Older individuals sustaining traumatic brain injury (TBI) experience a much higher incidence of morbidity and mortality. This age-related exacerbated response to neurological insult has been demonstrated experimentally in aged animals, which can serve as a model to combat this devastating clinical problem. The reasons for this worse initial response are unknown but may be related to age-related changes in mitochondrial respiration. Evidence is shown that mitochondrial dysfunction occurs early following traumatic brain injury (TBI), persists long after the initial insult, and is severitydependent. Synaptic and extrasynaptic mitochondrial fractions display distinct respiration capacities, stressing the importance to analyze these fractions separately. Sprague- Dawley and Fischer 344 rats, two commonly used strains used in TBI and aging research, were found to show very similar respiration profiles, indicating respiration data are not strain dependent. Neither synaptic nor extrasynaptic mitochondrial respiration significantly declined with age in naïve animals. Only the synaptic fraction displayed significant age-related increases in oxidative damage, measured by 3-nitrotyrosine (3- NT), 4-hydroxynonenal (4-HNE), and protein carbonyls (PC). Alterations in respiration with age appear to be more subtle than previously thought. Subtle declines in respiration and elevated levels of oxidative damage may not to be sufficient to produce detectable deficits until the system is challenged. Following TBI, synaptic mitochondria exhibit dysfunction that increased significantly with age at injury, evident in lower respiratory control ratio (RCR) values and declines in ATP production rates. Furthermore, synaptic mitochondria displayed increased levels of oxidative damage with age and injury, while extrasynaptic mitochondria only displayed significant elevations following the insult. Age-related synaptic mitochondrial dysfunction following TBI may contribute to an exacerbated response in the elderly population.

Le remodelage osseux est un processus très complexe qui fait intervenir plusieurs phénomènes interdépendants. Ce mémoire de thèse porte sur la modélisation mathématique d'un de ces phénomènes - la mé́canotransduction - et sur les simulations numériques associées. Pour mieux comprendre la nature de l'information que reçoit une cellule afin de reconstruire l'ostéon le mieux adapté aux sollicitations mécaniques locales, plusieurs études ont été réalisées à partir d'une modélisation déjà existante. L'os cortical humain est considéré comme un milieu poreux multi échelle. Trois niveaux architecturaux sont mis en avant et l'utilisation de la théorie de l'homogénéisation permet de déterminer numériquement les tenseurs de perméabilité pour chacun d'eux. Une analyse sur les lois viscoélastiques est développée au niveau nanoscopique. Afin de proposer une explication plausible de la mécanotransduction indépendamment de la localisation dans l'os, une étude permettant de calculer tous les grandeurs physiques existant à une échelle donnée suite à un chargement appliqué à l'échelle macroscopique, a été mise en place. Le seul aspect fluide ne permet pas à la cellule de connaître son environnement et donc d'avoir une réponse cellulaire adaptée. Par contre, cette étude montre que les fibres de collagène, de par leur caractère piézoélectrique, transforment les sollicitations mécaniques existantes dans son entourage en un potentiel électrique auquel la cellule est sensible et peut réagir.

Les mesures ultrasonores en transmission transverse permettent d'évaluer un site osseux. Notre objectif est de mettre en évidence et d'exploiter les ondes qui se propagent circonférentiellement dans la coque corticale du col fémoral pour caractériser la résistance de la hanche à la fracture. Des simulations numériques de la propagation d'ondes dans des sections transverses de col du fémur ont été réalisées pour étudier les phénomènes mis en jeu. Nous avons montré que le premier signal (« first arriving signal », FAS) en transmission transverse est toujours associé aux ondes circonférentielles. Une forte corrélation entre le temps de vol du FAS (TOFFAS) et des paramètres géométriques liés à la résistance osseuse (R² = 0.87 pour le moment d'inertie minimum) a été observée. Les ondes circonférentielles se sont révélées être sensibles à la porosité et à l'élasticité de la coque corticale. Un montage ultrasonore expérimental a été conçu afin d'étudier la relation entre TOFFAS et la résistance à la fracture obtenue par test mécanique. Une première série de mesures sur neuf échantillons a montré que TOFFAS peut prédire la résistance mécanique de l'extrémité supérieure du fémur (R² = 0.79) au moins aussi bien que la technique de référence (R² = 0.78) utilisant les rayons-X. Ce montage expérimental peut être optimisé et combiné au scanner ultrasonore du col du fémur existant pour augmenter le niveau de prédiction du risque de fracture. Nous proposons comme perspective l'utilisation de la méthode DORT pour déterminer les vitesses de phase des ondes circonférentielles dans le col du fémur à partir desquelles la géométrie et les propriétés matérielles de l'os pourraient être déduites.

Bone cutting is widely used in orthopaedic, dental and neuro surgeries and is a technically demanding surgical procedure. Novel surgical methods are continually introduced in orthopaedic, neuro and dental surgeries and are aimed at minimising the invasiveness of the operation and allowing more precise cuts. One such method that utilises cutting with superimposed ultrasonic vibration is known as ultrasonically- assisted cutting (UAC). The main concern in bone cutting is the mechanical and thermal damage to the bone tissue induced by high-speed power tools. Recent technological improvements are concerned with the efforts to decrease the force required by the surgeon when cutting the bone as well as increases in surgery speed. A programme of experiments was conducted to characterise properties of a bone and get a basic understanding of the mechanics of bone cutting. The experiments included: (a) nanonindentation and tension tests to obtain the properties for the finite element (FE) bone cutting model, (b) high-speed filming to observe the chip formation process, which influences thermomechanics of the cutting process in conventional drilling (CD) and ultrasonically-assisted drilling (UAD) and, (c) plane cutting and drilling experiments to measure the levels of force and temperature rise in the bone tissue. Novel two-dimensional finite element (FE) models of cortical bone cutting were developed for conventional and ultrasonically-assisted modes with the MSC.MARC general FE code that provided thorough numerical analysis of thermomechanics of the cutting process. Mechanical properties such as the elastic modulus and strain-rate sensitivity of the bone material were determined experimentally and incorporated into the FE models. The influence of cutting parameters on the levels of stress, penetration force and temperature in the bone material was studied using conventional cutting (CC) and ultrasonically-assisted cutting (UAC). The temperature rise in the bone material near the cutting edge was calculated and the effect of cutting parameters on the level of thermal necrosis was analysed. The necrosis depth in bone was calculated as a distance from the cut surface to the point where the thermal threshold level was attained. Comparative studies were performed for the developed FE models of CC and UAC of bone and the results validated by conducting experiments and using data from scientific publications. The main outcome of the thesis is an in-depth understanding of the bone cutting process, and of its possible application in orthopaedics. Recommendations on further research developments are also suggested.

The mature central nervous system (CNS) has the capacity to reorganise when there is a change in sensory input. However, studies using the N1 cortical auditory evoked potential, or its magnetic homolog N1m, have not consistently demonstrated evidence of plasticity in adults with late onset unilateral deafness. In addition, little is known about the time course of experience-related plasticity in adults with unilateral deafness. The aim of the studies described in this thesis was to investigate plasticity in adults with unilateral deafness, using N1 auditory evoked potentials. Deafness occurred as a result of surgery for the removal of an acoustic neuroma. The stimuli were 500-Hz and 4-kHz tones presented monaurally to the intact ear, and the data were analysed using global field power and dipole source analysis. In the first study (Chapter 3), hemispheric asymmetries in the N1 response were measured in a group of 24 normally hearing adults at presentation levels of 40, 60 and 80 dB sensation level (SL). The results revealed that the mean hemispheric asymmetry was greater for the 4-kHz stimulus but there was no significant effect of presentation level. In addition, the results revealed that the magnitude of hemispheric asymmetry depended on the ear of stimulation; a trend for larger asymmetries was observed following stimulation of the left ear. The results of the study provide confidence that the methodology is suitable for measuring hemispheric asymmetries in individuals with unilateral deafness. The effect of stimulus level is important since this will vary in plasticity studies involving individuals with late onset unilateral deafness due to their pure tone sensitivity thresholds. Clarifying the effect of stimulus frequency in normally hearing adults is important since the effect of stimulus frequency on plasticity following unilateral deafness has not been reported previously.In the second study (Chapter 4), N1 responses were measured in 19 adults with unilateral deafness (10 and 9 right- and left-sided deafness respectively). Stimuli were typically presented at 60 dB SL. The results revealed that there was significantly greater mean activity and a shift towards reduced hemispheric asymmetries compared with 19 audiogram-matched controls. Similar changes were apparent after both right- and left-sided deafness, and for both 500-Hz and 4-kHz stimuli. Therefore the results reveal evidence of experience-related plasticity that mirrors the findings reported in animal models. The reduced hemispheric asymmetries were reflected in the dipole source model used in this thesis by changes in dipole strength, location and orientation. These findings may explain the inconsistencies reported in previous studies that have used N1 or N1m, where dipole location and orientation have not always been taken into adequate consideration.In the third study (Chapter 5), longitudinal measurements were made in six adults just prior to the onset of complete unilateral deafness, and at 1-, 3- and 6-months after the onset (4 right-sided and 2 left-sided deafness respectively). The results from the second study were further analysed by splitting the data into two groups: nine participants with <2 years deafness and 10 with ≥2 year's deafness. The results from the longitudinal data revealed that there was a significant difference in mean activity across the four conditions. For both stimulus types an increase in mean activity occurred after the onset of deafness, and hemispheric asymmetries were reduced. The biggest changes occurred within 1-month, although further increases were noted in some individuals with ≥2 year's duration of deafness. Changes that continue over this period of time suggest different physiological mechanisms for plasticity within the human central auditory system.

Une des caractéristiques les plus singulières de l’activité corticale est son degré élevé de variabilité. Ma thèse dedoctorat s’est focalisée sur l’étude de (i) l’irrégularité des intervalles entre potentiels d’action (PAs)successivement émis par un neurone, et (ii) la variabilité dans l’évolution temporelle de l’activité d’un ensemblede neurones. Premièrement, j’ai étudié l’irrégularité des neurones enregistrés dans le cortex moteur de singesmacaques performant une tâche d’estimation du temps et de préparation à l’action. J’ai montré que l’irrégularitén’est pas un paramètre libre de l’activité neuronale, contrairement au taux de PAs, mais est déterminée par lescontraintes structurelles des réseaux neuronaux. Deuxièmement, j’ai utilisé le modèle de Markov caché (MMC)pour analyser l’activité d’ensembles de neurones enregistrés dans plusieurs aires corticales, sensorielles etmotrices, de singes exécutant une tâche de discrimination tactile. J’ai montré que les processus sensoriels etdécisionnels sont distribués dans plusieurs aires corticales. Les résultats suggèrent que l’action et la décision surlaquelle elle est basée sont reliées par une cascade d’évènements non stationnaires et stochastiques. Finalement,j’ai utilisé le MMC pour caractériser l’activité spontanée d’un ensemble de neurones du cortex préfrontal d’unrat. Les résultats montrèrent que l’alternance entre les états UP et DOWN est un processus stochastique etdynamique. La variabilité apparaît donc aussi bien pendant l’activité spontanée que pendant le comportementactif et semble être contrainte par des facteurs structurels qui, à leur tour, contraignent le mode d’opération desréseaux neuronaux. / A hallmark of cortical activity is its high degree of variability. The present work focused on (i) the variability ofintervals between spikes that single neurons emit, called spike time irregularity (STI), and (ii) the variability inthe temporal evolution of the collective neuronal activity. First, I studied the STI of macaque motor corticalneurons during time estimation and movement preparation. I found that although the firing rate of the neuronstransmitted information about these processes, the STI of a neuron is not flexible and is determined by thebalance of excitatory and inhibitory inputs. These results were obtained by means of an irregularity measure thatI compared to other existing measures. Second, I analyzed the neuronal ensemble activity of severalsomatosensory and motor cortical areas of macaques during tactile discrimination. I showed that ensembleactivity can be effectively described by the Hidden Markov Model (HMM). Both sensory and decision-makingprocesses were distributed across many areas. Moreover, I showed that decision-related changes in neuronalactivity rely on a noise-driven mechanism and that the maintenance of the decision relies on transient dynamics,subtending the conversion of a decision into an action. Third, I characterized the statistics of spontaneous UP andDOWN states in the prefrontal cortex of a rat, using the HMM. I showed that state alternation is stochastic andthe activity during UP states is dynamic. Hence, variability is prominent both during active behavior andspontaneous activity and is determined by structural factors, thus rending it inherent to cortical organization andshaping the function of neural networks.

No description available.

No description available.

Intensive Language Action Therapy (ILAT) is a short-term aphasia therapy that emphasises massed-practise of language, where communication is framed through language action games that approximate everyday interactions. Despite increasing interest in ILAT, a comprehensive description of its methods has thus far been missing. Furthermore due to inconsistent results, further exploration of cortical reorganisation of language functions following ILAT is warranted. The underlying principles and practical features of ILAT methods and of language-action games are fully described, including the structure and materials for two specific games. 14 English speaking patients with chronic aphasia underwent two weeks of ILAT utilising the methods outlined. Pre and post measures of language performance were collected through standardised clinical assessments, along with functional Magnetic Resonance Imaging scans from a subset of 8 patients. Accuracy and response times for speech output and comprehension during language-action games were also recorded to measure success during the therapy interval. Data analysis showed significant improvements in clinical assessments of naming and comprehension, but not in auditory or syntactic processing tasks. Significant increases were also seen in patients’ self-ratings of quality of communication following therapy. Video and voice recordings during therapy sessions demonstrated significantly faster response times in production and comprehension of language, alongside an increase in the complexity of patients’ spoken output. Cortical activation was recorded whilst patients heard low-level noise, sentences containing ambiguous words and low-ambiguity sentences. Although the results showed no changes in cortical activation in the group of patients whilst processing low-level noise or low ambiguity sentences, increases in language-induced activation were seen in single-subject analyses in both the left and right hemispheres. Furthermore the group of patients recruited the right hemisphere significantly more than the left hemisphere following ILAT when processing complex sentences containing ambiguous words. iii Clinical assessments and measures of everyday communication showed undergoing two weeks of ILAT significantly improved speech output and comprehension in patients with chronic aphasia. Gains made in communicative performance during therapy highlight the importance of recording therapy sessions for additional assessment of therapy efficacy. Although conclusions regarding cortical reorganisation are not entirely clear, they indicate the important role of the right hemisphere in reorganisation of language after stroke.

Developmental cortical malformations are a major cause of intractable seizures. Determining the location and timing of susceptibility for epileptiform activity is critical to identifying what mechanisms contribute to epileptogenesis in any model. Using the freeze lesion rat model of polymicrogyria, we have identified, in lesioned cortex, these two aspects of epileptogenesis. Previous studies have demonstrated that epileptiform activity cannot be evoked prior to postnatal day (P) 12, but the malformed cortex is more susceptible to seizures as early as P10. An increase in excitatory afferents to the epileptogenic zone occurs before the onset of network epileptiform activity. Whether or not these afferents are a major contributor to the hyperexcitability of the malformed cortex can be investigated by determining if they specifically create a susceptibility for epileptiform activity. We have examined that here by measuring whether that timing coincides with an increased susceptibility for evoked and spontaneous epileptiform activity. We report that the malformed cortex is more susceptible to evoked epileptiform activity than control cortex as earlier as P7 and as late as P36. Further, we also find that the form of spontaneous epileptiform activity in malformed cortex is altered as early as P7. The timing of these early disruptions of cortical function found here suggests additional epileptogenic mechanisms exist prior to the reported increase in excitatory afferents at P10. Determining the location of the seizure initiation is an essential part of epilepsy research. Some patients with developmental cortical malformations have seizures initiated within the malformation, while others have seizures generated by the surrounding cortex. Previous data in the freeze lesion model of microgyria suggests that the timing of freeze lesion (from P0 to P1) can shift the epileptogenic focus from the malformation to the paramicrogyrial region (PMR). We report that both the timing of the freeze lesion and the survival age of the animal can alter the epileptogenic circuitry of the malformation and surrounding tissue. These findings provide new insight to the timeline of hyperexcitability in malformed cortex and will possibly lead to greater surgical success for patients with intractable epilepsy.