Assessing specificity testing in Lesion Network Mapping

Lesion Network Mapping (LNM) is a framework used for identifying symptom-related brain circuits by projecting lesion locations onto a normative connectome. Recent methodological investigations have raised concerns about the biological interpretation and specificity of the circuits derived using this method, with published LNM maps often showing high similarity across clinically unrelated conditions. Specificity testing has subsequently been put forward as the decisive step to ensure specificity to the symptom in question, accompanied by the argument that this step was not evaluated in the original methodological investigation. Yet, sensitivity testing, specificity testing, case-control LNM, permutation of group labels, and symptom-based LNM involve related operations on connectivity matrix C. We expand on specificity testing in LNM, clarify its relationship to other LNM steps and variants, and examine the persistent repetition among LNM specificity networks across studies. These considerations advance our understanding of the disease-specificity limitation of LNM and encourage the development of new methodological approaches for identifying brain circuits underlying psychiatric and neurological disorders.