Hjernetåge er et rødt flag: Neuroinflammation

A red flag indicates danger. It is a universal signal that we all understand and, before it, we become alert. The universal language for science is English and that is why in science we talk about Red Flags. If we take it to the field of medicine, a red flag is a warning. It warns us of the risk that behind these signs or symptoms there is a serious illness. But there are times when the red flag is there, warning us, and we are not able to see it, or even sense its existence.

What is neuroinflammation?

I want to talk to you today about a red flag that is rarely paid attention to. If I tell you that it is neuroinflammation, it is very possible that you think that ‘that does not happen to me’. But if I am talking about such common symptoms as a mental fog, decreased ability to stay focused, drowsiness, slow thinking… That has happened to you, right?

In most cases, these symptoms are transient, random and do not follow a specific pattern, so they are not usually given much importance. We tell ourselves things like ‘I didn’t sleep well’, ‘The food made me sick…’, ‘I shouldn’t have had that last drink…’, but in reality it is a very specific sign: your brain is inflamed.

Brain swelling?

This does sound strong to us. After all, the brain is the organ that defines and characterizes us as human beings. In terms of supplying energy or raw material, our entire physiology prioritizes the brain before other organs, and even processes such as pregnancy and childbirth are different from those of other species “because” of that enormous brain that allows us to think , choose, reason, be aware of our identity, memorize or argue. But, after all, the brain, like the rest of the organs, can suffer an inflammatory process. And this process can lead, it can lead us, to the loss of brain function. To slow down, to have that mental fog.

Because there are no nociceptors in the brain, neuroinflammation does not cause pain.
But it causes a lot of other things: loss of brain function, inability to get out of bed, loss of motivation… It makes a person not have great stamina, they are tired all the time. In other words, neuroinflammation puts a black and white filter on reality, everything seems sadder to us.

If you notice this happening to you, bring it up with your therapist. And, if you are a therapist, let me insist on this: in the face of clinical signs like the ones I have told you about, and others such as depression, difficulty concentrating (especially for a long time), lethargy, fatigue, lack of motivation, discomfort during exercise, need to sleep for many hours… You are facing a real Red Flag.

In this article I want to explain the most common causes of neuroinflammation, how it occurs and what changes in lifestyle can be incorporated to try to solve it.

How the brain swells

If we talk about brain cells, surely neurons come to mind. They are, without a doubt, the best known, but they are not the only ones… and neither are they the most abundant, far from it. The human brain is estimated to contain more than 80 billion neurons; well, for every neuron there are ten glial cells. This enormity accounts for 90% of brain cells and forms a substance called glia or neuroglia. And his study is today in full swing.

Indeed, with glial cells what happens with so many other structures: for a long time it was thought that they had no function… until it was discovered what they were for, and their importance. Identified in 1858 by the German physician Rudolf Virchow, for more than a century it was thought that they were simply fillers, occupying space between neurons (the Latin root for glia is glue). But today it is known, and this is how we see it in different studies, that its activity is decisive for good brain function.

There are several types of glial cells:

Schwann cells are the only cells found in the peripheral nervous system (PNS), that is, in the nerves that run throughout the body. In the central nervous system (CNS) we find three varieties of glial cells: microglia, oligodendrocytes and astrocytes. And these are the ones that interest us the most, because they are the ones that are especially involved in neuroinflammation.

In a normal state, the functions of these cells are important:

Support neural function

They improve the transmission speed produce neuronal growth factors regulating neurogenesis
They collect waste discharged by neurons into the extracellular space.
But not only do they perform functions of support and assistance to neurons, but they also have a determining role in neuroinflammation. The point is that, when faced with various stimuli that are perceived as an aggression, these cells completely change their pattern of activity and become immune cells, producing brain inflammation.

The paradigmatic example is that of microglia: 

To help you understand it, let’s remember what we told you in this article about what happens with macrophages and immunometabolism. We said that it has been seen that these are immunoregulatory cells that depend on their metabolic activity to generate one response or another, both a potentiation of inflammation and its modulation. Well, microglia follow a similar pattern. Thus, in stable conditions, they circulate through the brain fulfilling their functions: regulate neurogenesis, remodel synapses, collect waste… But, from that state of rest, they can evolve, similarly to macrophages, in two directions:

Towards an M1 proinflammatory phenotype, with the aim of eliminating a pathogen or repairing tissue damage
Towards an anti-inflammatory or M2 phenotype, whose purpose is to resolve an inflammation and thus return to homeostasis.
As you may well suspect, an imbalance of microglia towards M1 expression is what generates the symptoms associated with neuroinflammation.

Are we in time to stop neuroinflammation?

This question is essential. As with many other physiological processes, neuroinflammation also has different stages.

• Transient neuroinflammation
• Chronic neuroinflammation
• Neuroinflammation with imprint on glial cells
• Neurological autoimmunity

Where should we intervene? In the first stage. The aim is to identify those factors that can cause transient neuroinflammation and remedy them before they become chronic, because once the glial cells suffer a print they are no longer able to return to their resting state. They become extraordinarily reactive to any signal of immune activation from the periphery. As you can imagine, both the prognosis and the clinical expectations change drastically.

But how does neuroinflammation occur?

By now, you may be wondering how this activation of glial cells can occur, since they are located within the brain and are therefore ‘protected’ by the blood-brain barrier (BBB). The first thing we need to know is that this is not an insurmountable barrier, but a very selective permeable membrane in which the astrocytes are in charge of filtering what can pass to the other side. Thus, they allow oxygen and glucose (the food for neurons) to penetrate, but try to stop the entry of inflammatory substances produced by the body.

This is so in normal state. But the things can change. Do you remember what we have talked about so many times about intestinal hyperpermeability? Well, in a similar way, the blood-brain barrier can also be damaged, allowing the passage of inflammatory substances and, thus, causing the activation of glial cells.

This activation can be done through several mechanisms:

Passive diffusion after strong immune activity (remember that the BBB is not completely invulnerable, immunomessengers can pass through and influence the brain, mainly the hypothalamus).
Active transport of inflammatory mediators across the blood-brain barrier.
Release of glial cell activators by the vascular endothelium.
Vagus nerve-mediated activation.
These are complex mechanisms. The really important thing, what has to be clear to you, is how to act to prevent this activation or, if it has already occurred, to alleviate its effects and prevent it from evolving from a transitory neuroinflammation to a chronic one. And that’s what I’m going to talk to you about now.

Model of a person showing the brain and common points of inflammation.

How do you avoid neuroinflammation?

Change your life.

As I explained to you at the beginning, these symptoms of brain fog, confusion, lethargy, apathy… are a red flag: they can be the first signs that a person is suffering from neuroinflammation. And there are five factors to focus on: alcohol consumption, diet, sleep, stress and exercise. A quintet of risk factors that is familiar to us, since it is behind practically all pathological processes. If you have these signs, examine these aspects of your life. And, if you are a therapist and you identify them in a patient, sit down with him, go over these factors and explain how they affect him.

1.- Alcohol

Lack of stability and coordination, confusion, difficulty concentrating… A drunkenness is what he has, so if I tell you that the brain is one of the tissues that is most sensitive to alcohol, I don’t think you will be surprised. There are studies that confirm this. How does it happen?

First, alcohol is an inducer of the M1 response of microglia.
In addition, a stable population of macrophages known as Kuppfer cells resides in the liver, which can also be expressed as M1 (inflammatory) or M2 (anti-inflammatory). Alcohol induces an inflammatory response in the liver and, via the vagus nerve, influences the inflammatory response in the brain.
Not only that: in turn, alcohol causes permeability of the blood-brain barrier, which implies an increase in the passive diffusion of alcohol and other toxins to the brain.
In short, it seems that four consecutive days of exposure to alcohol increase the population of inflammatory microglia, and this is what we see in this study.

Do you want more? In case you hadn’t fallen, one of the clinical situations that most resembles neuroinflammation in symptoms is a hangover. The explanation for this is that, really, a hangover is nothing more than a transitory neuroinflammation.

2.- Physical activity

It is an issue in which we must be careful. It is true that exercise can trigger an anti-inflammatory response by releasing opioids and peptides that dampen inflammation in the vascular brain; In addition, as we see in this study, it improves the integrity of the blood-brain barrier. Thus, exercise can be a powerful tool to reduce neuroinflammation, since it activates the expression of M2.

Now, as we know, exercise can also promote inflammation. The problem is that the optimal dose of exercise is individual, and the line between pro and anti-inflammatory is very fine. Thus, two patients with similar symptoms are likely to follow the same high-intensity protocol, and while one will feel great for the rest of the day, the other could get worse. You must therefore find a balance between intensity and duration for physical activity to be neuroprotective.

You should also be aware that physical activity sometimes causes adverse reactions in an area of the brain affected by neuroinflammation that cannot handle the increased demand (this is not the same as neuroinflammation caused by exercise intensity). Thus, for example, performing balance exercises can affect the cerebellum, and those that require a lot of focus and concentration can affect the central cortex.

3.- Stress

Yes, too much stress is bad. We are not discovering anything new. But, being intangible and variable, it is actually rare for us to be able to associate that what happens to us is due to excess stress. Even so, keep in mind that this excess could make you lose the ability to walk, speak, keep your balance, play sports, drive… And all this, as we see in this study, because your brain is inflamed and it doesn’t work as it should.

4.- Dream

Nor is it news that sleeping poorly harms us. After a bad night, how do we feel? We have a hard time concentrating, we think more slowly, we are less motivated, we have less verbal fluency… It has happened to all of us, and we see it as something natural, as a logical sequence: I sleep badly, I feel bad. The thing is, when those bad nights become chronic, when sleep isn’t restful, we’re building a highway to neuroinflammation. During chronic sleep deprivation, inflammatory mediators increase and trigger the activation of glial and microglial cells, with consequent neuroinflammation. And remember that low-grade neuroinflammation due to chronic lack of sleep leads to anxiety and learning and memory problems.

5.- Food

It could not be otherwise. Just as our diet can lead to a state of low-grade inflammation, there are also different nutritional factors that lead to neuroinflammation.

Consumption of saturated, fried or oxidized fats in a context of high levels of carbohydrates: The fearsome high fats-high carbs combination is clearly obesogenic and induces the production of proinflammatory substances from adipose cells. This metabolic context produces neuroinflammation. (Study) (Study). It is important to highlight this, because the ketogenic diet, rich in quality fats and very low in carbohydrates, is perhaps one of the most performed interventions to treat neuroinflammation. But, in addition, high insulin levels mean that fats cannot be used as fuel by the body, nor can they be transformed into ketone bodies to ‘feed’ our neurons. Insulin is capable, by itself, of activating glial cells.
Consumption of proteins with a high inflammatory potential (such as wheat or dairy): This wonderful study, published in 2014 in the Journal of Nutrients, shows how, out of a population sample of 400 people, between 15 and 17% tested positive for some antibody against a wheat or milk protein. Even more: of the people who tested positive, 50% have markers of brain inflammation. Therefore, the inflammatory context that is generated by high consumption of these foods carries an enormous inflammatory potential.
Excess frequency of intake: Every time we eat food, there is an increase in intestinal permeability. As well as a greater translocation of bacterial products into the bloodstream and a postprandial inflammatory response. Not surprisingly, there is multiple evidence of the positive effect of meal spacing, or intermittent fasting, on neuroinflammation.
The consumption of nutrients with the ability to modulate neuroinflammation and/or cross the blood-brain barrier.
Among them, we have some of our old friends, those fellow travelers who are always there to balance our diet:

Bioflavonoids:

Flavonoids such as resveratrol, curcumin or apigenin have shown their effect as modulators of inflammation. Including them in the diet -or even as supplements- is crucial for the prevention and treatment of neuroinflammation. Keep in mind that the key to bioflavonoids is diversity. Well, in order to cross the blood-brain barrier, they must be transformed by the intestinal microbiota. Therefore, the same flavonoids will not have the same effects on all people.
Essential fatty acids:

All inflammation regulation processes require the necessary raw material to produce anti-inflammatory substances. The main raw material for this function is the omega 3 fatty acids EPA and DHA, as we see in this study.
Short-chain fatty acids:

The metabolism of fiber by the microbiota produces this type of fatty acids with a high regulatory potential of neuroinflammation. So you see it in this study.
Magnesium:

Magnesium has also shown certain neuroprotective effects and is usually included in different treatment protocols, this study reflects.

Conclusions on neuroinflammation

Brain swelling is more normal than we think. It is known as neuroinflammation and it manifests itself with specific symptoms -lack of concentration, mental slowness, lethargy…- that affect brain function.
These symptoms are so common and nonspecific that therapists have come to normalize the clinical signs. As a consequence, they do not treat them as a Red Flag.
Glial cells of the CNS are involved in neuroinflammation. The treatment to correct this widespread dysfunction involves:

• Avoid alcohol.
• Regain metabolic flexibility with tools like the ketogenic diet and intermittent fasting.
• Respect the hours of sleep.
• Modulate stress.
• Include key nutrients in the diet for proper brain function and the modulation of glial cells.
• Include physical activity in daily routines.