Baroreflex modulation during sleep and in obstructive sleep apnea syndrome

This review focuses on the complex integration between cardiovascular reflexes and central autonomic influences controlling physiological sleep-dependent changes in arterial blood pressure and heart rate. A brief introduction on the anatomic and functional organization of the arterial baroreflex and the methods available to assess its function in humans is followed by an analysis of the functional interaction between autonomic nervous system and sleep mechanisms at the highest levels of brain organization. An insight into these interactions is important to shed light on the physiopathology of the most frequent complications of obstructive sleep apnea syndrome, such as sustained arterial hypertension, and excessive daytime sleepiness.     

Autonomic cardiovascular reflexes in Wilson's disease

We studied autonomic cardiovascular function in fourteen patients with Wilson's disease. Four had abnormalities on autonomic testing and, of these, three had evidence of severe central nervous system abnormalities. In contrast, of the remaining ten patients with normal cardiovascular reflexes, only two had severe deficits of the central nervous system. We suggest that autonomic impairment in Wilson's disease is due to involvement of central autonomic neurons. Received: 1 December 2001, Accepted: 2 April 2002     

An exploration of central dysregulation of erectile function as a contributing cause of diabetic impotence

Diabetic impotence is generally presumed to be secondary to peripheral abnormalities of the vascular or autonomic nervous system, although central nervous control of the autonomic nervous system has not previously been studied. Measures of rapid eye movement (REM) sleep as potential indicators of central autonomic dysfunction were studied along with sleep-related tumescence for 10 impotent diabetics, nine psychogenically impotent men, and 10 men whose impotence was secondary to pelvic trauma. Low REM density was found in the diabetics with REM density correlating with measures of tumescence. These results suggest that central autonomic dysfunction may be a contributing factor in the impotence of diabetic men. A metabolic disturbance in the central nervous system of diabetics which might alter both sleep and autonomic nervous system activity is proposed to explain these results and may help in the understanding of other observed abnormalities in both the sleep and autonomic dysfunction of diabetics.     

Neurophysiologic studies in Morvan syndrome.

This study was conducted to clarify the clinical and neurophysiologic characteristics of patients with Morvan syndrome, and to compare and contrast this syndrome with other forms of autoimmune encephalitis. A retrospective chart review of the clinical features and neurophysiologic studies of two cases of Morvan syndrome seen at the Mayo Clinic was performed. Neurophysiologic studies included polysomnography, comprehensive autonomic testing, MRI, positron emission tomography, EEG, and single-photon emission computed tomography. In two cases of Morvan syndrome, the clinical features, electrophysiologic findings, and immunologic studies (high levels of voltage-gated potassium channel antibodies) were consistent with previously reported findings. Several novel observations were made. Autonomic testing demonstrated peripheral autonomic neuropathy in addition to autonomic hyperactivity. Polysomnography showed complete absence of sleep. Neuroimaging study findings were largely normal. Morvan syndrome is an autoimmune disorder affecting both the peripheral and central nervous system. Neurophysiologic studies demonstrate hyperexcitability of peripheral nerves, autonomic dysfunction, and severe insomnia. The absence of abnormalities on imaging studies suggests that central nervous system symptoms are related to functional rather than structural disruption of neural networks.     

Angiotensin II-derived reactive oxygen species underpinning the processing of the cardiovascular reflexes in the medulla oblongata

The brainstem is a major site in the central nervous system involved in the processing of the cardiovascular reflexes such as the baroreflex and the peripheral chemoreflex. The nucleus tractus solitarius and the rostral ventrolateral medulla are 2 important brainstem nuclei, and they play pivotal roles in autonomic cardiovascular regulation. Angiotensin II is one of the neurotransmitters involved in the processing of the cardiovascular reflexes within the brainstem. It is well-known that one of the mechanisms by which angiotensin II exerts its effect is via the activation of pathways that generate reactive oxygen species (ROS). In the central nervous system, ROS are reported to be involved in several pathological diseases such as hypertension, heart failure and sleep apnea. However, little is known about the role of ROS in the processing of the cardiovascular reflexes within the brainstem. The present review mainly discussed some recent findings documenting a role for ROS in the processing of the baroreflex and the peripheral chemoreflex in the brainstem.     

Nocturnal body core temperature falls in Parkinson's disease but not in Multiple-System Atrophy.

OBJECTIVE: To evaluate whether the circadian rhythm of body core temperature (CRT degrees ) can differentiate Multiple-System Atrophy (MSA) from Idiopathic Parkinson's disease (IPD). METHODS: We evaluated 14 patients with probable MSA, seven with IPD, and eight controls. After a preliminary evaluation of cardiovascular autonomic function, rectal temperature and sleep-wake cycle were monitored continuously for 48 hours in a temperature-controlled room, at constant bed rest with controlled food intake and fixed light-dark schedule. RESULTS: MSA patients showed cardiovascular autonomic sympathetic and parasympathetic failure. IPD had normal cardiovascular autonomic function. A 24-hour rhythm of body core temperature (BcT degrees ) was present in all subjects. IPD had CRT degrees comparable to controls. In MSA the mesor was higher and mean BcT degrees of each hour was significantly higher from 11 p.m. to 7 a.m. The analysis of mean BcT degrees during the different sleep phases showed significantly higher values during both NREM (1--2, 3--4) and REM sleep stages in MSA. CONCLUSIONS: The physiological nocturnal fall of BcT degrees is blunted in MSA patients mainly because BcT degrees did not decrease during sleep. This CRT degrees pattern is not justified by differences in sleep structure and may reflect an impairment of central sympathetic nervous system function.     

Sleep stage transition and changes in autonomic function in newborn infants

The relationships between sleep stage, startle response, electroencephalogram (EEG) pattern, and autonomic function in sleeping full-term infants was examined. Using autoregressive analysis of heart rate variability (HRV), 12 infants at a mean post-conception age of 41.1 weeks were studied. Based on HRV characteristics, the present study shows sympathetic nervous system activation during active sleep (AS) and distinct changes in autonomic function based on the startle response and EEG features during quiet sleep (QS). The findings might reflect structural and functional maturation of the central nervous system of newborn infants.     

Multifactorial sleep disturbance in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, ranking only behind Alzheimer's disease and affecting 2% of the population over the age of 65. Pathophysiologically, PD is characterized by selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and striatal dopamine depletion. Patients may also exhibit mild-to-severe degeneration of other central and peripheral nervous tissues. The most dramatic symptoms of the disease are profound dopamine-responsive motor disturbances, including bradykinesia, akinesia, rigidity, resting tremor, and postural instability. PD patients commonly present with debilitating non-motor symptoms, including cognitive impairment, autonomic nervous system dysfunction, and sleep disturbance. Of these, sleep disturbance is the most consistently reported, and likely represents a disorder integrative of PD-related motor impairment, autonomic nervous system dysfunction, iatrogenic insult, and central neurodegeneration. The pathophysiology of PD may also indirectly disrupt sleep by increasing susceptibility to sleep disorders, including sleep disordered breathing, periodic limb movements, and REM behavior disorder. In this review, we will discuss these systems representing a multifactorial etiology in PD sleep disturbance.     

Autonomic control of circulation in fish: a comparative view

The autonomic nervous system has a central role in the control and co-ordination of the cardiovascular system in all vertebrates. In fish, which represent the largest and most diverse vertebrate group, the autonomic control of the circulation displays a vast variation with a number of interesting deviations from the typical vertebrate pattern. This diversity ranges from virtually no known nervous control of the circulation in hagfish, to a fully developed dual control from both cholinergic and adrenergic nerves in teleost, much resembling the situation found in other vertebrate groups. This review summarizes current knowledge on the role of the autonomic nervous system in the control of the cardiovascular system in fish. We set out by providing an overview of the general trends and patterns in the major fish groups, and then a summary of how the autonomic nervous control is involved in normal daily activities such as barostatic control of blood pressure, as well as adjustments of the cardiovascular system during feeding and environmental hypoxia.     

Methods of quantitative evaluation of the autonomic nerve system

Dysfunction of the autonomic nervous system is a frequent finding in many neurological and internal diseases. The quantitative assessment of cardiovascular and sudomotor function is important for diagnosing the autonomic impairment. In this review article, we focus on standard tests that allow evaluation of cardiovascular and sudomotor autonomic functions and describe methods of quantitative assessment that are better suited for research.     

Cardiac autonomic function during sleep and wakefulness in multiple sclerosis

Some studies in multiple sclerosis (MS) patients have shown evidence of autonomic dysfunction involving the cardiovascular system. However, the findings in these studies have not been completely consistent. The discrepancy may be related to the limits of the traditional autonomic tests during wakefulness. In our study, after the investigation of the cardiovascular reflexes during wakefulness, heart rate (HR) variations were considered during sleep in order to avoid the limits of cooperation and the emotional state of the patient. We evaluated tonic (vagal activity) HR modifications in relation to the deepening of sleep, as well as phasic (sympathetic activity) HR modifications in relation to spontaneous body movements during sleep, in 25 MS patients and 25 age-matched controls. No difference was found between the two groups in autonomic function during wakefulness. A reduced parasympathetic activity was observed in MS subjects during both rapid eye movement (REM) and non-REM sleep, while no difference was found in sympathetic function between patients and controls. No significant correlation was found between cardiac autonomic data during sleep and MRI lesion load in the infratentorial areas and, in particular, of the brain stem. The findings of our study suggest that autonomic nervous system evaluation during sleep could show impairment earlier than the traditional autonomic tests during wakefulness.     

The autonomic effects of deep brain stimulation--a therapeutic opportunity

Deep brain stimulation (DBS) is an expanding field in neurosurgery and has already provided important insights into the fundamental mechanisms underlying brain function. One of the most exciting emerging applications of DBS is modulation of blood pressure, respiration and micturition through its effects on the autonomic nervous system. DBS stimulation at various sites in the central autonomic network produces rapid changes in the functioning of specific organs and physiological systems that are distinct from its therapeutic effects on central nervous motor and sensory systems. For example, DBS modulates several parameters of cardiovascular function, including heart rate, blood pressure, heart rate variability, baroreceptor sensitivity and blood pressure variability. The beneficial effects of DBS also extend to improvements in lung function. This article includes an overview of the anatomy of the central autonomic network, which consists of autonomic nervous system components in the cortex, diencephalon and brainstem that project to the spinal cord or cranial nerves. The effects of DBS on physiological functioning (particularly of the cardiovascular and respiratory systems) are discussed, and the potential for these findings to be translated into therapies for patients with autonomic diseases is examined.     

Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep

This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.     

Autonomic Dysfunction in Sleep Disorders: From Neurobiological Basis to Potential Therapeutic Approaches

Sleep disorder has been portrayed as merely a common dissatisfaction with sleep quality and quantity. However, sleep disorder is actually a medical condition characterized by inconsistent sleep patterns that interfere with emotional dynamics, cognitive functioning, and even physical performance. This is consistent with sleep abnormalities being more common in patients with autonomic dysfunction than in the general population. The autonomic nervous system coordinates various visceral functions ranging from respiration to neuroendocrine secretion in order to maintain homeostasis of the body. Because the cell population and efferent signals involved in autonomic regulation are spatially adjacent to those that regulate the sleep-wake system, sleep architecture and autonomic coordination exert effects on each other, suggesting the presence of a bidirectional relationship in addition to shared pathology. The primary goal of this review is to highlight the bidirectional and shared relationship between sleep and autonomic regulation. It also introduces the effects of autonomic dysfunction on insomnia, breathing disorders, central disorders of hypersomnolence, parasomnias, and movement disorders. This information will assist clinicians in determining how neuromodulation can have the greatest therapeutic effects in patients with sleep disorders.     

Basal cardiac autonomic tone is normal in patients with periodic leg movements during sleep

The relationship between the autonomic nervous system and periodic leg movements during sleep (PLMS) is not completely understood. We aimed to determine whether patients with PLMS exhibit any changes in their basal heart rate variability (HRV), excluding episodes of leg movements and arousals. To investigate this, we conducted a cross-sectional study including 13 patients with PLMS (PLMS ≥ 20) and 13 matched controls, free of cardiovascular diseases and medications. Time-and frequency-domain HRV measures [mean R–R interval, low frequency (LF), high frequency (HF), LF/HF] were calculated across all sleep stages as well during wakefulness just before and after sleep during one-night polysomnography. We only took ECG segments of sleep without arousals and excluded periods of 30 s before and after the leg movements. No statistical differences between PLMS and control subjects were found in any of the time- or frequency-domain HRV measures across sleep stages. Basal cardiac autonomic modulation in patients with PLMS is similar to that of control subjects. Our results argue against a role for a basal disturbance of the cardiac autonomic nervous system in the pathogenesis of PLMS.     

Cardiovascular and respiratory consequences of bilateral involvement of the medullary intermediate reticular formation in syringobulbia

We studied five patients with clinical and radiological evidence of syringobulbia (SB) to determine whether the distribution of lesions in relationship to the cardiorespiratory control networks in the medullary intermediate reticular zone (IRt) correlates with the presence of abnormalities in autonomic cardiovascular and respiratory control in these patients. All patients underwent high resolution MRI to characterize the size, volume and distribution of the SB lesions, cardiovascular autonomic function testing and polysomnography. One patient with bilateral IRt involvement at both the rostral and caudal medulla had orthostatic hypotension (OH), absent HR_DB, abnormal Valsalva ratio, exaggerated fall of BP during phase II and absent phase IV during VM, and a dramatic fall of BP during head up tilt; this patient also had severe obstructive sleep apnea (OSA) and exhibited BP drops during each respiratory effort. A second patient, with bilateral IRt involvement restricted to the caudal medulla, had less severe cardiovascular autonomic dysfunction but also exhibited severe OSA. The other three patients had small SB cavities sparing the IRt and had sleep apnea but no autonomic dysfunction. Autonomic dysfunction could not be related to the size of the syrinx or the degree of atrophy in the cervical spinal cord in any of the five patients. Bilateral involvement of the IRt by SB produces cardiovascular autonomic failure and sleep apnea. In patients with more restricted lesions, autonomic and respiratory dysfunction may be dissociated. Clinico-radiological correlations using high resolution MRI assessment of medullary lesions can provide insight into the central organization of cardiovascular and respiratory control in humans. Received: 6 August 2002, Accepted: 26 September 2002 Correspondence to Dr. Martín Nogués     

Emotional and state-dependent modification of cardiorespiratory function: role of orexinergic neurons

Our daily life not only involves calm, resting states but is filled with perturbations that induce active conditions, such as movements, eating, and communicating. During such active periods, cardiorespiratory regulation must be adjusted for bodily demands, which differ from those during resting states, by modulating or resetting baseline levels. To explore neural mechanisms of state-dependent adjustments of central autonomic regulation, we recently focused on the following two states: 1), stress-induced defense (fight-or-flight) responses, because stressors induce both cognitive, emotional, and behavioral changes and autonomic alterations, and 2), sleep/wake differences. Basal respiration and respiratory reflex regulation significantly differ during waking and sleep states. In this review, we will summarize our recent findings with orexin knockout and orexin neuron-ablated mice to determine possible contributions of orexin, a hypothalamic neuropeptide, to state-dependent adjustments of central autonomic regulation. The diversity of synaptic control of cardiovascular and respiratory neurons appears to be necessary for animals to adapt to ever-changing life circumstances and behavioral states. The orexin system likely functions as one essential modulator for coordinating circuits controlling autonomic functions and behaviors.     

Epilepsy and autonomic diseases

This review article focuses on the functional anatomy of the central autonomic nervous system and the autonomic symptoms and dysfunctions occurring with epileptogenic activity involving areas of the central autonomic nervous system. Clinical experiences have demonstrated a close relation between epileptic and central autonomic activity. Autonomic symptoms are frequent signs of epileptic seizures and may cause dysfunctions in almost every organ system. Cardiorespiratory dysfunction has been described interictually. The increased frequency of sudden unexplained death in epilepsy patients may be related to disturbances in cardiac autonomic control. In contrast, electrical vagal stimulation reduces epileptogenic activity by influencing the central autonomic nervous system.     

Neuropathology of autonomic dysfunction in synucleinopathies

The synucleinopathies—Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society     

Quantitative studies of autonomic function

Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity.