From Lesion Network Mapping in Humans to Causal Circuit Validation in Animals for Defining Neuromodulation Targets: A Narrative Review

Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), have demonstrated efficacy across several neuropsychiatric disorders, yet identifying symptom-specific and biologically informed stimulation targets remains a major challenge. Lesion network mapping (LNM) addresses this problem by treating focal brain lesions as natural perturbations and mapping anatomically heterogeneous lesion locations onto normative connectomes to identify convergent symptom-relevant circuits. Since its introduction in 2015, LNM has generated candidate neuromodulation targets across diverse neurological and psychiatric conditions, with several studies showing overlap between lesion-derived networks, independent neuroimaging findings, and therapeutic neuromodulation targets. However, these observations do not establish whether the identified networks connected to lesion sites are causally responsible for symptom expression or how they should be therapeutically modulated. Because LNM relies on correlation-based connectivity measures, it cannot determine which circuit components or pathways causally mediate the relevant symptom, or whether candidate neuromodulation targets should be activated or inhibited. We therefore propose a translational framework in which LNM-derived circuit hypotheses are examined through cross-species anatomical and functional mapping, region-, cell-, and projection-specific perturbation in animal models, and concurrent behavioral and whole-brain functional readouts, before clinical evaluation. This framework positions LNM as a tool for identifying candidate circuits that are first tested in animal models for causal relevance and perturbation direction, and then evaluated clinically for therapeutic relevance.