https://doi.org/10.4081/cc.2025.15778

Exploring the cortical effect of monoclonal antibodies against CGRP ligand: a pilot study of the cortical silent period in migraine

Vol. 35 No. 1 (2025)
Submitted: 14 January 2025
Accepted: 22 April 2025
Published: 9 May 2025
Transcranial magnetic stimulation, monoclonal antibody, CGRP, cortical inhibition, chronic migraine, medication overuse headache
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Authors

Gabriele Sebastianelli
gabrielesebastianelli@gmail.com
https://orcid.org/0000-0002-4231-4417
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.
Giulia Rosaria Melis
Department of Systems Medicine, University of Rome Tor Vergata, Italy.
Chiara Abagnale
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.
Francesco Casillo
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.
Cherubino Di Lorenzo
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.
Mariano Serrao
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.
Gianluca Coppola
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.

Background: Evidence from animal studies suggests that monoclonal antibodies targeting the calcitonin gene-related peptide (anti-CGRP mAbs) may only minimally penetrate the blood-brain barrier due to their high molecular weight. However, neuroimaging and electrophysiological studies revealed indirect neuromodulatory effects originating peripherally and moving toward the central nervous system. This pilot study aimed to investigate the cortical inhibitory activity by recording the cortical silent period (SP) triggered by transcranial magnetic stimulation (TMS) in migraine patients before and after anti-CGRP mAbs treatment.

Methods: We prospectively recorded 8 individuals with episodic or chronic migraine who had not responded to at least three preventive migraine therapies. We applied high-intensity TMS to the primary motor cortex to evaluate the cortical SP from contracted perioral muscles. Electrophysiological data were gathered at baseline (T0), one month (T1), and two months (T2) before each anti-CGRP mAbs administration.

Results: Anti-CGRP mAbs treatment diminished the average monthly headache days (MHD). The duration of SP was reduced at T1 (82.49 ms at T0 vs. 66.59 ms at T1, p<0.001) but reverted to baseline levels at T2 (82.11 ms). The percentage variations in SP length assessed at T1 and T2 relative to T0 did not correlate with the percentage decrease in MHD measured at T1.

Conclusions: Our pilot study findings suggest that anti-CGRP mAbs not only have their known peripheral effects but also influence cortical inhibitory mechanisms in an indirect and transient manner. This provides a valuable foundation for further research, especially studies with larger sample sizes to confirm and expand on these preliminary results.

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Citations

Crossref
Scopus
Google Scholar
Europe PMC
Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia 2019;39:366-73.
Edvinsson L, Haanes KA, Warfvinge K, Krause DiN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 2018;14:338-50.
Tepper SJ. History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment. Headache 2018;58:238-75.
Johnson KW, Morin SM, Wroblewski VJ, Johnson MP. Peripheral and central nervous system distribution of the CGRP neutralizing antibody [125 I] galcanezumab in male rats. Cephalalgia 2019;39:1241-8.
Noseda R, Schain AJ, Melo-Carrillo A, Tien J, Stratton J, Mai F, et al. Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier. Cephalalgia 2020;40:229-40.
Ziegeler C, Mehnert J, Asmussen K, May A. Central effects of erenumab in migraine patients: An event-related functional imaging study. Neurology 2020;95:e2794-802.
De Tommaso M, Delussi M, Gentile E, Ricci K, Quitadamo SG, Libro G. Effect of single dose Erenumab on cortical responses evoked by cutaneous a-delta fibers: A pilot study in migraine patients. Cephalalgia 2021;41:1004-14.
Thiele A, Klehr L, Strauß S, Angermaier A, Schminke U, Kronenbuerger M, et al. Preventive treatment with CGRP monoclonal antibodies restores brain stem habituation deficits and excitability to painful stimuli in migraine: results from a prospective case-control study. J Headache Pain 2021;22:149.
De Icco R, Fiamingo G, Greco R, Bottiroli S, Demartini C, Zanaboni AM, et al. Neurophysiological and biomolecular effects of erenumab in chronic migraine: An open label study. Cephalalgia 2020;40:1336-45.
Casillo F, Sebastianelli G, Di Renzo A, Cioffi E, Parisi V, Di Lorenzo C, et al. The monoclonal CGRP-receptor blocking antibody erenumab has different effects on brainstem and cortical sensory-evoked responses. Cephalalgia 2022;42:1236-45.
Szabo E, Ashina S, Melo-Carrillo A, Bolo NR, Borsook D, Burstein R. Peripherally acting anti-CGRP monoclonal antibodies alter cortical gray matter thickness in migraine patients: A prospective cohort study. Neuroimage Clin 2023;40:103531.
Schwedt TJ, Nikolova S, Dumkrieger G, Li J, Wu T, Chong CD. Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab. J Headache Pain 2022;23:159.
Basedau H, Sturm LM, Mehnert J, Peng KP, Schellong M, May A. Migraine monoclonal antibodies against CGRP change brain activity depending on ligand or receptor target - an fMRI study. Elife 2022;11:e77146.
Filippi M, Messina R, Bartezaghi M, Cetta I, Colombo B, Grazzi L, et al. The effect of erenumab on brain network function in episodic migraine patients: a randomized, placebo-controlled clinical trial (RESET BRAIN). J Neurol 2023;270:5600-12.
Szabo E, Bolo NR, Borsook D, Burstein R, Ashina S. Peripherally acting anti-CGRP monoclonal antibodies attenuate cortical resting-state connectivity in migraine patients. Cephalalgia 2025;45:3331024241313377.
Currà A, Modugno N, Inghilleri M, Manfredi M, Hallett M, Berardelli A. Transcranial magnetic stimulation techniques in clinical investigation. Neurology 2002;59:1851-9.
Leis AA, Kofler M, Stokic DS, Grubwieser GJ, Delapasse JS. Effect of the inhibitory phenomenon following magnetic stimulation of cortex on brainstem motor neuron excitability and on the cortical control of brainstem reflexes. Muscle Nerve 1993;16:1351-8.
Cruccu G, Inghilleri M, Berardelli A, Romaniello A, Manfredi M. Cortical mechanisms mediating the inhibitory period after magnetic stimulation of the facial motor area. Muscle Nerve 1997;20:418-24.
Neverdahl JP, Omland PM, Uglem M, Engstrøm M, Sand T. Reduced motor cortical inhibition in migraine: A blinded transcranial magnetic stimulation study. Clin Neurophysiol 2017;128:2411-8.
Aurora SK, al-Sayeed F, Welch KM. The cortical silent period is shortened in migraine with aura. Cephalalgia 1999;19:708-12.
Curra A, Pierelli F, Coppola G, Barbanti P, Buzzi MG, Galeotti F, et al. Shortened cortical silent period in facial muscles of patients with migraine. Pain 2007;132:124-31.
Ozturk V, Cakmur R, Donmez B, Yener GG, Kursad F, Idiman F. Comparison of cortical excitability in chronic migraine (transformed migraine) and migraine without aura. A transcranial magnetic stimulation study. J Neurol 2002;249:1268-71.
Currà A, Coppola G, Gorini M, Porretta E, Bracaglia M, Di Lorenzo C, et al. Drug-induced changes in cortical inhibition in medication overuse headache. Cephalalgia 2011;31:1282-90.
Melo-Carrillo A, Noseda R, Nir R, Schain AJ, Stratton J, Strassman AM, et al. Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody. J Neurosci 2017;37:7149-63.
Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 2004;142:1171-81.
Coppola G, Vandenheede M, Di Clemente L, Ambrosini A, Fumal A, De Pasqua V, et al. Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks. Brain 2005;128:98-103.
Pierelli F, Iacovelli E, Bracaglia M, Serrao M, Coppola G. Abnormal sensorimotor plasticity in migraine without aura patients. Pain 2013;154:1738-42.
Coppola G, Di Lenola D, Abagnale C, Ferrandes F, Sebastianelli G, Casillo F, et al. Short-latency afferent inhibition and somato-sensory evoked potentials during the migraine cycle: surrogate markers of a cycling cholinergic thalamo-cortical drive? J Headache Pain 2020;21:34.
Middleton FA, Strick PL. Basal-ganglia ‘projections’ to the prefrontal cortex of the primate. Cereb Cortex 2002;12:926-35.
Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions. Progr Brain Res 1990;85:119-46.

How to Cite

1.
Sebastianelli G, Melis GR, Abagnale C, Casillo F, Di Lorenzo C, Serrao M, et al. Exploring the cortical effect of monoclonal antibodies against CGRP ligand: a pilot study of the cortical silent period in migraine. Confinia Cephalal [Internet]. 2025 May 9 [cited 2025 May 9];35(1). Available from: https://www.confiniacephalalgica.com/site/article/view/15778
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