The neurometabolic cascade of concussion (NMCC) refers to the complex biochemical processes that occur following a concussion and can lead to significant brain energy deficits and prolonged recovery from a concussion when not adequately addressed. Prioritizing the treatment of the neurometabolic cascade of concussion (NMCC) is a key factor in Dr. Dane’s remarkable success with patients suffering from both acute concussions and post-concussion syndrome. Dr. Dane is deeply committed to addressing this often under-treated aspect of concussion management. Recognizing its importance, she will conduct a training session for her colleagues in October 2024, where she will share her expertise on the NMCC and effective treatment strategies. As a trailblazer in her field, Dr. Dane’s colleagues consistently value her insights as she seamlessly integrates cutting-edge medical research into everyday patient care—resulting in outstanding outcomes.
The Neurometabolic Cascade of Concussion
In 2001, Giza and Hovda defined the NMCC and then expanded their research in 2014. Since then, over 400 other research articles have cited this landmark information.
The cascade starts immediately following the biomechanical injury which includes the impact and neuronal stretching. The main issue that results from the NMCC is an energy crisis in the brain. This means the energy demand is greater than energy production. What causes the energy crisis is multifactorial and described in detail by the NMCC. The goal of this article is to highlight and summarize the main causes associated with the NMCC: (1) increased glutamate, (2) a massive efflux of potassium, and (3) poor mitochondrial function. It is also essential to understand that the NMCC is happening in the presence of decreased cerebral blood flow, which further contributes to the energy crisis.
Increased Glutamate Levels
A concussion’s impact leads to increased release of an excitatory amino acid called glutamate. Glutamate hinders cellular transport of glucose into cells, where the mitochondria can turn glucose into ATP (adenosine triphosphate) the fuel substrate for all cells. High glutamate levels also promote the efflux of potassium out of the cells, which leads to excitotoxicity and is associated with noise and light sensitivity and irritability.
Potassium Efflux
The sodium-potassium (Na-K) pump is essential for regulating cellular homeostasis. The pump runs on ATP. ATP, or adenosine triphosphate, is the energy currency of cells. When there is a massive efflux (moving out of the cell) of potassium, the Na-K pump’s demand for ATP increases to get the potassium back in the cell. This creates a high demand for glucose so that ATP can be produced in higher quantities. At this point, there is an increase in glycolysis, which leads to lactate accumulation.
Mitochondrial Dysfunction
The increased need for ATP production by the mitochondria is impaired by calcium overload. This leads to poor mitochondrial function and ATP production due to impaired oxidative metabolism. The process by which glucose is turned into ATP is an oxidative process.
Other important components of the NMCC
Lactate accumulation – Elevated lactate levels can impair neuronal function through a series of mechanisms:
- Inducing acidosis
- Causing membrane damage
- Altering blood-brain barrier permeability
- Leading to cerebral edema
- Promoting Amyloid-β protein deposition
Lactylation-associated pathology includes cancer, neuropsychiatric illness, multiple sclerosis, and Alzheimer’s disease.
Reductions in Magnesium
Intracellular magnesium levels are also immediately reduced after TBI and remain low for up to 4 days. This reduction has been correlated with post-injury neurologic deficits.
- Both glycolytic and oxidative generation of ATP are impaired when magnesium levels are low.
- Magnesium is necessary for maintaining the cellular membrane potential and initiating protein synthesis.
- Low magnesium levels may effectively unblock the NMDA receptor channel more easily, leading to a greater influx of Ca2+.
Immunoexcitotoxicity
Recent studies suggest that mild TBI triggers inflammatory changes. The studies report extensive upregulation of cytokine and inflammatory genes after TBI.
Microglial activation after adult FPI (fluid percussion injury) has been associated with damage to the substantia nigra and implicated in the increased risk for parkinsonism after TBI.
A theory relating glutamate release and activation of immune receptors to oxidative stress and potentially later cellular injury has been proposed and termed “immunoexcitotoxicity.”
Treating the Neurometabolic Cascade of Concussion
At Carolina Brain Center, Dr. Dane, has developed protocols specifically to address the NMCC. The treatments dampen increased levels of glutamate, increase fuel, improve mitochondrial function, dampen inflammatory responses, and improve cerebral blood flow.
Ketones1,2,3,4,5
Ketone bodies, specifically Beta-Hydroxybutyrate (BHB), can be produced by your own body by following a ketogenic diet or taken exogenously. BHB provides alternative fuel when glucose availability is compromised and have garnered interest for their potential health benefits and applications in concussion and other types of traumatic brain injuries. Studies suggest that administering ketones to TBI patients could significantly aid in their recovery and provide a promising nonpharmacologic treatment for TBI.
- Ketone bodies (KBs) can help address post-traumatic cerebral energy deficits. Exogenous ketone ester supplementation has been shown to be the brain’s preferred energy source, even when glucose is readily available.
- Ketone bodies reduce inflammation, oxidative stress, and neurodegeneration. KBs directly regulate mitochondrial permeability transition, thus affecting the regulation of intracellular calcium levels.
- Ketone bodies limit glutamate release and upregulate GAD1, increasing glutamate conversion to GABA.
- Preliminary evidence suggests that inducing ketosis with exogenous ketones may help improve cognitive and motor performance in conditions such as seizure disorders, mild cognitive impairment, Alzheimer’s disease, and neurotrauma.
Transcranial Low-Level Laser Therapy (tLLLT)6,7
The NMCC results in an energy crisis involving mitochondrial function in an environment with reduced cerebral blood flow. Vascular damage causes hypoxia associated with high levels of glycolysis, reduced ATP generation, increased formation of reactive oxygen species (ROS), and apoptosis (cell death).
Light absorption in the electron transport chain of the mitochondria reduces brain damage and supports the brain’s natural repair processes after injury by producing a shift in the mitochondria’s redox state, leading to the regulation of transcription factors and redox-sensitive genes.
Transcranial low-level laser profoundly and positively affects mitochondrial function, decreases tissue edema and inflammation, decreases excitotoxicity, improves cerebral blood flow, and increases angiogenesis, synaptogenesis, neurotrophins, and neural progenitor cells.
Combining low-level lasers with specific energy sources and substances that influence energy production significantly enhances the therapy’s neuroprotective and therapeutic effects. This combined approach holds great promise, particularly in tissues with low energy production, such as the injured brain. It has shown encouraging results in protecting the hippocampal region and restoring cognitive and learning abilities and motor function.
Mild Hyperbaric Oxygen Therapy8,9,10
Hyperbaric oxygen therapy targets TBI-induced ischemia by producing an increased O2 concentration in the plasma and, thus, improved delivery of O2 for diffusion to brain tissue.
Cerebral blood flow is normally regulated by cerebral metabolism. This metabolic coupling is improved by HBOT.
Apoptosis within the hippocampus and general hippocampal neuronal integrity have also been repeatedly shown to benefit from HBO2, potentially through an anti-inflammatory mechanism. Biomarkers, including neutrophil infiltration, TNF-a, IL-1b, IL-6, IL-10, and MCP1, were reduced following HBOT, and subjects had consistently better functional outcomes and reduced lesion volumes.
Additional support for HBOT’s neuroprotective effect after TBI includes findings of reduced blood-brain barrier (BBB) permeability and dysfunction and infarction volume, as well as increased neuronal density, neuronal integrity, neurogenesis, synaptogenesis, and axonal integrity.
Mild hyperbaric oxygen improves oxidative metabolism in cells and tissues without barotrauma and excessive production of reactive oxygen species. Symptom improvement was greatest at 1.3ATM.
Your Concussion Rehabilitation Starts at Carolina Brain Center
After reading all this, you might wonder, “Why has no one ever mentioned this?” The positive takeaway is that you are now more educated about the pathophysiology of concussions and other types of traumatic brain injuries than most people. Knowledge is POWER!
For the person who just had a concussion, many times, you don’t feel well enough to start treatment, and sometimes, all you need is help in calming down the NMCC. If you can lie in bed, you can lie in our extra-large hyperbaric chamber. For the acute patient, we do a combination of hyperbaric oxygen ketone therapy and transcranial low-level laser therapy to start you on the road to recovery. Because many concussions are self-limiting, this may be the only treatment you need!
For the post-concussive patient who is not recovering on their own, we still need to reverse the effects of the NMCC using these same innovative strategies. In addition, we tailor a rehabilitation journey just for you that will be done at home and here in the office. Combination home and office strategies save you time and money. For more complex cases, we offer intensive therapy here at the office before moving to the blended in-office and at-home strategy.
To start the conversation, fill out our phone consultation request form. The call is free but the knowledge is priceless.
References
1 Daines, S. A. (2021). The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury. Frontiers in Neurology, 12, 723148. https://doi.org/10.3389/fneur.2021.723148
2 Edwards, M. G., Andersen, J. R., Curtis, D. J., Riberholt, C. G., & Poulsen, I. (2024). Diet-induced ketosis in adult patients with subacute acquired brain injury: A feasibility study. Frontiers in Medicine, 10, 1305888. https://doi.org/10.3389/fmed.2023.1305888
3 Paoli, A., Moro, T., Bosco, G., Bianco, A., Grimaldi, K. A., Camporesi, E., & Mangar, D. (2015). Effects of n-3 polyunsaturated fatty acids (ω-3) supplementation on some cardiovascular risk factors with a ketogenic Mediterranean diet. Marine drugs, 13(2), 996–1009. https://doi.org/10.3390/md13020996
4 Poff, A. M., Moss, S., Soliven, M., & P., D. (2021). Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Frontiers in Nutrition, 8, 783659. https://doi.org/10.3389/fnut.2021.783659
5 Sethi, S., Wakeham, D., Ketter, T., Hooshmand, F., Bjornstad, J., Richards, B., Westman, E., Krauss, R. M., & Saslow, L. (2024). Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial. Psychiatry Research, 335, 115866. https://doi.org/10.1016/j.psychres.2024.115866
6 Khuman J, Zhang J, Park J, Carroll JD, Donahue C, Whalen MJ. Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice. J Neurotrauma 2012;29:408–417
7 Thunshelle, C., & Hamblin, M. R. (2016). Transcranial Low-Level Laser (Light) Therapy for Brain Injury. Photomedicine and Laser Surgery, 34(12), 587-598. https://doi.org/10.1089/pho.2015.4051
8 Daly, S., Thorpe, M., Rockswold, S., Hubbard, M., Bergman, T., Samadani, U., & Rockswold, G. (2018). Hyperbaric Oxygen Therapy in the Treatment of Acute Severe Traumatic Brain Injury: A Systematic Review. Journal of neurotrauma, 35(4), 623–629. https://doi.org/10.1089/neu.2017.5225
9 Harch P. G. (2022). Systematic Review and Dosage Analysis: Hyperbaric Oxygen Therapy Efficacy in Mild Traumatic Brain Injury Persistent Postconcussion Syndrome. Frontiers in neurology, 13, 815056. https://doi.org/10.3389/fneur.2022.815056
10 Ishihara A. (2019). Mild hyperbaric oxygen: mechanisms and effects. The journal of physiological sciences : JPS, 69(4), 573–580. https://doi.org/10.1007/s12576-019-00678-5