The close proximity of the Nicoya Peninsula to the Cocos-Caribbean Subduction zone plate boundary makes it a prime location to use GPS to study episodic tremor and slip. Nicoya Peninsula currently has operating networks of both continuous GPS (CGPS) and seismic stations designed to identify and characterize the pattern of episodic tremor and slip (ETS) events along the seismogenic zone under Costa Rica's Pacific Margin. The occurrence of slow slip events has been previously postulated in this region based on correlated fluid flow and seismic tremor events recorded near the margin wedge in 2000 and from sparse GPS observations in 2003. Paucity of data prevented details of these events from being resolved. In May 2007 a slow slip event was recorded on our densified GPS network. This slow slip event was also accompanied by seismic tremor, worked up by colleagues at the University of California - San Diego. I will present the GPS time series, correlated with the seismic tremor for the event in May 2007. I will also present the inferred pattern of slip on the plate interface from elastic half space inversion modeling compared with the tremor and Low Frequency Earthquake (LFE) locations. The geodetic slip and seismic tremor co-locate temporally very well. Spatially the seismic tremor and LFE locations are offset but not independent of both the up dip and down dip patches of geodetic slip. The identification of these slow slip events enhances our understanding of the nuances of the interseismic period. Previous studies of the interseismic strain accumulation patterns in the region of the Nicoya Peninsula have not accounted for the occurrence of slow slip, thus underestimating the magnitude of locking on the fault plane. My study resolves this bias by using our CGPS network to estimate the interseismic surface velocity field, accounting for the May 2007 slow slip event. I will present the results of this velocity field estimation and the results of inversions for locking patterns on the fault plane. My study has also elucidated a potential temporal variability in the locking pattern on the fault plane beneath Nicoya.

Background: The birth of stereotactic functional neurosurgery in 1947 was to a great extent dependent on the development of ventriculography. The last decades have witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders. Initially, these procedures were largely based on the same imaging technique that had been used since the birth of this technique, and that is still used in some centers. The introduction of new imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provided new potentials, but also new challenges for accurate identification and visualisation of the targets in the basal ganglia and the thalamus with an urge to thoroughly evaluate and optimize the stereotactic targeting technique, as well as evaluate accurately in stereotactic space the location and extent of stereotactic Radiofrequency (RF) lesions and the position of deep brain stimulation (DBS) electrodes. Aims: To study the differences between CT and MRI regarding indirect atlas coordinates in thalamic and pallidal procedures and to evaluate and validate visualisation of the pallidum and the subthalamic nucleus in view of direct targeting irrespective of atlas-derived coordinates. Furthermore, to evaluate the contribution of RF parameters on the size of stereotactic lesions, as well as the impact of size and location on clinical outcome. Method: The coordinates in relation to the landmarks of the 3rd ventricle of the targets in the pallidum and ventrolateral thalamus were compared between CT and MRI in 34 patients. In another 48 patients direct visualization  of the pallidum was evaluated and compared to indirect atlas based targeting. The possibility and versatility of visualizing the Subthalamic Nucleus (STN) on short acquisition MRI were evaluated in a multicentre study, and the use of alternative landmarks in identification of the STN was demonstrated in another study. In 46 patients CT and MRI were compared regarding the volume of the visible RF lesions. The volume was analysed with regard to coagulation parameters, and the location and size of the lesions were further evaluated concerning the clinical outcome. Results:Minor deviations were seen between MRI and  CT coordinates of brain targets. The rostro-caudal direction of these deviations were such that they would be easily accounted for during surgery, why MRI can obviate the need for CT in these procedures. MRI using a proton density sequence provided detailed images of the pallidal structures, which demonstrated considerable inter-individual variations in relation to the landmarks of the 3rd ventricle. By using a direct visualization of the target, each patient will act as his or her own atlas, avoiding the uncertainties of atlas-based targeting. The STN could be visualized on various brands of MRI machines in 8 centers in 6 countries with good discrimination and with a short acquisition time, allowing direct visual targeting. The same scanning technique could be used for postoperative localization of the implanted electrodes. In cases where the lateral and inferior borders of the STN cannot be easily distinguished on MRI the Sukeroku sign and the dent internal-capsule-sign signs might be useful. The volume of a stereotactic RF lesion could be as accurately assessed by CT as by MRI. The lesion´s size was most strongly influenced by the temperature used for coagulation. The lesions´ volumes were however rather scattered and difficult to predict in the individual patient based solely on the coagulation parameters. For thalamotomy, the results on tremor was not related to the lesion´s volume. For pallidotomy, larger and more posterior-ventral lesions had better effect on akinesia while effects on tremor and dyskinesias were not related to size or location of the lesions. Conclusions: The minor deviations of MRI from CT coordinates can be accounted for during surgery, why MRI can obviate the need of CT in these procedures. Direct visualized targeting on MRI of the pallidum is superior to atlas based targeting. The targets in the pallidum and the STN, as well as the location of the electrodes, can be well visualized with short acquisition MRI. When borders of the STN are poorly defined on MRI the Sukeroku sign and the dent internal-capsule-sign signs proved to be useful. The volumes of RF lesions can be accurately assessed by both stereotactic thin slice CT and MRI. The size of these lesions is most strongly influenced by the temperature of coagulation, but difficult to predict in the individual patient based on the coagulation parameters. Within certain limits, there were no clear relationships between lesions´ volume and location and clinical effects of thalamotomies and pallidotomies.

El temblor en la fenilcetonuria es un trastorno del movimiento muy prevalente entre pacientes de diagnóstico precoz y tardío. Se trata de un temblor rápido y muy regular, localizado fundamentalmente en extremidades superiores, cuya amplitud aumenta con el movimiento sobre todo en los pacientes de diagnóstico tardío, en quienes puede causar una discapacidad para las tareas cotidianas. Los datos neurofisiológicos sugieren que el temblor está causado por una disfunción de circuitos neuronales a nivel del sistema nervioso central, pudiendo ser considerado como un indicador de daño cerebral. El temblor en la PKU se asocia a un descenso en las concentraciones plasmáticas de CoQ10 en los pacientes con un adecuado control metabólico, así como a una edad tardía de diagnóstico de la enfermedad. Debido a la asociación descrita entre el déficit de CoQ10 y el aumento del estrés oxidativo en la PKU, nuestros resultados sugieren que el déficit de coenzima Q10 podría actuar induciendo un daño oxidativo a nivel de los circuitos implicados en la fisiopatología del temblor en estos enfermos. Los pacientes fenilcetonúricos en tratamiento dietético presentan alteraciones significativas en el volumen de la sustancia blanca y sustancia gris, cuya aparición está relacionada con la duración y el adecuado cumplimiento del tratamiento dietético. Existe una distribución específica de esta pérdida de volumen a nivel de las áreas motoras corticales, ganglios basales y sustancia blanca periventricular, cuyo significado clínico deberá ser ampliado en futuros trabajos. En cuanto a las nuevas opciones terapéuticas en la PKU, la prueba de sobrecarga combinada con Phe/BH4 es una herramienta muy útil para la selección de los pacientes candidatos a iniciar un tratamiento con BH4. Considerando lo difícil que resulta predecir la respuesta a la BH4 a partir del genotipo, recomendamos realizar la prueba de sobrecarga a todos los pacientes PKU, exceptuando solo aquellos pacientes con mutaciones nulas en ambos alelos. Finalmente, consideramos que el tratamiento con BH4 es seguro y eficaz en un grupo seleccionado de pacientes PKU con fenotipos leves y moderados. La utilización de dosis bajas de BH4 permite liberalizar la dieta y retirar la fórmula especial, garantizando un desarrollo nutricional y cognitivo adecuados sin que se hayan observado efectos indeseados. En conclusión, pese a un adecuado control metabólico, los pacientes fenilcetonúricos en tratamiento dietético presentan signos clínicos de disfunción neurológica así como anomalías estructurales en el parénquima cerebral. En su origen están implicados múltiples factores; en primer lugar relacionados con el inicio, la duración y el adecuado cumplimiento dietético, pero también alteraciones metabólicas secundarias como el déficit de CoQ10 y el aumento del estrés oxidativo. El tratamiento con tetrahidrobiopterina representa una alternativa terapéutica a la dieta restrictiva en Phe en un grupo seleccionado de pacientes con fenotipos leves y moderados, en quienes permite optimizar el control metabólico y garantizar un adecuado desarrollo cognitivo y nutricional. / BRAIN INJURY IN PHENYLKETONURIA: PATHOPHYSIOLOGY AND NOVEL THERAPEUTIC APPROACH” Tremor is a common sign in phenylketonuric patients under dietary treatment. It is more frequent and severe among late-treated PKU patients. The cause of tremor is unknown, but neurophysiological data suggest that it is more dependen ton abnormalities in central nervous system neural networks than on peripheral circuits involving mechanical oscillations. If such is the case, tremor may be an index of cerebral damage in PKU patients. Tremor is associated with low concentrations of CoQ10 in patients under dietary treatment, potentially leading to increased oxidative stress damage in central neural networks. Treated patients may show significant gray and white matter volume changes related to the duration and strict observation of dietary treatment. Voxel-based maps revealed a significant gray and white matter reduction in motor and premotor cortex, thalamus and periventricular white matter. Further studies are needed to investigate whether the presence of neurologic symptoms may be explained by specific anatomic alterations. Regarding new therapeutic options in PKU, we found that Phe/BH4 loeading should be recommended for al PKU patients before starting BH4 therapy considering the difficulties in predicting a good response on the basis of patients genotype. Finally, our data confirm that BH4 is a safe and effective therapy in a selected group of mild and moderate PKU patients. Low doses of BH4 in monoteraphy allow for withdrawal of the special formula and guarantee a good clinical and nutritional outcome with no adverse side effects in PKU patients.

Ogg Vorbis is a rather new audio format with some similarities with other more known formats such as MP3 and WMA. It is generally accepted to have a better audio quality than most competing formats and it is in contrast to many of its competitors totally licence and royalty free. The goal with this thesis is to port the existing fixed point decoder Tremor, which is written in C, to Motorola's DSP56002. The DSP has a very limited amount of memory so some optimizations has to be made to be able to run Tremor successfully. The report presents the necessary steps taken to port Tremor to the DSP and the difficulties of this process. It also describes the memory and CPU usage of the DSP when running Tremor and other results of the port. A description as well as examples and workarounds of bugs found in the compiler g56k is attached to this report.

The work presented in this thesis investigates novel modalities to guide Transcranial Magnetic Resonance guided Focused Ultrasound (TcMRgFUS). TcMRgFUS is an emerging and promising non-invasive technique for the treatment of neurological disorders, such as essential tremor or Parkinsonian tremor. A novel Magnetic Resonance Acoustic Radiation Force Imaging (MRARFI) has been used to image the location of the ultrasonic beam produced by a preclinical prototype: an accelerated 2D spin-echo MR ARFI pulse sequence has been introduced to generate undistorted ultrasound-induced displacement maps in ex vivo veal brains with minimum energy deposition. We then investigated direct effects of the ultrasonic beam on brain activity by conducting in vivo ultrasonic neuromodulation, similarly to what is currently achieved with transcranial magnetic stimulation (TMS) but with the millimetric targeting capabilities of the ultrasound. Experiments have been first conducted in an anesthetized rat model to investigate the motor threshold. Numerical simulations have shown that the acoustic pattern in the rat head is affected by reverberations and that special care must be taken when relating acoustic parameters to neurostimulation effects, especially at a low frequency and for small animals. Finally, for the first time, we used low intensity FUS stimulation to causally modulate behavior in an awake nonhuman primate brain. We showed that the latency of an anti-saccade task was delayed significantly in the presence of ultrasonic beam focused in the Frontal Eye Field. Sham experiments did not show any significant change in the latencies.

Copies of author's previously published articles inserted. / Bibliography: leaves 193-228. / xvi, 235 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The aim of this thesis is to provide evidence of a training related effect on neural control of a muscle in individuals who have long standing different patterns of use of their muscles. The study examines the motor unit (MU) discharge properties in first dorsal interosseous muscle of individuals who had experienced very different usage patterns of their hand muscles and explores the relationship between different muscle usage patterns and involuntary force fluctuations (tremor). It evaluates the importance of the shared branched-axon inputs to motor neurons in the production of common drive and investigates the relationship between different measures of MU sychronization. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1997?

Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the FMR1 premutation. Carriers of the FMR1 premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS), which involves progressive symptoms of tremor, ataxia and cognitive decline. Evidence also suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. The present study aimed to investigate and delineate neurodegenerative and neurodevelopmental aspects of the premutation utilising primarily fMRI, clinical assessments and molecular measurements in 17 premutation carrier participants and 17 age-matched control participants, aged between 20 and 70 years. The functional imaging protocol included a motor task and an emotional processing task. A battery of clinical and neuropsychological tests outside of the scanner and blood-based measurements of FMR1 CGG repeat length, FMRP levels and FMR1 mRNA levels were also carried out. In the motor task, premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Quantative real-time PCR analysis revealed that mean age-matched FMR1 mRNA levels display a trend towards being higher in carriers and clinical testing of motor skills additionally showed significantly worse tremor and co-ordination scores in non-FXTAS carriers. No significant associations were seen between these measurements and neuroimaging data. During the emotional processing task, carriers exhibited significantly lower activation compared to controls (FWEcorr < 0.001) at the bilateral superior parietal lobe, bilateral Brodmann Area (BA) 17 (V1), right intraparietal area and right BA18 (V2) when comparing high arousal and low arousal conditions. Group by age interaction analyses indicated no significant between group differences at a whole brain level. Clinical assessment revealed that carriers displayed significantly worse symptoms of obsessive-compulsiveness, anxiety, global severity of psychiatric symptoms, facial emotion recognition and autistic traits compared to controls and FMRP levels were comparable between groups. No significant associations were seen between these measurements and neuroimaging data. Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability. Additionally, we show significantly altered emotional processing at neuropsychological, clinical and functional neuroimaging levels in carriers compared to controls, which appear to display stability over age. Overall, we present new evidence in keeping with possible neurodegenerative and neurodevelopmental traits in FMR1 premutation carriers.

In recent years, soft materials have seen increased prevalence in the design of robotic systems and wearables capable of addressing the needs of individuals living with disabilities. In particular, pneumatic artificial muscles (PAMs) have readily been employed in place of electromagnetic actuators due to their ability to produce large forces and motions, while still remaining lightweight, compact, and flexible. Due to the inherent nonlinearity of PAMs however, additional external or embedded sensors must be utilized in order to effectively control the overall system. In the case of external sensors, the bulkiness of the overall system is increased, which places limits on the system’s design. Meanwhile, the traditional cylindrical form factor of PAMs limits their ability to remain compact and results in overly complex fabrication processes when embedded fibers and/or sensing elements are required to provide efficient actuation and control. In order to overcome these limitations, this thesis proposed the design of flat pneumatic artificial muscles (FPAMs) capable of being fabricated using a simple layered manufacturing process, in which water-soluble masks were utilized to create collapsed air chambers. Furthermore, hyperelastic deformation models were developed to approximate the mechanical performance of the FPAMs and were verified through experimental characterization. The feasibility of these design techniques to meet the requirements of human centered applications, including the suppression of hand tremors and catheter ablation procedures, was explored and the potential for these soft actuation systems to act as solutions in other real world applications was demonstrated. We expect the design, fabrication, and modeling techniques developed in this thesis to aid in the development of future wearable devices and motivate new methods for researchers to employ soft pneumatic systems as solutions in human-centered applications.

Introduktion: Extrapyramidala systemet är ett nätverk i det centrala nervsystemet(CNS) som har en viktig roll i att samordna kroppsrörelser. De komponenter somtillhör det extrapyramidala systemet är basala ganglier, cerebellum och flera olikaledningsbanor och bland dessa har basala ganglier störst betydelse. Extrapyramidalasymtom, även kallade EPS, är ett samlingsbegrepp för motoriska biverkningar,exempelvis muskelkramper, muskelstelhet och skakningar, som uppkommer omextrapyramidala systemet i hjärnan utsätts för störningar. Vissa läkemedelsgrupper,såsom äldre antipsykotiska och antidepressiva läkemedel, är kända för att orsaka EPSgenom sin påverkan på det extrapyramidala systemet. Det finns även andra läkemedelsom också kan orsaka EPS, vilket inte är lika välkänt. Ett exempel på detta ärciprofloxacin, ett ofta förskrivet antibiotikum. Trots att extrapyramidala symtom kanupplevas besvärliga för patienter och trots att ciprofloxacin är ett mycket välanväntläkemedel, finns det inte mycket publicerad/beskriven information om risken attdrabbas av EPS vid användning av ciprofloxacin. Därför är det värdefullt att ta reda påom ciprofloxacin kan ge EPS och hur detta läkemedel kan påverka nervsystemet. Syfte: Syftet med denna studie är att ta reda på eventuellt samband mellan intag avciprofloxacin och EPS. Syftet är även att undersöka möjliga mekanismer bakom dessasymtom. Metod: Detta är en litteraturstudie som baseras på fallstudier inhämtade fråndatabasen PubMed samt inkomna biverkningsrapporter i Läkemedelsverkets databas,Biverkningsrapportering och Signaldetektion (BiSi), och den amerikanskaläkemedelsmyndighetens (The Food and Drug Administration) databas, FDA AdverseEvent Reporting System (FAERS). Resultat/Diskussion/Slutsats: Denna studie visar att det, trots att frekvensen avEPS är låg, är troligt att användning av ciprofloxacin kan utlösa EPS, framförallttremor, muskelkramper och muskuloskeletal stelhet. Detta resultat kan dock, på grundav det begränsade materialet, inte generaliseras till att omfatta alla patienter. Det äroklart om ciprofloxacin, även hos en frisk person, kan orsaka EPS och om andrafysiologiska faktorer såsom lever- eller njurfunktion hos patienten har betydelse förframkallande av EPS eftersom nedsatt lever- eller njurfunktion ökar toxiciteten avläkemedlet. Det går heller inte att utesluta påverkan av läkemedelsinteraktion medsamtidigt intagna läkemedel. För att kunna ge ett svar med högre tillförlitlighetangående frågeställningen: eventuellt samband mellan intag av ciprofloxacin ochextrapyramidala symtom, krävs det vidare forskning, exempelvis genom att studerasamtliga biverkningsrapporter som innehåller information om patientens profil,dosering av ciprofloxacin och samtidig medicinering. Möjliga mekanismer bakomuppkomsten av EPS vid användning av ciprofloxacin anses vara att ciprofloxacinfungerar som en GABA-A-antagonist i basala ganglier och den förändrade GABA-ergahämningen, på grund av antagonismen, stör den normala rörelsereglerande funktionenhos de basala ganglierna. Avslutningsvis, baserat på resultatet av denna studie kan detvara av värde att iaktta försiktighet vid förskrivning av ciprofloxacin till patienter somhar nedsatt njur- eller leverfunktion och till patienter som har samtidig medicinering,särskilt med läkemedel som är kända för benägenhet att orsaka EPS såsomantipsykotiska och antidepressiva läkemedel.

The movement disorder essential tremor can be treated with deep brain stimulation (DBS), where electric current is delivered to deep brain structures through permanently implanted electrodes. In this study, brain activity during working memory performance was measured with functional magnetic resonance imaging in thirteen essential tremor patients with DBS in caudal Zona incerta, a diencephalic nucleus. With active stimulation less exertion of certain working memory areas was required to achieve the same level of performance in a manipulation and a maintenance-type working memory task. At the same time, a relatively higher activation was reached for the more demanding manipulation task. These results indicate that DBS can make the brains of tremor patients more efficient in working memory tasks, in accordance with the “efficiency hypothesis” proposed by Nyberg et al. (2014). / Rörelsestörningen essentiell tremor kan behandlas med djup hjärnstimulering (DBS), vid vilken elektrisk ström tillförs djupa hjärnstrukturer genom permanent inopererade elektroder. I den här studien mättes hjärnaktivering under arbetsminnesbelastning med funktionell magnetresonans-tomografi hos tretton essentiell tremor-patienter med DBS i kaudala Zona incerta, en kärna i mellanhjärnan. Med stimuleringen påslagen krävdes en lägre hjärnaktivering i arbetsminnes-relaterade områden för att nå samma resultat i två arbetsminnesuppgifter där den enda krävde manipulation och den andra enbart kvarhållande av information. Samtidigt kunde en relativt sett högre aktiveringsnivå uppnås för den mer krävande manipulationsuppgiften. De här resultaten tyder på att DBS kan göra tremorpatienters hjärna mer effektiv i arbetsminnesuppgifter, i enlighet med den “effektivitetshypotes” som lagts fram av Nyberg m fl (2014).