Functional to anatomical brain image registration is needed for accurate localization of brain activation maps. Due to the presence of nonlinear distortions, it is more effective to consider non-rigid transformations to achieve such a registration. In this paper, a non-rigid registration technique based on the B-spline free-form deformation model and mutual information similarity measure is introduced. An optimization formulation is devised to achieve a fast and robust registration. This formulation differs from the previous formulations by utilizing a limited-memory, second-order optimization algorithm instead of the usual first-order gradient-based algorithms. It also enforces hard parameter constraints instead of constraints based upon physics or Jacobian smoothness. The results obtained indicate that this registration technique provides improvements over rigid and affine techniques when registering functional to anatomical magnetic resonance brain images.