A critical review of connectome validation studies.

Diffusion MRI tractography is the most widely used macroscale method for mapping connectomes in vivo. However, tractography is prone to various errors and biases, and thus tractography-derived connectomes require careful validation. Here, we critically review studies that have developed or utilized phantoms and tracer maps to validate tractography-derived connectomes, either quantitatively or qualitatively. We identify key factors impacting connectome reconstruction accuracy, including streamline seeding, propagation and filtering methods, and consider the strengths and limitations of state-of-the-art connectome phantoms and associated validation studies. These studies demonstrate the inherent limitations of current fiber orientation models and tractography algorithms and their impact on connectome reconstruction accuracy. Reconstructing connectomes with both high sensitivity and high specificity is challenging, given that some tractography methods can generate an abundance of spurious connections, while others can overlook genuine fiber bundles. We argue that streamline filtering can minimize spurious connections and potentially improve the biological plausibility of connectomes derived from tractography. We find that algorithmic choices such as the tractography seeding methodology, angular threshold, and streamline propagation method can substantially impact connectome reconstruction accuracy. Hence, careful application of tractography is necessary to reconstruct accurate connectomes. Improvements in diffusion MRI acquisition techniques will not necessarily overcome current tractography limitations without accompanying modeling and algorithmic advances.