Abnormal sensorimotor plasticity in migraine without aura patients Francesco Pierelli a,⇑ , Elisa Iacovelli b , Martina Bracaglia c , Mariano Serrao c , Gianluca Coppola d a IRCCS Neuromed, Pozzilli (IS), Italy b ‘‘Sapienza’’ University of Rome, Department of Medicosurgical Sciences and Biotechnologies, Neurology Section, Rome, Italy c ‘‘Sapienza’’ University of Rome, Department of Medicosurgical Sciences and Biotechnologies, Latina, Italy d G.B. Bietti Foundation-IRCCS, Department of Neurophysiology of Vision and Neurophthalmology, Rome, Italy Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info Article history: Received 11 September 2012 Received in revised form 5 April 2013 Accepted 14 May 2013 Keywords: High-frequency oscillations Paired associative stimulation Thalamocortical fibers Transcranial magnetic stimulation abstract The period between migraine attacks is characterized by paradoxical responses to repetitive sensory and transcranial magnetic stimulation (TMS). Abnormal long-term cortical functional plasticity may play a role and can be assessed experimentally by paired associative stimulation (PAS), in which somatosensory peripheral nerve stimuli are followed by TMS of the motor cortex. Changes in motor-evoked potential (MEP) amplitudes were recorded in 16 migraine without aura patients (MO) and 15 healthy volunteers (HV) before and after PAS, which consisted of 90 peripheral electrical right ulnar nerve stimulations and subsequent TMS pulses over the first dorsal interosseous (FDI) muscle activation site with a delay of 10 ms (excitability depressing) or 25 ms (excitability enhancing). As a control experiment of the 31 subjects studied, 8 (4 MO and 4 HV) also underwent PAS10 earlier, the recording of somatosensory high-frequency oscillations (HFOs) reflecting thalamocortical activation (early HFOs). Although PAS10 reduced MEP amplitudes in HV (À17.7%), it significantly increased amplitudes in MO (+35.9%). Although in HV MEP amplitudes were significantly potentiated (+55.1) after PAS25, only a slight, nonsignificant increase was observed in MO (+18.8%). In the control experiment, performed on 8 subjects pooled together, Pearson’s correlation showed an inverse relationship between the percentage of MEP amplitude changes after PAS10 and early HFO amplitudes (r = À0.81; P = .01). Because we observed that the more deficient the long-term PAS-induced change, the more the thalamocortical activation decreased, we hypothesize that the abnormalities in long-term cortical plasticity observed in the interictal period between migraine episodes could be due to altered thalamic control. Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 1. Introduction Abnormalities in cortical information processing in the periods between migraine attacks have been revealed through neurophysi- ological studies [11,36]. On the one hand, with evoked potentials, a deficient habituation mechanism has been repeatedly observed in migraine both with and without aura. On the other hand, studies with repetitive transcranial magnetic stimulation (rTMS) have re- ported abnormal cortical excitability manifesting as paradoxical ef- fects in response to both depressing or enhancing rTMS methodologies, particularly in migraine with aura [6,7,9,10,16]. There is as yet no unifying hypothesis explaining these cortical abnormalities in migraine. Changes in cortical excitability and diminished cortical preactivation due to an insufficient thalamo- cortical drive have been considered to be possible culprits [2,8,11]. However, both the paradoxical rTMS response and habit- uation deficit point to altered synaptic plasticity mechanisms, which prevent the immediate and longer-lasting cortical changes that reflect adaptation to repeated stimulations, ie, learning and memory [12]. One of the experimental ways to induce durable changes in the excitability of cortical output circuits is to pair peripheral stimula- tion of somatosensory afferents with low-frequency TMS over the contralateral cortical hand motor area [39]. Paired associative stimulation (PAS), in fact, is a protocol that uses in humans a de- sign principle very similar to those leading to long-term associative depression (LTD) or potentiation (LTP) in cortical slide preparations or in animal studies [3–5]. It has been shown in healthy subjects that delivering PAS at an interstimulus interval shorter than the time needed for the afferent inputs to reach the cerebral cortex (10 ms) the excitability decreases, and at an interstimulus interval 0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.05.023 ⇑ Corresponding author. Address: Department of Medicosurgical Sciences and Biotechnologies, ‘‘Sapienza’’ University of Rome, Polo Pontino, Corso della Repubb- lica 79-04100, Latina, Italy. Tel.: +39 0773 6513313; fax: +39 0773 6513333. E-mail address: francesco.pierelli@uniroma1.it (F. Pierelli). www.elsevier.com/locate/pain PAIN Ò 154 (2013) 1738–1742