Beyond a one-track mind: understanding blood flow to the brain in humans

Cerebral blood flow regulation is often investigated using Doppler imaging techniques allowing optimal time resolution to determine rapid changes in blood flow through the brain. Other measurement techniques, including the Kety–Schmidt method and xenon-133 inhalation, quantify steady state brain blood flow but make it difficult to measure dynamic blood flow responses. Despite the usefulness of transcranial Doppler imaging to assess such acute changes in velocity of the middle cerebral artery (MCA), posterior cerebral artery (PCA) or basilar artery (BA) in response to changes in arterial blood gas concentrations, orthostatic stress, or cognitive testing, the major experimental limitation is that this measured velocity may not accurately represent changes in flow. Previous studies using MR imaging have shown that the MCA diameter does not change (during hypocapnia/hypercapnia or orthostatic challenge), suggesting that the MCA velocity represents changes in cerebral blood flow (Serrador et al. 2000). The theory that velocity = flow is under constant scrutiny, which is a reminder that transcranial Doppler has limitations and its use should be dependent on the experimental questions under investigation. In this context, two papers published in the current issue of The Journal of Physiology investigate the changes in cerebral blood flow velocity over a range of CO2 concentrations (Sato et al. 2012; Willie et al. 2012). Although the objectives and primary results of these two papers were independent, both groups question whether differences in sensitivity or responsiveness to CO2 exist when comparing extracranial arterial flow (using duplex ultrasound in the neck) and intracranial arterial velocity (using transcranial Doppler) responses. Without the limitation of the scull, imaging extracranial arteries allows for the quantification of both velocity and diameter and this is then compared to the changes in velocity measured in the intracranial arteries (MCA, PCA or BA). Interestingly, if the results of these two studies are combined, they demonstrate that extracranial artery diameters do increase slightly but non-significantly (∼5–6% in vertebral artery and ∼2–6% in internal carotid artery) in response to hypercapnia at ∼55 mmHg. In addition, the study by Willie et al. reports a 20% change in internal carotid artery diameter in the range of 15–65 mmHg and an 11% increase just during hypercapnia. Therefore, when expressed as flow, the sensitivity to arterial blood gas concentrations is greater than when expressed as velocity in the intracranial arteries. Although these data might suggest that transcranial Doppler is not appropriate for measuring blood velocity changes, eliminating the use of transcranial Doppler may not be the answer. The idea that middle cerebral artery flow velocity does not always equal flow is an important consideration but does not obscure the clinical usefulness of this method in detecting disease risks (i.e. cerebrovascular stroke) and important physiological alterations with ageing, obesity, or diabetes. Furthermore, regional differences in CO2 reactivity and thus blood flow regulation between arteries that supply the brainstem vs. the cortex were evident, regardless of whether this is expressed as flow or velocity (Sato et al. 2012; Willie et al. 2012). However, if regional differences are expressed as flow in the extracranial artery, the reactivity to hypercapnia is 50% greater and the response to hypoxia more than doubled, when compared to reactivity expressed as velocity in the intracranial arteries (Willie et al. 2012). Taken together, this suggests that regional differences in cerebrovascular reactivity between the brainstem and cortex exist, and may be underestimated when expressed as velocity. Moreover, these two papers highlight how little is known about acute cerebrovascular regulation. Extensive work has been done demonstrating how blood flow is regulated in the peripheral tissues, but most data suggest that cerebral blood flow is controlled by the arteriolar pial vessels (Fog, 1938). Importantly, based on the papers by Sato et al. and Willie et al., the large extracranial arteries in humans may also contribute to cerebrovascular regulation. The large arteries may regulate flow to the brain through shear stress-mediated mechanisms via the endothelium, provided that downstream cerebrovascular resistance is not excessive. Importantly, if taken one step further, this provides a mechanistic link between age- or disease-related changes in large artery mechanics, again in the case of ageing, obesity, or diabetes, and the risk of developing white matter hyperintensity and cognitive impairments. For example, increased central arterial stiffness is associated with exaggerated flow pulsatility ultimately causing greater end-organ damage in the kidney and this has recently been demonstrated in the brain (Mitchell et al. 2011). The ability of the large arteries to regulate flow to the brain appears operative in young healthy humans, the population studied by both Sato et al. and Willie et al., but does it deteriorate with ageing and disease? In summary, a few key points should be emphasized: (1) blood flow regulation in the brain is complex and we are only beginning to understand it; (2) the combination of duplex ultrasound techniques, advanced imaging techniques, and transcranial Doppler may be necessary to clarify regional mechanisms of control; (3) because the significance of the large conduit arteries in regulating blood flow to the brain may been uncertain, the consequences of unfavourable changes to arterial structure and function on cerebrovascular function thus far may have been seriously underestimated. Therefore, it would be very timely for future studies to examine the mechanisms of vascular signalling that produce these marked regional differences in the cerebrovascular responses to both arterial CO2 and O2.