**5. Heart rate variability as a measure of autonomic nervous system in migraine**

The autonomic nervous system (ANS) has important functions in maintaining homeostasis by adjustment of the body to internal and environmental demands. Beside key functions con‐ trolled by the ANS such as respiration, blood pressure, heart rate, hormonal regulation, etc., ANS is also involved in regulating emotional behavior and cognitive functions.

The sympathetic nervous system (SNS) controls of the heart coming from the upper thoracic region of the spinal cord. Preganglionic fibers synapse with postganglionic sympathetic fibers and release acetylcholine, which binds to nicotinic receptors on the postganglionic fibers. Through sympathetic adrenergic efferent fibers extend to the sinoatrial and atrioventricular nodes in the heart where they release norepinephrine at synapses with beta‐adrenergic receptors [98]. Stimulation of the SNS increases heart rate (positive chronotropy), ventricular contraction (positive inotropy), conduction velocity (positive dromotropy), and rate of relaxation (positive lusitropy). The parasympathetic nervous system (PNS) control of the heart coming from vagal nuclei within the medulla oblongata in the brainstem, and efferent nervous outflow occurs via the 10th cranial nerve (vagus nerve). The long preganglionic efferent nerve fibers extent to the heart and synapse with a ganglia located near the sinoatrial and atrioven‐ tricular nodes. Acetylcholine is released, binds to nicotinic receptors, and activates short postganglionic efferent nerve fibers. These postganglionic fibers synapses with muscarinic receptors in the sinoatrial and atrioventricular nodes, and is activated by acetylcholine. For heart PNS decreases heart rate (negative chronotropy), force of atrial contraction (negative inotropy), rate of relaxation (negative lusitropy), and negative dromotropy [98].

The actions of the SNS and PNS are often opposing in their effects and normally the SNS and PNS activities are in dynamic balance thus indicating a healthy and flexible physiological system [99]. The autonomic imbalance described by increased SNS activity and suppressed PNS activity is associated with an increased risk of diseases [99]. The central control of cardiovascular system involved several areas throughout spinal, bulbopontine, pontomesen‐ cephalic, and forebrain. The medullary centers work through reflex cardiovascular mecha‐ nisms such as baroreflex, chemoreflex, and cardiopulmonary reflex [100]. The afferent fibers of the cardiovascular reflexes are terminated in the nucleus tractus solitarii [100]. The reticular formation of the ventrolateral medulla (VLM) is the primary central site that regulates sympathetic outflow, thus contributing to the regulation of BP and heart rate (HR). In the rostral VLM part are excitatory neurons which synapse in the intermediolateral gray column of the spinal cord, and in the caudal VLM are inhibitory neurons that sent projections to the rostral VLM. The preganglionic parasympathetic neurons located in the nucleus ambiguous and the dorsal motor nucleus of vagus are involved in the parasympathetic regulation of the cardiac reflexes [101]. Also parabrachial nucleus, Kolliker‐Fuse nucleus, the cluster of A5 cells are the brainstem centers involved in the control of the cardiovascular system.

techniques to measure the vegetative biomarkers in headaches provide a robust basis for new

The autonomic nervous system (ANS) has important functions in maintaining homeostasis by adjustment of the body to internal and environmental demands. Beside key functions con‐ trolled by the ANS such as respiration, blood pressure, heart rate, hormonal regulation, etc.,

The sympathetic nervous system (SNS) controls of the heart coming from the upper thoracic region of the spinal cord. Preganglionic fibers synapse with postganglionic sympathetic fibers and release acetylcholine, which binds to nicotinic receptors on the postganglionic fibers. Through sympathetic adrenergic efferent fibers extend to the sinoatrial and atrioventricular nodes in the heart where they release norepinephrine at synapses with beta‐adrenergic receptors [98]. Stimulation of the SNS increases heart rate (positive chronotropy), ventricular contraction (positive inotropy), conduction velocity (positive dromotropy), and rate of relaxation (positive lusitropy). The parasympathetic nervous system (PNS) control of the heart coming from vagal nuclei within the medulla oblongata in the brainstem, and efferent nervous outflow occurs via the 10th cranial nerve (vagus nerve). The long preganglionic efferent nerve fibers extent to the heart and synapse with a ganglia located near the sinoatrial and atrioven‐ tricular nodes. Acetylcholine is released, binds to nicotinic receptors, and activates short postganglionic efferent nerve fibers. These postganglionic fibers synapses with muscarinic receptors in the sinoatrial and atrioventricular nodes, and is activated by acetylcholine. For heart PNS decreases heart rate (negative chronotropy), force of atrial contraction (negative

**5. Heart rate variability as a measure of autonomic nervous system**

ANS is also involved in regulating emotional behavior and cognitive functions.

inotropy), rate of relaxation (negative lusitropy), and negative dromotropy [98].

The actions of the SNS and PNS are often opposing in their effects and normally the SNS and PNS activities are in dynamic balance thus indicating a healthy and flexible physiological system [99]. The autonomic imbalance described by increased SNS activity and suppressed PNS activity is associated with an increased risk of diseases [99]. The central control of cardiovascular system involved several areas throughout spinal, bulbopontine, pontomesen‐ cephalic, and forebrain. The medullary centers work through reflex cardiovascular mecha‐ nisms such as baroreflex, chemoreflex, and cardiopulmonary reflex [100]. The afferent fibers of the cardiovascular reflexes are terminated in the nucleus tractus solitarii [100]. The reticular formation of the ventrolateral medulla (VLM) is the primary central site that regulates sympathetic outflow, thus contributing to the regulation of BP and heart rate (HR). In the rostral VLM part are excitatory neurons which synapse in the intermediolateral gray column of the spinal cord, and in the caudal VLM are inhibitory neurons that sent projections to the rostral VLM. The preganglionic parasympathetic neurons located in the nucleus ambiguous and the dorsal motor nucleus of vagus are involved in the parasympathetic regulation of the cardiac

and more efficient therapeutic strategies.

56 Current Perspectives on Less-known Aspects of Headache

**in migraine**

The upper brainstem level includes the periaqueductal gray matter (PAG), which integrates the autonomic control with pain modulation and behavioral responses to stress [102]. The forebrain level includes the paraventricular and related nuclei of the hypothalamus, thalamus, amygdala, and anterior cingulate cortex, the insular and medial prefrontal cortex that inte‐ grates autonomic and endocrine responses [102]. The anterior limbic circuit (insula, the anterior cingulate cortex, and amygdala) assures integration of specific sensations with emotional and goal‐related autonomic responses [102]. Electrical stimulation of the prefrontal and cingulate cortex, left insula, lateral nucleus of hypothalamus decreased heart rate and blood pressure, whereas electrical stimulation of right insula, ventromedial nucleus of hypothalamus increased heart rate and blood pressure [103]. Stimulation of the basolateral nucleus of amygdala increases blood pressure and decreases heart rate; stimulation of the rostral nucleus of amygdala results in depressor effects and variable changes in heart rate [103].

The normal sympathovagal regulation induces an increase in heart rate during inspiration and decrease during expiration, and this physiological phenomenon is known as respiratory arrhythmia. The intrinsic heart rate is 105 beats/minute while resting heart rate is only 60–80 beats/minute, indicating that the heart is under "vagal dominance" [104].

The electrical signal produced by the heart can be measured with an electrocardiogram. Electrocardiogram registers depolarization of the atria (P‐wave), depolarization of the ventricles (the QRS complex), and repolarization of the ventricles (T‐wave). Using these points we can measure heart period or inter beat interval which measure the time between two consecutive heart beats in milliseconds [105]. Heart rate (HR) measures the numbers of consecutive heart beats in 1 min (beats per min). The analysis of consecutive sinus rhythm R‐ R intervals is known as heart rate variability (HRV), a noninvasive electrocardiographic marker reflecting the activity of the ANS on sinus node function.

HRV parameters can be calculated in time domain (statistical and geometrical), frequency domain (power spectral density), and nonlinear measures. In time domain methods HRV parameters are standard deviation between normal intervals during recording—SDNN (ms), standard deviation of the average values of NN intervals calculated from all 5‐min segments of the entire recording—SDANN (ms), square root of the mean of the sum of the squares of differences between adjacent NN intervals—RMSSD (ms), percentage of differences between adjacent NN intervals differing more than 50 ms—pNN50% [105]. A lot of studies indicate that SDNN, RMSSD, and pNN50%, time domain indicators of the HRV, represent the activity of the vagal nerve.

Using simultaneously the Fast Fourier transform method and parametric– autoregressive method (AR), HRV can be analyzed in frequency domain (power spectral analyses of HRV) in which can be measured low‐frequency component (LF < 0.15 Hz) taken as an indicator of both vagal and sympathetic functions, high‐frequency component (HF ≥ 0.15 Hz) as an indicator of parasympathetic function, very low‐frequency component (VLF—the frequency band in the range 0.003–0.04 Hz), ultra‐low‐frequency (ULF—the frequency band below 0.003 Hz), and the total power (TP) [105, 106]. VLF is related to the thermoregulatory sympathetic vascular activity and to oscillations in the renin‐angiotensin system [107]. The ratio of LF/HF is considered as an index of cardiac sympathetic/parasympathetic tone balance.

Abnormalities in the SNS or PNS have been found in migraine patients during the headache‐ free phase [108, 109]. Some researchers revealed sympathetic hypofunction and parasympa‐ thetic hyper‐function in migraine patients during the same period [83, 110]. Other study found that older patients with migraine may have sympathetic hyper‐function and a parasympathetic hypofunction during headache‐free intervals [111]. Martin et al. [112] found a reduction of HR during deep breathing, and after 2 min of tilting. Appel et al. [113] revealed increase of the low‐frequency band of HRV analysis in migraineurs, suggesting an increase in sympathetic activity.

We tried to analyze the ANS involvement in migraine using the HRV on long‐term 24‐h ECG. We investigated 27 subjects with migraine (10 with migraine with aura and 17 without aura) during headache‐free periods and 10 age‐matched healthy control subjects. We found a significant decrease in SDNN, RMSSD, and HF indicating parasympathetic dysfunction in migraine groups during night headache‐free periods, and the most affected were migraine with aura patients (**Figures 1** and **2**). LF and LF/HF ratio were increased during the night in migraine with aura patients (**Figures 3** and **4**). In both groups of migraine patients, we discovered an autonomic nervous system dysfunction. The most marked ANS impairment being present in the group of migraine with aura sufferers where we found sympathetic hyperfunction associated with parasympathetic hypofunction especially at night with loss of circadian rhythms [114].

**Figure 1.** Square root of the mean of the sum of the squares of differences between adjacent NN intervals—RMSSD (ms) in study groups (C, control group; M, migraine without aura group, MA, migraine with aura group).

**Figure 2.** High‐frequency component of power spectral analyses of HRV in study groups.

the total power (TP) [105, 106]. VLF is related to the thermoregulatory sympathetic vascular activity and to oscillations in the renin‐angiotensin system [107]. The ratio of LF/HF is

Abnormalities in the SNS or PNS have been found in migraine patients during the headache‐ free phase [108, 109]. Some researchers revealed sympathetic hypofunction and parasympa‐ thetic hyper‐function in migraine patients during the same period [83, 110]. Other study found that older patients with migraine may have sympathetic hyper‐function and a parasympathetic hypofunction during headache‐free intervals [111]. Martin et al. [112] found a reduction of HR during deep breathing, and after 2 min of tilting. Appel et al. [113] revealed increase of the low‐frequency band of HRV analysis in migraineurs, suggesting an increase in sympathetic

We tried to analyze the ANS involvement in migraine using the HRV on long‐term 24‐h ECG. We investigated 27 subjects with migraine (10 with migraine with aura and 17 without aura) during headache‐free periods and 10 age‐matched healthy control subjects. We found a significant decrease in SDNN, RMSSD, and HF indicating parasympathetic dysfunction in migraine groups during night headache‐free periods, and the most affected were migraine with aura patients (**Figures 1** and **2**). LF and LF/HF ratio were increased during the night in migraine with aura patients (**Figures 3** and **4**). In both groups of migraine patients, we discovered an autonomic nervous system dysfunction. The most marked ANS impairment being present in the group of migraine with aura sufferers where we found sympathetic hyperfunction associated with parasympathetic hypofunction especially at night with loss of

**Figure 1.** Square root of the mean of the sum of the squares of differences between adjacent NN intervals—RMSSD

(ms) in study groups (C, control group; M, migraine without aura group, MA, migraine with aura group).

considered as an index of cardiac sympathetic/parasympathetic tone balance.

58 Current Perspectives on Less-known Aspects of Headache

activity.

circadian rhythms [114].

**Figure 3.** Low‐frequency component of power spectral analyses of HRV in study groups.

```
Figure 4. LF/HF ratio in study groups.
```
HRV is associated with highly functional prefrontal cortex inhibitory activity over subcortical structures that make the body to well adapt to the environment. Low HRV is associated with reduced prefrontal inhibitory control over subcortical structures and failure to recognize safety signals [104]. Failure of inhibition leads to continue to process fear information and is linked with anxiety and depression [115]. Chronic psychological stress and depressed mood have been shown to be associated with SNS dominance and vagal withdrawal, highlighted by decreased HRV [115, 116]. In our study, we found an increased frequency of anxiety and depressive symptoms in migraine patients, especially in migraine with aura group [114]. Individuals with high level of stress, anxiety, and depression display an imbalance between PNS and SNS activities. Prolonged stress may influence health via several different pathways, i.e., alterations in autonomic nervous system (increased SNS and decrease PNS), neuroendo‐ crine activity, immune, behavioral, and cognitive functions.

Many other factors such as alcohol, nicotine, physical exercise, age, gender, diabetes, hyper‐ tension, cardiovascular disease, sleep apnea, chronic respiratory disease, or medications (sex steroid hormones, antidepressants, μ‐ blockers, etc.) may influence the autonomic nervous system [117–121]. Moreover, the ANS exhibits a circadian variation [122].

The ANS involvement during the premonitory phase of a migraine attack is suggested by many symptoms and signs with potential involvement of the hypothalamus (depression, irritability, fatigue, food cravings, and increase yawning), brainstem (neck stiffness), and cortex (abnormal sensitivity to light, sound, and smell) [123]. Nausea, vomiting, dizziness, cutaneous vasocon‐ striction or vasodilation, conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, piloerection, and diaphoresis can occur during pain phase [108, 109]. Also accompanying psychological and cognitive symptoms can appear—inability to organize thoughts and plans, physical exhaustion, confusion, agitation, aggressiveness, depression, and anxiety.

Migraine can be initiated by diverse triggers including bright lights, sounds, hunger, and mental exertion; poor sleep quality, menses, excess consumption of alcohol, chocolate, and fermented cheese. Sleep usually calms the pain.

In our study when we asked patients about sleep quality and dreaming, they complained about bad sleep quality. The majority experience negative sensations such as anxiety, fear, or terror and contents such as perception of fall and unsuccessful efforts to do various things [114]. These observations suggest that there is some malfunction in the prefrontal cortex, limbic system, amygdala, and hypothalamus, elements involved in dream and migraine pathophysi‐ ology [124]. Activation of the limbic system, amygdala, and anterior cingulate cortex observed in rapid eye movement sleep are involved in cardiovascular regulation and could reflect responses to intense emotions such as fear and anxiety found in migraine patients during night [125].

When physiological stressors, such as migraine attacks, are frequent and persistent allostatic responses can become maladaptive, resulting in changes of the body system. Migraine patients were found to have elevated plasma levels of cortisol in headache‐free periods [126] and during pain period [127]. Increased chronic levels of cortisol can induce atrophy in the PFC, decrease dopamine in the brain pleasure circuits, deplete the norepinephrine from the LC, and reduce frontal lobe serotonin receptors levels, thus contributing to flatness of emotion, concentration weakening, mood dysfunctions, and bad quality of sleep [128]. Neurogenesis and apoptosis in hippocampus are suppressed [129] and also dysregulation of the autonomic nervous system and hypothalamic‐pituitary‐adrenal axis with alterations in hormone regulation are revealed during chronic stress. Chronic migraineurs show decreased amygdala volume [130] that can be related to the high levels of anxiety or fear in these patients [131]. In chronic migraine, beside cortisol, other dysfunction in hormone secretion has been reported for prolactin, and melato‐ nin [132]. Sleep deprivation and circadian disruption can have negative consequences for body functions including increased appetite, increased levels of proinflammatory cytokines, decreased parasympathetic and increased sympathetic tone, increased blood pressure, and elevated insulin and blood glucose [133]. Hormonal dysfunctions in estrogen and progesterone regulation are frequent in migraine patients, and migraine improves after menopause or with hormonal therapies [134].

The cumulative effects of migraine over the body, as well as its treatment represents allostat‐ ic load [135]. Early interruption of a feed‐forward vicious cycle with different techniques (medication and stress reduction) is important to diminish allostatic load [135].
