**4. Trigger sites and peripheral nerve irritation hypothesis**

Because of its complex and multifactorial etiology, the exact pathophysiology of migraine headaches has yet to be completely elucidated. There are several commonly accepted theories based on central and peripheral mechanisms. In the context of onabotulinumtoxinA injection for migraine headaches, local inflammation sensitizes sensory neurons and upregulates the recruitment of sensory nociceptors [31–38]. As alluded to earlier, migraine pathophysiology involves irritation of peripheral nerves. Specifically, it involves several branches of the trigeminal nerve. Subsequent repeated irritation of the nerve causes an augmented perception of pain. The trigger point hypothesis attempts to explain this cycle of inflammation and trigeminal neuronal hypersensitivity. It takes into account that patients are often able to describe the origin of their migraine pain in a specific area, and that each site of origin leads to a different constellation of symptoms. Among other mechanisms, irritation of extracranial nerves in the periphery can be caused by overactivity of surrounding musculature, tight fascial bands, and intimate neurovascular relationships. Therefore, irritation of peripheral nerves by adjacent muscular contraction or other contact points can cause release of inflammatory factors, triggering the onset of migraine headaches. In this context, onabotulinumtoxinA can be targeted to these potential trigger sites in an attempt to prevent or inhibit the inflammatory cycle leading to peripheral and central sensitization. This theory and its implication in the success or failure of migraine surgery should not influence the fact that anatomical knowledge of the nerve locations can improve BTX-A injection techniques. Even if some neurologists do not hold the peripheral nerve compression theory correct, evidence now shows that BTX-A is most effective when deposited closer to nerves, acting by means of either direct reduction of chemoreceptors on the nociceptor membrane surface, or indirect decrease in activity by reducing mechanosensitivity [25, 26].

Trigger sites are identified by regions where the pain originates, rather than other final locations where the pain may travel. To assess which sites are active, a Migraine Diary should be completed by patients each day for at least 4 weeks. Since patients often do not pay especially close attention to the exact location where pain begins, this log is very useful in keeping track of trigger origin sites. In addition to the migraine diary, a thorough history should be obtained to differentiate between sites where pain begins and sites where pain may radiate to. Because trigger sites are where the pain originates, injection of targeted BTX-A should be focused in these sites and not where the pain ends. However, a more liberal approach to targeted injection is to inject all the regions. Currently, there are six major trigger sites relevant to available treatment methods, which can be categorized into several "regions": frontal (Site I), temporal (Site II), rhinogenic (Site III), occipital (Sites IV and VI), and auriculotemporal (Site V). **Site I** refers to headaches beginning in the lateral and central forehead areas, with central and cephalad radiation. Patients often describe the pain beginning above the eye and moving from outside to inside. At times, palpation with a single finger at the area of the supraorbital and supratrochlear nerve will reveal tender areas where the supraorbital nerve (SON) and supratrochlear nerve (STN) are involved. In some cases, hypertrophy of the corrugator supercilii muscle may be visible on physical exam. **Site II**, or the temporal trigger site, is associated with headaches originating in the temple. Often times, pain radiates toward the lateral temporal and posterior auricular areas. The temporalis muscle may be larger than normal, or tighter than usual. However, it is important to differentiate temporomandibular joint (TMJ) pathology, as it is not a trigger site for migraine headaches. In this region, the zygomaticotemporal branch of the trigeminal nerve (ZTBTN) is involved in the generation of pain. **Site III** refers to pain of nasoseptal origin. This pain is usually associated with weather changes and atmospheric pressure changes, usually beginning in the early hours of the morning. Patients may complain of rhinitis, hyposmia, anosmia, halitosis, and dental pain. Because of this, they can also complain of breathing problems. In addition, this pain is generally described as starting behind the eye and radiating outward. Oxymetazoline nasal spray is used to temporarily abort headaches originating from this site. Of note, septal triggers should be considered if pain persists despite BTX-A injection in other trigger sites. To confirm an active trigger site in the septal area, imaging via computed tomography scan is required. Intranasal pathology such as septal deviation contacting turbinates, concha bullosae, and other masses can be identified and surgically treated. It is important to rule out septonasal origin, as BTX-A generally does not improve pain originating from site III. **Site IV** occipital trigger site refers to headaches originating in the back of the neck and radiating anteriorly. This area usually correlates with the anatomical course of the greater occipital nerve (GON). Palpation in this area usually reveals a point of maximal tenderness that corresponds to the location where the nerve pierces the semispinalis capitis muscle. Some injection techniques target the semispinalis and splenius capitis, as well as the occipitalis muscle, but generally BTX-A is deposited as close to the nerve as possible. Patients may also complain of retroauricular pain associated with this site. Of note, it is possible that an intimate neurovascular relationship between the greater occipital nerve and occipital artery at this trigger site plays a major role in migraine development [6, 18, 20, 39]. The close relationship of the greater occipital nerve with the occipital artery can cause pain to fluctuate with weather, as arterial vascular tone changes. In general, pain in the occipital region mostly involves the GON, while the third occipital nerve (TON) may be involved to a lesser degree. **Site V** refers to pain in the area corresponding to the auriculotemporal nerve (AT). Pain in this area is caused by TMJ facial bands inferiorly and the temporal artery more superiorly, causing irritation to the AT nerve [40]. Finally, **Site VI** refers to the area around the lesser occipital nerve.

While these areas are the major sites relevant to currently available treatment modalities, a number of other sites have been reported to cause significant pain. The trapezius muscle group, TMJ muscle group, sternocleidomastoid muscle, and masseter are few examples. While patient description should aid in the selection and specific location of injection sites, actual injection is based on the anatomy of the culprit nerves and surrounding tissue.
