Physiology and Pathophysiology of the Autonomic Nervous System.pdf

REVIEW ARTICLE  Physiology and C O N T I N UU M A UD I O I NT E R V I E W A V AI L A B L E ONLINE Pathophysiology of the Autonomic...

REVIEW ARTICLE  Physiology and C O N T I N UU M A UD I O I NT E R V I E W A V AI L A B L E ONLINE Pathophysiology of the Autonomic Nervous System By Eduardo E. Benarroch, MD, FAAN ABSTRACT PURPOSE OF THE REVIEW: This article reviews the anatomic, functional, and neurochemical organization of the sympathetic and parasympathetic outputs; the effects on target organs; the central mechanisms controlling autonomic function; and the pathophysiologic basis for core symptoms of autonomic failure. RECENT FINDINGS: Functional neuroimaging studies have elucidated the areas involved in central control of autonomic function in humans. Optogenetic and other novel approaches in animal experiments have provided new insights into the role of these areas in autonomic control across behavioral states, including stress and the sleep-wake cycle. SUMMARY: Control of the function of the sympathetic, parasympathetic, and CITE AS: enteric nervous system functions depends on complex interactions at all C O N T I N U U M ( M I N N E AP M I N N ) levels of the neuraxis. Peripheral sympathetic outputs are critical for 2020;26(1, AUTONOMIC DISORDERS): maintenance of blood pressure, thermoregulation, and response to stress. 12–24. Parasympathetic reflexes control lacrimation, salivation, pupil response to Address correspondence to light, beat-to-beat control of the heart rate, gastrointestinal motility, Dr Eduardo E. Benarroch, micturition, and erectile function. The insular cortex, anterior and 200 First St SW, Rochester, MN 55905, benarroch@ midcingulate cortex, and amygdala generate autonomic responses to mayo.edu. behaviorally relevant stimuli. Several nuclei of the hypothalamus generate coordinated patterns of autonomic responses to internal or social RELATIONSHIP DISCLOSURE: Dr Benarroch serves as a section stressors. Several brainstem nuclei participate in integrated control of editor for Neurology, has autonomic function in relationship to respiration and the sleep-wake received personal compensation cycle. Disorders affecting the central or peripheral autonomic pathways, for speaking engagements from Lundbeck Pharmaceuticals, and or both, manifest with autonomic failure (including orthostatic receives publishing royalties hypotension, anhidrosis, gastrointestinal dysmotility, and neurogenic from Oxford University Press. bladder or erectile dysfunction) or autonomic hyperactivity, primary UNLABELED USE OF hypertension, tachycardia, and hyperhidrosis. PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Benarroch reports no disclosure. © 2020 American Academy of Neurology. 12 FEBRUARY 2020 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  KEY POINTS INTRODUCTION E valuation and management of the autonomic manifestations of The sympathetic nervous neurologic disorders require a basic understanding of the anatomy, system mediates patterns physiology, and pathophysiology of the autonomic nervous system. of responses critical for maintenance of blood The initial section of this article focuses on the anatomic organization pressure, local regulation and neurotransmission of the peripheral autonomic system; this is of blood flow, followed by a review of forebrain and brainstem areas controlling autonomic thermoregulation, and function and the mechanisms involved in control of blood pressure, heart rate, response to exercise and stress. body temperature, bladder, and gastrointestinal function. The aim is to provide the basis for understanding the pathophysiology and management of autonomic Autonomic dysreflexia disorders discussed in other articles of this issue of Continuum. results from interruption of supraspinal pathways coordinating the activity of ANATOMY, NEUROTRANSMISSION, AND FUNCTIONS OF THE preganglionic sympathetic AUTONOMIC NERVOUS SYSTEM neurons. The peripheral control of visceral organs is exerted by the sympathetic and parasympathetic systems, enteric nervous system, and visceral afferents. The sympathetic and parasympathetic outputs consist of preganglionic neurons located in the brainstem or spinal cord and autonomic ganglion neurons that innervate the target organ. Preganglionic neurons have small myelinated axons and use acetylcholine (ACh) as their neurotransmitter. ACh elicits fast excitation of all autonomic ganglion and enteric neurons via ganglion type (α3/β4) nicotinic receptors. Autoantibodies directed against the α3 subunit produce autoimmune autonomic ganglionopathy, resulting in sympathetic, parasympathetic, and enteric nervous system failure, in several combinations.1 Neurons of autonomic ganglia contain unmyelinated axons and primarily use either ACh or norepinephrine as their neurotransmitter. Sympathetic System The sympathetic preganglionic neurons are located in the thoracolumbar spinal cord at the T1 to L2 segments, primarily in lamina VII forming the intermediolateral column (FIGURE 1-1). These preganglionic neurons form functional units that are activated in a selective manner in response to orthostatic stress, exposure to heat or cold, hypoglycemia, hemorrhage, exercise, or emotion.2,3 Whereas these neurons may be individually activated by segmental visceral or somatic afferents (primarily via local interneurons), in normal conditions the preganglionic sympathetic subunits are differentially recruited to mediate distinct patterns of sympathetic responses coordinated by descending inputs from the medulla and hypothalamus.4 The sympathetic output is critical for maintenance of blood pressure, local regulation of blood flow, thermoregulation, and responses to exercise and internal or external stressors. Interruption of supraspinal descending autonomic pathways above the spinal T5 level results in massive, unpatterned reflex activation of sympathetic preganglionic neurons in response to segmental inputs such as visceral distension or nociceptor stimulation. This constitutes autonomic dysreflexia, which manifests primarily with severe hypertension.5 The preganglionic sympathetic axons terminate on paravertebral, prevertebral, and terminal ganglia as well as the adrenal medulla (FIGURE 1-1).6 Paravertebral ganglia innervate all tissues and organs except those in the abdomen, pelvis, and perineum; prevertebral ganglia innervate the viscera and blood vessels of the abdomen and pelvis. The adrenal medulla releases epinephrine to the bloodstream. CONTINUUMJOURNAL.COM 13 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM FIGURE 1-1 General organization of the sympathetic system. The primary neurotransmitter in sympathetic ganglion neurons is norepinephrine; the exception is sympathetic ganglion neurons innervating the sweat glands, which are cholinergic. Norepinephrine and epinephrine act via different subtypes of α1, α2, and β adrenoceptors. The α1 receptors mediate excitation of the smooth muscle in blood vessels, iris (pupil dilator), vas deferens, bladder neck, and internal sphincter of the rectum. The α2 receptors are located mostly in presynaptic terminals, and their main effect is presynaptic inhibition of the release of norepinephrine from sympathetic terminals (inhibitory autoreceptors) or other neurotransmitters from parasympathetic or afferent terminals. The β1 receptors are present in the heart and stimulate automatism of the sinus node, excitability of the His-Purkinje system, and contractility of the myocardium. The β2 receptors elicit smooth muscle relaxation, including vasodilation, bronchodilation, and relaxation of smooth muscle in the bladder and uterus. Parasympathetic System The preganglionic parasympathetic neurons are located in the general visceral efferent column of the brainstem or at the sacral spinal cord segments S2 through S4 (FIGURE 1-2). From the functional standpoint, the parasympathetic output can be subdivided into outputs to cranial effectors; outputs mediated by the vagus nerve to the thoracic and abdominal viscera; and sacral preganglionic outputs to the bladder, rectum, and sexual organs. Preganglionic axons innervate target ganglia located just outside or within the wall of the target organ. Thus, each parasympathetic output mediates organ-specific reflexes. The oculomotor nerve (cranial nerve III) provides inputs to the ciliary ganglion, which mediates pupil 14 FEBRUARY 2020 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 1-2 General organization of the parasympathetic system. constriction and accommodation reflexes. The facial nerve (cranial nerve VII) provides inputs to the pterygopalatine (sphenopalatine) ganglion to elicit lacrimation and cranial vasodilation and to submaxillary and submandibular ganglia to elicit salivation. The glossopharyngeal nerve (cranial nerve IX) innervates the otic ganglion that promotes parotid gland secretion. The vagus nerve (cranial nerve X) provides the preganglionic innervation to autonomic ganglia in the thorax and abdomen. Vagal preganglionic neurons located in the dorsal motor nucleus of the vagus nerve innervate ganglia of the cardiac, pulmonary, and enteric nervous system plexuses, whereas neurons of the nucleus ambiguus provide vagal output to cardiac ganglion neurons controlling the sinus node. Vagal reflexes are critical for beat-to-beat control of the heart rate and activation of upper gastrointestinal motility. The sacral preganglionic nucleus controls micturition, defecation, and erectile function. Acetylcholine (ACh) is the primary neurotransmitter of most parasympathetic ganglion and enteric nervous system neurons. In target organs, the effects of ACh are primarily mediated by muscarinic receptors, including excitatory M1-like (M1 and M3 subtypes) and inhibitory M2 receptors. The M3 subtype mediates most of the excitatory effects of ACh on the visceral targets of parasympathetic neurons, including smooth muscle contraction, exocrine gland secretion, and endothelial synthesis of nitric oxide. The M3 receptors also mediate the excitatory action of cholinergic sympathetic neurons on the sweat gland. The M2 receptors mediate the inhibitory effects of the vagus by decreasing the automatism of the sinus CONTINUUMJOURNAL.COM 15 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM node and atrioventricular conduction. Activation of presynaptic M2 receptors inhibit neurotransmitter release in most organs. The parasympathetic output is also mediated by noncholinergic neurons that release nitric oxide and vasoactive intestinal polypeptide. These neurons elicit smooth muscle relaxation, secretory function, and vasodilation; nitric oxide is the major mediator for cranial vasodilation and penile erection. The main effects of the sympathetic and parasympathetic system on target organs and the neurochemical mediators and receptors are summarized in TABLE 1-1. Disorders affecting the peripheral autonomic nerves may result in a variety of symptoms of combined sympathetic and parasympathetic failure (CASE 1-1). TABLE 1-1 Effects of the Sympathetic and Parasympathetic Systems on Different Targets Sympathetic Target (Receptor) Parasympathetic (Receptor) Pupil Dilation (α1) Constriction (M3) Ciliary muscle NA Accommodation (M3) Salivary and lacrimal glands Inhibition (α2?) Stimulation (M3, vasoactive intestinal polypeptide receptors) Heart Stimulation (β1) Inhibition (M2) Bronchi Dilation (β2) Constriction (M3) Skeletal muscle vessels Constriction (α1) NA Dilation (β2) Skin vessels Constriction (α1) NA Dilation? (nitric oxide?) Cranial and visceral vessels Constriction (α1) Dilation (nitric oxide, vasoactive intestinal polypeptide) Sweat glands Stimulation (M3) NA Gastrointestinal motility Inhibition (β2) Contraction (M3) Relaxation (nitric oxide, vasoactive intestinal polypeptide receptors) Gastrointestinal secretion Inhibition (α2) Gastric acid secretion (M1); intestinal secretion (M3, vasoactive intestinal polypeptide receptors) Bladder detrusor Inhibition (β2, β3) Stimulation (M3) Bladder neck Stimulation (α1) Inhibition (nitric oxide) Rectal smooth muscle Inhibition (β2) Stimulation (M3) Erectile tissue Constriction (α1) Dilation (nitric oxide) Vas deferens Contraction (α1) NA NA = not applicable. 16 FEBRUARY 2020 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Central Control of Autonomic Function The central control of the autonomic output involves several interconnected areas distributed throughout the forebrain and brainstem that control the activity of preganglionic sympathetic and parasympathetic neurons (FIGURE 1-3). This central autonomic network is involved in moment-to-moment modulation of visceral functions, maintenance of homeostasis, and adaptation to internal or external challenges.7,8 FOREBRAIN AREAS. The primary forebrain autonomic areas identified in both animals and humans are the insular cortex, anterior and midcingulate cortex, amygdala, and hypothalamus.9–18 The posterior insular cortex receives and integrates visceral, pain, and temperature sensations, which together are referred to as interoception, or bodily sensation. The dorsal posterior insula contains a sensory representation of all these modalities and is therefore the primary interoceptive cortex.19 The posterior insula projects to the anterior insula, which integrates interoceptive signals with emotional and cognitive processing and is involved in conscious experience of bodily sensation,19 A 42-year-old man with a 7-year-history of non–insulin-dependent CASE 1-1 diabetes mellitus presented for evaluation of a 2-year history of bilateral foot pain and numbness and a 1-year history of episodes of dizziness upon standing. He also described increased intolerance to heat, early satiety, constipation, difficulty emptying his bladder, and erectile dysfunction. He was taking glyburide and simvastatin and had stopped taking his antihypertensive medication because of his orthostatic symptoms. Neurologic examination showed difficulty walking on his heels, absent ankle jerks, and sensory loss to all modalities in the feet, which were red and dry. His blood pressure in the supine position was 150/90 mm Hg with a heart rate of 98 beats/min; in the standing position, his blood pressure was 90/60 mm Hg and heart rate was 102 beats/min. An autonomic reflex screen showed length-dependent sudomotor impairment, blunted heart rate responses to deep breathing and Valsalva maneuver, exaggerated fall of blood pressure with impaired recovery during the Valsalva maneuver, and orthostatic fall of arterial pressure of 40 mm Hg with no compensatory increase in heart rate. Postvoid residual volume was 300 mL (normal