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 second-order neurons within the CST, it results in an amplification of the neurobiological signal at the level of the central nervous system generating sensitization of the central pathways (Smart et al. 2010). This form of plasticity induces an increase in the nociceptive signal, the activation threshold of neurons decreases, the neuronal response increases for a given stimulation and the receptive field increases.
This sensitization of the trigeminal sensory complex is the cause 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). It can be cephalic, generally around the eye, on the face and scalp, and extracephalic, then extending over the body and 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 stimulations produce reversible allodynia both cephalic and extracephalic (Boyer et al. 2014). With repeated central sensitization, hyperexcitable trigeminovascular nociceptive neurons are persistently sensitized. These neuronal 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, 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 origin 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 habituation of thalamic neurons, which would lead to hyperexcitability of these neurons (Coppola et al. 2007).
In addition, functional magnetic resonance imaging (MRI) of migraineurs has shown activation of the contralateral thalamus to pain in acute migraine (Afridi et al. 2005). Furthermore, a study of migraine patients found reduced volume in several thalamic nuclei closely related to the limbic system (central, anterior, lateral, and dorsal nuclei) (Magon et al. 2015). Another study compared MRI scans of migraine patients with and without allodynia. This resulted in changes in connectivity between the posterior thalamus and regions involved in the emotional interpretation of pain (the limbic system, the parieto-occipital, temporoparietal, and prefrontal cortex) in patients with allodynia (Wang et al. 2015).
