**4. Autonomic system dysfunction in primary headaches**

The precise involvement of autonomous nervous system (ANS) in different types of primary headaches is still a subject of debate, as there is still not a clear‐cut explanation of the differences found across various studies, both in humans and in animals, concerning the modulation of sympathetic and parasympathetic nervous system. The different results on dysautonomic mechanisms in headache patients can be partially explained by the numerous methods used to quantify the ANS activity, therefore generating specific results for different systems, such as cardiac (e.g., heart rate variability), cardiovascular (e.g., hypotension), pupillary response, and also by the different time‐related variations with impact on the vegetative system dynam‐ ics [50, 51].

Autonomic dysfunction of different primary headache types have been investigated in several studies, most of them analyzing cardiovascular reflex mechanisms or biochemical changes [52– 54]. It is known today that different subtypes of primary headaches share common autonomic mechanisms implying different endogenous molecules and dysfunctional interactions between vegetative pathways and brain‐vessel system [55]. Findings indicate as central mechanisms both sympathetic hyperfunction and parasympathetic hypofunction in autonom‐ ic manifestations of headache patients [56, 57].

#### **4.1. Sympathetic nervous system and headache**

different quantities and combinations giving them a remarkable functional diversity. Calcito‐ nin gene‐related peptide is the most potent vasodilator transmitter identified in the cerebral circulation, and its action is endothelium independent and associated with an increase in vessel

Substance P is a nondecapeptide involved in nociceptive transmission. In many vascular beds, including the cerebral bed, substance P is a potent vasodilator and it also dilates both arteries and veins *in situ* [45]. Substance P can induce protein extravasation in the periphery and a similar response is seen in the dura with protein extravasation and mast cell degranulation [46]. Neurokinin A can relax cerebral vessels both *in vitro* and *in vivo*, although it is only one‐ tenth as potent as substance P [47]. Both substance P and NKA coexist in perivascular nerve

It is possible that the antinociceptive system to be activated not only by direct stimulation, but also by disinhibition in PAG. By researching the expression of the protein c‐FOS in the activated neurons, patterns different from the neuronal activity in the structures involved in controlling analgesia were found. The existence of these patterns different from the neuronal discharge especially in the spine and finding a background noise have suggested the existence of a tonic activity of the most nociceptive neurons in the posterior horn of the marrow determined by the supraspinal continuous discharges of the endogenous antinociceptive system defining the

The precise involvement of autonomous nervous system (ANS) in different types of primary headaches is still a subject of debate, as there is still not a clear‐cut explanation of the differences found across various studies, both in humans and in animals, concerning the modulation of sympathetic and parasympathetic nervous system. The different results on dysautonomic mechanisms in headache patients can be partially explained by the numerous methods used to quantify the ANS activity, therefore generating specific results for different systems, such as cardiac (e.g., heart rate variability), cardiovascular (e.g., hypotension), pupillary response, and also by the different time‐related variations with impact on the vegetative system dynam‐

Autonomic dysfunction of different primary headache types have been investigated in several studies, most of them analyzing cardiovascular reflex mechanisms or biochemical changes [52– 54]. It is known today that different subtypes of primary headaches share common autonomic mechanisms implying different endogenous molecules and dysfunctional interactions between vegetative pathways and brain‐vessel system [55]. Findings indicate as central mechanisms both sympathetic hyperfunction and parasympathetic hypofunction in autonom‐

wall cyclic AMP [42–44].

ics [50, 51].

fibers in peripheral and cerebral vessels [48].

52 Current Perspectives on Less-known Aspects of Headache

hypothesis of "prophylactic antinociceptive system" [49].

ic manifestations of headache patients [56, 57].

**4. Autonomic system dysfunction in primary headaches**

The sympathetic tracts involved in the vascular regulation in headache arise mainly from the ipsilateral superior cervical ganglion, while some nerve fibers that supply the vertebral and basilar arteries originate from the inferior cervical ganglion and the stellate ganglion [58, 59].

The vascular dynamics and regulation of the intracranial pressure are mediated by noradre‐ naline (NA) and neuropeptide Y (NPY) [60, 61]. Neuropeptide Y is widely distributed throughout sympathetic nerve endings together with NA and it is considered a marker of noradrenergic function. It has been shown that both mediators may be externally influenced, for instance, by sympathectomize, which in turns, stimulates the expression of parasympa‐ thetic fibers [62]. NPY participates in the autonomic control of cerebral circulation and can be involved in disorders characterized by neurogenically mediated changes in the cerebral blood flow, such as migraine, cluster headache, and stroke. Decreased NPY concentrations during symptoms‐free periods bring further evidence of the dysregulation of the sympathetic function in the course of migraine. The levels of NPY increase during attacks in migraine patients [63]. Microscopic and functional studies have revealed that NPY expression becomes prominent with the increase of sympathetic activity [64]. Furthermore, it has been proven that NA modulates the response of the small pial vessels on the cortical surface and that sympathetic fibers arise from central sources such as locus coeruleus (LC) or the hypothalamus [65–67]. Therefore, via direct influence, destruction of the LC induces a reduction in the number of noradrenergic nerve fibers in intracerebral vessels [59], while on contrary that stimulation of NA neurons in the hypothalamus is associated with an increase in hypothalamic blood flow which is not influenced by superior cervical ganglionectomy or by the β‐adrenoceptor antagonist propranolol [68]. These anatomic and physiological features showing central control may represent possible therapeutic targets in primary headaches.

#### **4.2. Parasympathetic nervous system**

As it is well known, cerebral blood vessels display perivascular nerves presenting parasym‐ pathetic activity (mediated by acetylcholine and acetylcholinesterase activity [69, 70]. The vast majority of parasympathetic nerve fibers to cerebral vessels implied sphenopalatine and otic ganglia [71]. Interesting enough, it has been shown that parasympathetic nerves may interact with sympathetic terminals in the close vicinity of the cerebrovascular smooth muscle effector [71]. Activation of trigeminal nerves and subsequent nociceptive signaling mediates a para‐ sympathetic reflex leading to the release of vasoactive neuropeptides [9, 72, 73]. Vasodilatation of the cranial vessels seems a common property of cranial neurovascular dynamics involving sensory and parasympathetic mechanisms [44, 74].

Along with acetylcholine, there are other neuro messengers that mediate neurogenic vasodi‐ latation, such as vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating polypeptide (PACAP), and nitric oxide (NO), as demonstrated both by experimental responses of isolated cerebral arteries and by hemodynamic measurements *in vivo* [75–77]. VIP is one of the parasympathetic signaling transmitters contributing to cranial parasympathetic outflow mediated through the sphenopalatine ganglia. It has been shown that VIP coexists with Ach in the perivascular nerve fibers around brain vessels [78]. Although, the VIP‐immunoreactive nerve supply is sparse in cerebral arteries or veins, it is considered that VIP concentrations are a marker of parasympathetic activation in migraine [79–81].

#### **4.3. Pathogenic autonomic mechanisms in headache**

Large body of data suggests a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. Studies have provided support for a dysbalance between parasympathetic and sympathetic nervous system, which trigger the pathogenic mechanisms and contribute to the clinical presentation in primary headaches. The activation of the parasympathetic cranial outflow during migraine and cluster headache (CH) attacks seems to be due to the activation of the trigeminovascular system, which was described previously. This implies the release of specific neuromediators, such as the neuropeptide calcitonin gene‐related peptide (CGRP) [82].

Some studies used transcranial Doppler sonography to assess vascular oscillations corre‐ sponding to myogenic cerebrovascular regulation in migraine and tension‐headache patients [55, 83]. Most of the data focus on migraine, a chronic neurovascular disorder, which is classically considered the result of the sympathetic system unbalance, generally meaning increased sympathetic activity, although some studies showed decreased sympathetic activity [53, 57]. Both in the prodromal phase and in the headache phase of a migrainous episode, there are vegetative symptoms, such as hunger, sleepiness, and orthostatic hypoten‐ sion initially, and later, in the headache phase, vomiting and nausea, pointing out a close relationship between the ANS and this type of headache [2]. The autonomic manifestations imply decreased plasma noradrenaline levels and increased adrenergic receptor sensitivity [53]. There are still contradictory data on the exact involvement of sympathetic system in migraine. Some studies investigated cardiac and cardiovascular reactions during vagal and sympathetic activation [84]. An increased basal sympathetic tone is also suggested by a frequent association of hypertension with migraine [85]. However, the association of migraine with blood pressure variations is still unclear, as there are studies showing an increased diastolic blood pressure in migraine and also an association of migraine with lower blood pressure [85]. Sympathetic hypofunction has been reported for migraine in studies of pupil diameter [82, 86], cardiovascular reflex responses, and heart rate recovery [87]. The heart rate variability in migraine patients across a longer time period was different compared to healthy controls during normal daily activity, which pointed out parasympathetic hypofunction in migraine patients [88].

Sympathetic skin responses [89] and salivary amylase levels as marker of sympathoadrenal medullary activity [90] seem decreased during migraine attacks, suggesting the dynamic involvement of the sympathetic system in this pathology.

Gass and Glaros [91] examined different vegetative biomarkers such as the heart rate varia‐ bility, skin temperature, skin conductance, and respiration in patients with migraine and compared to healthy controls, and found in migraine patients a decreased variability of the consecutive R‐to‐R intervals, therefore pleading for a sympathetic hyperfunction and de‐ creased parasympathetic tone in migraine patients [91]. Yerdelen et al. [87] examined heart rate recovery after physical exercise as an index for vagal parasympathetic activity in migraine and tension‐type headache patients (TTH) and controls and showed that even though parasympathetic function has not been affected in migraine and TTH patients, sympathetic tone in migraine patients is elevated compared to patients with episodic tension‐type head‐ ache [87].

In an interesting study, Tomé‐Pires and Miró [92] measured skin conductance responses (SCRs) in migraine versus control subjects while presenting pain descriptors, emotional negative words, and neutral words [92]. The authors showed no differences in the skin conductance responses in the two groups, but migraineurs recalled more emotional words than controls, thus suggesting possible new avenues to modulate migraine pain perception and autonomic responses.

#### **4.4. Cluster headache**

nerve supply is sparse in cerebral arteries or veins, it is considered that VIP concentrations are

Large body of data suggests a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. Studies have provided support for a dysbalance between parasympathetic and sympathetic nervous system, which trigger the pathogenic mechanisms and contribute to the clinical presentation in primary headaches. The activation of the parasympathetic cranial outflow during migraine and cluster headache (CH) attacks seems to be due to the activation of the trigeminovascular system, which was described previously. This implies the release of specific neuromediators, such as the neuropeptide

Some studies used transcranial Doppler sonography to assess vascular oscillations corre‐ sponding to myogenic cerebrovascular regulation in migraine and tension‐headache patients [55, 83]. Most of the data focus on migraine, a chronic neurovascular disorder, which is classically considered the result of the sympathetic system unbalance, generally meaning increased sympathetic activity, although some studies showed decreased sympathetic activity [53, 57]. Both in the prodromal phase and in the headache phase of a migrainous episode, there are vegetative symptoms, such as hunger, sleepiness, and orthostatic hypoten‐ sion initially, and later, in the headache phase, vomiting and nausea, pointing out a close relationship between the ANS and this type of headache [2]. The autonomic manifestations imply decreased plasma noradrenaline levels and increased adrenergic receptor sensitivity [53]. There are still contradictory data on the exact involvement of sympathetic system in migraine. Some studies investigated cardiac and cardiovascular reactions during vagal and sympathetic activation [84]. An increased basal sympathetic tone is also suggested by a frequent association of hypertension with migraine [85]. However, the association of migraine with blood pressure variations is still unclear, as there are studies showing an increased diastolic blood pressure in migraine and also an association of migraine with lower blood pressure [85]. Sympathetic hypofunction has been reported for migraine in studies of pupil diameter [82, 86], cardiovascular reflex responses, and heart rate recovery [87]. The heart rate variability in migraine patients across a longer time period was different compared to healthy controls during normal daily activity, which pointed out parasympathetic hypofunction in

Sympathetic skin responses [89] and salivary amylase levels as marker of sympathoadrenal medullary activity [90] seem decreased during migraine attacks, suggesting the dynamic

Gass and Glaros [91] examined different vegetative biomarkers such as the heart rate varia‐ bility, skin temperature, skin conductance, and respiration in patients with migraine and compared to healthy controls, and found in migraine patients a decreased variability of the consecutive R‐to‐R intervals, therefore pleading for a sympathetic hyperfunction and de‐ creased parasympathetic tone in migraine patients [91]. Yerdelen et al. [87] examined heart rate recovery after physical exercise as an index for vagal parasympathetic activity in migraine

involvement of the sympathetic system in this pathology.

a marker of parasympathetic activation in migraine [79–81].

**4.3. Pathogenic autonomic mechanisms in headache**

54 Current Perspectives on Less-known Aspects of Headache

calcitonin gene‐related peptide (CGRP) [82].

migraine patients [88].

This type of headache implies the ophthalmic division of the trigeminal nerve responsible for the pain manifestations. In addition, there are signs of parasympathetic over activity acting on the facial and cranial vasculature, such as lacrimation, nasal congestion, and injection of the eyes [2]. Cranial parasympathetic systems may be involved in mediating these dysfunctions, with the release of the VIP stimulating vasomotor facial symptoms [93]. Furthermore, it has been shown that noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino‐parasympathetic reflex, which may explain the involvement of autonomic pathway [94]. Animal models used superior salivatory nucleus as a model to measure cranial autonomic symptoms and changes in blood flow in the lacrimal gland/duct as a measure of cranial autonomic activation [95]. The superior salivatory nucleus projects to the cranial vessels through the sphenopalatine ganglion, via the greater pietrosal nerve of the facial nerve. Electrophysiological methods measured neural activity in response to superior salivatory nucleus stimulation. There were two populations of neurons with differential latencies in action. The longer latency neuronal response was mediated by activation of the parasympathetic outflow and that the action of oxygen—as the therapeutic approach, is likely via this pathway. The shorter latency response seemed most likely via antidromic activation of the trigeminal autonomic reflex [96]. Moreover, it has been shown also that posterior hypothalamus may play a central role in the CH, thus explaining the circadian and circannual periodicity of the symptoms [97].

#### **4.5. Tension‐type headache (TTH)**

Although very frequent, the relationship between the tension‐type headache and ANS activity is less documented [87]. It seems that chronic TTH along with migraine may be associated with increased sympathetic tonus, expressed by elevated resting heart rate, compared to episodic TTH [93]. TTH patients may also have a delayed adaptation in heart‐rate to stress and a reduced pain control system inhibition [97].

Even though the dynamics of ANS intervention in primary headaches is not yet fully under‐ stood, the emergence of translational research models and also the development of new techniques to measure the vegetative biomarkers in headaches provide a robust basis for new and more efficient therapeutic strategies.
