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Hand exoskeletons are wearable robotic devices which are used to compensate for impaired handmovements in patientswith impaired upper-limbs. These devices can either help patients to grasp objects for a therapeutic purpose or to performactivities of daily living. This Thesis describes the development of a novel hand exoskeleton, with a focus on the user, based on the product development methodology "the V-Model". Therefore, user needs are identified through interviews and a thorough literature review. Three potential concepts are developed and sub-sequential a concept is selected based on a logical decision process. A mathematical model of the selected concept is generated and then used for dimensioning the hand exoskeleton. Moreover, three variants of the hand exoskeleton are built as prototypes. Finally, the variants of the device are tested on a bench top. The result of the development process is a novel hand exoskeleton for the rehabilitation of upper motor neuron syndrome patients. Force and range of motion tests revealed, that a design with a higher level of underactuation is favourable. The design presented in this thesis does not reach the defined range of motion and force augmentation. However, the defined target values are the results of a conservative approach, thus are a challenge to reach. The augmented closing force and range of motion surpass other state of the art hand exoskeletons. Nevertheless, the augmented opening force under-performs in comparison with other designs. Decisively, a validation with users is needed for a usability assessment. / Exoskelett för händer är robotiska hjälpmedel som kan användas för att kompensera nedsatt muskelstyrka och rörlighet hos patienter med nedsatt muskelfunktion i armarna. Dessa hjälpmedel kan hjälpa patienter att greppa föremål i ett terapeutiskt syfte eller för att utföra vardagliga sysslor. Examensarbetet beskriver utvecklingsarbetet av ett nytt exoskelett med fokus på användaren genom att tillämpa produktutvecklingsmotodikens V-modell. Användarens krav och behov identifieras genom intervjuer och en gedigen litteraturstudie. Tre koncept utvecklas och ett vidareutvecklat koncept väljs slutligen baserat på en logisk beslutsprocess. En matematisk modell genereras och används för att dimensionera exoskelettet. Dessutom tillverkas tre prototyper av exoskelettet i olika utföranden för att slutligen utvärderas i en testrigg. Resultatet av utvecklingsprocessen är ett nytt handexoskelett ämnat för rehabilitering av patienter med övre motorneuronsjukdom. Tester som genomfördes för att mäta Kraft och rörlighet visade att en design med en högre grad av underaktuering är gynnsamt. Designen som presenteras här når inte upp till de krav som ställs på kraft och rörlighet, de målvärden som definieras är dock baserade på ett konservativt synsätt och är därmed svåra att uppnå. Exoskelettet producerar en högre stängningskraft och uppvisar bättre rörlighet än andra toppmoderna exoskelett. Exoskelettet underpresterar dock vad gäller den producerade öppningskraften jämfört med andra modeller och designen behöver valideras hos användarna för att användarbarheten ska kunna bestämmas.

<p>Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease with no known cause. Despite the efforts of investigators over the past 150 years, there remains no effective cure which substantially prolongs life. Therapeutic strategies have explored all of the proposed underlying pathological pathways of the disease from increased oxidative damage to impaired axonal transport, with little to no success. In the following pages, a novel perspective will be presented outlining the preliminary investigations of a new line of research demonstrating that Sonic hedgehog (Shh) protein and its agonists have cytoprotective effects on motor neurons. To begin these investigations, initial experiments were conducted <em>in vitro</em> utilizing a mouse hippocampal cell-line (HT-22) which served as a model for transient transfection and oxidative challenge assays. The results are reported in Chapter 2. Building upon these introductory findings, further investigations were conducted exploiting the SOD1^G93A mouse model of ALS. Chapter 3 summarizes key observations pertaining to the abundance of a key cellular organelle in the sensing of Shh signalling, the primary cilium, in the spinal cord of SOD1^G93A mice. In Chapter 4, a semi-quantitative analysis of the effects of Shh and Shh agonists pre-treatment <em>in vitro </em>on primary mixed spinal cord cultures are described. Subsequent challenge with an excitotoxic NMDA treatment was also conducted, as well as an <em>in vivo</em> survival study exploring the potential therapeutic effects of chronic Shh administration on SOD1^G93A mice. The cumulative research presented here represents the very first investigation into the unique application of Shh and its agonists as potential therapeutic agents for the treatment of ALS, and our findings indicate that Shh has the potential of becoming a novel therapeutic agent for the treatment of ALS.</p> / Doctor of Philosophy (Medical Science)

The activation of the p53 pathway has been associated with neuronal degeneration in different neurological disorders, including spinal muscular atrophy (SMA) where aberrant expression of p53 drives selective death of motor neurons destined to degenerate. Since direct p53 inhibition is an unsound therapeutic approach due carcinogenic effects, we investigated the expression of the cell death-associated p53 downstream targets c-fos, perp and fas in vulnerable motor neurons of SMA mice. Fluorescence in situ hybridization (FISH) of SMA motor neurons revealed c-fos RNA as a promising candidate. Accordingly, we identified p53-dependent nuclear upregulation of c-Fos protein in degenerating motor neurons from the severe SMNΔ7 and intermediate Smn2B/– SMA mouse models. Although motor neuron-specific c-fos genetic deletion in SMA mice did not improve motor neuron survival or motor behavior, p53-dependent c-Fos upregulation marks vulnerable motor neurons in different mouse models. Thus, nuclear c-Fos accumulation may serve as a readout for therapeutic approaches targeting neuronal death in SMA and possibly other p53-dependent neurodegenerative diseases.

Die vorliegende Arbeit befasst sich mit einer Reihe von Fragestellungen, die Forschungsfeldern wie rauschinduziertem Verhalten, Strukturbildung in aktiven Medien und Synchronisation nichlinearer Oszillatoren erwachsen. Die verwendeten nichtlinearen Modelle verfügen über erregbare, oszillatorische und bistabile Eigenschaften. Zusätzliche stochastische Fluktuationen tragen wesentlich zur Entstehung komplexer Dynamik bei. Modelliert wird, auf welche Weise sich extrazelluläre Kaliumkonzentration, gespeist von umliegenden Neuronen, auf die Aktivität dieser Neuronen auswirkt. Neben lokaler Dynamik wird die Ausbildung ausgedehnter Strukturen in einem heterogenem Medium analysiert. Die raum-zeitlichen Muster umfassen sowohl Wellenfronten und Spiralen als auch ungewöhnliche Strukturen, wie wandernde Cluster oder invertierte Wellen. Eine wesentliche Rolle bei der Ausprägung solcher Strukturen spielen die Randbedingungen des Systems. Sowohl für diskret gekoppelte bistabile Elemente als auch für kontinuierliche Fronten werden Methoden zur Berechnung von Frontgeschwindigkeiten bei fixierten Rändern vorgestellt. Typische Bifurkationen werden quantifiziert und diskutiert. Der Rückkopplungsmechanismus aus dem Modell neuronaler Einheiten und deren passiver Umgebung kann weiter abstrahiert werden. Ein Zweizustandsmodell wird über zwei Wartezeitverteilungen definiert, welche erregbares Verhalten widerspiegeln. Untersucht wird die instantane und die zeitverzögerte Antwort des Ensembles auf die Rückkopplung. Im Fall von Zeitverzögerung tritt eine Hopf-Bifurkation auf, die zu Oszillationen der mittleren Gesamtaktivität führt. Das letzte Kapitel befasst sich mit Diffusion und Transport von Brownschen Teilchen in einem raum-zeiltich periodischen Potential. Wieder sind es Synchronisationsmechanismen, die nahezu streuungsfreien Transport ermöglichen können. Für eine erhöhte effektiven Diffusion gelangen wir zu einer Abschätzung der maximierenden Parameter. / In this work problems are investigated that arises from resarch fields of noise induced dynamics, pattern formation in active media and synchronisation of self-sustained oscillators. The applied model systems exhibit excitable, oscillatory and bistable behavior as basic modes of nonlinear dynamics. Addition of stochastic fluctuations contribute to the appearance of complex behavior. The extracellular potassium concentration fed by surrounding activated neurons and the feeback to these neurons is modelled. Beside considering the local behavior, nucleation of spatially extended structures is studied. We find typical fronts and spirales as well as unusal patterns such as moving clusters and inverted waves. The boundary conditions of the considered system play an essential role in the formation process of such structures. We present methods to find expressions of the front velocity for discretely coupled bistable units as well as for the countinus front interacting with boundary values. Canonical bifurcation scenarios can be quantified. The feedback mechanism from the model for neuronal units can be generalized further. A two-state model is defined by two waiting time distributions representing excitable dynamics. We analyse the instantaneous and delayed response of the ensemble. In the case of delayed feedback a Hopf-bifurcation occur which lead to oscillations of the mean activity. In the last chapter the transport and diffusion of Brownian particles in a spatio-temporal oscillating potential is discussed. As a cause of nearly dispersionless transport synchronisations mechanisms can be identified. We find an estimation for parameter values which maximizes the effective diiffusion.

Sensorische Nervenzellen kodieren Informationen über die Umwelt mittels elektrischer Impulse, sogenannte Aktionspotentiale oder Spikes. Diese werden weitergeleitet zu postsynaptischen Neuronen im zentralen Nervensystem, welche unterschiedliche Auslesestrategien verwenden. Integratorzellen summieren alle ankommenden Aktionspotentiale auf, wodurch sie die Gesamtaktivität einer präsynaptischen Population messen. Koinzidenzdetektoren hingegen, werden nur durch das synchrone Feuern der zuführenden Neuronenpopulation aktiviert. Die grundlegende Frage dieser Dissertation lautet: Welche Information eines zeitabhängigen Signals kodieren die synchronen Spikes einer Neuronenpopulation im Vergleich zu der Summe all ihrer Aktionspotentiale? Hierbei verwenden wir die Theorie stochastischer Prozesse: wir berechnen Spektralmaße, die es ermöglichen Aussagen darüber zu treffen welche Frequenzkomponenten eines Signals vorwiegend transmittiert werden. Im Gegensatz zu früheren Studien, verstehen wir unter einem synchronen Ereignis nicht zwangsläufig, dass die gesamte Population simultan feuert, sondern, dass ein minimaler Anteil („Synchronizitätsschranke") gleichzeitig aktiv ist. Unsere Analyse zeigt, dass die synchrone Populationsaktivität als ein Bandpass-Informationsfilter agieren kann: die synchronen Spikes kodieren hauptsächlich schnelle Signalanteile. Damit stellt die Selektion simultaner Neuronenaktivität ein potentielles Mittel dar um gleichzeitig anwesende, konkurrierende Signale voneinander zu trennen. Dabei hängen die genauen Charakteristika der Informationsfilterung ausschlaggebend von der Synchronizitätsschwelle ab. Insbesondere zeigt sich, dass eine Symmetrie in der Schwelle vorliegt,die die Äquivalenz der Kodierungseigenschaften von synchronem Feuern und synchronem Schweigen offenlegt. Unsere analytischen Ergebnisse testen wir mittels numerischer Simulationen und vergleichen sie mit Experimenten am schwach elektrischen Fisch. / Populations of sensory neurons encode information about the environment into electrical pulses, so called action potentials or spikes. Neurons in the brain process these pulses further by using different readout strategies. Integrator cells sum up all incoming action potentials and are thus sensitive to the overall activity of a presynaptic population. Coincidence detectors, on the other hand, are activated by the synchronous firing of the afferent population. The main question of this thesis is: What information about a common time-dependent stimulus is encoded in the synchronous spikes of a neuronal population in comparison to the sum of all spikes? We approach this question within the framework of spectral analysis of stochastic processes, which allows to assess which frequency components of a signal are predominantly encoded. Here, in contrast to earlier studies, a synchronous event does not necessarily mean that all neurons of the population fire simultaneously, but that at least a prescribed fraction ('synchrony threshold') needs to be active within a small time interval. We derive analytical expressions of the correlation statistics which are compared to numerical simulations and experiments on weakly electric fish. We show that the information transmission of the synchronous output depends highly on the synchrony threshold. We uncover a symmetry in the synchrony threshold, unveiling the similarity in the encoding capability of the common firing and the common silence of a population. Our results demonstrate that the synchronous output can act as a band-pass filter of information, i.e. it extracts predominantly fast components of a stimulus. If signals in different frequency regimes are concurrently present, the selection of synchronous firing events can thus be a tool to separate these signals.

Unter Spikelets versteht man kleine Depolarisationen mit einer Spike-ähnlichen Wellenform, die man in intrazellulären Ableitungen von verschiedenen Neuronentypen messen kann. In kortikalen Pyramidenzellen wurde ausgeprägte Spikelet-Aktivität nachgewiesen, die erheblich das Membranpotential beeinflussen kann (Crochet et al., 2004; Epsztein et al., 2010; Chorev and Brecht, 2012). Nichtsdestotrotz bleibt der Ursprung von Spikelets in diesen Neuronen unbekannt. In der vorgelegten Arbeit nutzte ich theoretische Modellierung um die Mechanismen von Spikelet-Erzeugung in Pyramidenzellen zu untersuchen. Zuerst sah ich die verschiedenen Hypothesen über den Ursprung von Spikelets durch. In der Literatur entdeckte ich zwei verschiedene Typen von Spikelets. Diese Arbeit konzentriert sich auf den häufiger vorkommenden Typ von Spikelets, welcher durch relativ große Amplituden gekennzeichnet ist. Die Eigenschaften dieser Spikelets passen am besten zu einem axonal Erzeugungsmechanismus. Im zweiten Kapitel widmete ich mich der Hypothese, dass somatische Spikelets axonalen Ursprungs mit somato-dendritischen Inputs hervorgerufen werden können. Ich identifizierte Bedingungen, die es erlauben ein Aktionspotential (AP) am Initialsegment vom Axon (AIS) zu initiieren, welches sich entlang des Axons ausbreitet, aber kein AP im Soma auslöst. Schließlich simulierte ich extrazelluläre Wellenformen von APs und Spikelets und verglich sie mit experimentellen Daten (Chorev and Brecht, 2012). Dieser Vergleich zeigte auf, dass die extrazellulären Wellenformen von Spikelets, die innerhalb einer Zellen am AIS erzeugt werden, gut zu den Daten passen. Zusammenfassend unterstützen meine Ergebnisse die Hypothese, dass Spikelets in Pyramidenzellen am AIS entstehen. Dieser Mechanismus könnte ein Mittel zum Energiesparen bei der Erzeugung von Output-APs sein. Außerdem könnte dadurch die dendritische Plastizität, die auf der Rückwärtspropagierung von APs beruht, reguliert werden. / Spikelets are transient spike-like depolarizations of small amplitudes that can be measured in somatic intracellular recordings of many neuron types. Pronounced spikelet activity has been demonstrated in cortical pyramidal neurons in vivo (Crochet et al., 2004; Epsztein et al., 2010; Chorev and Brecht, 2012), influencing membrane voltage dynamics including action potential initiation. Nevertheless, the origin of spikelets in these neurons remains elusive. In thi thesis, I used computational modeling to examine the mechanisms of spikelet generation in pyramidal neurons. First, I reviewed the hypotheses previously suggested to explain spikelet origin. I discovered two qualitatively different spikelet types described in the experimental literature. This thesis focuses on the more commonly reported spikelet type, characterized by relatively large amplitudes of up to 20 mV. I found that the properties of these spikelets fit best to an axonal generation mechanism. Second, I explored the hypothesis that somatic spikelets of axonal origin can be evoked with somato-dendritic inputs. I identified the conditions allowing these orthodromic inputs to trigger an action potential at the axon initial segment, which propagates along the axon to the postsynaptic targets, but fails to elicit an action potential in the soma and the dendrites. Third, I simulated extracellular waveforms of action potentials and spikelets and compared them to experimental data (Chorev and Brecht, 2012). This comparison demonstrated that the extracellular waveforms of single-cell spikelets of axonal origin are consistent with the data. Together, my results suggest that spikelets in pyramidal neurons might originate at the axon initial segment within a single cell. Such a mechanism might be a way of reducing the energetic costs associated with the generation of output action potentials. Moreover, it might allow to control the dendritic plasticity by backpropagating action potentials.

TRPV channels play a role in both mammalian insulin signaling, with TRPV1 expression in pancreatic beta-cells, and in C. elegans insulin-like signaling through expression of OSM-9, OCR-1, and OCR-2 in stress response pathways. In response to a glucose-supplemented diet, C. elegans are know to have sensitivity to anoxic stress, exhibit chemotaxis attraction, and display reduced egg-laying rate. Transcriptome analysis reveals that glucose stimulates nervous system activity with increased transcript levels of genes regulating neurotransmitters. Ciliated sensory neurons are needed for a reduced egg-laying phenotype on a glucose-supplemented diet. Egg-laying rate is not affected when worms graze on glucose-supplemented Delta-PTS OP50 E. coli, which is defective in glucose uptake. This suggests a possible sensory neuron obstruction by exopolysaccharides produced by standard OP50 E. coli on glucose, eliciting a starvation response from the worm and causing reduced egg-laying rate. Glucose chemotaxis is affected in specific TRPV subunit allele mutants: ocr-2(vs29) and osm-9(yz6), serotonin receptor mutants: ser-1(ok345) and mod-1(ok103), and G-alpha protein mutant: gpa-10(pk362). TRPV deletion mutants had no effect on glucose chemotaxis, alluding to the modality role pf TRPV alleles in specific sensory neurons. The role of serotonin in a reduced egg-laying rate with glucose remains unclear.

Spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease type 2D (CMT2D)/distal SMA type V (dSMAV) are two incurable neuromuscular disorders that predominantly manifest during childhood and adolescence. Both conditions are caused by mutations in widely and constitutively expressed genes that encode proteins with essential housekeeping functions, yet display specific lower motor neuron pathology. SMA results from recessive inactivating mutations in the survival motor neuron 1 (SMN1) gene, while CMT2D/dSMAV manifests due to dominant point mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS. Using a number of different model systems, ranging from Caenorhabditis elegans to the mouse, this thesis aimed to identify potential novel therapeutic compounds for SMA, and to increase our understanding of the mechanisms underlying both diseases. I characterised a novel C. elegans allele, which possesses a point mutation in the worm SMN1 orthologue, smn-1, and showed its potential for large-scale screening by highlighting 4-aminopyridine in a screen for compounds able to improve the mutant motility defect. Previously, the gene encoding three isoforms of chondrolectin (Chodl) was shown to be alternatively spliced in the spinal cord of SMA mice before disease onset. I performed functional analyses of the three isoforms in neuronal cells with experimentally reduced Smn levels, and determined that the dysregulation of Chodl likely reflects a combination of compensatory mechanism and contributor to pathology, rather than mis-splicing. Finally, working with two Gars mutant mice and a new Drosophila model, I have implicated semaphorin-plexin pathways and axonal guidance in the GlyRS toxic gain-of-function disease mechanism of CMT2D/dSMAV.

L'épilepsie du lobe temporal (ELT) est la forme la plus fréquente de l'épilepsie chez l'adulte. Elle se traduit par des crises spontanées et récurrentes, qui sont résistantes à tout traitement dans 90% des cas. Une agression initiale du cerveau (traumatisme crânien, méningite, convulsions fébriles etc.), est souvent à l'origine de la transformation d'un cerveau « sain » en cerveau épileptique. L'ensemble des processus responsables de cette transition s'appelle l'épileptogenèse. Pouvoir bloquer et/ou retarder l'épileptogenèse chez les patients à risque est une question de santé majeure. En plus des crises, l'ELT soulève d'autres questions. Elle est souvent associée à des déficits cognitifs, qui sont la conséquence de la réorganisation des circuits neuronaux. Ces déficits pourraient être traités de façon indépendante de l'épilepsie elle-même. Le projet de recherche de cette thèse s'inscrit dans ce cadre général. / Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults. It translates into spontaneous and recurrent seizures, which are resistant to any treatment in 90% of cases. An initial brain insult (head injury, meningitis, febrile seizures etc.), is often the cause of the transformation of a "healthy" brain into an epileptic one. The process responsible for this transition is called epileptogenesis. Blocking and/or delaying epileptogenesis in at-risk patients is a key issue for public health. In addition to the seizures, TLE raises other problems. It is often associated with cognitive deficits, which are the result of the reorganization of neuronal circuits. These deficits may be treated independently of epilepsy itself. The work presented here fits into this general framework.