Transduction profiles in minipig following MRI guided delivery of AAV-5 into thalamic and corona radiata areas.

BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) was performed in patients with Parkinson's disease during deep brain stimulation of the subthalamic nucleus (three patients) and during deep brain stimulation of the ventral intermedius nucleus of the thalamus (one patient). All showed an increase in blood oxygenation level-dependent signal in the subcortical regions ipsilateral to the stimulated nucleus. This effect cannot be simply explained by a mechanism of depolarization blockade; rather, it is caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity. We confirm that fMRI during deep brain stimulation is a safe method with considerable potential for elucidating the functional connectivity of the stimulated nuclei.