23 Feb 2024

TBI Recovery and Photobiomodulation Research Paper Published | Dr. Lew Lim

This blog article summarizes a published study by Vielight’s founder, Dr. Lew Lim, on how PBM could potentially help with TBI.

Link to the full study.

Traumatic Brain Injury (TBI) is a big problem worldwide, but solutions are still unavailable. This is because TBI is complicated and involve different factors going wrong in the brain, like damage to brain cells, problems with how energy is made in cells, stress from harmful chemicals, and ongoing inflammation.

Researchers are looking at a new treatment called transcranial photobiomodulation (PBM). This treatment uses specific types of red and near-infrared light to try and fix different problems in the brain at once.

Here’s what this study covers:

How PBM works on a cellular level and how it might help with each problem in TBI.
What studies with real people say about how well PBM works for treating TBI.

The study found that PBM could be a good option for TBI treatment, but it’s important to get certain things right, like the type of wavelength used, how strong the energy density is, how long the treatment lasts, where the light is aimed, and how often the light is pulsed. These details seem to matter for how well PBM works.

Also, new research is looking at how PBM affects the way tubulins in the brain work, which could give us even more clues on how to make PBM work even better.

In short, transcranial PBM could be a powerful treatment for TBI, especially if we can figure out the best ways to use it. This means fine-tuning all those details mentioned earlier. And using artificial intelligence could help us with this discovery in the future.

Figure 1. Schematic structure of the reviews and discussion in this blog, starting with a review of the pathophysiological aspects of traumatic brain injury (TBI), matching with photobiomodulation (PBM) research on cellular mechanisms, supported by clinical data in the literature, and ending with discussions on future research for parameters to improve outcomes for TBI.

1. Introduction

Traumatic Brain Injury (TBI) is a big problem globally, caused by external forces, leading to death or disability. Symptoms range from coma to behavioral issues like amnesia and anxiety. TBI causes damage to brain cells and tissues, which can be permanent.

Traditional treatments might not work well because TBI is complex. New approaches, like using multiple methods to diagnose and treat TBI, are needed.

Photobiomodulation (PBM) is a promising new treatment. It involves shining red or near-infrared light on the brain. Studies show it can help people recover from TBI symptoms, even in severe cases like chronic traumatic encephalopathy (CTE).

PBM seems to work by protecting brain cells, reducing inflammation, and helping cells grow. More research will help make PBM even better for treating TBI.

Figure 2. Summary of the identified pathophysiological aspects of traumatic brain injury (TBI) from a trauma source that are addressable with photobiomodulation (PBM). For each of these, we can also identify cellular molecular mechanisms activated by PBM to address them.

2. Pathophysiological Aspects of TBI and Related PBM Research

The pathophysiological aspects of TBI can be grouped into axonal injury, excitotoxicity, mitochondrial dysfunction, release of reactive oxygen species and oxidative stress, neuroinflammation, axonal degeneration and growth inhibitors, apoptotic cell death, and dysfunctional autophagy.

A summary presentation of the physiological aspects is presented in Figure 2.

2.1. Axonal Injury

Axonal injury is a major issue in TBI, and its severity often reflects the seriousness of the injury. TBI commonly causes diffuse axonal injury, affecting about 70% of cases, due to the brain moving back and forth rapidly, resulting in layered brain hemorrhages.

PBM might help repair this damage by boosting the production of ATP, the energy currency of cells. This process involves controlling various substances in the body, like ROS, N, cAMP, and Ca2+, which are important for cell function. PBM can adjust these substances, activating pathways that encourage axon regeneration.

In a rat study, PBM treatment significantly improved nerve fiber repair. This improvement was linked to increased activity in certain enzymes that use ATP, specifically through the PI3K/Akt cellular signaling pathway, which is crucial for various cell functions, including energy management and growth.

Other issues in the brain post-TBI, like inflammation and cell death, are also important but often happen because of the initial nerve damage.

2.2. Mitochondrial Dysfunction

Mitochondria are crucial for producing energy and maintaining cell health. When they don’t work properly, it can lead to various neurological issues. After TBI, mitochondria often get damaged, causing problems like swelling and disruption of internal structures. This damage can trigger further cell death.

PBM is thought to work by targeting mitochondria, specifically a component called cytochrome c oxidase, which helps produce energy. By enhancing mitochondrial function, PBM may help cells recover faster, reduce oxidative stress, and promote healing.

2.3. Excitotoxicity

The blood-brain barrier (BBB) is like a shield that controls what enters the brain from the bloodstream. When TBI damages the BBB, it can cause a release of too much of a chemical called glutamate, leading to oxidative stress and prolonged excitotoxicity, which harms brain cells.

Excitotoxicity happens when glutamate overstimulates certain receptors in the brain, letting in too much calcium. This can trigger harmful reactions, damaging neurons. Studies suggest that PBM might help by balancing calcium levels in stressed cells. In a lab test, PBM reduced calcium levels in cells under stress caused by excess glutamate, while increasing it in healthy cells.

In short, TBI can damage the BBB and cause excitotoxicity, harming neurons. PBM seems to help by boosting cellular energy, controlling calcium levels, and improving mitochondrial health, offering a potential way to fight these damaging effects.

2.4. Reactive Oxygen Species, Reactive Nitrogen Species, and Oxidative Stress

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are normal byproducts of our body’s oxygen use, essential for many cell functions. However, after a traumatic brain injury (TBI), the brain can produce too much ROS and RNS, overwhelming its natural defenses. This leads to oxidative stress, damaging cell parts like lipids, proteins, and DNA, potentially causing diseases like chronic traumatic encephalopathy (CTE).

Transcranial photobiomodulation (PBM) therapy can help here. By emitting low levels of ROS, PBM actually boosts the activity of antioxidant enzymes in the brain, reducing oxidative stress. Interestingly, PBM seems to work better in cells under high stress, decreasing ROS levels and promoting healing.

Different types of PBM, like near infrared (NIR) therapy, have been studied. They show promising results in regulating ROS levels and increasing antioxidant capacity, even in high-glucose environments. Studies on healthy people also suggest that PBM can reduce oxidative damage after exercise and improve antioxidant activity.

In short, TBI causes an imbalance in ROS levels, but PBM therapy can restore balance by enhancing antioxidant activity, ultimately helping to protect brain cells from damage.

2.5. Neuroinflammation

Following a traumatic brain injury (TBI), certain supportive cells in the brain, called glial cells, become activated and release substances that cause inflammation. This inflammatory response can be harmful if it’s too strong or lasts too long. Additionally, TBI can disrupt the blood-brain barrier, allowing harmful substances to enter the brain and worsen inflammation and damage.

A recent study, conducted in 2023 using mice, looked at how PBM could affect inflammation triggered by a bacterial component called lipopolysaccharide (LPS). PBM was found to reduce levels of pro-inflammatory molecules (IL-1β and IL-18) while increasing levels of anti-inflammatory molecules (IL-10). This suggests that PBM could help calm inflammation and promote healing. The mice also showed improvements in cognitive abilities, indicating that PBM might alleviate some of the cognitive problems linked to inflammation after TBI.

Other research using animal models has shown that PBM could benefit various brain conditions related to inflammation, such as stroke, neurodegeneration, aging, epilepsy, depression, and spinal cord injury. Overall, PBM seems to be effective in reducing brain inflammation, which is a common problem after TBI. It does this by regulating both pro-inflammatory and anti-inflammatory substances. By reducing inflammation, PBM might help prevent further damage caused by the body’s exaggerated immune response.

2.6. Axonal Degeneration and Growth Inhibitors

In TBI, damage to axons, which transmit information in the nervous system, can lead to problems like disrupted communication between neurons, brain swelling, and cell death. This damage can also trigger neurodegeneration, similar to what’s seen in Alzheimer’s and Parkinson’s diseases, known as CTE in TBI.

After TBI, the brain produces molecules that stop neurons from regenerating axons, making it harder for the brain to repair itself. Glial cells, like astrocytes and microglia, contribute to this by forming barriers around the injury site and releasing substances that prevent axonal regrowth.

PBM has been found to help regenerate axons by improving the energy production and survival of neurons, which are essential for the repair process. Studies on animals and cells have shown that PBM can restore nerve function and promote axonal growth even under conditions of oxidative stress.

In essence, PBM works by enhancing the brain’s ability to regenerate axons and reducing the barriers created by growth inhibitors and inflammation. Research suggests that PBM could be useful not only in TBI but also in other conditions involving nerve damage and oxidative stress.

2.7. Apoptotic Cell Death

TBI can cause programmed cell death, called apoptosis, in brain cells, leading to significant loss of brain function and triggering inflammation. PBM has shown promise in reversing this process by targeting cellular mitochondria and activating pathways that prevent cell death.

Furthermore, PBM stimulates neurogenesis, the creation of new neurons from neural stem cells, which is crucial for brain recovery after injury. It does this by promoting the growth and specialization of neural progenitor cells in damaged areas and improving the brain’s environment by reducing inflammation and enhancing mitochondrial function.

Angiogenesis, the formation of new blood vessels, also plays a vital role in supporting neurogenesis post-TBI. PBM has been shown to promote angiogenesis by improving endothelial function and aiding in wound healing.

In human cases, PBM treatment has been associated with increased brain volume, improved brain connectivity, and better cognitive function, suggesting its potential in reducing cell death and enhancing brain repair.

Animal studies further support the anti-apoptotic effects of PBM, showing fewer apoptotic cells in injured brain tissue treated with PBM compared to controls. Cell culture studies provide insights into the molecular mechanisms behind PBM’s anti-apoptotic effects.

In summary, PBM not only helps prevent further cell loss but also contributes to the restoration of brain function by promoting cell survival and neurogenesis. This multifaceted approach shows promise for improving outcomes in both acute and chronic TBI cases.

2.8. Autophagy and Lysosomal Pathways Dysfunction

Autophagy is a process where cells break down and recycle damaged parts, keeping themselves healthy. Lysosomes are like cell garbage disposals, helping with this process. TBI messes up these systems, making it hard for cells to clean up properly. This can lead to harmful substances building up and causing cell death.

PBM might help by controlling levels of harmful substances, which could improve the cleaning process. Specifically, it could help cells get rid of damaged mitochondria, which are crucial for cell health. By doing this, PBM could support cell function and recovery after TBI.

3. Additional Relevant Systemic and Secondary PBM Mechanisms

Certain PBM mechanisms have systemic effects, with availability across the different pathophysiological elements related to TBI.

3.1. Increased Cellular Energy Production

In PBM, when photons from the light source interact with cytochrome c oxidase in mitochondria, it can lead to increased ATP production. This enhanced energy production improves cellular function and repairs damaged brain tissues.

3.2. Enhanced Blood Flow and Oxygenation

PBM is believed to enhance cellular energy availability by improving blood circulation through the photodissociation of nitric oxide (NO). This improves blood flow and oxygen delivery to the injured brain region. It promotes tissue repair and reduces hypoxic conditions that can exacerbate TBI-related damage. A 2016 published animal study suggested that 660 and 810 nm wavelengths pulsing at 10 Hz produced the best outcomes in TBI by improving blood flow and oxygenation.

3.3. Modulation of Synaptic Plasticity

PBM may influence synaptic plasticity, which is the ability of synapses to strengthen or weaken over time, affecting neuronal signaling. By promoting synaptic plasticity, PBM could enhance cognitive recovery and functional improvements in TBI patients.

The above literature on the effects of PBM on the pathophysiology of TBI shows the promise of PBM for treating TBI. The real value will lie in the translation to human use, as confirmed by clinical study data.

3.4. Effect on Ferroptosis

Ferroptosis can play a significant role in neuronal death and brain damage following the injury. It is a form of regulated cell death characterized by iron-dependent lipid peroxidation linked to oxidative stress and inflammation. PBM has been observed to reduce oxidative stress and modulate inflammatory responses, which could influence ferroptosis pathways.

4. Clinical Data on PBM Effects on Human TBI

For years, we’ve relied on animal studies to understand TBI outcomes. However, because the human brain is vastly different in size from a mouse brain, what works for mice may not work the same for humans. Therefore, it’s crucial to focus more on human studies now for better relevance.

In this section, we reviewed human clinical studies to see how PBM could improve TBI recovery. We searched through databases up to December 2023 and found limited human studies with different methods and devices used, making direct comparisons challenging. Instead, we focused on extracting key insights to improve PBM for TBI treatment.

Here’s a summary of the findings from these human studies, listed in chronological order:

In 2011, Naeser et al. reported positive outcomes in two TBI cases treated with PBM.
In 2014, an open study by Naeser et al. showed improved sleep and function in 11 subjects.
In 2015, Hesse et al. found improved alertness in five patients treated with low-level lasers.
In 2018, Hipskind et al. treated 12 veterans with chronic TBI and reported cognitive improvements.
In 2020, Figueiro Longo et al. studied 68 subjects and found significant brain changes with PBM.
Chao et al. reported neurogenesis in a professional hockey player treated with PBM at home.
Rindner et al. used a different approach in 2022 but found potential cognitive benefits.
Chan et al. analyzed data from previous studies and suggested PBM could affect brain connectivity.
Naeser et al. detailed the recovery of four retired football players from CTE symptoms in 2023.
Additionally, Liebel et al. found significant improvements in depression, PTSD, and other symptoms in athletes treated with PBM.

These studies show promise for PBM in treating TBI, but more research is needed to understand its full potential and optimize treatment methods

Key Findings:

The common denominator is that PBM applied to the brain is safe, with no report of significant adverse effects.
PBM shows promise for treating chronic TBI in a degenerative state, particularly for suspected CTE.
The efficacy outcomes were inconsistent.
Many studies were case series that lacked sham control.
Imaging studies through diffusion and structural MRI reveal clearer objective measured outcomes than clinical studies by partially overcoming the challenging heterogeneity of TBI.
Data based on time-course were more conclusive than across-group comparison (such as sham and severity) due to TBI heterogeneity.
The parameters used varied widely between studies.
The more recent studies appear to favor higher power densities; devices that pulse produce improved clinical outcomes. This indicates that parameters used in some studies were suboptimal and compromised outcomes.
Larger randomized controlled clinical trials are required to validate the findings.
At the ongoing pace, and with the challenges of conducting controlled human studies, it will be many years before PBM can reach consensus on optimal parameters.

For details of the parameters, please refer to the original text, which also provides detailed nuances of clinical outcomes.

In summary, the findings indicate that PBM holds promise for the treatment of TBI. This potential can be progressively realized through continuing investments in research, facilitating new discoveries in the field.

5. New Discoveries in Cellular Mechanisms Inform Future PBM Treatments

In a recent systematic review by Stevens et al. in 2021, they found that PBM has positive effects on TBI outcomes. However, they also noted that continuous wave and pulsed PBM, as well as energy delivery, didn’t show much difference in outcomes. Another systematic review in 2022 suggested that power density might affect mental outcomes, indicating the need for more research in this area.

Since then, more studies have been conducted by various groups, showing that while PBM has a significant effect on TBI, adjusting certain parameters could lead to even better outcomes. We’re striving to find effective PBM treatments not only for TBI but for various brain conditions by exploring how different parameters affect brain functions.

This drive for more detailed research was sparked by findings in 2019 showing that specific pulse frequencies, like gamma at 40 Hz, can modify EEG waveforms. Since TBI brains often have distinct waveforms, this discovery is particularly relevant. Additionally, the amount of energy delivered, measured as power density (mW/cm2), has also been found to impact brain activity and structures.

While the precise cellular and physiological mechanisms of PBM in TBI are still under investigation, several key mechanisms have emerged based on research findings:

5.1. Increase in Cellular Current Flow and Resistance

Living cells regulate the flow of charged ions across their membranes, a key feature of their function. PBM has been found to enhance this ion flow, while also increasing cellular resilience, which is crucial for the health of axon myelin sheaths. This effect was observed with PBM using a wavelength of 810 nm at 10 Hz. Further research is needed to understand how other pulse frequencies might impact cellular characteristics.

5.2. Polymerization of Tubulins

Microtubules, made up of α- and β-tubulin dimers, are crucial for neuron structure. They can assemble and disassemble rapidly. PBM pulsed at 10 Hz and 810 nm has been shown to break down tubulins and disrupt microtubule structure, potentially affecting neuron health. Understanding this process better could be important for TBI recovery and preventing CTE progression.

5.3. The Significance of Pulse Frequency

Recent studies go beyond exploring the molecular effects of PBM and suggest that different parameters like wavelength, power density, and pulsing rates could impact physiological outcomes. This idea is supported by research showing that pulse frequencies can influence brain responses.

In 2019, Zomorrodi et al. discovered that applying PBM at 810 nm wavelength and 40 Hz frequency (gamma) to specific brain areas changed brain waveforms. This increased faster oscillations like alpha, beta, and gamma, while reducing slower oscillations like delta and theta.

In 2023, Tang et al. conducted a randomized study with 56 healthy subjects, finding that pulsed waves at 40 Hz and 100 Hz had better cognitive effects than continuous waves or sham treatment. They also observed increased gamma waveforms, especially with the 40 Hz frequency, using wavelengths of 660 nm and 830 nm.

These studies show that:

PBM affects brain function through various cellular mechanisms.
Pulse frequency can alter brain waveforms, providing insights into brain states for diagnosis.

6. Perspective on Effective Parameters and Further Research

The reviewed evidence indicates that certain generalized parameters involving near-infrared (NIR) wavelengths and pulsing have the potential to offer benefits to individuals experiencing post-TBI symptoms. However, it underscores the necessity for further research to yield more predictable and efficacious clinical outcomes. Generalizing with a simplified protocol is anticipated to be particularly challenging, given the inherent variability among individual subjects. A potential solution to this challenge lies in finding the ideal personalized parameter settings.

Research based on healthy and diseased subjects as well as in vitro and animal studies have suggested that different wavelengths [28,90,91,92], power and dose densities [93,94,95], and pulse frequencies [83,96] influence outcomes. With this state of knowledge, we can conclude that more work is needed to narrow down effective parameters in the quest for better applications and outcomes. In addition, the Inverse Square Law suggests that the distance between the light source (laser or LED) and the target surface should influence landed/irradiated power [97], and the position of the light source on the head, such as the hubs of the default mode network [98], could influence neurological outcomes.
With this background, further research on effective parameters could include the following:

Extend the investigation on tubulin polymerization [86] using a spread of different parameters.
Extend the investigation with Raman spectroscopy [87] covering a wide range of parameters.
Extend the EEG investigation using gamma at 40 Hz [83], alpha at 10 Hz, theta/delta at 4 Hz and other frequencies. In addition, we can seek real-time EEG readings for a better understanding of pulse frequency effects on brain waveforms and functions.
Measure the real-time response of the brain to various PBM parameters using fMRI. The precedence has been set with a real-time fMRI study by Nawashiro et al. published in 2017 on four cases. It demonstrated regional blood oxygen level dependency (BOLD) increases with laser at 810 nm wavelength, 204 mW/cm² power density, and continuous wave for 90 s on and 60 s off for 3 times [99]. In 2020, Dmochowski et al. published a real-time fMRI study using a laser with 808 nm wavelength, 318 mW/cm² power density, continuous wave, and 10 min duration on 20 subjects [100] The BOLD response in this study was more significant than that in Nawashiro et al. The difference in the level of response could be due to the treatment time. These studies can lead to new studies to determine whether applying different parameters such as wavelength, pulse frequencies, and light source positioning on the head will make a difference.
The efficacy of interventions for TBI is challenged by factors such as TBI’s heterogeneity and the variability in brain states and structures. Moreover, PBM presents a range of interventional parameters that can impact outcomes. The key to determining the most effective treatment may reside in a methodology involving iterative cycles of feedback and the careful selection of parameters from a wide array of choices. Incorporating artificial intelligence (AI) into this methodology could greatly expedite the process, enhancing the ability to personalize and optimize outcomes for individual patients.

7. Limitations of the Study

The limited number of human clinical studies available, along with a lack of common basis factors, hinders the conduct of a meaningful quantitative or meta-analytical synthesis. Based on the existing literature, clinical outcomes have been inconsistent. This inconsistency may stem from the wide variety of device parameters and study methodologies employed. Although PBM is known to alter physiological markers, which might lead to clinical outcomes, current data are insufficient to establish a general set of parameters that consistently predict outcomes with high confidence. The idea that personalizing treatment by adjusting pulse frequency, wavelengths, and other parameters can enhance effectiveness is primarily based on limited peer-reviewed research and preliminary data from ongoing studies. These ongoing studies are not yet published or peer-reviewed, and the discussions in this study include insights from the author’s forward-looking perspective.

8. Conclusions

The evidence reviewed suggests that certain parameters involving near-infrared (NIR) wavelengths and pulsing could help people with post-TBI symptoms, but more research is needed to make treatment outcomes more predictable and effective. It’s challenging to generalize a simplified protocol due to variations among individuals, so finding personalized parameter settings might be the solution.

Research on both healthy and diseased subjects, as well as in vitro and animal studies, has shown that different wavelengths, power and dose densities, and pulse frequencies can affect outcomes. This indicates the need for more work to narrow down effective parameters for better applications and outcomes. Additionally, factors like the distance between the light source and the target surface and the position of the light source on the head could also influence neurological outcomes.

Further research on effective parameters could involve:

– Continuing investigation on tubulin polymerization and Raman spectroscopy using a range of parameters.
– Expanding EEG investigation to include various frequencies and real-time readings to better understand the effects of pulse frequency on brain waveforms and functions.
– Using fMRI to measure the real-time response of the brain to different PBM parameters. Previous studies have shown promising results, suggesting that exploring different parameters could lead to new insights.

Treating TBI is complicated due to its heterogeneity and the variability in brain states and structures, compounded by the diverse range of interventional parameters offered by PBM. To find the most effective treatment, an iterative approach involving careful parameter selection and feedback loops may be necessary. Incorporating artificial intelligence (AI) into this process could help speed up the process and improve outcomes for individual patients.

This article was written by

Dr. Lew Lim

Vielight | CEO and Founder

Dr Lew Lim founded Vielight in 2012. With his background in electrical engineering and neuroscience, he developed the field of home-use brain photobiomodulation technology in 2014 and has co-authored multiple papers and lectured extensively.

PhD Electrical Engineering, University of California (Berkeley)

MBA, Sheffield University

Certificate of Neuroscience, Duke University

Meet the author

Utah Neurotrauma Study | Advanced Diffusion MRI & Brain Resilience | Vielight Neuro