Personalized Rendering of Motor System Functional Plasticity Potential to Improve Glioma Resection and Quality of Life

Summary

Background Lower-grade-gliomas affect young patients, thus the longest progression-free-survival (PFS) with a high level quality of life is crucial. Surgery most significantly impacts on tumor natural history, postponing recurrence, improving symptoms, decreasing the need of adjuvant therapies, with extent of resection, gross-total and supra-total (GTR and STR), strongly associating with longest PFS. Achievement of GTR or STR depends on the degree of functional reorganization induced by glioma. Consequently, a successful treatment fostering neural circuit reorganization before surgery, would increase the chance of GRT/STR. Hypothesis The plastic potential of motor system suggests that reorganization of circuits controlling hand movements could be presurgically fostered in LGG patients by enhancing plasticity with up-front motor-rehabilitation and/or by decreasing tumor infiltration with up-front chemotherapy. Advanced neuroimaging allows to infer the neuroplasticity potential. Intraoperative assessment of the motor circuits functionality will validate reliability of preoperative analyses. Aims The project has 4 aims, investigating: A) the presurgical functional (FC) and structural (SC) connectomics of the hand-motor network to picture the spontaneous reorganization and the influence of clinical, imaging and histomolecular variables; B) the dynamic of FC and SC after tumor resection; C) changes in FC and SC maps after personalized upfront motor rehabilitation and/or chemotherapy; D) the effect of FC and SC upfront treatment on the achievement of GTR/STR preserving hand dexterity. Experimental Design Resting-state fMRI and diffusion-MRI will provide FC and SC maps pre- and post-surgery; personalized up-front motor rehabilitation and/or chemotherapy will be administered; Intraoperative brain mapping procedures will generate data to validate the maps. Expected Results 1. Provide a tool to render the motor functional reorganization predictive of surgical outcome. 2. Identify demographic, clinical and imaging variables associated with functional reorganization. 3. Describe the gain induced by up-front treatment. 4. Distinguish "patterns" predicting chance for GTR/STR from "patterns" suggesting need for up-front treatment. Impact On Cancer Results will increase the achievement of GTR/STR, preserving motor integrity, with dramatic impact on LGGs natural history.

Timeline

Start

2024-03-07

Primary completion

2028-02-28

Completion

2028-02-28

Publications

• Background Bello L, Riva M, Fava E, Ferpozzi V, Castellano A, Raneri F, Pessina F, Bizzi A, Falini A, Cerri G. Tailoring neurophysiological strategies with clinical context enhances resection and safety and expands indications in gliomas involving motor pathways. Neuro Oncol. 2014 Aug;16(8):1110-28. doi: 10.1093/neuonc/not327. Epub 2014 Feb 4.
• Background Castellano A, Donativi M, Ruda R, De Nunzio G, Riva M, Iadanza A, Bertero L, Rucco M, Bello L, Soffietti R, Falini A. Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps. Eur Radiol. 2016 May;26(5):1263-73. doi: 10.1007/s00330-015-3934-6. Epub 2015 Aug 30.
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• Background Fornia L, Ferpozzi V, Montagna M, Rossi M, Riva M, Pessina F, Martinelli Boneschi F, Borroni P, Lemon RN, Bello L, Cerri G. Functional Characterization of the Left Ventrolateral Premotor Cortex in Humans: A Direct Electrophysiological Approach. Cereb Cortex. 2018 Jan 1;28(1):167-183. doi: 10.1093/cercor/bhw365.
• Background Fornia L, Rossi M, Rabuffetti M, Leonetti A, Puglisi G, Vigano L, Simone L, Howells H, Bellacicca A, Bello L, Cerri G. Direct Electrical Stimulation of Premotor Areas: Different Effects on Hand Muscle Activity during Object Manipulation. Cereb Cortex. 2020 Jan 10;30(1):391-405. doi: 10.1093/cercor/bhz139.
• Background Fornia L, Rossi M, Rabuffetti M, Bellacicca A, Vigano L, Simone L, Howells H, Puglisi G, Leonetti A, Callipo V, Bello L, Cerri G. Motor impairment evoked by direct electrical stimulation of human parietal cortex during object manipulation. Neuroimage. 2022 Mar;248:118839. doi: 10.1016/j.neuroimage.2021.118839. Epub 2021 Dec 25.
• Background Howells H, Puglisi G, Leonetti A, Vigano L, Fornia L, Simone L, Forkel SJ, Rossi M, Riva M, Cerri G, Bello L. The role of left fronto-parietal tracts in hand selection: Evidence from neurosurgery. Cortex. 2020 Jul;128:297-311. doi: 10.1016/j.cortex.2020.03.018. Epub 2020 Apr 10.
• Background Kong NW, Gibb WR, Badhe S, Liu BP, Tate MC. Plasticity of the Primary Motor Cortex in Patients with Primary Brain Tumors. Neural Plast. 2020 Jul 3;2020:3648517. doi: 10.1155/2020/3648517. eCollection 2020.
• Background Puglisi G, Howells H, Sciortino T, Leonetti A, Rossi M, Conti Nibali M, Gabriel Gay L, Fornia L, Bellacicca A, Vigano L, Simone L, Catani M, Cerri G, Bello L. Frontal pathways in cognitive control: direct evidence from intraoperative stimulation and diffusion tractography. Brain. 2019 Aug 1;142(8):2451-2465. doi: 10.1093/brain/awz178.
• Background Raffin E, Siebner HR. Use-Dependent Plasticity in Human Primary Motor Hand Area: Synergistic Interplay Between Training and Immobilization. Cereb Cortex. 2019 Jan 1;29(1):356-371. doi: 10.1093/cercor/bhy226.
• Background Rossi M, Fornia L, Puglisi G, Leonetti A, Zuccon G, Fava E, Milani D, Casarotti A, Riva M, Pessina F, Cerri G, Bello L. Assessment of the praxis circuit in glioma surgery to reduce the incidence of postoperative and long-term apraxia: a new intraoperative test. J Neurosurg. 2019 Jan 1;130(1):17-27. doi: 10.3171/2017.7.JNS17357. Epub 2018 Feb 23.
• Background Rossi M, Ambrogi F, Gay L, Gallucci M, Conti Nibali M, Leonetti A, Puglisi G, Sciortino T, Howells H, Riva M, Pessina F, Navarria P, Franzese C, Simonelli M, Ruda R, Bello L. Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome. J Neurosurg. 2019 May 17;132(6):1692-1705. doi: 10.3171/2019.2.JNS183408. Print 2020 Jun 1.
• Background Rossi M, Conti Nibali M, Vigano L, Puglisi G, Howells H, Gay L, Sciortino T, Leonetti A, Riva M, Fornia L, Cerri G, Bello L. Resection of tumors within the primary motor cortex using high-frequency stimulation: oncological and functional efficiency of this versatile approach based on clinical conditions. J Neurosurg. 2019 Aug 9;133(3):642-654. doi: 10.3171/2019.5.JNS19453. Print 2020 Sep 1.
• Background Rossi M, Sciortino T, Conti Nibali M, Gay L, Vigano L, Puglisi G, Leonetti A, Howells H, Fornia L, Cerri G, Riva M, Bello L. Clinical Pearls and Methods for Intraoperative Motor Mapping. Neurosurgery. 2021 Feb 16;88(3):457-467. doi: 10.1093/neuros/nyaa359.
• Background Rossi M, Gay L, Ambrogi F, Conti Nibali M, Sciortino T, Puglisi G, Leonetti A, Mocellini C, Caroli M, Cordera S, Simonelli M, Pessina F, Navarria P, Pace A, Soffietti R, Ruda R, Riva M, Bello L. Association of supratotal resection with progression-free survival, malignant transformation, and overall survival in lower-grade gliomas. Neuro Oncol. 2021 May 5;23(5):812-826. doi: 10.1093/neuonc/noaa225.
• Background Rossi M, Vigano L, Puglisi G, Conti Nibali M, Leonetti A, Gay L, Sciortino T, Fornia L, Callipo V, Lamperti M, Riva M, Cerri G, Bello L. Targeting Primary Motor Cortex (M1) Functional Components in M1 Gliomas Enhances Safe Resection and Reveals M1 Plasticity Potentials. Cancers (Basel). 2021 Jul 28;13(15):3808. doi: 10.3390/cancers13153808.
• Background Sanes JN, Donoghue JP. Plasticity and primary motor cortex. Annu Rev Neurosci. 2000;23:393-415. doi: 10.1146/annurev.neuro.23.1.393.
• Background Simone L, Fornia L, Vigano L, Sambataro F, Rossi M, Leonetti A, Puglisi G, Howells H, Bellacicca A, Bello L, Cerri G. Large scale networks for human hand-object interaction: Functionally distinct roles for two premotor regions identified intraoperatively. Neuroimage. 2020 Jan 1;204:116215. doi: 10.1016/j.neuroimage.2019.116215. Epub 2019 Sep 24.
• Background Southwell DG, Hervey-Jumper SL, Perry DW, Berger MS. Intraoperative mapping during repeat awake craniotomy reveals the functional plasticity of adult cortex. J Neurosurg. 2016 May;124(5):1460-9. doi: 10.3171/2015.5.JNS142833. Epub 2015 Nov 6.
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• Background van Dokkum LEH, Moritz Gasser S, Deverdun J, Herbet G, Mura T, D'Agata B, Picot MC, Menjot de Champfleur N, Duffau H, Molino F, le Bars E. Resting state network plasticity related to picture naming in low-grade glioma patients before and after resection. Neuroimage Clin. 2019;24:102010. doi: 10.1016/j.nicl.2019.102010. Epub 2019 Oct 24.
• Background Vigano L, Fornia L, Rossi M, Howells H, Leonetti A, Puglisi G, Conti Nibali M, Bellacicca A, Grimaldi M, Bello L, Cerri G. Anatomo-functional characterisation of the human "hand-knob": A direct electrophysiological study. Cortex. 2019 Apr;113:239-254. doi: 10.1016/j.cortex.2018.12.011. Epub 2018 Dec 24.
• Background Vigano L, Howells H, Fornia L, Rossi M, Conti Nibali M, Puglisi G, Leonetti A, Simone L, Bello L, Cerri G. Negative motor responses to direct electrical stimulation: Behavioral assessment hides different effects on muscles. Cortex. 2021 Apr;137:194-204. doi: 10.1016/j.cortex.2021.01.005. Epub 2021 Jan 29.
• Background Vigano L, Howells H, Rossi M, Rabuffetti M, Puglisi G, Leonetti A, Bellacicca A, Conti Nibali M, Gay L, Sciortino T, Cerri G, Bello L, Fornia L. Stimulation of frontal pathways disrupts hand muscle control during object manipulation. Brain. 2022 May 24;145(4):1535-1550. doi: 10.1093/brain/awab379.
• Background Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8.
• Background Zhao Z, Wang X, Fan M, Yin D, Sun L, Jia J, Tang C, Zheng X, Jiang Y, Wu J, Gong J. Altered Effective Connectivity of the Primary Motor Cortex in Stroke: A Resting-State fMRI Study with Granger Causality Analysis. PLoS One. 2016 Nov 15;11(11):e0166210. doi: 10.1371/journal.pone.0166210. eCollection 2016.

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Indications