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This video was created to support their published research. The authors did research using several lasers and slices of a sheep’s brain to try and determine the best parameter for treating TBI (Traumatic Brain Injury) with a desired fluency of 0.9 to 15 joules/cm2 at a depth of 2 cm. They state that getting the energy through the skull is especially difficult so they test multiple options so test the transfer rate. They started out using a continuous output split 980/810nm system (the only company that makes that type of split system, 80% of the power at 980nm and 20% of the power at 810nm, is LiteCure with their LightForce series). The result was less than 1/2% of the energy reached a depth of 2cm. Then they switched to pulsing and got an increase in the energy transfer. When they switched to a 810nm-only 15 watt system with pulsing the transfer rate increased to 16% of the output energy reached the target depth.

 Here are some rough numbers to review the feasibility of using this system for treatment. If the duty cycle is 70%, the system will deliver 1.68 joules per second at a depth 2cm (15wattS*70%*16%). To get 5 joules/cm2 over 15 x 15 cm treatment area would require a total of 1125 joules at depth. This would take 23 minutes.

This research shows that only class 4 systems can delivery the level of power needed for this kind of therapy in a typical rushed doctor's office. A class 3b system with 1 watt would take 4 - 5 hours per treatment to get the same dosage.

The original research publication is titled " Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy"

 

video length: (9:18)

 

Original Source: https://www.youtube.com/watch?v=iZbP2IVekh0

Abstract:

Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm2 at 810 nm or 9 W/0.89 cm2 at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration. Keywords: infrared, traumatic brain injury, TBI, transcranial infrared light therapy, transcranial laser therapy 

INTRODUCTION

Traumatic brain injury (TBI) has recently moved into the limelight due to the recognition of its impact on professional athletes and military personnel. Yet, TBI is neither a new problem nor limited to those two populations. The Centers for Disease Control and Prevention estimated that 1.5 million Americans sustained TBI annually in 2000.1 As of 2006, the estimates had risen to 1.7 million brain injuries annually.2,3 Undoubtedly, these point prevalence proportions will increase as military personnel return home,4 and the problem of repeated mild TBI (mTBI) becomes more recognized in sports.5 Current estimates of the prevalence of TBI among veterans range from 9.6%6 to 20%,7 with an estimated total of more than 300,000 cases of TBI among military personnel since 2000.4 The current estimates of the combined number of sportsrelated concussions and brain injuries in the US are 1.6-3.8 million annually.8-10 TBI results in a wide spectrum of neurological, psychiatric, cognitive, and emotional consequences. In part, the variation is related to the severity of the injury (mild, moderate, severe TBI), which is stratified based on Glasgow Coma score, periods of unconsciousness, and degrees of amnesia. Furthermore, the diversity of sequalae can be related to the areas of the brain that are injured, the severity of the injury (highly variable within the classification of “mild” and “moderate”), and the evolution of the injury over time due to neuroinflammatory processes.11,12 Additional mechanisms thought to underlie the damage of TBI include decreased mitochondrial function, calcium and magnesium dysregulation, excitotoxicity, disruption of neural networks, free radicalinduced damage, excessive nitric oxide, ischemia, and damage to the blood-brain barrier. Together, these can contribute to a progression of the damage over time. Patients with TBI can experience headache, visual disturbances, dizziness, cognitive impairment, loss of  executive skills, memory impairment, fatigue, impulsivity, impaired judgment, emotional outbursts, anxiety, and depression.3,13-23 The situation can be further clouded by secondary and/ or comorbid posttraumatic stress disorder (PTSD), depression, and anxiety,17-25 which can have symptoms that overlap with those described above and appear to be increasingly likely with repetitive concussive or subconcussive brain injury.5,24,26

TREATMENTS FOR TBI

Pharmacological treatments Pharmacological treatment largely targets the neuropsychiatric sequalae of TBI, rather than providing any means of healing or repairing injury. In general, pharmacological treatment is focused on the modulation of major neurotransmitter systems – dopaminergic, serotonergic, noradrenergic, acetylcholinergic, and glutaminergic.20 Disruption of the major neurotransmitter pathways may result from direct injury or excitotoxicity and other cytotoxic mechanisms. The treatment of depression secondary to TBI is often approached with serotonin reuptake inhibitors. Several studies have examined the benefit of sertraline in post- TBI depression.27-29 Other serotonin reuptake inhibitors also have been examined. Tricyclic antidepressants appear to have some use in the treatment of post-TBI depression, although cautious dose titration is required. Patients with TBI are at greater vulnerability to sedation and cholinergic side effects of confusion and memory impairment. With serotonergic agents other than sertraline, cognitive effects also have been reported.30 Similarly, lithium may be a less desirable agent in this  population due to sedation and cognitive impairment. Patients with TBI may respond at lower doses and lower blood levels than expected. Modulation of the dopaminergic system may improve alertness, attention, and cognitive processing speed. The stimulants are most commonly used for this purpose. Methylphenidate facilitates the release of dopamine and slows its reuptake. Dextroamphetamine strongly inhibits reuptake of dopamine, slows down the breakdown of dopamine by monoamine oxidase, and somewhat increases the release of dopamine. These subtle differences are sometimes imperceptible to the patient, but at other times, a patient will do best on one or the other stimulant. Increasing dopamine in the reticular activating system leads to enhanced arousal. Increasing dopamine within the frontal cortex and the striatum leads to enhanced processing speed and attention. Some evidence suggests that the stimulants may enhance neuronal recovery after injury.31-33 There are numerous potential side effects with stimulants, including abnormal heart rhythms, decreased seizure threshold, and death, but these severe side effects are extremely rare. The most common side effects with stimulants are decreased appetite, stomach upset, and headache. These are most severe at the beginning of treatment and improve over time for most patients. Insomnia is another common side effect, which may be more frequent in those with a TBI. Amantadine and bromocriptine may also increase dopamine. Studies of these agents have shown reduced abulia, anergia, and anhedonia in those with TBI.34,35 Amantadine may cause confusion, hallucinations, and hypotension. Small studies have suggested some benefits of bromocriptine in cognitive function.36,37 Arousal-enhancing agents also have found a use in the treatment of the neurocognitive sequalae of TBI. Modafinil is the oldest form of these medications, and armodafinil is an isomer of modafinil with longer activity and less side effects. These medications help to increase alertness and wakefulness. The precise mechanism of action of odafinil is unclear. It appears to increase histamine in parts of the brain involved in controlling the sleep-wake cycle; however, knock-out mice that lack histamine receptors still show increased wakefulness with modafinil.38,39 The picture is also murky  for modafinil’s effect on orexins, which are wakefulness molecules in the hypothalamus.40 Modafinil has been shown to weakly bind to the dopamine transporter – like the stimulants,41 and dopamine transporter knock-out mice show no response to modafinil.42 A number of research studies have examined the benefit of these agents in fatigue associated with multiple sclerosis, TBI, cancer, and other conditions. Cognitive and memory impairments after TBI may reflect disruption of cholinergic function. The impact of anticholinergic agents on cognitive function of those with TBI supports this contention. Donepezil is the safest and most widely used of the cholinesterase inhibitors. Several easonably large studies have shown improved memory and cognitive function.43-45 Donepezil has benefits in memory and cognition even several years after injury.45,46  Anticonvulsants are often prescribed initially after a TBI due to heightened risk for seizures. Post-TBI mania or mood lability may respond well to anticonvulsants, such as carbamazepine or sodium valproate. They are also often used to treat aggression after TBI. The anticonvulsant agent, topiramate, has been shown to adversely affect cognitive function in the TBI patients.47 While insomnia is a significant issue for patients with TBI, affecting between 15% and 84% (mean of 40%),3,13,19,21,23,48,49 little has been published on the treatment of this aspect of TBI. Benzodiazepines may  be effective but carry a risk of disinhibition. Kemp et al48 found that commonly used sleep aid, melatonin, was not effective. Antidepressants, including serotonin reuptake inhibitors and tricyclic antidepressants, are not effective in resolving insomnia in this population.49 No single agent has emerged as a good solution for this symptom. Cognitive rehabilitation Cognitive rehabilitation now takes many forms and is often individualized to the particular needs of the patients. Protocols have been devised to remediate cognitive difficulties often encountered in those with TBI, such as impaired concentration, executive dysfunction,  inattention, visual disturbances, memory dysfunction, and impaired language function. They range from simple strategies (using a planner to aid memory and organization) to specific protocols targeting particular cognitive functions (eg, short-term memory) that can be monitored with sequential neuropsychological testing. These interventions have been extensively reviewed elsewhere.50,51 Comprehensive programs which include psychotherapy and social skills components have been shown to have greater efficacy.50,52,53 Overall, reports of benefits have been mixed.54,55 Behavioral therapies Behavioral remediation strategies to eliminate problematic  behaviors following TBI have met with mixed success, most often in terms of the poor generalization of specific skills to the outside world. Behavioral deficits that create difficulties for those with TBI and their families include poor hygiene, decline in tidying/cleaning habits, social withdrawal, reduced social comprehension, impaired memory, and poor organization. Behavioral excesses that create difficulties for those with TBI and their families include aggression, sleep disruption, and perseverations. These have been reviewed elsewhere.56 Nutritional supplements Nutritional supplements, herbs, and nootropics have been utilized for many years and are increasingly popular among the patient populations. There remains little clinical research on many of these agents, perhaps reflecting a lack of funding more than a lack of efficacy. Acetyl-l-carnitine is an ester of l-carnitine and is thought to protect brain cells after injury when glucose metabolic pathways are compromised. During this period, acetyll- carnitine supports alternative ketogenic pathways for metabolism.57 It is also believed to enhance cholinergic function. While there are several clinical studies on patients with Alzheimer’s disease and preclinical data on animal models of TBI, the clinical literature on TBI remains sparse. Ginkgo biloba is a natural product of the tree by the same name. It has been shown to improve membrane fluidity and increase resistance to free-radical damage. It provides some subtle benefits to cognitive function in clinical studies of stroke, dementia, aging, and hypoxia damage.58 It has not been systematically studied in TBI but is used extensively in clinic, often in combination with meclofenoxate which is an avid scavenger of free radicals.59 S-Adenosylmethionine (SAMe) is a nutritional supplement which improves cell membrane fluidity and promotes the production of glutathione, an antioxidant. The benefit of SAMe has been assessed in a single clinical study of TBI.60 Patients receiving SAMe had a 77% improvement in clinical scores of post-concussive symptoms. Citicholine provides a source of choline which can cross the bloodbrain barrier. It has been used extensively in Europe and Japan as a treatment for TBI, stroke, and dementia. However, two large US studies failed to demonstrate significant benefit.61,62 Piracetam and the related oxiracetam and phenylpiracetam have shown some promise as nootropic agents. In one double-blind, placebo-controlled study, piracetam improved several symptoms of postconcussive syndrome, including headache and vertigo.63 More recent clinical studies have shown marginal benefit.64 Huperzine-A, an extract of Japanese club moss, is a natural acetylcholinesterase inhibitor. It may serve as a natural alternative to donepezil, rivastigmine, or galantamine. Galantamine warrants special mention as it appears to also modulate nicotinic  eceptors and appears to have more persistent benefit in the treatment of Alzheimer’s disease. It appears to modulate neuroimmune responses, in addition to its effects on acetylcholinesterase.65 Cerebrolysin is a polypeptide that purportedly mimics the actions of neurotrophic factors.66,67 Studies have shown that it can reduce beta amyloid and phosphorylated tau protein accumulation. It may promote neurogenesis, synapse formation, and functional recovery.66 In animal models of acute TBI, cerebrolysin-treated rats had more surviving neurons in the area of impact and showed greater functional recovery.67 In a clinical trial of acute TBI, patients were recruited within 24 hours of injury and treated for 3 months with daily intravenous infusion of cerebrolysin. At 3 months, those receiving cerebrolysin performed significantly better on the Cognitive Abilities Screening Instrument.68 It remains unclear if cerebrolysin provides long-term nootropic benefit. The elevation of free radicals in TBI suggests that antioxidants should be beneficial. Clinical trials of pharmacological antioxidants over the past 30 years have not yielded a useful agent in acute TBI.69 Agents, such as tirilazad70 and polyethylene glycol- onjugated superoxide dismutase, have failed to show benefit in acute TBI. Omega-3 fatty acids may enhance brain repair and recovery, based on animal and clinical studies.71 Similarly, vitamin D may offer neuroprotective and restorative benefits72 in the acute TBI setting. In chronic TBI, vitamin D and omega-3 fatty acids may work synergistically, as they both may reduce neuroinflammation, apoptosis, and oxidative stress.73 Other nutritional supplements have been recommended, but prolonged therapy is necessary to possibly see benefits in TBI. A 6-month trial of ginkgo, vinpocetine, acetyl-lcarnitine, huperzine, alpha-lipoic acid, n-acetyl-cysteine, multivitamins, and over 5 g of omega-3 fatty acids daily yielded improved performance in cognitive testing and increased perfusion (function) in single-photon emission computed tomography (SPECT) scan.74 Long-term use of dietary flavanols may improve cognition in mTBI.75 Transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) has shown some promise in animal models of TBI.76 However, a Cochrane review of the clinical application of TMS for depression noted no difference between repetitive TMS (rTMS) and sham rTMS using the Beck Depression Inventory (BDI) or the Hamilton Depression Rating Scale, except during the initial 2-week period.77 The application of TMS in the post-TBI patients is limited by the risk of seizure induction.78 Hyperbaric oxygen Hyperbaric oxygen treatment has been explored as a treatment for TBI.79-91 Hyperbaric oxygen therapy is neither a benign treatment, given the concerns of oxygen toxicity,79 nor a clear treatment in that the placebo condition of moderate hyperbaric room air also effectively improves cognitive function.80,81 The most carefully performed study compared a group in a cross-over design with an interval of both null treatment and hyperbaric oxygen at 100% oxygen and 1.5 atm.82 The study described improvement in many of the symptoms associated with persistent TBI including headache, tinnitus, vision disturbance, memory dysfunction, and impaired cognitive function. Cognitive testing also showed improvement in attention, information processing speed, and a battery of cognitive tests. In an uncontrolled case series of 16 subjects, Harch et al83 demonstrated that an abbreviated series of hyperbaric treatments using 100% oxygen at 1.5 atm could mitigate subjective symptoms of TBI (eg, headache, sleep disruption, irritability), improve cognitive testing scores, and improve cortical function based on SPECT imaging.83 A study of a higher dose (2.4 atm) did not reveal any significant benefit of hyperbaric oxygen therapy compared to a sham-control group treated with 1.3 atm,84 and this result has been extended and confirmed by a related group.85 However, this may reflect an inverse dose- esponse curve, rather than an absence of benefit, in that the low-dose sham group demonstrated significant changes in cognitive testing and symptom frequency.86 Hyperbaric oxygen remains a controversial area in both acute TBI86-89 and chronic TBI.82,83,85,86,90,91 Physical exercise High-energy activities and exercise programs completed through a health club facility or comprehensive rehabilitation program should focus on the same parameters of an age-adjusted and diagnosis-specific program for aerobic conditioning – flexibility, stabilization, and strength. Though it appears safe and is an accepted intervention for TBI, there is a need for further welldesigned studies.92 Exercise was a part of a 6-month study of lifestyle changes described above which yielded improved function based on cognitive testing and perfusion SPECT scans.74

A NEW TREATMENT FOR TBI

Unfortunately, little has been found to reverse the damage of TBI or repetitive concussion which is the root cause of residual cognitive and psychological impairment following TBI.20,93 One potential avenue of treatment for TBI is infrared light, which has shown promising data in a number of applications. Near-infrared (NIR) light has been investigated for its ability to modulate intracellular mechanisms related to healing. The application of NIR light by low-power laser or by light-emitting diode (LED) is also known as laser phototherapy94 or near-infrared photobiomodulation.92 NIR irradiation can facilitate wound healing,95,96 promote muscle repair,95 and stimulate angiogenesis.95,96 NIR phototherapy has been studied and applied clinically in a wide array of ailments, including skin ulcers,97 osteoarthritis,98 peripheral nerve injury,95,96 low back pain,99 myocardial infarction,100 and stem cell induction.101 The finding that NIR light passes relatively efficiently through bone has spurred interest in its application to treating disorders of the brain. Over the past decade, transcranial near-infrared light therapy (NILT)102 has been studied in animal models to understand its ability to repair damaged or dysfunctional brain tissue resulting from stroke and TBI. The first published study of NILT for TBI in humans described two cases of chronic mTBI with significant disability.103 Each patient was treated with an LED device delivering low-level low-level light therapy (LLLT) in the red and NIR range for 6-10 minutes per area daily for several months. Both patients had marked neuropsychological improvement after a minimum of 7-9 months of LLLT treatment. The precise mechanisms underlying photobiomodulation and its therapeutic benefits are not fully understood. The purported effects of NIR are illustrated in Figure 1. Light in the wavelength range of 600-1,200 nm has significant photobiomodulation capability.104 Current data most strongly support that absorption of NIR photons by cytochrome c oxidase in the mitochondrial respiratory chain is the key initiating event in photobiomodulation.95,96,104,105 This induces an increase in cytochrome c oxidase activity which in turn increases adenosine triphosphate (ATP) production. Such an increase in ATP in wounded or underperfused cells may be sufficient to activate cells in areas of injury or metabolic derangement.106 Data from numerous tissue culture and animal studies point to the importance of several secondary molecular and cellular events. For example, NIR photonic energy can modulate reactive oxygen species,95,96,102 activate mitochondrial DNA replication,95,96 increase early-response genes,95 increase growth factor expression, induce cell proliferation, and alter nitric oxide levels.95,96,102 These mechanisms are more fully described in the companion paper.105 When examined in the specific model of neural tissue injury, NIR phototherapy can lead to demonstrable neural repair and recovery. For example, LLLT of a power density of 0.9-36 J/cm2 applied at 24 hours poststroke in a rodent model yielded a 32% reduction in neurological deficits, as well as histochemical evidence of neuron proliferation and migration.106-108 LLLT had similar benefits in a rodent model of TBI.96,109-111 Interestingly, these cellular changes evolved over a period of days after light exposure and persisted for considerably longer than the interval of actual NIR exposure. These findings are consistent with a progressive regeneration cascade set in motion by the NIR light exposure. NILT in stroke NILT, predominately in the form of LLLT, has been investigated in laboratory models of stroke. LLLT applied in a single dose to an ischemic stroke model appeared to induce expression of the growth factor transforming growth factor – beta 1 and suppress the production of peroxynitrite.112 In a rat model of middle cerebral artery occlusion, LLLT at a dose of 0.5-7.5 mW/ cm2 using continuous wavelength light at 808 nm was administered at 24 hours after the acute stroke.108,113 This single application was estimated to deliver 1.8 J/cm2 in total to the cortex surface and resulted in demonstrable neurological improvement. Functional changes were not manifested until approximately 2 weeks after the single treatment. While there was no significant change in the size of the stroke lesion, histochemical evidence of neurogenesis and migrating neurons108 indicate that a cascade of secondary processes was initiated by NILT. A rabbit model of stroke utilizing injection of a blood clot embolus also demonstrated benefit from LLLT.102,114,115 Herein, 808 nm light was applied with an LED delivering 7.5 mW/cm2 and an estimated 0.9-2.6 J/cm2 to the cortical surface. Cortical ATP levels were increased, indicative of increased mitochondrial activity.114 Significant behavioral recovery was also noted; however, neither ATP increased nor neurological function changed at doses less than 0.3-0.7 J/cm2.114,115 At higher doses of 0.9-15 J/cm2, neurological improvement was seen.114,115 The clinical trials of NILT in acute stroke, the Neuro- Thera Effectiveness and Safety Trials 1, 2, and 3 (NEST- 1,-2, -3), were conducted between 2006 and 2009. The Phase II clinical trial (NEST-1) involved 120 patients in a double-blind, placebo- ontrolled study of the effects of NILT within 24 hours of ischemic stroke.116,117 Approximately 60% of the patients experienced clinical benefit, and the safety profile was very good. Thus, NEST-2, a Phase III clinical trial, was undertaken in 2007. A total of 660 patients were enrolled.118 Somewhat surprisingly, the study did not demonstrate statistical clinical improvement using a different outcome measure.119 Post hoc analysis revealed that a portion of the patients who were moderately affected and/or had strokes limited to the cerebral cortex did realize clinically and statistically significant improvement.102 The NEST-3 trial was halted midpoint when it failed to demonstrate statistical benefit on futility analysis.120 A key factor in the interpretation of the results of NEST-3 is that, different from NEST-1, all types of stroke were included as opposed to just cortical strokes. Continuous laser light has a limited depth of penetration (#1 cm into brain tissue) which likely prevents an effect on deeper brain matter. Therefore, the lack of significant benefits from NIR phototherapy in NEST-3 could be related to the fact that ischemic penumbra was not reached by the light (Luis DeTaboada, personal communication, January 2015). While pulsed NIR was not used in the NEST-3 study, it is estimated that pulsed NIR could penetrate up to 3 cm in depth from the cortical surface, therefore possibly extending the therapeutic target to deeper strokes (Luis DeTaboada, personal communication, January 2015). Figure 1 Hypothesized mechanism of action of NiR light therapy. Notes: NiR light (600-980 nm) penetrates tissue to variable depths depending on wavelength, the tissue involved, coherence, and time. A fraction of the photonic energy reaches the mitochondria and is absorbed by cytochrome c oxidase. This activates increased ATP production, increases production of ROS and RNS, and possibly increases NO. Downstream events include increased early-response genes (c-fos and c-jun) and activation of NF-?B, which in turn induces increased transcription of gene products leading to synaptogenesis, neurogenesis, and increased production of inflammatory mediators and growth factors. Abbreviations: NiR, near-infrared; ATP, adenosine triphosphate; ROS, reactive oxygen species; RNS, reactive nitrogen species; NO, nitric oxide; NF-?B, nuclear factor kappa B. NILT in TBi Oron et al109 conducted the first animal studies of NILT for TBI. They found that a single application of NIR light at 808 nm from a 200 mW emitter at 4 hours post-injury resulted in a significant reduction in lesion size by 5 days.109 To date, several groups have studied NILT in animal models, and this material has previously been reviewed.95,121-123 Single applications of 800-810 nm NIR light within 4 hours of injury have been shown to improve neurological function significantly.110,124-126 The same dose of NIR light at 6 hours was less effective125 and at 8 hours had no appreciable benefit.125 NIR photonic energy at other wavelengths was less effective. Wu et al110 examined red light (670 nm) at 4 hours and found a similar improvement in neurological function; however, 730 nm and 980 nm had no neurological benefit. Similar data for lesion volume have been reported. A single dose of 800-810 nm NIR light (fluence of 36 J/cm2) yielded an approximate 50% reduction in the volume of the lesion at 3-4 weeks110,111,124-126 and a possible reduction in the initial spread of neurological injury, based on the marked reduction in lesion volume found at 5 days post-injury.109 Repeated NIR phototherapy treatments appear to have some benefit, but the frequency and number of treatments are critical factors. While a single NIR light application had benefit, daily applications for 3 days yielded much greater neurological benefit126,127 with smaller lesion size,126 fewer degenerating neurons,126 more proliferating cells,126 and greater levels of brain-derived neurotrophic factor (BDNF)127 compared to a single treatment in a mouse model. In contrast, daily treatment for 7 days128 or 14 days126 showed no difference from controls. NIR energy densities in the range of 0.9-36 J/cm2 resulted in significant biochemical and behavioral changes.109-111,124-127 Pulsing of NIR light appears to yield a greater neurological response but only within certain parameters. Pulsing at 10 Hz yielded greater neurological improvement and a significant reduction in lesion size compared to either continuous-wave or pulsed NIR at 100 Hz.111 In the mouse model of moderate TBI, NILT (800-810 nm) improved learning and memory (Morris water maze performance),128 as well as behaviors associated with depression and anxiety (immobility during tail suspension).111,124 The finding that NILT brought about a smaller lesion in the rodent model of TBI compared to untreated mice suggests that decreased apoptosis, reduced spreading lesion penumbra, and/or neurogenesis are induced by NILT. Indeed, NILT can decrease BAX expression, a pro-apoptosis gene,129 increase expression of BCL-2, an anti-apoptosis gene,129 increase nerve growth factor,95 increase BDNF,127 decrease inflammatory markers,130 and decrease numbers of degenerating neurons.126 Together, these mechanisms may reduce the enlargement of the initial lesion during the first day following the lesion.109 Moreover, increased BDNF and nerve growth factor may contribute to synaptogenesis as shown by increased levels of synapsin-1,127 and neurogenesis, as shown by increased numbers of proliferating cells.127 In a double-blind study in healthy volunteers, NILT was beneficial – compared to sham – in memory and attention.131 In this study, the authors shed only one application of NIR light to the right forehead, targeting the right frontal pole of the cerebral cortex (Brodmann’s area 9 and 10). The device was a Class IV laser CG-5000 (Cell Gen Therapeutics, Dallas, TX, USA), and the parameters were as follows: wavelength 1,064 nm, irradiance 250 mW/cm2, fluence 60 J/cm2, and time 4 minutes per site (two sites).131 The subjects who received the NIR treatment had better attention after 2 weeks, measured by the psychomotor vigilance test. They also had better delayed visual memory at the Delayed Match-to-Sample test. This is the only published controlled trial assessing the impact of NILT on cognition; however, other reports have shown the therapeutic effects of NILT in small numbers of TBI patients. In a two-case report in TBI patients,103 NILT (870 nm) improved sustained attention, memory, and executive functions. Both patients were treated with an instrument with three separate LED cluster heads. The parameters used for the treatment were the following: NIR wavelength 870 nm and 633 nm (red light), irradiance 2.2-25.8 mW/cm2, fluence 13.3 J/cm2, and time 10 minutes per site.103 The same group reported on a cohort of eleven subjects with persistent cognitive dysfunction and treated with a similar NILT protocol for chronic mTBI.132 The eleven subjects received NILT with a device with three LED cluster heads (Model 1100; MedX Health, Toronto, ON, Canada). The parameters used for the treatment were the following: NIR wavelength 870 nm and 633 nm (red light), irradiance 22.2 mW/cm2, fluence 13 J/cm2, and approximate time 10 minutes per site. The NIR light was applied three times per week for 6 weeks (18 sessions), on eleven sites for 10 minutes per site (the total duration of each session was 20 minutes).132 The sites on the skull were chosen on the midline, and bilaterally on frontal, parietal, and temporal areas. At the follow-up neuropsychological testing, NILT had a powerful effect on attention, inhibition, and inhibition switching in the Stroop task, and similarly improved verbal learning and memory, as well as enhanced long-delay free recall on the California Verbal Learning Test. Eight subjects, from the same cohort, were identified as having mild, moderate, or severe depression based on the BDI-II total score (range: 15-34).132 The three cases, who entered the study with only mild depression, remained the same after NILT treatment. Results for the five cases with moderate-severe depression were as follows: two moderate cases improved to mild/minimal depression 8 weeks after the end of NILT series, and one severe case improved to moderate depression. Two moderate or severe depression cases remained the same after 8 weeks of follow-up from the last NILT session.132 Dose response and photonic penetration A prevailing theory in photobiomodulation postulates that a bimodal response curve exists for the biological effects of NIR light.95 The so-called Arndt-Schulz curve (a fundamental principle in homeopathic medicine) is frequently used to describe this biphasic dose response. Some data indicate that low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. Laboratory studies of cells in culture have demonstrated a bimodal dose response to light exposure in lymphocytes133 and fibroblasts.134,135 For example, Chen et al135 found that a range of 0.03-0.3 J/cm2 was beneficial in activating transcription factors in culture, while 3-30 J/cm2 inhibited the activation of these factors. In contrast, an order-of-magnitude greater dose (2 J/cm2) was best at activating fibroblasts in a superficial wound model.136 Furthermore, an order-ofmagnitude greater dose (30 J/cm2) proved to be best in a rodent joint inflammation model.137 Thus, a dosedependent effect for many biological responses to NIR light has been demonstrated,95,137-139 but the critical parameter is dose at the level of the target tissue, rather than at the surface.137,140 The amount of energy that reaches a volume of tissue at depth is determined by the attenuation of the photonic energy as it passes through the overlying tissue. For example, only 2.45% of the energy from a 980 nm laser emitter penetrates to the level of the peroneal nerve.140 Nevertheless, the biphasic dose response does not appear to be universally true. In primary microglial cell culture, a dose-dependent response to NIR was demonstrated with no detrimental effects at doses as high as 30 J/cm2.141 So a critical question in the use of NILT is that of radiant energy penetration. In particular, some authors have challenged the efficacy of low-power LEDs used in LLLT.142-144 In laboratory studies, LLLT radiant energy is almost entirely absorbed in the first 1 mm of skin.145,146 In two unrelated studies, LLLT diode devices proved to be ineffective in the treatment of diabetic neuropathy,142,144 in contrast with prior reports.147 Similarly, laboratory studies of NILT using LLLT transcranially have not consistently yielded positive results. For example, in a rat model of TBI, Giacci et al148 found no benefit from daily 30-minute irradiation with either 670 nm or 830 nm 0.5 W LED emitters for a period of 7 days. Doses at the skin surface were 28.4 J/cm2 and 22.6 J/cm2, respectively.148 Similarly, treatment of a rat model of contusive spinal cord injury with LLLT (830 nm at 22.6 J/cm2 or 670 nm at 28.4 J/cm2) for 30 minutes per day for 5 days resulted in no significant functional improvement and no reduction in lesion size, despite delivering 2.6 J/cm2 to the spinal cord.148 Lapchak102 reported that the physical parameters of NILT in the clinical trials for the treatment of stroke utilized in the NEST-1 and NEST-2 trials116-120 may have delivered insufficient energy to cortical tissues to be effective. Therein, NIR light of 808 nm wavelength with infrared energy densities of 0.9 J/cm2 was applied to the human scalp for a total of 40 minutes with applications at multiple sites during that time.116,118 Recall that animal models of both stroke and TBI suggest that NIR energy densities in the range of 0.9-36 J/cm2 resulted in significant biochemical and behavioral changes.96,106-115,125-127 The concern raised from the NEST studies102 is that current clinical trials testing the effectiveness of lowenergy NIR diodes to treat TBI may yield negative or inaccurate efficacy data, not because of a failure of infrared light to invoke a change but due to a dose error. Doses that are effective when directly applied to cells in a Petri dish149,150 or to 3-5 mm thick rodent brains96,109-111,125,126,128 may be insufficient to penetrate 2-4 cm into the human brain. In a companion paper, our own studies of photonic energy penetration are detailed.105 To summarize, the laboratory tissue studies showed that 0.5 W LED emitters did not penetrate the 2 mm thickness of human skin. No detectable energy from 0.5 W LED NIR light emitters could be detected penetrating a similar thickness (1-2 mm) of sheep skin or 3 cm thick section containing sheep skin, skull, and brain. In contrast, 11% of the photonic energy from a 10 W 810/980 nm coherent NIR laser penetrated 2 mm of human skin. Similarly, 17% of the photonic energy from a 15 W 810 nm coherent NIR laser penetrated the same distance.105 Energy from these more powerful NIR emitters could be detected penetrating 3 cm of sheep skin, skull, and brain with 0.4% of the 10 W 810/980 nm NIR laser’s energy reaching the depth of 3 cm and 2.9% of the 15 W 810 nm NIR laser’s energy traversing the same distance.105 Anders also has demonstrated penetration of 808 nm light to 40 mm in the brain using a 5 W laser emitter (JJ Anders, personal communication, January 2015). Prompted by the mixed results in the literature and the observations by Lapchak,102 Franzen-Korzendorfer et al,144 Wan et al151 and Lavery et al142 we have been utilizing relatively high-power (10- 5 W) lasers at the wavelengths of 810 nm and 980 nm in the clinic to treat patients with TBI. Clinically, the patients have shown excellent responses with resolution of many of their long-standing symptoms of TBI or post-concussive syndrome. Below is a retrospective series of such patients to illustrate the extent and character of response to this modality. Methods Patients in the case series were sequentially treated patients at a clinic which is engaged in ongoing NILT for a number of clinical conditions. The risks, benefits, and current state of research on the use of NILT were explained to each patient. Each patient consented to treatment. Institutional Review Board approval was obtained in a post hoc review, noting that the risk-benefit ratio was acceptable. Between March 16, 2011 and February 20, 2013, sequential new referrals for chronic mild-to-moderate TBI were evaluated for treatment and selected for NILT using Class IV lasers, either the LT1000 (LiteCure, Newark, DE, USA), a 10 W adjustable NIR laser emitter with wavelengths of 810/980 nm capable of delivering continuous or pulsed NIR light, or the Diowave 810 (Diowave, Riviera Beach, FL, USA), an adjustable NIR emitter up to 15 W with a wavelength of 810 nm capable of delivering continuous or pulsed NIR energy. Demographics and laser treatment settings are detailed in Table 1. The fluence delivered to the skin of patients ranged from 55 J/cm2 to 81 J/cm2. No other treatment modalities (medications, exercise regimen, supplements) were added, discontinued, or changed while receiving NILT. Symptoms were monitored clinically. A baseline Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR)152 was completed for all patients, and the BDI153 was administered to seven of the ten patients before and after the course of treatment. In addition, each patient was instructed on how to create and maintain a patient and spousal diary of symptoms and subjective progress. Each of six patients received a single series of ten treatments with the LT1000 Class IV laser. Three additional patients each received a single series of 20 treatments with the LT1000 Class IV laser. One patient was treated with the Diowave 810 nm Class IV laser device in a series of 20 treatments. The patients and treating clinician wore protective eyewear. There were no incidents of burns or thermal discomfort (Figure 2). The impact of high-watt NILT While the patient group represented a diverse mix (Table 1 presents demographics), some notable commonalities of symptoms emerged. Over 90% of the patients had complaints of anxiety, depression, irritability, and insomnia. Other symptoms included headache (60%), suicidal ideation (50%), cognitive difficulties (50%), attention problems (50%), short-term memory problems (40%), loss of libido (30%), substance abuse (20%), fatigue (20%), and panic attacks (20%). Six of the patients were unemployed prior to treatment. Three of the patients were experiencing severe marital difficulties. All carried or had a confirmed diagnosis of TBI, but other comorbid diagnoses included PTSD, major depressive disorder, generalized anxiety disorder, bipolar disorder, and attention deficit/hyperactivity disorder. The patients’ baseline scores on the BDI were 25.3±12.1 (moderate depression range), and baseline scores on the QIDS-SR were 12.9±4.6 (moderate depression range). During NILT treatments, skin temperature increased no more than 3°C with rapid cooling after removal of the NIR light. A continuous sweeping motion was utilized to minimize skin heating and cover a larger area. After a course of ten treatments of NILT (20 treatments in four patients), each patient experienced significant clinical improvement with resolution of many of their symptoms (Table 2). In addition, the BDI scores dropped to 12±6.5 (nondepressed range). This represented a significant decrease (P,0.01, Student’s t-test, one-tailed, Microsoft Excel). The QIDS-SR scores after treatment were 2.2±2.3 (nondepressed range), and the difference from baseline was highly significant (P,0.00001, Student’s t-test, one-tailed). Patients noted improvement in cognitive function, mood, anxiety, and sleep. None of the patients continued to have suicidal thoughts (50% at baseline). Other symptoms, such as anxiety and irritability, were markedly improved. Most notable were the nonquantifiable changes in patients’ lives. Patients reported improved cognitive ability and a desire to return to meaningful work. Five of the six unemployed patients have returned to work. The two patients who were Iraq/ Afghanistan veterans have found new careers in highly skilled trades. The patients with marital difficulties have reconciled and were purchasing homes or otherwise solidifying their marriages. The clinical change can be attributed to NILT because no changes in medications, supplements, or exercise regimen were permitted during the course of NILT treatment. All patients in the case series experienced significant clinical improvement which supports the conjecture that high-power NIR laser delivers sufficient energy to the human brain for photobiomodulation to occur. Insomnia and suicidal ideation, common symptoms in those with TBI or post-concussive syndromes,3,17-20,24,25 resolved in 100% of cases. Headache, another common symptom for patients following a TBI,6,14,15,23 was reduced or resolved in the six patients so afflicted. Symptoms such as anxiety,14,15,21,24 depression,21,24,25,27-29 and irritability resolved or were dramatically reduced in all patients. Cognitive function appeared to improve based on return to work or improved work performance, although cognitive tests were not performed. The quality of life dramatically improved in all cases, based on the observations of the patients, their family members, and the treating clinician. At follow-up intervals of 6-7 months post-treatment, patients have reported continued improvements in symptoms. The precise areas of brain injury were not elucidated in Figure 2 Treatment parameters per individual, based on area of the skull treated. Notes: Dimensions varied per head/skull size and hair line. Treatment was warm and comfortable for each patient. There were no incidences of discomfort. Areas treated were (A) temporal- ilateral, (B) frontal, and in patients 1-3, 5, and 6 (B) frontal only. Table 1: Infrared light treatment parameters for each of the ten patients in the case series Patient Area treated Sex Mechanism of TBI Interval since TBI Wavelength of Dosage per area Duration before treatment NIR-PT dual wave Scanning technique per area pulsed 10 Hz 1 B, bilateral frontal Male Concussive blast 2 years 810 and 980 nm 2,700 J 10 minutes Fluence – 20.45 J/cm2 2 areas Area – 132 cm2 10 visits 2 B, bilateral frontal Female MVA 18 years 810 and 980 nm 2,400 J 9 minutes Fluence – 18 J/cm2 2 areas Area – 133 cm2 10 visits 3 B, bilateral frontal Female MVA 5 years 810 and 980 nm 2,400 J 8 minutes Abuse Fluence – 18.3 J/ cm2 2 areas Area – 131 cm2 10 visits 4 A–B, bilateral frontal, left temporal Female MVA x2 8 years and 13 years 810 and 980 nm 2,400 J 8 minutes Fluence – 18.3 J/cm2 3 areas Area – 131 cm2 10 visits 5 B, bilateral frontal Male Vietnam Veteran 20+ years 810 and 980 nm 3,000 J 10 minutes Concussion Fluence – 28.3 J/cm2 2 areas Child abuse Area – 106 cm2 10 visits 6 B, bilateral frontal Male Concussion 5+ years 810 and 980 nm 2,400 J 12 minutes Fluence – 14.8 J/cm2 2 areas Area – 162 cm2 10 visits 7 B–A, bilateral frontal, left temporal Male Afghanistan, Iraqi Disability 810 and 980 nm 3,000 J 10 minutes Disability due to TBI 2 years Fluence – 22.7 J/cm2 3 areas Area – 132 cm2 20 visits  B–A, bilateral frontal, bilateral temporal Female Hypoxic encephalopathy Childbirth-related 810 and 980 nm 2,700 J 9 minutes injury, 8 years Fluence – 27.8 J/cm2 3 areas Area – 97 cm2 20 visits 9 B–A, bilateral frontal, bilateral temporal Male MVA-TBI Numerous episodes 810 and 980 nm 3,000 J 10 minutes Concussions Fluence – 22.72 J/cm2 3 areas Area – 132 cm2 20 visits 10 B–A, bilateral frontal, left temporal Female Bicycle vs car >30 days 810 nm single 2,700 J 9 minutes Concussion, amnesia, LOC wavelength – Fluence – 17.1 J/cm2 3 areas different device Area – 158 cm2 20 visits Note: All safety precautions were followed, including metal protective eyewear (laser eye protection). Abbreviation: LOC, loss of consciousness; MvA, motor vehicle accident; TBi, traumatic brain injury. the majority of these cases, so a correlation of symptoms changes and cortical function changes cannot be made; however, perfusion SPECT imaging in other patients has shown significant increases in perfusion in injured areas of the brain and overall improved cortical function following similar courses of high-watt NILT.154 One concern that has been expressed about high-watt NIR lasers is the risk of tissue heating.155 We explored this issue in our companion paper on NIR penetration.105 Temperature change was 1°C-3°C at the skin surface using continuous-wave NIR lasers in the range of 10-15 W. Using pulsed settings, the high-powered lasers showed no significant temperature change in tissue samples. The temperature change on human skin was 1°C or less in the in vivo penetration studies while maintaining continuous movement of the laser probe head.105 Clinically, patients in this case series reported only slight warming of the skin, but no discomfort, using the continuous motion technique. Laboratory studies have largely focused on treatment of acute brain injury. The processes involved in the benefits of NIR light in chronic TBI as seen in this clinical case series may be quite distinct. Nevertheless, Schiffer et al156 found that a single application of LLLT at 810 nm and 250 mW to the forehead over 8 minutes reduced depression and anxiety symptoms in ten patients for approximately 2 weeks. Similarly, the small case series by Naeser et al103 demonstrated some benefit using NIR light, albeit at very low power levels over a prolonged course of several months with only transient benefit. Together with our clinical data, these findings suggest that at least some of the photobiomodulatory effects of NIR energy likely do occur in chronic neurological conditions. Prior presentations on NILT for the treatment of TBI or stroke in humans have focused on getting photonic energy through the skull to the cortex surface which traverses a distance of about 6-10 mm; however, this model is flawed in that the distance to the areas of damage may be far greater. In other words, the cortex immediately subjacent to a portion of the skull may be 10 mm from the surface, but the NIR light energy may need to penetrate 3-7 cm to reach areas of damage. Much of the cortical surface is actually lining the walls and floors of sulci, rather than immediately subjacent to the skull. Analysis of NIR spectroscopy reveals that light propagation through varying media with irregular boundaries is subject to high levels of scatter.157 In addition, review of the neuroimaging literature on TBI has revealed that the most common areas injured in TBI are the orbitofrontal cortex (at the ventral surface of the frontal lobe) and the anterior and medial temporal lobes.158 It is not anatomically possible to position an NIR light emitter immediately exterior to the skull overlying these areas. Indeed, the orbitofrontal cortex positioned immediately above the eyes can only be reached from the forehead by angling the light emitter. Similarly, the temporal lobes are separated from the surface by epidermis, dermis, subcutaneous fat, subcutaneous blood vessels, accessory head of the temporalis muscle, connective tissue, temporalis muscle, skull, and dura mater.159 Each of these structures has different absorption and refraction properties, and each interface between different materials also creates a barrier to transmission of photonic energy.157 Blood flowing in the subcutaneous vessels is believed to create a unique barrier to transmission.160 In summary, effectively targeting the areas most commonly injured in TBI with sufficient photonic energy to initiate reparative processes represents a significant challenge in NILT. This appears to have been overcome with the high-power laser protocol presented here and in a related paper.154 As yet, the mechanism of action of NILT in treating TBI is not entirely clear. Moreover, the neurological benefits are not immediately apparent. Rather, a delay of 1-4 weeks was noted, consistent with a progressive regeneration cascade set in motion by the NILT.96,103,105 ,107,109,121,122,124,127,135 Similarly, most of the patients in the present case series did not notice benefits immediately or within the first few treatments. Instead, they reported benefits emerging over an interval of weeks, and in some cases, continuing after completion of the course of NILT. In addition, the clinical improvement reported by the patients in the above case series is more profound than that reported by patients treated with LLLT or low-powered lasers.103 In fact, we observed that among seven subjects with documented moderate depression, per BDI scores, four had an antidepressant response (≥50% decrease of depression severity). In contrast, Naeser et al132 reported that out of eight subjects with TBI and comorbid depression, only three had a significant improvement in their depressive symptoms (37.5%). Our results may be due to the greater penetration of more powerful, coherent, and pulsed NIR light from a laser source. A unique outcome measure was developed for this protocol (Morries and Henderson, unpublished data, 2015). A patient diary and separate spousal diary provided a weekly update of patient’s response in his or her home environment. This novel approach to capturing the patient treatment experience provided the patient and family with tangible and pertinent documentation of the clinical response. While time consuming, the experiences recorded in these diaries proved to be valuable clinical tools to the treating clinicians.

CONCLUSION

To date, there has been little progress in developing effective treatments for chronic mild-to-moderate TBI or repetitive concussions. This area of need has become even more pressing with the return of veterans from military conflicts in Iraq and Afghanistan4,6,7,16,17,19,161 and the recognition of the magnitude of sport-related TBI.5,8-10 In addition, the dramatic growth in the geriatric population with attendant proprioceptive dysfunction has resulted in a rising incidence of fall-related TBI.162 NILT has shown promise as a tool for the treatment of TBI. A critical issue is to assure that adequate photonic energy reaches the injured areas of the brain. The use of high-wattage lasers, as we have demonstrated, results in marked clinical improvement in patients with chronic TBI. Moreover, symptoms consistent with PTSD, anxiety, and/or depression also improved considerably or resolved in this group of patients. Further work in the use of highwattage NILT in the treatment of TBI, depression, and other neurological disorders is encouraged.

ACKNOWLEDGMENTS

The authors would like to acknowledge the technical assistance of Mr Charles Vorwaller (Aspen Lasers) and Lite Cure Corporation. The authors also acknowledge the contribution of Ms. Taylor Tuteur in the artistic creation of Figure 1.

DISCLOSURE

Dr. Larry D Morries is the CEO of Neuro-Laser Foundation, a nonprofit foundation. He has a private practice in Lakewood, CO. Theodore A Henderson is the president of The Synaptic Space, a medical consulting firm. He is Table 2 NiLT case series with demographics, symptoms, and treatment response

PRETREATMENT POSTTREATMENT

Patient # Sex Occupation Mechanism of TBI Diagnoses Sleep Symptoms Suicidal BDI Sleep Symptoms Suicidal BDI 1 M Veteran, Blast – 5 years; TBI, PTSD, MDD Primary and H, S, I, D, X, L, A, M, + – Resolved None, back No – unemployed Iraqi middle C, SL with spouse, insomnia working 2 F Nurse, MVA – 8 years TBI, PTSD Middle and H, F, I, X, C, A, STM, L, + 18 Resolved A and HA – No 15 unemployed terminal HA, SL but mild, insomnia return to work 3 F Unemployed Assault and TBI, PTSD, MDD, Primary and D, X, P, M, L, HA, S, + 23 Resolved HA – mild, No – MVA, 5 years GAD, ADHD middle insomnia, SA, C, N, STM back with Prior nightmares spouse, no SA, working 4 F Unemployed MVA – 3 years, TBI, PTSD, MDD Primary and D, X, HA, I, M, SA, S, N + 23 Resolved None, marriage No 17 assault middle insomnia, improved, numerous violent nightmares no SA, working 5 M Veteran, Blast – 20+ years TBI, MDD, GAD Primary and D, X, I, S, SL + 18 Resolved None No 1 unemployed 1960s; Vietnam middle insomnia 6 M executive Trauma – TBI, GAD, MDD Primary D, X, I, P, HA, A, S – – Resolved HA, X, and P – No – chronic insomnia but improved 7 M Veteran, Multiple blasts TBI, MDD, GAD Primary and S, D, I, X, C, A, S, STM, – 22 Resolved HA and C – No 16 disability (>12); Afghan middle HA mild, new and Iraqi wars insomnia career 8 F Student Childbirth TBI, learning Primary D, I, X, C, A, SL, F, STM – 16 Resolved, STM improved, No 7 disorder insomnia no bads reading .20% dream more animated 9 F Sales MVA and TBI, LOC Primary and HA, SL, N, D, I, X, H, A – 29 Resolved Mild HA, No 9 sports TBI middle insomnia, job nightmares promotion 10 F Physicist Recent car– TBI, LOC, amnesia Primary and D, I, X, neck, knee pain – 51 Resolved No loss No 19 bicycle middle of skills, accident insomnia maintain intellectual job Notes: Demographics for each of the ten patients in this case study is presented. Also presented is their history of mechanism of injury, diagnosis, and related symptoms. Changes in anxiety levels, sleep patterns, depression, and suicidal ideation were important symptoms and outcomes to track. Patients were instructed for no medication changes, with their primary treatment provider’s approval. Cognitive difficulties, attention problems, and short-term memory difficulties were by patient interpretation of their symptomatic improvement and patient diary changes. Symptom occurrence % was as follows: Anxiety – 100%, Depression – 90%, Irritability – 90%, Primary And Middle Insomnia – 90%, Headache – 60%, Sadness – 60%, Suicidal Ideation – 50%, Cognitive Difficulties – 50%, Attention Problems – 50%, Short-Term Memory Problems – 40%, Marital Difficulties – 30%, Loss Of Libido – 30%, Substance Abuse – 20%, Fatigue – 20%, Panic Attacks – 20%. Abbreviations: NILT: Near-Infrared Light Therapy, TBI: Traumatic Brain Injury, PTSD: Post-traumatic Stress Disorder, MDD: Major Depressive Disorder, GAD: General Anxiety Disorder, ADHD: Attention Deficit/Hyperactivity Disorder, H: Hyperarousal, S: Sadness, I: Irritability, D: Depression, X: Anxiety, L: Loss Of Libido, A: Attention Problems, M: Marital Difficulties, C: Cognitive Problems, SL: Sleep Issues, F: Fatigue, STM: Short- erm Memory Problems, HA: Headache, P: Panic Attacks, SA: Substance Abuse, N: Nightmares, BDI: Beck Depression Inventory, LOC: Loss of Consciousness, MVA: Motor Vehicle Accident. the president of Dr. Theodore Henderson, Inc., a clinical service firm. He is the co-owner of Neuro-Luminance, a clinical service organization. He is the president of the International Society of Applied Neuroimaging. He is the CFO of the Neuro-Laser Foundation, a nonprofit foundation. Dr. Paolo Cassano received funding from the Brain and Behavior Research Foundation; Photothera Inc and from the Dupont Warren Fellowship (Harvard Medical School) to conduct research on NIR light for the treatment of major depressive disorder.

ABOUT THE AUTHORS:

Larry D. Morries, DC brings a distinguished 30-year career studying and treating the brain and body through his private practice based in Lakewood, Colorado. As Neuro-Laser Foundation’s co-founder, his chiropractic expertise is complemented with extensive study of near infrared-light therapy applications, clinical radiology, clinical neurology and sports injury and rehabilitation. In practice since 1973, Dr. Morries has contributed extensively to both chiropractic and medical professions throughout his career. He is a recognized expert often called upon for review services, treatment utilizations, and documentation presentations. In recent years, he has guided the Colorado State of Colorado Workers Compensation Board with a review of treatment guidelines for Chronic Pain, and Complex Regional Pain Syndrome, Shoulder Pain, Low Back Pain, Traumatic Brain Injury, and was asked to present in 2016 on Thoracic Outlet Syndrome.

Other professional involvement include:

• Colorado Chiropractic Association, Board member, President in 1982, Chairman in 1984

• Colorado Chiropractic Society, Vice President and Secretary in 1995-2004

• Colorado Chiropractic Journal Club, Chairman,since 2008

Dr. Morries has continued his study of the human body and brain with postgraduate work in Neurodiagnostic testing at the American Academy of Neurology, and Harvard Medical School-Massachusetts General Hospital. He is also educated on Spinal Mechanics at Chicago Rehabilitation Institute. He earned his Doctorate in Chiropractic from Logan Chiropractic College, with recognition as Student Clinical Director, Teaching Assistant in Radiology. Dr. Morries is most proud of his research papers and awards, in America Academy of Pain Medicine, Sciatic and Suprascapular Nerve Blocks with Dr. Steve Gulevich, MD. He was asked to share two Poster presentations at the North American Laser Foundation in 2011on Low Back Pain, plus Polyneuropathy treatment with Laser (NIR) therapy. His Podium Presentation and publication on Hip dysplasia, in American Board of Chiropractic Sports Physicians®. Additionally, he has given presentations abroad at State of Chiropractic Research, Foundation of Chiropractic Education and Research, in Bournemouth England and Vancouver, BC, Canada. Dr. Theodore Henderson has extensive training and experience to the practice of Psychiatry. He trained in Psychiatry at the prestigious Barnes/Jewish Hospitals at Washington University in St. Louis. Dr. Henderson completed a fellowship in Child & Adolescent Psychiatry at the University of Colorado. He also has training in Radiology, Nuclear Medicine, and the genetics of psychiatry. He established his private practice in Centennial Colorado in July of 2000. Dr. Henderson brings a unique blend of expertise in psychopharmacology, neurobiology, and an understanding of human nature to the practice of psychiatry. Dr. Henderson attended medical school at Saint Louis University School of Medicine. While in medical school, he began studying heart pathology under Dr. Vernon Fischer. He earned an American Heart Association Medical Student Research Fellowship. With this fellowship, he spent one year at the University of Washington studying the pathology of atherosclerosis. In 1991, Dr. Henderson founded the Child Abuse Prevention Task Force at Saint Louis University. This program taught children, parents, and teachers about child sexual abuse and how to prevent it. Each year, this program reached over 8,000 children throughout the metro St. Louis area, primarily in the poor inner-city schools. The program was awarded numerous awards, including a Saint Louis University Community Service Award, Commendations from the school districts, and an award from the American Medical Student Association. Dr. Henderson was nominated for a Student Life Leadership Award and earned a Departmental Award from the Department of Community and Family Medicine. He also received a Weis Humanitarian Award recognizing outstanding humanitarian care as a medical student. Dr. Henderson wrote a training manual on this program that was implemented at other medical schools and he cowrote a book chapter in the book, A Parent’s & Teacher’s Handbook on Identifying and Preventing Child Abuse (1998). During graduate school and medical school, Dr. Henderson published numerous research studies. He published 9 articles and 27 abstracts about his research in brain development. He also published a book chapter on brain development in collaboration with his research professor, Dr. Mark Jacquin. His research focused on the role of neural growth factors and impulse activity on the development of brain organization. He collaborated with leading researchers, including Drs. Thomas Woolsey, Eugene Johnson, and Thomas Rhoades. While a medical student, Dr. Henderson wrote two research grants (as part of program project grants). Both were funded. He continued conducting research at Saint Louis University and Washington University throughout his residencies. Dr. Henderson trained for one year in Radiology, focusing on neuroimaging and pediatrics. With this strong base, he then undertook a residency in Psychiatry at Washington University’s program at Barnes/Jewish Hospitals in St. Louis. His residency included extended training in general pediatrics at St. Louis Children’s Hospital. In 1997, He was awarded the National Institute of Mental Health Outstanding Resident Award for his ongoing work in child abuse prevention and his neurobiological research while a resident. Dr. Henderson completed a residency in Adult (or General) Psychiatry and then undertook a fellowship in Child Psychiatry at the University of Colorado. This included additional specialization in Autism and Autism Spectrum Disorders. He compl

There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600-1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death, in the brain. There is evidence that PBM can help the brain to repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women) PBM has been shown to increase regional cerebral blood flow, tissue oxygenation and improve memory, mood and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports of improvements in executive function, working memory, and improved sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).

Keywords: photobiomodulation, low-level laser therapy, traumatic brain injury, stroke, chromophores, animal studies, clinical trials, human studies

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1. Introduction

Photobiomodulation (PBM) formerly known as low-level laser (light) therapy (LLLT) is approaching its 50th anniversary, after being discovered by Endre Mester working in Hungary in 1967 (Hamblin et al. 2016). Originally thought to be a property of red lasers (600-700 nm), PBM has broadened to include near-infrared (NIR) wavelengths 760-1200 nm, and even blue and green wavelengths. Moreover the advent of inexpensive and safe light emitting diodes (LEDs) has supplanted the use of expensive lasers in many indications. The better tissue penetration properties of NIR light, together with its good efficacy, has made it the most popular wavelength range overall. The best-known medical applications of PBM have been for indications such as stimulation of wound healing (Hopkins et al. 2004; Kovacs et al. 1974), reduction of pain and inflammation in orthopedic and musculoskeletal conditions (Aimbire et al. 2006; Gam et al. 1993), and mitigation of cancer therapy side-effects (Zecha et al. 2016a; Zecha et al. 2016b). However in recent years there has been growing interest in the use of PBM in various brain disorders (Hamblin 2016b; Hennessy and Hamblin 2016; Naeser and Hamblin 2011; Naeser and Hamblin 2015). The almost complete lack of any adverse side-effects of PBM, coupled with growing disillusion with pharmaceutical drugs that affect brain function, have combined together to suggest an alternative physical therapy approach to improving brain function.

Traumatic brain injury (TBI) is caused by some type of trauma to the head, often resulting from road traffic accidents, assaults, falls, sports injuries, or blast injuries suffered in military conflict. TBI is classified as mild (loss of consciousness 0-30 minutes; altered mental state <24 hours; post-trauma amnesia <1 day); moderate (loss of consciousness 30 minutes to 24 hours; altered mental state >24 hours; post-trauma amnesia >1-7 days), or severe (loss of consciousness >24 hours; altered mental state >24 hours; post-trauma amnesia >7 days) (Blennow et al. 2016). There are three cases of TBI sustained each minute in the US (Faul et al. 2010). Repeated mild episodes of TBI (also known as concussions) even without loss of consciousness, may have devastating cumulative effects (Kamins and Giza 2016). Chronic traumatic encephalopathy is a recently recognized condition resulting from repeated head trauma, found in boxers, football players, and military personnel (McKee et al. 2016; Safinia et al. 2016). There is presently no accepted treatment for TBI, although some investigational approaches are being tested in both the acute (neuroprotection) and chronic (neurorehabilitation) settings (Loane and Faden 2010). One of these novel approaches is PBM or LLLT (Hamblin 2016a; Hamblin 2016b; Huang et al. 2012; Thunshelle and Hamblin 2016).

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2. Mechanisms of action

Uncertainties about the mechanism of action of PBM at the molecular and cellular levels, have undoubtedly held back its acceptance in the wider biomedical community. However in recent years substantial progress has been made in this regard (de Freitas and Hamblin 2016). In the following section the state-of-the-art knowledge about the mechanisms of PBM is summarized. Figure 1 shows a graphical representation of the cellular and molecular mechanisms of PBM.

Figure 1

Molecular mechanisms of tPBM

Light passes through the scalp and skull, where depending on the wavelength it is absorbed by two different chromophores. Red and NIR (up to 940nm) is primarily absorbed by cytochrome c oxidase in the mitochondrial respiratory chain of the cortical neurons. Longer wavelength NIR light (980nm, 1064nm) is primarily absorbed by heat and light-sensitive transient receptor potential ion channels. In both cases cell signaling and messenger molecules are upregulated as a result of stimulated mitochondrial activity, including reactive oxygen species (ROS), and adenosine triphosphate (ATP). hv is light, TRPV is transient receptor potential vanilloid (ion channels).

2.1 Chromophores

The first law of photobiology states that a photon must be absorbed by some molecule within the tissue to have any biological effect. The identity of these chromophores has been the subject of much scientific investigation and speculation. Largely due to the efforts of Tiina Karu in Russia, the enzyme cytochrome c oxidase (CCO) has been identified as a major chromophore of red/NIR light (Karu 1999; Karu and Kolyakov 2005; Karu et al. 2004a; Karu et al. 2004b). CCO is unit IV in the mitochondrial respiratory chain and has absorption peaks reaching well into the NIR spectral region (up to 900 nm) as well as in the red and blue regions. The most discussed hypothesis to explain exactly how photon absorption can stimulate the activity of CCO involves the photodissociation of inhibitory nitric oxide (NO) that can bind to the copper and heme centers in the enzyme and prevent oxygen from gaining access to the active sites (Lane 2006). In experimental models (such as isolated mitochondria) oxygen consumption and ATP production are increased, and the mitochondrial membrane potential is raised (Passarella et al. 1984).

A less well-appreciated mechanism involves light and heat-gated ion channels. These cation ion channels are thought to be members of the transient receptor potential (TRP) superfamily consisting of over 28 distinct members organized into six subfamilies, based on their primary amino acid structures (Caterina and Pang 2016). TRPV (vanilloid sub-family) members including TRPV1 (capsaicin receptor) have been shown to be activated by various wavelengths of light including green, red and NIR.

2.2 Cellular mechanisms

After the primary photon absorption event occurs, whether that the photons are absorbed by CCO, or by TRP ion channels a series of secondary events occurs. One of these events is the generation of reactive oxygen species (ROS), which are thought to be produced inside the mitochondria due to an increase in electron transport, and a rise in the mitochondrial membrane potential above the baseline levels (Suski et al. 2012). It should be noted that mitochondrial ROS can be produced when MMP is raised above normal, and also when ROS is reduced below normal. It is thought that the ROS produced when MMP is lowered (mitochondrial dysfunction) are more damaging than ROS produced when MMP is raised (mitochondrial stimulation). Nitric oxide is produced after PBM (Hamblin 2008), possibly by photodissociation from CCO where it inhibits oxygen consumption and electron transport (Lane 2006). Cyclic adenosine monophosphate (cAMP) (Gao and Xing 2009) and intracellular calcium are increased (Alexandratou et al. 2002). Many of these secondary mediators in the signaling pathways triggered by PBM, can induce activation of transcription factors, that go on to upregulate or downregulate expression levels of a large number of genes. One of the best-known transcription factors is NF-kB that can regulate expression of over one hundred genes including proteins with antioxidant, anti-apoptotic, pro-proliferation, and pro-migration functions. PBM (810 nm 3J/cm2) was shown to activate NF-kB in mouse embryonic fibroblasts via ROS production (Chen et al. 2011a). Since NF-kB is known to be a pro-inflammatory transcription factor, it might be thought that PBM would be pro-inflammatory. However it was shown that NF-KB was decreased in already activated (treated with Toll-like receptor ligands) inflammatory dendritic cells by PBM (810 nm 3J/cm2) (Chen et al. 2011b).

2.3 Tissue mechanisms

The changes in expression levels of proteins involved in antioxidant and redox-regulation, anti-apoptotic and pro-survival, cellular proliferation, etc mean that distinct changes in tissue homeostasis, healing and regeneration can be expected after PBM. For instance, structural proteins such as collagen are newly synthesized in order to repair tissue damage (Tatmatsu-Rocha et al. 2016). Cells at risk of dying in tissue that has been subjected to ischemic or other insults are protected (Sussai et al. 2010). Stem cells are activated to leave their niche, proliferate and differentiate (Oron and Oron 2016; Zhang et al. 2016). Pain and inflammation are reduced (Chow et al. 2009). Blood flow is increased (Samoilova et al. 2008) (possibly as a result of the release of NO (Mitchell and Mack 2013)), which also stimulates lymphatic drainage thereby reducing edema (Dirican et al. 2011).

2.4 Brain specific mechanisms

In addition to the foregoing, there are some PBM tissue mechanisms that are specific to the brain. One of the most important is an increase in cerebral blood flow often reported after transcranial photobiomodualtion (tPBM) (Salgado et al. 2015), leading to increased tissue oxygenation, and more oxidized CCO as measured by NIR spectroscopy (Rojas and Gonzalez-Lima 2013). tPBM has been shown to reduce activated microglia in the brains of TBI mice as measured by IBA1 (ionized calcium-binding adapter molecule-1) expression thus demonstrating reduced neuroinflammation (Khuman et al. 2012). tPBM has been shown to increase neurogenesis (formation of new brain cells derived from neuroprogenitor cells) (Xuan et al. 2014), and synaptogenesis (formation of new connections between existing brain cells) (Xuan et al. 2015) both in TBI mice. Figure 2 shows a graphical representation of a variety of these brain-specific tissue mechanisms.

Figure 2

Brain-specific mechanisms of tPBM

The gene transcription process described in Figure 1 can lead to decreases in neuronal apoptosis and excitotoxicity and lessening of inflammation and reduction of edema due to increased lymphatic flow, which together with protective factors such as antioxidants, will all help to reduce progressive brain damage. Increases in angiogenesis, expression of neurotrophins leading to activation of neural progenitor cells and more cell migration, and increased synaptogenesis may all contribute to the brain repairing itself from damage sustained in the trauma. AUC is area under the curve.

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3. Transcranial photobiomodulation

Transcranial PBM is a growing approach to many different brain disorders that may be classified as sudden onset (stroke, TBI, global ischemia), neurodegenerative (Alzheimer's, Parkinson's, dementia), or psychiatric (depression, anxiety, posttraumatic stress disorder)(Hamblin 2016b; Hennessy and Hamblin 2016; Thunshelle and Hamblin 2016). In the following section some issues concerning where the light should be delivered, and the effects of PBM on uninjured mice and humans are addressed.

3.1 Light penetration

Several laboratories working in the field of tissue optics, have investigated the penetration of light of different wavelengths though the scalp and the skull, and to what depths into the parenchyma of the brain this light can penetrate. Answering the question “can light shone on the head sufficiently penetrate to reach the brain?” is difficult. The main reason is that at present it is unclear exactly what threshold of power density is necessary (expressed in mW/cm2) at some depth inside the brain to have a biological effect. There clearly must be a minimum value below which, the light can be delivered for an infinite time without having any effect, but whether this threshold is in the region of μW/cm2 or mW/cm2 is unknown at present.

Haeussinger et al. estimated that the mean penetration depth (5% remaining intensity) of NIR light through the scalp and skull was 23.6 + 0:7 mm (Haeussinger et al. 2011). Other studies have found comparable results with some variations depending on the precise location on the head and the precise wavelength studied (Okada and Delpy 2003; Strangman et al. 2014).

Jagdeo et al. (Jagdeo et al. 2012) used human cadaver heads (skull with intact soft tissue) to measure penetration of 830 nm light, and found that penetration depended on the anatomical region of the skull (0.9% at the temporal region, 2.1% at the frontal region, and 11.7% at the occipital region). Tedord et al. (Tedford et al. 2015) also used human cadaver heads to compare penetration of 660 nm, 808 nm, and 940 nm light. They found that 808 nm light penetrated best, and could reach a depth in the brain of 40–50 mm. Lapchak et al. compared the transmission of 810 nm light through the skulls (no soft tissue) of four different species, and found the mouse skull transmitted 40%, while for rat it was 21%, for rabbit it was 11.3 and for the human skull it was only 4.2% (Lapchak et al. 2015). Pitzschke and colleagues compared penetration of 670 nm and 810 nm light into the brain when delivered by a transcranial or a transphenoidal approach, and found that the best combination was 810 nm delivered transphenoidally (Pitzschke et al. 2015). Yaroslavsky et al. examined light penetration of different wavelengths through different parts of the brain tissue (white brain matter, gray brain matter, cerebellum, and brainstem tissues, pons, thalamus). Best penetration was found with wavelengths between 1000 and 1100 nm (Yaroslavsky et al. 2002). Henderson and Morries found that between 0.45% and 2.90% of 810 nm or 980 nm light penetrated through 3 cm of scalp, skull and brain tissue in ex vivo lamb heads (Henderson and Morries 2015a).

3.2 Local vs systemic effects of light

It is possible that the beneficial effects of PBM on the brain cannot be entirely explained by penetration of light through the scalp and skull into the brain itself, at a sufficient intensity to have an effect on the brain cells. The surface power density that can be safely applied to the head, is limited by heating of the skin. Perceptible heating of the skin starts to be felt when the power density is over about 500 mW/cm2, and can become severe at 1 W/cm2.

There has been one study that explicitly addressed whether direct transcranial PBM or indirect PBM is best for the brain. In a study of PBM for Parkinson's disease in a mouse model, Mitrofanis and colleagues compared the direct delivery of light to the mouse head, and they also covered up the head with aluminum foil so that the light was delivered to the remainder of the mouse body. They found that there was a highly beneficial effect on brain histology with light delivered to the head, but nevertheless there was also a statistically significant although less pronounced benefit (referred to as an “abscopal effect”) when the head was shielded from light. Moreover Oron and co-workers (Farfara et al. 2015) have shown that delivering NIR light to the mouse tibia (using either surface illumination or a fiber optic) resulted in improvements in memory and spatial learning in a transgenic mouse model of Alzheimer's disease. They proposed the mechanism involved PBM stimulating c-kit-positive mesenchymal stem cells (MSCs) that were normally resident in autologous bone marrow. These MSCs were proposed to be able to infiltrate the brain, and clear β-amyloid plaques (Oron and Oron 2016). It should be noted in general that the calvarial bone marrow of the skull contains substantial numbers of stem cells (Iwashita et al. 2003).

3.3 PBM for brain in uninjured animals

Several laboratories have reported that shining light onto the head of uninjured healthy mice or rats can improve various cognitive and emotional parameters. The first study reported that exposure of the middle aged (12 months) CD1 female mice to 1072 nm LED arrays (Michalikova et al. 2008) produced improved performance in a 3D maze compared to sham treated age-matched controls. Gonzalez-Lima and coworkers (Gonzalez-Lima and Barrett 2014) showed that transcranial PBM (9 mW/cm2 with a 660 nm LED array) delivered to rats induced dose-dependent increases in oxygen consumption (5% after 1 J/cm2 and 16% after 5 J/cm2) [113]. They also found that tPBM reduced fear renewal and prevented the reemergence of the extinguished conditioned fear-responses (Rojas et al. 2012).

3.4 PBM for enhancement of brain function in uninjured human volunteers

Gonzalez-Lima et al delivered transcranial PBM (1064 nm laser, 60 J/cm2 at 250 mW/cm2) to the forehead in uninjured human volunteers in a placebo-controlled, randomized study. The goal was to improve performance of cognitive tasks related to the prefrontal cortex, including a psychomotor vigilance task (PVT), a delayed match-to-sample (DMS) memory task, and improved mood as measured by the positive and negative affect schedule (PANAS-X) (Barrett and Gonzalez-Lima 2013). Subsequent studies in uninjured humans showed that tPBM with 1064 nm laser could improve performance in the Wisconsin Card Sorting Task (considered the gold standard test for executive function) (Blanco et al. 2015). They also showed that tPBM to the right forehead (but not the left forehead) could improve attention bias modification (ABM) in humans with depression (Disner et al. 2016).

Salgado et al. applied transcranial LED to enhance cerebral blood flow in healthy elderly women, as measured by transcranial Doppler ultrasound (TCD) of the right and left middle cerebral artery and basilar artery. Twenty-five non-institutionalized elderly women (mean age 72 years), with cognitive status > 24, were assessed using TCD before and after transcranial LED therapy. tPBM (627 nm, 70 mW/cm2, 10 J/cm2) was performed at four points of the frontal and parietal region for 30 s each twice a week for 4 weeks. There was a significant increase in the systolic and diastolic velocity of the left middle cerebral artery (25 and 30%, respectively) and the basilar artery (up to 17 and 25%), as well as a decrease in the pulsatility index and resistance index values of the three cerebral arteries analyzed (Salgado et al. 2015).

3.5 PBM for acute stroke

Transcranial PBM delivered to the head, has been investigated as a possible treatment for acute stroke (Lapchak 2010). Animal models such as rats and rabbits, were first used as laboratory models, and these animals had experimental strokes induced by a variety of methods and were then treated with light (usually 810 nm laser) within 24 h of stroke onset (Lampl 2007). In these studies intervention by tLLLT within 24 h had meaningful beneficial effects.

Treatment of acute stroke in human patients was then addressed in a series of three clinical trials called “Neurothera Effectiveness and Safety Trials” (NEST-1 (Lampl et al. 2007), NEST-2 (Huisa et al. 2013), and NEST-3 (Zivin et al. 2014)). The protocol used an 810 nm laser applied to the shaved head (20 separate points in the 10/20 EEG system) within 24 h of patients suffering an ischemic stroke. The first study, NEST-1, enrolled 120 patients between the ages of 40 to 85 years of age and found a significantly improved outcome (p < 0.05 real vs sham, NIH Stroke Severity Scale) 5 days after a single laser treatment had been administered (Lampl et al. 2007). This significantly improved status was still present 90 days post-stroke in 70% of the PBM patients (but only 51% of the sham patients). The second clinical trial, NEST-2, enrolled 660 patients, aged 40 to 90, who were randomly assigned to one of two groups (331 to PBM, 327 to sham) (Zivin et al. 2009). Significant improvements (p < 0.04) were found in the moderate and moderate-severe (but not for the severe) stroke patients. The last clinical trial, NEST-3, was planned for 1000 patients enrolled, but the study was prematurely terminated by the DSMB for futility (an expected lack of statistical significance) (Lapchak and Boitano 2016). Many commentators have asked how tPBM could work so well in the first trial, yet fail in the third trial. Insufficient light penetration, too long an interval between stroke onset and PBM, inappropriate stroke severity measurement scale, use of only one single tPBM treatment, and failure to illuminate different specific areas of the brain for individual patients, have all been suggested as contributory reasons (Hamblin 2016b). It is undoubtedly the case that the failure of NEST-3 has cast a cloud over the whole application of PBMT for TBI as well as for stroke. Many commentators have asked “Why are you testing PBMT for TBI, if it has been shown not to work for stroke?” The failure of the investigators not to take into account the anatomical location of the stroke (and also whether it was deep or superficial) was also likely to have played a role in the failure of NEST-3. It is logical that light should be applied to the same side of the head where the lesion was located, not both sides of the head (Naeser et al. 2012). In my opinion the use of a single application of PBMT also bore some of the responsibility. Although a single application of PBM to the head works very well for experimental animals (mice, rats, rabbits) who have suffered a stroke or a TBI, the same may not apply to humans.

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4. Animal studies of PBM in acute TBI models

4.1 Studies from the Oron laboratory

Oron's group was the first (Oron et al. 2007) to demonstrate that a single exposure of the head of a mouse a few hours after creation of a TBI lesion using a NIR laser (808 nm) could improve neurological performance and reduce the size of the brain lesion. A weight-drop device was used to induce a closed-head TBI in the mice. An 808 nm diode laser with two energy densities calculated at the surface of the brain (1.2-2.4 J/cm2 delivered by 2 minutes of irradiation with 200mW laser power to the scalp) was delivered to the head 4 hours after TBI was induced. Neurobehavioral function was assessed by the neurological severity score (NSS). There was no significant difference between the control and laser-treated group in NSS between the power densities (10 vs 20 mW/cm2), and no significant difference at early time points (24 and 48 hours) post TBI. However, there was a significant improvement (27% lower NSS score) in the PBM group at times between 5 days and 4 weeks. The laser treated group also showed a smaller loss of cortical tissue than the sham group (Oron et al.). In another study (Oron et al. 2012) they varied the pulse parameters (CW, 100Hz, or 600Hz) and tested whether the tPBM was equally effective when delivered at 4, 6, or 8 hours post-TBI. They first established that a calculated dose to the cortical surface of 1.2 J/cm2 of 808nm laser at 200mW applied to the head, was more effective when delivered at 6 hours post TBI than at 8 hours. They then selected an even shorter time post-TBI (4 hours) and compared CW with 100Hz and 600Hz. At 56 days, more mice in the 100Hz group (compared to the CW and 600 Hz groups) had fully recovered. The 600Hz group had lower NSS scores than the CW and 100Hz groups up to 20 days. Magnetic resonance imaging (MRI) analysis demonstrated significantly smaller lesion volumes in PBM-treated mice compared to controls.

4.2 Studies from the Hamblin laboratory

Wu et al. (Wu et al. 2012) first explored the effect of varying the laser wavelengths of PBM had on closed-head TBI in mice. Mice were randomly assigned to a PBM treatment group with a particular wavelength, or to a sham treatment group as a control. Closed-head injury (CHI) was induced via a weight- drop apparatus. To analyze the severity of the TBI, the neurological severity score (NSS) was measured and recorded. The injured mice were then treated with varying wavelengths of laser light (665, 730, 810 or 980 nm) at an energy density of 36 J/cm2 directed onto the scalp at 4 hours post-TBI. The 665 nm and 810 nm laser groups showed significant improvement in NSS when compared to the control group between days 5 to 28. By contrast, the 730 nm and 980 nm laser groups did not show any significant improvement in NSS (Wu et al. 2012) (Figure 3). The tissue chromophore cytochrome c oxidase (CCO) is proposed to be responsible for the underlying photon absorption process that underlies many PBM effects. CCO has absorption bands around 665 nm and 810 nm while it has a low absorption region at the wavelength of 730 nm (Karu et al.). It should be noted that this particular study (Wu et al. 2012) found that the 980 nm did not produce the same positive effects as the 665 nm and 810 nm wavelengths did; nevertheless previous studies did find that the 980 nm wavelength was an active one for PBM (Anders et al. 2014). Wu et al. suggested that these dissimilar results may be due to differences in the energy density, irradiance etc. between the other studies and the Wu study (Wu et al. 2012). In particular a much lower dose of 980 nm might have been effective had it been tested (Wang et al. 2016). Ando et al. (Ando et al. 2011) next used the 810 nm wavelength produced by a Ga-Al-As diode laser delivered at parameters used in the Wu study, and varied the pulse modes of the laser. These modes consisted of either pulsed wave at 10 Hz or at 100 Hz (50% duty cycle) or continuous wave laser. They used a different mouse model of TBI induced with a controlled cortical impact device directly inflicting a lesion on the cortex via an open craniotomy. A single treatment with a power density of 50 mW/m2 and an energy density of 36 J/cm2 (duration of 12 minutes) was given via tLLLT to the closed head in mice at 4 hours post CCI. At 48 hours to 28 days post TBI, all laser treated groups had significant decreases in the measured neurological severity score (NSS) when compared to the controls. Although all laser treated groups had similar NSS improvement rates up to day 7, the PW 10 Hz group began to show even greater improvement beyond this point as seen in Figure 4. At day 28, the forced swim test for depression and anxiety was used and showed a significant decrease in the immobility time for the PW 10 Hz group. In the tail suspension test, which measures depression and anxiety, there was also a significant decrease in the immobility time at day 28, and also at day 1, in the PW 10 Hz group.

Figure 3

Effect of different laser wavelengths of tPBM in closed-head TBI in mice

(A) Sham-treated control versus 665 nm laser. (B) Sham-treated control versus 730 nm laser. (C) Sham-treated control versus 810 nm laser. (D) Sham-treated control versus 980 nm laser. Points are means of 8–12 mice and bars are SD. *P < 0.05; **P < 0.01; ***P < 0.001 (one-way ANOVA). Reprinted with permission from (Wu et al. 2012)

Figure 4

Effects of pulsing in tPBM for CCI-TBI in mice

(A) Time course of neurological severity score (NSS) of mice with TBI receiving either control (no laser-treatment), or 810 nm laser (36 J/cm2 delivered at 50 mW/cm2 with a spot size of 0.78 cm2 in either CW, PW 10 Hz or PW 100 Hz modes. Results are expressed as mean +/- S.E.M ***P < 0.001 vs. the other conditions. (B) Mean areas under the NSS-time curves in the two-dimensional coordinate system over the 28-day study for the 4 groups of mice. Results are means +/- SD (n = 10). Reprinted from (Ando et al. 2011) (open access).

Studies using immunofluorescence staining of sections cut from mouse brains showed that tPBM increased neuroprogenitor cells (incorporating BrdU) in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) at 7 days after the treatment (Xuan et al. 2014). The neurotrophin known as brain derived neurotrophic factor (BDNF) was also increased in the DG and SVZ at 7 days, while the protein marker (synapsin-1) for synaptogenesis and neuroplasticity was increased in the cortex at 28 days but not in the DG, SVZ or in any location at 7 days (Xuan et al. 2015). Learning and memory as measured by the Morris water maze was also improved by tPBM (Xuan et al. 2014).

4.3 Studies from the Wu laboratory

Zhang et al. (Zhang et al. 2014) first showed that secondary brain injury occurred to a worse degree in mice that had been genetically engineered to lack “Immediate Early Response” gene X-1 (IEX-1). When these mice were exposed to a gentle head impact (thought to closely resemble mild TBI in humans) they had a worse NSS than uninjured mice with the same TBI. Exposure of IEX-1 knockout mice to PBM (150 mW/cm2, 4 min, and 36 J/cm2) delivered at 4 hours post injury, restored the NSS to almost baseline levels, suppressed proinflammatory cytokine expression of interleukin (IL)-Iβ and IL-6, but upregulated TNF-α. The original lack of IEX-1 decreased ATP production, but exposing the injured brain to LLLT elevated ATP production back to near normal levels.

Dong et al. (Dong et al. 2015) asked whether the beneficial effects of PBM on TBI in mice could be enhanced by combining PBM with administration of metabolic substrates such as pyruvate and/or lactate. The goal was to even further improve mitochondrial function in the brain. This combinatorial treatment was able to reverse memory and learning deficits in TBI injured mice back to normal levels as well as leaving the hippocampal region completely protected from tissue loss; a stark contrast to control TBI mice that exhibited severe tissue loss from secondary brain injury.

4.4 Studies from the Whalen laboratory

Khuman et al (Khuman et al. 2012) delivered PBM (800nm) either directly to the injured brain tissue (through the craniotomy) or transcranially in mice beginning 60-80 min after CCI TBI. At a dose of 60J/cm2 (500mW/cm2) the mice showed increased performance in the Morris water maze (latency to the hidden platform, p<0.05, and probe trial, p<0.01) compared to non-treated controls. When PBM was delivered via open craniotomy there was reduced microgliosis at 48h (IbA-1+ cells, p<0.05). Little or no effect of tPBM on post-injury cognitive function was observed using lower or higher doses, a 4-h administration time point or 60J/cm2 at 7-days post-TBI.

4.5 Studies from the Whelan laboratory

Quirk et al (Quirk et al. 2012) studied Sprague-Dawley rats who had received a severe CCI TBI and were divided into three groups: real TBI, sham surgery, and anesthetization only. Each group received either real or sham PBM consisting of 670nm LED treatments of 15J/cm2, 50mW/cm2, 5min, given two times per day for 3 days (chemical analysis) or 10 days (behavioral analysis using a TruScan nose-poke device). Significant differences in task entries, repeat entries, and task errors were seen in the TBI rats treated with PBM vs untreated TBI mice, and in sham surgery mice treated with PBM vs untreated sham surgery mice. A statistically significant decrease was found in the pro-apoptotic marker Bax, and increases in the anti-apoptotic marker Bcl-2 and reduced glutathione (GSH) levels in tPBM TBI mice.

4.6 Studies from the Marques laboratory

Moreira et al used a different model of TBI (Moreira et al. 2009). Wistar rats received a craniotomy and a copper probe cooled in liquid nitrogen was applied to the surface of the brain to create a standardized cryogenic injury. They treated the rats with either a 780nm or 660nm laser at one of two different doses (3J/cm2 or 5J/cm2) twice (once immediately after the injury and again 3 hours later). Rats were sacrificed 6h and 24h after the injury. The 780nm laser was better at reducing levels of pro-inflammatory cytokines (TNFα, IL1β, IL6) particularly at early timepoints (Moreira et al. 2009). In a follow-up study using 3 J/cm2 (Moreira et al. 2011) these workers reported on the healing of the injuries in these rats at timepoints 6h, 1, 7 and 14 days after the last irradiation. Cryogenic injury created focal lesions in the cortex characterized by necrosis, edema, hemorrhage and inflammatory infiltrate. The most striking findings were: PBM-treated lesions showed less tissue loss than control lesions at 6h. During the first 24h the amount of viable neurons was significantly higher in the PBM groups. PBM reduced the amount of GFAP (glial fibrillary acidic protein, a marker of astrogliosis) and the numbers of leukocytes and lymphocytes, thus demonstrating its anti-inflammatory effect.

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5. Patients with chronic TBI

The majority of studies of PBM for TBI in laboratory animals have been conducted in the acute setting, while the majority of human studies of PBM for TBI have been conducted in patients who have suffered head injuries at various times in the past (sometimes quite a long time ago).

5.1 Naeser case reports

In 2011 Naeser, Saltmarche et al., published the first report describing two chronic, TBI cases treated with tPBM (Naeser et al. 2011). A 500 mW CW LED source (mixture of 660 nm red and 870 nm NIR LEDs) with a power density of 22.2 mW/cm2 (area of 22.48 cm2), was applied all over the head, for 10 minutes at each placement location (13.3 J/cm2). In the first case study the patient reported that she could concentrate on tasks for a longer period of time (the time able to work at a computer increased from 20 minutes to 3 hours). She had a better ability to remember what she read, decreased sensitivity when receiving haircuts in the spots where PBM was applied, and improved mathematical skills after undergoing PBM. The second patient had statistically significant improvements compared to prior neuropsychological tests after 9 months of treatment. The patient had a 2 standard deviation (SD) increase on tests of inhibition and inhibition accuracy (9th percentile to 63rd percentile on the Stroop test for executive function and a 1 SD increase on the Wechsler Memory scale test for the logical memory test (83rd percentile to 99th percentile) (Naeser et al. 2011).

5.2 Naeser case series

Naeser et al then went on to report a case series containing a further eleven patients (Naeser et al. 2014). This was an open protocol study that examined whether scalp application of red and NIR LED could improve cognition in patients with chronic, mild TBI (mTBI). This study enrolled 11 participants ranging in age from 26 to 62 years (6 males, 5 females) who suffered from persistent cognitive dysfunction after mTBI. The injuries in the participants had been caused by motor vehicle accidents, sports related events and for one participant, an improvised explosive device (IED) blast. tPBM consisted of 18 sessions (Monday, Wednesday, and Friday for 6 weeks) and was started anywhere from 10 months to 8 years post-TBI. A total of 11 LED cluster heads (5.25 cm in diameter, 500 mW, 22.2 mW/cm2, 13 J/cm2) were applied for 10 minutes per set (5 or 6 LED placements per set, Set A and then Set B, in each session). Neuropsychological testing was performed pre-LED application and 1 week, 1 month and 2 months after the final treatment. They found that there was a significant positive linear trend for the Stroop Test for executive function, in trial 3 inhibition (p = 0.004); Stroop, trial 4 inhibition switching (p = 0.003); California Verbal Learning Test (CVLT)-II, total trials 1-5 (p = 0.003); CVLT-II, long delay free recall (p = 0.006). Improved sleep and fewer post-traumatic stress disorder (PTSD) symptoms, if present beforehand, were observed after treatment. Participants and family members also reported better social function and a better ability to perform interpersonal and occupational activities. Although these results were significant, the authors suggested that further placebo-controlled studies would be needed to ensure the reliability of this approach (Naeser et al. 2014).

Naeser has proposed (Naeser et al. 2016; Naeser et al. 2014) that specific scalp placements of the LED cluster heads may affect specific cortical nodes in the intrinsic networks of the brain, such as the default mode network (DMN), the salience network (SN), and the central executive network (CEN). These intrinsic networks are often dysregulated after TBI (Sharp et al. 2014). Naeser proposed that the specific areas of the head to receive light, to target cortical nodes in these networks were as follows:

1. For the DMN, placement of the LED cluster head on the midline of face, centered on the upper forehead and the front hairline, targeted the left and right mesial prefrontal cortex; and on a midline, scalp location half-way between the occipital protuberance and the vertex of the head, targeted the precuneus; and on left and right LED placements superior to the tip of each ear and posterior to each ear, targeted the inferior parietal cortex/angular gyrus areas.

2. For the SN, placement of LED cluster heads on the left and right temple areas, to target the anterior insula (but due to depth of insula, unknown if the photons reached the target); midline of the vertex of the head, to target the left and right presupplementary motor areas; and the LED cluster head placed on the midline of face, centered on the upper forehead and the front hairline, also targeted the left and right dorsal anterior cingulate cortex.

3. For the CEN, left and right scalp LED placements immediately posterior to the front hairline (on a line directly superior from the pupils of the eyes), targeted the dorso-lateral prefrontal cortex areas; and the left and right LED placements superior to the tip of each ear and posterior to each ear, also targeted the posterolateral inferior parietal cortex/angular gyrus areas (also treated as part of the DMN).

 

Further studies from Naeser and colleagues (Naeser et al. 2016) tested an intranasal LED (iLED) device. Two small iLEDs (one red and the other NIR) were clipped into each nostril and used at the same time for 25 min. The parameters were as follows: red, 633nm, 8mW CW, 1 cm2, energy density 12 J/cm2 (25 min); NIR 810nm, 14.2mW, pulsed 10Hz, 1cm2, 21.3J/cm2. The first mTBI participant (24-year old female) who had sustained four sports-related concussions (two during snowboarding and two during field hockey), received iLED PBM three times per week for 6 weeks. Significant improvements were observed in tasks measuring executive function and verbal memory as well as attention and verbal fluency. At 1 week after the 18th iLED treatment, the average total time asleep had increased by 61 min per night and her sleep efficiency (total sleep time divided by total time in bed) had increased by 11%. At 12 weeks after the last iLED treatment, she was able to discontinue all sleep medications that she had previously been using. The second, mTBI participant who received the intranasal only, LED treatment series is a 49 Yr. M (non-Veteran) who sustained mTBI in a MVA, 30 years prior to receiving the intranasal LED treatment series. He showed significant improvement on the Controlled Oral Word Association-FAS Test post- the iLED treatment series, improving by +1.3 SD and +1.5 SD at 1 and 2 months post- the 18th iLED treatment. His sleep data indicated he was already a good sleeper, at entry.

5.3 Bogdanova and Naeser studies

Bogdanova reported (Bogdanova et al. 2014) a case report of two patients (1 female) with moderate TBI (medical records and clinical evaluation) and persistent cognitive dysfunction (as measured by neuropsychological tests of executive function and memory). Patients received 18 sessions of transcranial LED therapy (3×/week for 6 weeks) using the mixed red/NIR cluster described above (Naeser et al. 2011).

Standardized neuropsychological tests for executive function, memory, depression, PTSD and sleep measures (PSQI, actigraphy) were administered to participants pre-(T1), mid-(T2), and one week (T3) post-PBM treatment. Both PBM treated cases (P1 and P2) showed marked improvement in sleep (actigraphy total sleep) 1 week post-LED treatment (T3), as compared to pre-treatment (T1). P1 also improved in executive function, verbal memory, and sleep efficiency; while P2 significantly improved on measures of PTSD (PCL-M) and depression. No adverse events were reported.

5.4 Studies from Henderson and Morries

Henderson and Morries (Henderson and Morries 2015b) used a high-power NIR laser (10-15 W at 810 and 980 nm) and applied it to the head to treat a patient with moderate TBI. The patient received 20 NIR applications over a 2-month period. They carried out anatomical magnetic resonance imaging (MRI) and perfusion single-photon emission computed tomography (SPECT). The patient showed decreased depression, anxiety, headache, and insomnia, whereas cognition and quality of life improved, accompanied by changes in the SPECT imaging.

They next reported (Morries et al. 2015) a series of ten patients with chronic TBI (average time since injury 9.3 years) where each patient received ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm2 equivalent to 14.6 W/cm2 at 810nm; or 9 W/0.89 cm2 equivalent to 10.11 W/cm2 at 980nm). A continuous sweeping motion over the forehead was utilized to minimize skin heating and cover a larger area. Skin temperature increased no more than 3°C. Overall symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. These authors have proposed that high power lasers are preferable for tPBM treatments because the photons can better reach the brain (Henderson and Morries 2015a).

5.5 Case study from Nawashiro

Nawashiro et al (Nawashiro et al. 2012) treated a single patient who had suffered a severe TBI. The patient survived but was left in a persistent vegetative state for 8 months after the accident. He showed no spontaneous movement of limbs and a CT scan of the head 8 months after the accident showed a focal low-density area in the right frontal lobe. The device had 23 individual 850nm LEDs (13mW each; total power 299mW, total area 57cm2). A treatment time of 30 min per session delivered 20.5 J/cm2 over the left and right forehead areas repeated twice daily (6h apart), for 73 days. Five days after beginning the PBM (after 10 treatments), the patient began to spontaneously move his left arm and hand, which had not occurred during the previous 8 months. Single-photon emission computed tomography with N-isopropyl-[123I]p-iodoamphetamine (IMP-SPECT) was performed twice. The IMP-SPECT scans showed a focal increase (20% higher) in cerebral blood flow in the uninjured left anterior frontal lobe 30 min after the last (146th) PBM treatment, compared to before PBM began.

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6. Conclusion and future prospects

As was mentioned above, one of the most important questions to be answered when contemplating clinical treatment of TBI patients with tPBM, is what is the best time to administer the treatment? All the available reports of studies using PBM in laboratory animal models of TBI and stroke, and also in patients treated for stroke, have been in the acute phase where the overall goal of the intervention can be best described as neuroprotection. Not only that but there are several reports (Lapchak et al. 2007; Oron et al. 2012) that PBM for both TBI and stroke is most effective when it is delivered as soon as possible after the actual event (head impact or ischemic stroke). The protocols for the series of NEST clinical trials specified that patients should be treated with PBM within 24 hours of the stroke occurring. By contrast, all the clinical trials of PBM for patients with TBI, that have so far been carried out, have been with chronic TBI, after varying periods of time having elapsed after the original head injury, sometimes as long as 8 years. Although it would be generally supposed that tPBM would be effective when delivered to acute TBI patients, this has not yet been actually tested. If tPBM were to be used for acute TBI patients, then presumably the PBM should be delivered perhaps beginning at 4 to 6 hours post-TBI, for a limited number of times after the injury; perhaps once a day for 7 days?

The dosimetry and optimum delivery apparatus of tPBM is still uncertain. Although there is some consensus that wavelengths in the region of 800-900nm will penetrate the scalp and skull, other workers have used longer NIR wavelengths, 980nm, 1064nm, or 1072nm. Pulsing or CW is another unresolved question. The exact locations on the head that should receive the light are still unknown. Naeser has proposed (Naeser et al. 2016) some interesting considerations regarding the scalp placements of the tLEDS, and their effect on various intrinsic cortical networks of the brain. Targeted LED placements could promote better neuromodulation (activation/deactivation) in specific cortical nodes. It is possible that communication between nodes within one single network, and/or across networks could be improved. Moreover preliminary data indicate that intranasal, red plus near-infrared LEDs can also benefit TBI patients, although the degree to which light incident on the nasal mucosa, and possibly delivered transsphenoidally (Pitzschke et al. 2015) can penetrate directly into the brain, remains to be determined.

An advantage of intranasal and/or transcranial LED PBM therapy is that it can be performed in the home, for long-term use (Naeser et al. 2011). Also, 5 chronic, mild to moderately-severe dementia cases recently showed significant improvement on the Mini-Mental State Examination (p<0.003), and on the Alzheimer's Disease Assessment Scale-Cognitive subscale (p<0.023) after 12 weeks of daily, at-home, intranasal, near-infrared LED PBM treatments (810nm, pulsed at 10 Hz), and once-a-week in-office, tLED treatments applied to the cortical nodes of the Default Mode Network (Saltmarche et al. 2017). Anecdotally, there was also improved sleep, fewer angry outbursts, and less wandering. When all LED treatments were withdrawn after 12 weeks of active LED PBM treatment, there was precipitous decline in cognition and behavior. Thus, at-home, long-term use of iLED plus tLED PBM offers a potential therapy to mitigate the sequelae of Alzheimer's disease and possibly other neurodegenerative disorders, as well as TBI and stroke.

One highly distressing aspect of TBI symptomatology that has not so far been addressed by PBM, is that of post-traumatic epilepsy (PTE). TBI is the most significant cause of symptomatic epilepsy in people from 15 to 24 years of age. The frontal and temporal lobes are the most frequently affected regions, but imaging (MRI) often fails to show the precise cause. During PTE seizures there is an abnormal electrical discharge in the brain, with staring and unresponsiveness, stiffening or shaking of the body, legs, arms or head; strange sounds, tastes, visual images, feelings or smells; inability to speak or understand, etc (Cotter et al. 2017). Epilepsy has traditionally been considered to be a contra-indication for PBMT (Navratil and Kymplova 2002). However the knowledge that has recently been gained concerning the beneficial effects of PBMT on the damaged brain, suggests that this view may need to be critically revisited.

Moreover there is also potential of tPBM to treat a wide range of brain disorders only loosely associated with TBI, including Parkinson's disease (Purushothuman et al. 2013), depression, anxiety, post-traumatic stress disorder, autism spectrum disorder and so on (Hamblin 2016b).

The ongoing and accelerating clinical research efforts in testing PBM for TBI, are expected to lead to the answering of many of these questions in the coming years.

Original Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803455/

Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or “brain caps”. This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.

Keywords: Photobiomodulation, Low level laser (light) therapy, Ischemic stroke, Traumatic brain injury, Alzheimer's disease, Parkinson's disease, Major depression, Cognitive enhancement

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Graphical abstract

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1. Introduction

Photobiomodulation (PBM) as it is known today (the beneficial health benefits of light therapy had been known for some time before), was accidently discovered in 1967, when Endre Mester from Hungary attempted to repeat an experiment recently published by McGuff in Boston, USA [1]. McGuff had used a beam from the recently discovered ruby laser [2], to destroy a cancerous tumor that had been experimentally implanted into a laboratory rat. However (unbeknownst to Mester) the ruby laser that had been built for him, was only a tiny fraction of the power of the laser that had previously been used by McGuff. However, instead of curing the experimental tumors with his low-powered laser, Mester succeeded in stimulating hair regrowth and wound healing in the rats, in the sites where the tumors had been implanted [3], [4]. This discovery led to a series of papers describing what Mester called “laser biostimulation”, and soon became known as “low level laser therapy” (LLLT) [5], [6], [7].

LLLT was initially primarily studied for stimulation of wound healing, and reduction of pain and inflammation in various orthopedic conditions such as tendonitis, neck pain, and carpal tunnel syndrome [8]. The advent of light emitting diodes (LED) led to LLLT being renamed as “low level light therapy”, as it became more accepted that the use of coherent lasers was not absolutely necessary, and a second renaming occurred recently [9] when the term PBM was adopted due to uncertainties in the exact meaning of “low level”.

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2. Mechanisms of action of photobiomodulation

2.1. Mitochondria and cytochrome c oxidase

The most well studied mechanism of action of PBM centers around cytochrome c oxidase (CCO), which is unit four of the mitochondrial respiratory chain, responsible for the final reduction of oxygen to water using the electrons generated from glucose metabolism [10]. The theory is that CCO enzyme activity may be inhibited by nitric oxide (NO) (especially in hypoxic or damaged cells). This inhibitory NO can be dissociated by photons of light that are absorbed by CCO (which contains two heme and two copper centers with different absorption spectra) [11]. These absorption peaks are mainly in the red (600–700 nm) and near-infrared (760–940 nm) spectral regions. When NO is dissociated, the mitochondrial membrane potential is increased, more oxygen is consumed, more glucose is metabolized and more ATP is produced by the mitochondria.

2.2. Reactive oxygen species, nitric oxide, blood flow

It has been shown that there is a brief increase in reactive oxygen species (ROS) produced in the mitochondria when they absorb the photons delivered during PBM. The idea is that this burst of ROS may trigger some mitochondrial signaling pathways leading to cytoprotective, anti-oxidant and anti-apoptotic effects in the cells [12]. The NO that is released by photodissociation acts as a vasodilator as well as a dilator of lymphatic flow. Moreover NO is also a potent signaling molecule and can activate a number of beneficial cellular pathways [13]. Fig. 2 illustrates these mechanisms.

Fig. 2

Tissue specific processes that occur after PBM and benefit a range of brain disorders. BDNF, brain-derived neurotrophic factor; LLLT, low level light therapy; NGF, nerve growth factor; NT-3, neurotrophin 3; PBM, photobiomodulation; SOD, superoxide dismutase. ...

2.3. Light sensitive ion channels and calcium

It is quite clear that there must be some other type of photoacceptor, in addition to CCO, as is clearly demonstrated by the fact that wavelengths substantially longer than the red/NIR wavelengths discussed above, can also produce beneficial effects is some biological scenarios. Wavelengths such as 980 nm [14], [15], 1064 nm laser [16], and 1072 nm LED [17], and even broad band IR light [18] have all been reported to carry out PBM type effects. Although the photoacceptor for these wavelengths has by no means been conclusively identified, the leading hypothesis is that it is primarily water (perhaps nanostructured water) located in heat or light sensitive ion channels. Clear changes in intracellular calcium can be observed, that could be explained by light-mediated opening of calcium ion channels, such as members of the transient receptor potential (TRP) super-family [19]. TRP describes a large family of ion channels typified by TRPV1, recently identified as the biological receptor for capsaicin (the active ingredient in hot chili peppers) [20]. The biological roles of TRP channels are multifarious, but many TRP channels are involved in heat sensing and thermoregulation [21].

2.4. Signaling mediators and activation of transcription factors

Most authors suggest that the beneficial effects of tPBM on the brain can be explained by increases in cerebral blood flow, greater oxygen availability and oxygen consumption, improved ATP production and mitochondrial activity [22], [23], [24]. However there are many reports that a brief exposure to light (especially in the case of experimental animals that have suffered some kind of acute injury or traumatic insult) can have effects lasting days, weeks or even months [25]. This long-lasting effect of light can only be explained by activation of signaling pathways and transcription factors that cause changes in protein expression that last for some considerable time. The effects of PBM on stimulating mitochondrial activity and blood flow is of itself, unlikely to explain long-lasting effects. A recent review listed no less than fourteen different transcription factors and signaling mediators, that have been reported to be activated after light exposure [10].

Fig. 1 illustrates two of the most important molecular photoreceptors or chromophores (cytochrome c oxidase and heat-gated ion channels) inside neuronal cells that absorb photons that penetrate into the brain. The signaling pathways and activation of transcription factors lead to the eventual effects of PBM in the brain.

Fig. 1

Molecular and intracellular mechanisms of transcranial low level laser (light) or photobiomodulation. AP1, activator protein 1; ATP, adenosine triphosphate; Ca2 +, calcium ions; cAMP, cyclic adenosine monophosphate; NF-kB, nuclear factor kappa ...

Fig. 2 illustrates some more tissue specific mechanisms that lead on from the initial photon absorption effects explained in Fig. 1. A wide variety of processes can occur that can benefit a correspondingly wide range of brain disorders. These processes can be divided into short-term stimulation (ATP, blood flow, lymphatic flow, cerebral oxygenation, less edema). Another group of processes center around neuroprotection (upregulation of anti-apoptotic proteins, less excitotoxity, more antioxidants, less inflammation). Finally a group of processes that can be grouped under “help the brain to repair itself” (neurotrophins, neurogenesis and synaptogenesis).

2.5. Biphasic dose response and effect of coherence

The biphasic dose response (otherwise known as hormesis, and reviewed extensively by Calabrese et al. [26]) is a fundamental biological law describing how different biological systems can be activated or stimulated by low doses of any physical insult or chemical substance, no matter how toxic or damaging this insult may be in large doses. The most well studied example of hormesis is that of ionizing radiation, where protective mechanisms are induced by very low exposures, that can not only protect against subsequent large doses of ionizing radiation, but can even have beneficial effects against diseases such as cancer using whole body irradiation [27].

There are many reports of PBM following a biphasic dose response (sometimes called obeying the Arndt-Schulz curve [28], [29]. A low dose of light is beneficial, but raising the dose produces progressively less benefit until eventually a damaging effect can be produced at very high light [30]. It is often said in this context that “more does not mean more”.

Another question that arises in the field of PBM is whether the coherent monochromatic lasers that were used in the original discovery of the effect, and whose use continued for many years, are superior to the rather recent introduction of LEDs, that are non-coherent and have a wider band-spread (generally 30 nm full-width half-maximum). Although there are one or two authors who continue to believe that coherent lasers are superior [31], most commentators feel that other parameters such as wavelength, power density, energy density and total energy are the most important determinants of efficacy [8].

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3. Tissue optics, direct versus systemic effects, light sources

3.1. Light penetration into the brain

Due to the growing interest in PBM of the brain, several tissue optics laboratories have investigated the penetration of light of different wavelengths through the scalp and the skull, and to what depths into the brain this light can penetrate. This is an intriguing question to consider, because at present it is unclear exactly what threshold of power density in mW/cm2 is required in the b5rain to have a biological effect. There clearly must be a minimum value below which the light can be delivered for an infinite time without doing anything, but whether this is in the region of μW/cm2 or mW/cm2 is unknown at present.

Functional near-infrared spectroscopy (fNIRS) using 700–900 nm light has been established as a brain imaging technique that can be compared to functional magnetic resonance imaging (fMRI) [32]. Haeussinger et al. estimated that the mean penetration depth (5% remaining intensity) of NIR light through the scalp and skull was 23:6 + 0:7 mm [33]. Other studies have found comparable results with variations depending on the precise location on the head and wavelength [34], [35].

Jagdeo et al. [36] used human cadaver heads (skull with intact soft tissue) to measure penetration of 830 nm light, and found that penetration depended on the anatomical region of the skull (0.9% at the temporal region, 2.1% at the frontal region, and 11.7% at the occipital region). Red light (633 nm) hardly penetrated at all. Tedord et al. [37] also used human cadaver heads to compare penetration of 660 nm, 808 nm, and 940 nm light. They found that 808 nm light was best and could reach a depth in the brain of 40–50 mm. Lapchak et al. compared the transmission of 810 nm light through the skulls of four different species, and found mouse transmitted 40%, while for rat it was 21%, rabbit it was 11.3 and for human skulls it was only 4.2% [38]. Pitzschke and colleagues compared penetration of 670 nm and 810 nm light into the brain when delivered by a transcranial or a transphenoidal approach, and found that the best combination was 810 nm delivered transphenoidally [39]. In a subsequent study these authors compared the effects of storage and processing (frozen or formalin-fixed) on the tissue optical properties of rabbit heads [40]. Yaroslavsky et al. examined light penetration of different wavelengths through different parts of the brain tissue (white brain matter, gray brain matter, cerebellum, and brainstem tissues, pons, thalamus). Best penetration was found with wavelengths between 1000 and 1100 nm [41].

Henderson and Morries found that between 0.45% and 2.90% of 810 nm or 980 nm light penetrated through 3 cm of scalp, skull and brain tissue in ex vivo lamb heads [42].

3.2. Systemic effects

It is in fact very likely that the beneficial effects of PBM on the brain cannot be entirely explained by penetration of photons through the scalp and skull into the brain itself. There have been some studies that have explicitly addressed this exact issue. In a study of PBM for Parkinson's disease in a mouse model [43]. Mitrofanis and colleagues compared delivering light to the mouse head, and also covered up the head with aluminum foil so that they delivered light to the remainder of the mouse body. They found that there was a highly beneficial effect on neurocognitive behavior with irradiation to the head, but nevertheless there was also a statistically significant (although less pronounced benefit, referred to by these authors as an ‘abscopal effect”) when the head was shielded from light [44]. Moreover Oron and co-workers [45] have shown that delivering NIR light to the mouse tibia (using either surface illumination or a fiber optic) resulted in improvement in a transgenic mouse model of Alzheimer's disease (AD). Light was delivered weekly for 2 months, starting at 4 months of age (progressive stage of AD). They showed improved cognitive capacity and spatial learning, as compared to sham-treated AD mice. They proposed that the mechanism of this effect was to stimulate c-kit-positive mesenchymal stem cells (MSCs) in autologous bone marrow (BM) to enhance the capacity of MSCs to infiltrate the brain, and clear β-amyloid plaques [46]. It should be noted that the calvarial bone marrow of the skull contains substantial numbers of stem cells [47].

3.3. Laser acupuncture

Laser acupuncture is often used as an alternative or as an addition to traditional Chinese acupuncture using needles [48]. Many of the applications of laser acupuncture have been for conditions that affect the brain [49] such as Alzheimer's disease [50] and autism [51] that have all been investigated in animal models. Moreover laser acupuncture has been tested clinically [52].

3.4. Light sources

A wide array of different light sources (lasers and LEDs) have been employed for tPBM. One of the most controversial questions which remains to be conclusively settled, is whether a coherent monochromatic laser is superior to non-coherent LEDs typically having a 30 nm band-pass (full width half maximum). Although wavelengths in the NIR region (800–1100 nm) have been the most often used, red wavelengths have sometimes been used either alone, or in combination with NIR. Power levels have also varied markedly from Class IV lasers with total power outputs in the region of 10 W [53], to lasers with more modest power levels (circa 1 W). LEDs can also have widely varying total power levels depending on the size of the array and the number and power of the individual diodes. Power densities can also vary quite substantially from the Photothera laser [54] and other class IV lasers , which required active cooling (~ 700 mW/cm2) to LEDs in the region of 10–30 mW/cm2.

3.5. Usefulness of animal models when testing tPBM for brain disorders

One question that is always asked in biomedical research, is how closely do the laboratory models of disease (which are usually mice or rats) mimic the human disease for which new treatments are being sought? This is no less critical a question when the areas being studied include brain disorders and neurology. There now exist a plethora of transgenic mouse models of neurological disease [55], [56]. However in the present case, where the proposed treatment is almost completely free of any safety concerns, or any reported adverse side effects, it can be validly questioned as to why the use of laboratory animal models should be encouraged. Animal models undoubtedly have disadvantages such as failure to replicate all the biological pathways found in human disease, difficulty in accurately measuring varied forms of cognitive performance, small size of mice and rats compared to humans, short lifespan affecting the development of age related diseases, and lack of lifestyle factors that adversely affect human diseases. Nevertheless, small animal models are less expensive, and require much less time and effort to obtain results than human clinical trials, so it is likely they will continue to be used to test tPBM for the foreseeable future.

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4. PBM for stroke

4.1. Animal models

Perhaps the most well-investigated application of PBM to the brain, lies in its possible use as a treatment for acute stroke [57]. Animal models such as rats and rabbits, were first used as laboratory models, and these animals had experimental strokes induced by a variety of methods and were then treated with light (usually 810 nm laser) within 24 h of stroke onset [58]. In these studies intervention by tLLLT within 24 h had meaningful beneficial effects. For the rat models, stroke was induced by middle cerebral artery occlusion (MCAO) via an insertion of a filament into the carotid artery or via craniotomy [59], [60]. Stroke induction in the “rabbit small clot embolic model” (RSCEM) was by injection of a preparation of small blood clots (made from blood taken from a second donor rabbit) into a catheter placed in the right internal carotid artery [61]. These studies and the treatments and results are listed in Table 1.

Table 1

Reports of transcranial LLLT used for stroke in animal models.

CW, continuous wave; LLLT, low level light therapy; MCAO, middle cerebral artery occlusion; NOS, nitric oxide synthase; RSCEM, rabbit small clot embolic model; TGFβ1, transforming growth factor β1.

4.2. Clinical trials for acute stroke

Treatment of acute stroke was addressed in a series of three clinical trials called “Neurothera Effectiveness and Safety Trials” (NEST-1 [65], NEST-2 [66], and NEST-3 [67]) using an 810 nm laser applied to the shaved head within 24 h of patients suffering an ischemic stroke. The first study, NEST-1, enrolled 120 patients between the ages of 40 to 85 years of age with a diagnosis of ischemic stroke involving a neurological deficit that could be measured. The purpose of this first clinical trial was to demonstrate the safety and effectiveness of laser therapy for stroke within 24 h [65]. tPBM significantly improved outcome in human stroke patients, when applied at ~ 18 h post-stroke, over the entire surface of the head (20 points in the 10/20 EEG system) regardless of stroke [65]. Only one laser treatment was administered, and 5 days later, there was significantly greater improvement in the Real- but not in the Sham-treated group (p < 0.05, NIH Stroke Severity Scale). This significantly greater improvement was still present at 90 days post-stroke, where 70% of the patients treated with Real-LLLT had a successful outcome, while only 51% of Sham-controls did. The second clinical trial, NEST-2, enrolled 660 patients, aged 40 to 90, who were randomly assigned to one of two groups (331 to LLLT, 327 to sham) [68]. Beneficial results (p < 0.04) were found for the moderate and moderate-severe (but not for the severe) stroke patients, who received the Real laser protocol [68]. These results suggested that the overall severity of the individual stroke should be taken into consideration in future studies, and very severe patients are unlikely to recover with any kind of treatment. The last clinical trial, NEST-3, was planned for 1000 patients enrolled. Patients in this study were not to receive tissue plasminogen activator, but the study was prematurely terminated by the DSMB for futility (an expected lack of statistical significance) [67]. NEST-1 was considered successful, even though as a phase 1 trial, it was not designed to show efficacy. NEST-2 was partially successful when the patients were stratified, to exclude very severe strokes or strokes deep within the brain [66]. There has been considerable discussion in the scientific literature on precisely why the NEST-3 trial failed [69]. Many commentators have wondered how could tPBM work so well in the first trial, in a sub-group in the second trial, and fail in the third trial. Lapchak's opinion is that the much thicker skull of humans compared to that of the other animals discussed above (mouse, rat and rabbit), meant that therapeutically effective amounts of light were unlikely to reach the brain [69]. Moreover the time between the occurrence of a stroke and initiation of the PBMT may be an important factor. There are reports in the literature that neuroprotection must be administered as soon as possible after a stroke [70], [71]. Furthermore, stroke trials in particular should adhere to the RIGOR (rigorous research) guidelines and STAIR (stroke therapy academic industry roundtable) criteria [72]. Other contributory causes to the failure of NEST-3 may have been included the decision to use only one single tPBM treatment, instead of a series of treatments. Moreover, the optimum brain areas to be treated in acute stroke remain to be determined. It is possible that certain areas of the brain that have sustained ischemic damage should be preferentially illuminated and not others.

4.3. Chronic stroke

Somewhat surprisingly, there have not as yet been many trials of PBM for rehabilitation of stroke patients with only the occasional report to date. Naeser reported in an abstract the use of tPBM to treat chronic aphasia in post-stroke patients [73]. Boonswang et al. [74] reported a single patient case in which PBM was used in conjunction with physical therapy to rehabilitate chronic stroke damage. However the findings that PBM can stimulate synaptogenesis in mice with TBI, does suggest that tPBM may have particular benefits in rehabilitation of stroke patients. Norman Doidge, in Toronto, Canada has described the use of PBM as a component of a neuroplasticity approach to rehabilitate chronic stroke patients [75].

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5. PBM for traumatic brain injury (TBI)

5.1. Mouse and rat models

There have been a number of studies looking at the effects of PBM in animal models of TBI. Oron's group was the first [76] to demonstrate that a single exposure of the mouse head to a NIR laser (808 nm) a few hours after creation of a TBI lesion could improve neurological performance and reduce the size of the brain lesion. A weight-drop device was used to induce a closed-head injury in the mice. An 808 nm diode laser with two energy densities (1.2–2.4 J/cm2 over 2 min of irradiation with 10 and 20 mW/cm2) was delivered to the head 4 h after TBI was induced. Neurobehavioral function was assessed by the neurological severity score (NSS). There were no significant difference in NSS between the power densities (10 vs 20 mW/cm2) or significant differentiation between the control and laser treated group at early time points (24 and 48 h) post TBI. However, there was a significant improvement (27% lower NSS score) in the PBM group at times of 5 days to 4 weeks. The laser treated group also showed a smaller loss of cortical tissue than the sham group [76].

Hamblin's laboratory then went on (in a series of papers [76]) to show that 810 nm laser (and 660 nm laser) could benefit experimental TBI both in a closed head weight drop model [77], and also in controlled cortical impact model in mice [25]. Wu et al. [77] explored the effect that varying the laser wavelengths of LLLT had on closed-head TBI in mice. Mice were randomly assigned to LLLT treated group or to sham group as a control. Closed-head injury (CHI) was induced via a weight drop apparatus. To analyze the severity of the TBI, the neurological severity score (NSS) was measured and recorded. The injured mice were then treated with varying wavelengths of laser (665, 730, 810 or 980 nm) at an energy level of 36 J/cm2 at 4 h directed onto the scalp. The 665 nm and 810 nm groups showed significant improvement in NSS when compared to the control group at day 5 to day 28. Results are shown in Fig. 3. Conversely, the 730 and 980 nm groups did not show a significant improvement in NSS and these wavelengths did not produce similar beneficial effects as in the 665 nm and 810 nm LLLT groups [77]. The tissue chromophore cytochrome c oxidase (CCO) is proposed to be responsible for the underlying mechanism that produces the many PBM effects that are the byproduct of LLLT. COO has absorption bands around 665 nm and 810 nm while it has low absorption bands at the wavelength of 730 nm [78]. It should be noted that this particular study found that the 980 nm did not produce the same positive effects as the 665 nm and 810 nm wavelengths did; nevertheless previous studies did find that the 980 nm wavelength was an active one for LLLT. Wu et al. proposed that these dissimilar results may be due to the variance in the energy level, irradiance, etc. between the other studies and this particular study [77].

Fig. 3

tPBM for TBI in a mouse model. Mice received a closed head injury and 4 hours later a single exposure of the head to one of four different lasers (36 J/cm2 delivered at 150 mW/cm2 over 4 min with spot size 1-cm diameter) ...

Ando et al. [25] used the 810 nm wavelength laser parameters from the previous study and varied the pulse modes of the laser in a mouse model of TBI. These modes consisted of either pulsed wave at 10 Hz or at 100 Hz (50% duty cycle) or continuous wave laser. For the mice, TBI was induced with a controlled cortical impact device via open craniotomy. A single treatment with an 810 nm Ga-Al-As diode laser with a power density of 50 mW/m2 and an energy density of 36 J/cm2 was given via tLLLT to the closed head in mice for a duration of 12 min at 4 h post CCI. At 48 h to 28 days post TBI, all laser treated groups had significant decreases in the measured neurological severity score (NSS) when compared to the control (Fig. 4A). Although all laser treated groups had similar NSS improvement rates up to day 7, the PW 10 Hz group began to show greater improvement beyond this point as seen in Fig. 4. At day 28, the forced swim test for depression and anxiety was used and showed a significant decrease in the immobility time for the PW 10 Hz group. In the tail suspension test which measures depression and anxiety, there was also a significant decrease in the immobility time at day 28, and this time also at day 1, in the PW 10 Hz group.

Fig. 4

tPBM for controlled cortical impact TBI in a mouse model. (A) Mice received a single exposure (810 nm laser, 36 J/cm2 delivered at 50 mW/cm2 over 12 min) [121]. (B) Mice received 3 daily exposures starting 4 h post-TBI ...

Studies using immunofluorescence of mouse brains showed that tPBM increased neuroprogenitor cells in the dentate gyrus (DG) and subventricular zone at 7 days after the treatment [79]. The neurotrophin called brain derived neurotrophic factor (BDNF) was also increased in the DG and SVZ at 7 days , while the marker (synapsin-1) for synaptogenesis and neuroplasticity was increased in the cortex at 28 days but not in the DG, SVZ or at 7 days [80] (Fig. 4B). Learning and memory as measured by the Morris water maze was also improved by tPBM [81]. Whalen's laboratory [82] and Whelan's laboratory [83] also successfully demonstrated therapeutic benefits of tPBM for TBI in mice and rats respectively.

Zhang et al. [84] showed that secondary brain injury occurred to a worse degree in mice that had been genetically engineered to lack “Immediate Early Response” gene X-1 (IEX-1) when exposed to a gentle head impact (this injury is thought to closely resemble mild TBI in humans). Exposing IEX-1 knockout mice to LLLT 4 h post injury, suppressed proinflammatory cytokine expression of interleukin (IL)-Iβ and IL-6, but upregulated TNF-α. The lack of IEX-1 decreased ATP production, but exposing the injured brain to LLLT elevated ATP production back to near normal levels.

Dong et al. [85] even further improved the beneficial effects of PBM on TBI in mice, by combining the treatment with metabolic substrates such as pyruvate and/or lactate. The goal was to even further improve mitochondrial function. This combinatorial treatment was able to reverse memory and learning deficits in TBI mice back to normal levels, as well as leaving the hippocampal region completely protected from tissue loss; a stark contrast to that found in control TBI mice that exhibited severe tissue loss from secondary brain injury.

5.2. TBI in humans

Margaret Naeser and collaborators have tested PBM in human subjects who had suffered TBI in the past [86]. Many sufferers from severe or even moderate TBI, have very long lasting and even life-changing sequelae (headaches, cognitive impairment, and difficulty sleeping) that prevent them working or living any kind or normal life. These individuals may have been high achievers before the accident that caused damage to their brain [87]. Initially Naeser published a report [88] describing two cases she treated with PBM applied to the forehead twice a week. A 500 mW continuous wave LED source (mixture of 660 nm red and 830 nm NIR LEDs) with a power density of 22.2 mW/cm2 (area of 22.48 cm2), was applied to the forehead for a typical duration of 10 min (13.3 J/cm2). In the first case study the patient reported that she could concentrate on tasks for a longer period of time (the time able to work at a computer increased from 30 min to 3 h). She had a better ability to remember what she read, decreased sensitivity when receiving haircuts in the spots where LLLT was applied, and improved mathematical skills after undergoing LLLT. The second patient had statistically significant improvements compared to prior neuropsychological tests after 9 months of treatment. The patient had a 2 standard deviation (SD) increase on tests of inhibition and inhibition accuracy (9th percentile to 63rd percentile on the Stroop test for executive function and a 1 SD increase on the Wechsler Memory scale test for the logical memory test (83rd percentile to 99th percentile) [89].

Naeser et al. then went on to report a case series of a further eleven patients [90]. This was an open protocol study that examined whether scalp application of red and near infrared (NIR) light could improve cognition in patients with chronic, mild traumatic brain injury (mTBI). This study had 11 participants ranging in age from 26 to 62 (6 males, 5 females) who suffered from persistent cognitive dysfunction after mTBI. The participants' injuries were caused by motor vehicle accidents, sports related events and for one participant, an improvised explosive device (IED) blast. tLLLT consisted of 18 sessions (Monday, Wednesday, and Friday for 6 weeks) and commenced anywhere from 10 months to 8 years post-TBI. A total of 11 LED clusters (5.25 cm in diameter, 500 mW, 22.2 mW/cm2, 13 J/cm2) were applied for about 10 min per session (5 or 6 LED placements per set, Set A and then Set B, in each session). Neuropsychological testing was performed pre-LED application and 1 week, 1 month and 2 months after the final treatment. Naeser and colleagues found that there was a significant positive linear trend observed for the Stroop Test for executive function, in trial 2 inhibition (p = 0.004); Stroop, trial 4 inhibition switching (p = 0.003); California Verbal Learning Test (CVLT)-II, total trials 1–5 (p = 0.003); CVLT-II, long delay free recall (p = 0.006). Improved sleep and fewer post-traumatic stress disorder (PTSD) symptoms, if present beforehand, were observed after treatment. Participants and family members also reported better social function and a better ability to perform interpersonal and occupational activities. Although these results were significant, further placebo-controlled studies will be needed to ensure the reliability of this these data [90].

Henderson and Morries [91] used a high-power NIR laser (10–15 W at 810 and 980 nm) applied to the head to treat a patient with moderate TBI. The patient received 20 NIR applications over a 2-month period. They carried out anatomical magnetic resonance imaging (MRI) and perfusion single-photon emission computed tomography (SPECT). The patient showed decreased depression, anxiety, headache, and insomnia, whereas cognition and quality of life improved, accompanied by changes in the SPECT imaging.

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6. PBM for Alzheimer's disease (AD)

6.1. Animal models

There was a convincing study [92] carried out in an AβPP transgenic mouse of AD. tPBM (810 nm laser) was administered at different doses 3 times/week for 6 months starting at 3 months of age. The numbers of Aβ plaques were significantly reduced in the brain with administration of tPBM in a dose-dependent fashion. tPBM mitigated the behavioral effects seen with advanced amyloid deposition and reduced the expression of inflammatory markers in the transgenic mice. In addition, TLT showed an increase in ATP levels, mitochondrial function, and c-fos expression suggesting that there was an overall improvement in neurological function.

6.2. Humans

There has been a group of investigators in Northern England who have used a helmet built with 1072 nm LEDs to treat AD, but somewhat surprisingly no peer-reviewed publications have described this approach [93]. However a small pilot study (19 patients) that took the form of a randomized placebo-controlled trial investigated the effect of the Vielight Neuro system (see Fig. 5A) (a combination of tPBM and intranasal PBM) on patients with dementia and mild cognitive impairment [94]. This was a controlled single blind pilot study in humans to investigate the effects of PBM on memory and cognition. 19 participants with impaired memory/cognition were randomized into active and sham treatments over 12 weeks with a 4-week no-treatment follow-up period. They were assessed with MMSE and ADAS-cog scales. The protocol involved in-clinic use of a combined transcranial-intranasal PBM device; and at-home use of an intranasal-only PBM device and participants/ caregivers noted daily experiences in a journal. Active participants with moderate to severe impairment (MMSE scores 5–24) showed significant improvements (5-points MMSE score) after 12 weeks. There was also a significant improvement in ADAS-cog scores (see Fig. 5B). They also reported better sleep, fewer angry outbursts and decreased anxiety and wandering. Declines were noted during the 4-week no-treatment follow-up period. Participants with mild impairment to normal (MMSE scores of 25 to 30) in both the active and sham sub-groups showed improvements. No related adverse events were reported.

Fig. 5

tPBM for Alzheimer's disease. (A) Nineteen patients were randomized to receive real or sham tPBM (810 nm LED, 24.6 J/cm2 at 41 mW/cm2). (B) Significant decline in ADAS-cog (improved cognitive performance) in real but not sham (unpublished ...

An interesting paper from Russia [95] described the use of intravascular PBM to treat 89 patients with AD who received PBM (46 patients) or standard treatment with memantine and rivastigmine (43 patients). The PBM consisted of threading a fiber-optic through a cathéter in the fémoral artery and advancing it to the distal site of the anterior and middle cerebral arteries and delivering 20 mW of red laser for 20–40 min. The PBM group had improvement in cerebral microcirculation leading to permanent (from 1 to 7 years) reduction in dementia and cognitive recovery.

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7. Parkinson's disease

The majority of studies on PBM for Parkinson's disease have been in animal models and have come from the laboratory of John Mitrofanis in Australia [96]. Two basic models of Parkinson's disease were used. The first employed administration of the small molecule (MPTP or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to mice [97]. MPTP was discovered as an impurity in an illegal recreational drug to cause Parkinson's like symptoms (loss of substantia nigra cells) in young people who had taken this drug [98]. Mice were treated with tPBM (670-nm LED, 40 mW/cm2, 3.6 J/cm2) 15 min after each MPTP injection repeated 4 times over 30 h. There were significantly more (35%–45%) dopaminergic cells in the brains of the tPBM treated mice [97]. A subsequent study showed similar results in a chronic mouse model of MPTP-induced Parkinson's disease [99]. They repeated their studies in another mouse model of Parkinson's disease, the tau transgenic mouse strain (K3) that has a progressive degeneration of dopaminergic cells in the substantia nigra pars compacta (SNc) [100]. They went on to test a surgically implanted intracranial fiber designed to deliver either 670 nm LED (0.16 mW) or 670 nm laser (67 mW) into the lateral ventricle of the brain in MPTP-treated mice [101]. Both low power LED and high power laser were effective in preserving SNc cells, but the laser was considered to be unsuitable for long-term use (6 days) due to excessive heat production. As mentioned above, these authors also reported a protective effect of abscopal light exposure (head shielded) in this mouse model [43]. Recently this group has tested their implanted fiber approach in a model of Parkinson's disease in adult Macaque monkeys treated with MPTP [102]. Clinical evaluation of Parkinson's symptoms (posture, general activity, bradykinesia, and facial expression) in the monkeys were improved at low doses of light (24 J or 35 J) compared to high doses (125 J) [103].

The only clinical report of PBM for Parkinson's disease in humans was an abstract presented in 2010 [104]

Original Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066074/

Intro: Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm(2) at 810 nm or 9 W/0.89 cm(2) at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration.

Background: Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm(2) at 810 nm or 9 W/0.89 cm(2) at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration.

Abstract: Abstract Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm(2) at 810 nm or 9 W/0.89 cm(2) at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration.

Original Source: http://www.ncbi.nlm.nih.gov/pubmed/26347062