Kurt J. Smith

Regional brain blood flow in man during acute changes in arterial blood gases

•  The partial pressures of arterial carbon dioxide () and oxygen () has a marked influence on brain blood flow. •  It is unclear if the larger brain arteries are also sensitive to changing and and if different areas of the brain possess different sensitivities. •  We separately altered and and measured the diameter and blood flow in the main arteries delivering blood to the cortex and brainstem. •  During alterations in and , the large arteries changed diameter and blood flow to the brainstem changed more than that to the cortex. •  These findings change the basis of our understanding of brain blood flow control in humans.

Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function

There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored.

Reductions in cerebral blood flow during passive heat stress in humans: partitioning the mechanisms

Non‐technical summary  Heat stress reduces brain blood flow and impairs orthostatic tolerance. Brain blood flow is largely controlled by the partial pressure of arterial . Indeed, hyperthermia‐induced over‐breathing and related reductions in arterial account for ∼50% of the reduction in brain blood flow. This investigation tested the unique hypothesis that the distribution of cardiac output during heat stress (challenged by thermoregulatory increases in skin blood flow and sweat loss) contributes to the remaining 50%. We show that cardiac output is not related to brain blood flow, but rather arterial plays a much larger role than previously suggested. These findings help us understand the mechanisms relating heat stress with an increased likelihood of fainting, and are also relevant to pathological conditions that are accompanied by elevations in body temperature.

Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m

The interindividual variation in ventilatory acclimatization to high altitude is likely reflected in variability in the cerebrovascular responses to high altitude, particularly between brain regions displaying disparate hypoxic sensitivity. We assessed regional differences in cerebral blood flow (CBF) measured with Duplex ultrasound of the left internal carotid and vertebral arteries. End-tidal Pco2, oxyhemoglobin saturation (SpO2), blood pressure, and heart rate were measured during a trekking ascent to, and during the first 2 wk at, 5,050 m. Transcranial color-coded Duplex ultrasound (TCCD) was employed to measure flow and diameter of the middle cerebral artery (MCA). Measures were collected at 344 m (TCCD-baseline), 1,338 m (CBF-baseline), 3,440 m, and 4,371 m. Following arrival to 5,050 m, regional CBF was measured every 12 h during the first 3 days, once at 5-9 days, and once at 12-16 days. Total CBF was calculated as twice the sum of internal carotid and vertebral flow and increased steadily with ascent, reaching a maximum of 842 ± 110 ml/min (+53 ± 7.6% vs. 1,338 m; mean ± SE) at ∼ 60 h after arrival at 5,050 m. These changes returned to +15 ± 12% after 12-16 days at 5,050 m and were related to changes in SpO2 (R(2) = 0.36; P < 0.0001). TCCD-measured MCA flow paralleled the temporal changes in total CBF. Dilation of the MCA was sustained on days 2 (+12.6 ± 4.6%) and 8 (+12.9 ± 2.9%) after arrival at 5,050 m. We observed no significant differences in regional CBF at any time point. In conclusion, the variability in CBF during ascent and acclimatization is related to ventilatory acclimatization, as reflected in changes in SpO2.

Differential cerebrovascular CO2 reactivity in anterior and posterior cerebral circulations

The potential differences in cerebrovascular responses between the anterior and posterior circulations to changes in CO₂ are unclear in humans. Using transcranial Doppler ultrasound, we compared the CO₂ reactivity of the (1) BA and PCA and (2) MCA and PCA during hyperoxic rebreathing in supine position. The reactivity in the BA and PCA was similar in both absolute (1.27 ± 0.5 and 1.27 ± 0.6 cm/s/Torr; P=0.992) and relative (3.98 ± 1.3 and 3.66 ± 1.5%/Torr CO2; P=0.581) measures, suggesting that the PCA is an adequate surrogate measure of reactivity for the BA. The MCA reactivity was greater than the PCA in absolute (2.09 ± 0.7 and 1.22 ± 0.5 cm/s/Torr CO₂; P<0.001), but not relative measures (3.25 ± 1.0 and 3.56 ± 1.6%/Torr CO₂; P=0.629). Our findings (a) confirm regional differences in the absolute reactivity in the human brain and (b) suggest that in cerebrovascular studies investigating functions mediated by posterior brain structures (e.g., control of breathing), the posterior vasculature should also be insonated.

Impact of transient hypotension on regional cerebral blood flow in humans.

We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICABF and VABF respectively) were also obtained. Overall, blood pressure was reduced by ~20% from baseline in both trials (P<0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg (P<0.001) with hypotension. The decline in the ICABF with hypotension was comparable between trials (-139 ± 82 ml; ~30%; P<0.0001); however, the decline in the VABF was -28 ± 22 ml/min (~21%) greater in the poikilocapnic trial compared with the isocapnic trial (P=0.002). Regardless of trial, the blood flow reductions in ICA (-26 ± 14%) and VA (-27 ± 14%) were greater than the decline in MCA (-21 ± 15%) and PCA (-19 ± 10%) velocities respectively (P ≤ 0.01). Significant reductions in the diameter of both the ICA (~5%) and the VA (~7%) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation.

Regional cerebral blood flow distribution during exercise: influence of oxygen.

We investigated regional changes in cerebral artery velocity during incremental exercise while breathing normoxia (21% O2), hyperoxia (100% O2) or hypoxia (16% O2) [n=10; randomized cross over design]. Middle cerebral and posterior cerebral arterial velocities (MCAv and PCAv) were measured continuously using transcranial Doppler ultrasound. At rest, only PCAv was reduced (-7%; P=0.016) with hyperoxia. During low-intensity exercise (40% workload maximum [Wmax]) MCAv (+17 cms(-1); +14cms(-1)) and PCAv (+9cms(-1); +14 cms(-1)) were increased above baseline with normoxia and hypoxia, respectively (P<0.05). The absolute increase from rest in MCAv was greater than the increase in PCAv between 40 and 80% Wmax with normoxia; this greater increase in MCAv was also evident at 60% Wmax with hypoxia and hyperoxia. Hyperoxic exercise resulted in larger absolute (+19 cms(-1)) and relative (+40%) increases in PCAv compared with normoxia. Our findings highlight the selective changes in PCAv during hyperoxic incremental exercise.

Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery

This study assessed the dynamic response of global cerebral blood flow (CBF) and cerebral fuel utilization during and following incremental supine exercise to exhaustion. Global CBF increased more during exercise and recovery at high altitude (HA) compared with sea level (SL) such that cerebral oxygen delivery ( CDO2 ) was maintained. The increase in cerebral metabolic rate of oxygen during maximal exercise at HA was half the increase observed at SL. Arterial lactate production during exercise at the same absolute intensities was greater at HA compared with SL, but reduced at the same relative intensities. Cerebral carbohydrate uptake (lactate and glucose) is greater than oxygen uptake at HA compared with SL, indicating a shift towards an increased non‐oxidative metabolic utilization. These results suggest that CBF increases to maintain CDO2 during exercise at HA while changes in arterial lactate concentration and exercise intensity augment the oxidative and non‐oxidative pathways to cerebral metabolism at HA.

Indomethacin‐induced impairment of regional cerebrovascular reactivity: implications for respiratory control

Anterior and posterior cerebral circulations have differential reactivity to changes in arterial blood gases, but the implications for the chemoreflex control of breathing are unclear. Indomethacin‐induced blunting of cerebrovascular flow responsiveness did not affect central or peripheral respiratory chemoreflex magnitude using steady‐state end‐tidal forcing techniques. Posterior reactivity was related to hypoxic ventilatory decline, suggesting that CO2 washout from central chemoreceptors modulates hypoxic ventilatory dynamics. Our data indicate that steady‐state end‐tidal forcing techniques reduce the arterial–venous gradients, attenuating the effect of brain blood flow on ventilatory responses. Our study confirms the importance of measuring posterior cerebrovasculature when investigating the link between cerebral blood flow and the chemical control of breathing.

Impact of prolonged sitting on vascular function in young girls

What is the central question of this study? Children are spending more than 60% of their waking day sedentary. The consequences of excessive sedentary behaviour are not well understood in the child, but there is growing evidence that with increasing sedentary time, cardiovascular risk in childhood also increases. What is the main finding and its importance? Our findings show that a 3 h period of uninterrupted sitting causes a profound (33%) reduction in vascular function in young girls. Importantly, we also demonstrate that breaking up sitting with regular exercise breaks can prevent this.