What Rate Should Blood Flow in the Brain in Order to Maintain Normal Function?

Neuroscience for neurologists

Cerebral perfusion and stroke

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1. H S Markus

1. Correspondence to:
 Professor Hugh Markus
 Clinical Neuroscience, St George'due south Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK; h.markussghms.ac.u.k.

Abstract

Stroke is a heterogeneous syndrome acquired by multiple disease mechanisms, but all result in a disruption of cerebral claret flow with subsequent tissue damage. This review covers the mechanisms responsible for regulation of the normal cerebral circulation, and how they are disrupted in disease states. A primal concept in treating patients with acute ischaemic stroke is the being of an ischaemic penumbra of potentially salvageable tissue, and the evidence for its existence in humans is reviewed.

• stroke
• cerebrovascular illness
• cognitive blood flow
• ischaemic penumbra
• cerebral circulation

• ADC, credible diffusion coefficient
• AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole
• CBF, cerebral blood flow
• CBV, cerebral blood volume
• CMRo _two, cerebral metabolic rate of oxygen
• CPP, cerebral perfusion force per unit area
• CVR, cerebrovascular resistance
• DWI, diffusion weighted imaging
• eNOS, endothelial nitric oxide synthase
• IMP, inosine 5′-monophosphate
• iNOS, inducible nitric oxide synthase
• MTT, mean transit time
• NMDA, N-methyl-D-aspartate
• nNOS, neuronal nitric oxide synthase
• NOS, nitric oxide synthase
• OEF, oxygen extraction fraction
• PET, positron emission tomography
• SPECT, single photon emission computed tomography
• ^99mTcHMPAO, technetium-99m hexamethylpropylene amine oxime

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• stroke
• cerebrovascular disease
• cognitive blood menstruation
• ischaemic penumbra
• cerebral apportionment

• ADC, apparent diffusion coefficient
• AMPA, α-amino-iii-hydroxy-v-methyl-four-isoxazole
• CBF, cognitive blood flow
• CBV, cognitive blood book
• CMRo ₂, cerebral metabolic rate of oxygen
• CPP, cerebral perfusion pressure
• CVR, cerebrovascular resistance
• DWI, improvidence weighted imaging
• eNOS, endothelial nitric oxide synthase
• IMP, inosine 5′-monophosphate
• iNOS, inducible nitric oxide synthase
• MTT, mean transit time
• NMDA, North-methyl-D-aspartate
• nNOS, neuronal nitric oxide synthase
• NOS, nitric oxide synthase
• OEF, oxygen extraction fraction
• PET, positron emission tomography
• SPECT, single photon emission computed tomography
• ^99mTcHMPAO, technetium-99m hexamethylpropylene amine oxime

The cognitive circulation has developed several specialised features to cope with the high metabolic demands of the brain and the devastating consequences of cerebral ischaemia. Unlike other organs, the brain uses glucose nearly exclusively as its sole substrate for energy metabolism. As information technology is unable to store energy it requires a constant supply of oxygenated claret containing an adequate glucose concentration to maintain its function and structural integrity. The brain oxygen requirement in the adult human accounts for about xx% of that of the whole body, for a relative size of only 2%. Brain oxygen uptake is even higher in children in the beginning decade of life, where it may exist up to 50% of the full body oxygen supply.¹ This high metabolic demand is matched by a disproportionately large amount of the full cardiac output passing to the brain. Full cerebral blood menstruum (CBF) at rest is about 800 ml/min, which is fifteen–20% of full cardiac output.^two Cognitive perfusion is a high menstruation, low pressure organisation with relatively preserved diastolic flow. This can exist appreciated by comparing Doppler waveforms from cerebral vessels with systemic vessels; the ratio of diastolic to systolic flow is much higher for the cerebral apportionment. Anatomical features and functional responses, including cerebral autoregulation, allow this high flow and provide protection confronting ischaemia.

CEREBROVASCULAR Anatomy

The cerebral circulation has a well developed collateral apportionment which plays an important protective function. Of crucial importance are communications between the basal cognitive arteries at the circle of Willis.³ Natural variation in its integrity will determine whether carotid apoplexy results in massive hemispheric stroke or is asymptomatic. Collateral supply may likewise occur through anastomoses between the external carotid artery branches and the intracerebral circulation, and there is a well developed plexus of anastomoses betwixt cerebral vessels on the surface of the encephalon.^iv Despite this collateral supply, there are regions of the brain that are particularly vulnerable to a fall in perfusion pressure level. Such border zone areas include those at the boundaries between the anterior and center and the eye and posterior cognitive arteries, and the "internal" border zone areas in the corona radiata and centrum semiovale. Territories supplied by the penetrating or perforating arteries that supply the white matter and subcortical grey affair nuclei are particularly vulnerable to ischaemia. These arteries are end arteries and therefore ischaemia in their territory results in more rapid cell expiry.

METHODS FOR MEASUREMENT OF CEREBRAL Claret Flow

Diverse different techniques (table 1) allow measurement of regional cerebral perfusion, although many are only semiquantitative. Such techniques crave a tracer or contrast amanuensis and an imaging technique allowing its concentration to be measured. Commonly used techniques include positron emission tomography (PET), single photon emission computed tomography (SPECT), xenon computed tomography (CT) and contrast CT perfusion, and magnetic resonance imaging (MRI) perfusion studies.

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Table 1

Methods of measurement of cerebral claret flow

Nuclear medicine methods

Nuclear medicine methods use radionucleides as tracers and the tomographic arroyo in prototype reconstruction. These tin can exist distinguished on the footing of the concrete characteristics of the radionucleides. SPECT uses low energy, photon emitting radionucleides. PET uses coincidence radiations employing positron emitting radionucleides which, after annihilation, produce two 511 keV τ rays. PET allows quantification, while with SPECT simply semiquantification is possible. Both involve exposure to significant radiations doses. The tracer virtually ordinarily used for PET CBF measurements is ¹⁵O labelled water. Only PET allows measurement of oxygen utilisation and therefore the oxygen extraction fraction (OEF). SPECT is more widely available and uses lipophilic tracers that easily cantankerous the blood–brain barrier and ideally are fully extracted during the first pass through the cerebral circulation. ^99mTcHMPAO is almost widely used. Information technology is stable for about half dozen hours subsequently beingness reconstituted, making it convenient for clinical use. A good correlation with CBF values has been obtained.^v Xenon is unremarkably used in cerebral perfusion measurement both with CT and SPECT. Xenon gas can be inhaled in significant quantities with little risk, although at high concentrations it is an anaesthetic. It dissolves into claret and readily diffuses through the blood–encephalon barrier. Xenon has a high diminutive number relative to air and soft tissues and as a result its presence tin can be measured by CT. A washout method tin can exist used; when an initial equilibrium of substance has been reached in the tissue and the supply is acutely discontinued, the substance concentration decays in an exponential fashion and the decay of the exponential contains information on perfusion.⁶

Computed tomography

Perfusion CT involves sequential acquisition of stationary cerebral CT sections during intravenous assistants of a bolus of iodinated contrast material.^vii Assay of the resultant contrast enhancement curves according to the central book principle allows calculation of cerebral blood volume (CBV), mean transit fourth dimension (MTT), and CBF.

Magnetic resonance imaging

Increasingly, MRI methods are used to measure perfusion. These autumn into two categories.

Exogenous dissimilarity methods are most widely used and rely on an intravenous bolus injection of a paramagnetic tracer and acquisition of rapid images, using echo-planar imaging, every bit the tracer passes through the cerebral vasculature.⁸ The effect of the tracer is to reduce signal from tissue in its immediate vicinity owing to dephasing effects caused by the magnetic field gradients induced. This signal loss is closely related to the flow of the tracer through the brain and thus to cerebral perfusion. This method likewise offers the ability to measure CBV and MTT. Its advantage is that paramagnetic substances have a large issue on signal intensity, and therefore the bespeak to racket ratio is loftier. Recent studies have suggested that a degree of quantification is possible if an arterial input function is obtained by imaging through a supplying vessel,^viii although whether absolute quantification is reliable is debated.

Endogenous methods such equally arterial spin labelling employ blood water equally an endogenous contrast agent for the measurement of perfusion. This is completely non-invasive and can be repeated as often as desired, but the signal to dissonance ratio is depression.

Ultrasound

Ultrasound methods are non-invasive. Carotid and vertebral neck ultrasound uses either Doppler based⁹ or non-Doppler based methods¹⁰ to quantify volume flow in the major supplying arteries, rather than regional perfusion. In dissimilarity, transcranial Doppler, most ordinarily of the middle cerebral artery, measures velocity and not flow and therefore only gives an accurate judge of changes in flow if the diameter of the vessel being insonated does non change. Tissue perfusion can now exist estimated using transcranial imaging ultrasound, but quantification using this technique is still being adult.¹¹

REGULATION OF THE NORMAL CEREBRAL CIRCULATION

Basal cognitive blood flow regulation

Nether normal conditions CBF is determined by both cerebral perfusion pressure level (CPP) and cerebrovascular resistance (CVR). CVR is adamant by the diameter of the intracranial arteries and also blood viscosity. CPP tin can be calculated from the difference between systemic arterial pressure and venous back pressure. In weather were CPP remains abiding any change in CBF must event from a change in CVR, usually as a consequence of alteration in the diameter of the small intracranial arteries, which are the predominant resistance vessels. Thus under normal circumstances in that location is a directly correlation between CBF and cerebral blood volume, which volition both increment as vessels dilate and subtract as vessels constrict. This relation is disturbed in pathological states such equally cerebral ischaemia.

Various physiological variables influence CBF, including arterial blood gases, cognitive autoregulation, and metabolic charge per unit through vasoneuronal coupling. One important mediator controlling basal CBF is nitric oxide. In 1980¹² it was shown that an intact endothelial prison cell layer is required if isolated arterial segments were to relax in response to perfusion with acetylcholine. It was subsequently institute that this "endothelium derived relaxing gene" is nitric oxide (NO), synthesised past endothelial cells from the amino acid 50-arginine past the enzyme NO synthase (NOS).¹³ There are iii isoforms of this enzyme: endothelial NOS (eNOS), neuronal NOS (nNOS), and an inducible NOS (iNOS). Endothelium derived NO plays a crucial role in maintenance of claret vessel calibre and therefore blood catamenia throughout the vasculature. Information technology is likewise important in preventing thrombosis through inhibition of platelet adhesion, activation, and aggregation, and in preventing atherosclerosis by inhibition of vascular smooth musculus cell proliferation. Nether normal weather condition at that place appears to be a functional balance between the endothelium dependent vasodilator effects of NO and the endothelium derived constrictor substances such as endothelin, thromboxane, and angiotensin II. Extensive animal data in a variety of species have shown that tonic release of NO plays an important part in maintaining resting CBF.¹⁴ More recently the role of NO in maintaining basal CBF has been shown in the human: inhibition of NO by the NO synthase inhibitor N-monomethyl-L-arginine (50-NMMA) resulted in a xxx% fall in CBF.^{15, sixteen}

Cognitive autoregulation

CBF remains relatively constant despite moderate variations in perfusion pressure. This phenomenon, described as "cerebral autoregulation," plays an important protective part against the danger of hypoxia at low perfusion force per unit area, and the risk of encephalon oedema at higher arterial pressure.¹⁷ As a crude approximation the lower and upper limits of autoregulation occur at mean arterial pressures of 60 and 150 mm Hg in the normotensive human. Between these limits CBF is relatively but not admittedly constant. Once the limits of autoregulation are reached, CBF increases or decreases passively with increases or reductions in perfusion pressure.

Reductions in CBF below the limit of autoregulation result in brain hypoperfusion. In an attempt to compensate for this, the extraction coefficient of oxygen from the blood increases. Clinical symptoms of functional disruption are not observed until the reduction in CPP exceeds the power of the increase in oxygen extraction to satisfy the metabolic demands of cerebral tissues. If mean arterial pressure increases higher up the upper limit of autoregulation, resistance arteries in the brain cannot sustain vasoconstriction. An early sign is the appearance of "sausage stringing," characterised by an alternating pattern of dilated arterial segments with focal regions of constriction. The dilated segments correspond regions of passive dilatation, and the constricted segments regions of sustained autoregulation. Farther increases in CPP outcome in dilatation along the unabridged length of the arterioles, and CBF increases passively. This is accompanied by damage to the cerebrovascular endothelium and disruption of the claret–encephalon barrier. The latter results in extravasation of plasma proteins through the vessel wall and subsequent oedema. These events are important in acute hypertensive encephalopathy.

The upper and lower limits of autoregulation are not fixed but vary nether both physiological stimuli and disease states. Activation of the sympathetic fretfulness results in upward shift of both the lower and upper limits—a potentially protective response because acute elevations in arterial pressure are usually accompanied by sympathetic activation. The autoregulatory plateau is shifted to higher values in patients with chronic hypertension.¹⁸ This protective response can have deleterious effects if blood pressure is excessively reduced, when symptoms of ischaemia may occur at a relatively higher blood pressure.

Cerebral autoregulation is impaired in various illness states including head injury,¹⁹ ischaemic stroke,^twenty and subarachnoid haemorrhage.²¹ This may result in an already damaged brain existence excessively sensitive to fluctuations in perfusion pressure.

Assessment of cerebral autoregulation in the man

Traditionally, studies in the man take estimated "static" autoregulation. Steady state values of CBF are determined beyond a range of blood pressures. This is achieved past the use of drugs or shifts in blood book—for example, using tilt tables or negative pressure.²² Conclusion of the full range of autoregulation requires blood pressure level to exist manipulated across a broad range, and the long time interval between measurements fabricated at different pressures can brand estimation of studies difficult. More recently methods for estimating "dynamic" autoregulation in humans take been adult. These determine the rate of response of CBF or flow velocity subsequently a sudden alter in arterial blood pressure. A technique assuasive measurement of CBF with very high temporal resolution is required. The only technique that can provide this is transcranial Doppler ultrasound. In the most widely used technique a sudden fall in blood pressure level is induced by inflating leg cuffs above venous force per unit area and then rapidly deflating them.²³ The rate of ascent of CBF velocity in the heart cognitive artery is and then compared with the charge per unit of rise of blood pressure level continuously monitored using a non-invasive device such equally a Finapres. Using this technique, autoregulation has been shown to be impaired distal to carotid artery stenosis,²⁴ following head injury,²⁵ and in ischaemic stroke.²⁶ Although the measurement of dynamic autoregulation gives a useful gauge of how the cerebral circulation tin can compensate for fluctuations in perfusion pressure, it may not necessarily be measuring the aforementioned mechanisms that decide static autoregulation.

Physiological mechanisms of autoregulation

The mechanisms responsible for CBF autoregulation in the human are not fully understood. Traditional hypotheses are that neurogenic, myogenic, and metabolic factors play a office. More than recently NO has been implicated. Autoregulation is preserved in animals that take undergone sympathetic and parasympathetic denervation, suggesting that neurogenic factors are not of master importance.²⁷

The myogenic hypothesis states that smooth muscle in the resistance arteries responds directly to alterations in perfusion force per unit area past contracting during increases in pressure, and relaxing during reductions in pressure level. This would provide a machinery whereby responses in cerebral resistance arteries could occur within seconds of an autoregulatory stimulus. In vitro animal experiments support this hypothesis, with constriction of isolated arteries occurring following a rapid increase in intravascular pressure. In vivo experiments take not, in general, provided such strong support.²⁷ The metabolic hypothesis states that reductions in CBF stimulate the release of vasoactive substances from the brain, which in plow stimulates the dilatation of cerebral resistance arteries. Several candidates for this function accept been proposed—including carbon dioxide, hydrogen ions, oxygen, adenosine, potassium, and calcium—but no definite part has been demonstrated for any of these.²⁸

Endothelial factors, particularly NO, take been suggested as mediators of cerebral autoregulation. In some creature studies, impaired autoregulation has been reported following inhibition of NO, but others have constitute no consequence.²⁹ In eNOS knockout mice there was a greater autumn in CBF during haemorrhagic hypotension than in wild type mice, consequent with an alteration in the lower limit of autoregulation.³⁰ In humans the NOS inhibitor L-NMMA resulted in a significant impairment of dynamic autoregulation.²⁹

Arterial blood gases, the hypercapnic response, and CBF

CBF is very sensitive to changes in blood CO₂ concentrations, largely mediated by concomitant changes in the pH of brain tissue.³¹ Apart from this direct outcome of pH on cerebral vessels, secondary mechanisms may mediate vasoactive effects through a pH dependent alteration in the release of other vasoactive factors. Prostaglandins have been suggested as mediators of CO₂ dependent changes in CBF, based on the effects of the inhibitor of cyclo-oxygenase, indomethacin. However, farther studies in animals³¹ and humans³² cast doubt on this mechanism in adults, although it does announced to be important in newborn animals.³¹

Studies in rats suggested NO dependence of the hypercapnic response, although this NO production is primarily through nNOS rather than eNOS. Notwithstanding, results in higher species have been less consistent, and studies in primates accept shown conflicting results.^{33, 34} A complicating cistron in animal studies is that amazement may alter cerebrovascular responses. A written report in humans showed that inhibition of eNOS by intravenous North^G-monomethyl-L-arginine (L-NNMA) did not alter the hypercapnic response.¹⁵

Reducing arterial Po _ii results in an increase in CBF, whereas an increment in arterial Po ₂ above normal values has a much lesser effect. Hypoxia appears to act both through a direct effect on cerebral resistance vessels, and through indirect effects including the release of vasoactive factors such every bit hydrogen ions, adenosine, and potassium ions.³¹ It has also been suggested that pH dependent mechanisms—mainly the production of lactate—participate in hypoxic vasodilatation.³⁵

Clinical relevance of the hypercapnic response

The response of CBF to hypercapnia is widely used in humans to estimate cerebral perfusion reserve, nearly often in patients with carotid stenosis or occlusion. The haemodynamic consequences of a carotid stenosis—for example, during a autumn in claret force per unit area—will depend on distal collateral supply, particularly through the circle of Willis. An estimate of this cognitive perfusion reserve can be obtained by measuring CBF during both normocapnia and hypercapnia (with concentrations of 5–eight% CO₂ in air). In the presence of impaired reserve, resistance vessels are already vasodilated, and the capacity to increase CBF further is reduced (fig 1). A wide range of imaging methods has been used to mensurate the hypercapnic response, including PET, SPECT, MRI, and xenon based techniques. For techniques that practice not let absolute quantification (such as SPECT), side to side differences are calculated; this makes interpretation hard in bilateral carotid stenosis. Transcranial Doppler monitoring of middle cerebral avenue flow velocity has go widely adopted in this context.³⁶ Its validity is suggested by angiographic studies showing that the diameter of the middle cerebral avenue does not change during hypercapnia.³⁷ Acetazolamide, a carbonic anhydrase inhibitor, can be used as the vasodilator stimulus instead of CO_ii.

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Figure i

Measurement of cognitive perfusion reserve or cerebral reactivity in a patient with unilateral right internal carotid avenue occlusion. Claret menses velocity is recorded continuously from both middle cerebral arteries. As the patient breaths a 6% and then an viii% mixture of carbon dioxide in air, period velocity increases on the left but not on the right. This indicates severely dumb perfusion reserve ipsilateral to the occlusion. MCA, middle cerebral artery.

Prospective studies have shown that a reduced hypercapnic response ipsilateral to a carotid apoplexy is associated with an increased risk of stroke or transient ischaemic attacks (TIA).^{38– xl} It has been suggested this test may identify a subgroup of patients with carotid occlusion who benefit from extracranial–intracranial featherbed, although this hypothesis has however to be tested. At that place is some evidence from prospective studies that patients with tight carotid stenosis, as opposed to occlusion, and who have impaired perfusion reserve are at increased risk of stroke, but the clan appears less strong than for carotid occlusion.³⁹

Local coupling of cerebral blood menses and metabolism

Local CBF is tightly coupled to changes in neuronal metabolism, and this forms the basis of functional encephalon imaging using BOLD MRI. Over a century ago Roy and Sherrington suggested that "...(the brain) is well fitted to provide for a local variation of the blood supply in accordance with local variations of the functional activity".⁴¹ Numerous studies take shown that local increases in neuronal activity result in a local increase in glucose utilisation, accompanied past local increases in CBF. The precise mechanisms linking neuronal activation, metabolism, and flow are not fully understood. Various factors are likely to contribute to this coupling process, including potassium release with neuronal depolarisation, and H⁺ and adenosine release when there is a mismatch between oxygen commitment and utilisation. NO may play a key mediator office, probably through production via nNOS rather than eNOS. In animal models, cerebral vasodilatation associated with simple somatosensory stimulation appears to be mediated by nNOS derived NO.⁴² In the homo, Fifty-NMMA given intravenously did not alter the local CBF response to learned sequential movements, just, because of its poor blood–brain barrier penetration, it probably just inhibits eNOS.¹⁶

CEREBRAL Circulation RESPONSES TO FOCAL ISCHAEMIA

Protective responses to a progressive autumn in cerebral perfusion pressure

CPP can fall because of systemic arterial hypotension, or severe stenosis in an extracranial or intracranial supplying artery, or a combination of the 2. Every bit CPP falls, intracranial resistance vessels amplify to maintain CBF; this results in an increase in CBV. When vasodilatation is maximal, further falls in CPP issue in a autumn in CBF. Considering oxygen commitment to the encephalon normally greatly exceeds demand, metabolic activity is maintained initially by increasing the OEF from claret. When oxygen extraction becomes maximal, menses is inadequate to meet metabolic demands, cellular metabolism is impaired, and the cognitive metabolic rate of oxygen (CMRo ₂) begins to autumn. This sequence of events is illustrated in fig two.

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Figure 2

A schematic illustration of the consequences of a progressive fall in cerebral perfusion pressure. This can occur because of a progressive fall in arterial blood pressure, or because of a stenosis or apoplexy of a major supplying artery to the brain. As CPP falls, CBF is maintained past vasodilatation. This results in a progressive rise in CBV. When vasodilatation is maximal, cerebral autoregulation is exhausted, and a farther reduction in CPP results in a decrease in CBF. As CBF falls, oxygen extraction is increased and functional consequences of reduced CBF only occur when OEF is maximal.

Critical flow thresholds

Every bit cerebral autoregulation is impaired or lost in moderate to astringent ischaemia, CBF varies passively with CPP. This relation has allowed investigators to gradually reduce CBF and assess disquisitional menses thresholds at which certain functions are lost.⁴³ Experimental studies in primates⁴⁴ and cats,⁴⁵ and clinical studies in humans during carotid endarterectomy,⁴⁶ have shown that spontaneous and evoked electric activity ceases when CBF falls beneath 16–18 ml/100 k/min. This level of ischaemia therefore represents a threshold for loss of neuronal electrical function (that is, electrical failure). It was later on shown that at that place is a lower threshold (10–12 ml/100 thousand/min) for loss of cellular ion haemostasis (that is, membrane failure). At this lower threshold, Grand⁺ is released from and Caⁱⁱ⁺ taken up by the cells.⁴⁷ Rapid efflux of K⁺ and uptake of Ca²⁺ represents a generalised collapse of membrane role and at this signal cells also take up Na⁺ and Cl⁻ with osmotically obligated water.⁴³ The threshold for infarction appears similar to that for energy failure/loss of membrane haemostasis, but it varies with the elapsing of the insult.

More than contempo studies suggest that the pattern of thresholds may be more complex, although the general principle of two major critical flow thresholds (loss of electrical function and then loss of cellular ion haemostasis) still applies.⁴⁸ Protein synthesis is inhibited get-go (at a CBF of about 50 ml/100 g/min), and is completely suppressed beneath 35 ml/100 g/min. This is in a higher place the level at which glucose utilisation and energy metabolism are disrupted. Glucose utilisation transiently increases at menstruum rates below 35 ml/100 thou/min, before it sharply declines beneath 25 ml/100 thou/min. This corresponds to anaerobic glycolysis with the beginning of acidosis and the aggregating of lactate. At period rates below 26 ml/100 g/min, tissue acidosis becomes pronounced and both phosphocreatine and ATP begin to decline.⁴⁸ Anoxic depolarisation, as assessed past recording extracellular potassium and calcium activities, occurs at even lower values (<15 ml/100 m/min) (fig iii).

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Figure three

Thresholds of ischaemia for the consecration of functional, metabolic, and histological lesions. Verbal levels vary slightly in different animal models and also with the duration of ischaemia for certain variables. CMRG, cerebral metabolic rate of glucose; PCr, phosphocreatine. Modified from Hossman,⁴⁸ fig one.

THE ISCHAEMIC PENUMBRA

The concept of an ischaemic penumbra is crucial to the treatment of astute stroke. Information technology follows on from the finding of split thresholds for electrical failure and loss of ion haemostasis. The concept is that following a focal ischaemic insult a penumbral region exists around a core of densely ischaemic and irreversibly damaged tissue. This penumbral region contains electrically inexcitable but feasible cells. It follows that if perfusion is restored to this region, tissue salvage may be possible. The concept originated in the mid 1970s from experiments done on baboons.⁴⁹ Afterwards eye cognitive artery occlusion, brain tissue could be identified which had lost its electrical office simply did not prove the release of potassium that characterises cell death. This functionally silent tissue was nevertheless viable because it regained its function and did not undergo necrosis if flow was restored early enough. This tissue was named the ischaemic penumbra. Topographically the penumbra was shown to exist mainly cortical surrounding the ischaemic cadre, which in the birdie, equally in the human, predominantly involves the subcortical structures supplied by the perforating arteries. In later on studies it was found that the duration of ischaemia, as well every bit the absolute flow, plays a crucial function in determining the fate of ischaemic tissue. For instance, in the macaque monkey, tissue with CBF of effectually 15 ml/100 g/min could withstand most three hours of occlusion, while tissue with a perfusion of around 5 ml/100 g/min would stand only ii hours.⁵⁰ This fourth dimension dependence has crucial significance when considering acute treatment in humans, and implies that treatment will be most successful when it is given every bit early on as possible. A crucial question when assessing the potential for astute stroke therapy is how extensive the ischaemic penumbra is in the human.

Is there an ischaemic penumbra in the human?

PET studies have suggested that there is a significant ischaemic penumbra in humans, and that reversibly ischaemic tissue may persist for much longer than initial experiments in smaller animals suggested.⁵¹ These studies used oxygen-PET and quantitatively measured the main physiological variables involved in tissue ischaemia—namely CBF, CMRo _two, OEF, and CBV. Using this technique, a pattern of changes termed "misery perfusion" can exist identified. This is characterised past reduced CBF with relatively preserved or even normal CMRo ₂, thus fitting the concept of penumbra with tissue of reduced perfusion only relatively maintained neuronal function. The authentication of misery perfusion is an increased OEF, ranging from the normal value of about 30–xl% up to a theoretical maximum of 100%, where the tissue extracts all the oxygen supplied by the blood menstruum reaching information technology.

In the late 1980s and early 1990s several groups applied PET to investigate the pathophysiology of ischaemic stroke. In the acute phase in patients with anterior circulation stroke, misery perfusion was found to affect mainly the cortex, while the capsule–basal ganglia region ofttimes showed markedly reduced CMRo ₂, and only moderately increased OEF.^{52, 53} Deterioration of CMRo _two from the acute to subacute stage of stroke was reported, and this was interpreted every bit the transition from ischaemia to necrosis. However, no report direct documented the presence of tissue that was nonetheless metabolically active within a region that went on to infarction, as determined past follow upwardly CT or MRI.⁵¹

Baron and colleagues studied 30 patients with commencement always center cerebral artery territory ischaemia within 18 hours of stroke onset and co-registered these early PET scans with late CT scans done to assess last infarct size.⁵⁴ Those voxels or regions within the finally infarcted tissue with preserved CMRo ₂ on acute phase PET were identified. Of the 30 patients, there were eight who survived until the late CT, had follow up PET, had a middle cerebral artery territory infarct of >16 ml equally measured on late CT scanning, and had technically acceptable PET studies. In seven of these, voxels were found which progressed to infarction but initially had CMRO_ii values above the threshold for irreversible damage. The tissue identified represented substantial volumes of the final infarct, being a mean of 35% and every bit high as 52% in i patient. Furthermore "penumbral" tissue was observed in ii cases at xvi hours and in another case at thirteen hours subsequently stroke onset.

Proving that this is indeed penumbral tissue requires intervention studies in which the penumbra is salvaged by treatment that restores flow. Nevertheless, the concept is supported by the results of clinical trials showing that thrombolysis improves issue,⁵⁵ and also past more recent MRI studies (come across below). Further support is provided by PET studies in the baboon which showed that tissue with acute misery perfusion went on to infarction if the middle cerebral artery was permanently occluded, but escaped infarction if the avenue was reopened at six hours.⁵⁶ Interestingly, the time window for reperfusion in the birdie was much longer than in previous macaque experiments,⁴⁸ and considerably longer than PET studies in the true cat.⁵⁷ These meaning species differences emphasise the importance of undertaking studies in humans.

Tin MRI identify an ischaemic penumbra?

Although PET studies give quantitative information on CBF and oxygen metabolism they are not widely available, difficult to exercise in large numbers of patients, and involve the administration of radioisotopes. The ability to place potentially salvageable tissue using more widely available techniques has great attraction. In that location is considerable involvement in the potential of MRI to identify an "ischaemic penumbra," based on a combination of perfusion and diffusion weighted imaging techniques. Well-nigh studies accept used exogenous perfusion techniques to mensurate the perfusion deficit. The nigh promising technique for identifying ischaemic tissue is diffusion weighted imaging (DWI). Diffusion imaging is dependent on the apparent diffusion coefficient (ADC) of water in tissue. Following ischaemia, ADC values quickly decline, respective to a region of high signal on DWI. This ADC decline is probable to reflect the accumulation of intracellular water, cytotoxic oedema, disruption of high energy metabolism, and loss of ion homeostasis. These ADC changes do not occur uniformly in the ischaemic region, and in experimental stroke models ischaemic tissue with the virtually severe perfusion deficit has the earliest and most severe fall in ADC. Serial DWI studies in animate being models take demonstrated the evolution of ADC changes over fourth dimension, and shown that mild declines in ADC early later on stroke are potentially reversible.

The concept of diffusion–perfusion mismatch has been developed as a possible mode of identifying potentially salvageable tissue in the human. The rationale is that tissue that is abnormal on DWI and has low perfusion is destined for infarction. In contrast, tissue that is normal on DWI simply has perfusion reduced to penumbral levels may either recover, particularly if flow is restored, or progress to infarction. In that location is considerable support for this hypothesis. Within vi hours of stroke onset approximately 70% of acute patients will have a perfusion book greater than the diffusion book, xx% will have equal volumes, and in ten% the perfusion volume will be smaller, representing spontaneous reperfusion.⁵⁸ Baird et al studied xiii patients with ischaemic stroke in whom both DWI and perfusion imaging were measured at an initial time bespeak (two to 53 hours) and at follow up time points (vii to 725 days).⁵⁹ Lesion volume increased past 230% when the perfusion volume exceeded the initial DWI volume, but decreased by 47% when perfusion volume was smaller than or equivalent to the DWI volume. Barber et al reported an increase of 62% in the DWI lesion volume between acute (<24 hours) and subacute (3–5 days) time points, when the perfusion volume was greater than the DWI lesion volume (11 of 17 patients).⁶⁰ The remaining six patients in whom the perfusion volume was less than the DWI volume had a stable DWI lesion volume.

Studies in patients receiving thrombolysis provide further evidence that this mismatch does represent reversibly ischaemic tissue. Patients undergoing intravenous thrombolysis, who underwent successful reperfusion, had reduced lesion volume as defined by DWI and subsequently by T2 weighted MRI.⁶¹ Similar results have been found in patients receiving intra-arterial thrombolytic treatment.⁶² MRI studies also emphasised the heterogeneity of human stroke. In some patients mismatch is still present many hours subsequently stroke, consequent with the PET studies,⁵¹ while in others there is no mismatch early on afterwards stroke. This may partly explain why acute stroke trials have been disappointing and it has led to the suggestion that treatment needs to exist tailored to the patient more effectively. Current therapeutic trials are targeting patients with persisting mismatch for treatment with thrombolytic and other agents.

Recent data have suggested that the diffusion–perfusion concept is more complex. Initially it was idea that tissue appearing abnormal on DWI in humans was nearly ever destined to infarction. Example reports were published showing reversibility of DWI changes, and a more recent serial has confirmed that DWI abnormalities may recover,⁶³ although probably in a minority of patients. Furthermore on repeat scanning at 7 days such recovered areas may remain normal, or DWI and T2 abnormalities may reappear. This is consistent with animate being studies showing secondary delayed ADC declines after temporary focal occlusion. The clinical significance of these changes is not fully understood, but if they predict a worse clinical result they may represent a therapeutic target for post-reperfusion neuroprotective targets. Despite the MR improvidence–perfusion concept being more complicated than initially appreciated, at that place is considerable evidence that it does allow "penumbral" tissue to be identified. Its clinical employ will depend upon current prospective randomised trials showing that it tin identify a subgroup of patients who benefit peculiarly from therapeutic interventions such as thrombolysis.

MRI is much more than widely available than PET, but nevertheless few units can offer information technology to all patients with acute stroke. This has led to attempts to use the more available applied science of CT perfusion to identify the extent of reversibly ischaemic tissue. Compared with DWI, non-contrast CT imaging is poor at showing ischaemic tissue in the outset few hours. However, with the use of a rapid intravenous injection of iodinated dissimilarity in combination with newer multislice CT scanners, maps tin exist obtained of CBF, CBV, and MTT, in add-on to conventional non-contrast CT images, with conquering times of less than 10 minutes.^seven CT perfusion measurements have been found to correlate well with stable xenon-CT estimates.⁶⁴ Using this method, an ischaemic cerebral expanse (penumbra plus irreversibly damaged tissue) has been defined every bit a CBF reduction of more than than 34% compared with the contralateral hemisphere.⁶⁵ Within this area, regions with a CBV below a predefined cut off (2.v ml/100 g) were selected as irreversibly damaged tissue, with the remainder divers as penumbra. In a validation study against MRI in 13 subjects, a highly significant correlation was found between the CT defined irreversibly damaged tissue and the region of MR DWI abnormality.⁶⁵ The ischaemic cognitive area correlated strongly with the MR defined MTT defect, merely less well with the MRI perfusion defect obtained from CBF maps. The authors suggested that CT perfusion provides a similar degree of information to MRI on penumbral tissue. Other pocket-sized studies accept as well shown correlations with MRI estimates,⁶⁶ merely much more than data from larger series are required, ideally including comparisons with PET as well equally with MRI.⁶⁷ This should both ostend these findings, and show that the CT derived data allows prediction of upshot and selection of a grouping who may benefit from thrombolytic and other treatments. A further limitation of CT perfusion in comparison with MRI is that slice coverage is limited.

MECHANISMS OF INFARCTION IN PENUMBRAL TISSUE

A complex pour of mechanisms is responsible for the progression of penumbral tissue to infarction. Understanding these processes is of crucial importance for developing potentially effective handling strategies. Mechanisms determining both flow and the cellular and metabolic consequences of hypoperfusion are of import.

Key factors determining outcome are the presence and extent of collateral flow, and the time at which recanalisation occurs. Cerebral autoregulation is disrupted within the ischaemic penumbra, which may brand the tissue especially vulnerable to alterations in blood pressure level. Continued embolisation and thrombus propagation may also play a part.⁶⁸ Experimental evidence suggests that progressive microvascular obstruction contributes to the progression of ischaemic damage post-obit stroke.⁶⁹ Various processes may contribute to the activation of cerebral microvessels following ischaemia, including alterations in integrin–matrix interactions, leucocyte endothelial prison cell adhesion, blood–brain bulwark permeability changes, and microvascular occlusion owing to adhesion of leucocytes, activated platelets, and fibrin deposition.⁶⁹

A complex cascade of cellular and metabolic consequences follows focal ischaemic injury. This is illustrated in fig 4 and has been reviewed in detail elsewhere.^{58, seventy} Only some of the more important aspects are covered below.

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Effigy iv

Mechanisms mediating tissue injury in focal cerebral ischaemia. Modified from fig four.5 in Fisher, 2002.⁵⁸ Multiple mechanisms which interact with each other are involved. This may partly explain why neuroprotective approaches inhibiting 1 pathway have failed in the treatment of human being ischaemic stroke. AMPA, α-amino-3-hydroxy-5-methyl-iv-isoxazole; NMDA, N-methyl-D-aspartate; NNOS, neuronal nitric oxide synthase; (.....)i, intracellular; (.....)e, extracellular.

Excitotoxicity appears to play a crucial function.⁷¹ Glutamate release activates postsynaptic N-methyl-D-aspartate (NMDA) and α-amino-iii-hydroxy-5-methyl-4-isoxazole (AMPA) receptors. This results in calcium and sodium influx into cells, leading to cellular oedema and activation of the catabolic processes that destroy cellular integrity. These initial events are amplified by farther increases in intracellular calcium through activation of voltage mediated calcium channels.⁷² The intracellular calcium increase induces protein kinases and calmodulin regulated enzymes. Glutamate release appears to be a primary process in a pour of molecular reactions mediated by NO and free radicals. NO generated in neurones and microglia causes cell decease by inhibiting mitochondrial functions, including apoptosis, and promoting the germination of free radicals such as the highly toxic peroxynitrite radicals. Knockout mice which lack nNOS develop infarcts of smaller size.⁷³ Glutamate diffusion from areas with high concentration and more severe ischaemia to less severely ischaemic regions may besides lead to progression of injury. Cerebrospinal fluid and plasma concentrations of glutamate are higher in patients with progressing ischaemic stroke than in those with non-progressing stroke.⁷⁴

Peri-infarct depolarisations may play an important role in progression of damage.⁷⁵ These depolarisations are similar to the phenomena of spreading depression observed afterward mechanical or chemical injury to normal cortical tissue in fauna models. DWI studies of rat stroke models have shown that peri-infarct depolarisations lead to an increase in the size of the ischaemic lesion.⁷⁶ The underlying machinery may be an increase in energy demands upon already compromised tissue by this energy consuming process.⁵⁸ In normal tissue, this increased energy demand is met by an increase in perfusion, but this is not possible when CBF is reduced. The relevance of peri-infarct depolarisations in human stroke has not been determined, although with DWI monitoring it may be possible to show an imaging correlate.

Inflammation is probably important in extending ischaemic injury. Near inflammatory reactions are mediated past cytokines. These have been implicated in several mechanisms that may potentiate ischaemic encephalon injury,⁷⁷ including release of NO from inducible NOS past astrocytes, recruitment, activation, and adhesion to the endothelium of infiltrating leucocytes, the promotion of a local procoagulant state, and the regulation of apoptotic processes.

SUMMARY

Many anatomical and physiological responses ensure that the brain receives adequate blood supply, and protect it against the devastating consequences of cognitive ischaemia. The disruption of these past focal ischaemia tin can now be investigated by an e'er increasing range of methods to guess perfusion, many of which can be implemented on routine clinical neuroimaging equipment. PET studies in humans accept demonstrated reversibly ischaemic penumbral tissue following focal ischaemia; its extent varies markedly between patients simply in a subgroup it may persist for hours. It is hoped that imaging techniques will allow patients with salvageable tissue to exist identified for specific therapeutic interventions.

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