Is radiosurgery a neuromodulation therapy? A 2009 Fabrikant Award Lecture

Radiosurgery is commonly considered to be effective through a destructive physical mechanism on neural tissue. Since its invention by Leksell in the 1950s, clinical and experimental experience of radiosurgery has demonstrated that for classical indications, for example arteriovenous malformations and benign tumors, radiosurgery is effective because of its specific histological effects of thrombotic endothelial proliferation and apoptosis, not simple coagulative necrosis. In functional neurosurgery, the strategy is either to target a small volume of normal tissue (i.e., ventrointermediate nucleus, capsulotomy, trigeminal neuralgia, etc.) with a high dose (80-140 Gy at maximum) or to target a large volume of tissue (i.e., 5-9 cc in epilepsy radiosurgery) with a moderate dose (17-24 Gy at the marginal isodose). These procedures have been proposed, technically performed, and evaluated on the basis of the hypothesis that their mechanism of action is purely destructive. However, modern neurophysiological, radiological and histological studies are leading us to question this assumption. Tissue destruction is turning out to be either absent or minimal and in almost all cases insufficient to explain the clinical effects obtained. Therefore, one possibility is that radiosurgery is inducing changes in the functioning of the neural tissue, by inducing remodeling of the glial environment, and is leading to the modulation of function while preserving basic processing. Thus, most radiosurgery procedures may induce the desired biological effect without requiring the histological destructive effect for completion of the therapeutic objective. Therefore the concept of "lesional" radiosurgery may be incorrect and a completely hidden world of neuromodulatory effects may remain to be discovered.