Spatial Bias in Lesion Network Mapping Is Connectome-Independent

Lesion network mapping (LNM) is increasingly used to link focal brain lesions to distributed functional networks. Recent work has raised concerns that LNM results may be spatially biased by dominant features of the normative connectome. If this were the case, three testable predictions would follow: (i) a consistent spatial pattern of false positives across LNM studies, (ii) that this pattern can be consistently explained by intrinsic connectome organization, and (iii) that symptom-associated LNM findings preferentially occur in regions with high spatial bias. We tested these predictions across three independent LNM datasets (n = 49/101/200), evaluating each prediction in all cohorts. Spatial bias maps derived from 4,000,000 random permutations under the null hypothesis showed minimal correspondence across cohorts (R2 = 0.4-0.8%), indicating strong cohort specificity. Moreover, dominant connectome features--captured by the first 10 principal components of connectivity profiles from 1,000 atlas regions--did not systematically explain these bias maps. Finally, symptom-associated results showed no enrichment in high-bias regions. Together, these findings provide strong evidence that spatial bias in LNM is not driven by dominant connectome features. With appropriate inferential statistics and rigorous study design, LNM remains a valid approach for mapping symptom-related brain networks.