Brain Systems for Baroreflex Suppression During Stress in Humans

studies using a variety of methods (transcranial Doppler ultrasonography,133Xe inhalation, and single-photon emission computerized tomography) have shown a reduction (∼10–20%) in cerebral blood flow (CBF) during non-rapid-eye-movement (NREM) sleep and an increase (∼20–35%) during rapid-eye-

the benefits of exercise and exercise training are numerous, varying from increasing skeletal muscle strength to enhancing cardiovascular and respiratory fitness. These attributes of exercise are key elements to the maintenance of good health and the improvement of athletic performance. But are

Introduction Hypertension is a major contributing factor for heart disease, with nearly half of US adults meeting criteria. While studies have begun to examine the relationship between insomnia and blood pressure (BP), little is still known regarding the relationship between daily fluctuations in sleep and BP. This study aimed to provide further clarification on the role insomnia plays in the development of hypertension, including the impact that daily fluctuations in sleep have on fluctuations in BP. Methods Participants included 61 adults from the greater Northwest Arkansas area (63.9% White, 67.2% Female, 30-79 y) who completed 10 consecutive days of sleep and blood pressure monitoring. Insomnia status was determined by an Insomnia Severity Index (ISI) score of 8 or higher. Sleep was assessed objectively through actigraphy and subjectively through sleep diaries. BP was measured during the morning and evening using an ambulatory BP monitor. Variables examined included actigraphy and diary based total sleep time (TST), total wake time (TWT), and sleep efficiency (SE), as well as morning, evening, and daily systolic and diastolic BP. A series of multiple regressions were used to examine differences in BP between those with and without insomnia. Mixed effects models were used to explore the relationship between deviations in sleep and BP. Results Insomnia status was not found to be associated with average systolic or diastolic BP in the morning (β = 0.09, p = 0.44, β = 0.07, p =0.51), evening (β = 0.15, p = 0.20, β = 0.13, p =0.25), or daily (β = 0.12, p =0.28, β = 0.10, p =0.35). Decreases in actigraphy derived TST were associated with increased next day morning systolic (β = -0.01, p < 0.01) and diastolic (β = -0.01, p = 0.02) BP when controlling for TWT. Conclusion The results of this study did not show support for insomnia serving as a predictor for hypertension. However, a nightly increase of total sleep time significantly decreased morning BP on the following day. Additional analyses will further dissect the association between daily fluctuations in sleep and BP. Support (if any) Graduate-Professional Student Congress Tiffany Marcantonio Research Grant

Cardiovascular Responses in Turkeys as Affected by Diurnal Variation and Stressors

Both human and animal studies have shown that obstructive sleep apnea (OSA) is associated with a rise in systemic blood pressure (BP). OSA-related hypertension is thought to result from a combination of several mechanisms, mainly centering on hypoxia and arousal. However, the following question remains: between hypoxia and arousal, which one is primarily responsible for BP changes in patients with OSA? Numerous studies have attempted to examine this question, but there are conflicting data for delineating more significant mechanisms accounting for the OSA–hypertension relationship. Nevertheless, episodic hypoxia as an etiological mechanism in the OSA–hypertension relationship is gaining further support. I read with great interest the recently published article by Hu et al. (1). In this study of 1,370 male patients with OSA, the association between systolic BP (SBP), diastolic BP (DBP), glucose, lipids, apnea–hypopnea index, oxygen desaturation index, and arousal index was evaluated after adjustment for BMI and waist and hip circumference. Their data suggest that DBP, but not SBP, is associated with the exacerbation of apnea–hypopnea, hypoxemia, and arousal, independent of obesity and other risk factors. I have some concerns regarding the article and proper clinical explanations. There is some evidence that repetitive arousals (RA) result in elevation of DBP without significant change in SBP (2). Elevation of DBP is typically considered as an increase in peripheral resistance, which is mainly produced by small arterioles, whereas resistance in the conductance vessels is predominantly responsible for SBP elevation. A rise in DBP without SBP rising proposes a more prominent impact of RA on peripheral vessels, rather than on the moderate to large vessels. Increase in peripheral arterial resistance induced by RA may be associated with sympathetic activation (2). RA during sleep are commonly accompanied by brief bursts of sympathetic vasoconstriction and transient increases in heart rate (HR) and BP, and it appears that this remains long after the HR and BP return to baseline (3). Furthermore, one of the main factors affecting BP fluctuation by change in arousal intensity and frequency is sleep stages. Elderly individuals, because of having less stage N3, more stage N1 sleep, and more arousals, are less likely to show the predictable nocturnal BP dipping (4). Different sleep stages are related to variations in the neuroendocrine and autonomic systems that control BP. Slow-wave sleep (N3 sleep) or “deep sleep” is described as decreased sympathetic tone, increased vagal tone, and subsequently reduced HR and BP. Lower N3 sleep is an independent predictor of incident hypertension, and experimental studies of N3-sleep suppression provide support for a role of N3 sleep in nocturnal BP fluctuations (3). Interestingly, in middle-aged males with hypertension, the percentage of N1 is positively related to 24-hour and diurnal DBP variability, without significant effects on SBP variability. N1 sleep is the switch from wakefulness to other sleep stages or following arousal during sleep. A higher N1 percentage represents more wakefulness, arousal, sleep fragmentation, and sympathetic activation during sleep. Sleep architecture could add important clinical information about BP fluctuation in OSA-related hypertension (5).

In familial dysautonomia (FD), cerebral autoregulation (CA) must adjust cerebral blood flow to extreme and rapid fluctuations in systemic blood pressure. Compromised CA during systemic blood pressure (BP) fluctuations might contribute to central autonomic dysfunction in FD. To evaluate CA during rapid BP changes, we monitored heart rate (HR), radial artery BP and middle cerebral artery blood flow velocity (CBFV), using transcranial Doppler sonography, in eight FD patients and twelve age-matched controls in supine position at baseline and during a Valsalva maneuver (VM, 40 mmHg expiratory pressure for 15 seconds). The best of four VM recordings was analyzed. We calculated two autoregulation parameters. CA(II) reflects BP related autoregulatory CBFV increase in late phase II of VM. CA(II) = [(CBFV(II late)-CBFV(II early))/CBFV(II early)]/[(BP(II late)-BP(II early))/BP(II early)]. CA(IV) reflects BP and HR related autoregulatory CBFV increase in phase IV of VM. CA(IV) = (CBFV(IV)/CBFV(I))/(BP(IV)/BP(I))/(HR(IV)/HR(I)). Baseline systemic BP, but not CBFV, was higher in the patients than the controls. During VM, both groups had similar CBFV and BP values, but CAIV and especially CA(II) were significantly lower in the patients than the controls. We have documented that FD patients maintain stable CBFV during rapid BP fluctuations associated with early and late phase II and phase IV of VM suggesting that small intracerebral vessels of FD patients are less responsive to rapid systemic blood pressure fluctuations. To compensate for decreased sympathetic vascular innervation, we propose that FD patients may alter the myogenic component of CA by vessel wall thickening resulting in increased rigidity of intracerebral resistance vessels. The resulting vasoconstriction would allow maintenance of normal baseline CBFV in spite of chronic recumbent hypertension.

This study examined the influence of electroencephalographic (EEG) arousal on the magnitude and morphology of the pressor response to Cheyne-Stokes respiration (CSR) in subjects with congestive heart failure (CHF). Thirteen subjects with stable CHF (left ventricular ejection fraction, 26 +/- 7%) and CSR (apnea-hypopnea index 52 +/- 15 h(-1)) underwent overnight polysomnography with beat-to-beat measurement of systemic arterial blood pressure (BP). CSR events were divided into those with or without an EEG arousal defined according to the criteria of the American Sleep Disorders Association. The pressor response was quantified in terms of the delta BP change (difference between the minimum BP during apnea and maximum BP during hyperpnea). Changes in the morphology of the pressor response were assessed by subdividing individual respiratory events into six periods (three during apnea: A1, A2, A3; and three during hyperpnea: H1, H2, H3). Considerable fluctuations in BP and heart rate (HR) were observed across the CSR cycle (delta mean BP 20.2 +/- 6.5 mmHg). The presence of an EEG arousal did not alter the amplitude of fluctuations in BP. Mean blood pressure (MBP) increased 21.0 +/- 7.5 mmHg with arousal versus 19.3 +/- 5.8 mmHg without arousal (NS). A repeated measures ANOVA showed no significant interaction between the presence of arousal and the proportional change in mean BP across the six periods, indicating that an EEG arousal had no effect on the morphology of MBP change during CSR [F(5,60) = 1.44, P = 0.22]. This study showed that EEG-defined arousal does not amplify the pressor response to CSR in CHF.

We investigated the hypothesis that beat-to-beat variability in hemodynamic parameters reflects the dynamic interplay between ongoing perturbations to circulatory function and the compensatory response of short-term cardiovascular control systems. Spontaneous fluctuations in heart rate (HR), arterial blood pressure, and respiration were analyzed by spectral analysis in the 0.02- to 1-Hz frequency range. A simple closed-loop model of short-term cardiovascular control was proposed and evaluated in a series of experiments: pharmacological blockades of the parasympathetic, alpha-sympathetic, beta-sympathetic, and renin-angiotensin systems were used to open the principal control loops in order to examine changes in the spectral pattern of the fluctuations. Atrial pacing was used to examine blood pressure variability in the absence of HR variability. We found that respiratory frequency fluctuations in HR are parasympathetically mediated and that blood pressure fluctuations at this frequency result almost entirely from the direct effect of centrally mediated HR fluctuations. The sympathetic nervous system appears to be too sluggish to mediate respiratory frequency variations. Low-frequency (0.02-0.09 Hz) fluctuations in HR are jointly mediated by the parasympathetic and beta-sympathetic systems and appear to compensate for blood pressure fluctuations at this frequency. Low-frequency blood pressure fluctuations are probably due to variability in vasomotor activity which is normally damped by renin-angiotensin system activity. Blockade of the alpha-adrenergic system, however, does not significantly alter low-frequency blood pressure fluctuations.

Objective To evaluate the effect of dezocine on the c-fos expression in neurons in the midbrain periaqueductal gray in a rat model of incisional pain. Methods Thirty-six pathogen-free healthy adult male Wistar rats, weighing 250-300 g, were divided into 3 groups (n=12 each) using a random number table: control group (group C), incisional pain group (group I) and dezocine group (group D). A 1 cm longitudinal incision was made through skin, fascia and muscle of the plantar aspect of the right hind paw in sevoflurane-anesthetized rats.In group C, the rats were only anesthetized and underwent no operation.In group I, 0.9% sodium chloride solution 2 ml was injected via the caudal vein at 15 min before the model was established.In group D, dezocine 1 mg/kg (diluted to 2 ml in 0.9% sodium chloride solution) was injected via the caudal vein at 15 min before the model was established.At 24 h before operation (T0) and 2, 6 and 24 h after operation (T1-3), the mechanical paw withdrawal threshold (MWT) and cumulative pain score were measured.After measurement of the pain threshold at T3, the whole brain was removed for determination of the c-fos expression in neurons in the midbrain periaqueductal gray by immunohistochemistry. Results Compared with group C, the MWT was significantly decreased, cumulative pain scores were increased, and the expression of c-fos in neurons in the midbrain periaqueductal gray was up-regulated at T1-3 in I and D groups (P<0.05). Compared with group I, the MWT was significantly increased, the cumulative pain score was decreased, and the expression of c-fos protein in neurons in the midbrain periaqueductal gray was down-regulated at T1-3 in group D (P<0.05). Conclusion Dezocine mitigates incisional pain through inhibiting the expression of c-fos in neurons in the midbrain periaqueductal gray of rats. Key words: Analgesics, opioid; Pain, postoperative; Periaqueductal gray; Proto-oncogene proteins c-fos

This study used between-breed embryo transfer in the horse to investigate the effects of maternal size and uterine capacity on fetal growth and postnatal cardiovascular and neuroendocrine functions. Equine embryos were transferred to establish eight Thoroughbred-in-Thoroughbred (TinT), seven Pony-in-Pony (PinP), five Thoroughbred-in-Pony (TinP) and eight Pony-in-Thoroughbred (PinT), pregnancies. Maternal and foal weights and placental microscopic area were measured at birth. At 6 days of postnatal life, arterial blood pressure and heart rate were monitored and blood samples were taken for hormone analysis before, during and after a 10 min period of nitroprusside-induced hypotension. Values for maternal and foal weights and placental area at birth were larger in TinT than in PinP pregnancies (P < 0.05). PinT pregnancies resulted in larger placentae and heavier foals relative to PinP (P < 0.05). TinP had smaller placentae and lighter foals relative to TinT (P < 0.05). Growth-enhanced (PinT) foals showed elevated basal arterial blood pressure and baroreflex threshold, reduced baroreflex sensitivity, diminished plasma catecholamine responses to acute stress, and increased cortisol responsiveness to ACTH. Conversely, growth-restricted (TinP) foals showed no change in basal arterial blood pressure, baroreflex threshold or adrenocortical responsiveness to ACTH, but had enhanced baroreflex sensitivity and augmented plasma catecholamine responses to acute stress. The data show that fetal growth acceleration as well as fetal growth restriction, resulting from between-breed embryo transfer in the horse, leads to altered postnatal regulation of blood pressure and the circulating concentrations of cortisol. These findings suggest that deviations in the pattern and rate of fetal growth both above and below the normal trajectory may influence cardiovascular function in postnatal life.

Imaging of Eating Disorders: Multiple Techniques to Demonstrate the Dynamic Brain

The current definition of sinus tachycardia is a heart rate >100 beats per minute (bpm).1 This limit was set arbitrarily when heart rate was not yet regarded as a risk factor for cardiovascular disease, probably with the main purpose of distinguishing between a disease state (fever, thyrotoxicosis, anemia, congestive heart failure, etc) and a normal condition. In recent years, interest has been aroused by the awareness that fast heart rate is a potent precursor of hypertension, atherosclerosis, and their sequelae.2 3 4 5 6 7 8 9 10 In addition, many leading epidemiological studies have shown that tachycardia is associated with an increased risk of death from cardiovascular and noncardiovascular causes. This relationship has been found in general populations,3 4 5 6 7 in elderly individuals,9 and in hypertensive cohorts.10 In all of these studies, the heart rate value above that in which a significant increase in risk was observed was below the 100 bpm threshold (Table 1⇓). Only in the study by Levy et al3 was tachycardia defined as a heart rate >99 bpm, but in that study the cutoff between normal and high heart rate was chosen arbitrarily, and the highest heart rate value measured during the examination was taken to define the subject’s heart rate. In all the other studies, the threshold level between normal and fast heart rate was between 79 and 90 bpm. View this table: Table 1. Heart Rate Values Above Which a Significant Increase in Risk Was Found: Data From 9 Epidemiological Studies The normalcy limits of a clinical variable can be established according to different criteria. For many parameters, such as most biochemical indexes, the 95% confidence interval is calculated to identify the upper normal limit of the variable. This statistical approach does not appear suitable for those clinical variables …

No association between cardiometabolic risk and neural reactivity to acute psychosocial stress

A number of control mechanisms are comprised within blood pressure regulation, ranging from events on the cellular level up to circulating hormones. Despite their vast number, blood pressure fluctuations occur preferably within a certain range (under physiological conditions). A specific class of dynamic systems has been extensively studied over the past several years: nonlinear coupled systems, which often reveal a characteristic form of motion termed "chaos". The system is restricted to a certain range in phase space, but the motion is never periodic. The attractor the system moves on has a non-integer dimension. What all chaotic systems have in common is their sensitive dependence on initial conditions. The question arises as to whether blood pressure regulation can be explained by such models. Many efforts have been made to characterise heart rate variability and EEG dynamics by parameters of chaos theory (e.g., fractal dimensions and Lyapunov exponents). These method were successfully applied to dynamics observed in single organs, but very few studies have dealt with blood pressure dynamics. This mini-review first gives an overview on the history of blood pressure dynamics and the methods suitable to characterise the dynamics by means of tools derived from the field of nonlinear dynamics. Then applications to systemic blood pressure are discussed. After a short survey on heart rate variability, which is indirectly reflected in blood pressure variability, some dynamic aspects of resistance vessels are given. Intriguingly, systemic blood pressure reveals a change in fractal dimensions and Lyapunov exponents, when the major short-term control mechanism--the arterial baroreflex--is disrupted. Indeed it seems that cardiovascular time series can be described by tools from nonlinear dynamics [66]. These methods allow a novel description of some important aspects of biological systems. Both the linear and the nonlinear tools complement each other and can be useful in characterising the stability and complexity of blood pressure control.

Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Annals of Neurology 2011;70:838-845. Objective: The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine. Methods: Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain-free state, versus 17 genderand age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia. Results: Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases, whereas a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions, and anterior cingulate compared to migraineurs without allodynia. Interpretation: These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory circuits, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas. Comments: Functional neuroimaging techniques have helped elucidate the underlying physiology of migraines. Unlike traditional functional magnetic resonance imaging scans done during a task, resting state functional connectivity is a relatively new neuroimaging technique in which participants are scanned at rest, and the lowfrequency spontaneous fluctuations found to be highly correlated are thought to represent brain areas that are functionally connected at baseline. Mainero et al recently conducted this study to assess the functional connectivity of the periaqueductal gray (PAG) (a region previously implicated in the pathogenesis of migraine) to other brain regions in 17 migraineurs interictally compared with 17 age-/gendermatched controls. They found that compared with the controls, the migraineurs had increased resting state functional connectivity between the PAG, and somatosensory and nociceptive processing pathways. The connections between the PAG and the supramarginal gyrus, anterior insula, and hypothalamus were increased in migraineurs with more frequent attacks, while the connections between PAG and the prefrontal cortex, anterior cingulate, amygdala, and medial thalamus were decreased in migraineurs with more frequent attacks. The 5 migraineurs with allodynia also had significantly reduced connectivity between the PAG and the anterior insula, anterior cingulate, and prefrontal cortex vs genderand age-matched migraineurs without allodynia. This study is one of the first to use resting state functional connectivity analyses to compare the intrinsic neural connections in migraineurs vs controls. As expected, many of the connections between the PAG, and nociceptive and sensory processing pathways were increased in the migraineurs, and some of those connections were stronger in those with more frequent attacks. However, unexpectedly, those with more frequent migraines and those with allodynia had decreased connections between the PAG and areas involved in the cognitive modulation of pain. This suggests that From the Graham Headache Center, Faulkner/Brigham and Women’s Hospital, Boston, MA,