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Targeting Microglia and Mitochondria for Effective Chronic TBI Treatment

Traumatic brain injuries (TBI) lead to a cascade of cellular disruptions and physiological changes, with the microglia and mitochondria being especially affected. At Driftless Integrative Psychiatry, we have centered our approach to chronic TBI care around these two vital cellular components - they matter so much! By understanding their critical functions and vulnerabilities, we can offer tailored treatments to our patients, promoting faster and more comprehensive recovery.



Why Microglia and Mitochondria Matter in TBI Care


Microglia:

  • Brain's Immune Responders: Microglia are the primary immune cells in the brain, responsible for detecting disturbances and maintaining brain health. After a TBI, their activation becomes a double-edged sword.

  • Pro-inflammatory Response: Once activated, microglia release inflammatory cytokines like TNF-alpha, IL-1beta, and IL-6. A balance is crucial; while inflammation is needed for tissue repair, its excess can compound brain damage.

  • Chronic Activation Concerns: Persistent activation of microglia post-TBI leads to ongoing inflammation, potentially contributing to long-term complications or even neurodegenerative diseases.

Mitochondria:

  • Cellular Power Plants: Mitochondria are the energy factories of our cells, generating ATP essential for numerous cellular functions. Their well-being is directly linked to the cell's health and vitality.

  • Vulnerability to TBI: A TBI can disrupt mitochondrial functions, limiting ATP production and, in turn, affecting cellular recovery and health.

  • ROS Production: Dysfunctional mitochondria can also produce harmful reactive oxygen species (ROS), further stressing or damaging the cell.

Given the roles of microglia and mitochondria in brain health, their dysregulation post-TBI can be seen as a root cause of many of the condition's symptoms and long-term effects. Our integrative approach aims to address these foundational disturbances, providing care that is more aligned with the body's innate healing mechanisms.



Sleep, Hormonal Balances, and TBI


Post-TBI, patients often experience:

  1. Circadian Rhythm Disruptions: Impacting sleep-wake cycles due to injury in brain regions that manage our body clock. This in turn, can negatively impact mood and increase anxiety.

  2. Hormonal Shifts: Altered cortisol levels can greatly affect sleep quality, further underscoring the interconnected nature of TBIs.

Cortisol is an important hormone that we talk about frequently in integrative psychiatry. It is produced by the adrenal glands, often termed the "stress hormone" because its secretion increases in response to stress. Cortisol plays several pivotal roles in metabolism, immune function, blood pressure regulation, and maintaining circadian rhythms.


Traumatic brain injuries can disrupt the hypothalamus and pituitary gland – key components of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol production.


When TBIs disrupt the HPA axis and alter cortisol levels, this can have cascading effects on other hormonal processes, including:

  1. Thyroid Function: Cortisol can influence the production and action of thyroid hormones. High levels of cortisol can decrease the production of thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH), potentially leading to hypothyroid symptoms.

  2. Sex Hormones: Elevated cortisol can suppress the hypothalamic-pituitary-gonadal (HPG) axis, leading to reduced secretion of sex hormones like testosterone in men and estrogen and progesterone in women. This can impact reproductive health, libido, and other bodily functions tied to these hormones.

  3. Blood Sugar Regulation: Cortisol plays a role in blood sugar regulation by promoting gluconeogenesis in the liver. Dysregulated cortisol can lead to imbalances in insulin sensitivity and blood sugar levels.

These different hormones can be measured and along with clinical symptoms, a personalized plan can then be developed to optimize hormones and improve metabolic health.



Innovations in TBI Treatment


Ketamine:

  • Offers both neuroprotective qualities, safeguarding neurons from further post-injury damage, and anti-inflammatory effects, potentially moderating the overactivity of microglia.

  • Additionally, ketamine can enhance synaptic plasticity, fostering neural connections critical for recovery (i.e. help with brain cell growth).

  • Can help with mood dysregulation, commonly experienced among those with traumatic brain injuries

Photobiomodulation:

  • Targets cellular recovery, especially within mitochondria, by using red and near-infrared light. This can rejuvenate mitochondrial functions, enhancing ATP production, which gives us more energy and decreases fatigue.

  • The method also helps reduce microglial-driven inflammation and bolsters cerebral blood flow, nourishing damaged brain regions.

Low Dose Naltrexone:

Low Dose Naltrexone (LDN) has an interesting mechanism of action that involves the modulation of microglial cells.


How LDN Targets Microglial Cells:
  1. Opioid Receptor Modulation: Naltrexone, at its typical doses, is an opioid antagonist (blocker), primarily blocking the mu-opioid receptors. However, at low doses, its transient blockade of these receptors seems to lead to a compensatory increase in endogenous opioids, particularly endorphins and enkephalins.

  2. Microglial Regulation: Microglial cells have opioid receptors, and it's believed that LDN's influence on these receptors can impact microglial activity. Specifically, LDN appears to attenuate the activation of microglia, reducing their pro-inflammatory actions.


Why Targeting Microglial Cells is Beneficial for TBIs:
  1. Inflammation Control: As the resident immune cells of the brain, activated microglia release pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-6. While inflammation is necessary for tissue repair, excessive or prolonged inflammation can exacerbate brain damage, especially after a TBI. By moderating microglial activation, LDN may help control this inflammatory response, potentially mitigating further neural damage.

  2. Neuroprotection: Chronic activation of microglia has been associated with neurodegenerative processes. By potentially reducing chronic microglial activation, LDN may offer neuroprotective effects, safeguarding neurons from secondary injury processes that can follow the primary TBI event.

  3. Symptom Alleviation: By curbing excessive inflammation, LDN might play a role in reducing symptoms associated with TBIs, such as fatigue, headaches, cognitive difficulties, or mood disturbances, although direct evidence for this is still emerging.


Our Dedicated Approach to Chronic TBI Care

By understanding and targeting the central roles of microglia and mitochondria in TBI, we can offer treatments that address the root causes of TBI symptoms and complications. Combined with innovative treatments like ketamine, photobiomodulation, and low dose naltrexone, our holistic approach ensures patients receive the best possible care, built on the latest scientific understanding. We provide an evidence-informed and integrative pathway to recovery for those navigating the challenges of chronic TBI.


If you're interested in becoming a patient at Driftless Integrative Psychiatry and working with Dr. Burger for a personalized, holistic, and root-cause approach to mental health including the assessment for and treatment of chronic traumatic brain injury, you can learn more here.


Recommended further reading:


Traumatic Brain Injuries (TBI) and Inflammation:

  1. Postolache et al, (2021). Inflammation in Traumatic Brain Injury. J Alzheimers Dis.

  2. Kumar & Loane (2012). Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention, Brain Behav Immun.

Microglia's Role in TBI:

  1. Kumar & Loane (2016). Microglia in the TBI brain: The good, the bad, and the dysregulated, Experimental Neurology.

Mitochondrial Dysfunction in TBI:

  1. Cheng G, Kong RH, Zhang LM, Zhang JN (2012). Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol.

  2. Hiebert JB, Shen Q, Thimmesch AR, Pierce JD (2015). Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci.

Ketamine and Neurological Implications:

  1. Rueda Carrillo L, Garcia K, Yalcin N, et al. (2022). Ketamine and Its Emergence in the Field of Neurology. Cureus

Low Dose Naltrexone (LDN) for Neurological Conditions:

Photobiomodulation in Brain Disorders:


This blog post is designed as a general guide. This is not a substitute for personalized medical advice, nor is a patient-physician relationship established in this blog post.

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