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1.  Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12–18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of –20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high–frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm. Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; Baroreflex sensitivity; Chronic fatigue syndrome; Autonomic nervous system; Cardiovascular regulation
2.  Blood Pressure Variability and Closed-loop Baroreflex Assessment in Adolescent Chronic Fatigue Syndrome during Supine Rest and Orthostatic Stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS.
We included a consecutive sample of 14 adolescents 12 to 18 years old with CFS diagnosed according to a thorough and standardized set of investigations, and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of −20 mm Hg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high-frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm.
Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control.
CFS in adolescents is characterized by reduced systolic blood pressure variability, and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; baroreflex sensitivity; chronic fatigue syndrome; autonomic nervous system; cardiovascular regulation
3.  Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression 
OBJECTIVES—Patients with chronic fatigue syndrome complain of physical and mental fatigue that is worsened by exertion. It was predicted that the cognitive and motor responses to vigorous exercise in patients with chronic fatigue syndrome would differ from those in depressed and healthy controls.
METHODS—Ten patients with chronic fatigue syndrome, 10 with depressive illness, and 10 healthy controls completed cognitive and muscle strength testing before and after a treadmill exercise test. Measures of cardiovascular functioning and perceived effort, fatigue, and mood were taken during each stage of testing.
RESULTS—Depressed patients performed worst on cognitive tests at baseline. During the treadmill test, patients with chronic fatigue syndrome had higher ratings of perceived effort and fatigue than both control groups, whereas patients with depression reported lower mood. After exertion, patients with chronic fatigue syndrome showed a greater decrease than healthy controls on everyday tests of focused (p=0.02) and sustained (p=0.001) attention, as well as greater deterioration than depressed patients on the focused attention task (p=0.03). No between group differences were found in cardiovascular or symptom measures taken during the cognitive testing.
CONCLUSIONS—Patients with chronic fatigue syndrome show a specific sensitivity to the effects of exertion on effortful cognitive functioning. This occurs despite subjective and objective evidence of effort allocation in chronic fatigue syndrome, suggesting that patients have reduced working memory capacity, or a greater demand to monitor cognitive processes, or both. Further insight into the pathophysiology of the core complaints in chronic fatigue syndrome is likely to be realised by studying the effects of exercise on other aspects of everyday functioning.


PMCID: PMC2170292  PMID: 9771781
4.  Differences in cardiovascular responses to supine exercise and to standing after exercise in two clinical subgroups of Shy-Drager syndrome (multiple system atrophy). 
BACKGROUND: In chronic autonomic failure of varying aetiologies, there are differences in the cardiovascular responses to supine leg exercise and to standing after exercise. Whether this occurs between the different subgroups with Shy-Drager syndrome (SDS) is unknown. METHODS: Fourteen patients with the cerebellar form (SDS-C) and 11 patients with parkinsonian features (SDS-P) were studied. RESULTS: Both groups had a similar degree of autonomic failure and postural hypotension. Their responses were compared with nine patients with idiopathic Parkinson's disease (IPD) and 15 normal subjects (controls), all with normal autonomic function. With supine exercise, blood pressure and heart rate rose similarly in controls and patients with IPD and there was no fall in blood pressure on standing after exercise. In both SDS groups there were abnormal responses to exercise: blood pressure fell in SDS-C, but did not fall or rise in SDS-P. Heart rate increased similarly in both SDS groups, calculated systemic vascular resistance fell similarly, but cardiac index rose more in SDS-P than SDS-C. Resting plasma noradrenaline concentrations were subnormal in both forms of SDS, and did not increase with exercise. Postural hypotension was enhanced after exercise to the same extent in SDS-C and SDS-P. CONCLUSIONS: The greater cardiovascular abnormalities in response to exercise in SDS-C suggests that cerebellar or brain stem autonomic pathways are impaired to a greater extent in SDS-C than in SDS-P. Pooling SDS subgroups, therefore, may obscure pathophysiological differences to certain stimuli. Clinically when postural hypotension is being assessed, separation of the subgroups may not be essential, as they responded similarly.
Images
PMCID: PMC486554  PMID: 8795602
5.  A Randomized Controlled Trial on the Effects of Yoga on Stress Reactivity in 6th Grade Students 
There is an increasing interest in developing school programs that improve the ability of children to cope with psychosocial stress. Yoga may be an appropriate intervention as it has demonstrated improvements in the ability of children to manage psychosocial stress. Yoga is thought to improve the control of reactivity to stress via the regulation of the autonomic nervous system. The current study examined the effects of yoga compared to a physical education class on physiological response (blood pressure (BP) and heart rate (HR)) to behavioral stressor tasks (mental arithmetic and mirror tracing tasks). Data analysis of BP and HR was performed using a 2 × 2 × 4 repeated measures ANOVA (time × group × stressor time points). 30 (17 male) 6th graders participated in the study. Yoga did not provide significant differences in stress reactivity compared to a physical education class (group × time: systolic (F(1,28) = .538, P = .470); diastolic (F(1,28) = .1.061, P = .312); HR (F(1,28) = .401, P = .532)). The lack of significant differences may be due to the yoga intervention failing to focus on stress management and/or the stressor tasks not adequately capturing attenuation of stressor response.
doi:10.1155/2013/607134
PMCID: PMC3572691  PMID: 23431341
6.  QT interval and dispersion in primary autonomic failure. 
Heart  1996;75(5):498-501.
OBJECTIVE: To investigate the role of the autonomic nervous system in determining QT interval and dispersion. PATIENTS AND METHODS: 32 patients with chronic primary (idiopathic) autonomic failure (19 men, mean age 60 years) and 21 normal controls (11 men, mean age 59) without symptoms of ischaemic heart disease were studied retrospectively. Autonomic failure was diagnosed by a combination of symptomatic postural hypotension, subnormal plasma noradrenaline response to head-up tilt, and abnormal cardiovascular responses to standing, Valsalva manoeuvre, mental stress, cutaneous cold, isometric exercise, and deep breathing. QT intervals were measured from surface electrocardiograms and QT dispersion was defined as maximum QT--minimum QT occurring in any of the 12 leads. RESULTS: Mean heart rate (RR intervals) was similar in patients with autonomic failure and controls (S2 lead: 865 (132) v 857 (108) ms, P = NS; V2 lead: 865 (130) v 868 (113) ms, P = NS). QT intervals measured from electrocardiogram leads S2 and V2 were significantly longer in patients than in controls (401 (40) v 376 (16) ms, P < 0.01; and 403 (41) v 381 (20) ms, P < 0.05 respectively). The mean maximum QT interval in any lead, which is the best estimate of the maximum duration of electrical systole, was significantly longer in the patients than in controls (417 (48) v 388 (23) ms, P < 0.005). Linear regression analysis of QT and RR intervals for both groups showed a significant difference between the slopes of the two regression lines (F = 8.4, P < 0.001). However, QT dispersions were similar between patients and controls. CONCLUSIONS: Patients with primary autonomic failure have prolongation of QT intervals, indicating that the autonomic nervous system is an important determinant of QT interval. However, QT dispersion does not seem to be affected by chronic primary autonomic denervation.
PMCID: PMC484349  PMID: 8665344
7.  Early atherosclerosis and cardiac autonomic responses to mental stress: a population-based study of the moderating influence of impaired endothelial function 
Background
Acute mental stress may contribute to the cardiovascular disease progression via autonomic nervous system controlled negative effects on the endothelium. The joint effects of stress-induced sympathetic or parasympathetic activity and endothelial function on atherosclerosis development have not been investigated. The present study aims to examine the interactive effect of acute mental stress-induced cardiac reactivity/recovery and endothelial function on the prevalence of carotid atherosclerosis.
Methods
Participants were 81 healthy young adults aged 24-39 years. Preclinical atherosclerosis was assessed by carotid intima-media thickness (IMT) and endothelial function was measured as flow-mediated dilatation (FMD) using ultrasound techniques. We also measured heart rate, respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP) in response to the mental arithmetic and speech tasks.
Results
We found a significant interaction of FMD and cardiac RSA recovery for IMT (p = 0.037), and a significant interaction of FMD and PEP recovery for IMT (p = 0.006). Among participants with low FMD, slower PEP recovery was related to higher IMT. Among individuals with high FMD, slow RSA recovery predicted higher IMT. No significant interactions of FMD and cardiac reactivity for IMT were found.
Conclusions
Cardiac recovery plays a role in atherosclerosis development in persons with high and low FMD. The role of sympathetically mediated cardiac activity seems to be more important in those with impaired FMD, and parasympathetically mediated in those with relatively high FMD. The development of endothelial dysfunction may be one possible mechanism linking slow cardiac recovery and atherosclerosis via autonomic nervous system mediated effect.
doi:10.1186/1471-2261-10-16
PMCID: PMC2862016  PMID: 20350311
8.  Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome 
PLoS ONE  2012;7(11):e49518.
Background
Cognitive difficulties and autonomic dysfunction have been reported separately in patients with chronic fatigue syndrome (CFS). A role for heart rate variability (HRV) in cognitive flexibility has been demonstrated in healthy individuals, but this relationship has not as yet been examined in CFS. The objective of this study was to examine the relationship between HRV and cognitive performance in patients with CFS.
Methods
Participants were 30 patients with CFS and 40 healthy controls; the groups were matched for age, sex, education, body mass index, and hours of moderate exercise/week. Questionnaires were used to obtain relevant medical and demographic information, and assess current symptoms and functional impairment. Electrocardiograms, perceived fatigue/effort and performance data were recorded during cognitive tasks. Between–group differences in autonomic reactivity and associations with cognitive performance were analysed.
Results
Patients with CFS showed no deficits in performance accuracy, but were significantly slower than healthy controls. CFS was further characterized by low and unresponsive HRV; greater heart rate (HR) reactivity and prolonged HR-recovery after cognitive challenge. Fatigue levels, perceived effort and distress did not affect cognitive performance. HRV was consistently associated with performance indices and significantly predicted variance in cognitive outcomes.
Conclusions
These findings reveal for the first time an association between reduced cardiac vagal tone and cognitive impairment in CFS and confirm previous reports of diminished vagal activity.
doi:10.1371/journal.pone.0049518
PMCID: PMC3498107  PMID: 23166694
9.  Strength and physiological response to exercise in patients with chronic fatigue syndrome 
OBJECTIVE—To measure strength, aerobic exercise capacity and efficiency, and functional incapacity in patients with chronic fatigue syndrome (CFS) who do not have a current psychiatric disorder.
METHODS—Sixty six patients with CFS without a current psychiatric disorder, 30 healthy but sedentary controls, and 15 patients with a current major depressive disorder were recruited into the study. Exercise capacity and efficiency were assessed by monitoring peak and submaximal oxygen uptake, heart rate, blood lactate, duration of exercise, and perceived exertion during a treadmill walking test. Strength was measured using twitch interpolated voluntary isometric quadriceps contractions. Symptomatic measures included physical and mental fatigue, mood, sleep, somatic amplification, and functional incapacity.
RESULTS—Compared with sedentary controls, patients with CFS were physically weaker, had a significantly reduced exercise capacity, and perceived greater effort during exercise, but were equally unfit. Compared with depressed controls, patients with CFS had significantly higher submaximal oxygen uptakes during exercise, were weaker, and perceived greater physical fatigue and incapacity. Multiple regression models suggested that exercise incapacity in CFS was related to quadriceps muscle weakness, increased cardiovascular response to exercise, and body mass index. The best model of the increased exercise capacity found after graded exercise therapy consisted of a reduction in submaximal heart rate response to exercise.
CONCLUSIONS—Patients with CFS were weaker than sedentary and depressed controls and as unfit as sedentary controls. Low exercise capacity in patients with CFS was related to quadriceps muscle weakness, low physical fitness, and a high body mass ratio. Improved physical fitness after treatment was associated with increased exercise capacity. These data imply that physical deconditioning helps to maintain physical disability in CFS and that a treatment designed to reverse deconditioning helps to improve physical function.


doi:10.1136/jnnp.69.3.302
PMCID: PMC1737090  PMID: 10945803
10.  Discrete and Effortful Imagined Movements Do Not Specifically Activate the Autonomic Nervous System 
PLoS ONE  2009;4(8):e6769.
Background
The autonomic nervous system (ANS) is activated in parallel with the motor system during cyclical and effortful imagined actions. However, it is not clear whether the ANS is activated during motor imagery of discrete movements and whether this activation is specific to the movement being imagined. Here, we explored these topics by studying the baroreflex control of the cardiovascular system.
Methodology/Principal Findings
Arterial pressure and heart rate were recorded in ten subjects who executed or imagined trunk or leg movements against gravity. Trunk and leg movements result in different physiological reactions (orthostatic hypotension phenomenon) when they are executed. Interestingly, ANS activation significantly, but similarly, increased during imagined trunk and leg movements. Furthermore, we did not observe any physiological modulation during a control mental-arithmetic task or during motor imagery of effortless movements (horizontal wrist displacements).
Conclusions/Significance
We concluded that ANS activation during motor imagery is general and not specific and physiologically prepares the organism for the upcoming effortful action.
doi:10.1371/journal.pone.0006769
PMCID: PMC2728546  PMID: 19707571
11.  Stress Response and the Adolescent Transition: Performance versus Peer Rejection Stressors 
Little is known about normative variation in stress response over the adolescent transition. This study examined neuroendocrine and cardiovascular responses to performance and peer rejection stressors over the adolescent transition in a normative sample. Participants were 82 healthy children (ages 7-12 years, n=39, 22 females) and adolescents (ages 13-17, n=43, 20 females) recruited through community postings. Following a habituation session, participants completed a performance (public speaking, mental arithmetic, mirror tracing) or peer rejection (exclusion challenges) stress session. Salivary cortisol, alpha amylase (sAA), systolic and diastolic blood pressure (SBP, DBP), and heart rate (HR) were measured throughout. Adolescents showed significantly greater cortisol, sAA, SBP and DBP stress response relative to children. Developmental differences were most pronounced in the performance stress session for cortisol and DBP, and in the peer rejection session for sAA and SBP. Heightened physiological stress responses in typical adolescents may facilitate adaptation to new challenges of adolescence and adulthood. In high-risk adolescents, this normative shift may tip the balance toward stress response dysregulation associated with depression and other psychopathology. Specificity of physiological response by stressor type highlights the importance of a multi-system approach to the psychobiology of stress and may also have implications for understanding trajectories to psychopathology.
doi:10.1017/S0954579409000042
PMCID: PMC2700625  PMID: 19144222
adolescent; child; stress; cortisol; cardiovascular; amylase; depression
12.  Cardiovascular responses to cognitive stress in patients with migraine and tension-type headache 
BMC Neurology  2007;7:23.
Background
The purpose of this study was to investigate the temporal relationship between autonomic changes and pain activation in migraine and tension-type headache induced by stress in a model relevant for everyday office-work.
Methods
We measured pain, blood pressure (BP), heart rate (HR) and skin blood flow (BF) during and after controlled low-grade cognitive stress in 22 migraineurs during headache-free periods, 18 patients with tension-type headache (TTH) and 44 healthy controls. The stress lasted for one hour and was followed by 30 minutes of relaxation.
Results
Cardiovascular responses to cognitive stress in migraine did not differ from those in control subjects. In TTH patients HR was maintained during stress, whereas it decreased for migraineurs and controls. A trend towards a delayed systolic BP response during stress was also observed in TTH. Finger BF recovery was delayed after stress and stress-induced pain was associated with less vasoconstriction in TTH during recovery.
Conclusion
It is hypothesized that TTH patients have different stress adaptive mechanisms than controls and migraineurs, involving delayed cardiovascular adaptation and reduced pain control system inhibition.
doi:10.1186/1471-2377-7-23
PMCID: PMC2048502  PMID: 17683636
13.  Spectral analysis of heart rate and blood pressure variability in primary Sjögren's syndrome 
Annals of the Rheumatic Diseases  2002;61(3):232-236.
Background: Autonomic dysfunction has been described in primary Sjögren's syndrome (SS).
Objective: To investigate the circulatory autonomic regulation in patients with primary SS by power spectral analysis of heart rate and blood pressure variability.
Methods: Forty three (42 female) patients with primary SS, mean age 52 years (range 23–80), with a mean disease duration of eight years (range 1–30) and 30 (15 female) healthy controls, mean age 43 years (range 21–68) were studied. In each patient blood pressure, heart rate, and respiration were measured continuously during supine rest and orthostatic challenge (60° head-up tilt). Power spectral analysis was performed to determine possible differences in short term sympathetic and parasympathetic autonomic regulation between patients and controls. Furthermore, spectral parameters were studied in relation to illness severity and disease duration of the patients with primary SS.
Results: After controlling for differences in age, heart rate variability of the mid-frequency band and the variation coefficient of systolic blood pressure were significantly lower in patients with primary SS than in controls during supine rest. During 60° tilt patients with primary SS showed a significantly higher mean heart rate, mean systolic blood pressure, and variation coefficient of diastolic blood pressure, and a significantly lower baroreflex index than controls. After controlling for age, no differences were found either in heart rate variability, blood pressure results, and baroreflex sensitivity during supine rest and tilt between the subgroups divided according to disease duration, Schirmer test results, or between the subgroups with different fatigue scores. No differences were found in spectral data between the groups with and without positive antinuclear antibody serology.
Conclusion: For the group no differences in sympathetic and parasympathetic cardiac control were seen between patients with primary SS and controls, as assessed by spectral techniques, although some cardiovascular differences were found, particularly during orthostatic challenge.
doi:10.1136/ard.61.3.232
PMCID: PMC1754013  PMID: 11830428
14.  Physiological differences between burnout patients and healthy controls: blood pressure, heart rate, and cortisol responses 
Occupational and Environmental Medicine  2003;60(Suppl 1):i54-i61.
Objectives: To investigate differences between burnout patients and healthy controls regarding basal physiological values and physiological stress responses. Measures of the sympathetic-adrenergic-medullary (SAM) axis and the hypothalamic-pituitary-adrenal (HPA) axis were examined.
Methods: SAM axis and HPA axis activity was compared between 22 burnout patients and 23 healthy controls. SAM axis activity was measured by means of heart rate (HR) and blood pressure (BP). HPA axis activity was investigated by means of salivary cortisol levels. Resting levels of HR, BP, and cortisol were determined as well as reactivity and recovery of these measures during a laboratory session involving mental arithmetic and speech tasks. In addition, morning levels of cortisol were determined.
Results: Burnout patients showed higher resting HR than healthy controls. BP resting values did not differ between burnout patients and healthy controls, nor did cardiovascular reactivity and recovery measurements during the laboratory session. Basal cortisol levels and cortisol reactivity and recovery measures were similar for burnout patients and healthy controls. However, burnout patients showed elevated cortisol levels during the first hour after awakening in comparison to healthy controls.
Conclusions: The findings provided limited proof that SAM axis and HPA axis are disturbed among burnout patients. Elevated HR and elevated early morning cortisol levels may be indicative of sustained activation.
doi:10.1136/oem.60.suppl_1.i54
PMCID: PMC1765727  PMID: 12782748
15.  Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia Syndrome 
Journal of internal medicine  2011;271(1):64-81.
Objectives
To determine mRNA expression differences in genes involved in signaling and modulating sensory fatigue, and muscle pain in patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia Syndrome (FM) at baseline, and following moderate exercise.
Design
Forty eight Patients with CFS-only, or CFS with comorbid FM, 18 Patients with FM that did not meet criteria for CFS, and 49 healthy Controls underwent moderate exercise (25 minutes at 70% maximum age predicted heart-rate). Visual-analogue measures of fatigue and pain were taken before, during, and after exercise. Blood samples were taken before, and 0.5, 8, 24, and 48 hours after exercise. Leukocytes were immediately isolated from blood, number coded for blind processing and analyses, and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic, and immune functions was compared between groups at baseline, and following exercise. Changes in amounts of mRNA were correlated with behavioral measures, and functional clinical assessments.
Results
No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor’s transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM only patients showed no post-exercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than Controls.
Conclusions
At least two subgroups of CFS patients can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the CFS patients with orthostatic intolerance, showed no post-exercise increases in any gene, and was defined by decreases in mRNA for α-2A. FM only patients can be identified by baseline increases in 3 genes. Post-exercise increases for 4 genes meet published criteria as an objective biomarker for CFS, and could be useful in guiding treatment selection for different subgroups.
doi:10.1111/j.1365-2796.2011.02405.x
PMCID: PMC3175315  PMID: 21615807
chronic fatigue syndrome; fatigue; orthostatic symptoms; autonomic dysfunction; gene expression; fibromyalgia
16.  Autonomic imbalance: prophet of doom or scope for hope? 
Diabetic Medicine  2011;28(6):643-651.
It has long been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity and mortality can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function. New and emerging syndromes include orthostatic tachycardia, orthostatic bradycardia and an inability to use heart rate as a guide to exercise intensity because of the resting tachycardia. Recent studies have shown that autonomic imbalance may be a predictor of risk of sudden death with intensification of glycaemic control. This review examines an association of autonomic dysregulation and the role of inflammatory cytokines and adipocytokines that promote cardiovascular risk. In addition, conditions of autonomic imbalance associated with cardiovascular risk are discussed. Potential treatment for restoration of autonomic balance is outlined.
doi:10.1111/j.1464-5491.2010.03184.x
PMCID: PMC3123705  PMID: 21569084
17.  The Postural Tachycardia Syndrome (POTS): Pathophysiology, Diagnosis & Management 
Postural tachycardia syndrome (POTS), characterized by orthostatic tachycardia in the absence of orthostatic hypotension, has been the focus of increasing clinical interest over the last 15 years 1. Patients with POTS complain of symptoms of tachycardia, exercise intolerance, lightheadedness, extreme fatigue, headache and mental clouding. Patients with POTS demonstrate a heart rate increase of ≥30 bpm with prolonged standing (5-30 minutes), often have high levels of upright plasma norepinephrine (reflecting sympathetic nervous system activation), and many patients have a low blood volume. POTS can be associated with a high degree of functional disability. Therapies aimed at correcting the hypovolemia and the autonomic imbalance may help relieve the severity of the symptoms. This review outlines the present understanding of the pathophysiology, diagnosis, and management of POTS.
PMCID: PMC1501099  PMID: 16943900
Postural Tachycardia Syndrome; Pathophysiology; Diagnosis; Management
18.  Autonomic dysfunction in dementia 
Background
There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).
Aims
To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification.
Results
There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p<0.001) and AD (all p<0.03). DLB showed impairment of parasympathetic function (all p<0.05) and one of the sympathetic tests in comparison with controls (orthostasis; p = 0.02). PDD had significantly more impairment than DLB in some autonomic parameters (Valsalva ratio: p = 0.024; response to isometric exercise: p = 0.002). Patients with VAD showed impairment in two parasympathetic tests (orthostasis: p = 0.02; Valsalva ratio: p = 0.08) and one sympathetic test (orthostasis: p = 0.04). These results were in contrast with AD patients who only showed impairment in one sympathetic response (orthostasis: p = 0.004). The prevalence of orthostatic hypotension and autonomic neuropathies was higher in all dementias than in controls (all p<0.05).
Conclusion
Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications.
doi:10.1136/jnnp.2006.102343
PMCID: PMC2117678  PMID: 17178816
19.  Lifetime Adversity Leads to Blunted Stress Axis Reactivity: Studies from the Oklahoma Family Health Patterns Project 
Biological Psychiatry  2011;71(4):344-349.
Background
Can stressful events in early life alter the response characteristics of the human stress axis? Individual differences in stress reactivity are considered potentially important in long-term health and disease, however little is known about the sources of these individual differences. We present evidence that adverse experience in childhood and adolescence can alter core components of the stress axis, including cortisol and heart rate reactivity.
Methods
We exposed 354 healthy young adults (196 women) to public speaking and mental arithmetic stressors in the laboratory. Stress responses were indexed by self-report, heart rate, and cortisol levels relative to measures on a nonstress control day. Subjects were grouped into those who had experienced 0, 1, or 2 or more significant adverse life events including Physical or Sexual Adversity (mugged, threatened with a weapon, experienced a break-in or robbery; or raped or sexually assaulted by a relative or nonrelative) or Emotional Adversity (separation from biological mother or father for at least 6 months prior to age 15).
Results
Experience of adversity predicted smaller heart rate and cortisol responses to the stressors in a dose-dependent fashion (0 > 1 > 2 or more events; (Fs = 5.79 and 8.11, ps < .004) for both men and women. This was not explained by differences in socioeconomic status, the underlying cortisol diurnal cycle, or subjective experience during the stress procedure.
Conclusion
The results indicate a long-term impact of stressful life experience on the reactivity of the human stress axis.
doi:10.1016/j.biopsych.2011.10.018
PMCID: PMC3264696  PMID: 22112928
gender; heart rate; cortisol; stress reactivity; lifetime adversity; mental stress
20.  The effects of water ingestion on orthostatic hypotension in two groups of chronic autonomic failure: multiple system atrophy and pure autonomic failure 
Background: Oral ingestion of water increases seated blood pressure in patients with chronic autonomic failure by mechanisms that remain unclear. As orthostatic hypotension is common in chronic autonomic failure, and is not always adequately controlled by medication, the potential benefits of water ingestion on standing blood pressure were studied in two types of autonomic failure: multiple system atrophy (MSA), in which the lesion is central and pre-ganglionic, and pure autonomic failure (PAF), in which the lesion is post-ganglionic.
Methods: In 14 patients with autonomic failure (seven PAF and seven MSA) standing blood pressure and heart rate were measured before, and 15 and 35 minutes after ingestion of 480 ml distilled water. Patients remained seated for 15 minutes after water ingestion, with beat to beat cardiovascular indices measured with the Portapres II device with subsequent Modelflow analysis.
Results: Standing prior to water ingestion caused a significant fall in blood pressure in all patients. After water ingestion there was a rise in seated blood pressure. Seated and standing blood pressure at 15 and 35 minutes after water ingestion was significantly higher than before water, with an improvement in orthostatic symptoms. The time to first significant rise in seated blood pressure occurred at 5 minutes post water ingestion in PAF and at 13 minutes in MSA. These increases were accompanied by increases in total peripheral resistance, reaching significance by 5 minutes in PAF and 13 minutes in MSA. There were no significant changes in cardiac output, stroke volume, or ejection fraction.
Conclusions: Water is thus beneficial in improving standing BP in AF, acting within 15 minutes in both MSA and PAF. The earlier onset of the pressor effect in PAF may reflect the differing lesion site and underlying pathophysiology between these conditions.
doi:10.1136/jnnp.2004.038471
PMCID: PMC1738857  PMID: 15548493
21.  Cardiovascular tests of autonomic function and sympathetic skin responses in patients with major depression. 
To assess the function of the autonomic nervous system in major depression, a series of cardiovascular tests, together with the recording of sympathetic skin response, were performed in 18 depressed patients (melancholic type, DSM-III-R criteria) and in 18 healthy control subjects. Depressed patients showed significantly poorer performance in Valsalva's, deep breathing, and lying to standing manoeuvres than controls, indicating an impairment of parasympathetic function. Depressed patients developed a significantly larger sympathetic skin response than controls during the lying to standing and hand grip manoeuvres, whereas cardiovascular sympathetic performance (as assessed by the responses to hand grip, cold, mental arithmetic, explosive sound, or hyperventilation) was similar in both groups. The results are compatible with the view that a diminished parasympathetic reactivity, and presumably an increased sympathetic reactivity, occur in patients with major depression.
PMCID: PMC486034  PMID: 7673960
22.  Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome 
CFS (chronic fatigue syndrome) is commonly co-morbid with POTS (postural tachycardia syndrome). Individuals with CFS/POTS experience unrelenting fatigue, tachycardia during orthostatic stress and ill-defined neurocognitive impairment, often described as ‘mental fog’. We hypothesized that orthostatic stress causes neurocognitive impairment in CFS/POTS related to decreased CBFV (cerebral blood flow velocity). A total of 16 CFS/POTS and 20 control subjects underwent graded tilt table testing (at 0, 15, 30, 45, 60 and 75°) with continuous cardiovascular, cerebrovascular, and respiratory monitoring and neurocognitive testing using an n-back task at each angle. The n-back task tests working memory, concentration, attention and information processing. The n-back task imposes increasing cognitive challenge with escalating (0-, 1-, 2-, 3- and 4-back) difficulty levels. Subject dropout due to orthostatic presyncope at each angle was similar between groups. There were no n-back accuracy or RT (reaction time) differences between groups while supine. CFS/POTS subjects responded less correctly during the n-back task test and had greater nRT (normalized RT) at 45, 60 and 75°. Furthermore, at 75° CFS/POTS subjects responded less correctly and had greater nRT than controls during the 2-, 3- and 4-back tests. Changes in CBFV were not different between the groups and were not associated with n-back task test scores. Thus we conclude that increasing orthostatic stress combined with a cognitive challenge impairs the neurocognitive abilities of working memory, accuracy and information processing in CFS/POTS, but that this is not related to changes in CBFV. Individuals with CFS/POTS should be aware that orthostatic stress may impair their neurocognitive abilities.
doi:10.1042/CS20110241
PMCID: PMC3368269  PMID: 21919887
cerebral blood flow; chronic fatigue syndrome (CFS); graded tilt testing; neurocognition; orthostatic stress; postural tachycardia syndrome (POTS)
23.  Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome 
Heart  2001;86(1):39-44.
OBJECTIVE—To study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients.
DESIGN—Case-control study.
MAIN OUTCOME MEASURES—QT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored.
PATIENTS—16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects.
INTERVENTIONS—Three types of mental stress tests and a submaximal exercise stress test.
RESULTS—Heart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms), and LQT2 patients (-30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress.
CONCLUSIONS—QT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.


Keywords: exercise; long QT syndrome; mental stress; potassium channel
doi:10.1136/heart.86.1.39
PMCID: PMC1729799  PMID: 11410559
24.  Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects 
BMC Physiology  2005;5:5.
Background
Chronic fatigue syndrome (CFS) is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge.
Results
Women with CFS and healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum workload. Blood was obtained before and after the challenge, total RNA was extracted from mononuclear cells, and signal intensity of the labeled cDNA hybridized to a 3800-gene oligonucleotide microarray was measured. We identified differences in gene expression among and between subject groups before and after exercise challenge and evaluated differences in terms of Gene Ontology categories.
Exercise-responsive genes differed between CFS patients and controls. These were in genes classified in chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport, and G protein-coupled receptor ontologies. Differences in ion transport and ion channel activity were evident at baseline and were exaggerated after exercise, as evidenced by greater numbers of differentially expressed genes in these molecular functions.
Conclusion
These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.
doi:10.1186/1472-6793-5-5
PMCID: PMC1079885  PMID: 15790422
25.  Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics 
BMC Medicine  2013;11:205.
Background
‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.
Discussion
There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.
Summary
This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.
doi:10.1186/1741-7015-11-205
PMCID: PMC3847236  PMID: 24229326
Encephalomyelitis disseminata; Myalgic encephalomyelitis; Chronic fatigue syndrome; Inflammation; Autoimmunity; Oxidative and nitrosative stress; Mitochondria

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