Primer on the Autonomic Nervous System

Front Cover
PRIMER ON THE AUTONOMIC NERVOUS SYSTEM
PRIMER ON THE AUTONOMIC NERVOUS SYSTEM
Copyright
Contents
Contributors
Preface
Acknowledgments
I - Introduction
1 - Evolution of the cardiovascular autonomic nervous system in vertebrates
The autonomic nervous system in vertebrates
Anatomy of the cardiovascular system in vertebrates
Autonomic regulation of the heart
Innervation of the systemic vasculature
Autonomic regulation of the pulmonary circulation
Cardiorespiratory integration and respiratory sinus arrythmia
The evolution of adrenergic and muscarinic receptors
Cardiovascular responses to altered pressure, exercise, and hypoxia
Further reading
2 - Central autonomic control
Central autonomic control: overview
Lower brainstem and autonomic reflexes
Upper brainstem and integration of autonomic with arousal and stress responses
Hypothalamus: central pattern generator for homeostasis and adaptation
Amygdala: tagging of stimulus valence and innate survival responses
Insular cortex: interoception, bodily awareness, and autonomic control
Anterior cingulate cortex, predictive motor commands to autonomic nuclei
Further reading
3 - Peripheral autonomic nervous system
Introduction
Sympathetic nervous system (SNS)
Origin
Outflow
Neurotransmitters
Central autonomic network
Organization of SNS
Sympathoadrenal axis and the adrenal gland
Parasympathetic nervous system (PNS)
Origin and outflow
Neurotransmitters
The concept of plurichemical transmission and chemical coding
Visceral afferent neurons and autonomic nervous system
Functional neuroanatomy and biochemical pharmacology
Psychosocial stress and autonomic dysfunction
Synucleinopathies and autonomic dysfunction
Acknowledgments
Further reading
II - Biochemical and pharmacological mechanisms
4 - Noradrenergic neurotransmission
Norepinephrine synthesis
Norepinephrine storage
Norepinephrine release
Norepinephrine disposition and metabolism
Noradrenergic innervation of the cardiovascular system
Acknowledgment
Further reading
5 - Antidepressant-sensitive norepinephrine transporters: structure and regulation
NET structure, localization, and function
Regulation of NET
NET genetic variation and clinical implications
Further reading
6 - α1-Adrenergic receptors
α1-Adrenergic receptor (α1-AR) subtypes
Structure of α1-adrenergic receptors
Ligand binding and activation of α1-adrenergic receptors
Signaling of α1-adrenergic receptors
Regulation of α1-adrenergic receptors
Function of α1-adrenergic receptors
Acknowledgments
Further reading
7 - Alpha2-adrenergic receptors
Further reading
8 - β-Adrenergic receptors
β-Adrenoreceptor subtypes
Ligand binding and activation
β-Adrenoreceptor desensitization
Biological functions of β-adrenoreceptors
Further reading
9 - Dopaminergic neurotransmission
Introduction
Central dopamine systems
Disorders of central dopamine systems
Peripheral dopamine systems
Further reading
10 - Dopamine receptors
Introduction
Distribution and expression of dopamine receptors
Central nervous system
Autonomic nervous system
Dopamine receptor structure
Gene structure
Receptor structure
Dopamine receptor function: signal transduction pathways
G protein dependent signaling
Signal regulation
β-Arrestin-dependent signaling
Oligomerization
Dopamine receptor pharmacology
Ligand specificity
Functional selectivity
Further reading
11 - Cholinergic neurotransmission
Acetylcholine biosynthesis and metabolism
Acetylcholine receptors
Cholinergic pharmacologic agents
Further reading
12 - Acetylcholine and muscarinic receptors
Cholinergic neurotransmission: sites and receptors
Muscarinic agonists
Muscarinic antagonists
Further reading
13 - Nicotinic acetylcholine receptors in the autonomic nervous system
Subtype diversity and distribution of nicotinic receptors
Physiologic events associated with receptor activation
Pharmacology of ganglion–type nicotinic receptors
Further reading
14 - Neuropeptide Y and the autonomic nervous system
Introduction
NPY structure and receptors
NPY functions
Feedback in the autonomic nervous system
Vasoconstriction
Angiogenesis
Myocardial contractility
Cardiac remodeling
NPY in the gastrointestinal tract
Neuropeptide Y and cardiovascular disease
Hypertension
Atherosclerosis and plaque vulnerability
Post myocardial infarction
Arrhythmia
Heart failure
Conclusion
Further reading
15 - Serotonin receptors
Serotonin
Synthesis and metabolism
Neurotransmission
Receptors
Pharmacology and role in disease
Role in autonomic processes
Further reading
16 - Purinergic neurotransmission and nucleotide receptors
Purinergic neurotransmission
Receptors for purines and pyrimidines
Conclusions
Further reading
17 - Nitric oxide and the autonomic nervous system
NO synthesis and actions
Central NO–autonomic nervous system interactions
NO–autonomic nervous system interactions in the periphery
NO–autonomic nervous system interactions in heart rate control
Conclusions
Further reading
18 - Glutamatergic neurotransmission
Synthesis and vesicular release
Receptors
Clearance of glutamate
Glutamate metabolism
Glutamate in the autonomic nervous system
Glutamatergic drugs and the autonomic nervous system
Summary
Further reading
19 - Pharmacology: GABAergic neurotransmission
Overview of GABA mediated signaling
GABA responses are mediated by both ionotropic and metabotropic receptors
GABAA receptors mediate multiple modes of neuronal signaling
Neurotransmission is mediated by a diverse set of GABAA receptor subtypes
Subtype-preferring drugs allow for selective components of GABA signaling
Further reading
20 - Renin-angiotensin
Introduction
Components and features of the RAS
Angiotensin II pathways
Angiotensin-(1-7) pathways
Emerging RAS pathways
RAS: autonomic interactions for cardiovascular control
RAS in clinical populations
RAS therapies
RAS in fetal programming of cardiovascular autonomic impairments
RAS in cardiovascular autonomic disorders
Adolescent orthostatic intolerance (OI)
Postural orthostatic tachycardia syndrome (POTS)
Primary autonomic failure
Summary and gaps in knowledge
Further reading
21 - Aldosterone, the mineralocorticoid receptor, and sympathetic nervous system
The sympathetic nervous system and RAAS interact to maintain hemodynamic homeostasis
Further reading
Z2 - Vasopressin in central autonomic regulation
VP structure, brain synthesis and release
Modes of VP neurotransmission
Vasopressin receptors in the brain—structure, distribution, and function
VP in central autonomic regulation of circulation
Hyperadrenergic conditions and central VP
Central VP in regulation of respiration
Central VP in regulation of body temperature
Central VP in regulation of gastrointestinal tract, nausea, and vomiting
Central VP in pain modulation
Perspectives
Further reading
23 - Calcitonin gene-related peptide and adrenomedullin
Introduction
α-CGRP peptide structure
CGRP synthesis, localization, and release
CGRP receptor
CGRP-mediated cell signaling
CGRP and CGRP agonists in the treatment of cardiovascular disease
CGRP-antagonists for treatment of migraine
Adrenomedullin and its role in the cardiovascular system
Conclusion
Acknowledgment
Further reading
24 - Leptin signaling and energy homeostasis
Introduction
Leptin: from discovery to utility in understanding energy balance dysfunction
Leptin receptor activation drives a variety of second messenger responses in the central nervous system
Neuropeptide Y (NPY)/agouti-related peptide and anorexic pro-opiomelancortin cells are important mediators of leptin action ...
Hypothalamic leptin and the regulation of metabolic homeostasis through actions at AGRP and POMC neurons
Leptin acts as an important regulator of metabolism during fasting conditions
Leptin influences autonomic outflow via POMC and NPY/AgRP neurons
Leptin action outside of NPY/AgRP and POMC neurons also contributes to metabolic homeostasis
Leptin regulation outside of NPY/AgRP and POMC action on autonomic sensory neuron activity in the periphery
Questions for future study
Further reading
25 - The endothelin system
Introduction: endothelin system components
Effects of preproET-1 or ET receptor gene deletion
Mechanism of action of ET
Pathophysiology of the endothelin system in experimental models
Renal effects of ET-1
Cardiac effects of ET-1
ET-1 in essential hypertension
Molecular genetics of the endothelin system
Endothelins and the nervous system
Role of endothelins (ETs) in the brain and sympathetic nervous system
Conclusion
Acknowledgments
Further reading
26 - Pharmacology of the neurotransmission of the baro- and chemoreflex in the Nucleus Tractus Solitarius
Introduction
A logical analogy for a better view of NTS function
Anatomy and physiology of NTS
Major neurotransmitters in the NTS
Glutamate and its receptors
Postsynaptic glutamate receptors
Presynaptic glutamate receptors
Extrasynaptic glutamate receptors
Astrocytes, glutamate receptors, and synaptic modulation
Glutamate receptors and activation of GABA neurons
Glutamate receptors and autonomic and respiratory function
GABA and its receptors in the NTS
GABAA receptors
GABAC receptors
GABAB receptors
Astrocytes, GABA, and synaptic modulation
GABA receptors and the autonomic and respiratory functions
Other neurotransmitters and modulators in the NTS
Further reading
III Autonomic physiology
27 - Rhythms in sympathetic nerve activity
Ubiquitous nature of biological rhythms
The diversity of rhythms in SNA
Functions of rhythms in SNA
Using the rhythms in SNA to identify central sympathetic neurons
Further reading
28 - Circadian rhythms and autonomic function
The master clock
SCN output and autonomic control
Circadian and sleep control of the autonomic nervous system
Circadian autonomic regulation: cardiovascular variables and metabolic control
Conclusion
Further reading
29 - Cardiorespiratory interactions in health and disease
Introduction
Cardiorespiratory interactions under resting conditions and physiological challenges
The origin of cardiorespiratory coupling: the duet between the autonomic nervous system and respiratory central pattern gen ...
Do changes in the respiratory-autonomic interactions play a role in cardiorespiratory diseases?
Further reading
30 - Baroreceptor reflexes
Neural pathways and effector mechanisms
Arterial baroreflex
Cardiopulmonary baroreflex
Determinants of afferent baroreceptor activity
Rate sensitivity of baroreceptors
Large artery compliance
Mechanoelectrical transduction and action potential discharge
Baroreflex resetting and sensitivity in hypertension and other diseases
Baroreflex adaptation and resetting in acute hypertension
Baroreflex dysfunction in chronic hypertension, heart failure, and other diseases
BRS: a determinant of cardiovascular risk and therapeutic target
Further reading
31 - Cardiac and other visceral afferents
Introduction
Reflex control of the cardiovascular and viscera
Structural and functional organization of visceral afferent signaling
Afferents as central drivers of adverse remodeling of ANS in cardiovascular diseases
Summary and conclusions
Acknowledgments
Further reading
32 - Sympathetic control of the heart
Introduction
A brief history
Anatomy and physiology
How cardiac myocytes receive and respond to sympathetic stimulation
Pathophysiology
Sympathetic-induced arrhythmic triggers
Myocardial infarction
Heart failure
Inherited syndromes
Future perspectives and therapeutic opportunities
Further reading
33 - Cardiac vagal ganglia
Extrinsic and intrinsic cardiac innervation
Physiology of intracardiac neurons
Anatomy and heterogeneity of intrinsic cardiac ganglia
Pathophysiology in the intracardiac ganglia and therapeutic strategies
Further reading
34 - Physiology of the upright posture
Introduction
Regulatory mechanisms involved in the adjustments of the human body to orthostatic stress
Arterial baroreceptors
Local vasoconstrictor mechanisms
Role of capacitance vessels in orthostatic reflex adjustments
Role of skeletal muscle pump
Humoral mechanisms
Further reading
35 - Cerebral circulation
Basic considerations
Neurovascular coupling
Regulation of cerebral circulation
Cerebral autoregulation
Clinical considerations
Role of autonomic innervation
Cerebrovascular reactivity (CVR)
Conclusion
Further reading
36 - Autonomic control of the pupil
Parasympatholytic (anticholinergic) drugs
Parasympathomimetic (cholinergic) drugs
Sympathomimetic (adrenergic) drugs
Sympatholytic drugs (adrenergic blockers)
Other agents
Iris pigment and pupillary response to drugs
Pupil sympathetic defects
Pupil parasympathetic defects
Pupil combined sympathetic and parasympathetic defects
Acknowledgments
Further reading
37 - Gastrointestinal function
Introduction
Gastrointestinal secretory functions
Salivary secretion
Gastric secretion
Pancreaticobiliary secretion
Bile
Intestinal secretion and absorption
Components controlling gastrointestinal motor functions
Gastrointestinal muscle
The enteric nervous system
Extrinsic neural (autonomic nervous system) control
The vagus nerve
Normal gastrointestinal motor function
Derangement of autonomic nervous system in disease states
Further reading
38 - Extrinsic control of gastrointestinal function
Parasympathetic control of the gastrointestinal tract
Sympathetic control of the gastrointestinal tract
Further reading
39 - The splanchnic circulation
Overview
Anatomy of the splanchnic circulation
Local regulation of blood flow through the splanchnic organs
Local regulation of blood storage in the splanchnic circulation
Effects of the splanchnic circulation on overall circulatory function
Sympathetic control of the splanchnic circulation—general features
Sympathetic control of the splanchnic circulation in special circumstances
Sympathetic control of the splanchnic circulation in disease
Impaired splanchnic sympathetic drive
Increased splanchnic sympathetic drive
Neuromodulation therapy targeting the splanchnic sympathetic nerves
Further reading
40 - Autonomic control of the kidney
Introduction
Innervation of the kidney
Autonomic receptors in the kidney
Reflex regulation of blood volume
The inhibitory reno-renal reflex
Autonomic control of the kidney in pathophysiological states
Further reading
41 - Autonomic control of the lower urinary tract
Introduction
Neural circuits involved in reflex micturition control
Peripheral nervous system
Parasympathetic pathways
Sympathetic pathways
Somatic pathways
Central neural control
Organization of storage reflexes
Spinal reflex pathways
Supraspinal pathways
Organization of voiding reflexes
Spino-bulbo-spinal reflex pathways
Neural circuits involved in voluntary micturition control
Further reading
42 - Bladder function in health and disease
Structure of the lower urinary tract
Properties of the healthy lower urinary tract
Clinical evaluation
Clinical conditions
Incontinence
Bladder outlet obstruction
Neurourology
Painful bladder syndrome
Conclusions
Further reading
43 - Physiology and pathophysiology of female sexual function
Physiology of the female sexual response cycle
Sexual arousal
Afferent and central pathways
Neurotransmitters
Innervation of female sexual function
Hormones influencing female sexual function
Common etiologies of female sexual dysfunction
Neurogenic etiologies
Assessment of female sexual dysfunction
Laboratory investigation
Common therapeutic approaches in female sexual dysfunction
Further reading
44 - Regulation of sweating
Anatomy and function of the sweat gland
Type
Density and distribution
Physiology of sweat glands
Function
Innervation of sweat gland
Denervation
Further reading
45 - Autonomic innervation of the skeleton
Bone sympathetic innervation: anatomy and ontogeny
Sympathetic nerves and bone remodeling
Sympathetic nerves, hematopoietic and cancer cell trafficking in the skeleton
Sympathetic nerves and the endocrine function of the skeleton
Conclusion
Further reading
46 - Regulation of metabolism by the autonomic nervous system
Basic considerations
Contribution of the parasympathetic nervous system to satiety
Contribution of the sympathoadrenal system to components of total daily energy expenditure
Contribution of sympathetically stimulated organs/tissues to resting metabolic rate
Mobilization/utilization of specific macronutrients: carbohydrate
Mobilization/utilization of specific macronutrients: lipid
Mobilization/utilization of specific macronutrients: protein
Sympathetic regulation of Brown fat
Role of the sympathoadrenal system in the dysregulation of metabolism
Further reading
47 - Sex differences in autonomic function
Introduction
Physiological conditions
Sympathetic activity
Baroreflex function
Neural-hemodynamic balance
Pathophysiological conditions
Obesity and related hypertension
Hypertension and cardiovascular disease
Conclusions
Further reading
48 - Autonomic control during pregnancy
Pregnancy activates the sympathetic nervous system
Pregnancy impairs the baroreceptor reflex
Mechanisms of pregnancy-induced baroreflex impairment
Preeclampsia
Summary and conclusions
Further reading
49 - Aging and the autonomic nervous system
Age-related changes in sympathetic activity
Age-related changes in parasympathetic function
Central autonomic pathways
End-organ responsiveness
Autonomic integration and baroreflex function
Volume regulation
Cerebral autoregulation
Clinical consequences of age-related changes in autonomic function: hypertension and orthostatic hypotension
Acknowledgments
Further reading
50 - Autonomic function in sleep and sleep deprivation
Stages of sleep
Autonomic function during sleep
NREM sleep
REM sleep
Autonomic responses to sleep deprivation
Sleep deprivation
Sleep restriction
Insomnia
Sleep apnea
Conclusion
Further reading
51 - Telemetric autonomic monitoring
Introduction—why assess autonomic function using telemetry?
Designing your experiment to maximize success and minimize stress
Implantation for long-term nerve recordings
Validating your nerve signal
Quantifying your nerve signal
Summary
Further reading
IV Autonomic response to environmental challenges
52 - Exercise
Introduction
Acute exercise
Exercise training
Exercise as a non-drug therapy
Conclusion
Further reading
53 - Psychological stress and the autonomic nervous system
Introduction
Psychological stress and autonomic activity
Normal psychological stresses and autonomic activity
Patterns of autonomic response to stress
Heart rate variability and cardiac disease
Gastrointestinal (GI) control
Psychosomatic disorders and the autonomic nervous system
Posttraumatic stress disorder, panic, and anxiety
Acknowledgment
Further reading
54 - Hypoglycemia
Normal mechanisms of glucose regulation
Impaired counterregulatory responses to hypoglycemia in diabetes (DM)
Impaired counterregulatory responses to hypoglycemia in autonomic failure (AF)
Hypoglycemia-associated autonomic failure (HAAF)
Further reading
55 - Autonomic response to hypovolemic shock
Introduction
Mechanisms of autonomic compensation
Other factors that influence compensatory responses to hypovolemia
Conclusion
Disclaimer
Further reading
56 - Physiology of thermoregulation: central and peripheral mechanisms
Introduction
Peripheral (outside the brain) physiological mechanisms of thermoregulation
Regulation of body temperature in thermoneutral environments
Physiological responses to cold exposure
Physiological responses to heat exposure
Skin blood flow
Sweating
Assessment of integrative physiological thermoregulation in humans
Central neural control of thermoregulation
Central responses to thermal stimulation of the skin surface
Integration of afferent and efferent neural signals in the POA
Thermoregulatory effector drive from the dorsomedial hypothalamus
Rostral raphe pallidus area contains premotor neurons for thermoregulatory effectors
Spinal sympathetic mechanisms controlling thermal effectors
Summary of central mechanisms
Overall summary
Disclaimer
Further reading
57 - Effects of high altitude
Introduction
Hyperacute altitude exposure
Acute altitude exposure
Acute mountain sickness (AMS) and high altitude cerebral edema (HACE)
High altitude pulmonary edema (HAPE)
Chronic altitude exposure and chronic mountain sickness (CMS)
Summary and key unanswered questions
Further reading
58 - Space physiology
Introduction
Space motion sickness
Orthostatic intolerance
Clinical interactions
Further reading
59 - Noise, air pollution, and the autonomic nervous system
Background
Health risks
Epidemiological evidence suggesting autonomic involvement
Animal studies
Human investigations
Underlying mechanisms
Areas of uncertainty
Further reading
V Pathophysiological mechanisms
60 - The autonomic inflammatory reflex
The autonomic inflammatory reflex
What is an inflammatory reflex?
Is there a role for the vagus nerve in the systemic inflammatory reflex?
The splanchnic sympathetic nerve mediates an inflammatory reflex
The efferent limb of the inflammatory reflex and its reach within abdominal organs
The afferent limb of the inflammatory reflex: neural and/or humoral?
What is the significance of the splanchnic inflammatory reflex?
Concluding comments
Acknowledgments
Further reading
61 - Reactive oxygen species and oxidative stress
Introduction
Biochemistry of reactive oxygen species
Production of reactive oxygen species in the ANS
Xanthine oxidase
Uncoupled nitric oxide synthase
Mitochondrial respiratory enzymes
Endoplasmic reticulum and reactive oxygen species generation
ROS-generating NADPH oxidases
NADPH oxidases
Regulation of noxs
Protecting against oxidative stress—antioxidant defenses
Molecular and cellular effects of oxidative stress
Redox signaling
Oxidative posttranslational modifications
ROS and the autonomic nervous system
Physiology of ROS in the ANS
Oxidative stress and pathological processes in the ANS
Conclusions
Acknowledgment
Further reading
62 - Insulin resistance and the autonomic nervous system
Introduction
Obesity and insulin resistance
Obesity and sympathetic activity
Contribution of sympathetic activity to insulin resistance in obesity
Contribution of sympathetic activity to insulin resistance in PCOS
Conclusions
Further reading
63 - Salt sensitivity of blood pressure
Prognosis of SSBP
Mechanisms of SSBP
Interstitial Na+ and SSBP
Immunity and SSBP
Genetics of SSBP
Environmental factors
Diagnosis of SSBP
Treatment of SSBP
Further reading
64 - Airway afferent nerves
Introduction
Extrinsic innervation of airway afferents
Characterization of airway afferent subtypes
C-fibers
A-fibers
Mechanisms of activation
C-fiber activation
Transient receptor potential (TRP) channels
A-fiber activation
Voltage-gated sodium channels (NaV)
Physiological consequence of airway afferent activation
Consequences of airway C-fiber activation
Consequences of A-fiber activation
Role of airway afferent nerves in respiratory diseases
Summary
Suggestions for further reading
VI Evaluation of autonomic function
65 - Clinical evaluation of autonomic disorders
Approach in history taking
Assessment: bedside and laboratory testing
Final thoughts
Further reading
66 - Autonomic function testing
Introduction
Aims of and clinical indications for autonomic testing
The autonomic reflex screen
Evaluation of cardiovagal function
Heart rate response to deep breathing
Valsalva ratio
Tests of cardiovascular adrenergic function
Blood pressure responses to the Valsalva maneuver
Blood pressure response to head-up tilt
Further reading
67 - Tilt table testing
Head-up tilt table (HUTT) test: background
What is HUTT?
Physiology of the HUTT
Are there different types of HUTT testing protocols?
What kind of monitoring is involved during HUTT testing?
Indications for HUTT testing
Utility and clinical applications of HUTT testing
“Sweet-Spot” for HUTT
HUTT in postural tachycardia syndrome (POTS)
HUTT in orthostatic hypotension (OH)
Conclusions
Further reading
68 - Patient symptom and rating scales: OHQ, COMPASS, UMSARS
Introduction
The orthostatic hypotension questionnaire (OHQ)
The composite autonomic symptom score (COMPASS)
The unified multiple system atrophy rating scale (UMSARS)
Further reading
69 - Sympathetic microneurography and clinical applications
Microelectrode recordings of sympathetic nerve activity in humans
Analysis of multiunit sympathetic nerve activity
Muscle sympathetic nerve activity in health and disease
Orthostatic hypotension and syncope
Cardiovascular, respiratory, and renal disease
Neurological and psychiatric disorders
Skin sympathetic nerve activity in health and disease
Disorders of thermoregulation
Conclusions
Further reading
70 - Assessment of the autonomic control of the cardiovascular system by a frequency domain approach
Introduction
The frequency domain approach for exploring cardiovascular and sympathetic discharge variability and their relationship wit ...
The frequency domain approach for exploring baroreceptor function during carotid baroreceptor rhythmic stimulation
The frequency domain approach for exploring autonomic and baroreceptor abnormalities during orthostatic presyncope
Conclusions
Further reading
71 - Evaluation of sudomotor function
Introduction
Quantitative sudomotor axon reflex test
Neurophysiology
Technique
Clinical implications
Quantitative direct and indirect test of sudomotor function
Silicone imprint
Neuropad
Sympathetic skin response
Electrochemical skin conductance
Thermoregulatory sweat test
Summary
Further reading
72 - Plasma catechols
Primer on the autonomic nervous system
Sources and meanings of plasma levels of catechols
DHPG
DA
DOPAC
EPI
DOPA
Cys-DOPA
Cys-DA
Diagnostic abnormal patterns of plasma catechols
DBH deficiency
LAAAD deficiency
Menkes disease
Supportive abnormal patterns of plasma catechols
Evoked changes in plasma catechol levels
Orthostatic NE responses to identify neurogenic orthostatic hypotension (nOH)
Orthostatic catecholamines in chronic orthostatic intolerance syndromes
Conclusions
Acknowledgment
Further reading
73 - Imaging cortical and subcortical sites involved in cardiovascular control
Functional identification of the medullary circuitry subserving the arterial baroreflex in humans
Functional identification of areas above the brainstem involved in blood pressure control
Functional significance of the sympathetic connectome
Conclusions
Acknowledgments
Further reading
74 - Clinical sympathetic neuroimaging
Sympathetic imaging and methods
Sympathetic neuroimaging in clinical autonomic disorders
Sympathetic neuroimaging in the diagnosis of LBDs
Sympathetic neuroimaging as a biomarker of catecholaminergic dysfunction in LBDs
Further reading
75 - Cutaneous autonomic innervation: assessment by skin biopsy
Introduction
Cutaneous neuroanatomy
Sweat glands
Hair follicles
Arrector pilorum muscles
Blood vessels
Skin biopsies to evaluate specific autonomic disorders
Recent advances in skin biopsies
Summary
Further reading
76 - Sympatho-effector transduction
Sympatho-effector transduction
Assessment of sympatho-effector transduction
Sympatho-effector transduction in health and disease
Conclusions
Further reading
VII - Cardiovascular disorders
77 - Neurally mediated syncope (Autonomically mediated syncope)
Background
Pathophysiology of vasovagal syncope
Natural history of VVS
Diagnosis of VVS
Role of head-up tilt table testing
Management strategies
Other specific NMS/AMS entities
Hypersensitive carotid sinus syndrome (HSCSS)
Situational syncope
Conclusions
Further reading
78 - Orthostatic hypotension
Autonomic mechanisms that maintain upright blood pressure
Definition, epidemiology, and clinical relevance
Etiology
Evaluation of the patient with orthostatic hypotension
Conclusions
Further reading
79 - Spectrum of orthostatic hypotension
Introduction
Initial OH
Delayed OH
Hyperadrenergic OH
Management of orthostatic hypotension
Conclusions
Further reading
80 - Baroreflex failure
Introduction
Causes of baroreflex failure
Clinical presentation
Diagnosing baroreflex failure
Treatment
Further reading
81 - Essential hypertension
Guidelines' recommendation
Consequences of differences between recommendations
Sympathetic overdrive
Hypertension-related target organ damage
Therapeutic implications
Further reading
82 - Obesity-associated hypertension
Epidemiology and significance
Increased sympathetic activity in obesity—association studies
Not all obesity is associated with sympathetic activation
Mechanisms explaining sympathetic activation in obesity
Does sympathetic activation provide any beneficial effect in obesity?
Potential deleterious effects of sympathetic activation in obesity
Implications
Further reading
83 - Pheochromocytoma and paraganglioma
Introduction
Clinical presentation
Genetics
Biochemical diagnosis
Tumor localization
Pre to postoperative patient management
Pathology and metastatic disease
Further reading
84 - Autonomic dysfunction in heart failure
Heart failure
Autonomic disturbances in heart failure with reduced ejection fraction
Autonomic disturbances in heart failure with preserved ejection fraction
Clinical considerations and future directions
Further reading
85 - Myocardial stunning and takotsubo cardiomyopathy
Introduction
Pathophysiology
Triggers
Cardiology findings
Autonomic studies in the acute phase
Autonomic studies after recovery
Predisposition and susceptibility
Further reading
86 - The autonomic nervous system and cardiac arrhythmias
Introduction
Anatomy of the cardiac autonomic nervous system
Neural remodeling and autonomic dysregulation in arrhythmias
Atrial fibrillation
Ventricular arrhythmias
Neuromodulatory interventions for arrhythmia management
Atrial fibrillation
Ventricular tachycardia
Conclusion
Further reading
VIII Congenital autonomic disorders
87 - Deficiencies of tetrahydrobiopterin, tyrosine hydroxylase, and aromatic L-amino acid decarboxylase
Biochemistry
Presentation and neurological symptoms
Diagnosis
Tetrahydrobiopterin deficiencies
Tyrosine hydroxylase deficiency
Aromatic L-amino acid decarboxylase deficiency
Treatment
BH4 deficiencies
TH deficiency
AADC deficiency
Further reading
88 - Congenital disorders of noradrenergic neurotransmission
Familial autonomic ganglionopathy
Dopamine-β-hydroxylase (DBH) deficiency
Cytochrome b561 deficiency
Norepinephrine transporter deficiency
Further reading
89 - Monoamine oxidase deficiency
Further reading
90 - Congenital central hypoventilation syndrome (CCHS) and PHOX2B pathogenic variants
Paired-like homeobox 2B (PHOX2B) gene
PHOX2B genotype and CCHS phenotype association
Continuous ventilatory dependence and other studies pertinent to respiratory control
Hirschsprung disease (HSCR)
Tumors of neural crest origin
Cardiac asystoles
Facial dysmorphology
Phenotype specific to NPARMs
Later-onset CCHS (LO-CCHS)
Comprehensive clinical evaluation
Further reading
91 - Hereditary autonomic neuropathies
Hereditary sensory and autonomic neuropathies
Fabry disease
Clinical manifestations
Autonomic impairment
Porphyria
Clinical manifestations of porphyria
Autonomic involvement in porphyria
Treatment of porphyria
Multiple endocrine neoplasia type 2B
Further reading
92 - Familial dysautonomia (Riley–Day syndrome)
Introduction
Clinical features
Autonomic features
Genetics
Pathological studies
Long-term consequences of baroreflex deafferentation
Treatment
Further reading
IX Autonomic synucleinopathies
93 - α-Synuclein and neurodegeneration
α-Synuclein—physiological function and association with disease
Parkinson disease
Multiple system atrophy
α-Synuclein toxicity and prion properties
Animal models of α-synucleinopathy
Models based on the overexpression of α-synuclein
Models based on spreading of α-synuclein
Anti-α-synuclein therapeutics
Conclusion
Further reading
94 - Multiple system atrophy
Background
Epidemiology
Pathophysiology
Clinical presentation
Diagnostic criteria
Motor features
Nonmotor features
Survival
Differential diagnosis
Autonomic testing in multiple system atrophy
Cardiovascular domain
Plasma catecholamines
Thermoregulatory domain
Urogenital, gastrointestinal, and respiratory domains
Treatment
Multidisciplinary approach
Symptom management
Motor symptoms
Nonmotor symptoms
Disease modifying approach
Further reading
95 - Parkinson disease
Summary
Further reading
96 - Dementia with Lewy bodies
Clinical aspects and differential diagnosis
Practical management
Therapy
Dementia
Hallucinations and psychosis
Parkinsonism
Autonomic failure
Declarations
Further reading
97 - Pure autonomic failure
Clinical manifestations
Diagnosis
Prognosis
The phenotype of nOH predicts prognosis in PAF
Is PAF “pure”?
Clinical laboratory separation of Lewy body versus non-Lewy body PAF
Lewy body PAF versus premotor MSA
Treatment
Summary
Acknowledgments
Further reading
X Peripheral autonomic disorders
98 - Small fiber neuropathy
Systemic disorders associated with SFN
Treatment
Conclusions
Further reading
99 - Diabetic autonomic dysfunction
Iris
Upper GI dysmotility
Gallbladder
Colon
Bladder
Penis
Vagina
Adrenal medulla
Sudomotor
Cardiovascular
Further reading
100 - Amyloidosis and autonomic failure
Overview of amyloidosis
Amyloidosis subtypes
Neuropathy patterns
Autonomic manifestations
Orthostatic intolerance
Gastrointestinal
Secretomotor
Urological
Pupillary
Case 1
Case 2
Treatment
Prognosis
Conclusion
Further reading
101 - Autoimmune autonomic syndromes
Autoimmune autonomic ganglionopathy
Clinical course of AAG
Pathogenesis of AAG
Diagnosis of AAG
Treatment for AAG
Paraneoplastic autonomic neuropathy
Immune-mediated sensory and autonomic neuropathy
Autoimmunity in postural orthostatic tachycardia syndrome
Other autoimmune conditions with associated autonomic dysfunction
Summary
Further reading
102 - Paraneoplastic autonomic dysfunction
Introduction
Immunobiology and immunopathology
Clinical disorders and their course
Autonomic neuropathy
Autoimmune autonomic ganglionopathy (AAG)
Lambert-Eaton syndrome
Morvan syndrome and related disorders
Progressive encephalomyelitis with rigidity and myoclonus (PERM)
Autoimmune encephalitis
Testing
Neurological testing
Antibody tests
Cancer tests
Management
Conclusion
Further reading
103 - Autonomic disturbances following spinal cord injury
Classification of spinal cord injury
Spinal shock
Cardiovascular system
Cutaneous circulation
Thermoregulation and sudomotor function
Gastrointestinal system
Urinary system
Respiratory system
Reproductive system
Functional recovery strategies
Further reading
104 - Drug-induced autonomic dysfunction
Introduction
Drug-induced hypertension
Drug-induced hypotension
Further reading
XI Autonomic syndromes
105 - Postural tachycardia syndrome. Pathophysiological mechanisms
Diagnostic challenges
Etiology and pathophysiology
“Primary” POTS
“Secondary” POTS
Hypovolemia
Autoimmune mechanisms
Deconditioning
The mosaic theory of POTS?
Implications for therapy
Further reading
106 - Postural tachycardia syndrome (POTS)
Introduction
Clinical features and phenotypes
Phenotypes of POTS
Neuropathic POTS
Hyperadrenergic POTS
POTS associated with poor conditioning
Role of hypovolemia, genetic mutations, connective tissue disorders, and autoimmunity
Follow-up
Management
Conclusions
Further reading
107 - Joint hypermobility and dysautonomia
Introduction
Epidemiology and pathophysiology
Clinical manifestation and diagnosis
Autonomic dysfunction in JHS
Mechanism of dysautonomia and orthostatic intolerance in JHS
Management
Further reading
108 - Mast cell activation and autonomic disorders
Introduction
MCAD and POTS: mechanistic insights
Diagnosis
Conclusion
Further reading
109 - Chronic fatigue syndrome and the autonomic nervous system
Chronic fatigue syndrome and the autonomic nervous system
Chronic fatigue syndrome and autonomic dysfunction
Chronic fatigue syndrome and orthostatic intolerance
Postural orthostatic tachycardia syndrome
Neurally mediated hypotension
Pathophysiology
Conclusions
Further reading
XII Special clinical conditions
110 - Neuroleptic malignant syndrome
Introduction
Clinical features
Medications and risk factors
Differential diagnosis
Pathogenesis
Treatment
Further reading
111 - Migraine and autonomic nervous system
Functional anatomy of migraine
Autonomic symptoms during the migraine attack
Interictal autonomic dysfunction in migraine
The pain of migraine
Migraine as a biobehavioral disorder
Migraine as a reflection of genetically determined adaptive Darwinian behavioral responses
Conclusion
Further reading
112 - Autonomic regulation in epilepsy
Introduction
Ictal autonomic dysfunction
From structures to symptoms
From symptoms to structures
Gastrointestinal autonomic symptoms
Urogenital autonomic symptoms
Cutaneous and pupillary autonomic symptoms
Respiratory autonomic symptoms
Cardiovascular autonomic symptoms
Status epilepticus
Sudden unexpected death (SUDEP)
Interictal autonomic dysfunction
Cardiovascular autonomic regulation in epilepsy patients
Effects of antiseizure treatment on autonomic regulation
Further reading
113 - Autonomic complications of acute brain injury and stroke
Introduction
Pathophysiology
Clinical manifestations
Differential diagnosis
Specific clinical scenarios
Traumatic brain injury
Acute stroke
Anoxic-ischemic global brain injury
Management considerations
Further reading
114 - Sleep apnea
Critical need for understanding the interactions between sleep apnea, the autonomic nervous system, and cardiovascular disease
Autonomic function during physiologic sleep
Obstructive sleep apnea
OSA and the autonomic nervous system
Acute changes during apneic episodes
Chronic changes with OSA
Individualized approach to OSA according to cardiovascular comorbidities
Atrial fibrillation and OSA
Sudden cardiac death and OSA
Heart rate variability in OSA
Central sleep apnea
Heart failure and CSA
Traditional and novel treatment modalities for sleep apnea
Further reading
115 - Panic disorder: Autonomic nervous mechanisms of risk
Resting sympathetic nervous system function in panic disorder
Sympathetic nervous activity and adrenal medullary epinephrine secretion rates
Autonomic nervous changes during a panic attack
Sympathetic nerve firing and secretion of epinephrine
Release of neuropeptide Y
Intensification of the sympathetic activation signal during panic attacks
Brain monoamine turnover in panic disorder
Increased brain serotonin release
Monoamine plasma assays, brain monoamine turnover calculation
Results
Abnormal sympathetic nerve biology in panic disorder
Reduction in neuronal norepinephrine reuptake by sympathetic nerves
Single-fiber sympathetic multiple firing salvos
Epinephrine cotransmission in sympathetic nerves
The “Toxic Trifecta” of sympathetic nervous changes in panic disorder
Mediating autonomic mechanisms of cardiac risk during a panic attack
Cardiac risk: clinical management
Acknowledgments
Further reading
116 - Disorders of sweating
Introduction
Hyperhidrosis
Hypohidrosis and anhidrosis
Distal anhidrosis
Global anhidrosis
Dermatomal, focal, or multifocal anhidrosis
Segmental anhidrosis
Regional anhidrosis
Hemianhidrosis
Further reading
117 - Complex regional pain syndrome
CRPS I is a neuronal disorder involving the central nervous system (CNS)
Sympathetic systems supplying skin
Cutaneous vasoconstrictor neurons and blood flow through skin
Sudomotor neurons and sweating
Sympathetic neurons and edema, inflammation, and trophic changes
Edema
Inflammation
Trophic changes
Sensory systems of the skin
Somatomotor changes
Initiating events
CRPS and sympathetically maintained pain (SMP)
Conclusions
Acknowledgment
Further reading
118 - Abdominal pain and cyclic vomiting
Cyclic vomiting syndrome (CVS)
Chronic abdominal pain
Further reading
119 - Male erectile dysfunction
Mechanism of erection
Etiology of erectile dysfunction
Neuromuscular junction disorders
Neurogenic erectile dysfunction
Endocrine disorders
Medical and surgical treatment
Further reading
XIII Management of neurogenic orthostatic hypotension
120 - Management of orthostatic hypotension. Introduction
Goal of treatment and overall strategy
Pathophysiological concepts relevant to orthostatic hypotension
Physiology of orthostatic tolerance
Sympathetic reserve
Denervation hypersensitivity
Cerebral autoregulation
Supine hypertension and pressure diuresis
Summary of pathophysiology and relevance to management
Nonpharmacologic approaches
Remove offending factors
Targeting sodium balance
Improve venous return
Pressor agents (Fig. 120.3)
“Norepinephrine enhancers”—engaging residual sympathetic tone
“Norepinephrine replacers”
Further reading
121 - Physical measures
Physical measures
Counterpressure maneuvers
External support
Respiratory maneuvers
Conclusion
Further reading
122 - Dietary sodium and fludrocortisone
Dietary sodium
Fludrocortisone
Further reading
123 - Water and the osmopressor response
Introduction
The water-induced pressor response
Evidence for water-induced sympathetic activation
A spinal sympathetic reflex?
Evidence for an osmosensitive mechanism involving Trpv4 in the liver
Therapeutic utility of water drinking
Speculation on the purpose of the osmopressor response
Further reading
124 - Midodrine
Introduction
Clinical development of midodrine
Use of midodrine in clinical practice
Further reading
125 - Droxidopa
Introduction
Historical background
Clinical studies
Droxidopa dose selection
Other therapeutic considerations
Further reading
126 - Pyridostigmine in autonomic disorders
Introduction
Pyridostigmine in the treatment of neurogenic orthostatic hypotension
Pyridostigmine in the treatment of orthostatic intolerance associated with postural tachycardia syndrome
Other indications of pyridostigmine in autonomic disorders
Further reading
127 - Norepinephrine transporter inhibitors in autonomic disorders
Introduction
Selective NET inhibition for the treatment of neurogenic orthostatic hypotension
NET inhibition as an adjuvant for the treatment of refractory neurogenic orthostatic hypotension
NET inhibition in neurally mediated syncope
Conclusion
Further reading
128 - Acarbose and octreotide for the treatment of postprandial hypotension
Introduction
Acarbose
Octreotide
Further reading
129 - Management of supine hypertension in patients with autonomic failure
Considerations for the management of supine hypertension
Management of supine hypertension
Treating nOH without worsening sHTN
Nonpharmacological treatment
Pharmacological treatment
Drugs targeting the renin–angiotensin–aldosterone system
Drugs that potentiate nitric oxide
Vasodilators
Sympatholytic drugs
Novel approaches
Conclusions
Further reading
130 - Anesthetic considerations in patients with autonomic dysfunction
Responses to surgery and anesthesia in a patient with intact autonomic function
Anticipated responses to surgery and anesthesia in a patient with autonomic failure
PAF versus MSA
Parkinson disease
Diabetes
Anesthetic approach to a patient with AF
Regional anesthesia
Preoperative screening
Conclusion
Further reading
131 - Chronic constitutional hypotension
Introduction
Epidemiology
Clinical profile of individuals with CHT
Pathophysiology of CHT
Management of subjects with CHT
Perspective
Funding
Further reading
XIV Autonomic neuromodulation as a treatment strategy
132 - Renal denervation as therapeutic intervention
Origins of catheter-based renal denervation therapy for cardiovascular disease
The Symplicity HTN-3 renal denervation trial
Improved RDN devices and RDN procedures
The modern era of RDN (post-2016): proof of efficacy and safety
Patient selection for RDN
Is it feasible to identify patients with neurogenic hypertension as the preferred target for RDN?
De-facto neurogenic hypertension: can sympathetic activation be assumed to be present in some hypertension phenotypes?
Uncontrolled hypertension, patient nonadherence, patient preference for RDN
Further optimization of the RDN procedure
Testing for renal denervation to guide the proceduralist
Post hoc testing for renal denervation: excretion of tyrosine hydroxylase in urine
Methods
Results
Conclusions
Guided renal nerve ablation
Reinnervation of the kidneys after catheter-based denervation?
Other clinical applications of renal denervation
RDN for cardiac failure?
Summary
Acknowledgments
Further reading
133 - Baroreflex amplification by carotid sinus stimulation
Background
Electrical carotid sinus stimulation
Mechanical carotid sinus stimulation
Perspectives
Further reading
134 - Targeting carotid body chemoreceptors as a therapeutic intervention
Introduction
Carotid body: a multimodal receptor
The chemoreflex
Transduction mechanisms within the carotid body
Carotid body transmission during hypoxia
Blood flow to the carotid body
Pathophysiology of the carotid body
Identifying pathological carotid bodies
Preclinical carotid body modulation
First-in-human studies
Hypertension
Congestive heart failure
Beyond resection—the next vista of carotid body therapy
Further reading
135 - Bionic baroreflex
Introduction
Theoretical background
Implementation of algorithm of artificial vasomotor center in BBS
Efficacy of BBS
Epidural catheter approach for human BBS
Feasibility study of BBS in patients with high cervical spinal cord injury
Implantable BBS
Further reading
136 - Therapeutic targeting of splanchnic nerves
Role of the splanchnic vascular compartment and splanchnic nerves in the regulation of vascular tone and blood volume shifts
Targeting the splanchnic compartment and splanchnic nerves for the treatment of cardiovascular disease
Splanchnic nerve blockade as a treatment for cardiovascular disease
Conclusion
Further reading
XV Novel approaches in autonomic neuroscience
137 - Modeling the autonomic nervous system
Hodgkin–Huxley type models
Activity-based models
Integrate and fire models
Boolean models
Phenomenological models
Black box models
Conclusions
Further reading
138 - Optogenetics: application to central autonomic regulatory pathways
Introduction
Optically activated molecules
Excitation
Inhibition
The genetics of optogenetics
How does optogenetics benefit central autonomic neuroscience research?
Identifying the function of anatomically dispersed neuronal populations
Identifying the function of specific neuronal phenotypes within a heterogeneous cell group
Modulating the activity of “life-essential” neuronal populations
Conclusion
Further reading
139 - Mapping the autonomic nervous system: the SPARC project
Introduction
2D flatmaps
3D organ scaffolds
A scaffold for the stomach: mapping data from flat preparations
A scaffold for the heart: mapping the intrinsic cardiac nervous system
3D body scaffolds
Geometric body coordinates and embedded organs
Conclusions and future work
Acknowledgments
Further reading
140 - Autonomic nervous system-gut-microbiome axis in chronic diseases
Gut microbiota in health and disease
Autonomic regulation of the GI tract
Sympathetic innervation in the GI tract
Vagal innervation in the GI tract
Links between autonomic dysfunction and gut dysbiosis
Neural gut-brain axis and microbiota
Question of cause and effect
Future directions and potential of probiotic and bioelectronic medicine
Further reading
141 - Novel fluid biomarkers in synucleinopathies
Introduction
Catecholamines and catechols
Neurofilament light chain
Alpha-synuclein and alpha-synuclein subspecies
Conclusion
Further reading
142 - Novel disease-modifying treatments for synucleinopathies
Introduction
Pathophysiology of synucleinopathies
Disease-modifying therapeutic approaches
(a) αSyn lowering and blocking
(b) αSyn spread
(c) αSyn clearance and autophagy
(d) Neurotrophic factor deficiency
(e) Neuroinflammation
(f) Dysfunctional iron metabolism
(g) Dysfunctional glucose metabolism
(h) Mitochondrial dysfunction
(i) Non-aSyn genetically validated targets
Conclusion
Further reading
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
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