Photobiomodulation and Brain Disorders

For decades, low-level light therapy has been used to stimulate wound healing and to reduce pain and inflammation in orthopedic conditions. Recently re-named “photobiomodulation,” the use of red or near-infrared light is being investigated as a therapy to heal and protect central nervous tissue. Animal studies comprise most of the research at this point. These pre-clinical studies suggest that photobiomodulation (PBM) could be therapeutic and possibly preventive for a range of brain disorders, including stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s, and psychiatric disorders. In his 2016 review article, Michael R. Hamblin explains photobiomodulation’s known mechanisms of action and summarizes key studies.¹

Light, depending on the wavelength and anatomical region of the skull, does penetrate into the brain, but response is not dependent on brain exposure. Hamblin reports that neurocognitive behavior in mice showed statistically significant improvement even when the animals’ heads were shielded with aluminum foil and the rest of the body was exposed. Red (600-700 nm) and infra-red (760-940 nm) wavelengths are absorbed by cytochrome c oxidase (CCO), an enzyme needed by the mitochondria to make ATP. The absorbed photons cause an increase in mitochondrial membrane potential, resulting in more ATP production and triggering multiple signaling pathways that stimulate cellular protection and repair mechanisms.

Hamblin notes that CCO may not be the only photoacceptor since wavelengths other than red/infra-red can also produce beneficial results in some situations. Both coherent, monochromatic red laser light and non-coherent LEDs have been used in therapeutic PBM studies; it is still being debated whether one is more effective than the other.

Despite growing interest in PBM, published research on humans is limited. A small 2017 study, led by Anita E. Saltmarche, investigated the effect of PBM on five patients diagnosed with mild to moderately severe cognitive impairment or possible Alzheimer’s disease.^2,3 PBM treatment was applied with a headset that held four separate LED cluster heads plus one intranasal LED (810 nm wavelength) for 20 minutes during in-clinic visits (twice per week for the first 2 weeks, then once weekly for the next 10 weeks). In addition, patients were supplied with an intranasal LED device with a single diode that automatically shut off after 25 minutes to use at home on non-clinic days. Both devices were provided by Vielight Inc. (Toronto, Canada), which sponsored the study.

At baseline, the patients scored between 10-24 on the Mini-Mental State Exam (MMSE), which has a scale of 0-30 (higher indicates better cognitive function) and between 14-58 on the Alzheimer’s Disease Assessment Scale (ADAS-cog), whose scale runs from 0-70 (higher indicates more impairment). Participants were re-tested at mid-way (week 6) and at the end (week 12) of treatment. Also, patients or family caregivers provided qualitative feedback during in-clinic interviews and from a daily home treatment journal. At the end of treatment, all PBM devices were withdrawn for a four-week, no-treatment period.

“After 12 weeks of PBM treatments, there were significant improvements on the MMSE (mean +2.60 points, p<0.003, two tailed) and the ADAS-cog (mean -6.73 points, p<0.023, two tailed),” report Saltmarche et al. In addition, patients and caregivers reported improved function (i.e., decreased incontinence, increased mobility), better sleep, less anxiety, fewer angry outbursts, and less wandering. Not surprisingly, caregivers reported that their own quality of life improved as their family member’s behavior improved during the treatment period.

The improvement was not sustained during the no-treatment period. In fact, one patient experienced a “’precipitous cognitive and functional decline’” after only one week without treatment. “Because this was causing a high level of emotional distress for family and patient, the authors made the decision to disrupt his participation in the study,” write Saltmarche, et al. “The family was then given an active, intranasal-only ‘810’ device and the [headset] device for home use, despite not completing the study. Later, the family reported anecdotally that behavioral improvements resumed.”

The small number of participants and lack of a placebo-control group are limitations of this study. In addition, the authors would like future studies to include other quantitative, standardized methods for assessing changes in sleep, communication, anxiety, depression, and disruptive behaviors. They also advise that PBM therapy not be discontinued once it has been initiated in future studies because the “erosion of the positive effects…was unexpected and difficult for both the participants and the caregivers.”

Non-Pharmaceutical Intervention for People with MS

In a pair of 2017 studies, Iowa researchers investigated the effects of a multimodal, home-based program on mood, cognitive function, gait, and balance in people with progressive multiple sclerosis (MS). The multimodal intervention consisted of a modified Paleolithic diet, an individualized exercise program for stretching and strengthening of the trunk and leg muscles, neuromuscular electrical stimulation (EStim) of the trunk and leg muscles, and stress management (meditation and self-massage). Medical doctor Terry L. Wahls is senior author on both studies. Dr. Wahls, herself a patient with secondary progressive MS, regained function (“scooter dependence to ability to walk without assistance”) using a similar program.

The first study, led by Jennifer E. Lee, was a one-arm, open-label feasibility trial that focused on mood and cognitive function.⁴ The study enrolled 21 people with progressive multiple sclerosis (mean diagnosis length was 13.6 ± 7.5 years) who had completed a two-week “run-in” period that showed they were able to adhere to the diet and exercise aspects of the intervention. In addition to completing daily home record logs (to document food intake, exercises, ESTim use, meditation, and self-massage), the participants completed several standardized tests to assess mood and cognitive function: the Beck Anxiety Inventory, The Beck Depression Inventory, the Cognitive Stability Index and Cognitive Screening Test, the Delis-Kaplan Executive Function System, the Wechsler Adult Intelligence Scale, Expanded Disability Status Scale, and Fatigue Severity Scale. These tests were taken at baseline and every three months for the duration of the 12-month study. Also, the researchers monitored for possible adverse effects with monthly side-effects questionnaires and blood analyses (complete blood count, creatinine, calcium, magnesium, and alanine aminotransferase).

The modified Paleolithic diet excluded gluten-containing grains, dairy foods, and eggs. Green leafy vegetables, sulfur-rich vegetables, and intensely colored fruits or vegetables were recommended (ideally, 3 cups of cooked or 6 cups raw of each category per day). In addition, daily intake of omega-3 oils (2 tablespoons), animal protein (4 or more ounces), plant protein (4 or more ounces), nutritional yeast (1 tablespoon), kelp (1/4 teaspoon), algae (1/4 -1 teaspoon), and nut milks were encouraged. Dr. Wahls taught the diet to participants and supportive family members and provided recipes and menus.

Patients showed a direct correlation between their participation in the intervention and improved mood and cognitive function; the more participation, the greater the improvement from baseline to 12 months. “Mood and cognitive improvements were more closely related to a higher intake of the modified Paleolithic diet than to exercise and stress management dosage,” say the authors. However, increased exercise dosage did correspond to greater improvement in anxiety and depression scores. Mood changes appeared after just a few months while cognitive improvement took longer. In addition, fatigue decreased.

“Many participants reported verbally that once they developed a daily dietary routine, the diet was not difficult to follow, and the reduction in fatigue motivated them to continue with the diet,” the authors write. “Indeed, study diet intake was impressive, with participants adhering to the food guidelines 94.5 to 98% of days during the 12-month intervention.”

The same cohort was used for a prospective longitudinal pilot study, led by physical therapist Babita Bisht.⁵ At baseline, 6 months, and 12 months, participants took part in a test that consisted of standing up from a chair, walking to a mark 10 feet away, turning around, walking back to the chair and sitting down. The only statistically significant finding was increased walking speed at the six-month point; neither gait nor balance showed a marked improvement in the group overall. The authors attribute the lack of significant results to the “high variability in baseline characteristics of study subjects.” One participant, however, with very poor walking speed at baseline (6.1 cm/sec) consistently improved throughout the study, achieving a speed of 24.3 cm/sec at 12 months. The authors note that this person had good family support and adhered to the diet 100 percent throughout the study.

As Lee, et al point out, pharmaceutical treatment for MS has undesirable effects and is extremely expensive.⁴ The researchers call for randomized, controlled trials of this multimodal intervention that follow larger numbers of patients for longer periods to ensure long-term safety of the diet as well as efficacy.

Mitochondria and Neuropsychiatric Disorders

Does mitochondrial dysfunction underlie neuropsychiatric disorders? Cellular, imaging, genetic, and post-mortem studies show that mitochondrial dysfunction contributes to bipolar disorder and schizophrenia, according to a 2018 review article by Josh Allen and colleagues. These authors believe that mitochondrial dysfunction underlies depression as well: “…recent evidence has opened the door to an expanded notion of the neurobiology of depression, such that a reduction in ATP levels, enhancement of oxidative stress, and acceleration of apoptosis are now considered to be important events….”⁶

The brain requires about 20 times more energy, by weight, than the rest of the body. It needs ATP, produced by mitochondria, to release neurotransmitters and activate downstream signaling as well as for neuron differentiation. Dysfunctional mitochondria fail to produce the needed energy. As a consequence, oxidative stress and inflammatory responses increase, damaging cells further.

In an opinion essay, Douglas C. Wallace, PhD, says, that a decrease in systemic mitochondrial production is going to affect the brain first because its needs are greater: “The milder the bioenergetic defect, the more brain-specific the symptoms, with hyperactivity or depression being likely examples.”⁷ He refers to animal studies in which animals with different mitochondrial gene variations have different physiological responses to stress as well as learning and memory capacities.

From another perspective, George B. Stefano and colleagues hypothesize that antibiotics that cause abnormal psychological symptoms and behaviors in some patients do so because of their effects on mitochondria.⁸ Minocycline, for example, inhibits ATP synthesis and calcium retention in the mitochondria in brain cells. “The commonality of these antibiotic-induced side-effects lead physicians to create a term for this phenomenon called antimicrobial-induced mania, or antibiomania, since it can occur in neural tissues due to higher metabolic rates,” they state.

Orthomolecular practitioners who treat mental disorders will not be surprised by the mitochondrial hypothesis. Nutrients that have shown benefits for their patients, nutrients such as niacin, pantothenic acid, and other B vitamins, are essential for healthy mitochondrial function.⁹

Digital Addiction

Do you go through “withdrawal” if you can’t use the internet or your smartphone? Or is it a welcome relief?

As a recent article in The Guardian explained, the tech industry has deliberately designed smartphones to be addictive; and even the designers themselves are struggling to curtail their use of Snapchat, Twitter, Facebook, and Reddit. Erik Peper and Richard Harvey, at San Francisco State University, explain that “the visual and auditory notifications activate neurological pathways that are powerful and similar to what would have been triggered by a surprise, or even…a danger signal in our environment…causing us to momentarily ‘freeze’ and orient to the source.”¹¹ The inconsistency of “reward” when we respond to the notification (sometimes the waiting message really is interesting) strengthens the urge to re-fresh the page or check automatically for other notifications in the hope of finding another bit of information to excite the neurons. Peper and Harvey say that “the behavioral addiction of smartphone use begins forming neurological connections in the brain in ways similar to how opioid addiction is experienced by people taking Oxycontin for pain relief—gradually.”

Being tied to smartphone use has consequences. First, the divided attention and multitude of interruptions that accompany smartphone/internet addiction foster distractibility and limit the ability to truly focus. Internet/smartphone addiction has also been associated with fewer social connections and higher levels of loneliness, depression, and anxiety. Perhaps most importantly, constant stimulation from this digital technology stresses the nervous system. Peper and Harvey say we need unprogrammed time for reflection, for silence, and for rest that permits regeneration: “Our nervous system, just like our muscular system, grows when there is enough time to regenerate after being stressed. Ongoing stress or stimulation without time to regenerate leads to illness and neural death.”

Peper and Harvey offer several suggestions for reducing smartphone dependence. First, turn off app notifications when you need to focus on work. Tech executive Justin Rosenstein took it a step further. He told The Guardian that he asked his assistant to put a parental-control feature on his new iPhone that prevents any apps from being downloaded.

Peper and Harvey also suggest checking email and social media only at specific times and letting friends and colleagues know that you respond only at those hours—instead of being ‘on-call’ throughout the day and evening. Peper and Harvey also urge making time for silence, for time without stimulation, to allow for self-reflection and regeneration.

This column was originally published in Townsend Letter, October 2018.

References

1. Hamblin MR. Shining light on the head: Photobiomodulation for brain disorders. BBA Clinical. 2016;6:113-124.
2. Johnstone DM, et al. Turning on Lights to Stop Neurodegeneration: The Potential of Near Infrared Light Therapy in Alzheimer’s and Parkinson’s Disease. Frontiers in Neuroscience. January 2016;9.
3. Saltmarche, AE, et al. Significant Improvement in Cognition in Mild to Moderately Severe Dementia Cases Treated with Transcranial Plus Intranasal Photobiomodulation: Case Series Report. Photomedicine and Laser Surgery. 2017;35:432-441.
4. Lee JE, et al. A Multimodal, Nonpharmacologic Intervention Improves Mood and Cognitive Function in People with Multiple Sclerosis. Journal of the American College of Nutrition. 2017;36(3):150-168.
5. Bisht B, et al. Effects of a multimodal intervention on gait and balance of subjects with progressive multiple sclerosis: a prospective longitudinal pilot study. Degenerative Neurological and Neuromuscular Disease. 2017;7:79-93.
6. Allen J, et al. Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Frontiers in Neuroscience. June 2018;12.
7. Wallace DC. A Mitochondrial Etiology of Neuropsychiatric Disorders. JAMA Psychiatry. June 14, 2017.
8. Stefano GB, Samuel J, Kream RM. Antibiotics May Trigger Mitochondrial Dysfunction Inducing Psychiatric Disorders. Med Sci Monit. 2017;23:101-106.
9. Depeint F. Mitochondrial function and toxicity: Role of the B vitamin family on mitochondrial energy metabolism. Chemico-Biological Interactions. 2006;163;94-112.
10. Lewis P. ‘Our minds can be hacked’: the tech insiders who fear a smartphone dystopia. The Guardian. October 6, 2017.
11. Peper E, Harvey R. Digital Addiction: Increased Loneliness, Anxiety, and Depression. NeuroRegulation. 2018;5(1):3-8.