This is a discussion of the metabolic requirements of normal neurological function, as well as the influences on these requirements in unusual physiological circumstances.

It is interesting and educational, and furthermore elements of it appear in Oh's Manual, making it a likely target for future questions. Specific questions regarding this material are more likely to appear in the primaries. The fellowship candidates are more likely to dip into this as a part of the "rationale" section in questions which ask them to critically evaluate some aspect of exotic neuromonitoring.

In summary:

  • Normal values for cerebral metabolic supply and demand:
    • Cerebral blood flow: 50ml per 100g of tissue, per minute.
    • Cerebral DO2150-300ml/min (Hb of 150)
    • CMRO2: Cerebral Metabolic Rate of Oxygen: 3.8ml/100g/min
    • Cerebral oxygen extraction ratio (CO2ER): 35-25%
    • Jugular bulb venous saturation (SjvO2): 55-75%
    • Cerebral glucose consumption: 6.3mg glucose per 100g per minute
  • Metabolic substrate:
    • The brain normally consumes glucose and oxygen, and its RQ is 1.0
    • Alternative substrates include ketones, lactate, mannose, and others
  • Factors which increase cerebral metabolic rate
    • Seizures
    • Hyperthermia
    • Amphetamines
  • Factors which decrease cerebral metabolic rate
    • Sleep
    • Anaesthesia (eg. propofol or thiopentone)
    • Hypothermia
    • Stroke
    • Encephalitis
    • Uraemia
    • Myxoedema

Metabolic substrate of the brain

In physiology textbooks, a consistent generalisation appears - that the human brain demands high octane fuel in the form of oxygen and glucose. Clarke & Sokoloff (1999) give an excellent short-form rundown of this in their chapter for Basic Neurochemistry, 6th ed. In short, the generalisation is accurate. The brain, under most normal circumstances, will preferentially use aerobic glucose metabolism and nothing else. Approximately 156 μmol of oxygen (or about 3.8ml) is consumed per 100 g brain tissue per minute. At the same time, those 100g of brain tissue require about 31 mmol per minute of glucose.  The result is the production of 156 μmol of carbon dioxide, supposedly giving a respiratory ratio of 1.0. 

The dependence on glucose is fairly inflexible. Unlike many other tissues, the brain is unable to quickly switch its metabolism to other substrates in a scenario where glucose is deficient. This is easily observed in the complete neurological collapse which is seen with profound hypoglycaemia. At risk of validating abhorrent research practices, one may with some difficulty and revulsion recall the mid-20th century hypoglycaemia experiments performed on (supposedly, consenting) mental patients. In that dark age, "insulin coma" was a well-accepted part of managing psychosis, and Kety et al (1948) took advantage of this to report on the effects of glucose deprivation on a group of schizophrenic individuals, through a study partly funded by the sinister-sounding National Committee for Mental Hygiene. As blood glucose fell from normal levels down to a BSL of 0.5 mmol/L, the individual submerged into a profound coma, and oxygen consumption of the brain decreased by 50%, from 3.8g/100g/min to 1.9/100g/min.

However, it would be inaccurate to say that the brain is completely inflexible in its choice of metabolic substrate. The hypoglycaemic brain, in desperation, will feed on other molecules if they are made available. An excellent example is the use of ketones in sustained fasting (acetate acetoacetate and β-hydroxybutyrate); though this modification takes time to achieve. This was clarified by Owen et al (1967), who tortured some obese patients with repeated blood tests over a month of total starvation (they were told that this was to "elucidate possible metabolic aberrations"). The cerebral venous samples demonstrated clearly that the arteriovenous difference in β-hydroxybutyrate under normal circumstances is zero, but with prolonged starvation, the brain starts using more and more of it, and by week five of fasting it accounts for about 50% of total cerebral metabolism.

Moreover, like a Japanese gameshow participant, under certain conditions the brain can be forced or fooled into eating weird things. For example, Sloviter & Kamimoto (1970) forced a rat brain to eat mannose, a monomeric sugar which resembles glucose so well that it fools hexokinase into phosphorylating it, plugging directly into the glycolytic pathway. The neonatal brain can feed on lactate, and lactate also becomes an important substrate wherever lactate is massively abundant (eg. during strenuous exercise).  Rat brains can metabolise ethanol. Theoretically, there could be a long list of such substances, as the brain tissue seems to contain numerous metabolic enzymes, and should be capable of either directly utilising or converting a whole range of metabolic substrates, but many of them are unable to penetrate the blood-brain barrier.

Cerebral metabolic requirements under normal conditions

In 1940, Wortis and Bowman published a paper detailing their research into the brain metabolism of "normal, schizophrenic, paretic and senile subjects". As interesting as that would be, it is not available for free consumption; those of us crippled by poverty must make do with the 1949 opus by Scheinberg and Stead, who measured the oxygen extraction ratios of young men strapped to a tilt-table. Their findings are representative of what is typically seen in textbooks, and are as follows:

Cerebral blood flow: Blood flow to the brain is about 50ml per 100g of tissue, per minute. The original study found the mean value to be 65ml/100g (in a range of 50 - 102, or 750-1530ml/minute for a 1.5kg brain). This is about 14% of normal cardiac output. The details of what cerebral blood flow can do are discussed elsewhere, and here it will suffice to say that this range is maintained by autoregulatory mechanisms, even if other haemodynamic conditions are fluctuating.

Cerebral DO2:  Oxygen delivery to the brain is about 150-300ml/min (if one assumes a Hb of 150g/L, an oxygen-carrying capacity of 1.34ml/g, and a saturation of 100%- which gives an oxygen content of about 200ml/L). Calculated from this, the brain receives somewhere around 150-300ml of O2 per minute, which could be 2-6 times the required amount. 

CMRO2: Cerebral Metabolic Rate of Oxygen: as already discussed above, that is 3.8ml/100g/min (in a range of 3.1 to 5.2 - thus, 46.5 - 78ml/minute for a 1.5kg brain). Using jugular venous oximetry (SjvO2), the CMRO2 can be calculated from this equation:  

CMRO2 = CBF × 1.39 × Hb ×  [ (SaO2 - SjvO2) + (0.03  × [PaO2 - PvO2]/100) ] 

where

  • CBF is cerebral blood flow in ml/100g
  • 1.39 is the oxygen-carrying capacity of haemoglobin
  • Hb is the haemoglobin concentration
  • SaO2 is the arterial oxygen saturation
  • SjvO2 is the jugular bulb oxygen saturation
  • 0.03 is the dissolved oxygen content, per ml of blood, per mmHg
  • PaO2 - PvOis the difference in partial pressures between arterial and venous blood

This is from Greeley (2019), and is basically "CBF × (CaO2 - CjvO2)" with extra steps. 

Cerebral oxygen extraction ratio (CO2ER): From the above calculations, it would seem the brain extracts approximately 35-25% of the delivered oxygen. This is consistent with the normally measured jugular venous saturation levels (55-75%).

Glucose consumption by brain tissue: The brain uses 6.3mg glucose per 100g (in a range of 3.9 to 9,5, or 58.5 - 142.5mg/minute for a 1.5kg brain). Thus, at a blood glucose level of 5.5mmol/L (1g/L), or 50mg/100g brain tissue, the brain receives well over ten times its normal requirement of glucose. That's a lot of redundancy. However, the whole liver is only producing it at a rate of about 100-200mg per minute. Thus, the brain actually consumes around 70% of the total hepatic glucose output.

Assessment of cerebral metabolism by jugular bulb oximetry

Given that it would be rude to inconvenience patients by shoving probes directly into their brains, the most popular methods of assessing cerebral metabolism are indirect. Jugular venous oximetry is the most commonly asked-about method, among a large selection of invasive and noninvasive techniques. 

Considering that the main energy substrates of the brain are oxygen and glucose, one should be able to determine the rate of metabolism by measuring the amount of blood oxygen used up during its transit through the brain.  This can be accomplished by measuring the oxygen saturation of the venous blood exiting the brain through the jugular vein. Schell & Cole (2000) describe this technique very well, albeit from an anaesthetic standpoint. In essence, the measurement involves pushing a thin fiberoptic probe up the jugular vein until it comes to rest in the jugular bulb, the confluence of the sigmoid and inferior petrosal cerebral venous sinuses. Unfortunately, most anatomical art of the cerebral venous circulation for some reason ends up being rotated in a way which blocks the jugular bulb completely (eg. the image on the left, from Snopek's Fundamentals of Special Radiographic Procedures), or lovingly rendered in charcoal but so zoomed in as to make the diagram incomprehensible (on the right, from Graham, 1975)

Jugular bulb anatomy

So, in short, that is an intracranial structure, and you really need to get right up there because otherwise the blood becomes mixed with venous return from the face and scalp. Up there, venous oxygenation can be measured by reflectance oximetry, just like SvO2. Ideally, you'd put this catheter on the side of the dominant hemisphere, as that is where the music lessons reside. Plus apparently the difference between hemispheres may be as great as 15%.

The normal range of jugular venous oxygenation is 55-75%. This value changes under the following circumstances:

  • SjvO2 increases when:
    • Cerebral metabolic rate is decreased
    • Cerebral oxygen delivery is excessive (eg. hypercapnia or hypertension)
  • SjvO2 decreases when
    • Oxygen delivery to the brain is reduced (eg. hypotension, hypoxia), or:
    • Cerebral metabolic rate is increased:

As oxygen delivery to the brain decreases, the oxygen extraction of the brain increases, and the SjvO2 decreases. This is (at least vaguely) related to clinical findings. In an excellent study by Lennox et al (1935), operating in the dark age of human research, subjects were asked to tap a telegraph key while the experimenters did various cruel things to decrease their cerebral blood flow (eg. boluses of sodium nitrite, or tilt-table acrobatics). The tapping stopped when the SjvO2 decreased under 25%. 

Factors which influence cerebral metabolism

As there is a nonzero chance that one day this will appear in somebody's exam paper, it was felt important to summarise all of the factors in one succinct list or table, before a deep-dive into pointless detail and historical digressions. Being a scalar quantity, cerebral metabolic rate can only be increased or decreased, which makes it a convenient subject for a table with two columns. Unfortunately, there is no single recent study which might summarise this answer, although Scheinberg & Jayne (1952) do a good job considering the age, and their article was the main source for the table produced below. Where possible, links to other literature are also made available.

Factors which Influence the Cerebral Metabolic Rate
  Increase Decrease
Vascular abnormalities
Infectious processes
  • Fever, systemic infection
Neoplasia
Drugs
  • General anaesthetics
Neurological disorders
Physiological phenomena
Trauma
Endocrine and metabolic disorders

The effect of hypothermia on brain metabolism

When you are getting your aortic arch operated on, you become the ideal substrate for the hypothermia researcher, because the anaesthetist has cooled you to a ridiculously low temperature (routinely around 15-20°C). Why he did it, he himself does not know, as the mysterious mechanisms of hypothermic neuroprotection are even today poorly understood. All the same, the environment of deep hypothermic circulatory arrest (DHCA) produces good studies of hypothermia.

Armed with the routine set of equations, one group of investigators managed to collect CMRO2 data from patients cooled to 15°. Compared to baseline (37°C) values, the CMRO2 of deeply hypothermic patients were down to around 15-16%. That would make the minute CMRO2 about 0.5-0.8mlO2 /100g/min. The entire brain would run on no more than 7.5-12ml of oxygen per minute. Well, "run" is perhaps a misnomer. It would survive. Little activity inside it would take place; certainly nothing we would be able to describe as consciousness. Burst suppression appears at anywhere around 24°, and at around 17° one experiences what the EEG scientists describe as electrocerebral silence, a finding which is so precisely defined mainly because it is usually associated with brain death.

The effect of hyperthermia on brain metabolism

Unlike hypothermia, most of our detailed knowledge of hyperthermia comes from exposing rats to such danger. On one such occasion, the rate of rise for cerebral metabolic activity was pretty linear - 5-6% per 1°C, at least up to a temperature of 42°. Extrapolated from this, with a fever of 41°, a human brain should have a metabolic rate which is increased by about 20-24%.

Unlike the deeply hypothermic aortic surgery patient, these days there are no therapeutic situations in which profound hyperthermia can be safely observed in the human. Certainly, they sometimes present to hospital in a state of severe hyperthermia, but in those circumstances, the attention is usually directed to their resuscitation rather than the careful collection of jugular venous samples.

However, in the past "therapeutic hyperthermia" was indeed a serious concept. In his book "Neurobiology of Hyperthermia", Hari S. Sharma recalls the fact that temperature above 41° kills cancer cells in a hypoxic environment. These days this is usually a loco-regional affair, like its natural extension- the radiofrequency ablation technique. But in the past there had been some interest in using whole body hyperthermia to treat cancer.

cerebral metabolic rate in hyperthermia

Interersting observations were made. For instance, cerebral blood flow autoregulation tends to break down at high temperatures (above 41°). On top of this, the mitochondrial utilisation of oxygen becomes less efficient, so the oxygen consumption may not increase as much as one might expect from a direct linear relationship. This seems to be unique to the brain; other tissues burn oxygen faster with increasing temperature.

The effect of anaesthetic drugs on cerebral metabolism

It would stand to reason that any pharmacological agent which decreases excitatory neurotransmission might act to decrease the cerebral metabolic rate in general. This, in turn, might be of benefit when cerebral blood flow is poor. The applications of anaesthetic drugs to neuroprotection are thus obvious, and thiopentone coma is still among the last-line recommendations in the list of management strategies for severe traumatic brain injury.

By decreasing the metabolic rate of the brain, it is supposed to grant a period of decreased demand, to match the period of decreased supply. The oft-quoted baboon study gives one the impression that this is indeed a workable solution, even though to derive maximal benefit from it the barbiturate-soaked baboons would have needed to already be in a coma when their stroke occurred.

So, precisely how much does anaesthesia affect cerebral O2 metabolism? Early in the 1960s a study was published which studied the effects of barbiturate coma on the cerebral metabolic rates of eleven healthy volunteers. The volunteers were anaesthetised and paralysed so that their PaCO2 could be precisely controlled (specifically, a Bird respirator was used). Cerebral oxygen consumption was calculated from the measured cerebral blood flow and carotid-jugular oxygen difference. In this study, thiopentone decreased the cerebral metabolic rate by an average of 55% from the baseline observed in alert individuals.

Even though thiopentone is the classical agent for this, propofol has also been investigated and we have measurements of the cerebral arteriovenous O2 difference in propofol-anaesthetised brain injury patients. Weirdly, with the use of propofol - even at a fairly vigorous dose- the A-V O2 difference remains unchanged. However, the cerebral blood flow is decreased by a large margin, almost 30%. Thus, it stands to reason that the cerebral metabolic rate must be decreased by a proportional fraction.

Why discuss this topic at all? Apart from satisfying a person's healthy natural interest in baboons, there is exam relevance around here somewhere. Specifically, Question 14 from the first paper of 2014 and Question 16 from the second paper of 2011 asked about the changes in cerebral blood flow, CMRO2 and jugular venous oximetry which occur as the effect of propofol and ketamine administration.

Effects of propofol on cerebral blood flow and CMRO2Propofol produces a dose-dependent decrease in CMRO2. And as CMRO2 is closely tied to the autoregulation of blood flow, it also decreases CBF, in a fairly proportional fashion.  Thus, because both oxygen consumption and oxygen delivery are decreased together, the total oxygen extraction ratio remains stable, and there is no change in the SjvO2. Such were the findings of a 2002 study by Oshima et al, who measured these variables in a group of relatively healthy ASA=1 patients undergoing some sort of elective orthopaedic surgery.

Effects of ketamine on cerebral blood flow and CMRO2: In short, if one had to give a short pithy viva answer, one would be forced to say that ketamine increases both, because one does not wish to start an ugly argument with a tired examiner. However, it may not be completely accurate. Specifically, the change in cerebral blood flow is demonstrated more reliably than the change in CMRO2, and in fact CMRO2 may actually be decreased by ketamine anaesthesia.  For instance, Takeshita et al (1972) demonstrated an almost-doubled cerebral blood flow in ten elective surgical outpatients, with CMRO2 remaining basically unchanged. Långsjö et al (2003) also found no effect on the CMRO2 in humans.  In contrast, Schwedler et al (1982) found that it has the opposite effect in goats (their CBF increased, but the CMRO2 dropped by 11%).  Other hedge their bets: for example, McMillan & Muthukumaraswamy (2020), whose massively detailed article concludes that ketamine may uncouple cerebral glucose consumption (which increases, potentially for reasons unrelated to energy production) from cerebral oxygen use (which doesn't).  Opdenakker et al (2019) hedge differently: for them, ketamine has "differential regional effects on CMRO2: frontal regions, the insula, and the anterior cingulate gyrus show an increase, while a decrease is observed in pons, cerebellum, and temporal lobe".

In short, the CMRO2-increasing effect of ketamine may be an old superstition. Where supporting references are offered in textbooks, they point to old work done in the 1970s (eg. Evans, 1971), and unfortunately, most textbooks parrot older textbooks, uncritically propagating this canard. This has far-reaching effects, among which is the need for CICM trainees to intentionally write exam answers which they know to be incorrect, in order to score marks.

References

Oh's Intensive Care manual

Chapter 52   (pp. 580)  Cerebral  protection by Victoria  Heaviside  and  Michelle  Hayes

WORTIS, JOSEPH, KARL M. BOWMAN, and WALTER GOLDFARB. "HUMAN BRAIN METABOLISM Normal Values and Values in Certain Clinical States."American Journal of Psychiatry 97.3 (1940): 552-565.

Scheinberg, Peritz, and Eugene A. Stead Jr. "The cerebral blood flow in male subjects as measured by the nitrous oxide technique. Normal values for blood flow, oxygen utilization, glucose utilization, and peripheral resistance, with observations on the effect of tilting and anxiety." Journal of Clinical Investigation28.5 Pt 2 (1949): 1163.

McCullough, Jock N., et al. "Cerebral metabolic suppression during hypothermic circulatory arrest in humans." The Annals of thoracic surgery 67.6 (1999): 1895-1899.

Stecker, Mark M., et al. "Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials." The Annals of thoracic surgery 71.1 (2001): 14-21.

Carlsson, C., M. Hägerdal, and B. K. Siesjö. "The effect of hyperthermia upon oxygen consumption and upon organic phosphates, glycolytic metabolites, citric acid cycle intermediates and associated amino acids in rat cerebral cortex." Journal of neurochemistry 26.5 (1976): 1001-1006.

Sharma, H. S. "Cerebral pathophysiology and clinical neurology of hyperthermia in humans." Neurobiology of Hyperthermia 162 (2011): 153.

Habash, R. W., et al. "Principles, applications, risks and benefits of therapeutic hyperthermia." Frontiers in bioscience (Elite edition) 3 (2010): 1169-1181.

van der Zee, Jacoba, et al. "Whole-body hyperthermia in cancer therapy: a report of a phase I–II study." European Journal of Cancer and Clinical Oncology19.9 (1983): 1189-1200.

SCHEINBERG, PERITZ, and HAROLD W. JAYNE. "Factors Influencing Cerebral Blood Flow and Metabolism A Review." Circulation 5.2 (1952): 225-236.

Myers, J. D. "Net splanchnic glucose production in normal man and in various disease states." Journal of Clinical Investigation 29.11 (1950): 1421.

HOFF, JULIAN T., ALLAN L. SMITH, and SURL L. NIELSEN. "Barbiturate protection from cerebral infarction in primates." Stroke 6.1 (1975): 28-33.

Kassell, Neal F., et al. "Alterations in cerebral blood flow, oxygen metabolism, and electrical activity produced by high dose sodium thiopental." Neurosurgery7.6 (1980): 598-603.

Pierce Jr, Ellison C., et al. "Cerebral circulation and metabolism during thiopental anesthesia and hyperventilation in man." Journal of Clinical Investigation 41.8 (1962): 1664.

Pinaud, Michel, et al. "Effects of propofol on cerebral hemodynamics and metabolism in patients with brain trauma." Anesthesiology 73.3 (1990): 404-409.

Doyle, P. W., and B. F. Matta. "Burst suppression or isoelectric encephalogram for cerebral protection: evidence from metabolic suppression studies." British journal of anaesthesia 83.4 (1999): 580-584.

Derdeyn, Colin P., et al. "Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited." Brain 125.3 (2002): 595-607.

Schell, Randall M., and Daniel J. Cole. "Cerebral monitoring: jugular venous oximetry." Anesthesia & Analgesia 90.3 (2000): 559-566.

Clarke, D. D., and L. Sokoloff. "Substrates of cerebral metabolism." Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th Edition, Lippincott-Raven, Philadelphia, PA. https://www. ncbi. nlm. nih. gov/books/NBK28048 (1999).

Sokoloff, Louis. "The metabolism of the central nervous system in vivo." Handbook of Physiology, section, I, Neurophysiology 3 (1960): 1843-64.

Kety, S. S., et al. "Cerebral blood flow and metabolism in schizophrenia: the effects of barbiturate semi-narcosis, insulin coma and electroshock." American Journal of Psychiatry 104.12 (1948): 765-770.

Sloviter, H. A., and T. Kamimoto. "The isolated, perfused rat brain preparation metabolizes manmose but not maltose 1." Journal of Neurochemistry 17.7 (1970): 1109-1111.

Owen, O. E., et al. "Brain metabolism during fasting.The Journal of clinical investigation 46.10 (1967): 1589-1595.

Kasischke, Karl. "Lactate fuels the neonatal brain." Frontiers in neuroenergetics 3 (2011): 4.

Dienel, Gerald A. "Brain lactate metabolism: the discoveries and the controversies." Journal of Cerebral Blood Flow & Metabolism 32.7 (2012): 1107-1138.

Pawlosky, Robert J., et al. "Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat." Alcoholism: Clinical and Experimental Research 34.2 (2010): 375-381.

Schell, Randall M., and Daniel J. Cole. "Cerebral monitoring: jugular venous oximetry." Anesthesia & Analgesia 90.3 (2000): 559-566.

Greeley, William J. "Assessment of CNS Function: Cerebral Blood Flow and Metabolism." Brain Injury and Pediatric Cardiac Surgery (2019): 12.

Lennox, William G., Frederic A. Gibbs, and Erna L. Gibbs. "Relationship of unconsciousness to cerebral blood flow and to anoxemia." Archives of Neurology & Psychiatry 34.5 (1935): 1001-1013.

Dujovny, Manuel, Mukesh Misra, and Ronald Widman. "Cerebral oximetry—techniques." Neurological research 20.sup1 (1998): S5-S12.

Greeley, William J., et al. "The effect of hypothermic cardiopulmonary bypass and total circulatory arrest on cerebral metabolism in neonates, infants, and children." The Journal of thoracic and cardiovascular surgery 101.5 (1991): 783-794.

Snopek, Albert M. Fundamentals of Special Radiographic Procedures-E-Book. Elsevier Health Sciences, 2013.

Graham, Malcolm D. "The jugular bulb: Its anatomic and clinical considerations in contemporary otology." Archives of Otolaryngology 101.9 (1975): 560-564.

SCHEINBERG, PERITZ, and HAROLD W. JAYNE. "Factors influencing cerebral blood flow and metabolism: A review." Circulation 5.2 (1952): 225-236.

Oshima, T., F. Karasawa, and T. Satoh. "Effects of propofol on cerebral blood flow and the metabolic rate of oxygen in humans." Acta anaesthesiologica scandinavica 46.7 (2002): 831-835.

Schwedler, Margaret, David J. Miletich, and Ronald F. Albrecht. "Cerebral blood flow and metabolism following ketamine administration.Canadian Anaesthetists’ Society Journal 29.3 (1982): 222-226.

Takeshita, Hiroshi, Yoshiaki Okuda, and Atuo Sari. "The effects of ketamine on cerebral circulation and metabolism in man." Anesthesiology: The Journal of the American Society of Anesthesiologists 36.1 (1972): 69-75.

Slupe, Andrew M., and Jeffrey R. Kirsch. "Effects of anesthesia on cerebral blood flow, metabolism, and neuroprotection." Journal of Cerebral Blood Flow & Metabolism 38.12 (2018): 2192-2208.

Långsjö, Jaakko W., et al. "Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans." Anesthesiology: The Journal of the American Society of Anesthesiologists 99.3 (2003): 614-623.

Evans, J., et al. "Ketamine in neurosurgical procedures.The Lancet 297.7688 (1971): 40-41.

McMillan, Rebecca, and Suresh D. Muthukumaraswamy. "The neurophysiology of ketamine: an integrative review." Reviews in the Neurosciences 1.ahead-of-print (2020).