Which higher brain region is not involved in the control of the autonomic nervous system?

Autonomic Nervous System Function

A topographic arrangement of autonomic function exists in the hypothalamus; parasympathetic control stems mainly from anterior and medial regions, whereas the lateral and posterior areas control sympathetic responses. Parasympathetic activity results in slowing of the heart rate, peripheral vasodilation, and increased gastrointestinal motility. Alternatively, sympathetic stimulation results in pupillary dilation, increased heart rate and blood pressure, and other responses associated with increased emotional stress.2

Heart rate, heart rate variability, and other cardiac measures are often used as markers when one is assessing fetal and neonatal autonomic function.42,43 Fetuses at a gestational age of 20 weeks demonstrate heart rate stability and show differences among individuals. The fetal heart rate, beginning at 24 weeks of gestation, may be predictive of postnatal heart rate, but fetal heart rate variability does not become predictive of postnatal heart rate variability until 6 weeks later. This finding likely reflects a later maturation of the neuroregulatory system that controls heart rate variability.42 The reduction in heart rate variability in fetuses with increasing gestational age also suggests that the autonomic nervous system continues to develop throughout gestation.43

Autonomic activity in fetuses varies over the course of a day. For instance, in normal fetuses, the fetal autonomic activity that controls heart rate follows a 12-hour cycle, as opposed to the maternal 24-hour rhythm. This 12-hour rhythm disappears immediately after birth, although the 24-hour circadian rhythm does not become established until 2 to 4 weeks later.44

Paroxysmal Sympathetic Hyperactivity

Disturbance in autonomic nervous system function may present after any brain injury, and a brain suffering from global ischemia, as in cardiac arrest, is particularly susceptible. Historical reports estimate that up to 8% to 33% of patients suffering TBI and 6% to 29% of patients with global anoxic injuries may exhibit paroxysmal sympathetic hyperactivity (PSH). PSH is characterized by sudden, paroxysmal changes in vital signs manifest as hyperthermia, tachycardia, hypertension, and/or tachypnea. Associated findings on examination may include pupillary dilatation and diaphoresis. Patients suffering from PSH may exhibit agitation and hypertonia with extensor posturing during events.

A recent retrospective analysis examined the medical records of 249 children admitted to an intensive care unit with acute brain injuries (TBI, global ischemia, focal ischemia, CNS infection) over a 7-year period. Overall, 13% of patients had treatment for dysautonomia. Most individuals with PSH manifest symptoms over a week after the initial CNS insult.

The timing of onset of symptoms of PSH is variable, and identification of PSH requires a high index of suspicion. To establish the diagnosis the clinician should assess for other events that might cause similar physiologic derangements, including narcotic or other drug withdrawal, pain in response to an occult injury (fracture, dislocation), urinary retention or ileus, seizure, and occult infections. Treatment of acute bouts of PSH includes administration of medications aimed at providing symptomatic relief and reducing sympathetic tone, including propranolol or clonidine, narcotics (morphine), benzodiazepines (lorazepam), and antipyretic agents (acetaminophen or ibuprofen). No single drug has proven effective, but combinations of long-acting benzodiazepines, gabapentin, and baclofen are often used.

Organization and General Functions of the Autonomic Nervous System

The two divisions of the autonomic nervous system are thesympathetic nervous system (SNS) and theparasympathetic nervous system (PNS). (The enteric nervous system of the gastrointestinal tract, which is discussed inChapter 22, is also sometimes considered to be part of the autonomic nervous system). In many cases, the SNS and PNS have opposing actions on various organs and processes, and regulation of bodily functions often involves reciprocal actions of the two divisions. For example, heart rate is elevated by SNS activity and decreased by PNS activity.

As a generalization, the SNS is said to mediatestress responses, such as the classicfight-or-flight response, and the PNS mediates “vegetative” responses, such as digestion. The fight-or-flight response is a generalized reaction to extreme fear, stress, or physical activity and results in a patterned response in many organ systems. The response includes elevated heart rate, cardiac output, and blood pressure, as well as bronchial dilation, mydriasis (dilation of pupils), and sweating. Although the sympathetic nervous system often responds in such patterned manners, the PNS may produce more selective effects—for example, during the sexual response.

The autonomic nervous system has as its central components the hypothalamus, brainstem, and spinal cord; peripherally, it consists of sympathetic and parasympathetic nerves. Areas within the hypothalamus and brainstem regulate and coordinate various processes through the autonomic nervous system, including temperature regulation, responses to thirst and hunger, micturition, respiration, and cardiovascular function. This regulation is in response to sensory input and occurs through the reciprocal regulation of the SNS and PNS.

The fight-or-flight response was originally described in 1915 by Walter Canon, who also coined the term “homeostasis.” The fight-or-flight response can be characterized as the physiologic response to acute stress in which general­ized sympathetic activation occurs, resulting in effects such as tachycardia, bronchial dilation, mydriasis (dilation of the pupils), vasoconstriction in much of the body, piloerection, and inhibition of gastrointestinal motility. It has long been appreciated that the acute stress responses also involve activation of the hypothalamic-pituitary-adrenocortical endocrine axis (described in Section 7).

Peripherally, axons ofpreganglionic neurons of the SNS and the PNS emerge from the spinal cord and synapse withpostganglionic neurons at sympathetic and parasympathetic ganglia, respectively; in both cases,acetylcholine is the neurotransmitter, acting atnicotinic receptors on postganglionic neurons (Fig. 7.1). Postganglionic neurons then send motor axons to effector organs and tissues. The catecholaminenorepinephrine is released by postganglionic sympathetic axons and acts atadrenergic receptors of effector organs. One exception is the postganglionic axons that innervate sweat glands, which release acetylcholine. Furthermore, the adrenal medulla functions as part of the SNS. Preganglionic axons of the SNS extend to the adrenal gland, where they stimulate chromaffin cells of the adrenal medulla to releaseepinephrine (and to a lesser degree norepinephrine) into the bloodstream. Notably, in addition to releasing catecholamines (norepinephrine and epinephrine), some sympathetic postganglionic nerves release a number of adrenergiccotransmitters, includingneuropeptide Y, ATP, andsubstance P, among others. In the PNS, acetylcholine, acting atmuscarinic receptors, is the postganglionic neurotransmitter. These and other aspects of the two divisions of the autonomic nervous system are compared inTable 7.1 and illustrated inFigures 7.2 and7.3. Actions of the autonomic nervous system in various organ systems and tissues are listed inTable 7.2, along with the receptor types involved.

Sweat gland secretion is stimulated by activation of the SNS. Most of the postganglionic sympathetic neurons innervating these glands are atypical, releasing the neurotransmitter acetylcholine instead of norepinephrine. Acetylcholine acts on muscarinic receptors, inducing sweat secretion. However, in some specific areas, such as the palms of the hands, adrenergic nerves stimulate sweat glands through the release of norepinephrine, which acts at α1 receptors to stimulate secretion.

6.09.3.2.2 Biofeedback

Biofeedback is the regulation of autonomic nervous system functions, such as blood pressure, heart rate, and sweating, by the subject continually monitoring that function and being rewarded (usually simply by the knowledge of his or her success) for changing that activity in a desired direction. Feedback is usually conveyed either auditorily by the pitch of a continuous tone or by using a visual display.

The idea that a person, with training, can selectively influence the activity of a particular autonomic function, notably in the direction of diminished arousal, has been in existence for a long time and is traditionally associated with Eastern practices such as meditation and yoga. It has been claimed that practitioners of these forms of meditation have the ability to attenuate their vital functions (e.g. heart rate) to an extraordinary degree. In contrast, Western scientific interest in autonomic control has been a recent development and was stimulated by the work of Miller and his colleagues on the operant conditioning of autonomic responses in animals, particularly the curarized rat. This research was significant from a theoretical standpoint because the findings suggested that autonomic and visceral responses, hitherto held only to be amenable to alteration by classical conditioning, could be modified by positive reinforcement within an instrumental or operant-conditioning paradigm. Around that time also, interest had been shown (Kamiya, 1969) in the operant conditioning of the alpha EEG rhythm (as a means of achieving altered states of consciousness) and of changes in skin conductance (Shapiro, Crider, & Tursky, 1964) and heart rate (Engel & Hansen, 1966). However, these studies on humans were criticized by Katkin and Murray (1968) for their lack of controls for mediating responses such as breathing.

Despite the many problems encountered in replicating some of the above animal laboratory work, it proved very influential and a wide range of clinical applications have been investigated since then and have focused mainly on two types of problem. First, anxiety and stress disorders, where the aim of biofeedback is to reduce general arousal levels; and, second, disorders presenting as somatic problems (e.g., pain, tension headaches, and irritable bowel syndrome), which may be triggered or exacerbated by overarousal and where again the biofeedback is either aimed at general relaxation or is targeted more specifically to the affected organ or function in order to achieve self-regulation.

Biofeedback techniques associated with generalized arousal reduction have included from the outset alpha rhythm EEG feedback (Budzynski & Stoyva, 1973) and other methods such as electrodermal (skin conductance) feedback (usually from the hand) and surface EMG feedback, for example, from the frontalis muscle, or in combination. The latter techniques are now more commonly used and may also be employed to augment systematic in vitro or in vivo desensitization by enabling closer monitoring of the return-to-relaxation phase, and thereby assisting patients to achieve this (Stoyva & Budzynski, 1993).

Procedurally, treatment by biofeedback begins with an assessment of the patient's presenting problem and an explanation of the rationale of biofeedback. Initial training sessions with the therapist enable the patient to become more attuned to cognitions and bodily events that are associated with increase in arousal. This training has been reported to be productive in establishing anxiety-evoking cognitions in the case of generalized anxiety (Budzynski & Stoyva, 1973). This stage is followed by daily practice at home (multiple short sessions) until mastery of the target response has been achieved and the patient can be weaned off the biofeedback device. Again, it should be noted that biofeedback is often combined in treatment with other self-relaxation methods, such as autogenic training or progressive relaxation (Lehrer et al., 1993).

Functions of the autonomic nervous system

The ANS carries all motor outflow from the CNS to the major organs of the body, with the exception of the motor outflow to skeletal muscles. The parasympathetic and sympathetic systems are entirely linked to the CNS. Although part of the enteric nervous system receives autonomic input, most of the enteric system has local networks that are independent of the CNS. The ANS is not under voluntary control and regulates essential physiological processes such as:

Rate (chronotropic) and force (inotropic) of contraction of heart muscle (Ch. 11)

Secretions of exocrine glands: bronchial, salivary, sweat, etc.

Vascular smooth muscle and thus blood pressure

Smooth muscle contraction and relaxation: bronchial, enteric, eye, etc.

Energy metabolism, e.g. hepatic glycogenolysis, skeletal muscle glycogenolysis, fat cell lipolysis, pancreatic insulin secretion (seeCh. 3)

Some endocrine secretion (seeCh. 10).

The ANS is important pharmacologically because:

It controls the functions of almost all the major human organ systems.

The relative simplicity of the ANS in terms of receptor subtypes and the fact that there are only two main transmitters – ACh and norepinephrine – make study of the chemical transmission relatively easy.

The action of neurotransmitters can be mimicked and modified by drugs, which are synthetic analogues.

Diseases with ANS dysfunction are relatively common.

Autonomic Nervous System

The age-related changes in autonomic nervous system (ANS) function are very diverse, and are likely to be associated with many of the age-related changes observed in drug response and toxicity across many therapeutic classes of drugs. Cardiovagal function is diminished, as indicated by age-related decreases in resting heart rate and beat-to-beat heart rate variability. Older individuals have lower vagal tone, as indicated by less increase in heart rate with atropine administration. Other findings consistent with this conclusion are that older individuals have decreased heart rate variation with deep breathing and reduced increases in heart rate in response to standing. Baroreflex function is also impaired in the healthy elderly, and this is accentuated in the presence of illness common in older patients, such as hypertension and diabetes mellitus [56]. Cardiac sympathetic function is also altered, as demonstrated by decreased tachycardic response to isoproterenol and increased circulating plasma norepinephrine concentrations [57, 58]. An integrated response that reflects many of these age-related changes is that of orthostatic hypotension, which is substantially increased in older individuals [59]. The degree of orthostatic decrease in blood pressure in older patients may be particularly evident in the postprandial state, and may be exacerbated when older patients are treated with diuretics [60, 61]. Thermoregulatory homeostasis is also impaired in the elderly, who have a higher thermoreceptor threshold and decreased sweating when perspiration is initiated [56].

Data that conclusively establish that altered drug effects result from impaired ANS function are sparse, perhaps due to the difficulty in ascribing a particular drug effect to a particular ANS function. However, increased orthostatic hypotension seen at baseline, in addition to drugs that cause sympathetic blockade, such as typical neuroleptics and tricyclic antidepressants, is likely to be a contributing factor to the increased incidence of hip fracture noted in patients receiving these drugs [62]. Similarly, the anticholinergic effects of many drugs, including antihistamines and neuroleptics, may not only accentuate orthostatic blood pressure changes but also be associated with greater cognitive impairment in older individuals. Impaired thermoregulation under baseline conditions may also be accentuated by administration of these drugs because they have potent anticholinergic effects that further disable thermoregulatory responses. It is unclear at this time how age-related ANS changes may relate to the cardiac proarrhythmic effects of drugs that prolong the electrocardiographic QT interval. However, there is a clear association of increasing age with the proarrhythmic effects of neuroleptic drugs [63]. It is clear that these ANS changes markedly alter systemic cardiovascular responses to a drug such as the α- and β–adrenergic blocking drug labetalol, which, as shown in Figure 26.6, lowers blood pressure to a greater extent in older than in younger hypertensive patients while decreasing heart rate to a much lesser extent [64].

C Other Peripheral Nervous System-Mediated Functions

α2AR genetics have been linked with abnormal peripheral autonomic nervous system functions. Finley and colleagues demonstrated an association between the α2AAR DraI RFLP and susceptibility to stress-induced motion sickness as well as increased exercise-induced sweat sodium concentrations, both used as readouts of the autonomic stress response (Finley et al., 2004). Other studies have linked the α2BAR Del301-303 polymorphism with altered autonomic function, specifically relatively lower autonomic tone, in obese male and female subjects (Sivenius et al., 2003; Ueno et al., 2006). These studies indicate a contribution of α2AR genotype in both stress response and autonomic tone in relation to metabolism.

Investigations

Investigations can be considered to detect or confirm polyneuropathy, to test ANS function, and to test the function and nerve supply of the bladder and EUS.

Peripheral nerve conduction studies, often supplemented by needle EMG examination of distal limb muscles, supports a diagnosis of polyneuropathy and distinguishes the demyelinating from the axonal type. The involvement of somatic nerve fibers in the lower sacral segments can be demonstrated by needle EMG of the EAS muscle (and other striated muscles of the perineum and pelvic floor) and by testing of sacral reflex responses. However, even in patients with proven polyneuropathy and LUTD, the electrophysiologic abnormalities in lower-limb nerves are more pronounced (easier to demonstrate) than the abnormalities of the pudendal nerve function. All mentioned studies evaluate only the large-diameter nerve fibers that are less relevant in LUTD. There is no routine electrophysiologic test for bladder smooth muscle and its innervation. Thermal thresholds assess the function of small-diameter nerve fibers.

Autonomic tests may be performed to demonstrate involvement of the ANS. If abnormalities are found, it is inferred that the bladder may be similarly affected. The potential pitfalls are evident, as bladder autonomic innervation itself is not tested. Tests include the thermoregulatory sweat test, quantitative sudomotor axon reflex test, sympathetic skin response test, and quantitative sensory testing Santiago et al., 2000; Low et al., 2003). A skin biopsy with a quantification of pilomotor nerves may also be performed to evaluate involvement of thin autonomic nerve fibers.

Assessment of LUT should include history and determination of residual urine as a minimum.

Urodynamic tests will reveal bladder sensory and motor function. Pressure–flow cystometry directly reveals the function of bladder afferents, but any lesion of autonomic (motor) fibers can only be inferred.

In summary, laboratory testing of the neurogenic causation of bladder dysfunction in the context of polyneuropathy provides mostly indirect proof, requires particular expertise, and has significant limitations. It is often more appropriate to make the neurologic diagnosis on clinical grounds, as treatment of LUT dysfunction would only in rare exceptions rely on the diagnosis of the neurologic lesion. LUT dysfunction, of course, needs to be appropriately assessed to allow for rational management (see Chapters 9 and 26).

Introduction

A host of neurophysiological techniques have been developed over the last century to measure autonomic nervous system function (Low, 2003). These methodologies were developed, in part, because of the general inaccessibility of the autonomic nervous system to direct measurement. Autonomic testing, with the exception of microneurography, indirectly measures functional responses to pharmacological or physiological provocation (Hilz and Dutsch, 2006). Similar challenges have been faced in the evaluation of the peripheral nervous system, where functional testing has predominated in the clinical investigation of disease. Structural assessments of peripheral nerve fibers are typically obtained through sural nerve biopsies, a relatively invasive technique (Bosboom et al., 2001; Jann et al., 2003; Malik et al., 2005; Bennett et al., 2008). Sural nerve biopsies are limited both by their location (they are constrained to a single anatomical site) and their repeatability (only a single biopsy from each side is traditionally performed).

In the 1990s, a technique to measure cutaneous peripheral nerve fibers was developed. This technique, utilizing a standard dermatological punch skin biopsy, was combined with immunoflorescent staining of nerve fibers using the panaxonal marker protein gene product 9.5 (PGP 9.5) (McCarthy et al., 1995; Kennedy and Wendelschafer-Crabb, 1996). Epidermal nerve fibers can be easily identified and quantified (Lauria et al., 2010b). The direct clinical applicability of this technique was quickly recognized and several laboratories began to publish reports of skin biopsy findings across various disease states. Since then, the rapid dissemination of this technique has resulted in the widespread utilization of skin biopsy in the evaluation of small fiber neuropathy.

During this period of time there was interest in the study of autonomic innervation of the skin, largely pioneered by Dr. William Kennedy. Kennedy developed several confocal immunoflorescent staining protocols to visualize sweat glands, blood vessels, hair follicles, and other dermal structures (Kennedy et al., 1994). Over the past decade, the use of skin biopsies has expanded from the original study of small unmyelinated sensory nerve fibers to widespread investigation of cutaneous autonomic nerve fibers in a variety of disease states (Dabby et al., 2006; Nolano et al., 2006, 2010; Gibbons et al., 2009, 2010a).

The skin provides a unique window into the autonomic nervous system. Peripheral adrenergic and cholinergic fibers innervate a number of cutaneous structures and can easily be sampled through punch skin biopsies. Skin biopsies allow for both regional sampling, in diseases with patchy distribution, and the opportunity for repeated sampling in progressive disorders.

4.4 Bed Nucleus of the Stria Terminalis

The BNST has a central role in regulating stress responses, including effects on endocrine, immune and autonomic nervous system function [92–95]. As noted earlier, only IL-1β-activated cells located in the vBNST project to the mPVN cell group [14, 88]. Selective BNST lesions that encompass the vBNST reduce not only the expression of ACTH secretagogues [96], but also the mPVN CRF cell response to systemic IL-1β [88]. Recruitment of BNST neurons in response to systemic IL-1β may occur via afferent inputs from the CeA and parabrachial nucleus. Like the CeA, neurons of the parabrachial nucleus also innervate the BNST [89, 97–99]. Furthermore, lesions of the parabrachial nucleus significantly reduce the numbers of Fos-positive cells observed in both the dBNST and vBNST after systemic IL-1β [87], suggesting parabrachial projections recruited by IL-1β may influence the activation of the BNST.