Behaviourally, every subject improved at the discrimination task using the trained frequency. However, only three subjects demonstrated transfer to both untrained frequencies. In the EEG data, the P2-Nl amplitude increased in five of the six subjects and the Nllatency decreased in all six for the 2040Hz set. These two findings were statistically significant (p<0.05) for the group. There were no statistically significant findings for the side frequencies. The change in the 40 Hz steady-state response was also not significant, increasing in three subjects and decreasing in the other three. These findings indicate that changes are expressed in the secondary auditory cortex. These findings may also be applicable to the treatment of tinnitus. </p> / Thesis / Master of Science (MSc)

L’hypodynamie-hypokinésie est une situation correspondant à une diminution de l’activité motrice (hypokinésie) couplée à une diminution des charges corporelles (hypodynamie). Chez l’homme, cette situation est retrouvée lors d’une immobilisation, d’un alitement prolongé, d'un séjour en microgravité, ou lors du vieillissement (syndrome d’immobilité). L’hypodynamie-hypokinésie entraine une sévère altération de la performance motrice, notamment de l’équilibre, de la posture et de la locomotion. Cette altération est due à une dégradation du système musculaire (atrophie, changements phénotypiques), mais également à une modification des propriétés fonctionnelles du cortex sensorimoteur (réorganisation corticale, changements d’excitabilité corticale, modifications morphologiques). Si l’altération du système musculaire est bien décrite dans la littérature, les mécanismes impliqués dans la plasticité corticale restent mal connus. Une meilleure compréhension des systèmes mis en jeu dans l’hypodynamie-hypokinésie permettrait de développer des stratégies de prévention et/ou de récupération chez les patients soumis à cette situation. Dans cette optique, un modèle animal est communément utilisé au laboratoire. Il s'agit du modèle d'élévation du train postérieur pendant 14 jours chez le rat. Ainsi, les charges corporelles, s’exerçant habituellement sur les membres postérieurs, sont prévenues et l’activité musculaire limitée. Ce modèle animal reproduit la plupart des effets de l'hypodynamie-hypokinésie décrits chez l'homme.L’objectif de cette étude a été d’explorer les mécanismes de la réorganisation corticale induite par l’hypodynamie-hypokinésie. Notre intérêt s’est plus particulièrement porté sur l’insulin-like growth factor 1 (IGF-1), une protéine ubiquitaire possédant de nombreux rôles au niveau cérébral. En effet, en se fixant à son récepteur, l’IGF-1, parmi une multitude de phénomènes, stimule l’angiogenèse, la neurogenèse, et participe à la plasticité synaptique. De plus, il est reconnu comme étant un acteur central des effets bénéfiques de l’exercice physique au niveau cérébral.Aussi, dans un premier temps, nous avons déterminé les effets de cette hypoactivité sur l’IGF-1 et les voies de signalisation associées dans plusieurs structures impliquées dans la régulation de la performance motrice (cortex sensorimoteur, striatum, cervelet). Nos résultats montrent une sévère diminution des taux d’IGF-1 et de l’activation de la voie PI3K-AKT, et ce spécifiquement dans le cortex sensorimoteur.Dans un second temps, nous avons voulu déterminer si en maintenant le taux d’IGF-1 pendant toute la durée de l’hypodynamie-hypokinésie, il était possible de prévenir la réorganisation corticale et ses conséquences délétères sur le comportement moteur. Pour cela, dans une première partie, notre étude a porté sur le cortex somesthésique et la sensibilité tactile. Nos résultats montrent que l’IGF-1 prévient partiellement la réorganisation corticale et l’altération de la sensibilité tactile induites par l’hypoactivité. Dans une seconde partie, nous nous sommes intéressés à l’analyse du cortex moteur et de la performance motrice. Il apparait qu’un maintien des taux d’IGF-1 prévient une partie de l’altération du système moteur retrouvée en situation d’hypodynamie hypokinésie. Ainsi, l’ensemble de ces données suggère que la diminution des taux d’IGF-1 observée en condition d’hypoactivité joue un rôle clé dans la réorganisation corticale. De plus, notre étude montre qu’une prévention, même partielle, de cette réorganisation corticale peut induire une amélioration fonctionnelle de la performance motrice. / Hypodynamia-hypokinesia is a condition in which the motor activity (hypodynamia) as well as the weight exerted on the lower limbs (hypokinesia) are reduced. In humans, this condition is induced in immobilization, bed-rest, spaceflight or ageing (immobility syndrome) and is characterized by a chronic reduction in neuromuscular activity. This hypoactivity results in a profound alteration of motor task performances, in particular posture, gait and locomotion. These impairments are due to alterations in the muscular system (atrophy, phenotypic changes), but also to plastic changes in neural functions (cortical reorganization, alterations in cortical excitability, morphologic modifications). While degradation of the muscular system is described in the literature, the mechanisms involved in cortical plasticity are still unclear. A better understanding of the systems involved in hypodynamia-hypokinesia would allow the development of preventive and / or recovery strategies for patients affected by this hypoactivity. In this regard, hindlimb unloading is a disuse rodent model in which the elevation of the hindlimbs, during 14 days, prevents the weight to be normally exerted on the hindlimbs and reduces the normal muscular activity, finally causing hypoactivity. Studies performed on this model have shown that hindlimb unloading and human hypoactivity have similar effects. Today, our interest is turned towards insulin-like growth factor 1 (IGF-1), a ubiquitous protein involved in many cerebral functions. Indeed, IGF-1 is known to improve, inter alia, angiogenesis, neurogenesis and to be involved in synaptic plasticity in the whole brain. Moreover, several publications suggest that IGF-1 might mediate the beneficial effects of exercise on the brain.The aim of this study is to characterize the role of IGF-1 in cortical reorganization induced by hindlimb unloading as well as its functional consequences on motor performance. In the first part of the study, we have determined the effects of hindlimb unloading on IGF-1 level and the impact of its downstream main molecular pathways in motor control (sensorimotor cortex, striatum, cerebellum). Our results indicate that hindlimb unloading induces a decrease in IGF-1 level specifically in the sensorimotor cortex. This alteration is associated to a decrease in activation of the PI3K-AKT pathway. The second part of this study is dedicated to the effects of a restoration of IGF-1 levels, during the whole unloading period, on cortical reorganization and behavioral alterations focusing on sensory cortex and tactile sensory discrimination as well as motor cortex and motor performances. Our results show that treatment with IGF-1 partially prevents cortical reorganization and degradation of tactile sensory discrimination. Additionally, it appears that restoration IGF-1 levels prevent some of the effects of hindlimb unloading on the motor system.Taken together, ours results suggest that the decrease in the level of IGF-1 in the sensorimotor cortex during hindlimb unloading plays a key role in the cortical reorganization induced by hypoactivity. Moreover, our study shows that the prevention of this cortical reorganization, even when partial, can induce functional improvement in motor performance.

No description available.

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23102号 / 医博第4729号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 髙橋 良輔, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Rett syndrome (RTT), a severe neurodevelopmental disorder, affects females resulting from loss-of-function mutations in the X-linked transcription factor methyl-CpG-binding protein 2 (MECP2). RTT patients show severe verbal, motor, respiratory, and intellectual impairments. We studied two forms of activity-dependent plasticity in Mecp2 mutant mice to better understand the loss of MECP2 function in neuronal circuit and sensory processing. Sensory deprivation was applied by trimming one whisker to 3 mm to study long-term cortical plasticity in Mecp2-/y mice. Intrinsic optical signaling (IOS) imaging showed the neuronal response to wiggling a non-trimmed was consistent from day 0 to 14 but reduced for the trimmed whisker by 49.0 ± 4.3% in wild type (WT) and 22.7 ± 4.6% (p=0.0135) in RTT mice. Primary hindlimb (HL) somatosensory cortical responses to vibratory stimulation were assessed by IOS and intracortical local field potential (LFP). Responses were assessed before, during and, after 1 hour of repeated HL vibratory stimulation (100Hz,1sec, ISI 6 sec) in symptomatic male (4-6 week), female (10-12 month) and pre-symptomatic young female (4 week) RTT model mice. After 1-hour, cortical responses to test vibrations were reduced by approximately 40% in RTT and WT mice as assessed by both methods. Recovery of the IOS responses (1 sec vibration at 100Hz) and LFP (300µm below pia, 7 stimuli, 100mse ISI) were tested at 15 min intervals for 1 hour after ceasing the repeated stimulation. Reduced responses persisted for at least 60 min in WT but recovered to 90-100% of normal within 15-30 min in RTT. Analysis of the LFP responses within the test train indicated that the reduced cortical sensitivity during and after continuous stimulation resulted primarily from an increase in adaptation during the 7-stimulus test train rather than a reduction in the response to a single vibratory stimulus in all groups. Retention of this increased STA is the primary cause of the persistently reduced tactile response in young WT female mice, while in RTT mice the rapid recovery of tactile sensitivity was due to the return of STA to lower, baseline levels. Male RTT mice exhibited a marked increased excitability to the first stimulus in the test train resulting in hypersensitivity to a single vibration by 45 minutes. Old females exhibited the same pattern of adaptation and recovery but retention of adaptation was less pronounced in both WT and RTT compared to younger animals suggesting an age-dependent reduction in neural plasticity may mask deficits specific to RTT. Recording sciatic nerve sensory afferent activity did not reveal any STA, persistent adaptation or sensitization of peripheral afferent endings in any groups. I propose persistent sensory adaptation mediated by increased short-term adaptation may reflect enhanced feedback by inhibitory elements of circuits within the sensory pathway. The rapid recovery of responsiveness in young female RTT mice may therefore reflect a deficit in the capacity for activity dependent plasticity to consolidate and thus could provide a platform to understand the causes of learning and cognitive deficits in RTT patients. / Graduate

<p>Tinnitus is an auditory disorder characterized by the perception of a ringing, hissing or buzzing sound with no external stimulus. Because the most common cause of chronic tinnitus is hearing loss, this neurological disorder is becoming increasingly prevalent in our noise-exposed and ageing society. With no cure and a lack of effective treatments, there is a need for a comprehensive understanding of the neural underpinnings of tinnitus. This dissertation outlines the development and validation of a comprehensive theoretical model of cortical correlates of tinnitus that is used to shed light on the development of tinnitus and to propose improvements to tinnitus treatment strategies.</p> <p>The first study involved the development of a computational model that predicts how homeostatic plasticity acting in the auditory cortex responds to hearing loss. A subsequent empirical study validated a more biologically plausible version of this computational model. The goal of these studies was to determine whether and how a form of plasticity that maintains balance in neural circuits can lead to aberrant activity in the auditory cortex. The final study extends the validated computational model to develop a comprehensive theoretical framework characterizing the potential role of homeostatic and Hebbian plasticity in the development of most major cortical correlates of tinnitus.</p> <p>These theoretical and empirical studies provide a novel and complete description of how neural plasticity in adult auditory cortex can respond to hearing loss and result in the development of tinnitus correlates.</p> / Doctor of Philosophy (PhD)

L'objectif de ce travail est de modéliser la formation, la maintenance et la réorganisation des cartes corticales somesthésiques en utilisant la théorie des champs neuronaux dynamiques. Un champ de neurones dynamique est une équation intégro-différentiel qui peut être utilisée pour décrire l'activité d'une surface corticale. Un tel champ a été utilisé pour modéliser une partie des aires 3b de la région du cortex somatosensoriel primaire et un modèle de peau a été conçu afin de fournir les entrées au modèle cortical. D'un point de vue computationel, ce modèle s'inscrit dans une démarche de calculs distribués, numériques et adaptatifs. Ce modèle s'avère en particulier capable d'expliquer la formation initiale des cartes mais aussi de rendre compte de leurs réorganisations en présence de lésions corticales ou de privation sensorielle, l'équilibre entre excitation et inhibition jouant un rôle crucial. De plus, le modèle est en adéquation avec les données neurophysiologiques de la région 3b et se trouve être capable de rendre compte de nombreux résultats expérimentaux. Enfin, il semble que l'attention joue un rôle clé dans l'organisation des champs récepteurs du cortex somato-sensoriel. Nous proposons donc, au travers de ce travail, une définition de l'attention somato-sensorielle ainsi qu'une explication de son influence sur l'organisation des cartes au travers d'un certain nombre de résultats expérimentaux. En modifiant les gains des connexions latérales, il est possible de contrôler la forme de la solution du champ, conduisant à des modifications importantes de l'étendue des champs récepteurs. Cela conduit au final au développement de zones finement cartographiées conduisant à de meilleures performances haptiques / The aim of the present work is the modeling of the formation, maintenance and reorganization of somatosensory cortical maps using the theory of dynamic neural fields. A dynamic neural field is a partial integro-differential equation that is used to model the cortical activity of a part of the cortex. Such a neural field is used in this work in order to model a part of the area 3b of the primary somatosensory cortex. In addition a skin model is used in order to provide input to the cortical model. From a computational point of view the model is able to perform distributed, numerical and adaptive computations. The model is able to explain the formation of topographic maps and their reorganization in the presence of a cortical lesion or a sensory deprivation, where balance between excitation and inhibition plays a crucial role. In addition, the model is consistent with neurophysiological data of area 3b. Finally, it has been shown that attention plays a key role in the organization of receptive fields of neurons of the somatosensory cortex. Therefore, in this work has been proposed a definition of somatosensory attention and a potential explanation of its influence on somatotopic organization through a number of experimental results. By changing the gains of lateral connections, it is possible to control the shape of the solution of the neural field. This leads to significant alterations of receptive fields sizes, resulting to a better performance during the execution of demanding haptic tasks