Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.

Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.

Adaptive Brain-Computer Interface Systems For Communication in People with Severe Neuromuscular Disabilities

Brain-computer interfaces (BCI) have the potential to restore communication or control abilities in individuals with severe neuromuscular limitations, such as those with amyotrophic lateral sclerosis (ALS). The role of a BCI is to extract and decode relevant information that conveys a user's intent directly from brain electro-physiological signals and translate this information into executable commands to control external devices. However, the BCI decision-making process is error-prone due to noisy electro-physiological data, representing the classic problem of efficiently transmitting and receiving information via a noisy communication channel.

This research focuses on P300-based BCIs which rely predominantly on event-related potentials (ERP) that are elicited as a function of a user's uncertainty regarding stimulus events, in either an acoustic or a visual oddball recognition task. The P300-based BCI system enables users to communicate messages from a set of choices by selecting a target character or icon that conveys a desired intent or action. P300-based BCIs have been widely researched as a communication alternative, especially in individuals with ALS who represent a target BCI user population. For the P300-based BCI, repeated data measurements are required to enhance the low signal-to-noise ratio of the elicited ERPs embedded in electroencephalography (EEG) data, in order to improve the accuracy of the target character estimation process. As a result, BCIs have relatively slower speeds when compared to other commercial assistive communication devices, and this limits BCI adoption by their target user population. The goal of this research is to develop algorithms that take into account the physical limitations of the target BCI population to improve the efficiency of ERP-based spellers for real-world communication.

In this work, it is hypothesised that building adaptive capabilities into the BCI framework can potentially give the BCI system the flexibility to improve performance by adjusting system parameters in response to changing user inputs. The research in this work addresses three potential areas for improvement within the P300 speller framework: information optimisation, target character estimation and error correction. The visual interface and its operation control the method by which the ERPs are elicited through the presentation of stimulus events. The parameters of the stimulus presentation paradigm can be modified to modulate and enhance the elicited ERPs. A new stimulus presentation paradigm is developed in order to maximise the information content that is presented to the user by tuning stimulus paradigm parameters to positively affect performance. Internally, the BCI system determines the amount of data to collect and the method by which these data are processed to estimate the user's target character. Algorithms that exploit language information are developed to enhance the target character estimation process and to correct erroneous BCI selections. In addition, a new model-based method to predict BCI performance is developed, an approach which is independent of stimulus presentation paradigm and accounts for dynamic data collection. The studies presented in this work provide evidence that the proposed methods for incorporating adaptive strategies in the three areas have the potential to significantly improve BCI communication rates, and the proposed method for predicting BCI performance provides a reliable means to pre-assess BCI performance without extensive online testing.