Transcranial Photobiomodulation For Depression: Near-Infrared Light & Laser Therapy

Photobiomodulation involves the targeted administration of light frequencies to modulate biological function for the treatment of medical conditions and/or to expedite healing in the aftermath of a physical injury.  It was Niels Ryberg Finsen who was among the first to showcase the potential of photobiomodulation when he proved that sunlight rays were capable of killing skin bacteria and stimulating bodily tissues; for this discovery he would win a Nobel Prize in 1903.  Though the early work by Finsen was intriguing, using photobiomodulation never received much attention as possible medical intervention until the late 1900s.

Laser technology wasn’t invented until 1960, and in the proximate years after its discovery, lights from lasers were perceived as possibly dangerous to human bodily tissue.  Preliminary testing of lasers on human tissues revealed unexpected effects such as accelerated hair growth and expedited wound healing.  As human testing continued, researchers realized that with certain parameters, low-level light stimulation was not only safe, but useful as an adjunct therapy for a myriad of medical conditions.

Knowing the usefulness of photobiomodulation therapy, researchers speculated that the technique may be able to favorably modulate brain activity.  Specifically, it was hypothesized that application of light within the near-infrared range (NIR) could penetrate the skull and alter neuronal activity in the outermost portions of the cortex.  It turned out that photobiomodulation was able to alter brain activity, and it seems as though low-level light stimulation may facilitate a therapeutic response for the treatment of major depression.

Transcranial Photobiomodulation for Depression (How It Works…)

Transcranial photobiomodulation, synonymously referred to as laser/light therapy involves the deliberate administration of light to a person’s head with the intention of therapeutically altering neurological function.  The technique has been used to enhance recovery from brain damage such as resulting from neurodegeneration, stroke, and/or traumatic brain injury (TBI).  Interestingly, it is also currently being investigated as a cognitive enhancer (among those with normative brain function), as well as for the treatment of major depressive disorder (MDD).  Below is a brief explanation regarding how transcranial photobiomodulation therapy works.

1. Laser/Light device (often “low level”): A low level laser device is acquired and programmed with the intention of targeting a particular region of the brain. Photobiomodulation devices that fail to emit light in the near-infrared range will be unable to penetrate the skull to alter brain activity, hence the need for near-infrared frequencies. Light in the near-infrared range exhibits a wavelength within the range of 0.75 to 1.4 micrometers or a frequency within the range of 214 to 400 THz (terahertz).  An example of a low-level laser device capable of modifying brain activity with near-infrared light is the NeuroThera.
2. Prefrontal targeting: If the intention is to treat major depression (and/or enhance cognitive function), the prefrontal cortex becomes the primary target for stimulation. During a transcranial photobiomodulation session, the low-level laser device delivers near-infrared light to the forehead which penetrates the skull and modifies activity within the prefrontal cortex. Multiple sites on the forehead (around 7.1 square centimeters each) are generally targeted for administration.
3. Near-infrared light administration: A transcranial photobiomodulation device like the NeuroThera has been shown effective for depression when administered bilaterally across the forehead 4 distinct sites. It seems as though stimulation of each distinct sites should be brief, lasting approximately 2 minutes per site. Keep in mind that the administration parameters may differ depending on the treatment protocol and the condition being treated.  In some cases, light is supplied in a “pulse wave” (or pulsations) rather than a continuous wave.  It has been noted that light can be applied to the entire head (up to 20 distinct sites) during a single session without any adverse effects.
4. Neural changes: The near-infrared light administered to the forehead penetrates the skull and induces neural changes within the prefrontal cortex. Molecules within neurons (in the prefrontal cortex) absorb near-infrared light are part of the mitochondrial respiratory enzyme known as “cytochrome oxidase.” Upon absorption of the light, cytochrome oxidase enzymatic activation increases to upregulate mitochondrial oxidative phosphorylation, ultimately yielding a greater amount of ATP-mediated metabolic energy.  The metabolic energy derived from low-level lasers is similar to that derived from dietary nutrients.  Assuming the optimal dose of near-infrared light is administered, ATP production and blood flow should increase.
5. Recovery: Those administering low-level light for the treatment of depression tend to receive multiple sessions per week. Some research suggests that ideal administration intervals might be approximately 2 times per week. Others may argue that 2 times per week is insufficient to provide symptomatic relief.  Usually there is a minimum of a 24 hour-duration between sessions and all session times are of short length (stimulation only takes ~2 minutes per site).  Without adequate recovery between photobiomodulation sessions, a person may experience deleterious side effects and/or unfavorable long-term effects.  Keep in mind that your brain will need some recovery time from the laser stimulation.
6. Ongoing stimulation: After a person has sufficiently recovered from their previous session, the goal is to maintain any remission in depressive symptoms. This will require determining optimal intervals of photobiomodulation administration for the specific individual. Waiting too long in between sessions and the depression is bound to return.  However, an insufficient amount of time between sessions may cause unwanted side effects and/or worsening of mood.  With repeated stimulation approximately 2 times per week, membrane stability and resistance to depolarization (associated with reduced neuronal excitability) should improve.  Over time, an upregulation in concentrations of cytochrome oxidase occurs in response to ongoing stimulation.  This leads to enhanced neuronal capacity for metabolic energy whereby your brain is functioning more efficiently, possibly keeping depression at bay while simultaneously bolstering cognitive performance.

Transcranial Photobiomodulation for Depression (Mechanism of Action)

The mechanism of action associated with photobiomodulation or low-level light therapy (LLLT) for the treatment of major depression involves the initial activation of cytochrome oxidase.  The activation of the cytochrome oxidase (COX) enzyme isn’t directly associated with mood improvement, however, downstream effects resulting from its activation are.  Activation of cytochrome oxidase facilitates reversal of mitochondrial dysfunction, enhanced prefrontal blood flow, reduced oxidative stress, lower neuroinflammation, and changes in glucose metabolism.  The culmination of the aforestated effects within the prefrontal cortex is thought to generate an antidepressant response.

Cytochrome-C-Oxidase activation:  The chief mechanism by which photobiomodulation functions is through activation of the cytochrome oxidase enzyme.  Near-infrared range (NIR) light (usually between 600 and 1150 nanometers) penetrates the skull and stimulates photon-sensitive molecules within neurons.  The molecules that absorb the near-infrared photons happen to be part of the cytochrome oxidase enzyme, an enzyme implicated in mitochondrial respiration.

After the light is absorbed by these molecules, activation of the cytochrome oxidase enzyme increases.  This leads to a greater amount of metabolic energy production through mitochondrial oxidative phosphorylation (OXPHOS).  Oxidative phosphorylation is a pathway by which mitochondria use enzymes to oxidize nutrients to release energy.  In this case, rather than nutrients being used for energy release, the low-level light is the energy source.

Specifically, the photobiomodulation-induced mitochondrial OXPHOS stimulates a pump of protons (H+’s).  This generates increases in the production of ATP (adenosine triphosphate).  Additionally, the stability of neuronal membranes is thought to increase through activation of ATP-dependent ion pumps in the membrane, ultimately decreasing odds of depolarization (implicated in hypoexcitability of neurons).

As of current doesn’t appear to be significant evidence that underactivation of cytochrome oxidase is associated with depression, however, its activation in the prefrontal cortex with photobiomodulation therapy appears useful for eliciting antidepressant-like effects.  It is likely that the downstream effects of photobiomodulation-induced cytochrome oxidase activity such as modified: blood flow, free radical production, glucose metabolism, nitric oxide, oxygen consumption, and possibly inflammation – each contribute (to varying degrees) for enhancement of mood.

ATP increases: As was already mentioned, the light-induced activation of cytochrome oxidase enzymes triggers increased production of ATP (adenosine triphosphate) through mitochondrial oxidative phosphorylation.  Upregulation of ATP within the prefrontal cortex may be responsible for alleviating symptoms of major depression among sufferers.  When ATP production increases, ATP-dependent membrane ion pumps stabilize membranes and reduce susceptibility to depolarization (implicated in hypoexcitability of neurons, and major depression).

Research by Cao, Li, Wang, et al. (2013) shows ATP concentrations are predictive of depressive behaviors in adult mice.  Deficits in concentrations of ATP are associated with chronic social defeat-based depression.  The researchers discovered that administration of exogenous ATP rapidly alleviated depressive symptoms in the depressed mice.

Though the aforestated study occurred in an animal model, it is reasonable to suspect similar outcomes in humans.  It is likely that certain humans with depression exhibit lower levels of ATP production.  Since ATP is understood to combine with methionine to generate SAM (S-adenosylmethionine) which facilitates production of neurotransmitters, it is reasonable to assume that deficient ATP (and its release from astrocytes) may lead to a host of neurochemical deficits.

Another study by Yamazaki and Fujii (2015) proves that extracellular ATP concentrations modulate plasticity of synapses induced by metabotropic glutamate receptors (mGluRs) in the hippocampus.  Without sufficient extracellular concentrations of ATP, it is reasonable to suspect that synaptic plasticity becomes impaired – possibly contributing to a depressed mood.  Research by Marsden (2013) documented lower synaptic plasticity in subregions of the prefrontal cortex (PFC) among those with depression.

Knowing that photobiomodulation using LLLT is directly increasing ATP in the prefrontal cortex, one might suspect that this normalizes synaptic plasticity for attenuation of depressive symptoms.  Optimal levels of ATP signify that mitochondria are functioning properly without interference.  The roles of ATP in the production of SAM, as well as fostering synaptic plasticity in the prefrontal cortex may partially explain how it might combat depression.

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Oxygenation of neurons: Another possible means by which photobiomodulation with LLLT enhances mood is through increasing oxygen levels in the prefrontal cortex.  It is understood that a subset of depressed individuals exhibit suboptimal concentrations of prefrontal oxygen.  A study by Uemura, Shimada, Makizako, et al. (2014) documented reductions in cerebral oxygenation within the prefrontal cortex of older adults with depression.

More specifically, results of the study found that severity of depressive symptoms was inversely correlated with oxygen levels in the prefrontal cortex; the more prominent the depression, the lower the oxygen (and vice-versa).  Prior work by Schecklmann, Dresler, Beck, et al. (2011) discovered lower prefrontal oxygenation in patients with depression (unipolar and bipolar) during a working memory task – perhaps partially explaining cognitive deficits implicated in depression.  Yet another finding to support the idea that lower prefrontal oxygenation is associated with depression comes from a study by Matsuo, Kato, Fukuda, and Kato (2000).

Their research showed that elderly patients with depression exhibited lower oxyhemoglobin than non-depressed counterparts in a verbal fluency test.  Research in animal models has shown that after low-level light therapy (LLLT), oxygen consumption in the prefrontal cortex significantly increases.  It is known that oxygen is used to form water within mitochondria, catalyzed through cytochrome oxidase.  For this reason, we may expect greater prefrontal oxygenation as a potential mechanism by which depressive symptoms are reduced and/or cognitive function is enhanced following LLLT.

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Blood flow to PFC: Another possible mechanism by which photobiomodulation (LLLT) treats depression is through enhancement of prefrontal blood flow.  It is widely documented that cerebral blood flow abnormalities are commonly implicated in depressive disorders.  Research by Ishizaki, Yamamoto, Takahashi, et al. (2008) discovered cerebral blood flow dysfunction among persons with late-life depression.

Specifically, the team of researchers documented reduced blood flow to regions of the brain such as the anterior ventral and dorsal medial prefrontal cortex.  When these individuals underwent successful treatment with pharmacological antidepressants, cerebral blood flow markedly increased within the left dorsolateral prefrontal cortex, thereby reversing hypofrontality.  More evidence to suggest blood flow abnormalities among those with depression is derived from research by Bench, Frackowiak, and Dolan (1995).

Their research revealed that persons with depression exhibited deficits in blood flow to the left dorsolateral prefrontal cortex compared to non-depressed controls.  Upon recovery from depressive symptoms (regardless of whether spontaneously or using a targeted treatment), regional cerebral blood flow significantly increased in the left dorsolateral prefrontal cortex and the medial prefrontal cortex.  An earlier study by Bench, Friston, Brown, et al. (1993) assessed cerebral blood flow of individuals with major depression using positron emission tomography (PET) neuroimaging.

Their findings revealed an inverse correlation between the severity of depressive symptoms and blood flow to the left dorsolateral prefrontal cortex.  Not only do those who experience significant mood improvement with pharmacological antidepressants exhibit increases in blood flow to the dorsolateral prefrontal cortex, but so do those who respond well to non-pharmacological interventions.  Kosel, Brockmann, Frick, et al. (2011) report that chronic vagus nerve stimulation appears effective for the treatment of refractory depression because it increases cerebral blood flow within the dorsolateral prefrontal cortex.

Based on the aforestated findings that deficient prefrontal blood flow is correlated with severity of depression AND enhancement of prefrontal blood flow is implicated in antidepressant responses, one might suspect that directly increasing prefrontal blood flow may be a mechanism by which depression could be treated.  Though it’s difficult to prove that transcranial photobiomodulation significantly increases cerebral blood flow, there’s strong reason to believe that it releases nitric oxide from cytochrome oxidase and intracellular stores.

Since nitric oxide exerts a vasodilatory effect through cGMP (cyclic guanine monophosphate), if released, blood flow should be expected to increase.  Animal model research suggests that nitric oxide is released as an acute response to photobiomodulation.  Assuming that transcranial photobiomodulation is capable of triggering the release of nitric oxide to enhance cerebral blood flow, this may counteract blood flow deficits to enhance mood.

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Free radical normalization: Transcranial photobiomodulation may improve mood among those with depression by altering concentrations of free radicals within neurons.  It is understood that certain subtypes of depression may be caused and/or exacerbated (in part) by levels of free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS).  The causes of elevated free radicals among persons with depression haven’t been elucidated.

That said, it appears as though individuals with depression exhibit lower levels of antioxidants such as coenzyme Q10 (CoQ10), glutathione (GSH), vitamin E, and zinc.  Furthermore, there are correlations between major depression and genes implicated in oxidation pathways of superoxide dismutase (SOD) and catalase (CAT).  Some experts suspect that free radicals may cause depression by interfering with neuroplasticity and neurogenesis, as well as by inducing neuroinflammation and excessive monoamine reuptake.

Some antidepressants are thought to exert therapeutic effects partially through an antioxidant effect.  Evidence that photobiomodulation alters free radicals in neurons derived from a study by Huang, Nagata, Tedford (2013).  Researchers administered low-level laser (light) therapy (LLLT) to cultured cortical neurons that were exposed to oxidative stressors (e.g. hydrogen peroxide, cobalt chloride, rotenone, etc.) as well as non-stressed cultured neurons.  They discovered that LLLT reduced reactive oxygen species in ROS-stressed neurons.

This effect was thought to rescue the neurons from oxidative stress-induced death.  Administration of LLLT to non-stressed neurons facilitates a transient increase in reactive oxygen species (ROS), but the ROS increase is not associated with neuronal damage.  In fact, the acute increase in ROS [after administration of LLLT to normal neurons] yields an enhanced mitochondrial membrane potential (MMP).  The enhanced mitochondrial membrane potential is neuroprotective and is though to reduce future concentrations of reactive oxygen species.

Low-level light therapy (LLLT) appears to activate an intraneuronal antioxidant response.  Research by Giuliani, Lorenzini, Gallamini (2009) tested the effect of pulsed low-infrared laser light irradiation on cultured neurons exposed to oxidative stress.  Results indicated that the red light irradiation protected neurons from oxidative stress as evidenced by mitochondrial membrane potential.

It was also noted that the LLLT stimulated neurite growth factor (NGF)-induced elongation which was is to protect axons.  At optimal doses, LLLT appears to facilitate antioxidant responses within neurons exposed to oxidative stress, but acutely increases oxidative stress in neurons devoid of oxidative stressors.  The net effect is an enhancement of mitochondrial membrane potential and neuroprotection.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/23281261
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Mitochondrial normalization: Knowing that photobiomodulation is capable of favorably modifying mitochondrial function (using a proven protocol), it is logical to suspect that transcranial photobiomodulation may reverse mitochondrial dysfunction within neurons to alleviate depressive symptoms.  A paper by Bansal and Kuhad (2016) highlights the role of mitochondrial dysfunction in the pathophysiology of major depression.  It mentions that dysfunction of mitochondria within the brain may induce a depressed mood.

Normative mitochondrial function is associated with plasticity of synapses, neuronal resilience, and antioxidant responses.  Mitochondrial function influences ATP production, intracellular calcium (Ca2+) signaling (whereby membrane stability is affected), reactive oxygen species (ROS), and neurotransmitter production.  Due to the important role of mitochondria in a myriad of neural processes, should someone exhibit mitochondrial dysfunction, major depression is one of many logical consequences.

A paper by Tobe (2013) suggests that mitochondrial dysfunction in specific areas of the brain is associated with major depressive disorder (MDD).  Research by Gardner and Boles (2011) also supports the idea that mitochondrial dysfunction may be a root cause of depressive disorders.  Furthermore, it appears as though nearly all antidepressant medications modulate function of mitochondria, possibly a means by which they’re able to reduce depressive symptoms.

For example, a study by Dubovický, Császár, Melicherčíková, et al. (2014) showed that when venlafaxine (Effexor) was administered to cell lines, it favorably affected mitochondrial membrane potential (MMP).  Additionally, agents that directly target mitochondrial function appear to show preliminary efficacy as treatments for many neurological disorders.  Since transcranial photobiomodulation exerts a direct effect upon mitochondria, this should be considered a critical mechanism by which it treats depression.

A study conducted by Gavish, Asher, Becker, and Kleinman (2004) discovered that low level laser therapy (LLLT) enhances mitochondrial membrane potential (MMP).  Mitochondrial membrane potential is necessary for generation of ATP and is often compromised among persons with depression and/or neurological disorders.  Impaired mitochondrial membrane potential deprives neurons of energy and ultimately leads to neuronal death and/or degeneration.

Reversal of impaired mitochondrial membrane potential of prefrontal neurons is associated with antidepressant responses.  Normalization and/or improvements in mitochondrial membrane potential will increase ATP, NADH, protein, ribonucleic acid (RNA), and oxygen consumption.  Moreover, properly functioning mitochondria should lead to greater production of monoamines, lower oxidative stress, and reduced inflammation.

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Neurotrophic factors: Another mechanism by which transcranial photobiomodulation might treat depression is through increasing BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor), and NT-3 (neurotrophin-3) in the prefrontal cortex.  Research by Rosas-Vidal, Do-Monte, Sotres-Bayon, and Quirk (2014) showed that infusions of BDNF into the infralimbic (IL) prefrontal cortex is useful for fear extinction of both new (within 1 day) and old (over 14 days) fear memories.

It is thought that fear extinction could be useful in treating certain types of depression (e.g. stress-induced).  More evidence to support the role of neurotrophic factors in depression comes from Castrén, Võikar, and Rantamäki (2007).  These researchers discuss the fact that major depression leads to decreased brain volume in the hippocampus and prefrontal cortex – as well as reductions in neurotrophic factors that may help counteract volume reductions.

Although most pharmacological treatments for depression affect levels of monoamines (e.g. 5-HT, NE, DA), they also affect prefrontal and hippocampal neurotrophic factors.  Many suspect that antidepressants take so long to work [for certain individuals] because neurotrophic factors don’t increase until between 4 and 8 weeks after starting treatment.  Among those that respond to antidepressants, BDNF levels tend to increase to facilitate neurogenesis, neuronal plasticity, and neuronal maturation.

Not only do neurotrophic factors modulate neuroplasticity, some believe they promote monoamine-containing neuron growth and function, thereby significantly affecting neurochemistry.  Research by Gomes, Dalmarco, and André (2012) showed that low-level laser therapy (LLLT) increased mRNA-mediated expression of BDNF and NGF within 14 days and peaked within 21 days – in an animal model.  Xuan, Agrawal, Huang, et al. (2015) documented the effect of low-level laser therapy among mice models of traumatic brain injury (TBI).

A near-infrared light at 810 nm was applied to the mice models and discovered to significantly upregulate BDNF, which ultimately lead to increased synaptogenesis.  Although a mouse model of TBI was used in this study, it is known that TBI can cause depression and that various cases of TBI share commonalities with cases of major depression.  Researchers suggested that the LLLT-induced upregulation in neurotrophic factors prove useful for many neurological conditions –(one of which could be depression).

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Neuroinflammation reduction: It is also possible that transcranial photobiomodulation reduces symptoms of depression by mitigating neuroinflammation within the prefrontal cortex.  Emerging evidence highlights a strong relationship between concentrations of pro-inflammatory biomarkers in the CNS and major depression.  Whether neuroinflammation is a root cause, partial cause, or consequence of depressive disorders remains unclear, however, minimizing inflammation has proven efficacious as a modality of mood enhancement.

It has been suggested that using anti-inflammatory drugs for depression might uplift mood by reducing systemic inflammation.  Additionally, animal model studies show that administration of pharmacological antidepressants significantly inhibits expression of inflammatory mediators, including cytokines.  These inflammatory mediators such as cytokines send signals that reach the brain and modulate an array of processes, including synthesis, release, and uptake of monoamines – leading to depression.

There are many other mechanisms by which inflammatory mediators exert a deleterious effect upon neural processes.  Most experts agree that neuroinflammation increases vulnerability to major depression, as well as that attenuation of the inflammatory response may be capable of enhancing mood.  A considerable amount of data is mixed regarding whether photobiomodulation increases or decreases inflammation.

Following a single session of LLLT, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) increases, indicative of a pro-inflammatory response.  This would lead many to suspect that transcranial photobiomodulation induces inflammation, rather than reduces it.  That said, after longer-term administration of LLLT to dendritic cells, concentrations of NF-κB and corresponding cytokines are significantly reduced.

This indicates that regular LLLT is likely to decrease neuroinflammation.  Hypothetical reasons as to why neuroinflammation may be reduces in the prefrontal cortex after LLLT include – upregulation of: superoxide dismutase, glutathione peroxidase, heat shock protein, and/or eicosanoid expression – as well as downregulation of: prostaglandin-2 (PGE2) and cyclooxygenase-2 (COX-2) (Sakurai et al., 2000).  A study by Gonçalves, Souza, and Lieberknecht (2016) applied LLLT to a mouse model of MS (multiple sclerosis) and conducted a histological analysis, discovering that LLLT reduced neuroinflammation by decreasing inflammatory cells in the CNS (e.g. lymphocytes); this effect was also associated with a substantial reduction in nitric oxide levels.

Other work by Boschi, Leite, Saciura, et al. found that low-level laser therapy at 660 nm decreased inflammatory biomarkers in a dose-dependent manner such as: NO, IL-6, MCP-1, IL-10, and TNF-alpha.  Though it’s still somewhat controversial as to whether reduced inflammation is a mechanism by which transcranial photobiomodulation improves mood, the possibility shouldn’t be dismissed.

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Note: At this juncture, it’s difficult to pinpoint one specific mechanism by which transcranial photobiomodulation improves mood.  It is likely that a combination of the aforestated mechanisms facilitate mood enhancement.  The increased ATP generation, enhancement of mitochondrial membrane potential (MMP), increased oxygenation and/or blood flow (to the dorsolateral PFC), generation of neurotrophic factors, plus reduced neuroinflammation may play the biggest roles in facilitation of LLLT’s antidepressant response.

That said, it is reasonable to suspect that effective mechanisms by which LLLT treats depression may be subject to individual variation based on variation in depressive subtype.  For example, an individual with severe mitochondrial dysfunction may benefit most from LLLT-induced normalization of prefrontal mitochondria.  Another individual may derive greater benefit from LLLT-induced reduction in neuroinflammation and/or increases in neurotrophic factors.

In addition to the mechanisms discussed in this article explaining how LLLT might treat depression, several others warrant consideration including: modulation of nitric oxide (NO), modification of gene expression, and alteration of opioidergic transmission.  Specifically, individuals with depression often exhibit nitric oxide abnormalities, suboptimal gene expression, and opioidergic dysfunction.  Normalization of nitric oxide levels and opioidergic transmission, plus favorably altering gene expression could prove useful in managing depression.

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Benefits of Transcranial Photobiomodulation for Depression (Possibilities)

Included below is a list of hypothetical benefits to be attained from using transcranial photobiomodulation as a treatment for depression.  Arguably the most notable benefit associated with using transcranial photobiomodulation to treat depression is its safety and tolerability – the technique doesn’t appear to provoke adverse reactions nor unwanted side effects.  Other benefits attributed to transcranial photobiomodulation as an intervention for depression include: its cost-effectiveness, intermittent administration, and savings on medical expenses as a result of its non-pharmacological status (no doctor visits nor pharmaceutical prescriptions are necessary).

• Adjunctive option: Although transcranial photobiomodulation hasn’t been tested in a trial as a co-treatment to pharmaceutical medications for the treatment of depression, it may turn out to be an effective adjunct. It’s possible that transcranial photobiomodulation may act synergistically with pharmaceutical antidepressants to potentiate therapeutic effects.  It is also possible that transcranial photobiomodulation may attenuate various unwanted side effects resulting from pharmaceutical antidepressants such as: brain fog, cognitive deficits, and/or fatigue – making it a favorable complementary intervention for some.
• Comorbidities: A significant percentage of individuals with major depression are diagnosed comorbid neuropsychiatric conditions and/or abnormalities such as: ADHD, anxiety disorders, cognitive impairment, dementia, PTSD, schizophrenia, traumatic brain injury, etc. Preliminary evidence suggests that transcranial photobiomodulation is capable of simultaneously treating symptoms of depression plus neuropsychiatric comorbidities.  It does this by reversing mitochondrial dysfunction, a biomarker implicated in nearly every neuropsychiatric condition.  Not only might transcranial photobiomodulation curb symptoms of comorbid neuropsychiatric conditions, but the same laser may improve general medical conditions such as: chronic pain, hair loss, inflammation, joint aches, et al.
• Cost-effectiveness: It is unknown as to whether a medical-grade near-infrared laser is necessary to reap substantial reduction in depressive symptoms from transcranial photobiomodulation. Some speculate that transcranial photobiomodulation can be administered with a cheap near-infrared LED purchased online for under $50.  Assuming the low-cost near-infrared LED delivers a therapeutic antidepressant effect analogous to costly laser devices, it may be one of the most cost-effective treatments on the market.  People can re-use the same near-infrared LED without paying for doctor visits and/or prescription refills (each of which cost more than the purchase of a cheap near-infrared LED).  Moreover, even if an expensive device ~$1,500 was required to attain an antidepressant effect, it may still be a more cost-effective antidepressant in the long-run compared 1-year of psychiatrist appointments, cognitive-behavioral therapy (CBT), and/or prescriptions.
• Depressive subtypes: Some theorize that high-power transcranial photobiomodulation may treat certain cases of depression that are unresponsive to pharmaceutical antidepressants. For example, individuals who experience depression as a result of a brain injury typically derive only modest benefit from pharmacological interventions.  It is thought that transcranial photobiomodulation generates a signaling cascade in the brain that upregulates growth factors to promote neurogenesis, synaptogenesis, neuroplasticity – each of which contributes to neuroregeneration and corresponding mood improvement.  Even among some depressed individuals devoid of brain injuries, it is possible that the mechanism of action associated with transcranial photobiomodulation (COX activation, increased ATP, etc.) is a better fit for their neurophysiology.
• Enhances extinction memory: Though not all cases of depression are caused by fear-based memories (e.g. traumatic experiences), it is evident that some are. If a stressor and/or fear is a root cause of your depression, transcranial photobiomodulation may be extremely useful for extinction of fear memories.  It is understood that the medial prefrontal cortex and amygdala are partners in the “fear circuit” of the brain.  Stimulation of the medial prefrontal cortex with transcranial photobiomodulation appears to eliminate fearful memories in animal models – and may do something similar in humans, possibly proving highly useful for certain cases of depression.
• Efficacy: Though the evidence isn’t strong, nearly every published study testing the efficacy of transcranial photobiomodulation as an intervention for depression and/or mood enhancement reported it as being effective. It should be noted that the strongest evidence supporting its ability to enhanced mood is derived from a few randomized controlled trials in which it was significantly more effective than a sham (placebo) control.  While more research needs to be conducted to substantiate preliminary efficacy of transcranial photobiomodulation for depression, it’s possible that various protocols (e.g. twice-per-week stimulation of the prefrontal cortex, 810 nm light, 2-5 minutes per site, etc.) are highly-effective treatments.  It may turn out that transcranial photobiomodulation is equally as effective (or possibly more effective) than antidepressant medications.
• Fast onset of action: Some research suggests that transcranial photobiomodulation yields a noticeable antidepressant effect within just a few days of administration. Other research indicates that the technique tends to improve mood within 1 to 3 weeks.  Even if the antidepressant effect attained from transcranial photobiomodulation is not immediate, it may still be faster than the effect resulting from medications (most of which require 4 to 8 weeks to fully “kick in.”).  Since individuals with severe depression need symptomatic relief as soon as possible, transcranial photobiomodulation may be preferred over conventional pharmacology for its ability to deliver a quick antidepressant effect.
• Intermittent treatment: Another advantage of transcranial photobiomodulation over medications is that it doesn’t require daily administration. Medications necessitate daily administration to maintain an antidepressant effect.  If a person skips a day or two of his/her antidepressant medication, he/she may experience debilitating withdrawal symptoms such as: brain zaps, dizziness, headache, mood swings, etc.  Transcranial photobiomodulation only needs to be administered 1-3 times per week for therapeutic benefit – making it more convenient than taking a pill daily for life.
• Minimal side effects: There don’t appear to be any significant unwanted side effects associated with administration of transcranial photobiomodulation for the treatment of depression. While some individuals may experience a strange sensation as a result of the near-infrared stimulation to the prefrontal cortex, most do not report lingering side effects nor adverse events.  Overall the treatment is extremely well-tolerated.  When its side effects are compared to pharmacological antidepressant side effects such as: cognitive dysfunction, sexual dysfunction, and weight gain – transcranial photobiomodulation seems favorable.
• Non-invasive: No surgery is required to administer transcranial photobiomodulation, the light is simply placed upon the forehead. This differs from vagus nerve stimulation and/or deep brain stimulation that may require surgery.  In other words, you won’t need to undergo brain surgery to reap some noticeable mood-related benefits from transcranial photobiomodulation.
• Non-pharmacological: Some individuals refuse to pursue pharmacological antidepressant treatment because they don’t want to visit a doctor, pay for medication, manage side effects, and/or deal with long-term effects. The fact that transcranial photobiomodulation is non-pharmacological may appeal to a subset of individuals with depression that refuse medication (for various reasons).  If effective, transcranial photobiomodulation may serve as an alternative intervention for mood improvement in populations that would’ve otherwise continued to live with untreated depression.
• Safety: While there may be some risks associated with using transcranial photobiomodulation for the treatment of depression, the current literature suggests that its relatively safe. No adverse reactions nor severe side effects have been reported among recipients of transcranial laser stimulation.  Most speculate that it doesn’t cause interaction effects with pharmaceutical medications and no reports suggest that it’s contraindicated with medical conditions.  Assuming a tested protocol is followed, transcranial photobiomodulation seems to be safe.
• Short stimulation time: For the laser stimulation to treat depression and other neuropsychiatric conditions, it seems as though very little stimulation is needed to deliver its effect. Excessive stimulation and individuals may experience unwanted side effects and/or no mood improvement.  Most studies administer near-infrared light for a total duration of 2 to 5 minutes.  Unlike other forms of neurostimulation (e.g. transcranial magnetic stimulation) that may require hours to deliver an effect, just a few minutes (per site) are needed with transcranial photobiomodulation.
• Unique mechanism of action: The mechanism of action by which transcranial photobiomodulation is thought to alleviate symptoms of depression differs from that of conventional pharmacological treatments. Unlike pharmacological interventions, transcranial photobiomodulation enhances mitochondrial membrane potential and production of ATP.  It may also increase blood flow/oxygenation in the prefrontal cortex, reduce neuroinflammation, upregulate neurotrophic factors, and decrease reactive oxygen species.  This mechanism of action may be favorable for certain cases of refractory depression that don’t respond to pharmacological treatments.
• Zero withdrawal: A serious problem with antidepressant medications (e.g. SSRIs, SNRIs, TCAs, MAOIs, etc.) is that if a person wants to discontinue treatment, he/she will face an onslaught of severe withdrawal symptoms. In extreme cases, individuals even report experiencing post acute withdrawal syndrome (PAWS) following discontinuation of antidepressant medication after a long-term.  There don’t appear to be any withdrawal symptoms that occur following cessation of transcranial photobiomodulation.

Drawbacks of Transcranial Photobiomodulation for Depression (Possibilities)

While it seems as though transcranial photobiomodulation may be advantageous over many existing antidepressant therapies, there are some drawbacks associated with its usage.  The most notable drawback is that the technique does not have strong evidence to support its antidepressant efficacy.  It may turn out that the technique is completely ineffective and that those who use it with the intent of enhancing mood are wasting their time and money.  Furthermore, there are many unknowns associated with the treatment including: long-term effects, optimal administration parameters, and possibly a slow onset of action.

• Administration details: At this point the optimal protocols and parameters for administration of transcranial photobiomodulation remain unclear. In other words, the optimal wavelength of near-infrared light, duration of stimulation, sites of stimulation, and regularity of stimulation haven’t been determined for the treatment of depression.  Though the technique may be effective when administered properly, a subset of individuals may purchase near-infrared LED devices and attempt to self-administer the stimulation.  Self-administration of transcranial photobiomodulation increases likelihood of improper administration, potentially leading to zero antidepressant effect or adverse reactions.
• Cost: If effective, transcranial photobiomodulation may be a money-saving alternative to ongoing appointments with a psychiatrist and/or medications. That said, it’s unclear as to whether standard low-cost LED near-infrared lights are effective for administration of therapy (e.g. those under $50).  It’s possible that the only effective laser devices effective for the treatment of depression cost hundreds if not thousands of dollars to own.  Some individuals may prefer to take generic antidepressant prescriptions over forking over upwards of $1,000 for a special transcranial near-infrared laser device.  The greater the power and precision of a device, the more expensive it is likely to be.
• Ineffectiveness: Strong evidence from large-scale RCTs is lacking to support the idea that transcranial photobiomodulation is able to treat major depression. For this reason, it is impossible to conclude that the technique is an effective intervention.  At this point, its efficacy should be considered questionable.  If a person were to blindly assume that NIR transcranial photobiomodulation was able to treat depression, he/she may administer the therapy and fail to derive any mood improvement – possibly prolonging his/her misery.  Since science-based interventions exist for depression, those should be tested first because the evidence suggests that they are more likely than random chance to effectively attenuate depressive symptoms.  Moreover, even if transcranial photobiomodulation were effective for a majority of individuals with depression, it’s not guaranteed to work for everyone.
• Limited depth: Although transcranial photobiomodulation is capable of modulating neuronal and mitochondrial activity within the brain, its depth of cortical penetration is limited. In most cases, the depth of cortical penetration is likely within the range of millimeters to 1 cm – meaning only the outermost neurons are affected.  With higher-energy near-infrared light administered in pulse wave format (rather than continuous wave format), light may penetrate brain tissue up to 3 cm which is a bit deeper, but still leaves a lot of potentially dysfunctional neurons unaffected by the therapy.  Though it is possible that transcranial photobiomodulation technology will improve in forthcoming years to affect deeper regions of the brain, it’s reasonable to suspect that its limited depth of penetration may explain its ineffectiveness as an antidepressant [at least in a subset of users].  For example, if an etiological underpinning of an individual’s depression is hippocampal dysregulation, correcting hippocampal function may be impossible with transcranial photobiomodulation due to lack of penetration.
• Side effects: When near-infrared light is administered for brief durations at a low level, side effects don’t appear to occur. A myriad of transcranial photobiomodulation protocols have been tested in humans (in neurotypical/euthymic individuals as well as among those with neuropsychiatric conditions), yet no serious side effects or adverse reactions have been documented.  Still, many parameters/protocols haven’t been tested that could prove dangerous, especially over a long-term.  It is possible that administration of transcranial photobiomodulation with a suboptimal protocol may lead to unwanted reactions such as: brain fog, cognitive impairment, dizziness, fatigue, etc.  Some have also hypothesized that transcranial photobiomodulation may increase likelihood of tumor growth based on its ability to upregulate endogenous growth factors.
• Slow onset of action: The onset of action associated with transcranial photobiomodulation may be subject to differences based on the recipient as well as the condition being treated. Some studies suggest that a person’s mood may improve within just 24-48 hours of receiving stimulation.  That said, other studies show that the mood enhancing benefits do not appear until around 6 to 8 weeks after stimulation.  Assuming it takes between 6 and 8 weeks to attain the antidepressant effect from transcranial photobiomodulation for depression, this may be too long of a duration to wait for mood to improve, especially among those who feel suicidal.
• Unknowns: There remain numerous unknowns in the research of transcranial photobiomodulation for the treatment of depression (and other neurological conditions). Examples of unknowns associated with treatment include: optimal parameters (e.g. low-energy vs. high energy light, pulsed vs. continuous wave light, wavelength, sites of administration, duration of administration, etc.) and optimal protocol (e.g. administration 2 times per week, 48-hour intervals apart, etc.) for reducing depression.  Since no specific transcranial photobiomodulation parameters nor protocols are well-substantiated by research as an intervention for depression, those attempting to treat their depression with this technique could risk using parameters/protocols that are not only useless, but dangerous.  Furthermore, the long-term effects resulting from regular transcranial photobiomodulation are unknown, but may be unwanted.

Transcranial Photobiomodulation (e.g. LLLT) for Depression (Review of Evidence)

Included below are brief synopses of studies that documented the effect of transcranial photobiomodulation on mood and/or as treatment for major depression.  Realize that while most studies report transcranial photobiomodulation as being an effective mood enhancer and/or antidepressant, these studies are limited by small sample sizes and/or problematic designs (non-randomized, uncontrolled, non-blinded).  Also realize that parameters associated with stimulation may differ among studies, making it difficult to know whether they are of equal utility.

2016: Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis.

Cassano, Petrie, Hamblin, et al. (2016) conducted a literature review to determine the usefulness of transcranial photobiomodulation (near-infrared and red radiation) as an intervention for major depression.  Reason for conducting the review was due to the fact that photobiomodulation is an extremely low cost therapy and mounting evidence suggests that is capable of reducing depressive symptoms.  To conduct their review, researchers scoured scientific databases (e.g. PubMed) for all studies evaluating photobiomodulation as a treatment for depression.

Researchers also searched for studies analyzing the relationship of photobiomodulation and biological processes that may be disordered in cases of depression such as: inflammation, metabolism, neurogenesis, and oxidative stress.  Given the available evidence, researchers stated that there’s preliminary evidence to suggest photobiomodulation is an effective treatment for major depression, anxiety disorders, suicidal ideation, and TBI.  It was concluded that photobiomodulation is a low-risk, well-tolerated treatment for major depressive disorder (MDD), but its efficacy warrants substantiation in large-scale RCTs.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/26989758

2016: Transcranial Laser Stimulation as Neuroenhancement for Attention Bias Modification in Adults with Elevated Depression Symptoms.

It is well-established that there’s a relationship between major depressive disorder (MDD) and cognitive dysfunction.  Individuals with severe depression often report cognitive impairment, and those with severe cognitive impairment often report feeling depressed.  Knowing this, most have speculated that neurobiological underpinnings of each condition overlaps with that of the other – at least for those with comorbidities.

Many cognitive interventions employed for the management of depression involve retraining a person’s thoughts.  One cognitive intervention devised to reduce depressive symptoms by is referred to as ABM (attention bias modification), however, the antidepressant efficacy of ABM isn’t well-established.  For this reason, researchers Disner, Beevers, and Gonzalez-Lima (2016) organized a study testing the effect of ABM plus adjunct transcranial LLLT for the treatment of depression.

A total of 51 adults with severe depression were recruited to participate in the randomized, sham-controlled study.  Each of the participants were assigned to receive ABM before and after transcranial LLLT, however, the LLLT was randomized in that participants received either: right forehead, left forehead, or sham stimulation.  The transcranial LLLT was repeated 2 days after the initial stimulation, and all participants underwent depressive assessments at 1 and 2 weeks.

Results suggested that symptoms of depression improved the most among individuals that received ABM plus transcranial LLLT to the right forehead – compared to those receiving left-forehead and sham-LLLT.  Researchers concluded that the therapeutic potential of ABM for the treatment of depression is amplified with right prefrontal LLLT.  While this study is relatively small scale, it highlights the therapeutic effect of adjunct right prefrontal-targeted LLLT with ABM for the treatment of depression.

Based on the fact that all individuals received ABM, yet only the group receiving adjunct LLLT to the right prefrontal cortex responded, it may be that targeted (right prefrontal) LLLT facilitated the entire antidepressant effect without any contribution from ABM.  Since a “standalone LLLT” wasn’t compared to “LLLT plus ABM,” we cannot assume LLLT delivered the entire antidepressant effect.

Perhaps a future study should investigate the efficacy of right prefrontal LLLT devoid of ABM therapy.  Clearly a large-scale randomized controlled trial is needed to confirm the preliminary efficacy of right prefrontal LLLT as an intervention for adults with major depressive disorder.  The findings of this study showcase that LLLT may be capable of enhancing mood.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/27267860

2015: Near-Infrared Transcranial Radiation for Major Depressive Disorder: Proof of Concept Study

Cassano, Cusin, Mischoulon, et al. (2015) conducted a proof-of-concept trial investigating the effect of near-infrared transcranial radiation among individuals with major depression.  Researchers noted that evidence to support the usefulness of near-infrared transcranial radiation as an antidepressant was limited.  For this reason, they organized a small-scale study involving 4 adult patients diagnosed with major depressive disorder (3 men, 1 woman), testing the therapeutic efficacy and tolerability of near-infrared radiation.

A crossover, double-blind, randomized design was implemented comparing 6 sessions of near-infrared radiation (NIR) to a sham.  All 4 patients received irradiation at 700 mW/cm2 with a fluence of 84 J/cm2, delivering a total NIR energy of 2.40 kJ per session.  After receiving near-infrared radiation (NIR), symptoms of depression significantly decreased – as evidenced by reductions on the Hamilton Depression Rating Scale (HAM-D) from ~19.8 (pre-treatment) to ~13 (post-treatment).

There were zero issues with tolerability and no adverse reactions to near-infrared radiation (NIR).  It was noted that each of the participants had experienced a depressive episode lasting at least 18 months and none had taken medications nor received clinically efficacious forms of psychotherapy (e.g. CBT, IPT, etc.).  Moreover, 2 of the 4 participants attained complete symptomatic remission at Week 6 and Week 7, respectively.

The symptomatic remission (occurring between weeks 6 and 7) was consistent with responses to other antidepressants.  All 4 participants received the near-infrared radiation (NIR) within the first 3 weeks of the trial, but mood enhancement wasn’t noted until several weeks later, indicative of a carryover effect.  Previous studies suggested that NIR administration yields faster acting psychological effects within just 2 weeks of administration.

Researchers theorized that delayed onset of NIR efficacy may have been related to the higher irradiation (700 mW/cm2) and fluence (84 J/cm2).  They also noted that 2 weekly sessions of NIR at 4 distinct sites for 3 weeks may be a suboptimal protocol.  It is also known that high doses of NIR (high power and energy) may be less effective than moderate doses; the dose-response curve for NIR is thought to be highly sensitive.

Unlike a previous study by Schiffer et al. in which incoherent NIR was administered at 810 nanometers, this pilot administered coherent NIR from a 5W laser.  It is thought that coherent LLLT is capable of penetrating deeper beneath the cortex.  Though this study provides evidence supporting the efficacy of transcranial photobiomodulation (LLLT) for the treatment of severe major depression, results need to be confirmed with larger-scale trials.

Not only did this trial utilize an extremely small sample (of just 4 participants), but there was likely a carryover effect.  Nonetheless, researchers note some upsides associated with using LLLT for depression including: non-invasive nature, minimal side effects, and short-term of administration.  Moreover, it was mentioned that this therapy could be advantageous over first-line pharmacological antidepressant interventions via direct targeting of mitochondria.

• Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556873/

2015: Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy

Morries, Cassano, and Henderson (2015) highlight the fact that traumatic brain injury (TBI) is a serious neurological complication that substantially impairs a person’s ability to function in society.  The three researchers discussed interventions for the treatment of chronic TBI including medications, supplements, cognitive therapy, and hyperbaric oxygen therapy – documenting that most provide modest therapeutic benefit after an extended term of treatment.  Despite the modest effectiveness of many interventions, new treatments for TBI are being tested.

One of the newer interventions for TBI involves administration of near-infrared (NIR) light.  When delivered through the cortex, near-infrared light has proven useful for restoration of neurological function following a stroke or TBI in animal models and a subset of humans.  That said, the optimal parameters of NIR administration are unclear due to the fact that many unique parameters have been tested in research.

In their review, authors outline a case series in which high-level NIR is administered with a Class IV laser to treat TBI.  The high-level NIR laser therapy (10 to 15 W between 810 nm and 980 nm) was administered to 10 individuals with long-term TBI and given 10 treatments over a 2-month duration.  TBI-related measures of neurological function before and after the high-power NIR laser therapy were documented.

Measures were documented based on scores from depression rating scales and a patient diary crafted specifically for the study.  Results of the study indicated that measures of anxiety, cognitive function, headache, irritability, mood, and sleep disturbance – each improved following the high-power NIR.  Authors also reflected upon evidence suggesting that pulsing NIR at 10 Hz appears more useful than continuous-wave or pulsed NIR at 100 Hz for the treatment of TBI.

Furthermore, low-level NIR lasers appear significantly less effective as a treatment for TBI than high-level NIR lasers.  Another trial mentioned by authors tested near-infrared laser therapy (800-810 nm) on mouse models of moderate TBI and noted that it markedly enhanced cognitive performance plus attenuated depressive and anxious behaviors.  Though the precise mechanism of near-infrared laser therapy for the treatment of TBI isn’t known, preliminary evidence suggests it provides benefit.

Authors of the review emphasized the fact that benefits of high-level laser therapy for TBI aren’t always immediate.  It often takes between 1 to 4 weeks for therapeutic responses to emerge, likely stemming from an initial signaling cascade that signals neuroregeneration.  Another study mentioned in this review involved 7 persons with moderate depression (based on BDI scores) who underwent high-power NIR laser therapy.

A total of 4 out of the 7 individuals experienced at least a 50% reduction in depressive symptoms following the treatment.  In summary, it seems as though high-powered, pulsed, coherent NIR light is capable of penetrating the skull and repairing injury within the brain.  The injury repair for those with TBI tends to substantially combat neuropsychiatric symptoms of depression, anxiety, and PTSD.

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

2013: Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans.

Barrett and Gonzalez-Lima (2013) were first to conduct a controlled study showcasing the efficacy of transcranial laser therapy for enhancement of cognitive and emotional function in humans.  Researchers noted that photobiomodulation utilizing light within the red to near-infrared range is capable of modulating activation of neurons in animal models and cell cultures through photon receptors in cytochrome oxidase.  For their study, researchers recruited 40 healthy individuals to test the effect of low-level laser stimulation on cognitive performance (attention and memory) and emotion.

The 40 participants were divided into 2 groups of 20 and assigned at random to receive either: prefrontal LLLT or a sham-LLLT.  Stimulation with LLLT was delivered to the forehead region with the laser diode CG-5000.  Results from the study indicated that individuals receiving prefrontal LLLT stimulation exhibited substantial improvement in reaction time [as evidenced by psychomotor vigilance task performance] – compared to those receiving the sham-LLLT.

Participants who received prefrontal LLLT also experienced noticeably improved performance in a delayed match-to-sample (DMS) memory task (designed to track retrieval speed and accuracy) – compared to the sham (control) group.  What’s more, the emotional state of participants was measured prior to the study using the PANAS (Positive and Negative Affect Schedule).  The pre-study PANAS score was compared to a PANAS score collected 2-weeks post-treatment.

It appeared as though the mood of participants receiving LLLT significantly improved (as evidenced by sustained positive affect) compared to those who received the sham.  This study demonstrates that transcranial photobiomodulation simultaneously enhances cognition and mood among healthy individuals.  Researchers speculated that transcranial laser stimulation may be an effective treatment for cognitive and mood disorders, and a neuroenhancer among healthy persons.

Though results of the study suggest that transcranial photobiomodulation (with LLLT) is able to enhance cognition and mood, results may only apply to healthy individuals.  Individuals with neuropsychiatric disorders (e.g. major depression) didn’t participate in this study, making it difficult to know whether they would derive similar benefits.  Moreover, the trial was relatively small-scale and short-term, each of which may have influenced the results.  Nonetheless, this study provides additional support to suggest that LLLT promotes positive moods and attenuates negative moods.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/23200785/

2009: Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety.

Schiffer, Johnston, Ravichandran, et al. (2009) noticed emerging evidence suggesting that near-infrared (NIR) photobiomodulation appears useful among stroke patients when administered transcranially to the brain.  For this reason, they organized a study to determine if near-infrared (NIR) photobiomodulation would affect a person’s mood, cerebral blood flow (rCBF), and hemispheric emotional valence (HEV) – without unwanted side effects.  A total of 10 individuals (5 men, 5 women) with major depressive disorder (MDD) participated in the study.

It was further noted that 9 patients had comorbid anxiety disorders, 7 had a history of substance abuse, and 3 were diagnosed with PTSD.  At pre-trial baseline, symptomatic severity associated with neuropsychiatric disorders was measured with the following scales: Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and Positive and Negative Affect Schedule (PANAS).  All 10 participants underwent near-infrared (NIR) stimulation in 4-minute intervals.

Stimulation was delivered to the left forehead (F3), right forehead (F4), or participants were given a placebo (same device without the light) at the same left (F3) and right (F4) forehead sites.  As soon as stimulation was received at a site, measures of the HAM-D, HAM-A, and PANAS were readministered and post-stimulation scores were compared to baseline.  Scores from the aforestated scales were again collected post-treatment at 2-week and 4-week intervals.

Changes in cerebral blood flow were also monitored with near-infrared spectroscopy equipment capable of measuring total hemoglobin (cHb) in the prefrontal cortex.  Results indicated that within 2-weeks post-treatment, 6 of 10 and 7 of 10 participants experienced significant reductions on HAM-D and HAM-A scores, respectively.  Despite the fact that spectroscopy showed increases in regional cerebral blood flow (rCBF) after near-infrared photobiomodulation, these increases were not statistically significant.

It was also documented that PANAS scores substantially improved with near-infrared stimulation compared to the sham stimulation (light off) when hemispheric emotional valence (HEV) was positive (as opposed to negative).  Researchers observed zero unwanted side effects and concluded that near-infrared photobiomodulation may be an effective therapy among persons with major depression.  That said, it is necessary to consider that this trial was extremely small, conducted over a short-duration, and failed to implement randomization, controlling, and blinding – meaning no convincing evidence can be extracted.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/19995444

Limitations of Transcranial Photobiomodulation for Depression Research & Future Directions

Though mounting evidence suggests that transcranial photobiomodulation using near-infrared (NIR) lasers (low-level and high-level) is effective for the treatment of depression, limitations associated with the research compromise the strength of this evidence.  Limitations in the research of transcranial photobiomodulation include: designs (non-controlled, non-randomized, non-blinded), parameters (low vs. high level lasers, light frequencies, sites of stimulation, etc.), convincingness of sham controls, sample sizes, and duration of stimulation.  Until these limitations are addressed in further studies, it may remain difficult to recommend transcranial photobiomodulation as an antidepressant.

• Adjunct efficacy: Though most research has focused on testing the standalone efficacy of transcranial photobiomodulation for the treatment of depression, it is reasonable to suspect that it may be a useful adjunctive intervention when combined with pharmacology (e.g. antidepressant drugs) and/or other evidence-based non-pharmacological approaches (e.g. cognitive behavioral therapy). Unfortunately, no studies have investigated whether transcranial photobiomodulation may yield synergistic antidepressant effects as an adjunct treatment.  One study tested the effect of transcranial photobiomodulation plus ABM (attention bias modification), but there were obvious problems: ABM is not an evidence-based intervention for depression and the study was uncontrolled.
• Comparative efficacy: Another limitation associated with research of transcranial photobiomodulation for depression is that its efficacy hasn’t been compared to clinically effective antidepressant interventions (e.g. medications, therapies, TMS, etc.). Even if it is more efficacious than a placebo (sham) intervention for the treatment of depression, it could be less useful than other proven antidepressant options.  Another possibility is that transcranial photobiomodulation may yield a more substantial antidepressant effect than already-proven therapies, making it advantageous.  Future research should aim to evaluate the efficacy of transcranial near-infrared laser therapy compared to FDA-approved antidepressants.
• Cumulative term of therapy: Though the protocol/parameters associated with transcranial photobiomodulation, total number of sessions received, and time between sessions will influence the antidepressant effect of transcranial photobiomodulation, so might the cumulative term or duration of therapy. Someone that’s received a total of 2 sessions per week for 2 weeks may not respond well to transcranial photobiomodulation, whereas if that same individual received 2 sessions per week for 8 weeks, a robust antidepressant response might have occurred.  The cumulative duration over which transcranial photobiomodulation should be considered to affect trial results, possibly yielding misleading outcomes if the cumulative duration of administration was overly short (e.g. several days).
• Depressive subtypes: Most would agree that neurophysiological activity implicated in depression is likely to differ on a case-by-case basis. In other words, one person’s depression may be characterized by high levels of neuroinflammation, whereas another’s might be influenced by a gene complex that gave rise to an imbalance of monoamines (serotonin, norepinephrine, and/or dopamine).  Due to the fact that there are many potential etiologies and unique subtypes for depression, not all individuals may benefit from transcranial photobiomodulation as a treatment.  It may turn out that patients with specific depressive subtypes won’t respond well to laser therapy compared to others.  As a hypothetical example, patients with depression in which prefrontal abnormalities are evident may benefit from near-infrared stimulation, but those without prefrontal abnormalities may not benefit at all.  Further research should attempt to determine the specific biomarkers of persons most likely to benefit from transcranial photobiomodulation therapy.
• Maintenance of effect: Assuming an antidepressant effect is attained from transcranial photobiomodulation, how long will it last? Most researchers agree that if an antidepressant response is attained from transcranial photobiomodulation, ongoing stimulation must be continued (e.g. twice per week) to maintain symptomatic remission.  That said, the regularity of stimulation needed to avert the resurgence of depressive symptoms is unknown.  No studies have investigated how long the initial antidepressant effect derived from transcranial photobiomodulation is likely to persist.  It is also unclear as to whether responders to transcranial photobiomodulation are able to maintain their antidepressant response with ongoing regular stimulation OR if some sort of tolerance ensues after months or years (leading to relapse of depressive symptoms).
• Number of sessions: Some research suggests that transcranial photobiomodulation is a fast-acting antidepressant in that mood enhancement may occur within 24 hours of a single session. Other research documents that antidepressant responses tend to occur only after 4 to 16 sessions.  It’s possible that certain individuals exhibit antidepressant reactions after a fewer number of sessions compared to others based on individualized differences in etiological underpinnings of depressive symptoms.  For example, someone with depression resulting from brain damage may require upwards of 10 sessions to facilitate regeneration and thereafter, mood improvement.  On the other hand, someone with suboptimal levels of prefrontal ATP and poor mitochondrial membrane potential may experience noticeable mood improvement after just 1 or 2 sessions.  Keep in mind that the “average” number of sessions needed to induce an antidepressant effect may be contingent upon: cumulative term of therapy (e.g. 2 weeks), time between sessions, parameters of stimulation (e.g. high vs. low-level lasers), and the person receiving the treatment.  In other words, the effect of 4 sessions administered within a 1-week period may be different than the effect of those 4 sessions administered within a 1-month period.
• Sham control: In the few trials that implement a sham, it’s possible that the sham may have been unconvincing to the recipients to act as a credible control. The sham utilized in most studies consists of the same device being administered to the recipients’ forehead with the near-infrared light turned off.  This may be highly problematic in that participants may be able to visually detect (in their peripheral) that no light is actually shining on their head, leading to the realization that they received the sham.  Another problem with the sham controls is that since the lights will have been turned off, they won’t emit heat.  The lack of heat may be another means by which participants sense that they aren’t receiving legitimate near-infrared stimulation.  Personally, I think that future controlled studies should blindfold all participants and utilize a wavelength of light incapable of penetrating the cortex as a control (e.g. non-infrared).
• Small-scale studies: Most trials testing the efficacy of transcranial photobiomodulation as an intervention for depression lack randomized controlled designs, but even the trials that incorporate randomization and controlling tend to have small sample sizes. The small sample sizes may lead to inaccurate outcomes resulting from administration of transcranial photobiomodulation.  Though smaller trials are necessary to establish proof of concept (safety and efficacy), plenty of small trials been published.  There’s a need for larger-scale trials (with quality designs) to strengthen evidence of preliminary findings.
• Stimulation protocol: Another limitation associated with the research of transcranial photobiomodulation for depression is the inconsistency of stimulation protocols used in trials.  The stimulation protocols used in one trial may be radically different from those used in another, and if both appear efficacious as treatments, it will remain unclear as to whether one is preferable over the other.  If multiple stimulation protocols are documented as significantly effective in RCTs, further testing may be needed to determine whether one protocol yields a greater effect size than the other.  Additionally, researchers must consider that while transcranial photobiomodulation may appear ineffective for the treatment of depression in a subset of trials, its ineffectiveness in these trials may be indicative of suboptimal stimulation protocols.  More research is needed to pinpoint protocols of transcranial photobiomodulation most likely to enhance mood among populations with depression.
  • Duration: At this point it remains unknown as to what the ideal duration of stimulation (at each site on the cortex) would be for the treatment of depression. Most protocols stimulate sites on the cortex for around 2 minutes each, whereas others may deliver stimulation for around 5 minutes each.  The duration of stimulation could have a significant influence upon whether someone responds favorably to treatment or fails to respond.  Both understimulation (too little time) and overstimulation (too much time) may lead to unfavorable outcomes.  The key is pinpointing an optimal duration, especially in alignment with other parameters.  For example, stimulating each site for less time may be effective with higher power (but not lower power), whereas stimulating each site for more time may be effective with lower power (but not higher power).
  • Laser device: There are many types of laser devices that can deliver near-infrared stimulation. Some devices may be more effective than others for administration of targeted near-infrared stimulation to the prefrontal cortex.  It may be useful to compare the effectiveness of multiple laser devices for the treatment of depressive symptoms.  The specific device, year, make, model, etc. should be documented in the literature.
  • Light wavelength: It is thought that the wavelength of light emitted from a laser device may influence the effectiveness of transcranial photobiomodulation for depression. Most research suggests that light at a wavelength of 810 nanometers (nm) appears useful as an antidepressant and cognitive enhancer.  That said, some studies documented therapeutic effects from light administered within a range of 800 nm to 810 nm, as well as at 660 nm, and at 980 nm.  More research needs to be conducted to determine the wavelength of light in the red or near-infrared range that’s likely to induce the most pronounced antidepressant effect.
  • Power & fluence: The power of transcranial photobiomodulation (measured as mW/cm2) can be characterized as high-power, moderate-power, or low-power. Most studies have tested the effect of low-power light as a therapeutic intervention, but some research suggests that high-power light may yield a more pronounced therapeutic effect than low-power.  It is thought that high-power light is able to penetrate the cortex to a greater depth than low-power light, ultimately enhancing a greater number of mitochondria.  In addition, the fluence or number of light particles passing through the skull (measured as J/cm2) may affect the antidepressant efficacy of transcranial photobiomodulation.  More research should attempt to determine the optimal level of power and fluence for therapeutic effects.  Some evidence suggests that a dose-response curve exists in association with power.  For example, a 10.9 J/cm2 dose facilitates a 13.6% increase in COX activity, a 21.6 J/cm2 dose induces a 10.3% increase in COX activity, and a 32.9 J/cm2 dose yields just a 3% increase in COX activity.  This suggests that power exceeding a certain threshold may produce a negligible neuromodulatory effects.
  • Site(s) of stimulation: While most studies agree that administration of transcranial photobiomodulation to the prefrontal cortex is the most effective means for treating depression, details need to be considered. The most well-designed study to date documented that stimulating the right-prefrontal cortex with transcranial photobiomodulation was the only effective site for treating depression.  In this study, stimulating the left prefrontal cortex failed to improve mood.  That said, other research suggests that stimulating 4 sites laterally across the prefrontal cortex can reduce depression.  It should be considered that the locations of the specific sites stimulated, the total number of sites stimulated, the the size of stimulation (i.e. cm2) at each site – may influence outcomes.
  • Type of stimulation: The types of stimulation utilized in transcranial photobiomodulation therapy can differ in regards to whether they deliver “pulsed” or “continuous” stimulation. If the light is pulsed, there are different speeds of pulsation that can be administered, some of which may be more effective than others.  Furthermore, whether the light particles are “coherent” or “incoherent” could influence the extent of neuronal stimulation.  Additional research should attempt to investigate which types of stimulation (pulsed vs. continuous and coherent vs. incoherent) are most useful for attenuating depressive symptoms.
• Study designs: Most research testing the effect of transcranial photobiomodulation on mood and/or as a treatment for depression fails to implement robust randomized, controlled, double-blinded designs. In the event that transcranial photobiomodulation is discovered to improve mood in an uncontrolled and non-randomized study, it’s impossible to know if the intervention exerted a legitimate therapeutic effect OR if participants may have experienced a placebo effect.  Without randomization and controlling, no credible evidence will be attained regarding the technique’s therapeutic efficacy.  While several studies implemented randomization and controlling, only 1 study was reasonably sized and incorporated individuals diagnosed with major depression.  In this 1 RCT, factors such as: adjunct therapy, potentially unconvincing control, and small sample size – may have limited the credibility of its results.  It is blatantly obvious that transcranial photobiomodulation appears effective, but needs more testing in randomized controlled trials (RCTs).
• Time between sessions: The amount of time between transcranial photobiomodulation sessions may significantly influence its ability to treat depression and prevent symptomatic relapse. Too little time between sessions may lead to excessive laser stimulation which might provoke unwanted side effects and/or exacerbate depressive symptoms.  On the other hand, too much time between photobiomodulation sessions may lead to a depressive relapse due to an insufficient amount of stimulation necessary to maintain an antidepressant effect.  Many agree that multiple sessions should not be administered within a 24-hour duration.  It is generally recommended that sessions be spaced by at least 48-hours, sometimes 72-hours.  The optimal amount of time between sessions is unknown, but may be contingent upon stimulation parameters (e.g. power, fluence, duration of stimulation, number of sites stimulated, etc.).  More research is necessary to determine an optimal amount of time between sessions to attain and maintain an antidepressant effect based on useful parameters.
• Trial duration: Most currently-published trials documenting the efficacy of transcranial photobiomodulation for the treatment of depression are extremely short-term. The longest-term study thus far appears to have been conducted over a 2-month duration.  Most other studies were conducted over a period of 1 to 4 weeks.  The problem with short-term trials is that the long-term efficacy, safety, and side effects of transcranial photobiomodulation will remain unknown.  Even if transcranial photobiomodulation appears safe and effective over a short-term, it warrants testing over a moderate and long-term.

Is transcranial photobiomodulation effective for depression?

To determine the likelihood that transcranial photobiomodulation is an effective treatment for major depression, it is necessary to examine the strength of evidence in the literature.  Most evidence from published studies is weak based on the fact that the studies utilized: suboptimal designs (devoid of randomization and controlling), small sample sizes (10 or fewer), and/or suboptimal methods.  As was already mentioned, even among the trials that were controlled with a sham, many question as to whether the sham would’ve been convincing enough (due to lack of light/heat emission) to serve as a viable placebo control.

Despite serious limitations in the research, it is necessary to acknowledge that nearly all studies investigating the effect of transcranial photobiomodulation on mood reported statistically significant antidepressant responses.  Zero studies have documented ineffectiveness of transcranial photobiomodulation as a treatment for depression, nor have they documented a worsening of mood following administration.  A review of evidence by Cassano, Petrie, Hamblin, et al. (2016) suggested that transcranial photobiomodulation is effective for the treatment of major depression, anxiety disorders, suicidality, and TBI.

A randomized controlled trial by Disner, Beevers, and Gonzalez-Lima (2016) discovered that administration of LLLT plus ABM (attention bias modification) was effective as a treatment for depression when administered to the right-PFC.  Some would argue that the strongest evidence for transcranial photobiomodulation as an intervention for depression is from the aforestated trial by Disner, Beevers, and Gonzalez-Lima.  A study by Cassano, Cusin, Mischoulon, et al. (2015) showcases proof of the concept that NIR transcranial stimulation might enhance mood among those with depression.

Depression scores dropped from nearly 20 points on the HAM-D to approximately 13 points post-stimulation.  Still, since the study was uncontrolled and small with just 4 participants – the strength of evidence is negligible.  Other trials including one involving 10 patients with TBI and another involving 7 patients with TBI – documented improvements in cognitive plus anxiety/mood domains following administration of transcranial photobiomodulation.

Previous work by Barrett and Gonzalez-Lima (2013) showed that in a sham-controlled trial, transcranial photobiomodulation enhanced mood among 40 euthymic individuals.  An older trial by Schiffer, Johnston, Ravichandran, et al. (2009) also documented a significant therapeutic antidepressant effect resulting from transcranial photobiomodulation among 6 out of 10 participants with major depression.  Overall, the trend in research suggests that transcranial photobiomodulation is likely a safe, low-risk, and effective treatment for major depressive disorder.

Have you tried transcranial photobiomodulation (e.g. LLLT) for depression?

Many people with major depression fail to respond to medications and/or simply cannot put up with their side effects.  These individuals often pursue alternative, fringe treatments such as transcranial photobiomodulation that are supported with weak and/or modest evidence from small-scale trials.  That said, it’s possible that many fringe interventions such as transcranial photobiomodulation may prove more effective than expected, especially among a subset of self-experimenters.

If you’ve tested the effect of transcranial photobiomodulation for depression, be sure to share your experience with others by leaving a comment.  To help others get a better understanding of your situation, mention the parameters/protocol that you used for stimulation such as: continuous wave, low-level 810 nm light, 3 minutes of application to the right prefrontal cortex, one session per 3 days, etc.  Also share the specific device that you used for your stimulation (and how much it cost).

Assuming you’ve completed several weeks of transcranial photobiomodulation, note the degree to which symptoms of depression subsided.  Rate the extent of the transcranial photobiomodulation-induced antidepressant effect on a scale of 1 to 10 (with “1” being no effect and “10” being the strongest possible effect).  Did you notice any unwanted side effects during and/or after stimulation with transcranial photobiomodulation?

Also note whether you were using transcranial photobiomodulation as a standalone treatment for your depression OR if it was an adjunct to antidepressant medication, supplements, or other non-pharmacological approaches.  Realize that while preliminary evidence supports the effectiveness of transcranial photobiomodulation interventions (e.g. LLLT) for the treatment of depression, stronger evidence from large RCTs is necessary before the technique can be medically recommended.  Nonetheless, the low-risk and tolerability coupled with potentially high reward (in terms of mood enhancement) makes transcranial photobiomodulation a highly appealing experimental intervention for those with refractory depression.

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