Cerebral responses to exercise and the influence of heat stress in human fatigue

There are a number of mechanisms thought to be responsible for the onset of fatigue during exercise-induced hyperthermia. A greater understanding of the way in which fatigue develops during exercise could be gleaned from the studies which have examined the maintenance of cerebral blood flow through the process of cerebral autoregulation. Given that cerebral blood flow is a measure of the cerebral haemodynamics, and might reflect a level of brain activation, it is useful to understand the implications of this response during exercise and in the development of fatigue. It is known that cerebral blood flow is significantly altered under certain conditions such as altitude and exacerbated during exercise induced – hyperthermia. In this brief review we consider the processes of cerebral autoregulation predominantly through the measurement of cerebral blood flow and contrast these responses between exercise undertaken in normothermic versus heat stress conditions in order to draw some conclusions about the role cerebral blood flow might play in determining fatigue.     

Cerebrovascular circulation during blockade of angiotensin receptors

In experiments on anaesthetized rats, Losartan was found to cause an obvious decrease in the ABP in normotensive rats. The cerebral blood flow differed independence on cerebral vascular resistance and the ABP level. The autoregulation of the cerebral blood flow remained unaltered. In hypertensive rats Losartan caused a significant decrease in the ABP as compared with normotensive rats. A shift of lower limits of the cerebral blood flow autoregulation towards a lower ABP level, was observed.     

Failure of cerebral autoregulation as a cause of brain dysfunction in the elderly.

Cerebral blood flow in relation to change in arterial pressure was measured in 11 elderly patients with postural hypotension. Seven patients with symptoms showed bilateral or unilateral failure of cerebral autoregulation, while the four asymptomatic patients did not. Variations in cerebral autoregulation would explain why some elderly people with minor falls of systemic arterial pressure develop clinical signs of cerebral ischaemia whereas others with greater falls in blood pressure remain asymptomatic. Elderly patients with impaired autoregulation may be at risk of brain damage from minor falls in blood pressure.     

Cerebral Autoregulation Is Minimally Influenced by the Superior Cervical Ganglion in Two- Week-Old Lambs,and Absent in Preterm Lambs Immediately Following Delivery

Cerebral vessels in the premature newborn brain are well supplied with adrenergic nerves, stemming from the superior cervical ganglia (SCG), but their role in regulation of blood flow remains uncertain. To test this function twelve premature or two-week-old lambs were instrumented with laser Doppler flow probes in the parietal cortices to measure changes in blood flow during changes in systemic blood pressure and electrical stimulation of the SCG. In lambs delivered prematurely at ∼129 days gestation cerebral perfusion and driving pressure demonstrated a direct linear relationship throughout the physiologic range, indicating lack of autoregulation. In contrast, in lambs two-weeks of age, surgical removal of one SCG resulted in ipsilateral loss of autoregulation during pronounced hypertension. Electrical stimulation of one SCG elicited unilateral increases in cerebral resistance to blood flow in both pre-term and two-week-old lambs, indicating functioning neural pathways in the instrumented, anesthetized lambs. We conclude cerebral autoregulation is non-functional in preterm lambs following cesarean delivery. Adrenergic control of cerebral vascular resistance becomes effective in newborn lambs within two-weeks after birth but SCG-dependent autoregulation is essential only during pronounced hypertension, well above the normal range of blood pressure.     

Naloxone-like influence of TRH and ACTH-(4-7) on hypothalamic blood flow autoregulation in the rat

The influence of intracerebroventricularly (ICV) administered thyrotropin-releasing hormone pGlu-His-Pro-NH2 (TRH), pGlu-His-Phe-NH2 (TRH analog, (TRHa)), Met-Glu-His-Phe(ACTH-(4-7)) and His-Phe-Arg-Trp-Gly (ACTH-(6-10)) on autoregulation of cerebral blood flow was studied in anesthetized, ventilated rats. Autoregulatory capacity of the cerebrovascular bed was tested by hypothalamic blood flow (HBF) and total cerebral blood volume (CBV) determinations during consecutive stepwise lowering of the systemic mean arterial pressure to 80, 60 and 40 mmHg, by hemorrhage. None of the peptides caused a change in resting HBF or CBV upon ICV administration (5 micrograms/kg). However, the same dose of TRH, TRHa and ACTH-(4-7) resulted in impairment of autoregulation. ACTH-(6-10) was not effective. Thus, the disturbed autoregulation may be due to the presence of the dipeptide Glu-His which is common to TRH, TRHa and ACTH-(4-7).     

Autoregulation of Brain Circulation in Severe Arterial Hypertension

Cerebral blood flow was studied by the arteriovenous oxygen difference method in patients with severe hypertension and in normotensive controls. The blood pressure was lowered to study the lower limit of autoregulation (the pressure below which cerebral blood flow decreases) and the pressure limit of brain hypoxia. Both limits were shifted upwards in the hypertensive patients, probably as a consequence of hypertrophy of the arteriolar walls. These findings have practical implications for antihypertensive therapy.When the blood pressure was raised some patients showed an upper limit of autoregulation beyond which an increase of cerebral blood flow above the resting value was seen without clinical symptoms. No evidence of vasospasm was found in any patient at high blood pressure. These observations may be of importance for the understanding of the pathogenesis of hypertensive encephalopathy.     

Alteration of pial vessel responses to blood pressure changes in rats after hypoxia

Previous studies in newborn lamb have shown impairment of cerebral blood flow autoregulation after hypoxia followed by reoxygenation. The present study was done to see if such a phenomenon existed in the adult rat and if it could be demonstrated at the level of the pial arterioles. Using an open cranial window preparation, we assessed the changes in pial vessel diameter during blood pressure alterations induced by hemorrhage and reinfusion of blood, before and after 30 s of hypoxia, in 15 male Sprague-Dawley rats. Mean diameters of pial arteries in the study group of rats were 128 +/- 54 microns before hypoxia and 141 +/- 61 microns after normoxia following hypoxia. The corresponding diameters in rats serving as time controls were 136 +/- 52 and 138 +/- 52 microns. Slopes of pial vessel diameters as a function of mean arterial blood pressures decreased significantly (p less than 0.05) after hypoxia from -0.86 +/- 0.45 to 0.03 +/- 0.66 (mean +/- SD). In the control rats not subjected to hypoxia, the slopes remained unchanged over a similar time period (-0.60 +/- 0.16 and -0.42 +/- 0.19). The negative slopes indicate that pial vessels dilate during hypotension and constrict during hypertension. Such vascular responses may play a role in autoregulation of cerebral blood flow. We found that a relatively brief period of hypoxia can cause a long-lasting impairment of vascular responses even after restoration of normoxia. These findings are consistent with a previous report of persistent impairment of cerebral blood flow autoregulation after a brief period of hypoxia.     

Frequency response characteristics of cerebral blood flow autoregulation in rats

Transfer function analysis of blood pressure and cerebral blood flow in humans demonstrated that cerebrovascular autoregulation operates most effectively for slow fluctuations in perfusion pressure, not exceeding a frequency of approximately 0.15 Hz. No information on the dynamic properties of cerebrovascular autoregulation is available in rats. Therefore, we tested the hypothesis that cerebrovascular autoregulation in rats is also most effective for slow fluctuations in perfusion pressure below 0.15 Hz. Normotensive Wistar-Kyoto rats (n = 10) were instrumented with catheters in the left common carotid artery and jugular vein and flow probes around the right internal carotid artery. During isoflurane anesthesia, fluctuations in cerebral perfusion pressure were elicited by periodically occluding the abdominal aorta at eight frequencies ranging from 0.008 Hz to 0.5 Hz. The protocol was repeated during inhibition of myogenic vascular function (nifedipine, 0.25 mg/kg body wt iv). Increases in cerebral perfusion pressure elicited initial increases in cerebrovascular conductance and decreases in resistance. At low occlusion frequencies (<0.1 Hz), these initial responses were followed by decreases in conductance and increases in resistance that were abolished by nifedipine. At occlusion frequencies of 0.1 Hz and above, the gains of the transfer functions between pressure and blood flow and between pressure and resistance were equally high in the control and nifedipine trial. At occlusion frequencies below 0.1 Hz, the gains of the transfer functions decreased twice as much under control conditions than during nifedipine application. We conclude that dynamic autoregulation of cerebral blood flow is restricted to very low frequencies (<0.1 Hz) in rats.     

Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.     

Role of the autoregulatory component in the vascular reaction of the brain to euphylline

The method of hydrogen clearance used for the registration of cerebral blood flow in acute experiments on anesthetized white rats with artificial respiration has shown that aminophylline had a biphasic effect (dilatation-constriction) on cerebral vessels, particularly with stable blood pressure. Systemic hypotension provoked an increase in dilatation response. With blood pressure reduced, autoregulation levels lowered.     

Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.     

Implementation of intrinsic lumped parameter modeling into computational fluid dynamics studies of cardiopulmonary bypass

Stroke and cerebral hypoxia are among the main complications during cardiopulmonary bypass (CPB). The two main reasons for these complications are the cannula jet, due to altered flow conditions and the sandblast effect, and impaired cerebral autoregulation which often occurs in the elderly. The effect of autoregulation has so far mainly been modeled using lumped parameter modeling, while Computational Fluid Dynamics (CFD) has been applied to analyze flow conditions during CPB. In this study, we combine both modeling techniques to analyze the effect of lumped parameter modeling on blood flow during CPB. Additionally, cerebral autoregulation is implemented using the Baroreflex, which adapts the cerebrovascular resistance and compliance based on the cerebral perfusion pressure.     

Cerebral blood flow autoregulation in early experimental S. pneumoniae meningitis.

We studied cerebral blood flow (CBF) autoregulation and intracranial pressure (ICP) during normo- and hyperventilation in a rat model of Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal injection of S. pneumoniae. Mean arterial blood pressure (MAP), ICP, cerebral perfusion pressure (CPP, defined as MAP - ICP), and laser-Doppler CBF were measured in anesthetized infected rats (n = 30) and saline-inoculated controls (n = 30). CPP was either incrementally reduced by controlled hemorrhage or increased by intravenous norepinephrine infusion. Twelve hours postinoculation, rats were studied solely during normocapnia, whereas rats studied after 24 h were exposed to either normocapnia or to acute hypocapnia. In infected rats compared with control rats, ICP was unchanged at 12 h but increased at 24 h postinoculation (not significant and P < 0.01, respectively); hypocapnia did not lower ICP compared with normocapnia. Twelve hours postinoculation, CBF autoregulation was lost in all infected rats but preserved in all control rats (P < 0.01). Twenty-four hours after inoculation, 10% of infected rats had preserved CBF autoregulation during normocapnia compared with 80% of control rats (P < 0.01). In contrast, 60% of the infected rats and 100% of the control rats showed an intact CBF autoregulation during hypocapnia (P < 0.05 for the comparison of infected rats at normocapnia vs. hypocapnia). In conclusion, CBF autoregulation is lost both at 12 and at 24 h after intracisternal inoculation of S. pneumoniae in rats. Impairment of CBF autoregulation precedes the increase in ICP, and acute hypocapnia may restore autoregulation without changing the ICP.     

Effects of combination alfaxalone and alfadolone, anesthetic derivatives of pregnanedione, on cerebral hemodynamics in cats]

Intravenous injection of CT 1341 (a mixture of alphaxalone and alphadolone dissolved in cremophor el) induced a decrease in cerebral blood flow (CBF) measured by 133Xe clearance in cats with artificial respiration (the mean reduction in CBF was 2 ml/100 g/mn for 1,2 mg/kg or CT 1341. So, CBF was decreased by 22% when CT 1341 (7,2 mg/kg) was intravenously injected, (mean Pa CO2 equals 30 mm Hg). Changes in CBF following CT 1341 intravenous injection seems to be caused by cerebral vascular constriction evidenced by the direct observation of pial vessels. Following intravenous injection of CT 1341 (from 7, 2 mg/kg to 19,2 mg/kg), the cerebrovascular reactivity to hypercapnia or hypocapnia was not affected, but autoregulation of cerebral blood flow was transiently abolished. In animals with free respiration, CBF was increased in relation with the elevation in Pa CO2 caused by the depression of respiration.     

A multiscale 0-D/3-D approach to patient-specific adaptation of a cerebral autoregulation model for computational fluid dynamics studies of cardiopulmonary bypass

Neurological complication often occurs during cardiopulmonary bypass (CPB). One of the main causes is hypoperfusion of the cerebral tissue affected by the position of the cannula tip and diminished cerebral autoregulation (CA). Recently, a lumped parameter approach could describe the baroreflex, one of the main mechanisms of cerebral autoregulation, in a computational fluid dynamics (CFD) study of CPB. However, the cerebral blood flow (CBF) was overestimated and the physiological meaning of the variables and their impact on the model was unknown. In this study, we use a 0-D control circuit representation of the Baroreflex mechanism, to assess the parameters with respect to their physiological meaning and their influence on CBF. Afterwards the parameters are transferred to 3D-CFD and the static and dynamic behavior of cerebral autoregulation is investigated.     

A global mathematical model of the cerebral circulation in man

A mathematical model of the cerebral circulation has been formulated. It was based on non-linear equations of pulsatile fluid flow in distensible conduits and applied to a network simulating the entire cerebral vasculature, from the carotid and vertebral arteries to the sinuses and the jugular veins. The quasilinear hyperbolic system of equations was numerically solved using the two-step Lax-Wendroff scheme. The model's results were in good agreement with pressure and flow data recorded in humans during rest. The model was also applied to the study of autoregulation during arterial hypotension. A close relationship between cerebral blood flow (CBF) and capillary pressure was obtained. At arterial pressure of 80 mmHg, the vasodilation of the pial arteries was unable to maintain CBF at its control value. At the lower limit of autoregulation (60 mm Hg), CBF was maintained with a 25% increase of zero transmural pressure diameter of nearly the whole arterial network.     

Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains.

The dynamics of the cerebral vascular response to blood pressure changes in hypertensive humans is poorly understood. Because cerebral blood flow is dependent on adequate perfusion pressure, it is important to understand the effect of hypertension on the transfer of pressure to flow in the cerebrovascular system of elderly people. Therefore, we examined the effect of spontaneous and induced blood pressure changes on beat-to-beat and within-beat cerebral blood flow in three groups of elderly people: normotensive, controlled hypertensive, and uncontrolled hypertensive subjects. Cerebral blood flow velocity (transcranial Doppler), blood pressure (Finapres), heart rate, and end-tidal CO(2) were measured during the transition from a sit to stand position. Transfer function gains relating blood pressure to cerebral blood flow velocity were assessed during steady-state sitting and standing. Cerebral blood flow regulation was preserved in all three groups by using changes in cerebrovascular resistance, transfer function gains, and the autoregulatory index as indexes of cerebral autoregulation. Hypertensive subjects demonstrated better attenuation of cerebral blood flow fluctuations in response to blood pressure changes both within the beat (i.e., lower gain at the cardiac frequency) and in the low-frequency range (autoregulatory, 0.03-0.07 Hz). Despite a better pressure autoregulatory response, hypertensive subjects demonstrated reduced reactivity to CO(2). Thus otherwise healthy hypertensive elderly subjects, whether controlled or uncontrolled with antihypertensive medication, retain the ability to maintain cerebral blood flow in the face of acute changes in perfusion pressure. Pressure regulation of cerebral blood flow is unrelated to cerebrovascular reactivity to CO(2).     

Effect of plasma exchange on blood viscosity and cerebral blood flow.

The effects of plasma exchange using a low viscosity plasma substitute on blood viscosity and cerebral blood flow were investigated in eight subjects with normal cerebral vasculature. Plasma exchange resulted in significant reductions in plasma viscosity, whole blood viscosity, globulin and fibrinogen concentration without affecting packed cell volume. The reduction in whole blood viscosity was more pronounced at low shear rates suggesting an additional effect on red cell aggregation. Despite the fall in viscosity there was no significant change in cerebral blood flow. The results support the metabolic theory of autoregulation. Although changes in blood viscosity appear not to alter the level of cerebral blood flow under these circumstances, plasma exchange could still be of benefit in the management of acute cerebrovascular disease.     

Assessing Cerebral Autoregulation via Oscillatory Lower Body Negative Pressure and Projection Pursuit Regression

The process by which cerebral perfusion is maintained constant over a wide range of systemic pressures is known as “cerebral autoregulation.” Effective dampening of flow against pressure changes occurs over periods as short as ~15 sec and becomes progressively greater over longer time periods. Thus, slower changes in blood pressure are effectively blunted and faster changes or fluctuations pass through to cerebral blood flow relatively unaffected. The primary difficulty in characterizing the frequency dependence of cerebral autoregulation is the lack of prominent spontaneous fluctuations in arterial pressure around the frequencies of interest (less than ~0.07 Hz or ~15 sec). Oscillatory lower body negative pressure (OLBNP) can be employed to generate oscillations in central venous return that result in arterial pressure fluctuations at the frequency of OLBNP. Moreover, Projection Pursuit Regression (PPR) provides a nonparametric method to characterize nonlinear relations inherent in the system without a priori assumptions and reveals the characteristic non-linearity of cerebral autoregulation. OLBNP generates larger fluctuations in arterial pressure as the frequency of negative pressure oscillations become slower; however, fluctuations in cerebral blood flow become progressively lesser. Hence, the PPR shows an increasingly more prominent autoregulatory region at OLBNP frequencies of 0.05 Hz and below (20 sec cycles). The goal of this approach it to allow laboratory-based determination of the characteristic nonlinear relationship between pressure and cerebral flow and could provide unique insight to integrated cerebrovascular control as well as to physiological alterations underlying impaired cerebral autoregulation (e.g., after traumatic brain injury, stroke, etc.).     

Status of the "dead point" of blood flow in anastomoses of superficial cerebral arteries as affected by an acute increase of blood pressure

Changes in pial arteries diameter and the condition of blood flow "dead point" in arterial anastomoses were established using the brain window during an acute increase of mean arterial pressure (MAP) induced by intravenous injection of norepinephrine (NE) with microcineangiography and the analysis of films and frames on a montage table and TAS ("Leitz"). During an acute increase of MAP the movement of blood flow "dead point" in anastomoses and the expansion of plasma segments occurred much more frequently than in normotension. The stabilization of blood flow "dead point" was observed at high constant MAP. Pronounced dilation of both pial arteries and veins first occurred in anastomoses, then spread to arterial branches. It is assumed that high vulnerability of the brain vessels of the borderline zones is due to breakthrough in autoregulation of cerebral blood flow on its upper limit and depends on the repeatedly changing directions of the blood flow and its moving "dead point", as the peripheral resistance of arterial anastomoses-forming branches under these circumstances changes in an irregular manner.