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The authors evaluated semiautomatic, voxel-based registration methods for a new application, the assessment and optimization of interventional magnetic resonance imaging (I-MRI) guided thermal ablation of liver cancer. The abdominal images acquired on a low-field-strength, open I-MRI system contain noise, motion artifacts, and tissue deformation. Dissimilar images can be obtained as a result of different MRI acquisition techniques and/or changes induced by treatments. These features challenge a registration algorithm. The authors evaluated one manual and four automated methods on clinical images acquired before treatment, immediately following treatment, and during several follow-up studies. Images were T2-weighted, T1-weighted Gd-DTPA enhanced, T1-weighted, and short-inversion-time inversion recovery (STIR). Registration accuracy was estimated from distances between anatomical landmarks. Mutual information gave better results than entropy, correlation, and variance of gray-scale ratio. Preprocessing steps such as masking and an initialization method that used two-dimensional (2-D) registration to obtain initial transformation estimates were crucial. With proper preprocessing, automatic registration was successful with all image pairs having reasonable image quality. A registration accuracy of ≈3 mm was achieved with both manual and mutual information methods. Despite motion and deformation in the liver, mutual information registration is sufficiently accurate and robust for useful applications in I-MRT thermal ablation therapy.