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Chapter 3: Central Control of the Autonomic Nervous System and Thermoregulation

Patrick Dougherty, Ph.D., Department of Anesthesiology and Pain Medicine, MD Anderson Cancer Center

Last Review 20 Oct 2020

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Figure 3.1 Overview of the Central Autonomic Network

3.1 Defining the Central Autonomic Network

Because many students have been led to believe that the autonomic nervous system is relatively primitive, most have concluded that normal regulation of this system occurs at ganglionic, or at best, spinal levels. Thus, they are often quite surprised to discover that dysfunction of the brain is typically accompanied by autonomic dysfunction that can be life-threatening. For example, patients with spinal transection can have severe hypertensive crises provoked by a full bladder, impacted colon, or even stroking of the skin. This is not to say that the spinal cord and autonomic ganglia do not play important roles in autonomic regulation. But, that the organization of autonomic output takes place at supraspinal levels.

Extensive interconnection occurs between sites receiving visceral inputs and that control autonomic efferent outputs, between sites for the control of sympathetic versus parasympathetic nervous system output, and between sites for autonomic control and somatic, endocrine and limbic circuitry. Collectively, this set of interconnections is termed the central autonomic network.

3.2 Structure of the Central Autonomic Network

The central autonomic network is composed of both hypothalamic and extra-hypothalamic nuclei. Some of these sites regulate sympathetic outflow whereas others regulate parasympathetic outflow. This structure was first revealed in lesion studies that revealed multisynaptic connections descending from the hypothalamus and midbrain to preganglionic neurons in the brainstem and spinal cord. Similarly, connections from various limbic brain structures, most especially the amygdala, through the hypothalamus have been demonstrated. The net result of this network in full operation is the induction of autonomic responses to visceral and somatic stress stimuli, such as elevated heart rate and blood pressure with the onset of pain. Alternatively, chronic hypertension in type “A” or stressed individuals represents increased central autonomic outflow in response to increased limbic system input. Hierarchy in the autonomic network results in the loops from the brainstem to spinal cord being responsible for rapid short-term regulation of the autonomic nervous system, hypothalamic-brainstem-spinal cord pathways serving longer-term, metabolic and reproductive regulation, and finally limbic system-hypothalamic-brainstem-spinal cord loops serving anticipatory autonomic regulation.

1. Hypothalamic Structures. The single most important hypothalamic nucleus of the central autonomic network is the paraventricular nucleus (PVN). The PVN has two morphological classes of neurons that fall into three functional categories. The first morphological class is comprised of magnocellular (big) neurons. These neurons contain vasopressin and oxytocin and project their axons into the posterior pituitary where these hormones are released directly into the blood stream. The second morphological class is comprised of parvocellular (small) neurons. The parvocellular PVN neurons also include a neuroendocrine-related functional subset that project to the median eminence and secrete releasing hormones into the hypophyseal portal blood stream for control of anterior pituitary hormone secretion. More on these two functional groups will be covered in the next chapter. Finally, a group of parvocellular neurons comprise the third functional group of PVN neurons with these involved in central autonomic control.
   
   There are three types of pre-autonomic parvocellular neurons (Types A, B and C) separable based on anatomical and physiological criteria, as well as based on subnuclear location within the PVN. Pre-autonomic PVN neurons project directly onto preganglionic autonomic neurons in the dorsal motor nucleus of the vagus, the autonomic relay nuclei of the brainstem (A5, rostral ventral lateral medulla) and even directly to the intermediolateral spinal columns. These projections descend ipsilaterally through the brainstem and spinal cord with four points of decussation (supramammillary, pontine tegmentum, commissural part of the nucleus of the solitary tract (the major one), lamina X of the spinal cord) so that ultimately innervation is bilateral but with an ipsilateral dominance. Thus, the PVN, unlike any other brain site, has direct influence over both sympathetic and parasympathetic outflow. Furthermore, the PVN receives direct sympathetic and parasympathetic afferent inputs from trigeminal pars caudalis (sympathetic) and the nucleus of the solitary tract (parasympathetic). The PVN therefore is the only brain site in a closed efferent-afferent reflex loop with both the sympathetic and parasympathetic nervous systems.
   
   Other hypothalamic nuclei in the central autonomic network include the dorsomedial nucleus, the lateral hypothalamic area, the posterior hypothalamic nucleus and the mammillary nucleus. These nuclei send and receive projections from the PVN, the dorsal motor nucleus of the vagus, the central gray matter, the parabrachial nucleus, the nucleus of the solitary tract, the lateral and ventral medulla and the intermediolateral spinal columns. The lateral hypothalamus is especially involved in cardiovascular control as well as in control of feeding, satiety and insulin release.

Figure 3.2 Schematic for the Central Autonomic Network

2. Extra-hypothalamic Structures. Numerous brain structures were itemized above as innervation targets of the hypothalamic structures of the central autonomic network. These extra-hypothalamic sites can be roughly divided into those associated with control of the two components of the autonomic nervous system. The sites associated with control of sympathetic outflow include the norepinephrine-containing neurons of the dorsal mesencephalon (locus ceruleus) and the rostral and caudal ventrolateral medulla (the A5 and A1 regions) and the serotonin-containing neurons of the pontine and medullary raphe nuclei. The extra-hypothalamic sites associated with control of parasympathetic outflow include the central nucleus of the amygdala, the dorsal motor nucleus of the vagus, the nucleus ambiguous, the raphe nuclei, the periaqueductal gray, and the parabrachial nucleus. Finally, limbic cortices, including the cingulate, orbitofrontal, insular and rhinal cortices, and the hippocampus influence both sets of autonomic outflow.
   

3.3 Circuitry for Hypothalamic Control of the Autonomic Nervous System

The hypothalamus is interconnected with the remainder of the central autonomic network by way of three major pathways: the dorsal longitudinal fasciculus, the medial forebrain bundle, and the mammillotegmental tract.

The principal pathway of the hypothalamus in the central autonomic network is the dorsal longitudinal fasciculus (DLF). The DLF originates in the region of the paraventricular nucleus and descends along the most medial aspect of the third ventricle through the periaqueductal gray and mesencephalic reticular formation. The DLF continues caudally in the midline near the floor of the fourth ventricle until the closure of the open medulla where it becomes internalized near the central canal remnant. This position leaves the DLF in ideal position to innervate the periaqueductal gray, the parabrachial nucleus, the mesencephalic raphe nuclei, and the locus ceruleus rostrally and the dorsal motor nucleus of the vagus, the nucleus ambiguous and the medullary raphe more caudally. The centralized location of the DLF as it continues into the lower medulla and then the spinal cord renders it in perfect location to innervate the parasympathetic and sympathetic neurons of the intermediolateral spinal cord. As detailed above the DLF projections are bilateral, though with an ipsilateral dominance, due to several points of decussation. Afferent inputs from the periaqueductal gray, parabrachial nucleus, and the locus ceruleus ascend through the DLF to the hypothalamus.

The medial forebrain bundle (MFB) is the primary route for input to the hypothalamus from the septal nuclei and basal forebrain limbic structures. Inputs from the amygdala and hippocampus, though first arriving to the hypothalamus by way of the stria terminalis, ventral amygdalofugal pathway, and fornix, ultimately join with the MFB and thereby gain access to the paraventricular nucleus. The MFB also has fibers from the paraventricular nucleus that descend to innervate essentially the same nuclei as that by the DLF. Visceral afferents from the nucleus of the solitary tract ascend from the brainstem into the hypothalamus by way of the MFB. The MFB, like the DLF has several points of decussation so that there is input to bilateral structures but with an ipsilateral dominance.

The mammillotegmental tract is less prominent than either the DLF or MFB nevertheless, this pathway that originates in the mammillary nucleus sends projections into the mesencephalic and pontine reticular formations that in turn influence the activity of the brainstem autonomic nuclei listed above.

Somatic afferents ascend to the hypothalamus by way of the spinohypothalamic tract.

Figure 3.3 Circuitry for hypothalamic control of the autonomic nervous system

3.4 Disorders of the Central Autonomic Control

1. Autonomic Dysreflexia is a condition observed in about 85 percent of patients following spinal cord injury above C6. Exaggerated autonomic reflexes, especially sudden dramatic increases in blood pressure are provoked by inappropriate stimuli, such as pressure on the bladder.
2. Riley-Day Syndrome (familial dysautonomia) is an autosomal recessive disorder in Ashkenazi Jews associated with decreased tearing and sensitivity to pain and absent fungiform papillae on the tongue. Episodic abdominal crises and fever are very common as is orthostatic hypotension.
3. Shy-Drager Syndrome is a progressive degenerative condition of unknown origin affecting cells of the central autonomic network in the brainstem, intermediolateral cell column, locus ceruleus, dorsal motor nucleus of the vagus, and other nuclei including the substantia nigra caudate nucleus, and cerebellum. The presence of Lewy bodies in many of these areas suggests this syndrome may be related to Parkinson’s disease, in which there is also often a high degree of autonomic dysfunction. The hallmark sign is profound orthostatic hypotension without a compensatory increase in heart rate.
4. Sudden Infant Death Syndrome is thought to be a developmental defect in the central autonomic network of the brainstem involved with respiratory drive. An abrupt increase in facial skin temperature related to the onset of periods of apnea suggest there may be a broader developmental defect of central autonomic control.
5. Horner’s Syndrome typically results following damage to the dorsolateral pons or medulla and is characterized by a profound disturbance in sympathetic nervous system function. A common cause of this type of lesion is thrombosis of the posterior inferior cerebellar artery or following damage to the white matter of the cervical spinal cord where the hypothalamic-spinal tract descends. The most common signs in Horner’s syndrome are ipsilateral miosis, ptosis, anhidrosis and erythema.
   

3.5 The Central Autonomic Network and Control of Body Temperature

As noted above, the central autonomic network consists of three hierarchically ordered circuits or loops: the short-term brainstem-spinal loops, and the limbic brain-hypothalamic-brainstem-spinal cord loops mediating anticipatory and stress responses, and the intermediate length hypothalamic-brainstem-spinal cord loops mediating longer-term autonomic reflexes. Here we focus on this later loop in its role in thermoregulation. A later chapter will focus on this loop in the regulation of feeding.

The Hypothalamic Basis of Temperature Set-Point. Regulation of core temperature is essential because most of the metabolic processes necessary for life are strongly temperature-dependent. The normal body temperature set-point is primarily determined by the activity of neurons in the medial preoptic and anterior hypothalamic nuclei as well as by neurons in the adjoining medial septal nuclei. Collectively this region is often termed the preoptic anterior hypothalamus (POAH). The second region that also plays a critical, though subservient role to the POAH, in temperature regulation is the posterior hypothalamus.

3.6 Temperature-Sensitive Neurons

It was previously mentioned that the hypothalamus is one of the few brain areas where CNS neurons reside that are themselves directly sensitive to physical or chemical variables such as temperature, plasma osmolality, plasma glucose, and various hormones. The POAH has three types of neurons involved in determining the temperature set-point, warm-sensitive neurons, cold-sensitive neurons, and temperature-insensitive neurons, that are defined by changes in discharge rate following local warming or cooling of the POAH. Warm-sensitive neurons comprise about 30% of the neuronal pool in the POAH. These neurons have a firing rate versus temperature as shown in Figure 3.4. Change in temperature below 37 degrees has little effect on discharge rate. However, as temperature rises above 37 degrees the discharge rate of these neurons increases dramatically. Activation of warm-sensitive neurons results in an activation of neurons in the paraventricular nucleus (PVN) and lateral hypothalamus that result in heightened parasympathetic outflow to promote the dissipation of heat. Cold-sensitive neurons which are only about 5% of the cell population in the POAH, but more prevalent in the posterior hypothalamic nucleus, have discharge properties opposite that of warm-sensitive neurons. The cold-sensitive neurons show low rates of discharge at temperatures above 37 degrees, but increase firing rate steeply as temperature is lowered below 37 degrees. Increased discharges in cold-sensitive neurons results in activation of neurons in the PVN and the posterior hypothalamus that increase sympathetic outflow to promote the generation and conservation of heat. The relative concentration of warm-sensitive neurons in the POAH that promote heat loss and of cold-sensitive neurons in the posterior hypothalamus that promote heat generation has resulted in the POAH often being termed as the heat dissipation center and the posterior hypothalamus being labeled as the heat generation/conservation center. The final group of neurons found in the POAH and posterior hypothalamus is the temperature-insensitive neurons. These are by-far the most numerous of the neurons in these nuclei, comprising greater than 60 percent of those in the POAH. Although by definition not sensitive to changes in temperature these neurons play a crucial role in heat generation/conservation as discussed below.

Figure 3.4 Neuronal Mechanism for Body Temperature Set-Point. Click the octagon shapes.

3.7 Neural Mechanisms of Temperature Set-Point

The master circuit in regulation of body temperature is heat dissipation. The warm-sensitive neurons of the POAH have intrinsic membrane receptors that are sensitive to changes in brain and blood temperature above 37 degrees. These are non-specific cation channels that very likely are related to the vanilloid (capsaicin-sensitive) family of thermoreceptors. Warm-sensitive neurons also receive excitatory inputs from cutaneous and spinal thermoreceptors. As illustrated in Figure 3.4, inputs from cutaneous receptors induce a leftward bias in the firing rates of hypothalamic warm-sensitive neurons, so that baseline discharge rate is greatly elevated. Interestingly, though the firing rate of these cells continues to increase with increases in body temperature, the slope of this increase is reduced. Thus, the drive to dissipate heat is actively driven by inputs from thermal receptors. It is not clear that such is the case for heat generation and conservation. Cool-sensitive neurons do not appear to have intrinsic temperature-sensitive receptors. Rather, the increase in discharge observed in cool-sensitive cells with cooling results from the decreases in discharge of the warm-sensitive neurons and subsequent disinhibition so that the cool-sensitive neurons are now driven by tonic inputs from the thermal-insensitive neurons. Thus, the temperature set-point is principally a function of activity in warm-sensitive neurons of the POAH. The short-term effects of output from both warm- and cool-sensitive neurons on body temperature occur as a result of changes in autonomic tone to cutaneous arterioles and so the amount of cutaneous blood flow. Changes in sympathetic outflow to sweat glands and adipose tissue provide additional targets used for heat dissipation and generation. Longer-term effects of these groups of neurons in response to sustained changes in environmental temperature include the induction of behavioral and neuroendocrine responses to changes in environmental temperature.

Figure 3.5 Mechanism of Change in for Body Temperature Set-Point During Fever. Click the octagon shapes.

3.8 Disorders of Thermoregulation

Fever. The statement above highlights well the fact that fever has been a scourge battled by physicians since antiquity. However, recently fever has become recognized as in fact only one in a constellation of physiological adaptations that take place during infection referred to as the “sickness” or “acute phase response”. The sickness response includes behavioral, cognitive, metabolic, and neuroendocrine adaptations that are all geared to make the body less hospitable to pathogens and most primed for optimizing immunological defenses. Thus, fever is initiated because most bacteria proliferate poorly at temperatures above 39 degrees, whereas the function of lymphoid cells is optimal at this temperature. Fever is initiated during infection following the activation of macrophages and the subsequent synthesis and release of endogenous pyrogenic substances including interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), and the interferons (IFN). These pyrogens enter the blood stream and exert their effects in the CNS at the organum vasculosum of the lamina terminalis (OVLT). As discussed in the previous section, the OVLT is one of several sites in the CNS where the blood brain barrier is relatively permeable and so allows the brain to “taste” the internal milieu of the body. The endothelial cells of the OVLT have receptors for the endogenous pyrogens that when activated cause both the synthesis and release into the CNS of prostanoids, in particular, prostaglandin E2 (PGE2) as well as the synthesis and release within the CNS of IL-1, IL-6, TNF, and IFN. PGE2 gains access to the warm-sensitive cells of the POAH immediately adjacent to the OVLT where it binds to surface receptors and induces increases in cellular levels of cyclic AMP. The increased cAMP activates the protein kinase A system resulting in reduced excitability of the warm-sensitive neurons and lowering of their discharge rate. This allows the discharge rate of the cool-sensitive neurons to increase thus, establishing a new, higher temperature set-point. The use of antipyretics such as aspirin and indomethacin counteracts fever by interrupting the synthesis of PGE2 through antagonism of the cyclooxygenase enzyme system in the endothelium of the OVLT.

“Humanity has but three great enemies: fever, famine, and war, and of these by far the greatest, by far the most terrible, is fever.” - William Osler

Figure 3.6 Mechanism of Change in for Body Temperature Set-Point During Fever

Heat Exhaustion. Prolonged exposure or over-exertion in very warm environments can result in an excessive loss of fluids and electrolytes resulting in muscle cramps, dizziness, vomiting and fainting. In extreme conditions a degree of hypotension can develop. However, heat exhaustion is distinguished from heat stroke in that the body temperature set-point remains well regulated and the mechanisms mediating heat dissipation are intact. Thus, the skin is cool and moist and body temperature is normal or slightly below normal. Rest and replacement of fluids and electrolytes quickly remedy this condition.

Heat Stroke. If heat exhaustion is not remedied it can progress to heat stroke. Extreme hypotension will result in a drop in cutaneous blood flow and decrease in perspiration. Core temperature will subsequently rise. If this rise is too severe the brain’s normal functioning can be interrupted and control of the temperature set-point fails. This results in further deterioration of the heat dissipation mechanisms and allows core temperature to rise further so that tissue damage ensues which can lead to coma and then death. This heat stroke patient is in a medical emergency and requires urgent lowering of core temperature by fluid and electrolyte replacement. Hepatic damage is common in this condition and jaundice may develop 1 to 2 days after admission. Acute oliguric renal failure may occur. The development of coma and disseminated intravascular coagulation are very poor prognostic factors.

Malignant Hyperthermia is a group of inherited disorders characterized by sudden and extreme increases in core temperature following exposure to gaseous anesthetics including halothane, methoxyflurane, cyclopropane, or ethyl ether; or following exposure to muscle relaxants, particularly succinylcholine. These agents provoke an excessive release of calcium from the muscle sarcoplasmic reticulum resulting in activation of myosin ATPase and so excess heat generation. One form of the disease is inherited in an autosomal dominant fashion while a second is inherited in a recessive manner in boys and less often in girls that also have a number of other congenital abnormalities that comprise King’s syndrome. Malignant hyperthermia also sometimes occurs with other myopathies such as myotonia congenita and Duchenne’s muscular dystrophy. Some patients show an elevated creatinine phosphokinase, but most are normal between attacks. Biopsied muscle will show abnormal contraction on exposure to caffeine or gas anesthetic, but this is obviously a clumsy manner to screen for the condition. Careful history of surgical complications in relatives and identification of other contributing conditions is the best way to detect and prevent malignant hyperthermia. Occurrence is a medical emergency and requires immediate institution of the treatment protocol prescribed by the American Society of Anesthesiologists. The surgery and gas anesthetic is stopped, all tubing from the anesthetic devices are changed, and external cooling is initiated. One hundred percent oxygen, 1-2mg/kg sodium bicarbonate, and 1mg/kg dantrolene sodium are given. Drugs for cardiac arrhythmias are given as needed.

Figure 3.7 Emergencies of Thermoregulation

Hypothermia is defined as a core temperature of 35 degrees or lower and represents a potential medical emergency. Accidental hypothermia is common in winter following prolonged exposure, not necessarily to excessively low temperatures, and may accompany sepsis, hypothyroidism, pituitary or adrenal insufficiency, hypoglycemia, myocardial infarction and the ingestion of drugs - particularly alcohol. However, hypothermia can also occur in certain medical conditions without exposure, including congestive heart failure, uremia, drug overdose, acute respiratory failure, and hypoglycemia. Most of these patients are elderly. Patients presenting with a core temperature of less than 26.7 degrees are usually unconscious, miotic, bradypneic, bradycardic, and hypotensive with generalized edema. At core temperatures below 25 degrees patients are in coma, areflexic and may appear in rigor mortis. Treatment requires establishing an airway and providing oxygen. Blood volume can be expanded with warmed glucose while the blood gases and cardiac rhythm are carefully monitored. External warming is applied to the thorax only so that the limbs remain vasoconstricted to prevent a precipitous drop in blood pressure.

3.9 Summary

Several forebrain, diencephalic and brainstem structures are interconnected to organize the output of the autonomic nervous system. Collectively, this is referred to as the central autonomic network and is further organized into a hierarchy of functional loops.

The hypothalamus is the key brain site for central control of the autonomic nervous system, and the paraventricular nucleus is the key hypothalamic site for this control. The major pathway from the hypothalamus for autonomic control is the dorsal longitudinal fasciculus.

Regulation of body temperature is one example of hypothalamic control of brainstem and spinal autonomic nuclei related to longer-term autonomic reflexes. Thermoregulation is principally a function of warm-sensitive neurons of the preoptic anterior hypothalamus that directly control the dissipation of heat.

Fever is the most common disorder of thermoregulation. Fever is following the release of endogenous pyrogens that elevate the level of prostaglandin E2 in the preoptic anterior hypothalamus, which causes a decrease in activity of warm-sensitive neurons and subsequent disinhibition of cool-sensitive neurons.

 

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