Apologies for the long delay. I tried your suggested approach and found that fMRIPrep performs skull-stripping on the conformed T1w image (i.e., after RAS reorientation and resampling), whereas I can only run synthstrip on the raw T1w data. This leads to a spatial mismatch between the custom mask and the image that fMRIPrep actually uses for apply_mask . One potential solution is to resample my custom mask to the conformed space, but I’m not sure how to properly do this. I noticed similar issues have been mentioned in previous posts, so I was wondering if you could point me to the right direction.