Neuroinflammation is a broad term for an inflammatory response in the brain or the spinal cord.[1]
I have a different name for it—a hot brain.
One of most people’s first experiences of neuroinflammation is when they get the flu. When we get sick, the immune system uses inflammation to mobilise or activate its different components to respond to the infection.
This activation is an essential point. Inflammation is an integral part of helping our immune systems take action.
I just wanted to say that.
Mainly because it seems in the modern day a preoccupation with anti-everything and these binary responses, such as in the case of antibiotic overuse, have landed us in some unexpected and unintended situations.
Sorry I can get distracted easily. Maybe I have an inflamed brain!
Anyway, when we get an infection like the flu, for example, the inflammation that is needed to signal an immune response can also affect the brain and the way we behave. This effect is called “sickness behaviour.” [2]
The symptoms of sickness behaviour will sound all too familiar. Little motivation to eat, fatigue and reduced interest in anything that’s not rest and sinking into the couch are all synonymous with getting sick, but there are some mental symptoms too.
For example, there is a lot of crossover between the symptoms of depression and sickness behaviour.
Some key similarities are a lack of motivation or apathy, an inability to feel joy and the general desire to withdraw from the world. All three are signs of depressive behaviour, but they also make sense when it comes to the brain and the immune system working together to try and get you to rest and recover from an infection.
But what if the way you feel mentally and emotionally when you have the flu doesn’t get better alongside the infection?
In 1999, a psychobiologist named Raz Yirmiya was one of the first to connect the immune response from infection, the inflammation it caused and mental health, specifically depression. He initially did so in mice who were less sensitive to pleasurable things such as food and sex when injected with an inflammatory serum.[3]
It wasn’t until 2006 that researchers showed activation of the immune system induced depressive-like behaviour in mice independent of sickness.[4]
Although this research didn’t translate into human studies until much later, it presented us with the connection between the activation of the immune system both outside and inside the brain and different presentations of mental health.
Fast forward twenty or so years, and our understanding of neuroinflammation and how it affects us has undoubtedly evolved.
It’s possible now to identify potentially inflamed brain regions by the presenting symptoms. For example, inflammation of the frontal lobe in the brain can affect your executive function or the skills you need to get through your day.[5]
Another recent example in many of our minds is how SARS-CoV2 affected our sense of smell. One recent study connected this with the virus’s ability to invade the brain and inflame the regions associated with our ability to smell.[6]
An important note on this study is that it is yet to be peer-reviewed at the time of writing this, which means it may not be conclusive. My hope in mentioning it is to help build the connection between how neuroinflammation can cause symptoms with which we are familiar.
Neuroinflammation is closely related to a common symptom, brain fog.
Brain fog is a typical way of describing characteristics of poor cognition, such as difficulty concentrating, thinking and communicating.[7] Once again, post-pandemic, our understanding of brain fog has evolved.
Long haul syndrome, or long-COVID, has seen a significant increase in people experiencing symptoms such as memory impairment, difficulty finding words, dizziness, visual impairment and hearing problems, [8] all things associated with neuroinflammation.[9]
Other mild to moderate neuroinflammation symptoms are depression, sleepiness, fatigue and increased demand for sleep. I’ve had some patients describe the last symptoms as waking up after eight hours of sleep with the sensation of not having slept at all.
How do you know if you have neuroinflammation?
As part of my routine case-taking in the clinic, I always enquire about energy and fatigue with a two-part question you can use to help using yes or no answers.
The first part is whether you feel you have the physical capacity to run four hundred metres.
The second part is how you would assess your capacity to read a three thousand-word article, the equivalent of the main feature in a magazine.
Interestingly, most people tend to be okay with part one, with injuries and fitness accounted for. However, part two is often the question that ends with a resounding “no”.
One patient said, “it’s time out after the one hundred and forty-ninth word.”
Is this you?
Well, it’s most likely you are experiencing a mild to moderate form of neuroinflammation. An easy way to tell whether it’s mild or moderate is if you feel you are getting some of the symptoms we discussed earlier from sickness behaviour syndrome. Loss of appetite, motivation, and withdrawal is critical, along with difficulty starting and finishing things.
What causes neuroinflammation?
It’s fair to say that you don’t wake up one day just feeling all these symptoms; it develops over time. Some would call it a “slow burn.”
And a slow burn is almost a perfect way of articulating it, as the inflammation in the brain can come from two sources. One source comes from outside the brain, from the peripheral immune system or within the brain after the internal immune system gets activated by something crossing the blood-brain barrier.
Let’s unpack both causes a little bit, and this can also help us understand how to solve them by looking at one of the main “outside the brain” causes – the gut.
If you’re familiar with our focus on this website, it’s around the relationship between the brain and gut. As I write this, I’m surprised it’s taken so long for me to put a good article together, as neuroinflammation is one of the prime examples of this intersection between the brain, the gut and the immune system.
Introducing lipopolysaccharides.
When it comes to the microbiota and the effect of bacterial colonies in the gut, it’s the byproducts or endotoxins that these bacteria create that affect the brain. These byproducts are called lipopolysaccharides or more affectionately known as LPS.
Generally, the immune-based lining on top of the gastrointestinal tract lining protects the bloodstream from these endotoxins entering and causing trouble. Unfortunately, we have found over the last decade or more of research that the lining between these bacterial colonies and the bloodstream can be leaky, allowing for these endotoxins to slip through the cracks.
If you are new to this phenomenon, welcome to what is commonly called “leaky gut” or “intestinal permeability” in the science papers, “intestinal permeability.”
Now you can find almost every disease associated with a leaky gut, and it’s fair to say that natural and functional medicine has a particular fixation on its recovery. Still, if I was to offer my point of view, most people are going to have some level of this permeability in their digestive systems.
The problems begin after gut infections, like food poisoning, where some uninvited guests come in and set up a community and begin to create more and more of these LPS endotoxins that then get into the bloodstream and travel around the body.
Often a leaky gut can lead to a leaky brain.
It can be a little intense and scary when I explain this to patients. However, let me explain.
The blood-brain barrier, or BBB, is made of the same cells as the digestive lining we referred to above. This vulnerability means that under the right or wrong conditions, in this case, it can be just as vulnerable to the effects that cause the lining of the gut to become leaky.
Only with worse consequences.
The immune system is extremely sensitive to LPS. This sensitivity means that the inflammation it causes can be significantly higher when the two meet. Therefore, before even reaching the brain and causing inflammation, LPS can create a longstanding, low-grade inflammation across the body.
Outside of the neuroinflammatory picture we’re looking at here, this chronic low-grade inflammation is the developmental cornerstone of the most prevalent illnesses globally. For example, we see neuroinflammation in metabolic syndrome, type-2 diabetes, non-alcoholic fatty liver disease and cardiovascular disease.[10]
Back to LPS and the brain.
When LPS causes its inflammatory response, this inflammation can travel back up the vagal nerve to the brain in one fashion or can affect things at the site of the blood-brain barrier.
Alzheimer’s disease and stroke survivors see higher levels of LPS in their brains,[11] with Alzheimer’s disease patients seeing up to five to ten times more bacteria than healthy brains![12]
Inflammation from outside the brain can cause issues, but what happens when trauma is inside the brain?
An excellent example of when this occurs is a concussion. To put how frequent this is in context, around one point seven million people annually suffer a traumatic brain injury (TBI) in the US.[13] Gaining a lot of exposure due to its effects on rugby and contact sports players, TBIs can occur from a punch to the face, a car accident or an explosion in the case of the military.
To understand how these types of things can affect us from a neuroinflammatory point of view, we’ll need to introduce a particular group of cells in the brain called neuroglia.
Unbeknownst to most, including myself, before I trained specifically in the treatment of neuroinflammation, these neuroglia cells comprise around ninety per cent, depending on the region of the brain.[14]
The function of the different glial cells is broadly is maintain balance within the brain. This balance includes blood flow and an appropriate immune response when necessary.
For our article on neuroinflammation, we want to focus on the neuroglia’s immune portion, the microglial cells.
Think of these cells as the maintenance crew of the crew. They regulate the development of the brain, maintain the neural networks and repair injury when necessary.[15]
The problems occur when these microglia get activated. For example, in the case of the traumatic brain injury, we touched on earlier. Over time, as part of the ageing process, the microglial cells remain primed and produce inflammation within the brain, affecting the neurons’ ability to communicate with each other.
Whilst in most cases, inflammation can turn off once the immune system has attended to the stimulus or insult, microglia have difficulty turning themselves off once they are activated, leading to accelerated ageing of the brain in the process.[16]
As these microglial cells are left to continue to turn up the volume on inflammation, the brain slowly shows degenerative effects such as the signs and symptoms above but also in mental health, notably depression[17]and anxiety.
Interestingly, there is compelling evidence to suggest that the success of antidepressant medications such as SSRIs and SNRIs is largely down to their anti-inflammatory effects, particularly when it comes to neuroinflammation.[18]
The problem with this is that your brain doesn’t have pain receptors like your elbow or knee.
That means when the brain is inflamed, and these microglia are activated, you won’t know it’s occurring, like when your knee or elbow is sore. This absence of feedback that the brain is inflamed is precisely why neurodegenerative diseases such as Alzheimer’s disease and Multiple Sclerosis creep up on us over time.
If you are suffering from brain fog, particularly post-COVID, or from depression that doesn’t seem to respond to the traditional treatments, attending to neuroinflammation can be one the best places to start.
You might find that the cognitive shortfalls you are tolerating daily simply disappear!
Hope this helps x
References
[1] DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. 2016;139 Suppl 2(Suppl 2):136-153. doi:10.1111/jnc.13607
[2] Kelley KW, Bluthé RM, Dantzer R, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003;17 Suppl 1:S112-S118. doi:10.1016/s0889-1591(02)00077-6
[3] Yirmiya R, Weidenfeld J, Pollak Y, et al. Cytokines, “depression due to a general medical condition,” and antidepressant drugs. Adv Exp Med Biol. 1999;461:283-316. doi:10.1007/978-0-585-37970-8_16
[4] Frenois F, Moreau M, O’Connor J, et al. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology. 2007;32(5):516-531. doi:10.1016/j.psyneuen.2007.03.005
[5] Zhu Y, Zhou M, Jia X, et al. Inflammation Disrupts the Brain Network of Executive Function After Cardiac Surgery [published online ahead of print, 2021 Jul 2]. Ann Surg. 2021;10.1097/SLA.0000000000005041. doi:10.1097/SLA.0000000000005041
[6] de Melo, G. et al. (2022) “Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants”. bioRxiv.
[7] Ross AJ, Medow MS, Rowe PC, Stewart JM. What is brain fog? An evaluation of the symptom in postural tachycardia syndrome. Clin Auton Res. 2013;23(6):305-311. doi:10.1007/s10286-013-0212-z
[8] Jennings G, Monaghan A, Xue F, Duggan E, Romero-Ortuño R. Comprehensive Clinical Characterisation of Brain Fog in Adults Reporting Long COVID Symptoms. J Clin Med. 2022;11(12):3440. Published 2022 Jun 15. doi:10.3390/jcm11123440
[9] Stefano GB, Büttiker P, Weissenberger S, et al. Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19. Curr Neuropharmacol. 2022;20(6):1229-1240. doi:10.2174/1570159X20666211223130228
More references!
[10] Minihane AM, Vinoy S, Russell WR, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. Br J Nutr. 2015;114(7):999-1012. doi:10.1017/S0007114515002093
[11] Kurita N, Yamashiro K, Kuroki T, et al. Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia. J Cereb Blood Flow Metab. 2020;40(12):2505-2520. doi:10.1177/0271678X19899577
[12] Kim, H.s., Kim, S., Shin, S.J. et al. Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: pathologic roles and therapeutic implications. Transl Neurodegener 10, 49 (2021). https://doi.org/10.1186/s40035-021-00273-y
[13] Georges A, M Das J. Traumatic Brain Injury. [Updated 2022 Jan 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459300/
[14] Herculano-Houzel S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia. 2014;62(9):1377-1391. doi:10.1002/glia.22683
[15] Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol. 2017;35:441-468. doi:10.1146/annurev-immunol-051116-052358
[16] Wu Z, Yu J, Zhu A, Nakanishi H. Nutrients, Microglia Aging, and Brain Aging. Oxid Med Cell Longev. 2016;2016:7498528. doi:10.1155/2016/7498528
[17] Wang, H., He, Y., Sun, Z. et al. Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflammation 19, 132 (2022). https://doi.org/10.1186/s12974-022-02492-0
[18] Dionisie V, Filip GA, Manea MC, Manea M, Riga S. The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies. Inflammopharmacology. 2021;29(1):75-90. doi:10.1007/s10787-020-00777-5
