Kate N. Thomas

Influence of Changes in Blood Pressure on Cerebral Perfusion and Oxygenation

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of “normal” CA has not been clearly identified. While controlling for the influence of arterial Pco2, we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal Pco2, and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: ≈40 to ≈125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAvmean was altered by 0.82±0.35% per millimeter of mercury change in mean blood pressure (R2=0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=−0.18%/mm Hg; R2=0.60) and MCAvmean (slope=−0.26%/cm · s−1; R2=0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAvmean.

Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing

It is known that cerebral blood flow declines with age in sedentary adults, although previous studies have involved small sample sizes, making the exact estimate of decline imprecise and the effects of possible moderator variables unknown. Animal studies indicate that aerobic exercise can elevate cerebral blood flow; however, this possibility has not been examined in humans. We examined how regular aerobic exercise affects the age‐related decline in blood flow velocity in the middle cerebral artery (MCAv) in healthy humans. Maximal oxygen consumption, body mass index (BMI), blood pressure and MCAv were measured in healthy sedentary (n= 153) and endurance‐trained (n= 154) men aged between 18 and 79 years. The relationships between age, training status, BMI and MCAv were examined using analysis of covariance methods. Mean ±s.e.m. estimates of regression coefficients and 95% confidence intervals (95% CI) were calculated. The age‐related decline in MCAv was −0.76 ± 0.04 cm s−1 year−1 (95% CI =−0.69 to −0.83, r2= 0.66, P < 0.0005) and was independent of training status (P= 0.65). Nevertheless, MCAv was consistently elevated by 9.1 ± 3.3 cm s−1 (CI = 2.7–15.6, P= 0.006) in endurance‐trained men throughout the age range. This ∼17% difference between trained and sedentary men amounted to an approximate 10 year reduction in MCAv ‘age’ and was robust to between‐group differences in BMI and blood pressure. Regular aerobic‐endurance exercise is associated with higher MCAv in men aged 18–79 years. The persistence of this finding in older endurance‐trained men may therefore help explain why there is a lower risk of cerebrovascular disease in this population.

Human cerebrovascular and ventilatory CO2 reactivity to end-tidal, arterial and internal jugular vein PCO2

This study examined cerebrovascular reactivity and ventilation during step changes in CO2 in humans. We hypothesized that: (1) end‐tidal P  CO 2 (P  ET,CO 2 ) would overestimate arterial P  CO 2 (P  a,CO 2 ) during step variations in P  ET,CO 2 and thus underestimate cerebrovascular CO2 reactivity; and (2) since P  CO 2 from the internal jugular vein (P  jv,CO 2 ) better represents brain tissue P  CO 2, cerebrovascular CO2 reactivity would be higher when expressed against P  jv,CO 2 than with P  a,CO 2, and would be related to the degree of ventilatory change during hypercapnia. Incremental hypercapnia was achieved through 4 min administrations of 4% and 8% CO2. Incremental hypocapnia involved two 4 min steps of hyperventilation to change P  ET,CO 2, in an equal and opposite direction, to that incurred during hypercapnia. Arterial and internal jugular venous blood was sampled simultaneously at baseline and during each CO2 step. Cerebrovascular reactivity to CO2 was expressed as the percentage change in blood flow velocity in the middle cerebral artery (MCAv) per mmHg change in P  a,CO 2 and P  jv,CO 2. During hypercapnia, but not hypocapnia, P  ET,CO 2 overestimated P  a,CO 2 by +2.4 ± 3.4 mmHg and underestimated MCAv‐CO2 reactivity (P < 0.05). The hypercapnic and hypocapnic MCAv‐CO2 reactivity was higher (∼97% and ∼24%, respectively) when expressed with P  jv,CO 2 than P  a,CO 2 (P < 0.05). The hypercapnic MCAv–P  jv,CO 2 reactivity was inversely related to the increase in ventilatory change (R2= 0.43; P < 0.05), indicating that a reduced reactivity results in less central CO2 washout and greater ventilatory stimulus. Differences in the P  ET,CO 2, P  a,CO 2 and P  jv,CO 2 –MCAv relationships have implications for the true representation and physiological interpretation of cerebrovascular CO2 reactivity.

Human cardiorespiratory and cerebrovascular function during severe passive hyperthermia: effects of mild hypohydration

The influence of severe passive heat stress and hypohydration (Hypo) on cardiorespiratory and cerebrovascular function is not known. We hypothesized that 1) heating-induced hypocapnia and peripheral redistribution of cardiac output (Q) would compromise blood flow velocity in the middle cerebral artery (MCAv) and cerebral oxygenation; 2) Hypo would exacerbate the hyperthermic-induced hypocapnia, further decreasing MCAv; and 3) heating would reduce MCAv-CO2 reactivity, thereby altering ventilation. Ten men, resting supine in a water-perfused suit, underwent progressive hyperthermia [0.5 degrees C increments in core (esophageal) temperature (TC) to +2 degrees C] while euhydrated (Euh) or Hypo by 1.5% body mass (attained previous evening). Time-control (i.e., non-heat stressed) data were obtained on six of these subjects. Cerebral oxygenation (near-infrared spectroscopy), MCAv, end-tidal carbon dioxide (PetCO2) and arterial blood pressure, Q (flow model), and brachial and carotid blood flows (CCA) were measured continuously each 0.5 degrees C change in TC. At each level, hypercapnia was achieved through 3-min administrations of 5% CO2, and hypocapnia was achieved with controlled hyperventilation. At baseline in Hypo, heart rate, MCAv and CCA were elevated (P<0.05 vs. Euh). MCAv-CO2 reactivity was unchanged in both groups at all TC levels. Independent of hydration, hyperthermic-induced hyperventilation caused a severe drop in PetCO2 (-8+/-1 mmHg/ degrees C), which was related to lower MCAv (-15+/-3%/ degrees C; R2=0.98; P<0.001). Elevations in Q were related to increases in brachial blood flow (R2=0.65; P<0.01) and reductions in MCAv (R2=0.70; P<0.01), reflecting peripheral distribution of Q. Cerebral oxygenation was maintained, presumably via enhanced O2-extraction or regional differences in cerebral perfusion.

Initial orthostatic hypotension is unrelated to orthostatic tolerance in healthy young subjects

The physiological challenge of standing upright is evidenced by temporary symptoms of light-headedness, dizziness, and nausea. It is not known, however, if initial orthostatic hypotension (IOH) and related symptoms associated with standing are related to the occurrence of syncope. Since IOH reflects immediate and temporary adjustments compared with the sustained adjustments during orthostatic stress, we anticipated that the severity of IOH would be unrelated to syncope. Following a standardized period of supine rest, healthy volunteers [n=46; 25+/-5 yr old (mean+/-SD)] were instructed to stand upright for 3 min, followed by 60 degrees head-up tilt with lower-body negative pressure in 5-min increments of -10 mmHg, until presyncope. Beat-to-beat blood pressure (radial arterial or Finometer), middle cerebral artery blood velocity (MCAv), end-tidal PCO2, and cerebral oxygenation (near-infrared spectroscopy) were recorded continuously. At presyncope, although the reductions in mean arterial pressure, MCAv, and cerebral oxygenation were similar to those during IOH (40+/-11 vs. 43+/-12%; 36+/-18 vs. 35+/-13%; and 6+/-5 vs. 4+/-2%, respectively), the reduction in end-tidal CO2 was greater (-7+/-6 vs. -4+/-3 mmHg) and was related to the decline in MCAv (R2=0.4; P<0.05). While MCAv pulsatility was elevated with IOH, it was reduced at presyncope (P<0.05). The cardiorespiratory and cerebrovascular changes during IOH were unrelated to those at presyncope, and interestingly, there was no relationship between the hemodynamic changes and the incidence of subjective symptoms in either scenario. During IOH, the transient nature of physiological changes can be well tolerated; however, potentially mediated by a reduced MCAv pulsatility and greater degree of hypocapnic-induced cerebral vasoconstriction, when comparable changes are sustained, the development of syncope is imminent.

Effect of age on exercise-induced alterations in cognitive executive function: relationship to cerebral perfusion.

Regular exercise improves the age-related decline in cerebral blood flow (CBF) and is associated with improved cognitive function; however, less is known about the direct relationship between CBF and cognitive function. We examined the influence of healthy aging on the capability of acute exercise to improve cognition, and whether exercise-induced improvements in cognition are related to CBF and cortical hemodynamics. Middle cerebral artery blood flow velocity (MCAv; Doppler) and cortical hemodynamics (NIRS) were measured in 13 young (24±5 y) and 9 older (62±3 y) participants at rest and during cycling at 30% and 70% of heart rate range (HRR). Cognitive performance was assessed using a computer-adapted Stroop task (i.e., test of executive function cognition) at rest and during exercise. Average response times on the Stroop task were slower for the older compared to younger group for both simple and difficult tasks (P<0.01). Independent of age, difficult-task response times improved during exercise (P<0.01), with the improvement greater at 70% HRR exercise (P=0.04 vs. 30% HRR). Higher MCAv was correlated with faster response times for simple and difficult tasks at rest (R(2)=0.47 and R(2)=0.47, respectively), but this relation uncoupled progressively during exercise. Exercise-induced increases in MCAv were similar and unaltered during cognitive tasks for both age groups. In contrast, prefrontal cortical hemodynamic NIRS measures [oxyhemoglobin (O(2)Hb) and total hemoglobin (tHb)] were differentially affected by exercise intensity, age and cognitive task; e.g., there were smaller increases in [O(2)Hb] and [tHb] in the older group between exercise intensities (P<0.05). These data indicate that: 1) Regardless of age, cognitive (executive) function is improved while exercising; 2) while MCAv is strongly related to cognition at rest, this relation becomes uncoupled during exercise, and 3) there is dissociation between global CBF and regional cortical oxygenation and NIRS blood volume markers during exercise and engagement of prefrontal cognition.

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m

Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high‐altitude environment. Our results show that the balance of oxygen (O2) and carbon dioxide (CO2) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO2 differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

Influence of high altitude on cerebrovascular and ventilatory responsiveness to CO2

An altered acid–base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO2 sensitivity at high altitude. Likewise, if [H+] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO2 (termed cerebrovascular CO2 reactivity). However, the effect altered acid–base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO2 remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O2 and CO2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg−1; P < 0.01) and CO2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min−1 mmHg−1; P < 0.01). Likewise, the hypocapnic MCAv CO2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg−1; P < 0.01). The hypercapnic MCAv CO2 reactivity correlated with resting pH at high altitude (R2= 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R2= 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO2 reactivity and central chemoreflex may be partly attributed to an acid–base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid–base balance in the regulation in CBF and ventilatory control.

Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2 and breathing stability: the influence of PCO2 gradients

Indomethacin (INDO), a reversible cyclooxygenase inhibitor, is a useful tool for assessing the role of cerebrovascular reactivity on ventilatory control. Despite this, the effect of INDO on breathing stability during wakefulness has yet to be examined. Although the effect of reductions in cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is likely dependent upon the method used, no studies have compared the effect of INDO on steady-state and modified rebreathing estimates of ventilatory CO(2) sensitivity. The latter method includes the influence of PCO(2) gradients and cerebral perfusion, whereas the former does not. We examined the hypothesis that INDO-induced reduction in cerebrovascular CO(2) reactivity would 1) cause unstable breathing in conscious humans and 2) increase ventilatory CO(2) sensitivity during the steady-state method but not during rebreathing methods. We measured arterial blood gases, ventilation (VE), and middle cerebral artery velocity (MCAv) before and 90 min following INDO ingestion (100 mg) or placebo in 12 healthy participants. There were no changes in resting arterial blood gases or Ve following either intervention. INDO increased the magnitude of Ve variability (index of breathing stability) during spontaneous air breathing (+4.3 +/- 5.2 Deltal/min, P = 0.01) and reduced MCAv (-25 +/- 19%, P < 0.01) and MCAv-CO(2) reactivity during steady-state (-47 +/- 27%, P < 0.01) and rebreathing (-32 +/- 25%, P < 0.01). The Ve-CO(2) sensitivity during the steady-state method was increased with INDO (+0.5 +/- 0.5 l x min(-1) x mmHg(-1), P < 0.01), while no changes were observed during rebreathing (P > 0.05). These data indicate that the net effect of INDO on ventilatory control is an enhanced ventilatory loop gain resulting in increased breathing instability. Our findings also highlight important methodological and physiological considerations when assessing the effect of INDO on ventilatory CO(2) sensitivity, whereby the effect of INDO-induced reduction of cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is unmasked with the rebreathing method.

Technical recommendations for the use of carotid duplex ultrasound for the assessment of extracranial blood flow.

Duplex ultrasound is an evolving technology that allows the assessment of volumetric blood flow in the carotid and vertebral arteries during a range of interventions along the spectrum of health and chronic disease. Duplex ultrasound can provide high-resolution diameter and velocity information in real-time and is noninvasive with minimal risks or contraindications. However, this ultrasound approach is a specialized technique requiring intensive training and stringent control of multiple complex settings; results are highly operator-dependent, and analysis approaches are inconsistent. Importantly, therefore, methodological differences can invalidate comparisons between different imaging modalities and studies; such methodological errors have potential to discredit study findings completely. The task of this review is to provide the first comprehensive, user-friendly technical guideline for the application of duplex ultrasound in measuring extracranial blood flow in human research. An update on recent developments in the use of edge-detection software for offline analysis is highlighted, and suggestions for future directions in this field are provided. These recommendations are presented in an attempt to standardize measurements across research groups and, hence, ultimately to improve the accuracy and reproducibility of measuring extracranial blood flow both within subjects and between groups.