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This work explores the feasibility and impact of including both the motion correction and the image registration transformation parameters from positron emission tomography (PET) image space to magnetic resonance (MR), or stereotaxic, image space within the systemmatrix of PET image reconstruction. This approach is motivated by the fields of neuroscience and psychiatry, where PET is used to investigate differences in activation patterns between different groups of participants, requiring all images to be registered to a common spatial atlas. Currently, image registration is performed after image reconstruction which introduces interpolation effects into the final image. Furthermore, motion correction (also requiring registration) introduces a further level of interpolation, and the overall result of these operations can lead to resolution degradation and possibly artifacts. It is important to note that performing such operations on a post-reconstruction basis means, strictly speaking, that the final images are not ones which maximize the desired objective function (e.g. maximum likelihood (ML), or maximum a posteriori reconstruction (MAP)). To correctly seek parameter estimates in the desired spatial atlas which are in accordance with the chosen reconstruction objective function, it is necessary to include the transformation parameters for both motion correction and registration within the system modeling stage of image reconstruction. Such an approach not only respects the statistically chosen objective function (e.g. ML or MAP), but furthermore should serve to reduce the interpolation effects. To evaluate the proposed method, this work investigates registration (including motion correction) using 2D and 3D simulations based on the high resolution research tomograph (HRRT) PET scanner geometry, with and without resolutionmodeling, using the ML expectation maximization (MLEM) reconstruction algorithm. The quality of reconstructionwas assessed using biasvariance and root mean squared error analyses, comparing the proposed method to conventional post-reconstruction registration methods. An overall reduction in bias (for a cold region: from 41% down to 31% (2D) and 97% down to 65% (3D), and for a hot region: from 11% down to 8% (2D) and from 16% down to 14% (3D)) and in root mean squared error analyses (for a cold region: from 43% to 37% (2D) and from 97% to 65% (3D), and for a hot region: from 11% to 9% (2D) and from 16% down to 14% (3D)) in reconstructed regional mean activities (full regions of interest; all with statistical significance: p < 5 ✕ 10-10) is found when including the motion correction and registration in the system matrix of the MLEM reconstruction, with resolution modeling. However, this improvement in performance comes with an extra computational cost of about 40 min. In this context, this work constitutes an important step toward the goal of estimating parameters of interest directly from the raw Poisson-distributed PET data, and hence toward the complete elimination of post-processing steps. [ABSTRACT FROM AUTHOR]