Integrative regulation of human brain blood flow

Abstract

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60-150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.

Figure 1

The central figure depicts the cerebrovasculature, comprised of two pairs of large arteries that branch from the sublavian arteries, i.e. the internal carotid arteries (ICAs) that carry ∼70% of total cerebral blood flow (CBF) and the vertebral arteries (VAs) that distribute ∼30% of total CBF to the brainstem, cerebellum and occipital cortex. Both the ICAs and VAs anastomose to form the circle of Willis before branching out into the main intracerebral arteries that ramify extensively en route to the brain surface. At the surface, the vessels form a dense network of highly vasoactive arterioles within the pia mater before they penetrate into the cortex (inlay II). The driving pressure in this system is the cerebral perfusion pressure (CPP) that is determined by the difference between mean arterial pressure (MAP) and intracranial pressure (ICP), in conditions where central venous pressure (CVP) is lower than ICP. In these conditions, MAP approximates CPP. Thus, it is important to note that the figure shows a schematic diagram of the cerebrovascular state in a resting supine human, and does not consider the myriad complex adjustments that take place with orthostatic stress (Gisolf et al. ; Hicks & Munis, 2005). As a result of the enclosed nature of the skull, ICP acts as a Starling resistor for cerebral venous outflow, a mechanism that is likely to be of greater importance with marked elevations in ICP or CVP, or both. The cerebral arteries (including the ICAs and VAs) are sensitive to changes in blood gases (Heistad et al. ; Faraci et al. ; Willie et al. 2012) and to changes in perfusion pressure, thus serving as a first-line defense in maintaining brain perfusion (Faraci et al. , b; inlay I). These arteries are also densely innervated with branches of the cranial nerves, the carotid sinus nerve and branches from the superior cervical ganglion. The role of these nerves is contentious, but evidence favours cerebral constriction in response to increased sympathetic outflow and/or increased MAP, particularly at the tortuous segments where the ICA and VA vessels enter the skull. Turbulent blood flow through these segments increases resistance for a given luminal diameter according to Poiseuille's law; constriction of the vessel in these sections in the face of increased MAP attenuates pressure increases distal to the tortuous segment (inlay I). Inlay II shows a neurovascular unit. The pial vessels respond to changes in CPP, arterial partial pressures of O₂ () and CO₂ (), oxygen content, and proton concentration (Wolff & Lennox, ; Kontos et al. ; inlay III). The pial arteriole penetrates the pia mater through the Virchow–Robin space, where it becomes encapsulated by glial processes termed end-feet and pericytes that release vasoactive substances and respond mechanically by constricting or dilating with changes in metabolic demand of the surrounding neural matrix. Gap junctions between the endothelial and vascular smooth muscle cells allow for retrograde conductance of intramural vascular signals such that vasodilatory or constrictive signals pass to the pial arterioles. Thus, the neurovascular unit titrates blood flow to the metabolism of discrete cortical areas. Inlay III shows a qualitative schematic diagram of pial cross-sections against a hypothetical metabolic milieu spectrum. Note the vessels are not only exposed to arterial conditions but also to that of the cerebrospinal fluid that completely surrounds the pial vessel, tethered on all sides by thin processes to the pia mater. The vessels dilate with decreases in perfusion pressure, PaO² and/or arterial O₂ content () and increases in and/or [H⁺].

Figure 2

Cerebrovascular reactivity to changes in CO₂ and to hypoxia (%ΔCBF / mmHg CO₂) and %ΔCBF / %SaO₂) was found to be similar between vessels in the hypercapnic range, ∼10% greater for the VA than the ICA in the hypocapnic range, and 50% greater for the VA with extreme hypoxia.

Figure 3

Left panel is a stylized representation of the classical view of the relationships between mean arterial pressure (MAP) and cerebral blood flow (CBF), i.e. autoregulation, put forward by Lassen et al. (1959) based on the between-subject analysis of patients during various pharmacological interventions or pathologies. Right panel is a schematic diagram based on contemporary data indicating a small plateau region (Tan, 2012) and cerebral autoregulation hysteresis. Based on the within-subject reanalysis of 41 studies that reported concomitantly measured CBF and MAP during increases or decreases in blood pressure, the slope of the %ΔCBF versus %ΔMAP relationship was determined to be 0.81 ± 0.77 in the hypotensive range and 0.21 ± 0.47 in the hypertensive range. This indicates a far more pressure-passive CBF than is conventionally believed, and that more efficacious buffering capacity against increases than decreases in perfusion pressure (unpublished observations). See main text for details.

Figure 4

Note the abolishment of cerebrovascular reactivity with progressive hypotension. Values are calculated from the data of Harper & Glass (1965).