The unique role of the trigeminal autonomic reflex and its modulation in primary headache disorders

The trigeminal autonomic reflex is a physiological reflex with an important protective function which also plays a role in pathophysiological conditions, such as primary headache. It is not understood whether the autonomic symptoms in trigeminal autonomic cephalalgias and migraine are the consequence of severe trigeminal discharge or indeed directly driven by central generators as part of the pathophysiology, underlying these syndromes.

Modulating this reflex, and particularly the parasympathetic reflex arc, has been shown to be effective in treating headache. Among these modulators, left noninvasive vagal nerve stimulation has been shown to bilaterally inhibit the parasympathetic output of the reflex. Furthermore, the peripheral activation of the reflex, resulting in parasympathetic discharge, is not sufficient to provoke headache attacks in cluster headache patients, suggesting a central modulation.

Here, we review the anatomy and physiology of the trigeminal autonomic reflex and its involvement in primary headache. Possible candidates who have a modulating effect, including neurostimulation and pharmacological approaches, are described.