An understanding of basic brain physiology is vital to our ability to find ways to improve cerebral function. It is with this in mind and much trepidation that I will attempt to discuss the finer points of cerebral energetics (brain energy). I realise that this can be a bit daunting for those without a medical background but feel that some knowledge in basic science will improve overall understanding during our future discussions. I will not be delving into the complex world of brain anatomy and structure. Fortunately, there is an excellent blog written by Marc Dingman, a neuroscientist which covers this area in some detail and I refer the interested reader to his site at https://www.neuroscientificallychallenged.com
So, here we go …
The human brain is truly an amazing organ. Although most people spend their lives attempting to damage their brain by taking part in a variety of extreme sports, contact sports (head injuries – both minor and major), altitude sports (purposely exposing the brain to low Oxygen levels) or ingesting chemicals both legal and illegal (which can alter cerebral function in numerous ways) or poor diet and lack of exercise (leading to a slew of metabolic problems which impact the brain); the part of the brain which is not trying to kill us (not the conscious brain) works as a finely tuned machine. It is the ultimate computer. Fast, versatile and extremely adaptive to changes in both our internal and external environments.
SEPARATED FROM THE BODY
Although most cerebral metabolic pathways are similar to those found in the rest of the body, a structure exists which effectively isolates the brain from the external environment and that is the blood brain barrier or BBB. Essentially, the BBB is a highly selective membrane which acts as a barrier separating blood from the brain and extracellular fluid. While most membranes in the body allow substances to cross freely, the BBB keeps most things out or requires them to be actively transported across. This helps keep the brain protected from foreign substances in the blood that may cause injury. It also keeps out hormones and other neurotransmitters which may affect brain function. Only water, gases (oxygen and carbon dioxide), and a few fat-soluble substances are able to diffuse across. And while the BBB performs a vital function, it also means that energy containing molecules have to be transported across (the importance of which will be explored later) while getting drugs across to treat infections and cancers can be tricky.
For more details see:
Now, let’s look further into cerebral energetics...
SOME FACTS: THE HUNGRY BRAIN - ENERGY HOG
The average adult brain weighs in at around 1400 grams. That’s about 3 pounds for those of you who are metrically challenged. That equates to around 2% of the total body weight. However, from an energy standpoint, at rest the brain consumes ~20% of total energy utilized by the body (or basal metabolic rate). And in young children, the amount is significantly more, as much as 50% of BMR. That’s an astounding amount of energy consumed by a relatively small organ and explains why humans can’t hibernate (more on that later).
And where does all this energy come from? Well, mainly from glucose which is supplied in ample quantities from the blood stream. Glucose (C6H12O6) is a simple sugar. It is made mainly in plants and is the single most important source of energy in most organisms. It turns out that the adult brain under normal circumstances survives almost entirely on glucose and oxygen. This equates to the consumption of around 90 – 100 grams of glucose (about 23 teaspoons of sugar) and 68 - 86 litres of oxygen per day.
And what does the brain do with all this energy? Again it depends, but in adults, most of the energy (~ 75% - which is in the form of ATP – see later) is used for signalling activity, nerve transmission etc. The rest, ~ 25% is for basic housekeeping activities, synthesis of compounds the brain needs including proteins, fats and neurotransmitters.
BRAIN ENERGY UNDER A MICROSCOPE
That’s the overview of cerebral energy requirements. For the more adventurous reader, let’s look into this in a bit more detail......
It’s important to understand that glucose and oxygen are the main fuels for the brain and they cannot be completely replaced by other substances. Although alternative fuels such as ketones may play a role during development and starvation, they cannot sustain cerebral function in adults. Furthermore, the brain relies almost entirely on glucose supplied from the blood stream (although does maintain a small store for short term energy fluxes - but it's not very much). Based on resting storage, all brain glucose would be consumed in ~12.5 minutes if not replenished from the blood supply. This explains why hypoglycaemia (low blood sugar) or a decrease blood supply (shock, stroke etc.) needs to be corrected immediately as it rapidly leads to brain cell damage and death. And the same is true for oxygen where the brain relies entirely on blood supply as no oxygen is stored in cerebral tissue.
Aside – when I mention brain cells, I’m largely referring to neurones, the functional/signalling cells of the brain. Other cells found in the brain (glial cells such as astrocytes) are responsible for brain housekeeping functions. https://en.wikipedia.org/wiki/Neuron
To illustrate the importance of brain glucose/oxygen, let’s see what happens when these are not available.
During starvation, peripheral glucose levels remain stable due to the breakdown of muscle and brain energy requirements are supplementation with ketones. However, if hypoglycemia intervenes, the results can be devastating;
Blood glucose concentration in (mmol/l);
4 – 6 - normal
3 - symptoms of hypoglycemia including anxiety, dizziness, sweat etc.
2.6 - cognitive dysfunction
1.7 - confusion and delirium
1.1 - stupor and seizures
< 0.6 - coma and death
Similarly, with low oxygen levels;
21% (at sea level) - normal
15% (9000ft) - impairs complex learning
11% (17000ft) - loss of critical judgement
6% (31000ft) - loss of consciousness
Thus our brains are highly susceptible to loss of energy substrates. The above represents the effects of rapid changes in brain fuel. Some acclimatization is possible but is never complete. Consequently high-altitude climbers often suffer from cognitive dysfunction resulting from prolonged periods in low oxygen environments.
SUPPLYING ENERGY FOR THE BRAIN. IT’S ALL ABOUT PHOSPHATE
Ok, as we delve deeper into this mystery, things begin getting a little more complicated, but we will try to navigate this quagmire as best we can.
In order for the brain/body to function, it requires energy. ATP or adenosine triphosphate is the bodies main energy carrier and is utilized to drive most energy requiring processes such as muscle contraction, nerve impulses and chemical synthesis.
In humans ATP can be produced from 3 distinct processes;
Glycolysis – metabolism of glucose (sugar)
TCA (tricarboxylic acid) cycle/oxidative phosphorylation – main energy providing pathway
Beta-oxidation – from fat metabolism
Most ATP is produced in the energy organelle of the cell called the mitochondria. During this process, electrons are transferred from electron donors to an electron acceptor (oxygen) and ATP is produced. Although some ATP can be made in the absence of oxygen (called anaerobic glycolysis), this is insufficient to maintain metabolic processes for very long. This is why humans cannot survive very long without replenishing the bodies oxygen supply. As previously stated, the brain has no oxygen store and is therefore dependent on blood flow to supply. Even short periods of time without oxygen (several minutes) can lead to significant brain injury and death.
Now let’s focus more on brain energy requirements;
As previously noted, 75% of ATP used in brain (under normal conditions) is for signalling activities. The other 25% provides for housekeeping functions including synthesis of proteins/lipids and maintenance of membrane stability etc. Activation of neural pathways occurs rapidly, < 10 ms and requires immediate access to energy. Therefore, blood supply is closely linked to cerebral metabolism.
As mentioned, glucose is the main source of brain energy in humans and while other things like fats and proteins may play a role especially in extreme conditions such as starvation, they cannot replace glucose. We will therefore take a closer look at glucose metabolism.
JUST A SPOON FULL OF SUGAR …
As previously noted, the BBB is impervious to glucose and therefore for glucose to get into the brain, it requires transportation via the glucose transporter or GLUT molecule. And although the capacity to transport glucose is much higher then the utilization rate, during periods of high activity/utilization, it may take time to replenish brain reserves (which explain why we cannot undertake neurologically taxing activities such as intense concentration, difficult calculations etc. for long periods). Brain glucose levels follow changes in plasma concentrations.
Aside – ketones and lactate are also transported across the BBB via another transporter called the monocarboxylic acid transporter (MCT). More on this later.
Once in the brain, the story of glucose gets more interesting. As previously noted, the fate of glucose is to produce the energy storing molecule ATP (this is not entirely true as glucose is involved in the production of numerous other molecules). The process by which this takes place is called Glycolysis (stay with me. It gets better)
The fate of glucose during glycolysis is;
Metabolism to pyruvate with the eventual production of ATP
Stored as glycogen and used later. The brain has very limited glycogen stores
Production of NADPH via the pentose phosphate pathway which helps protect the cell against oxidative stress
Once pyruvate has been produced, two things can happen. If oxygen levels are low, (suffocation, shock, exercise etc.) then lactate will be produced (more on this later). Otherwise pyruvate will be metabolized to Acetyl Coenzyme A and enter the TCA cycle (tricarboxylic acid) where the metabolites will undergo oxidative phosphorylation, leading to the production of ATP (see figure 1 below).
Take a deep breath, we’re nearly at the end.
As you can imagine, this is an extremely complicated process. In fact, no less then 170 steps/processes are required to metabolize 1 molecule of glucose. This blows my mind. Not only that, but the speed with which this takes place is amazing. For example, during the time it takes for 1 synaptic transmission (nerve signal) to take place, ~ 1 ms, 1 molecule of glucose per synapse is taken up from blood into the cell and metabolised. Incredible! And this is going on every second, 24/7.
A few more facts
A total of 30-36 ATP are produced per molecule of glucose which also consumes 6 molecules of oxygen
The efficiency of metabolism is approx. 42% - the remaining energy is lost as heat
Glucose is uniform throughout brain but with differences in utilization – grey matter >>> white matter
Both glucose and oxygen are supplied above demand, providing a buffer
Blood flow, glucose and GLUT/MCT levels increase together and are locally regulated during increase activity
And that’s it. You have successfully navigated the glucose pathway and lived to tell the tale.
Figure 1: Glucose Pathway
A FEW MORE POINTS OF INTEREST;
Glycogen
Let’s take a few moments to discuss the role of glycogen, as our only store of glucose in the brain. Glycogen is produced from glucose in astrocytes (a type of brain cell) in low levels and is widely distributed. It acts as an energy buffer for short term increases in brain activity. It also has a role during periods of abnormal demand such as during seizures or hypoxia (lack of oxygen). Although turnover is very slow compared to glucose (4.4 hours versus 1.5 minutes), this increases rapidly in times of high demand.
Anaerobic glycolysis
Lack of oxygen also impairs the body's'/brain's ability to produce ATP. During these periods, the body/brain turns to a process called anaerobic glycolysis in an attempt to maintain energy levels until oxygen can be resupplied. In anaerobic glycolysis, pyruvate cannot enter the TCA cycle, but instead is converted to lactic acid. This process produces 2 ATP (as opposed to 30-36 ATP during normal conditions) and although much less efficient than aerobic glycolysis, can sustain cellular functions for a short period (10 seconds to 2 minutes). Although only a small amount of lactic acid is produced in brain cells themselves, during times of hyperlactemia, lactic acid from blood is transported across the BBB in increasing quantities and can be taken up by brain cells and potentially used for energy requirements. Once oxygen is restored, the lactate can be converted back to glucose in the liver.
Aside – some have postulated that brain cells may prefer lactate to glucose (lactate-shuttle) while others have suggested high cerebral lactate levels might be injurious to brain cells. The jury is still out.
Ok, so having survived our little tour of the brain’s energy metabolism, one might ask why bother? Aside from providing some context and background for future discussions, one needs to understand normal brain energetics to understand what happens when the energy supply is disrupted eg. low glucose or oxygen states.
For example, it is now evident why hypoglycemia is so devastating for the brain (see above). As glycogen stores can only maintain blood glucose concentrations for around 12 minutes, its crucial to restore glucose blood levels ASAP to avoid permanent injury.
Similarly, during times of low oxygen, increasing levels of lactate are produced in an attempt to prevent maintain cellular function, but will fail (certainly in the acute setting) when the partial pressure of oxygen drops below 35 mmHg as the brain is unable to store O2.
And lastly, when blood supply is completely removed (eg. Stroke), there is a rapid depletion in local glucose/glycogen stores leading to energy failure within 60 seconds.
Aside – brief periods of energy failure do not necessarily kill brain cells but oxidative damage during re-perfusion is often to blame (to be discussed in another topic)
Its therefore imperative to restore energy supply as quickly as possible. However, once energy supply has been restored, recovery can be a very slow as the cellular repair process is complicated and time consuming (restoration of ionic gradients, production of high energy compounds and repair of damage). It is therefore much preferable to avoid interruption of energy flows to the brain in the first place.
We have come to the end of our discussions about brain energy metabolism. Although we’ve only just scratched the surface (as glucose is involved in numerous other processes in the brain including the production of neurotransmitters, amino-acids, glycolipids and proteins) hopefully it has been enough to provide an overview of this amazing process which keeps our brain functioning like a well-oiled machine. It will also serve as background when we look at things, we can do to improve cerebral function.
Thank you for your attention
And as a passing quote –
“We spend a great deal of time looking for the answers outside when the miracles are taking place moment by moment inside each one of us” - Dr. Hayden
REFERENCES OTHER THAN IN-TEXT
Magistretti, Pierre J., and Igor Allaman. “Brain Energy Metabolism.” In Neuroscience in the 21st Century, edited by Donald W. Pfaff, 1591–1620. New York, NY: Springer New York, 2013. https://doi.org/10.1007/978-1-4614-1997-6_56.
Dienel, Gerald A. “Brain Glucose Metabolism: Integration of Energetics with Function.” Physiological Reviews 99, no. 1 (January 2019): 949–1045. https://doi.org/10.1152/physrev.00062.2017.
Dienel, Gerald A. “Energy Metabolism in the Brain.” In From Molecules to Networks, 53–117. Elsevier, 2014. https://doi.org/10.1016/B978-0-12-397179-1.00003-8.