Afferent pathways are the interface between the visceral organs and the CNS. Most afferent fibers are unmyelinated, but myelinated fibers can also conduct autonomic sensory information.15 There are two types of visceral afferents, primary afferent fibers and enteric afferent fibers. The latter respond to chemical and mechanical events and their cell bodies are located in the gastrointestinal tract walls.15,16 Primary afferent inputs are carried orthodromically to the spinal cord, brain stem or prevertebral sympathetic ganglia. The degree to which these afferent neurons are physiologically specific is determined by the responses evoked by chemical or mechanical stimulation.15–17 Most of these afferents transmit information from the viscera to the CNS,4,18–20 but some also make contact with sympathetic preganglionic neurons in the prevertebral ganglia.21 These anatomical relations indicate that in addition to their central actions, visceral primary afferents (and also enteric afferent fibers) may also play a role in peripheral regulatory reflexes, mainly those that are active in pathological conditions through positive feedback mechanisms.21

Afferent neurons are involved in two main functions: regulation of visceral actions, including organ-protective reflexes; and the transport of pain information, including pain from deep somatic tissues and regulation of hyperalgesia, deep pain and inflammation.15,16,22 This dual function makes them fundamentally different from somatic afferents, in which sensory and regulatory properties cannot be separated; afferent impulses from skin or muscle trigger reflexes and behavioral regulation simultaneously with sensory experience, which is not the case with visceral afferents, as some stimuli from the latter never reach the level of consciousness, such as changes in blood pressure (BP) or gut distension.15–17,23 The majority of the viscera show dual afferent innervation, with most afferent fibers traveling in mixed parasympathetic nerves, such as the vagus and pelvic nerves.24 The physiological significance of this dual innervation – afferent fibers being carried in sympathetic and parasympathetic nerves – is not fully understood, but data suggest that reflex and regulatory functions evoked by visceral stimulation are mainly triggered by activity in afferent fibers in the vagus and pelvic nerves, while visceral sensation, and in particular visceral pain, together with some visceral reflexes originating in the mesenterium, are mediated by afferent fibers in sympathetic nerves.15,16

Efferent pathways of the peripheral ANS have three major subdivisions: sympathetic, parasympathetic, and enteric. These systems are the building blocks of the motor part of the autonomic reflex arc and establish the final autonomic pathway,25 as each of them consists of a series of pre- and postganglionic neurons that are synaptically connected in autonomic ganglia, which function as the connection between the brain centers and the target organ.

Each autonomic nerve pathway extending from the CNS to an innervated organ is a two-neuron chain (except to the adrenal medulla that in effect functions as a sympathetic ganglion). The cell body of the first neuron, located in the CNS, synapses with a second-order neuron, the cell body of which lies within an autonomic ganglion.26 It is generally accepted that, except for the enteric nervous system, the organization of parasympathetic nervous pathways is simpler than that of the sympathetic nervous system. However, while this may be true for some pathways and target organs such as the pupillae and ciliary muscles, it seems unlikely to be the case for other target organs like the heart or the urinary bladder.13,27–29

Central autonomic pathways are organized at two levels, some for reflex adjustments of the end organ, while others are organized in a more complex fashion by connecting to higher neural centers, forming a central autonomic circuit capable of producing wide-ranging autonomic, endocrine, and behavioral responses (Figure 3).15,31

Figure 3.

Diagram of the two main types of visceral information processing by the central autonomic network. Information originating in the periphery is processed and produces either a reflex response or integrated autonomic, hormonal and behavioral output, the classic example of which is thermoregulation in the hypothalamus. Adapted from Loewy and Spyer.15

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Central control of autonomic function involves several interconnected areas distributed throughout the neuraxis.39 This central autonomic network has a critical role in moment-to-moment control of visceral function, homeostasis, and adaptation to internal or external challenges.14,15,31,39

The network functions on four closely interconnected hierarchical levels: spinal, bulbopontine, pontomesencephalic and forebrain (Figure 4). Of these, the bulbopontine level is involved in reflex control of circulation and respiration, and is the location of the nucleus tractus solitarii (NTS), the first relay station for reception of peripheral visceral information, and the rostroventrolateral medulla (RVLM), which contains bulbospinal neurons that are fundamental for the control of vasomotor, cardiac and respiratory function and for the coordination of various cardiovascular reflexes. These RVLM neurons also control hypothalamic function and neurons of the ventral respiratory group involved in respiratory rhythmogenesis.14,15,31,39 Located more rostrally, the parabrachial nucleus is a major relay center for the convergence of various types of sensory information (visceral, nociceptive and thermoreceptive), and contains separate subnuclei linked to gastrointestinal, cardiovascular and respiratory regulation together with clusters of neurons involved in osmo- and thermoregulation.14,15,31,39 The midbrain periaqueductal gray integrates autonomic, somatic and antinociceptive responses to stressful stimuli. Morphologically, it is divided into columns, which control cardiorespiratory and urinary function as well as pain, thermoregulation and reproductive function.14,15,31,39

Figure 4.

Central autonomic control areas and levels of interaction of autonomic control. DMV: dorsal motor nucleus of the vagus; HYP: hypothalamus; Lat HYP: lateral hypothalamus; NA: nucleus ambiguous; NTS: nucleus tractus solitarii; PVN: paraventricular nucleus of hypothalamus; RVLM: rostral ventrolateral medulla.

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The forebrain level includes the hypothalamus and components of the anterior limbic circuit, including the insular cortex, anterior cingulate cortex and amygdala. Playing a central role in neuroendocrine integration critical for homeostasis and integrative adaptive responses, the hypothalamus and periaqueductal gray are also involved in the defense reaction, an acute but active adaptation to stressful stimuli leading to sympathetic activation and tachycardia, hypertension, positive inotropism, increased stroke volume and cardiac output, redistribution of blood flow, tachypnea, baroreflex inhibition and facilitation of the chemoreceptor reflex.40 In this reaction, the paraventricular hypothalamic nucleus coordinates neuroendocrine integration, including sympathoexcitation, secretion of vasopressin (VP) and activation of the adrenomedullary and adrenocortical systems.

The baroreceptor reflex is the major mechanism for adjusting BP. It is initiated by stimulation of arterial baroreceptors, which are nerve endings found in vascular and cardiac reflexogenic areas that are sensitive to stretching during the cardiac cycle. In blood vessels, the most important baroreceptors are located in the carotid sinus, aortic arch and mesenteric circulation.49 The aortic arch receptors and medullar cardiovascular centers communicate through the vagus nerve, while it is Hering's nerve, a branch of the glossopharyngeal nerve, that conveys information from the carotid sinus receptors.50 Arterial baroreceptors play a key role in short-term adjustments of BP, maintaining it within a normal range by acting on cardiac output, peripheral resistance and inotropism.51,52

Baroreceptors respond to the distension and deformation that local BP changes elicited by phases of the cardiac cycle induce in the vessel and that change the frequency of nerve impulses that are carried to the NTS.53,54 Changes in baroreceptor activity also affect breathing. As an example, in vivo studies on anesthetized vagotomized dogs showed that the carotid body chemoreceptor reflex response was eliminated by surgically excluding the carotid bodies from the carotid sinus baroreceptor area.55

Baroreceptors are also involved in secretion of VP,56 particularly in response to hypotension, possibly due to neuronal projections from the NTS to the hypothalamus.57 When the baroreceptor reflex is activated by a reduction in BP, an increase in VP secretion is observed,58,59 and intact arterial baroreceptors are essential to maintain BP and VP secretion.60,61 However, in this situation, their action is reinforced by facilitation of the chemoreceptor reflex in the NTS, due to the nature of the stimulus.40

Several studies have examined the role of the baroreceptor reflex in the long-term regulation of sympathetic activity, as central resetting of the baroreceptor-sympathetic reflex may be an important component of the mechanism causing sustained changes in renal sympathetic activity. However, little is known about the mechanisms that could cause such resetting.62

Arterial chemoreceptors are highly specialized cells that can detect changes in the partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2) and pH in the blood. Peripheral chemoreceptors are more sensitive to changes in pO2 than in pCO2 or pH, while central chemoreceptors respond primarily to changes in pCO2 and pH.42

Peripheral chemoreceptors are mainly located in the aortic and carotid bodies, but may also be found in the mesenteric circulation. The carotid bodies are located bilaterally at the bifurcation of the common carotid artery, while aortic bodies are located between the pulmonary artery and the aortic arch.50 Carotid bodies are more sensitive to hypoxia and hypercapnia, and detect changes in blood gas tension, while aortic baroreceptors are more sensitive to anemia, carboxyhemoglobinemia and systemic hypotension.63 Thus, carotid bodies monitor the ventilation/perfusion ratio and aortic bodies are responsible for reflex control of systemic vascular resistance. Central chemoreception was initially localized to areas on the ventral medullary surface in the area prostrema, but there is substantial evidence that many sites participate in central chemoreception, some located at a distance from the ventral medulla.64

Changes in the partial pressure of gases or pH detected by peripheral chemoreceptors are sent to the NTS through the vagus or the glossopharyngeal nerve.65 Stimulation of chemoreceptors increases the activity of NTS cells. These cells simultaneously excite neurons in the vagal nuclei and RVLM, leading to an increase in sympathetic and parasympathetic tone, which results in ventilatory adjustments – increased air flow volume, respiratory rate and breathing volume – that play an important role in the reflex control of ventilation.66 In addition to ventilatory responses, chemostimulation also induces changes in the cardiovascular system such as tachycardia and vasoconstriction that maintain the chemical composition of the blood and tissue perfusion at optimal levels.

It has been suggested that peripheral chemoreceptors have a tonic excitatory influence on cardiovascular control due to sympathetic activation, thus contributing to maintenance of BP levels.67

There are also volume receptors located in the right atrium and venae cavae that respond to blood volume decreases by reducing their firing rates. The afferents of these receptors join the vagus nerve and terminate in the NTS, synapsing with neurons projecting to the PVN.68 This pathway is activated by changes in blood volume of as little as 8-10%.69,70 Overall, activation of atrial receptors induces inhibition of sympathetic vasomotor tone and an increase in VP secretion, affecting renal function.

Other cardiac reflexes that regulate BP are the Bainbridge and Bezold-Jarisch reflexes. In the Bainbridge reflex, BP is indirectly regulated through HR changes. When right atrial volume increases, low-pressure stretch receptors initiate a reflex that increases HR through sympathetic nerve activation.63 The Bainbridge reflex is not always active, its effect depending on HR, being stronger at lower than at higher HR values. In this way, the Bainbridge reflex acts in opposition to the baroreceptor reflex, which increases HR when stretching is decreased in hypotension or hypovolemia.71 The Bezold-Jarisch reflex is a cardiac reflex that is sensitive to chemicals, evoking a strong cardiovascular depressor response leading to bradycardia and hypotension as a direct consequence of chemical stimulation of receptors in the ventricles or coronary circulation. The fall in BP is due to both bradycardia and vasodilation caused by inhibition of sympathetic vasomotor activity, and is also modulated by renin release and VP secretion.72 Conversely, decreases in the activity of these inhibitory sensory receptors increase sympathetic activity, vascular resistance, plasma renin activity and VP secretion.72

The evaluation and data analysis protocols should be appropriate to the study. A standard and the most common evaluation protocol is the Ewing test battery,14 which assesses HR response to deep metronomic breathing, BP response to sustained handgrip and BP and HR response to the Valsalva maneuver and active standing.11,14,73,74 Other non-invasive maneuvers, including the cold pressor test, mental stress test and tilt table, are also used in autonomic evaluation.

In the Valsalva maneuver, which assesses the sympathetic and parasympathetic reaction to baroreflex activation, the subject maintains an expiratory pressure of 40 mmHg/15 s with an open glottis. The test response is divided into four phases, two of which are reflex in nature (II and IV) and two mechanical (I and III). The results depend on the subject's position, age and gender, as well as the duration and intensity of expiratory pressure. In patients with autonomic dysfunction, there is typically a loss of both BP overshoot and reflex bradycardia (Figure 6).

Figure 6.

The Valsalva maneuver. Data from a normal subject, in which the Valsalva maneuver has four phases: (I) there is a brief decrease in heart rate (HR) and increase in systolic blood pressure (BP) due to aortic compression; (II) BP first decreases and then increases; (III) in this phase, due to the release of strain, consecutive declines in BP and increases in HR are observed, preceding a BP overshoot due to persistent sympathetic activity, together with normalization of venous return (IV). The increased BP mediates baroreflex-induced bradycardia and is quantified using the Valsalva ratio, the ratio of the highest HR (II) to the lowest HR (IV). Results depend on the position, age and gender of the subject, as well as the duration and intensity of expiratory pressure. In patients with autonomic dysfunction, there is typically a loss of both BP overshoot and reflex bradycardia. VM: Valsalva maneuver. Adapted from Xavier et al.74

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The cold pressor test assesses sympathetic activation mediated by nociceptors, which is observed mainly through BP changes when the hand is immersed up to the wrist in ice-cold water at 4°C. This test, which is predominantly sympathetic, differs from the cold face test, in which the application of a cold stimulus to the face stimulates the trigeminal nerve and elicits bradycardia, and is related to the diving reflex. The cold pressor test, the mental stress test and the handgrip test are the provocative maneuvers mainly used for sympathetic evaluation.

On deep metronomic breathing, autonomic function is assessed with the patient breathing metronomically at a rate of six cycles/min for three minutes, which maximizes respiratory sinus arrhythmia (Figure 7). Changes in HR with deep breathing are a parameter of parasympathetic cardiac control.11,14 The subject's position and body weight, rate and depth of breathing, hypocapnia, sympathetic activity, and use of salicylates and other drugs influence HR variability during deep breathing.

Figure 7.

Heart rate response to deep breathing. A normal response showing the imprint of respiration in the heart rate recording during deep breathing. Adapted from Ducla-Soares et al.73

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The Ewing battery uses the 30:15 ratio together with blood pressure evaluation in order to assess cardiovascular responses to an active orthostatic challenge. The 30:15 ratio is calculated as the shortest RR interval around the 15th beat divided by the longest RR interval around the 30th beat after standing. Simultaneously with changes in HR there is a physiological decrease in BP. However, if this fall in systolic BP is at least 20 mmHg or in diastolic BP at least 10 mmHg within 3 min of standing, the BP changes are defined as orthostatic hypotension, a sign of cardiovascular autonomic failure.

Autonomic evaluation of active standing can be complemented by the head-up tilt test. In theory, this detects the hemodynamic modifications elicited by baroreceptor reflex activation without the interference of the muscular pump of the legs. However, in practice this rarely occurs, as subjects usually develop an alerting reaction when they see the bed beginning to tilt, which is superimposed on the changes in BP and HR caused by baroreflex activation. The hemodynamic changes associated with head-up tilt testing are considered to consist of two stages: an initial acute cardiovascular response lasting around 30 s, and a stabilization phase consisting of an adaptation period 1-2 min after orthostasis followed by a late response to prolonged orthostasis lasting more than 5 min11,14 (Figure 8).

Figure 8.

Normal heart rate and blood pressure responses to head-up tilt testing. In this test the subject lies on a tilt test table, which is then tilted upward at 60°-70° after a resting period of at least 5 min. Patients with different degrees of cardiovascular autonomic impairment may show delayed adaptation to the orthostatic challenge or may even be unable to adapt and have a syncopal event. HR: heart rate; SBP: systolic blood pressure. Adapted from Ducla-Soares et al.73

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