Treatment for TBI and PTSD

Can the ketogenic diet treat comorbid traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) at the same time?

The ketogenic diet can be an effective treatment for individuals suffering from both TBI and PTSD due to its ability to modify underlying shared mechanisms of pathology in both disorders. Ketogenic diets reduce neuroinflammation and oxidative stress, balance neurotransmitter hyperexcitability, improve brain energy and metabolism, and upregulate levels of brain-derived neurotrophic factor (BDNF). Ketogenic diets also exert neuroprotective effects that can reduce levels of subsequent neurodegenerative damage seen in those with one or both disorders.

Introduction

In this blog post, I will be referencing a specific research article.

Monsour, M., Ebedes, D., & Borlongan, C. V. (2022). A review of the pathology and treatment of TBI and PTSD. Experimental Neurology, 114009. https://doi.org/10.1016/j.expneurol.2022.114009

In the research article, the writers did a wonderful job of showing the shared underlying pathophysiology we see in the brains of people who have TBI and/or PTSD. It is an impressive article, and IMHO does an excellent review of the literature. My dismay set in when I noticed that while these researchers identified underlying pathologies and common treatments both currently in use and future potential treatments, the ketogenic diet was not included.

I was super surprised by this. So my plan is to write this blog post referring directly to their research that identifies underlying pathologies in TBI and PTSD and discuss how the ketogenic diet influences those same mechanisms while pulling from the research literature to make my case.

I will then share this blog post with the study authors and see what they think.

It might be that the ketogenic diet just wasn’t on their radar as a potential treatment. Or maybe it didn’t meet some kind of criteria they had for its inclusion. But these researchers had no competing interests that would make me think they wouldn’t want to know about it and be open to its consideration. And perhaps if we share what we know, they will be willing to consider it in a future publication on the topic.

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But first, let’s talk about these two disorders.

Traumatic brain injury (TBI) and post-traumatic brain injury at two separate diagnoses that are often seen together in a variety of populations but are seen co-occurring in those with military service overseas, victims of domestic violence, and physical accidents in which a head injury has occurred.

TBI is generally defined as a brain injury due to an external force and can range from mild to severe. Symptoms can include headaches, dizziness, tinnitus, and cognitive symptoms. Cognitive symptoms may include speech changes, concentration, and memory impairment. People who have suffered more severe TBI injuries may also have bruising of the brain (contusions), chronic inflammation, and other visible pathologies.

How are TBI and PTSD similar?

Many people who have developed PTSD have suffered physical trauma that has resulted in a TBI injury. While this associational link is both intuitively correct and has been proven in research, the similarities do not end there. Both present with both neurological and psychiatric complaints, which include:

• anxiety
• irritability
• insomnia
• cognition impairments

Not surprisingly, individuals who meet the criteria for both PTSD and TBI have more negative outcomes without effective treatment.

Both conditions are perpetuated by underlying mechanisms of neuroinflammation, oxidative stress, excitotoxic neurotransmitter imbalances, and, not surprisingly, changes in brain structure.

These underlying mechanisms do not just occur once during physical or emotional injury and then stop. These mechanisms unchecked contribute to neurodegenerative aging, causing progressive impairment and symptoms. It is not an unreasonable theory that the similarities in symptoms seen between both conditions are because of significant overlap in underlying mechanisms of pathology.

In the above-referenced research article, the authors discuss current treatment options for those disorders. Some of those that are relevant to our argument are exogenous stem cell procedures, Hyperbaric Oxygen Therapy (HBOT), and medications. The ketogenic diet should have been included in this article by the authors as an alternative treatment for both TBI and PTSD.

Why? For the following reasons:

• Stems cells are invasive. Invasive procedures have risks. Stem cells are a very expensive medical intervention.
• Not everyone with PTSD and TBI has access to HBOT at military hospitals or has insurance that will cover it, and they are suffering right now!
• If the medications were consistently helpful, we would not have so many still suffering. New medication development is expensive and time-consuming. And again, people are suffering right now.
• The ketogenic diet has already been reviewed in the scientific literature as a potential treatment for TBI, and a call for RCTs has been confirmed with the publication of a Phase I single trial.
• Animal studies have shown that trauma-exposed mice display cerebellar and multi-system metabolic reprogramming. PTSD develops from trauma exposure, and the ketogenic diet is a metabolic intervention for the brain.
• Published case studies and RCTs exist for specific mental illness populations in which metabolic alterations are seen as underlying pathology (e.g., Alzheimer’s disease, ALS, bipolar disorder, alcohol use disorder, and schizophrenia), showing positive treatment outcomes.
• Ketogenic diets require a much lower cost of intervention than stem cell therapies or even HBOT, and even medications. A lifetime of medications is an expensive prospect for insurance companies and patients alike. Ketogenic diets can be implemented at home by the patient and their family and may require only limited time support from a nutritionist or other type of ketogenic diet professional.

In this blog post, we will discuss the underlying pathological mechanisms identified in this article in people suffering from PTSD and/or TBI. Using the available literature on the effects of ketogenic diets on those mechanisms, we will make the case that the ketogenic diet should have been included in the research article.

By posting this article, we will attempt to help people with PTSD and/or TBI learn all the ways they can feel better.

Shared Pathophysiology between TBI and PTSD

The overlapping symptomology and comorbidity of TBI and PTSD may be related to the significant overlap in underlying pathophysiology. Both neurological disorders show substantial neuroinflammation, oxidative stress, excitotoxicity, and structural changes.

Monsour, M., Ebedes, D., & Borlongan, C. V. (2022). A review of the pathology and treatment of TBI and PTSD. Experimental Neurology, 114009. https://doi.org/10.1016/j.expneurol.2022.114009

Neuroinflammation

One of the most damaging factors that occur in TBI is neuroinflammation. Release of proinflammatory cytokines such as IL-1, IL-12, TNF-α, and IFN-γ are released by immune system activity in the brain. The immune system is activated in response to the physical (or emotional) assault that has happened. This activity increases immune cells in the brain called microglia. They create very high levels of inflammation and promote chronic neuroinflammatory cycles. These neuroinflammatory cycles lead to further cell damage and neuronal death. As neurons become more injured and die they release excitatory neurotransmitters like glutamate, which then promotes neurotransmitter imbalance. Damage to the blood-brain barrier (BBB) occurs because of additional cytokine release by astrocytes. This damage to the blood-brain barrier increases neuronal immune system reactivity and inflammatory processes. Perpetuating a neurotoxic environment far beyond the original physical or emotional trauma of TBI and/or PTSD.

PTSD has a similar neuroinflammation response to TBI. Both show increased pro-inflammatory cytokines, but the increased release comes after a stressful event instead of a physical brain injury, as seen in TBI. Both TBI and PTSD can show chronic microglia activity decades later, creating further damage to neurons for the entire time they remain activated.

Ketogenic diets are excellent modulators of neuroinflammation. There is a well-established effect documented, particularly in its use for treatment-resistant epilepsy. It is thought that the ketogenic diet modulates neuroinflammation through several different mechanisms, which can include modification of the gut microbiome, a reduction in blood sugar levels that perpetuate inflammation, and the actual ketone bodies themselves.

Ketones act as a signaling molecule that modulates gene expression involved in chronic inflammatory pathways. Multiple studies have shown that one type of ketone, known as β-hydroxybutyrate (BHB) has effects on particular receptors that control the activation and release of pro-inflammatory cytokines such as IL-1β and IL-18

These same ketone bodies have been seen to have beneficial effects on blood-brain barrier (BBB) functioning and repair processes. It is thought this happens due to improved energy to astrocytes that are able to repair and maintain the blood-brain barrier (BBB) and therefore reduce inflammatory molecules coming in from the peripheral immune system. This may be an important factor that has an improved likelihood of minimizing the chronic neuroinflammatory response we see post-TBI and PTSD.

The effects of ketones to modulate inflammation has been shown in vitro and in vivo. Why this would not be a primary treatment strategy, highlighted in the scientific literature to help treat underlying pathology in TBI and PTSD, is quite frankly beyond me. I just cannot figure out why it was not included in this excellent review by the authors.

But let’s continue to look at underlying pathology and see what else the ketogenic diet could do for people with TBI and PTSD.

Oxidative stress

Once you get a chronic immune response revved up in the brain with all that microglial activation, you build up something called oxidative stress. Oxidative stress occurs when the demands for cell repair are more than your internal antioxidant and micronutrient systems can handle. Cell membranes stop working well, micronutrient stores become depleted, and cells languish because they don’t have enough energy to repair, let alone fire, and function well. They die, and they often disrupt nearby neurotransmitter balance in the cells around them when they go. Oxidative stress drives neurocognitive aging faster than it otherwise would have happened.

People with TBI and PTSD both have higher levels of oxidative stress. And it is difficult to communicate the level at which oxidative stress disrupts normal brain function. But the authors do a pretty good job of making it clear in the following quote from the article.

In TBI, PTSD, and
the combined condition, reactive species lead to further BBB permeability,
alter neuronal plasticity, impair neurotransmission, and alter
neuronal morphology in veterans and animal models

Monsour, M., Ebedes, D., & Borlongan, C. V. (2022). A review of the pathology and treatment of TBI and PTSD. Experimental neurology, 114009. https://doi.org/10.1016/j.expneurol.2022.114009

So what does a ketogenic diet have to offer high levels of oxidative stress? Quite a lot, actually. Ketogenic diets, and the ketones those diets create, treat oxidative stress in a number of ways. First, they improve cell energy so that repairs to cells and upkeep can happen. This improved energy also helps the cell function better. The improved cell energy coming from ketones allows the cell membrane to work better, which means it is able to store more necessary nutrients for the creation of important cofactors in cell upkeep and neurotransmitter creation. So on ketogenic diets, we improve the energy and health of the cells in such a way that there are neuroprotective effects overwhelming levels of oxidative stress.

The other thing ketones do that directly influences oxidative stress levels in the brain is the upregulation of endogenous antioxidants, such as glutathione. Glutathione is a very powerful scavenger of reactive oxygen species, which are quat gets out of hand when a brain is overwhelmed with oxidative stress. If you had TBI and/or PTSD, wouldn’t you want your most powerful endogenous anti-inflammatory upregulated and working at full capacity?

These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.

Greco, T., Glenn, T. C., Hovda, D. A., & Prins, M. L. (2016). Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. Journal of Cerebral Blood Flow & Metabolism, 36(9), 1603-1613. https://doi.org/10.1177/0271678X15610584

There is actually an already impressive body of research using ketogenic diets as a treatment for TBI. So I am not understanding why the authors, who are making the argument that there is a shared underlying pathology, would not mention it as a potential treatment option for those suffering from one or both disorders.

Excitotoxicity, aka neurotransmitter imbalance

So all that neuroinflammation depletes the ability of the cells to repair. And when that balance between repair and damage gets out of whack, you have high levels of oxidative stress. And those high levels of oxidative stress do a couple of different things to neurotransmitters. So it is no surprise that in TBI and PTSD, we see excitability in the cortical and hippocampus areas of the brain that is thought to be due to increased glutamate production. There are supposed to be adequate amounts of an inhibitory neurotransmitter called GABA that is supposed to keep this system in balance. But when the environment in which your brain is trying to make neurotransmitters is full of oxidative stress and inflammation, it doesn’t balance these neurotransmitters.

In animal models of combined PTSD and TBI, we see alterations in the brain’s ability to modulate these two neurotransmitters. There is too much glutamate and not enough GABA in the right amounts or hanging out in the right places. This neurotransmitter imbalance can impair control in the frontal cortex, which needs to function in order to plan behavior, regulate emotion, and do a host of other important executive functions we often see impaired in people with TBI and/or PTSD.

So once again, I am perplexed as to why, if there are disruptions in the glutamate/GABA system in those with TBI and PTSD, the authors would not be singing the potential benefits of a ketogenic diet.

The effects of the ketogenic diet on the glutamate/GABA system are well documented, again in the literature on treatment-resistant epilepsy. Upregulation of the neurotransmitter GABA that happens on a ketogenic diet has been hypothesized as possibly one of the underlying mechanisms of seizure reduction in this population.

Another way that a ketogenic diet has been seen to improve neurotransmitter balance and reduce hyperexcitability is in its ability to improve neuronal membrane functioning. This has a direct effect on calcium ion channels, how often they fire and how excitatory they become. This has also been theorized as a mechanism by which the ketogenic diet helps reduce seizure frequency in the epilepsy population.

So again, with ketogenic diets having well-documented effects on neurotransmitter function and neuronal membrane function, I remain unsure as to why it was not referred to or discussed as a potential treatment for comorbid TBI and PTSD.

Brain morphology

In any disorder that has chronic neuroinflammation, high levels of oxidative stress, and neurotransmitter imbalances, you are going to see actual changes to the physical structures of the brain. Some parts will become bigger or smaller, and some parts will connect with other parts in abnormal ways. The health of your neurons is the basis for the actual functioning of all those structures. In people with TBI, these morphological changes and disrupted connections between brain structures may be additionally perpetuated by axonal shearing that has occurred as part of the injury.

So it is no surprise that the authors go on to speak about brain changes seen in those suffering from TBI and PTSD. Researchers have found substantial changes in brain structure and interconnectivity in those with TBI and PTSD.

Abnormalities of the fronto-cingulo-parietal cognitive control network, which is involved in cognition, memory, attention, and inhibition of fear processing is vital to understanding the pathology of TBI and PTSD

Monsour, M., Ebedes, D., & Borlongan, C. V. (2022). A review of the pathology and treatment of TBI and PTSD. Experimental neurology, 114009. https://doi.org/10.1016/j.expneurol.2022.114009

Patients with PTSD and TBI demonstrate similar changes in brain structures, and this is thought to contribute to shared symptomology through abnormal fear conditioning, emotional hyperactivity, and inhibited prefrontal cortex metabolism.

There are at least two mechanisms of action in the ketogenic diet that could be an effective treatment for these issues. While the prior mechanisms discussed would likely improve conditions in the brain so as to reduce the likelihood or severity of long-term brain morphology by reducing inflammation and oxidative stress, there are additional factors of the ketogenic diet that can help address abnormal brain morphology in this population.

First, ketogenic diets are a metabolic intervention. We already use them to improve brain metabolism in the prefrontal cortex, particularly in those with Alzheimer’s disease. Why would we not use a ketogenic diet to improve brain hypometabolism in the prefrontal cortex of those with TBI and PTSD?

Ketones provide a readily available fuel source that is easily metabolized and turned into energy by brain cells. The fuel gets right in there, no need to deal with broken or disordered transporters that may be a barrier in brains with TBI and PTSD.

Ketones upregulate brain metabolism not only by providing an alternative fuel source but by literally increasing the number and health of mitochondria. Mitochondria are the batteries of your cells. If you want more cell energy and better utilization of cell energy, you need a lot of healthy and functioning mitochondria. Upregulation in the number and functioning of mitochondria for the TBI and PTSD brain is a powerful intervention for brain structure hypometabolism. Not dealing with hypometabolism will lead to shrinkage of the frontal lobe and cause disordered connectivity to other structures over time.

The other thing that ketones do that would be helpful in a brain full of inadequate or disordered connections is to upregulate BDNF. BDNF stands for brain-derived neurotrophic factor, and it helps heal the brain and helps in learning and memory. And it plays an important role in synaptic connections. Need to rewire a brain back to normal? You are going to need BDNF. Lots of it and lots of extra energy are provided by the mitochondrial upregulation you see on ketogenic diets.

What do mitochondria do?

Conclusion

The authors acknowledge that while most TBI/PTSD patients receive rehabilitation therapy, such care is insufficient to address the progressive neurodegeneration factors that contribute to worsening disease and symptom progression.

They go on in the article to discuss promising therapies such as hyperbaric oxygen therapy (HBOT), of which I am a great fan, and also stem cell therapies. Both of these therapies would be amazing for people with TBI and PTSD, and have a good research base for support as effective treatments. They are, however, somewhat expensive, and not everyone has adequate access to these therapies even though we would want them to.

So for those that do not want or cannot afford a neuronal stem cell procedure or do not have access to hyperbaric oxygen at their local military hospital, I want you to know that the underlying mechanism for these therapies is accessible using the ketogenic diet. BHB, a type of ketone body produced on a ketogenic diet, can upregulate BDNF.

BHB can also upregulate the expression of brain-derived neurotrophic factor (BDNF) and may thereby promote mitochondrial biogenesis, synaptic plasticity and cellular stress resistance. 

Mattson, M. P., Moehl, K., Ghena, N., Schmaedick, M., & Cheng, A. (2018). Intermittent metabolic switching, neuroplasticity and brain health. Nature reviews. Neuroscience, 19(2), 63–80. https://doi.org/10.1038/nrn.2017.156

When neural stem cells are used in the study of Alzheimer’s disease, BDNF is identified as the major mechanism underlying favorable improvement. HBOT is also known to increase levels of BDNF significantly and is one of the mechanisms by which improvement in TBI is achieved.

So while I have no doubt that both HBOT and stem cell therapies would be effective treatments for TBI and/or PTSD, I think it is important for the article to be comprehensive. Especially since the ketogenic diet has research literature supporting it as a treatment for the underlying mechanisms the authors identified as similar between these two disorders. And it is my hope that they will include the ketogenic diet in their future work or even write some sort of addendum that will help inform clinicians and researchers of the ketogenic diet as a potential treatment for TBI and PTSD.

Ketogenic diets are accessible and sustainable interventions for a variety of neurological disorders, including TBIs and PTSD. If you are curious about the underlying mechanisms for other disorders, you may enjoy several posts available on the Mental Health Keto Blog.

Post-Traumatic Stress Disorder(PTSD)

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