Image-guided convection-enhanced delivery of muscimol to the primate brain

Abstract

Object: Muscimol is a potent gamma-aminobutyric acid-A 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 convection-enhanced 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 (3)H-muscimol (0.8 microM) and Gd-DTPA (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: Real-time MR imaging revealed that infusate (tritiated muscimol and Gd-DTPA) distribution was clearly discernible from the noninfused parenchyma. Real-time 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 Gd-DTPA closely correlated with the distribution of (3)H-muscimol, 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 Gd-DTPA and MR imaging. The ability to perform accurate monitoring and to control the anatomical extent of muscimol distribution during its convection-enhanced 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.

Figure 1

(A) Axial and (B) left parasagittal T1-weighted magnetic resonance images of primate brain after perfusion of each striatum with 35 microliters of muscimol co-infused with gadolinium-DTPA. Gadolinium-DTPA tracer provided a distinct region of magnetic resonance T1-weighted hyperintensity (white area) compared to the surrounding tissue and could be seen filling the striata.

Figure 2

There was a linear relationship (R= 0.92) between volume of infusion (Vi) and volume of distribution (Vd) in primates infused with gadolinium-DTPA. The mean Vd:Vi ratio was 8.2± 1.3 (mean ± S.D.).

Figure 3

Autoradiographic measurement of tissue concentrations across the perfused region demonstrated a relatively homogeneous “square-shaped” distribution profile with a steep concentration drop-off at the margins of the perfused tissue at the end of the infusion. Positive numbers refer to anterior spread and negative numbers to posterior spread of muscimol from the site of infusion.

Figure 4

Coronal T1-weighted magnetic resonance imaging after convection-enhanced delivery of 13.5 microliters of radiolabeled ³H-muscimol co-infused with gadolinium-DTPA (surrogate-imaging tracer) into the right striatum. (Inset) Corresponding autoradiogram of ³H-muscimol distribution demonstrates the anatomical and spatial accuracy obtained when utilizing gadolinium-DTPA as a surrogate tracer for muscimol.