In our cohort, variables that were significantly associated with improved clinical condition at the last follow-up included any treatment change prompted by the genetic diagnosis, either PM or other not directly related to a PM mechanism, emphasising how treatment guided by the underlying genetic abnormality can drive clinical improvement. Our findings also highlight that a genetic diagnosis should be pursued at any age (in our cohort, more adults had successful PM treatment than children), although the chance of improving outcome may fall over time (we found that lower age at genetic test was associated with better outcome): we acknowledge the small numbers of patients and outcomes on which these inferences are made.
The recent development of neuroprostheses generated different concepts for the interaction between electrodes and the peripheral nervous system [1], [2], [3]. These electrodes must offer the selective discrimination of the electrical activity inside the nerve and facilitate local fiber- or fascicle-specific stimulation without damaging neural integrity [4]. Multichannel cuff electrodes are one approach to this dilemma [5], [6]. These electrodes feature a large number of equally spaced contacts surrounding the nerve as an array of tripoles with a cathode in the middle of two anodes. These tripoles register the electrical activity on the surface of the nerve, but in contrast to invasive electrodes, the recorded signals must be processed using complex algorithms to find their sources inside the nerve [7], [8]. The electrodes have to match the nerve tissue, and the geometry of the electrode contacts has to be adjusted to the specific type of nerve and the nerve diameter. Therefore, cuff-electrode prototypes are mainly tested in vivo. The results are subsequently incorporated in new prototypes, which are again tested in animals. This procedure is both expensive and requires many laboratory animals before an electrode delivers valid results. Therefore, it would be favorable to move as much as possible of the electrode development into the computer and perform simulation studies to reduce costs and animal testing.
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One of the most interesting applications for cuff-electrodes involves the restoration of motor function, e.g. a lost limb. In this scenario, the cuff-electrode surrounds a peripheral nerve in the proximal stump. The electrode records the ENG of this nerve and detects the activation of myelinated motor fibers. A computer transforms the signals into movements and controls the limb prosthesis. Although the number of small unmyelinated fibers might exceed the number of myelinated axons in a nerve, its surface potential is primarily influenced by myelinated fibers [13], relevant for motor restoration.
The standard z-resolution was 0.8 µm, defined by the thickness of slices obtained using a microtome. We determined whether using every second or every third slice (thus increasing the z-interval to 1.6 µm or 2.4 µm, respectively) would accelerate segmentation or increase the tracing error rate. In this approach, the number of tracing abortions reflects the robustness of the region-growing algorithm Wildfire. However, increasing the slice-interval accelerates segmentation when the number of tracing abortions, which require manual interaction, does not increase, thereby effectively reducing the segmentation speed. We compared the relationship between the abortion rates and the inter-slice intervals. With 0.8 µm inter-slice intervals, 207 abortions occurred during the segmentation of 120 sample axons over 32 slices (0.054 abortion/axon/slice). At a 1.6 µm inter-slice interval, the abortion rate increased to 277 tracing abortions over 16 slices (0.14 abortion/axon/slice) and with a 2.4-µm inter-slice interval, the abortion rate further increased to 300 abortions over 11 slices (0.23 abortion/axon/slice). As expected, the inter-slice-intervals strongly influenced the abortion rates in a size-dependent manner.
In the final model, 625 slices of a 0.5 mm peripheral nerve with an inter-slice interval of 0.8 µm were used. The rendering time showed a linear correlation with the increasing number of included axons and slices. Reconstruct 1.1.0.1 did not benefit from a multicore processor, but relied on only one or two cores at a time. The model was stored as a VRML2.0-model, imported in Meshlab (version 1.3.0, ) for further processing.
Segmentation often relies on the region-growing technique. In this method, the user sets one or several seeding points and the algorithm starts growing until the boundaries of the structure are reached. The stopping criteria have to be adjusted individually and the structures should have a high contrast to the background for recognition. Despite the fact that there are several commercial and OpenSource software packages available (Table 2), these programs either cannot propagate a manually defined region over a stack of images, rely on a medical data format (e.g. DICOM) or only accept genuine isovoxel 3D datasets. In addition, the number of 338 individual objects (axons) exceeds the capacity of most programs. In the end, most of the available commercial alternatives are expensive. The OpenSource program Reconstruct (version 1.1.0.1) was the only software that could handle propagate several hundred objects over a large volume of slices. This program does not rely on isovoxel datasets and provides several ways to perform manual adjustments ( ). Reconstruct has previously been used to segment neural processes from a large fluorescent image stack containing 20,000 images [18]. Its region-growing tool Wildfire facilitates the definition of abort criteria (e.g. contrast, hue, brightness) and propagates the manually selected structure through the image stack until the abort criteria are met. The preprocessing of the original images using Adobe Photoshop could also be addressed using the open source software GIMP ( ). The segmentation precision significantly depended on the size of the axon. As shown in Fig. 6, axons with diameters below 4 µm (with inner cross-sectional areas below 12.57 µm2) delivered the highest abortion rates. Smaller axons also showed significantly larger area fluctuations than larger axons (Tab. 1 and Fig. 5B). We have not learned whether this latter effect is an inherent effect of smaller axons or, as we suspect, reflects the limited resolution of our optical system. As a rule of thumb, a resolution of 10 pixels per axon (if not smaller than 1 µm) should be used to avoid rendering abortions. The inter-slice interval strongly affects the tracing quality, and the tracing abortion rates significantly correlate with the increasing inter-slice distance. We recommend using an inter-slice interval range of 0.8 to 1.6 µm. The relative position of the axon to the center of the nerve only mildly affects the reconstruction quality independent from the distribution of the axon size across the distance from the nerve center, as this distribution was homogeneous, potentially reflecting imaging artifacts due to the handling and cutting of the slices. Better embedding technologies might result in less cutting artifacts.
Our 3D model represents the position and trajectories of myelinated fibers and is suitable for the simulation of mass signals or ENGs of the motoric neural portion. In addition, the selectivity of stimulation through a virtual electrode wrapped around the nerve model can be investigated. For simulation of nerves, including unmyelinated fibers, the histological processing has to be adapted to reach these axons. The electrical properties (for instance the type and speed of action potential propagation) can then be adjusted in the simulation environment. If a model for the simulation of penetrating nerve electrodes is necessary, then the axon diameter must be precisely reconstructed. Thus, our method would not be suitable.
For hypothesis two, based on our previous randomised trial using 3T fMRI we see activation in the representative cortex for motor studies with good signal-to-noise ratio. Participant numbers will allow for some loss of information due to participant refusal (10%) and scans where motion is a confounder (10%). With 40 participants in an analysis of baseline to week 20 changes on fMRI, this study will have 80% power to detect a difference between groups of 0.65 SD. If the supplementary motor area (SMA) is considered, given coefficient of variation (CV) for control participants performing motor tasks (CV of 11% in PM1 and 35% in SMA),26 and activation signal of 1.5%, we are able to detect differences in % activation levels over time as small as 0.47.
The percentage of eligible participants successfully recruited, and number of eligible participants who choose not to participate will be recorded. Participant retention will be recorded throughout the trial period. All data will be analysed by intention to treat, whereby a participant's assessment from the last available time-point is carried forward in the event of withdrawal or loss to follow-up. Treatment dose is automatically recorded by the Mitii program and will be monitored by the therapists. Strategies to manage engagement in the programme will be discussed with the participant and parent/guardian during their initial Mitii training. All participants will receive a Mitii rewards chart which segments the 20-week programme into four 5-week blocks and allows small rewards to be decided in advance for completing each stage. Other strategies such as parent/guardian involvement, feedback, positive reinforcement and incorporating Mitii into the family routine will also be discussed. Therapists will contact participants via email, telephone and Skype to troubleshoot any technical problems and to support engagement.
Current models of rehabilitation for children with CP are costly, limited by inequity of access and often not provided at sufficient intensity to drive neuroplasticity to improve outcomes. An effective web-based multimodal training that enhances motor and cognitive abilities using virtual trainers is likely to be a cost effective means of delivering therapy. It is also likely to lead to better translation of skills into the community as participants are responsible for their own training in the home environment. This study has the potential to establish a new cost-effective evidence-based therapy accessible equally by urban, rural and remote children and their families. Should our hypotheses be correct, Mitii has the potential to revolutionise delivery of intensive rehabilitation to children and adolescents with CP. 2ff7e9595c
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