Abstract

Introduction:
Background Neurodegenerative and traumatic brain disorders pose a particularly formidable challenge in Medicine. The World Health Organization projects that traumatic brain injury (TBI) will soon be the third most frequent source of disability worldwide. Currently, there are no recognized treatments for reversing the damage of TBI. Rehabilitation and accommodation are the predominate goals. Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, are characterized by the gradual deterioration and death of neurons within the central nervous system are also daunting medical challenges due to the current lack of treatments capable of stopping or reversing the advancement of the processes involved. These conditions progressively impair brain function and have proven resistant to therapeutic interventions aimed at halting or reversing their course. The complexity of these diseases, our incomplete understanding of the underlying pathological mechanisms, combined with the limited regenerative capacity of the central nervous system, has made the development of effective treatments a signicant hurdle in modern medicine. Current treatment approaches, including pharmacological interventions, gene therapy, immunotherapy, surgical interventions, and cell therapy, have shown limited efcacy in addressing the complex pathophysiological mechanisms underlying neurodegeneration. Given that neurodegenerative conditions are characterized by extended latent phases and gradual progression, it is crucial to investigate non-invasive therapeutic approaches which can be utilized early in the latent phase, as well as in the more advanced states of pathology. The longterm nature of these disorders necessitates gentle, sustainable interventions that can be applied over extended periods, making non-invasive physical therapies particularly promising in the management of neurodegenerative diseases and the improvement of patients' daily functioning and life quality. Photobiomodulation (PBM) has emerged as a promising non-invasive therapeutic approach that utilizes red and near-infrared light in the 600-1200nm wavelength range. This technique has gained signicant attention for its ability to stimulate, heal, regenerate, and protect tissues that are vulnerable to injury, degradation, or cell death. In the past twenty years, PBM has been increasingly recognized as an effective non-pharmacological intervention, demonstrating positive outcomes in pain management, inammation reduction, and tissue regeneration. The application of PBM has expanded into the elds of neurology and psychiatry, where extensive research has revealed its potential to inuence brain function through both mitochondrial and non-mitochondrial mechanisms across various cell types, including neurons. This growing body of evidence suggests that PBM could play a valuable role in addressing neurological and psychiatric conditions by modulating cellular processes and promoting neural health. However, a critical consideration in PBM therapy is the ability of light to effectively penetrate through the scalp, skull, and brain tissue to reach target areas with sufcient energy to activate therapeutic mechanisms. Recent evidence suggests that low-power LED devices may have limited penetration capability compared to higher-powered laser devices, raising important questions about optimal treatment parameters and delivery methods for achieving therapeutic benets in neurodegenerative conditions. This introduction provides context for the signicance of developing new treatments for neurodegenerative diseases while highlighting PBM as a promising therapeutic approach, though also noting important technical considerations that need to be addressed.. Study Design/Materials and Methods: This review evaluates the current evidence regarding photobiomodulation's mechanisms and efcacy in treating neurodegenerative diseases, with emphasis on addressing questions about light penetration and optimal treatment parameters. The review seeks to: 1. Examine the physical principles and limitations of near-infrared light penetration through biological tissues, focusing on the crucial differences between low-power versus high-powered light systems in achieving therapeutic uence levels in deep brain structures. 2. Analyze the reported mechanisms through which photobiomodulation inuences neuronal function and survival, both direct and indirect effects. 3. Evaluate existing preclinical and clinical evidence for efcacy of photobiomodulation in neurodegenerative conditions, particularly Alzheimer's disease and Parkinson's disease. This review addresses critical gaps in current understanding: 1. Clarifying misconceptions about light penetration capabilities of different devices. 2. Providing evidence-based analysis of required power densities and uence levels needed to achieve therapeutic effects in deep brain tissue. The signicance of this review lies in its potential to develop more effective therapeutic applications of photobiomodulation by establishing clearer parameters for treatment delivery. With the growing global burden of TBI and neurodegenerative diseases and the limited efcacy of current treatments, there is an urgent need to better understand how to optimize this promising noninvasive therapy. This review synthesizes evidence examining photobiomodulation for TBI and neurodegenerative conditions: 1. Penetration Studies to include a. Ex-vivo tissue studies using fresh lamb heads with intact skin, skull, and brain tissue; human cadaver skin samples measuring 1.9-2mm thickness; human cadaver skull samples of varying thickness (5.9-7.2mm); and living human tissue studies (hand, cheek, ear) for comparative analysis. b. Light measurement techniques: Calibrated light meters measuring power density and energy transmission; temperature monitoring using laser digital sensors; testing of various wavelengths (600-1200nm) and power outputs (0.5W-15W) 2. Treatment Parameter Analysis: a. Wavelengths: 810nm and 980nm b. Low-power (0.5-6.0W) vs high-power (10-15W) c. Treatment durations: 8-34 sessions. d. Delivery methods: Continuous and pulsed wave e. Surface uence measurements 55-81 J/cm² 3. Sample populations: a. TBI patients with comorbid depression b. Alzheimer's and Parkinson's disease patients 4. Assessment tools: a. Quick Inventory of Depression Symptomatology-Self Report b. Beck Depression Inventory c. Hamilton Depression Rating Scale d. Patient and spousal symptom diaries e. SPECT imaging for functional changes. 5. Data Analysis: a. Statistical analysis using paired t-tests for pre/post-treatment comparisons b. Power analysis for treatment response denition c. Calculation of penetration percentages and energy loss through tissues d. Temperature change during treatments e. Long-term follow-up assessments at 2-55 months post-treatment 6. Safety Monitoring a. Skin temperature monitoring during treatments b. Documentation of adverse events c. Tracking of medication changes/interactions d. Assessment of treatment tolerability The methodological approach focused on establishing both the physical parameters necessary for effective tissue penetration and the clinical outcomes associated with different treatment protocols. This dual focus allows for a correlation between theoretical requirements for therapeutic effects and observed clinical benets. This methods section emphasizes the comprehensive nature of the research, examining both physical light penetration characteristics and clinical applications while highlighting the rigorous approach to safety and efcacy assessment. Results: 1. Light Penetration Findings: High-power NIR lasers (10-15W) demonstrated signicantly greater tissue penetration than low-power LED devices (< 6W): a. 0.5W LED devices showed no detectable penetration through 2mm of skin b. 10W 810/980nm lasers achieved 9-11% penetration through 2mm of skin c. 15W 810nm lasers achieved up to 33% penetration through the skin d. At 3cm depth into brain tissue, 2.9% of energy from 15W 810nm laser penetrated e. Pulsed settings improved penetration compared to continuous wave delivery 2. Clinical Efcacy Findings In TBI patients with depression (n=39) a. Treatment Response: 1. 92% (36/39) achieved signicant clinical improvement 2. 82% (32/39) achieved remission from depression symptoms 3. QIDS scores decreased from 14.10 ± 3.39 to 3.41 ± 3.30 (p < 0.00001) 4. HAM-D scores decreased from 248 ± 5.24 to 6.0 ± 5.12 (p < 0.00001) 3. Symptom Improvements: a. 100% resolution of suicidal ideation in affected patients b. Signicant improvements in anxiety, sleep, cognition c. Benets observed often within the rst four treatment d. Improvements maintained at follow-up (up to 55 months) 4. Treatment Parameters for Optimal Results: a. Wavelength: 810nm and 980nm studied b. Power: 10-15W necessary for adequate penetration c. Treatment sessions: 8-34 (mean 16.82 ± 6.26) d. Surface uence: 55-81 J/cm² e. Estimated therapeutic uence at 3cm depth: 0.8-2.4 J/cm² 5. Safety Outcomes: a. Minimal adverse effects reported 1. Mild headache (15% of patients, rst 1-3 treatments only) 2. Temporary fatigue (28%, initial treatments only) 3. Maximum skin temperature increase of 3°C b. No serious adverse events reported c. No interference with concurrent medications Results indicate high-powered NIR photobiomodulation can safely and effectively penetrate brain tissue to achieve therapeutic benets, with sustained improvements in depression symptoms when delivered at appropriate parameters. The ndings demonstrate superior outcomes compared to low-power LED devices, with a clear correlation between adequate penetration depth and clinical efcacy. Discussion/Implications: 1. The ndings have several signicant implications for the therapeutic application of photobiomodulation (PBM) in treating neurological conditions: a. Power and Penetration Requirements 1. The demonstrated inadequacy of low-power LED devices (< 1W) to penetrate effectively through human tissue challenges many current clinical protocols. 2. High-powered lasers (10-15W) appear necessary to deliver therapeutic uence (0.9-15 J/cm²) to deep brain structures. 3. These ndings suggest a need to reevaluate many commercial PBM devices marketed for brain treatment that use only low-power LEDs. 2. Treatment Protocol Optimization a. The rapid response time (often within four treatments) and sustained benets (up to 55 months) suggest potential advantages over traditional pharmacological approaches b. The demonstrated safety prole supports PBM as a non-invasive alternative or complement to existing treatments c. The identication of optimal parameters (810/980nm wavelength, 10-15W power) provides clear guidance for future cliniAcal applications The ndings suggest that PBM, when properly delivered using adequate power levels, represents a promising therapeutic approach for neurological conditions. However, the signicant differences in penetration capabilities between device types emphasize the critical importance of proper parameter selection and delivery methods. These insights should guide both future research and clinical applications. Conclusion: This comprehensive review of photobiomodulation (PBM) research reveals several critical ndings that signicantly impact our understanding of its therapeutic application in neurological conditions. The evidence demonstrates that the efcacy of PBM therapy is fundamentally dependent on achieving adequate light penetration to reach target brain tissues with sufcient energy to trigger therapeutic mechanisms.