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.

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.

No description available.

Doenças do neurônio motor (DNM) representam um grupo de doenças que cursam com fraqueza muscular progressiva e inexorável, e o manejo clínico é baseado no controle dos sintomas. Estes doentes sofrem de acometimentos motores e não motores intensos e de evolução progressiva. Entretanto, além dos sintomas motores, de humor e de déficits cognitivos, uma caracterização mais profunda de sintomas não- motores nesses doentes raramente foi relatada. Este estudo transversal objetivou descrever os sintomas não motores na DMN e seu impacto na qualidade de vida e no estado funcional, com foco na dor e alterações sensoriais. Oitenta doentes (31 mulheres, 55,7 ± 12,9 anos) com DNM foram submetidos a exame clínico extenso, avaliação de dor (questionário de dor McGill, Inventário breve de dor, questionário douleur neuropathique-4), avaliação psicofísica [teste quantitativo da sensibilidade (TQS) e modulação condicionada da dor (MCD)], avaliações de humor e catastrofismo, e foram comparados com controles saudáveis (CS) pareados por sexo e idade. Dor crônica (presente a maior parte dos dias por mais de três meses) foi presente em 46% dos doentes (escala numérica da dor = 5,18 ± 2,0). A dor de origem musculo- esquelética ocorreu em 40,5% e foi localizada principalmente na região da cabeça/pescoço (51%) e da região lombar (35%). A dor neuropática não presente nesta amostra. Comparado aos CS, os doentes com DNM apresentaram menor limiar de detecção de frio (p < 0,002) e valores de MCD significativamente menores (4,9 ± 0,2% vs. 22,1 ± 0,2%, p = 0,012). Os resultados do TQS/MCD não diferiram entre os doentes com DNM com e sem dor. A intensidade da dor foi correlacionada estatisticamente com ansiedade, depressão e catastrofismo, e os escores de espasticidade foram correlacionados inversamente com a MCD (rho = -0,30, p = 0,026). A dor é um sintoma frequentemente relatado por doentes com DNM. Alterações somatossensoriais e de MCD existem em DNM e podem estar relacionadas com a natureza neurodegenerativa da doença. Estudos adicionais devem investigar formas de melhor quantificar estas alterações e explorar estratégias de tratamento mais apropriadas para o seu controle / Motor neuron disorders (MNDs) represent a group of diseases that curse with inexorable muscle weakness and medical management is based on symptom control. These patients suffer from intense motor and non-motor progressive symptoms. However, apart from motor symptoms, mood and cognitive impairments, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on clinical pain and sensory changes. Eighty patients (31 females, 55.7±12.9 years old) with MND underwent a extensive clinical examination, pain (McGill pain questionnaire, brief pain inventory, douleur neuropathique-4), psychophysics [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], mood and catastrophizing assessments, and were compared to sex- and age-matched healthy controls (HC). Chronic pain (present on most days for more than three months) was present in 46% of patients (numerical visual scale=5.18±2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9±0.2% vs. 22.1±0.2%, p=0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression, and catastrophism, and spasticity scores were inversely correlated with CPM (rho=-0.30, p=0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate ways to better quantify these changes and explore the treatment strategies most appropriated for their control

Doenças do neurônio motor (DNM) representam um grupo de doenças que cursam com fraqueza muscular progressiva e inexorável, e o manejo clínico é baseado no controle dos sintomas. Estes doentes sofrem de acometimentos motores e não motores intensos e de evolução progressiva. Entretanto, além dos sintomas motores, de humor e de déficits cognitivos, uma caracterização mais profunda de sintomas não- motores nesses doentes raramente foi relatada. Este estudo transversal objetivou descrever os sintomas não motores na DMN e seu impacto na qualidade de vida e no estado funcional, com foco na dor e alterações sensoriais. Oitenta doentes (31 mulheres, 55,7 ± 12,9 anos) com DNM foram submetidos a exame clínico extenso, avaliação de dor (questionário de dor McGill, Inventário breve de dor, questionário douleur neuropathique-4), avaliação psicofísica [teste quantitativo da sensibilidade (TQS) e modulação condicionada da dor (MCD)], avaliações de humor e catastrofismo, e foram comparados com controles saudáveis (CS) pareados por sexo e idade. Dor crônica (presente a maior parte dos dias por mais de três meses) foi presente em 46% dos doentes (escala numérica da dor = 5,18 ± 2,0). A dor de origem musculo- esquelética ocorreu em 40,5% e foi localizada principalmente na região da cabeça/pescoço (51%) e da região lombar (35%). A dor neuropática não presente nesta amostra. Comparado aos CS, os doentes com DNM apresentaram menor limiar de detecção de frio (p < 0,002) e valores de MCD significativamente menores (4,9 ± 0,2% vs. 22,1 ± 0,2%, p = 0,012). Os resultados do TQS/MCD não diferiram entre os doentes com DNM com e sem dor. A intensidade da dor foi correlacionada estatisticamente com ansiedade, depressão e catastrofismo, e os escores de espasticidade foram correlacionados inversamente com a MCD (rho = -0,30, p = 0,026). A dor é um sintoma frequentemente relatado por doentes com DNM. Alterações somatossensoriais e de MCD existem em DNM e podem estar relacionadas com a natureza neurodegenerativa da doença. Estudos adicionais devem investigar formas de melhor quantificar estas alterações e explorar estratégias de tratamento mais apropriadas para o seu controle / Motor neuron disorders (MNDs) represent a group of diseases that curse with inexorable muscle weakness and medical management is based on symptom control. These patients suffer from intense motor and non-motor progressive symptoms. However, apart from motor symptoms, mood and cognitive impairments, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on clinical pain and sensory changes. Eighty patients (31 females, 55.7±12.9 years old) with MND underwent a extensive clinical examination, pain (McGill pain questionnaire, brief pain inventory, douleur neuropathique-4), psychophysics [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], mood and catastrophizing assessments, and were compared to sex- and age-matched healthy controls (HC). Chronic pain (present on most days for more than three months) was present in 46% of patients (numerical visual scale=5.18±2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9±0.2% vs. 22.1±0.2%, p=0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression, and catastrophism, and spasticity scores were inversely correlated with CPM (rho=-0.30, p=0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate ways to better quantify these changes and explore the treatment strategies most appropriated for their control

<p>Amyotrophic lateral sclerosis is a fatal, progressive neurodegenerative disease with unknown ethiology. The aim of this study was to increase understanding of the pathophysiological mechanisms of dying motor neurons and wasting muscle tissue in this particular disorder.</p><p>Quantitative receptor autoradiographic methodology was applied on cervical spinal cord sections from patients with ALS to evaluate the specific binding of the acetylcholine transporter ³H-vesamicol in motor neurons. Despite a significant reduction of the number of ventral motor neurons in ALS, the ³H-vesamicol binding was not reduced in ALS compared to control cases, which suggests an increased metabolic activity in remaining motor neurons.</p><p>Motor neurons dying in ALS might go through apoptosis (programmed cell death), so immunohistochemical and TUNEL techniques were applied on thoracic spinal cord from ALS patients to evaluate the possibility of an apoptotic process. The increased Bax expression indicates an apoptotic process and further, motor neurons were TUNEL-positive, indicating DNA degradation caused by programmed cell death.</p><p>Muscle biopsies were obtained from ALS patients, and mRNA levels for the neurotrophic factors GDNF and BDNF were measured and compared to control subjects. GDNF levels were increased in muscle tissue in ALS whereas BDNF levels were unaltered.</p><p>Levels of GDNF and BDNF were also measured in cerebrospinal fluid from ALS patients and controls using ELISA methodology. Levels of BDNF were unaltered in ALS cornpared to controls. GDNF however was not detectable in controls whereas 12 out of 15 ALS patients had measurab1e levels of GDNW. A marked upregulation of endogenous GDNF and GDNF mRNA in ALS CSF and muscle respectively is of special interest in relation to clinical trials where GDNF is administered to this group of patients.</p>

Amyotrophic lateral sclerosis is a fatal, progressive neurodegenerative disease with unknown ethiology. The aim of this study was to increase understanding of the pathophysiological mechanisms of dying motor neurons and wasting muscle tissue in this particular disorder. Quantitative receptor autoradiographic methodology was applied on cervical spinal cord sections from patients with ALS to evaluate the specific binding of the acetylcholine transporter 3H-vesamicol in motor neurons. Despite a significant reduction of the number of ventral motor neurons in ALS, the 3H-vesamicol binding was not reduced in ALS compared to control cases, which suggests an increased metabolic activity in remaining motor neurons. Motor neurons dying in ALS might go through apoptosis (programmed cell death), so immunohistochemical and TUNEL techniques were applied on thoracic spinal cord from ALS patients to evaluate the possibility of an apoptotic process. The increased Bax expression indicates an apoptotic process and further, motor neurons were TUNEL-positive, indicating DNA degradation caused by programmed cell death. Muscle biopsies were obtained from ALS patients, and mRNA levels for the neurotrophic factors GDNF and BDNF were measured and compared to control subjects. GDNF levels were increased in muscle tissue in ALS whereas BDNF levels were unaltered. Levels of GDNF and BDNF were also measured in cerebrospinal fluid from ALS patients and controls using ELISA methodology. Levels of BDNF were unaltered in ALS cornpared to controls. GDNF however was not detectable in controls whereas 12 out of 15 ALS patients had measurab1e levels of GDNW. A marked upregulation of endogenous GDNF and GDNF mRNA in ALS CSF and muscle respectively is of special interest in relation to clinical trials where GDNF is administered to this group of patients.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.