Hyperbaric Oxygen Therapy in the Treatment of Concussion, Post-Concussion Syndrome, and Chronic Traumatic Encephalopathy: A Review of Current Evidence and Proposed Research Directions

1. Introduction

• 1.1 Background on Traumatic Brain Injury (TBI) and its Sequelae:
  Traumatic brain injury (TBI) represents a significant global health concern, with concussion, also known as mild TBI (mTBI), being the most common form 1. While many individuals recover from concussion within a few weeks, a subset continues to experience persistent physical, cognitive, and emotional symptoms, a condition termed post-concussion syndrome (PCS) 2. Studies indicate that 10 to 15 percent of people who experience a concussion may develop PCS, with symptoms potentially lasting for months or even years 2. These symptoms can include headaches, dizziness, memory loss, and personality changes, significantly impacting an individual’s quality of life and ability to function 3. The economic and social burdens associated with TBI and its sequelae are substantial, affecting individuals, families, and healthcare systems 1.
  The pathophysiology of concussion involves a complex cascade of events initiated by the initial mechanical force to the head. This primary injury can lead to diffuse shearing of axonal pathways and small blood vessels ⁴. Following this initial insult, a secondary injury phase often develops, characterized by ischemia resulting from decreased cerebral blood flow, leading to hypoxia and anaerobic metabolism ⁵. This secondary injury can exacerbate the initial damage and contribute to the development of persistent symptoms ⁶. In more severe or repetitive cases of TBI, there is a concern for the development of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease associated with a history of repetitive brain trauma ⁷. CTE is characterized by the accumulation of abnormal tau protein in the brain, leading to a range of neurological and psychiatric symptoms ⁷.
  Diagnosing and treating PCS and CTE present considerable challenges. The heterogeneity of symptoms in PCS and the lack of definitive diagnostic markers complicate clinical assessment ⁸. Currently, a definitive diagnosis of CTE can only be made through post-mortem neuropathological examination ⁷. This limitation makes it particularly difficult to study potential treatments for CTE in living individuals. The subjective nature of many PCS symptoms also poses a challenge for evaluating the efficacy of interventions, as patient-reported outcomes can be influenced by various factors ⁸.
• 1.2 Hyperbaric Oxygen Therapy (HBOT) – Mechanisms of Action:
  Hyperbaric oxygen therapy (HBOT) is a medical treatment that involves breathing 100% oxygen while enclosed in a chamber pressurized to levels higher than normal atmospheric pressure 5. Typically, pressures used in HBOT range from 1.5 to 3 atmospheres absolute (ATA) 6. This increased pressure environment allows the lungs to gather significantly more oxygen than would be possible at normal air pressure 15.
  The key physiological effect of HBOT is a dramatic increase in the amount of oxygen dissolved in the bloodstream (hyperoxia) and delivered to all body tissues, including the brain ⁵. This enhanced oxygen delivery can have several beneficial effects relevant to the treatment of TBI and its sequelae. Firstly, it can help to reduce inflammation and edema in the brain tissue, which are common consequences of TBI ³. Secondly, HBOT has been shown to promote angiogenesis, the formation of new blood vessels, and potentially neurogenesis, the generation of new nerve cells, which could contribute to long-term repair and recovery in the injured brain ³. Furthermore, research suggests that HBOT can modulate gene expression, influencing the activity of genes involved in tissue repair and growth, and may also stimulate the mobilization of stem cells ¹⁷. Additionally, HBOT can improve mitochondrial function and metabolic homeostasis, which are often disrupted following TBI ⁶.
• 1.3 Rationale for Investigating HBOT in Concussion, PCS, and CTE:
  Current treatment approaches for concussion and PCS often focus on symptom management and rehabilitation strategies, with limited evidence of efficacy in addressing the underlying biological damage 1. For CTE, there are currently no proven treatments to slow or reverse the disease progression 13. This lack of effective therapies highlights the need to explore novel interventions that target the pathophysiology of these conditions.
  Preliminary research suggests that HBOT may offer benefits for individuals with concussion, PCS, and potentially CTE ¹³. However, the existing literature exhibits significant variability in the HBOT treatment protocols used, including differences in pressure (ATA), frequency, duration of sessions, and total number of treatments. Furthermore, there are concerns regarding the independence and objectivity of some outcome measures used in these studies, with a reliance on self-reported symptom scales being a common limitation. The user’s observation of these inconsistencies and the desire to establish independently verifiable improvements underscore the need for more rigorous and standardized research in this area.
• 1.4 Objectives of the Report:
  This report aims to provide a comprehensive review of the current scientific literature on the use of HBOT for the treatment of concussion, PCS, and CTE. The objectives include identifying specific HBOT treatment parameters employed in research studies, analyzing the outcome measures used with a focus on independently verifiable methods, exploring correlations between treatment parameters and observed improvements, and synthesizing the findings to propose a potential research hypothesis for future investigation.

2. Review of Current Literature on HBOT for Concussion and Post-Concussion Syndrome (PCS)

• 2.1 Studies Demonstrating Positive Effects of HBOT:

• 2.1.1 Systematic Reviews and Meta-Analyses:
  A systematic review and dosage analysis by Andrews and Harch (2022, updated 2024) examined the efficacy of HBOT in treating persistent postconcussion syndrome (PPCS) resulting from mild traumatic brain injury (mTBI) 25. The analysis of eleven studies, including six randomized trials, found Level I evidence supporting the use of 40 HBOT sessions at 1.5 atmospheres absolute (ATA) of oxygen for achieving statistically significant symptomatic and cognitive improvements in patients with mTBI PPCS 8. This level of evidence, according to the Centre for Evidence-Based Medicine, indicates a high degree of confidence in the findings 2. Interestingly, the review suggested that increased pressure within a narrow range of 1.3 to 1.5 ATA appeared to be more critical for positive outcomes than the level of increased oxygen, which showed effectiveness across a broader range of doses 8. This observation implies a potentially non-linear relationship between pressure and therapeutic effect.
  A meta-analysis conducted by Wang et al. (2016) evaluated the outcomes of HBOT in patients with traumatic brain injury (TBI) ranging from mild to severe ²⁷. The analysis of eight prospective studies revealed that the HBOT group had significantly higher post-treatment Glasgow Coma Scale (GCS) scores, greater improvement in Glasgow Outcome Score (GOS), and lower overall mortality compared to the control groups ²⁷. These findings suggest that HBOT may have a positive impact on neurological function and survival in TBI patients, although the study did not specifically focus on concussion or PCS and did not observe a significant change in PTSD scores, which are often comorbid with PCS.
  A randomized controlled crossover trial by Harch et al. investigated the effects of 40 HBOT sessions at 1.5 ATA for 60 minutes on subjects with the persistent post-concussion syndrome (PPCS) of mTBI ²¹. The study demonstrated statistically significant improvements in the HBOT group compared to a no-treatment control period across various measures, including the Neurobehavioral Symptom Inventory, Memory Index, Automated Neuropsychological Assessment Metrics (ANAM), Hamilton Depression Scale, Hamilton Anxiety Scale, Post-Traumatic Stress Disorder Checklist, Pittsburgh Sleep Quality Index, and Quality Of Life after Brain Injury ²¹. Notably, the control group experienced near-identical significant improvements after crossing over to receive HBOT, further supporting the therapy’s effectiveness for a range of post-concussion symptoms and cognitive functions ²¹. The use of objective neuropsychological tests like ANAM and the crossover design strengthen the findings of this study ²¹.
• 2.1.2 Case Reports and Series:
  Two case reports by Stoller (2011) described the benefits of HBOT at 1.5 ATA for 60 minutes daily for 40 sessions in two football players with a history of TBI and suspected CTE 23. The retired NFL player in his early 50s showed marked improvement in 5 out of 6 indices on a neurocognitive assessment and improved brain blood flow on SPECT imaging after treatment 23. The 15-year-old high school player with post-concussion syndrome experienced improvements in verbal and visual memory, visual motor speed, and reaction time on the IMPACT test, along with a significant reduction in headaches and resolution of nausea 23. These cases suggest the potential for HBOT to provide benefits even years after the initial brain injury, with objective changes observed in both neurocognitive function and brain perfusion.
  A case report detailed the treatment of a patient with recurrent mild traumatic brain injury (mTBI) using a comprehensive approach that included HBOT ². While a 40-session protocol was initially recommended, the patient discontinued after 11 sessions but later underwent a renewed course of 40 HBOT sessions followed by an additional 40 sessions ²². This extended treatment, combined with neurofeedback, resulted in substantial improvements in cognitive function, emotional regulation, and overall quality of life, with the patient reporting a near-complete return to baseline after roughly 100 HBOT sessions ²². Successive neurofeedback sessions guided by quantitative electroencephalography (qEEG) assessments further enhanced decision-making, attentional focus, and mental flexibility ²². The Neurobehavioral Symptoms Inventory (NSI) data showed a statistically significant reduction in overall neurobehavioral symptoms ²². This case highlights the potential for cumulative benefits with prolonged HBOT treatment and the use of qEEG as an objective measure of brain function.
  Another case report by Harch et al. described a veteran with blast-induced chronic traumatic brain injury (post-concussion syndrome) and post-traumatic stress disorder (PTSD) who underwent 39 HBOT sessions at 1.5 atmospheres absolute ²⁸. The patient experienced a permanent marked improvement in post-concussive symptoms, physical exam findings, and brain blood flow as documented by SPECT imaging ²⁸. Notably, the patient also experienced a complete resolution of PTSD symptoms ²⁸. This case suggests that HBOT at this pressure may positively impact both the neurological and psychological sequelae of blast-induced TBI, with objective confirmation through SPECT imaging showing improved brain perfusion in previously affected areas.

• 2.2 Studies with Mixed or Negative Results:
  A systematic review by Raj et al. (2024) assessed the efficacy and safety of HBOT in traumatic brain injury (TBI) management 1. While the review of eight randomized controlled trials suggested potential benefits for patients with an acute history of cerebral injury, it found limited efficacy of HBOT for patients with chronic traumatic brain injury 1. The authors noted that variations in compression and decompression phases, pressure used (ranging from 1.5 to 2.5 ATA), and outcome measures across the included studies hindered meta-analysis comparability 1. This variability in protocols may contribute to the mixed findings regarding HBOT’s effectiveness for chronic TBI.
  A meta-analysis examined the effect of hyperbaric oxygen therapy on post-concussion syndrome (PCS) and found no significant difference in the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) or Post-Traumatic Stress Disorder Checklist (PCL) scores between groups receiving different oxygen doses or between HBO and sham groups ¹¹. This study suggests that, based on these symptom-based outcome measures, HBOT may not have a significant effect on PCS compared to a sham intervention ¹¹. However, the specific HBOT protocols used in the included studies varied, and the reliance on symptom questionnaires as primary outcomes may limit the conclusions drawn.
  Several randomized controlled trials sponsored by the Department of Defense/Veterans Administration (DoD/VA) investigated the use of HBOT for mild TBI ¹⁴. These trials reported no significant improvement in mean scores on post-concussive symptom checklists or quality of life outcomes with HBOT administered at 1.5 ATA or 2.4 ATA compared to sham controls. The sham conditions involved breathing either 10.5% oxygen at 2.0 ATA or room air at 1.2-1.3 ATA ¹⁴. These findings raise concerns about the efficacy of HBOT for mild TBI, particularly when compared to sham interventions that themselves involve increased pressure and potentially some level of increased oxygen.
  The protocol for the Hyperbaric Oxygen Therapy versus placebo for post-concussion syndrome (HOT-POCS) pilot study describes a randomized, double-blinded controlled trial comparing 20 HBOT sessions at 2.0 ATA with a true placebo gas system (10.5% O2 and 89.5% nitrogen at 2.0 ATA) for persistent PCS in a civilian population ¹⁰. This study aims to address some of the limitations of previous research by using a more rigorous placebo control that closely mimics the experience of HBOT without the increased oxygen concentration. The results of this ongoing study may provide clearer evidence regarding the efficacy of this specific HBOT protocol for civilian PCS.
• 2.3 Variability in Treatment Protocols and Outcome Measures:
  The current literature on HBOT for concussion and PCS reveals a significant variability in the treatment protocols employed across different studies. The pressure used, measured in atmospheres absolute (ATA), has ranged from as low as 1.2 ATA to as high as 2.5 ATA 1. Similarly, the number of HBOT sessions administered has varied considerably, from as few as 11 sessions to as many as 80 or even 100 in some cases 8. The duration of each treatment session has also shown some variation, typically ranging from 60 to 90 minutes 1. This lack of standardization in treatment parameters makes it challenging to compare the outcomes of different studies and to determine the optimal HBOT protocol for concussion and PCS.
  Another significant challenge in the field is the inconsistent use of sham controls in HBOT research. Some studies have used pressurized air as a sham, which may not be a true placebo due to the potential physiological effects of increased pressure ⁸. The nature and characteristics of the sham control can significantly influence the interpretation of study results.
  Furthermore, there is considerable heterogeneity in the outcome measures used to assess the effectiveness of HBOT for concussion and PCS. These measures include various symptom scales, such as the Neurobehavioral Symptoms Inventory (NSI), Rivermead Post-Concussion Questionnaire (RPQ), Hamilton Depression and Anxiety Scales, and Post-Traumatic Stress Disorder Checklist (PCL) ⁸. Cognitive function is often assessed using standardized neurocognitive tests like the IMPACT test, Automated Neuropsychological Assessment Metrics (ANAM), and the NIH Toolbox Cognition Battery ⁴. Neuroimaging techniques, including SPECT, fMRI, DTI, and EEG, have also been employed to evaluate changes in brain activity, structure, and function following HBOT ². This variability in outcome measures further complicates the comparison of findings across different studies and highlights the need for a more standardized approach to assessing HBOT efficacy.

3. HBOT in the Context of Chronic Traumatic Encephalopathy (CTE)

• 3.1 Limited Research on HBOT for CTE:
  Research specifically investigating the use of HBOT for chronic traumatic encephalopathy (CTE) is limited. The majority of the available evidence comes from case reports and small case series that have included individuals with a history of repetitive head trauma and clinical symptoms suggestive of CTE 7. A significant challenge in this area of research is the difficulty in definitively diagnosing CTE in living individuals, as the current gold standard for diagnosis is post-mortem neuropathological examination 7. This limitation means that studies often focus on individuals with suspected CTE based on their history and clinical presentation.
• 3.2 Case Reports Suggesting Potential Benefits:
  The case reports by Stoller (2011), discussed in Section 2, included two retired football players with a history of multiple concussions and clinical features suggestive of CTE 23. Both individuals showed improvements in neurocognitive function and brain blood flow on SPECT imaging following a course of 40 HBOT sessions at 1.5 ATA 23. These findings, while based on a small number of cases, suggest that HBOT at this specific protocol might have a positive impact on some of the symptoms and physiological changes associated with suspected CTE.
  A study by Harch et al. (2013) explored the effects of HBOT on former athletes with CTE ¹³. The researchers reported improvements in cognitive function, mood, and motor skills in these individuals following HBOT treatment. However, the specific details of the HBOT protocol used in this study (ATA, frequency, duration, total sessions) are not readily available in the provided snippets, necessitating a review of the original publication for this information. Nevertheless, the reported improvements across multiple domains suggest that HBOT could potentially mitigate some of the clinical manifestations of CTE and improve the quality of life for affected individuals.
• 3.3 Theoretical Rationale for HBOT in CTE:
  The theoretical rationale for using HBOT in the context of CTE is linked to its known mechanisms of action in TBI. One hypothesis is that HBOT, by improving cerebral oxygenation and promoting tissue healing, might help to reduce the accumulation of tau protein, which is a hallmark of CTE 7. While this remains largely theoretical and requires direct research, the potential for HBOT to influence the underlying pathology of CTE is an important area for investigation. Additionally, HBOT’s ability to reduce neuroinflammation and improve cerebral oxygenation could potentially counteract the neurodegenerative processes that are believed to occur in CTE 13. By addressing these key pathological mechanisms, HBOT might have the potential to slow the progression of CTE or alleviate some of its debilitating symptoms.

4. Critical Analysis of Treatment Parameters and Outcome Measures

• 4.1 Importance of Standardized Treatment Protocols:
  The significant variability in HBOT treatment parameters, including ATA, frequency, duration, and total number of sessions, across different studies investigating concussion and PCS, poses a major challenge for drawing definitive conclusions about the efficacy of this therapy 1. This lack of standardization makes it difficult to compare the outcomes of various studies and to determine the optimal treatment protocols for specific patient populations and injury characteristics. The conflicting results observed in the literature may, in part, be attributable to these differences in how HBOT is administered. Establishing standardized protocols for future research is crucial for advancing our understanding of HBOT’s therapeutic potential in TBI and its sequelae.
• 4.2 Limitations of Symptom-Based Outcome Measures:
  While symptom scales are commonly used to assess the impact of interventions for concussion and PCS, they have inherent limitations 9. The subjectivity of these measures means that patient reports can be influenced by various factors, including the placebo effect and expectation bias. Furthermore, symptom scales may not always accurately reflect underlying physiological changes in the brain. While capturing the patient’s experience is important, relying solely on symptom-based outcomes can limit the rigor and objectivity of HBOT research. Complementing these measures with more objective assessments is essential for providing stronger evidence of treatment efficacy.
• 4.3 Strengths and Limitations of Neurocognitive Assessments:
  Standardized neurocognitive assessments, such as the IMPACT test, ANAM, and NIH Toolbox Cognition Battery, offer a more objective way to evaluate cognitive function in individuals with concussion and PCS 4. These tests can assess various cognitive domains commonly affected by TBI, including memory, attention, processing speed, and executive functions. By providing quantifiable measures of cognitive performance, these assessments reduce the subjectivity associated with symptom scales. However, they also have limitations, such as the potential for practice effects with repeated testing, and they may not directly reflect the underlying neurological changes occurring in the brain. Nevertheless, neurocognitive assessments represent a valuable tool for objectively evaluating cognitive improvements following HBOT treatment.
• 4.4 Utility of Neuroimaging Techniques:
  Neuroimaging techniques offer the potential to provide independently verifiable measures of improvement following HBOT for concussion, PCS, and potentially CTE.

• 4.4.1 SPECT (Single Photon Emission Computed Tomography): SPECT imaging measures cerebral blood flow and can identify areas of hypoperfusion, which are often seen in TBI ². Studies have shown improvements in brain blood flow on SPECT scans following HBOT treatment in patients with TBI, PCS, and suspected CTE, providing objective evidence of a physiological change in the brain ²³. Increased cerebral perfusion suggests improved oxygen and nutrient delivery to previously damaged or underactive brain regions.
• 4.4.2 fMRI (Functional Magnetic Resonance Imaging): fMRI detects brain activity by measuring changes in blood flow and can be used to assess functional connectivity and neural network activity ¹³. Research has shown that HBOT can lead to changes in functional connectivity in individuals with TBI and related conditions like PTSD, indicating an impact on brain network function ³¹. fMRI offers a sophisticated and non-invasive way to examine how HBOT might be influencing brain activity underlying cognitive and emotional processes.
• 4.4.3 DTI (Diffusion Tensor Imaging): DTI measures the diffusion of water molecules in the brain, allowing for the assessment of white matter integrity and the detection of axonal damage, which is common in TBI ⁶. Studies have reported increased fractional anisotropy and decreased mean diffusivity on DTI after HBOT in TBI patients, suggesting potential regeneration of nerve fibers and improved white matter microstructure ¹⁸. This provides objective evidence of structural changes in the brain following HBOT.
• 4.4.4 EEG (Electroencephalography): EEG measures the electrical activity of the brain and can be used to assess overall brain function and identify abnormalities ². Quantitative EEG (qEEG) allows for more detailed analysis of brainwave patterns. Case reports have shown improvements in qEEG assessments correlating with cognitive and emotional gains in patients treated with HBOT for mTBI ². EEG offers a relatively accessible and non-invasive way to monitor changes in brain electrical activity in response to HBOT.
• 4.5 Limitations of Relying Solely on Blood Biomarkers:
  While blood biomarkers can provide valuable information about systemic inflammation and injury, their direct correlation with the complex and localized neurological changes occurring in the brain in concussion and CTE may be limited. The user specifically requested independent measures beyond blood biomarkers, indicating a need for assessments that directly evaluate brain structure and function. Therefore, while blood biomarkers might be included in a comprehensive research program, they should not be the sole or primary outcome measures for assessing the efficacy of HBOT for these conditions.

5. Independent and Verifiable Measures of Improvement

To address the user’s need for independently verifiable measures of improvement, future research on HBOT for concussion, PCS, and CTE should prioritize the use of standardized neurocognitive assessments and functional neuroimaging techniques.

• 5.1 Standardized Neurocognitive Assessments:
  Several standardized neurocognitive test batteries are available and have been used in HBOT research for TBI. The IMPACT (Immediate Post-Concussion Assessment and Cognitive Testing) battery has been used in studies to evaluate memory, brain processing speed, reaction time, and post-concussive symptoms 23. The Automated Neuropsychological Assessment Metrics (ANAM) is another computerized tool used to assess cognitive functions in TBI research 21. The NIH Toolbox Cognition Battery is a comprehensive set of cognitive tests that has also been included in study protocols investigating HBOT for persistent PCS 10. These standardized assessments provide quantifiable and reproducible data on cognitive performance across various domains, offering a relatively independent and verifiable measure of treatment effects.
• 5.2 Functional Neuroimaging Techniques:
  Functional neuroimaging techniques offer powerful tools for objectively assessing changes in brain structure and function following HBOT treatment.

• 5.2.1 SPECT: Studies have consistently shown improvements in cerebral blood flow on SPECT scans after HBOT in individuals with TBI, PCS, and suspected CTE ². This provides direct physiological evidence of improved brain perfusion, which is a key aspect of HBOT’s proposed mechanism of action in treating brain injury.
• 5.2.2 fMRI: Functional MRI allows for the assessment of changes in brain activity and functional connectivity patterns following HBOT in TBI and related conditions like PTSD ¹³. Alterations in brain network function, as measured by fMRI, can provide valuable insights into the neural correlates of clinical improvements.
• 5.2.3 DTI: Diffusion tensor imaging can detect microstructural changes in the brain’s white matter following HBOT, offering evidence of neural repair or regeneration in TBI patients ¹⁸. Improvements in white matter integrity, as measured by DTI metrics like fractional anisotropy and mean diffusivity, represent an objective and verifiable marker of structural brain changes.
• 5.2.4 EEG/qEEG: Electroencephalography, particularly when using quantitative analysis (qEEG), can objectively track changes in brain electrical activity in response to HBOT treatment for concussion and mTBI ². Changes in EEG patterns can reflect alterations in neuronal function and synchronization, providing a functional measure of treatment outcome that can be correlated with clinical improvements.

Table 1: Examples of Independent and Verifiable Outcome Measures in HBOT Research for TBI

6. Correlation Between HBOT Parameters and Measurable Improvements

• 6.1 ATA (Atmospheres Absolute):
  The existing research suggests that a pressure of 1.5 ATA is frequently associated with positive outcomes in the treatment of mTBI and PCS 2. Multiple systematic reviews, randomized controlled trials, and case reports have reported significant symptomatic and cognitive improvements using this pressure. In contrast, studies using lower pressures (1.2-1.3 ATA) have shown mixed results, and a study using a higher pressure of 2.4 ATA reported negative outcomes 8. This pattern indicates that the relationship between pressure and therapeutic efficacy might not be linear, and there may be an optimal pressure range for treating these conditions.
• 6.2 Frequency of Treatments:
  The majority of studies investigating HBOT for TBI and its sequelae have employed a treatment frequency of once daily, five days per week 18. This consistent use suggests that this frequency is considered feasible and potentially effective for delivering a therapeutic dose of hyperbaric oxygen. However, the total number of sessions has varied widely across studies, ranging from as few as 11 to as many as 80 or more 8. Studies reporting positive outcomes often involve a total of around 40 sessions 8, suggesting that a more extended course of treatment may be necessary to achieve significant and sustained improvements.
• 6.3 Length of Treatment Session:
  The duration of individual HBOT sessions in research studies typically falls within the range of 60 to 90 minutes 1. A session length of around 60 minutes appears to be common and may represent a balance between providing sufficient exposure to hyperoxia to elicit therapeutic effects and minimizing the risk of potential side effects associated with prolonged oxygen exposure at high pressures.
• 6.4 Total Length of Treatment Program:
  The total length of the HBOT treatment program, determined by the frequency and number of sessions, has varied from a few weeks to several months in the literature. Programs involving a higher total number of sessions, particularly those reaching 40 or more, seem to be associated with more consistently reported positive outcomes in individuals with concussion and PCS 8. This suggests that a cumulative effect of HBOT over a more extended period might be necessary to induce meaningful and lasting neurological recovery.

7. Proposed Research Hypothesis and Future Directions

• 7.1 Research Hypothesis:

• Null Hypothesis: There is no significant difference in measurable improvements (as assessed by standardized neurocognitive tests and functional neuroimaging) in individuals with persistent post-concussion syndrome (PCS) or chronic traumatic encephalopathy (CTE) who undergo different Hyperbaric Oxygen Therapy (HBOT) protocols varying in atmospheres absolute (ATA) (1.3 ATA vs. 1.5 ATA vs. 1.7 ATA), frequency (3 times per week vs. 5 times per week), and total length of treatment (20 sessions vs. 40 sessions).
• Alternative Hypothesis: Specific Hyperbaric Oxygen Therapy (HBOT) protocols, defined by variations in atmospheres absolute (ATA) (1.3 ATA vs. 1.5 ATA vs. 1.7 ATA), frequency (3 times per week vs. 5 times per week), and total length of treatment (20 sessions vs. 40 sessions), will result in statistically significant and measurable improvements in cognitive function (as assessed by standardized neurocognitive tests) and brain activity and structure (as assessed by functional neuroimaging, including fMRI and DTI) in individuals with persistent post-concussion syndrome (PCS) and potentially influence markers associated with chronic traumatic encephalopathy (CTE).
• 7.2 Future Research Directions:
  To definitively establish the efficacy of HBOT for concussion, PCS, and CTE and to determine optimal treatment parameters, future research should focus on conducting rigorous, well-designed studies. Randomized controlled trials (RCTs) with clearly defined and standardized HBOT protocols that systematically vary ATA levels (e.g., 1.3, 1.5, and 1.7 ATA), treatment frequency (e.g., 3 times per week vs. 5 times per week), and total treatment length (e.g., 20 sessions vs. 40 sessions) are needed. These trials should include a true placebo control group, such as the administration of an inert gas at the same pressure as the HBOT condition, to control for the potential effects of pressure alone.
  A comprehensive battery of outcome measures should be employed, including standardized neurocognitive assessments (e.g., NIH Toolbox, ANAM), functional neuroimaging techniques (fMRI, DTI, EEG/qEEG) to assess changes in brain activity, structure, and connectivity, and validated symptom scales to capture the patient’s subjective experience. Research should investigate the effects of HBOT on specific cognitive domains and neuroimaging markers that are particularly relevant to the pathophysiology of concussion, PCS, and CTE.
  Further studies are needed to explore the optimal number of HBOT sessions required for different conditions and the potential for maintenance treatments to sustain long-term benefits. Examining the long-term effects of HBOT on clinical outcomes and disease progression, particularly in the context of CTE, is also crucial. Conducting studies with larger sample sizes will increase the statistical power to detect meaningful treatment effects. Investigating the role of HBOT in different subgroups of patients based on factors such as injury severity, time since injury, and the presence of comorbidities may help to personalize treatment approaches. Exploring potential biomarkers (beyond blood) that could predict an individual’s response to HBOT would also be valuable. Finally, more research is needed to elucidate the mechanisms by which HBOT might affect CTE pathology, potentially through longitudinal studies that combine clinical and neuroimaging assessments with emerging diagnostic techniques for CTE in living individuals.

8. Conclusion

The current evidence regarding the use of HBOT for concussion, post-concussion syndrome, and chronic traumatic encephalopathy is promising but also marked by inconsistencies in treatment protocols and outcome measures. While several studies, particularly those using around 40 sessions at 1.5 ATA, have reported positive effects on symptoms, cognitive function, and brain physiology, other studies have yielded mixed or negative results. The lack of standardized treatment protocols and the variability in outcome measures, including the reliance on subjective symptom scales in some research, make it challenging to draw definitive conclusions about the efficacy of HBOT for these conditions.

Nevertheless, the potential of HBOT as a therapeutic intervention for TBI and its sequelae warrants further rigorous investigation. Future research should prioritize well-designed randomized controlled trials with standardized protocols that systematically examine the effects of varying HBOT parameters. The use of independently verifiable outcome measures, such as standardized neurocognitive testing and functional neuroimaging techniques, is essential for providing objective evidence of treatment efficacy. By addressing these methodological limitations, future research can more definitively establish the role of HBOT in the treatment of concussion, PCS, and potentially CTE, and ultimately lead to the development of evidence-based guidelines for its clinical application.

Copyright

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