Imageguided convectionenhanced delivery of muscimol to the primate brain

Object. Muscimol is a potent ãaminobutyric acidA receptor agonist that temporarily and selectively suppresses neurons. Targeted muscimol suppression of neuronal structures could provide insight into the pathophysiological processes and treatment of a variety of neurological disorders. To determine if muscimol delivered to the brain by convectionenhanced delivery could be monitored using a coinfused surrogate MR imaging tracer, the authors perfused the striata of primates with tritiated muscimol and Gd-diethylenetriamine pentaacetic acid (DTPA). Methods. Three primates underwent convective coinfusion of 3Hmuscimol (0.8 μ M) and GdDTPA (5 mM) into the bilateral striata. Primates underwent serial MR imaging during infusion, and the animals were killed immediately after infusion. Postmortem quantitative autoradiography and histological analysis was performed. Results. Realtime MR imaging revealed that infusate (tritiated muscimol and GdDTPA) distribution was clearly discernible from the noninfused parenchyma. Realtime MR imaging of the infusion revealed the precise region of anatomical perfusion in each animal. Imaging analysis during infusion revealed that the distribution volume (Vd) of infusate linearly increased (R = 0.92) with volume of infusion (Vi). Overall, the mean (± SD) Vd/Vi ratio was 8.2 ± 1.3. Autoradiographic analysis revealed that MR imaging of GdDTPA closely correlated with the distribution of 3Hmuscimol, and precisely estimated its Vd (mean difference in Vd, 7.4%). Quantitative autoradiograms revealed that muscimol was homogeneously distributed over the perfused region in a square-shaped concentration profile. Conclusions. Muscimol can be effectively delivered to clinically relevant volumes of the primate brain. Moreover, the distribution of muscimol can be tracked using coinfusion of GdDTPA and MR imaging. The ability to perform accurate monitoring and to control the anatomical extent of muscimol distribution during its convectionenhanced delivery will enhance safety, permit correlations of muscimol distribution with clinical effect, and should lead to an improved understanding of the pathophysiological processes underlying a variety of neurological disorders.