REVIEW OF TRANSCRANIAL PHOTOBIOMODULATION FOR MAJOR DEPRESSIVE DISORDER: TARGETING BRAIN METABOLISM, INFLAMMATION, OXIDATIVE STRESS, AND NEUROGENESIS
- By admin
- November 15, 2023
We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: “near-infrared radiation,” “NIR,” “low-level light therapy,” “low-level laser therapy,” or “LLLT” plus “depression.” We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.
Infrared (IR) light is ubiquitously present to most life on the earth. Of the total amount of solar energy reaching the human skin, 54% is IR and 30% is IR type A—near-infrared—(NIR; with a wavelength range of 760 to 1440 nm),1 which penetrates through the human skin and reaches deeply into tissue, depending on wavelength and energy.2
NIR is used to treat a variety of conditions such as muscle pain,3 wounds,4 neuropathic pain,5 and headache.6 NIR is also used for wellness and lifestyle purposes such as for cosmetic improvement in peri-orbital wrinkles.7,8 The clinical use of NIR light applied in NIR-spectroscopy dates from the mid-1980s, when it was used for monitoring of the brain in the neonate and the fetus.9
The use of transcranial phototherapy for treating brain disorders started with its application to acute stroke. Numerous preclinical animal studies1011.–12 suggested that the application of NIR laser (810 nm) to the head at various times (hours) after induction of an acute stroke had beneficial effects on subsequent neurological performance and reduced lesion size. Evidence was obtained for the anti-inflammatory, anti-apoptotic, and proneurogenesis effects in the brain stimulated by this approach.13,14 These promising animal studies led to the conduction of a series of clinical trials called NeuroThera Effectiveness and Safety Trials (NEST). All together there were three large studies conducted in 1410 stroke patients [NEST-1 (n=120″ role=”presentation”>n=120
), NEST-2 (n=660″ role=”presentation”>n=660), NEST-3 (n=630″ role=”presentation”>n=630
)] that demonstrated that NIR light delivered transcranially with a class-IV laser is safe, with no significant differences in rates of adverse events with NIR, when compared to sham exposure.1516.–17 Other preclinical studies and clinical trials have suggested that transcranial photobiomodulation (PBM: laser or light emitting diodes—LED) is safe and effective for acute1819.20.21.–22 and chronic2324.–25 traumatic brain injury (TBI) and has beneficial effects on neurodegenerative diseases (Alzheimer’s and Parkinson’s).26,27
For the transcranial treatment of major depressive disorder (MDD), both PBM LEDs and lasers have been experimentally tested, although PBM is not FDA-approved for the treatment of MDD. Certain forms of PBM treatment are also referred to as low-level light therapy (LLLT), since it utilizes light at a low power (0.1 to 0.5 W output at the source) to avoid any heating of tissue. The irradiance of the PBM medical devices (or power density) typically ranges from 1 to 10 times the NIR irradiance from sunlight on the skin (33.6 mW/cm2″ role=”presentation”>33.6mW/cm2
at the zenith). However, most PBM medical devices only deliver light energy at one or two selected wavelengths, as opposed to the whole spectrum of IR that is contained in sunlight. To our knowledge and to this date, transcranial PBM treatment has not caused any retinal injury—one of the most likely postulated adverse events, although care is taken routinely in such studies to protect the eyes with goggles or eye covers.28
In this review, we will first discuss the mechanisms of action by which NIR and red light (PBM) might improve symptoms of depression, and then present the clinical evidence for their use as a treatment for MDD and other comorbid psychiatric syndromes.
We found clinical and preclinical studies via PubMed search (December 15, 2015), using the following keywords: “near-infrared radiation,” “NIR,” “low-level light therapy,” “low-level laser therapy,” or “LLLT” plus “depression.” We chose studies that had a clinical focus, and we excluded studies involving NIR spectroscopy. We also located studies using the references from the articles found in the PubMed search. As the searched literature encompassed different conditions and disorders frequently comorbid with depression, a specific section of this review was devoted to the effect of PBM on psychiatric comorbidity. In the latter section, the following conditions were included, based on available literature: TBI, anxiety and post-traumatic stress syndromes, insomnia, and suicidal ideation. The literature search for the use of PBM to treat comorbid conditions was neither systematic nor extensive, but rather a secondary focus of this review. The information is presented in an organized fashion to allow the reader to easily grasp the potential applications of PBM for the treatment of depression and of its comorbid conditions. To attain this goal, the authors have allowed a margin of redundancy, by distributing different information derived from any given publication in separate sections of this review. To avoid an artificial inflation of the extant literature on the chosen topic, we referenced the main authors—and when appropriate their affiliation—when referring to the same articles more than once. The reader will find a table summarizing the six key clinical articles reviewed, also to avoid unintended inflation of the literature. The six clinical reports included in this review where extracted from a pool of 58 articles, that were originally identified with the literature search.
In addition, we used PubMed to find articles that examined the link between PBM and each of the various biological processes including metabolism, inflammation, oxidative stress, and neurogenesis.
TARGETING BRAIN METABOLISM
Multiple studies have reported regional and global hypometabolism in MDD, which could be related (either causally or consequentially) to the neurobiology of mood disorders.2930.31.–32 Positron emission tomography studies have shown abnormalities in glucose consumption rates and in blood flow in several brain regions of subjects with major depression.33 Moreover, metabolic abnormalities in the anterior cingulate, the amygdala-hippocampus complex, the dorsolateral prefrontal cortex (DLPFC), and inferior parietal cortex seem to improve after antidepressant treatment or after recovery.3435.–36
With phosphorus magnetic resonance spectroscopy (P31-MRS” role=”presentation”>31P-MRS
), the baseline pool of nucleotide triphosphate (NTP)—a product of the cellular utilization of glucose and a marker of the cellular energy availability—was low in subjects who subsequently responded to antidepressant treatment.32 Iosifescu et al.32 also demonstrated for the first time with P31-MRS” role=”presentation”>31P-MRS a correlation between treatment response (to a regimen that combined antidepressants and triiodothyronine) and restoration of a higher NTP pool (with compensatory decrease in phosphocreatine) in the anterior cingulate cortex. This study suggests a pathway to antidepressant response based on restoration of a high cellular energy state. In fact, phosphocreatine represents a long-term storage depot of energy, while NTP and ATP are energy-rich molecules that are readily available to the cell. The same authors replicated the aforementioned findings in MDD subjects treated with standard antidepressants (Iosifescu et al., unpublished). In this cohort, P31-MRS” role=”presentation”>31P-MRS
metabolite changes were noted in brain-only voxels of responders, but not in nonresponders to antidepressants.
In experimental and animal models, PBM (NIR and red light) noninvasively delivers energy to the cytochrome c oxidase and by stimulating the mitochondrial respiratory chain leads to increased ATP production (see Fig. 1).3738.–39 A study of the effects of NIR on patients with MDD found that a single session of NIR led to a marginally significant increase in regional cerebral blood flow.40 Whether the observed changes in cerebral blood flow resulted from fundamental changes in neuronal metabolism or changes in vascular tone remain to be clarified. Given the correlation of both hypometabolism and abnormal cerebral blood flow with MDD, the beneficial effect of NIR on brain metabolism is one potential mechanism for its antidepressant effect.
Cellular targets of NIR radiation mechanisms of transcranial NIR for psychiatric disease. The NIR photons are absorbed by cytochrome c oxidase in the mitochondrial respiratory chain. This mitochondrial stimulation increases production of ATP but also activates signaling pathways by a brief burst of ROS. This signaling activates antioxidant defenses reducing overall oxidative stress. Proinflammatory cytokines and neuroinflammation are reduced. Neurotrophins such as brain-derived neurotrophic factor are upregulated, which in turn activate synaptogenesis (formation of new connections between existing neurons) and neurogenesis (formation of new neurons from neural stem cells).
Animal and clinical research suggests that the inflammatory arm of the immune system contributes to MDD. Post-mortem gene expression profiling on tissue samples from Brodmann area 10 (BA10—prefrontal cortex) have shown that MDD is characterized by increased inflammation and apoptosis.41 In a case-control study, Simon et al.42 found that antidepressant-naive MDD subjects had significant elevations in the following cytokines and chemokines when compared to healthy controls: MIP-1α” role=”presentation”>MIP-1α
, IL-1α” role=”presentation”>IL-1α, IL-1β” role=”presentation”>IL-1β, IL-6, IL-8, IL-10, Eotaxin, GM-CSF, and IFNγ” role=”presentation”>IFNγ
. Although IL-10 is an anti-inflammatory cytokine, the results suggested that the elevated levels of this IL-10 were likely induced in response to the overall elevation of proinflammatory cytokine levels. In a review of the research on inflammation in MDD, Raison et al.43 proposed that proinflammatory cytokines might cause brain abnormalities that are characteristic of MDD. Indeed, animal research has shown that IL-1 mediates chronic depression in mice by suppressing hippocampal neurogenesis.44
One proinflammatory cytokine that may be of particular relevance to depression is CSF IL-6 (IL6 measured in cerebrospinal fluid). In a recent report, patients with MDD had significantly higher CSF IL-6 levels compared to healthy controls; CSF IL-6 levels were significantly higher than in the serum, and there was no significant correlation between CSF and serum IL-6 levels.45 These findings are consistent with a prior report showing a positive correlation between CSF IL-6 levels and the severity of depression and suicide attempts, with the strongest correlation found in violent suicide attempters.46 One report in a smaller sample of depressed patients has shown that CSF IL-647 was lower or comparable to healthy controls.
NIR light and red light (600 to 1600 nm) decreased synovial IL-6 gene expression (decreased mRNA levels) in a rat model of rheumatoid arthritis.48 In another study, NIR (810 nm) used as a treatment for pain in patients with rheumatoid arthritis decreased production of the following proinflammatory cytokines: TNF-α” role=”presentation”>TNF-α
, IL-1β” role=”presentation”>IL-1β
, and IL-8.49 Khuman et al.50 showed that transcranial NIR improved cognitive function and reduced neuroinflammation as measured by Iba1+ activated microglia in brain sections from mice that had suffered a TBI. Finally, NIR (970 nm) has been found to be an effective treatment for inflammatory-type acne.51 In summary, it is reasonable to predict that transcranial NIR treatment would likewise have an anti-inflammatory effect in patients suffering from MDD.
TARGETING OXIDATIVE STRESS
Research has demonstrated a correlation between MDD and vulnerability to oxidative stress.52 For example, depression-induced rats show a significant decrease in glutathione peroxidase (GSH-Px) activity in the cortex.53 Glutathione (GSH) is the most abundant and one of the important antioxidants in the brain; GSH-Px enzymes protect against oxidative stress via reducing hydroperoxides and scavenging free radicals.54 GSH also appears reduced in the brains of MDD subjects.55 Additionally, a study by Sarandol et al.52 demonstrated that MDD patients have higher levels of malondialdehyde, a toxic molecule and a biomarker of oxidative stress.56 Moreover, depressed patients have more red blood cell (RBC) oxidation compared to healthy controls.52 In the same study, the authors found a significant positive correlation between RBC superoxide dismutase (SOD) activity and depression severity. SOD serves to catalyze the removal of the toxic superoxide radical.57 Thus, elevated SOD activity in depressed patients might indicate higher levels of oxidative stress. Finally, catalase activity and nitric oxide (NO) levels have also been shown to be lower in depressed patients than in healthy controls.58 Catalase is an enzyme that protects cells against damaging reactive oxygen species (ROS) via degradation of hydrogen peroxide to water and oxygen.59 NO has protective effects against cell damage, which are likely due to its pleiotropic functions in regulating antioxidant enzymes and many other aspects of cell metabolism.60,61
Oxidative stress may be an effective target for antidepressant treatments. However, successful treatments for MDD vary in regard to their protective effects against oxidative stress.52,53,62 Animal research suggests that PBM may have beneficial effects on oxidative stress. In a rat model of traumatized muscle, NIR (904 nm) blocked the release of harmful ROS and the activation of the transcription factor, nuclear factor κB (NF-κB), both induced by muscle trauma. Trauma activates NF-κB by destroying a specific protein inhibitor of NF-κB called IκB, and this destruction was inhibited by NIR light. Furthermore, NIR reduced the associated overexpression of the inducible form of nitric oxide synthase (iNOS) and reduced the production of collagen.63 This regulation of iNOS is important because excessive levels of iNOS can lead to formation of large amounts of NO that combine with superoxide radicals to form the damaging species peroxynitrite, and can interfere with the protective benefits of other forms of NO synthase.64 These findings suggest that NIR protects against oxidative stress induced by trauma. Finally, an in vitro study of the effects of red light and NIR (700 to 2000 nm) on human RBCs found that NIR significantly protected RBCs against oxidation.65