cancers Article Targeting Primary Motor Cortex (M1) Functional Components in M1 Gliomas Enhances Safe Resection and Reveals M1 Plasticity Potentials Marco Rossi 1,† , Luca Viganò 1,† , Gugliemo Puglisi 1,2 , Marco Conti Nibali 1 , Antonella Leonetti 1 , Lorenzo Gay 1 , Tommaso Sciortino 1 , Luca Fornia 2,3 , Vincenzo Callipo 1 , Marta Lamperti 1 , Marco Riva 1,2 , Gabriella Cerri 2,3 and Lorenzo Bello 1, *   Citation: Rossi, M.; Viganò, L.; Puglisi, G.; Conti Nibali, M.; Leonetti, A.; Gay, L.; Sciortino, T.; Fornia, L.; Callipo, V.; Lamperti, M.; et al. Targeting Primary Motor Cortex (M1) Functional Components in M1 Gliomas Enhances Safe Resection and Reveals M1 Plasticity Potentials. Cancers 2021, 13, 3808. https:// doi.org/10.3390/cancers13153808 Academic Editor: Shinji Kawabata Received: 5 June 2021 Accepted: 21 July 2021 Published: 28 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milano, Italy; rossi.marco@gmail.com (M.R.); luca.vigano2@gmail.com (L.V.); guglielmo.puglisi@gmail.com (G.P.); marco.continibali@gmail.com (M.C.N.); antonellaleonetti80@gmail.com (A.L.); lorenzoggay@gmail.com (L.G.); tsciortino11@gmail.com (T.S.); vincenzo.callipo@yahoo.com (V.C.); lammar90@hotmail.it (M.L.); marco.riva@unimi.it (M.R.) 2 Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, 20147 Milano, Italy; luca.fornia@unimi.it (L.F.); gabriella.cerri@unimi.it (G.C.) 3 Laboratory of Motor Control, Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, 20147 Milano, Italy * Correspondence: lorenzo.bello@unimi.it † These authors contributed equally to this work. Simple Summary: Primary-Motor-Cortex (M1) hosts two functional components, at its posterior and anterior borders, the first being faster and more excitable than the second. Our study reports a novel technique for the on-line identification of these functional components during M1 tumors resection. It reports for the first time the potential plastic reorganization of M1 and specifically how its functional organization is affected by a growing tumor and correlated to clinical, tumor-related factors and patient motor functional performance. It also shows for the first time that detecting the M1 functional architecture and targeting the two M1 functional components facilitates tumor resection, increasing the rate of complete tumor removal, while maintaining the patient’s functional motor capacity. Abstract: Primary-Motor-Cortex (M1) hosts two functional components, at its posterior and anterior borders, being the first faster and more excitable. We developed a mapping-technique for M1 components identification and determined their functional cortical-subcortical architecture in M1 gliomas and the impact of their identification on tumor resection and motor performance. A novel advanced mapping technique was used in 102 tumors within M1 or CorticoSpinal-Tract to identify M1-two components. High-Frequency-stimulation (2–5 pulses) with an on-line qualitative and quantitative analysis of motor responses was used; the two components’ cortical/subcortical spatial distribution correlated to clinical, tumor-related factor and patients’ motor outcome; a cohort treated with standard-mapping was used for comparison. The two functional components were always identified on-line; in tumors not affecting M1, its functional segregation was preserved. In M1 tumors, two architectures, both preserving the two components, were disclosed: in 50%, a normal cortical/subcortical architecture emerged, while 50% revealed a distorted architecture with loss of anatomical reference and somatotopy, not associated with tumor histo-molecular features or volume, but with a previous treatment. Motor performance was maintained, suggesting functional compensation. By preserving the highest and resecting the lowest excitability component, the complete-resection increased with low morbidity. The real-time identification of two M1 functional components and the preservation of the highest excitability one increases safe resection, revealing M1 plasticity potentials. Keywords: primary motor cortex; brain mapping; gliomas; intraoperative neurophysiology; func- tional organization Cancers 2021, 13, 3808. https://doi.org/10.3390/cancers13153808 https://www.mdpi.com/journal/cancers