Part 2 - Neurovascular hypothesis:
Alteration of the trigeminal sensory complex and ascending pathways
A. Sensitization of the trigeminal sensory complex
When sensitization of the trigeminal sensory complex becomes central and reaches the second-order neurons within the TSC, it results in an amplification of the neurobiological signal at the level of the central nervous system generating a sensitization of the central pathways (Smart et al. 2010) . This form of plasticity induces an increase in the nociceptive signal, the neuronal activation threshold decreases, the neuronal response increases for a given stimulation and the receptive field increases.
This sensitization of the trigeminal sensory complex is at the origin of hyperalgesia and cutaneous allodynia, when a non-nociceptive stimulus is perceived as painful. Cutaneous allodynia is found in about two thirds of migraine patients, increases with the frequency of attacks and largely predominates in chronic migraines (Bigal et al. 2008). This may be cephalic, generally around the eye, on the face and the scalp, and extra cephalic then extending over the body and the limbs (Burstein et al. 2000). In animals, it has been shown that a single high-intensity stimulation is sufficient to produce reversible cephalic allodynia. Low-intensity but repeated stimulation produces reversible both cephalic and extracephalic allodynia (Boyer et al. 2014). With repeated central sensitization, trigeminovascular nociceptive neurons in a state of hyperexcitability are persistently sensitized. These neural changes are potentially a major risk factor in the development of chronic migraines (Boyer et al. 2014).
B. Sensitization in the thalamus
In several mammalian species, posterior thalamic structures have been shown to contain neurons that receive direct projections from Sp5C (Noseda et al. 2011). In the rat thalamus, the trigeminovascular neurons that process sensory information from the meninges are activated when an inflammatory soup is applied to them (Figure 5). These neurons then exhibit persistent hyperexcitability to cephalic and extracephalic cutaneous stimuli (R. Burstein et al. 2010). Sensitization of third-order neurons in the thalamus is thought to be the cause of contralateral extracephalic allodynia (R. Burstein 2000). In the pathophysiology of migraine, the thalamus is considered the central relay of ascending nociceptive information from the CST (Noseda et al. 2014). In humans, interictal electrophysiological studies have demonstrated a decrease in the habituation of the neurons of the thalamus, which would lead to hyperexcitability of these neurons (Coppola et al. 2007).
Additionally, functional magnetic resonance imaging (MRI) of migraine sufferers has shown activation of the pain-contralateral thalamus in acute migraine (Afridi et al. 2005). In addition, a study conducted with migraine patients found a reduction in the volume of several nuclei of the thalamus in close connection with the limbic system (central, anterior, lateral and dorsal nuclei) (Magon et al. 2015). Another study compared MRIs of migraine patients with and without allodynia. This results in patients with allodynia in changes in the connectivity between the posterior thalamus and regions involved in the emotional interpretation of pain (the limbic system, the parieto-occipital, temporoparietal region and the prefrontal cortex) (Wang et al. 2015).
