Migraine is one of the most prevalent neurological diseases and it is estimated that 14.4% of the global population suffers from it, representing a serious social issue. A recent analysis showed how migraine represents the second cause of years lived with disability after low back pain; however, if we consider only the population in the working age groups (second, third, fourth, and fifth decades of life), migraine reaches the first place [1]. Migraine may present with a variable frequency among different subjects and, even in the same subject, among different life epochs. The International Classification of Headache Disorders (ICHD-3) defines migraine as “chronic” when a patient complains of 15 or more days of headache per month (at least eight of which show migraine characteristics) for more than 3 months [2]. Indeed, chronic migraine constitutes a very burdening disease that limits patients’ lives [3]. Even if pain may not be present daily, several other disabling symptoms can occur. For instance, chronic migraineurs suffer from attention and memory impairments, as well as constant phono- or photophobia. Such symptoms depend on chronic cortical changes (i.e., hyperexcitability) and brainstem alterations (i.e., periaqueductal gray involvement) that lead to an impaired processing of external stimuli and to an altered pain modulation [4].Migraine episodes can be triggered by visual, auditory, or olfactive stimuli; furthermore, migraineurs show a hypersensitivity to environmental stimulation that manifests as phonophobia, photophobia, or osmophobia or cutaneous allodynia; these phenomena seem to be related to one another, as the exposure to stimuli of one modality (e.g., light) enhances even the sensitivity of other sensory modalities too (e.g., touch) [5]. These findings suggest an involvement of the mechanisms related to processing and integration of inputs from different sensory modalities. Therefore, multisensory integration represents an interesting mechanism to study in migraineurs. When different stimuli come from the same source from different sensory modalities, our brain tends to integrate them into a unique percept (e.g., lipreading allows one to better understand spoken words). Sometimes, this occurs when sensory stimuli are incongruent, and their interaction may cause perceptual illusions. An example of this is the sound-induced flash illusion (SIFI), which has been used to assess multisensory processing in migraine sufferers and its link to migraine pathophysiology. In the SIFI, when a visual stimulus (e.g., a white dot, i.e., a flash) is presented together with two or more auditory stimuli (i.e., beeps), a subject tends to perceive more than one flash (fission illusion); conversely, when multiple flashes are presented with just one beep, the subject tends to perceive less flashes than presented (fusion illusion) [6,7]. The SIFI is a very simple paradigm that can be administered by using computer software. Interestingly, it has been shown that fission and fusion effects are associated to changes in temporal and occipital cortical excitability; in fact, it is possible to modulate such illusions via transcranial direct current stimulation (tDCS) [8]. There is strong evidence that the SIFI is altered in migraine patients, suggesting that multisensory integration is altered in migraine. Particularly, episodic migraineurs show increased visual cortical excitability compared to healthy subjects, which is likely responsible for a reduced susceptibility to SIFI, both during migraine attacks and interictally [9]. In chronic migraine, the disruption of multisensory processing, as indexed by SIFI, is greater especially under triptan overuse [10]. Migraineurs’ cortical excitability can be modulated with pharmacological therapy, as demonstrated by studies with transcranial magnetic stimulation (TMS) in patients treated with valproate or topiramate [11,12].One of the main pathophysiological mechanisms of migraine chronification is represented by the sensitization of nociceptive pathways. It starts at peripheral nociceptors, particularly the ones in trigeminal innervated skin, and then moves to second-order neurons at the trigeminal nucleus (central sensitization) [13]. The last phenomenon is responsible for cutaneous allodynia that may be present during a migraine attack or even interictally. Moreover, a chronically persisting nociceptive activation is believed to cause the sensitization of higher central structures (e.g., thalamus), leading to a vicious circle that further worsens migraine [13]. The onabotulinumtoxinA or botulinum neurotoxin A (BoNT-A) is an approved therapy for resistant chronic migraine, with quarterly injections of 155–195 UI on 31–39 target muscles [14,15]. Preclinical studies showed how BoNT-A is able to reverse C-meningeal nociceptors’ sensitization, as well as to reduce the release of inflammatory mediators in the trigeminal ganglion [16,17] and calcitonin gene-related peptide (CGRP) plasma levels in chronic migraineurs [18]. Accordingly, BoNT-A is believed to be able to affect peripheral and central sensitization in chronic migraine [19].

The aim of the present study is to investigate whether BoNT-A preventive therapy in chronic migraineurs is able to modulate multisensory integration as measured by means of the SIFI.