2.4. Autonomic nervous system
2.4.1. General aspects
ANS controls visceral functions demanded for maintaining the homeostasis of the organism. ANS regulates the functions of the heart muscle, smooth muscle, secretory glands and hormone secretion (Appenzeller 1990, Ravits 1997). The peripheral part of the ANS consists of two different functional and anatomical divisions, the sympathetic (SNS) and parasympathetic (PNS) nervous systems (Shields 1993, Harati & Machkhas 1997). The SNS and PNS regulate visceral functions as an interactive, dynamic network to meet the requirements of the outer and inner environment and to maintain the homeostasis of the body (Appenzeller 1990). Both the SNS and PNS consist of a two-neuron chain. Between the neurons lies the ganglio that divides the chain into pre- and postganglionic parts, and where these neurons synapse (Figure 1.).
All the preganglionic neurons and postganglionic parasympathetic neurons release acetylcholine as a chemical transmitter, whereas postganglionic sympathetic neurons release norepinephrine. The sweat glands innervated by sympathetic fibers releasing acetylcholine are an exception of this pattern. It has been shown histologically that postganglionic neurons of both SNS and PNS also contain several immunoreactive peptides. (Collins 1999, Jänig & McLachlan 1999, Van Zwieten 1999)
The preganglionic neurons of the SNS are located in the lateral horn of the gray matter at the T1-L4 of the spinal cord called intermediolateral cell column. The myelinated axons of the preganglionic neurons synapse with the paravertebral ganglio located laterally to spinal cord. This pearl-chain-like ganglionic chain is called truncus sympathicus. The axons of the postganglionic neurons travel to the target organs with blood vessels. From the target organs axons travel back to the spinal cord and part of them travel on to the skin and muscles with the spinal nerves. (Collins 1999, Jänig & McLachlan 1999, Van Zwieten 1999)
The PNS consists of two parts: the cranial part in the brain stem (cranial nerves III, VII, IX, X) and the sacral part in the spinal cord at the level of S2-S4 in the intermediolateral cell column. On the contrary to the SNS, the parasympathetic postganglionic neurons form ganglia located near the target organ. (Gibbins 1990, Reid 1990, Jänig & McLachlan 1999)
The heart is one of the most important target organs of the peripheral ANS. Sympathetic innervation of the heart arises from the cervical and upper thoracic (stellate) ganglia, whereas the PNS innervates the heart via the vagal nerve. The SNS increases conduction, excitability and contractility of the heart, and opposite to this, activation of the PNS decreases these cardiac functions. There are important interactions between vagal and sympathetic influences on the heart, and an imbalance in the autonomic cardiovascular regulation may result in cardiac arrhythmias and other complications. (Benarroch et al. 1997c) Cardiovascular regulation is discussed in detail in the chapter 2.4.3.
2.4.2. Central autonomic network
Peripheral ANS is controlled by the CNS via complex neuronal interconnections functioning in relation to each other to form a functional entity called central autonomic network (CAN). The CAN has tonic, reflex and adaptive control over autonomic functions (Loewy 1990, Spyer 1990, Benarroch 1993, Benarroch 1997a). In addition, it regulates endocrine (Swanson 1991), behavioral motor (Bandler et al. 1991) and pain-controlling responses (Lovick & Li 1993) and contributes to the regulation of attention and emotional behaviour (Bechara et al. 2000) as well.
During the past several years, the rapid development of research techniques has provided the framework for the current understanding of the functional anatomy of the CAN. Neuronal activity within the CAN both controls and is affected by arterial pressure, respiration and other physiologic variables (Day & Sibbald 1989, Saper 1990). Activity within the CAN is state dependent and affected by the sleep-wake cycle, attention, and other internal influences (Ruggiero et al. 1987, Hosoya et al. 1991).
Transmission of information within the CAN involves virtually all neuroactive chemical substances so far described. In general, excitatory (e.g. L-glutamate) and inhibitory (e.g. GABA) substances mediate rapid communication within the central autonomic circuits e.g. baroreflex pathways (Sun 1985). Monoamines exert a more diffuse neuromodulatory effect, whereas neuropeptides commonly coexist with other neurotransmitters both in local and diffuse projecting pathways and may be involved in longer-term modulation and function as circulating signals (Gardiner & Bennet 1989). Nitric oxide has been recognised as an important intercellular messenger (Snyder & Bredt 1991, Togashi et al. 1992). On the other hand, steroid hormones rapidly cross the blood-brain barrier and have access to specific receptors abundantly distributed throughout the CAN (Stumpf 1990).
Disorders involving the CAN may manifest themselves as autonomic hyperactivity, e.g. hypertension, arrythmias, hyperhidrosis, or as autonomic failure, e.g. orthostatic hypotension, impotence, gastrointestinal tract dysmotility and neurogenic bladder. Some of these manifestations may be asymptomatic and detectable only on clinical examination or autonomic testing. Moreover, others may be life threathening such as ventricular arrythmias or produce severe impairment in daily activities such as orthostatic hypotension. In general, autonomic hyperactivity tends to occur in the context of acute neurologic disease, whereas neurodegerative disorders are most commonly associated with autonomic failure. (Benarroch 1997a)
2.4.2.1. Insular cortex
The insular cortex, lying deep in the temporal lobe is mainly a viscerosensory cortex. Electrical stimulation of the insular cortex in a variety of mammals elicits changes in BP, HR, respiration, gastrointestinal activity and epinephrine secretion as well as piloerection and pupillary dilatation (Cechetto & Chen 1990). In fact, in one experimental study with rats, prolonged stimulation of the insular cortex generated progressive degrees of heart block, increased plasma norepinephrine, and asystole resulting in death (Oppenheimer et al. 1991). Accompanying cardiac structural changes, myocytolysis and subendocardial hemorrhages, suggested that increased cardiac sympathetic activity was the reason for the observed changes (Oppenheimer et al. 1991).
Recently, functional MRI was used to identify regions of the human brain that were activated in response to tests designed to activate cardiovascular receptors (King et al. 1997). These tests included maximum inspiration, Valsalva´s maneuver, and maximum handgrip to elevate arterial BP. These maneuvers consistently resulted in discrete changes in activity in the anterior insular cortex with a time-course corresponding to the changes in arterial BP and HR they produced (King et al. 1997). There is also some evidence that stimulation of the insular cortex in humans elicits different results from each hemisphere (Oppenheimer et al. 1992a). Left insular cortex seems to be predominantly responsible for parasympathetic effects, whereas right insular cortex is more likely to produce sympathetic responses (Oppenheimer et al. 1992b).
2.4.2.2. Prefrontal cortex
Autonomic regions of the prefrontal cortex include ventromedial prefrontal cortex and the anterior cingulate gyrus. The ventromedial prefrontal cortex is involved in the regulation of high level emotional and cognitive functions whereas the anterior cingulate (infralimbic) cortex may constitute an autonomic premotor area (Cechetto & Saper 1990, Damasio et al. 1990).
The specific role of the prefrontal cortex in autonomic control is incompletely understood. However, various experimental studies suggest bradycardia and hypotension as the main results of the stimulation of the infralimbic cortex, and even a complete cessation of heart beat may occur in monkeys during stimulation of the cingulate gyrus (Cechetto & Saper 1990).
2.4.2.3. The amygdala
In the midbrain amygdala with adjacent areas (extended amygdala) integrates autonomic responses with emotional factors. Its functions are to interpret the emotional significance of incoming sensory information and to generate the appropriate autonomic, behavioral, motor, endocrine, and pain-suppressing responses to enviromental stimuli (Amaral et al. 1992, Davis 1992, LeDoux 1992).
The amygdala receives cardiopulmonary information and has direct projections to autonomic control sites, such as hypothalamus, parabrachial nucleus, NTS and the dorsal motor nucleus of the vagus which may be the anatomical substrate for descending control over the ANS (Cechetto 2000). The amygdala is also an important cardiovascular control center within the limbic system with reciprocal connections with the insular cortex and direct projections to other autonomic control centers in the hypothalamus, pons and medulla (Cechetto 2000).
Stimulation of the central nucleus of the amygdala produces changes in BP, HR, respiration and gastric secretion and motility (Al Maskati & Zbrozyna 1989, Davis 1992). In humans, electrical stimulation of the amygdala has been shown to produce fear sensations, and seizures evolving amygdala and its connections may result in various autonomic manifestations, including serious cardiac arrhythmias (Benarroch 1997b).
2.4.2.4. The hypothalamus
The preoptic region and the hypothalamus form an anatomicofunctional unit essential for integration of autonomic, endocrine, and behavioral responses critical for homeostasis and reproduction (Swanson 1987).
In hypothalamus, the periventricular area controls neuroendocrine functions as well as biological rhythms. The medial area has regulatory function over homeostasis and reproduction, and the dorsomedial nucleus especially contributes to the integration of cardiovascular responses to stress. The lateral area of the hypothalamus regulates behavioral functions, as well as vagal functions including cardiovascular regulation, gastrointestinal motility, and secretion, and insulin release. The zona incerta merging ventromedially with the lateral hypothalamic area has been implicated in arousal, locomotion, and autonomic regulation. (Benarroch 1997b)
The paraventricular nucleus has been called the ”master controller” of the autonomic system because it innervates all autonomic centers (Swanson 1987, Holstege 1990). It is a critical site for integrated responses to stress and it exerts multiple actions, including regulation of the cardiovascular function, energy metabolism and immune responses (Benarroch 1997b). The circumventricular organs located in the anterior wall of the third ventricle region are an integral component of the hypothalamic control of autonomic and endocrine function (Brody & Johnson 1980). These special sites of the ventricle walls lack blood-brain barrier and are highly vascularized (Brody & Johnson 1980).
2.4.2.5. Other components of the central autonomic network
All the midbrain areas are in connection with the autonomic centers in the brain stem and spinal cord. Periaquaductal gray matter in the midbrain integrates autonomic responses with antinociceptive and behavioural reactions. The parabrachial region in the pons functions as a mediator in processing visceral and somatosensory information and it plays a major role in cardiorespiratory regulation, and stimulation of it produces an increase in arterial BP and inhibition of the baroreflex. The lateral part of the parabrachial nucleus has connections to cerebellum, and the cerebellar uvula has been implicated in the control of cardiovascular and respiratory function, particularly in the setting of alerting or orienting responses. (Feldman 1986, Paton & Spyer 1992)
A5 group of the ventrolateral pons may be important in the integration of somatosensory and autonomic responses. Stimulation of the norepineprine-synthesizing neurons of the A5 group produces complex cardiovascular responses. (Huangfu et al. 1992)
In the medulla oblangata nucleus of the solitary tract (NTS) plays a critical role in medullary reflexes, and relays viscerosensory information to all regions of the CAN (Loewy 1990). Afferents from arterial, cardiac and pulmonary baroreceptors and carotid and aortic chemoreceptors are carried by branches of glossopharyngeal and vagus nerves, and relay in the NTS. The dorsolateral subnucleus of the NTS contains neurons that discharge in phase with the cardiac cycle and initiate vasodepressor and bradycardiac responses. The nucleus ambiguus also contributes to the innervation of the heart. (Anderesen & Kunze 1994)
There are several areas in the medulla that participate in the control of vasomotor tone, cardiac function and respiration. Neurons of the rostral ventrolateral medulla constitute an important station for various influences affecting central sympathetic activity (Benarroch 1997b). Stimulation of these neurons increases arterial BP, HR, sympathetic nerve activity, and releases adrenomedullary catecholamines (Amaral et al. 1992). On the other hand, the caudal ventrolateral medulla is a ”depressor” area containing sympathoinhibitory neurons and thus being an integral component of the baroreflex arc (Willette et al. 1984).
2.4.3. The physiology of cardiovascular regulation
The CNS controls cardiovascular functions via the ANS regulatory system consisted of the SNS and PNS as its peripheral part and the CAN as its central part (Talman & Kelkar 1993). The balance of the SNS and PNS influences is critical for the control of cardiac functions, such as excitability and contractility (Benarroch 1997c).
Beat-to-beat control of HR is determined largely by the level of vagal innervation to the sinus node. Cardiovagal cholinergic motoneurons are located in the nucleus ambiguus and in the dorsal vagal nucleus in the medulla oblongata. The peripheral afferent control is supplemented by central inputs that promote adjustments of HR during specific adaptive behavior. (Benarroch 1997c) The effectiveness of both reflex and behavioral influences on cardiovagal motoneurons is strongly modulated by respiration to maintain a balance between cardiac output and respiratory minute volume and to optimize tissue respiration (Spyer et al. 1994). Cardiovagal motoneurons of the nucleus ambiguus are an integrative element in the central control of circulation and they are excited by baroreflex and inhibited by hypothalamic and inspiratory influences (Benarroch 1997c). Figure 2 presents the main neural components participating in the regulation of the cardiovagal motoneurons.
Figure 2. Schematic diagram of the main neural components participating in the vagal control of the heart rate. The arrowheads indicate stimulation and the diamondheads inhibition of the cardiovagal motoneurons (Modified after Benarroch 1997c).
In humans, most cardiac branches of the vagus are given off in the thorax, near the origin of the recurrent nerve (Rossi 1994). There is an anatomicofunctional separation of the innervation of the SA and AV nodes. Therefore, the CNS is able to selectively influence the SA or the AV node either together or independentely. The cardiac ganglia, however, are not merely relay stations for vagal inputs. Previous studies (Randall & Wurster 1994) have shown a complex organization in intracardiac ganglia, giving rise to a ”cardiac brain” hypothesis. Studies in mammals have shown the presence of different functional cell types and thus, within the intracardiac ganglia there is a rich potential for complex interactions among vagal preganglionic neurons, primary afferents, local neurons, and collaterals from sympathetic fibers that control cardiac function (Loffelholz & Pappano 1985).
The parasympathetic innervation is more dense in the SA and AV nodes than in the surrounding myocardium, and the right and left vagal fibers provide partial bilateral innervation to both the SA and AV nodes (Loffelholz & Pappano 1985). In general, parasympathetic outflow decreases automatism of the SA node decreasing HR, hyperpolarizes the AV node decreasing AV conduction, inhibits atrial and ventricular contractility and exerts complex effects on cardiac excitability by shortening the refractory period in the atria and prolonging that of ventricles, Purkinje system, and accessory AV pathways. Thus, vagal input has an antiarrhythmic effect (Benarroch 1997c).
Similarly, there is a lateralized influence of the sympathetic system on cardiac function. The right sympathics predominantly innervate the SA node and increase HR, whereas the left sympathics mainly innervate AV node and ventricles increasing AV conduction, excitability within the His-Purkinje system node, cardiac contractility and oxygen consumption (Levy & Martin 1979). They receive inputs from the periventricular nuclei, ventrolateral medulla, lateral hypothalamic area, zona incerta and the periaquaductal gray matter (Benarroch 1997c).
In the intact animal, parasympathetic responses are of shorter latency and duration than those mediated by the sympathetics (Talman & Benarroch 1993). The complex interactions between the sympathetic and parasympathetic outflows to the heart not only control normal cardiac function, but also modulate the susceptibility to cardiac arrhythmias (Benarroch 1997c). Figure 3 presents the main neural components participating in the sympathetic control of the HR.
The baroreflex control of cardiovagal outflow appears to result from the algebraic sum of the effects of carotid and aortic receptors, unlike the redundant control of sympathetic vasomotor and cardiomotor outflows by these two receptors (Thames et al. 1994, Somer & Abboud 1994). The arterial chemoreflex in response to hypoxia is triggered primarily by stimulation of the carotid body chemoreceptors. This produces an increase in ventilation and selective, sympathetically mediated vasoconstriction and vagally mediated bradycardia (Somer & Abboud 1994).
Figure 4 presents the main neural components participating in the control of arterial BP.
