Maregaret Naeser about Default Mode Network PhotobiomodulationTo discuss photobiomodulation and the brain’s default mode network we reached out to Prof. Margaret Naeser, at the VA Boston Healthcare System. She is Research Professor of Neurology, Boston University School of Medicine. She kindly provided us with some in-depth, detailed information. We asked her to answer a few questions related to her research in photobiomodulation. We actually asked her the same three questions that we asked Prof. Michael Hamblin and Prof. Jay Sanguinetti. Prof. Naeser had a lot to share with us. We decided to split her answers into two parts. This is part one.

Q: What is photobiomodulation in general? 

Photobiomodulation (PBM) therapy is a safe, painless, noninvasive, nonthermal modality. It involves the use of primarily red, and/or near-infrared (NIR) wavelengths of light, approximately 600–1100 nm, to stimulate, heal, and repair damaged or dying cells and tissues. Multiple benefits are associated with application of red/NIR PBM to poorly functioning (compromised) cells that are low on oxygen (hypoxic). This includes increased production of adenosine tri-phosphate (ATP) by the mitochondria. Adequate levels of ATP are important for normal cellular energy and respiration.

There is also increased local blood flow after release of nitric oxide from cytochrome C oxidase in the hypoxic cells. Perhaps to put it more simply, PBM may promote a form of “self-healing” for damaged cells. No negative side effects or serious adverse events have been reported, since initial studies for wound healing began in the 1960’s by Endre Mester, MD in Budapest, Hungary.

Q: What is transcranial photobiomodulation specifically?

Transcranial PBM (tPBM) is the application of, primarily, near-infrared (NIR) wavelengths of light (for example, 810nm, 830nm, etc.) to the scalp, using light-emitting diodes (LEDs) or low-level laser therapy (LLLT). The goal of tPBM is to deliver enough NIR photons to the scalp, so that NIR photons will reach the surface brain cortex areas below the scalp placement areas. Perhaps only 2 to 3% of the photons will reach the surface brain cortex (Wan, Parrish, Anderson, Madden, 1981). Studies show the depth of penetration of some NIR (808 nm) photons into the brain, reach up to 4-5 cm (Tedford et al., 2015). The NIR photons are hypothesized to improve cellular function in damaged brain cells. These damaged brain cells are likely low on oxygen and functioning poorly.

Traumatic brain injury and transcranial photobiomodulation

When a traumatic brain injury (TBI) occurs, there is damage to nerve cells in brain cortex. There is also damage to the deeper white matter (axons) that connect specific brain cortex areas to each other. These connections are important for normal thinking and memory. When brain cortex is damaged, along with damage to the deeper white matter brain connections, cognitive tasks, such as problem solving and multi-tasking (executive function), cannot be performed with efficiency.

The brain anatomy and physiology relevant to Traumatic Brain Injury (TBI)

The frontal lobes, located behind the forehead and deep to the front sides of the head, are often damaged in TBI. An area of each frontal lobe, located closer to the middle of the brain, is the mesial prefrontal cortex (mPFC) area. This area of the brain has a high demand for glucose and energy in order to function properly (Raichle, 2015; Mormino et al., 2011).

Default Mode Network (DMN) and Traumatic Brain Injury (TBI)

The mPFC is part of an important neural network, the Default Mode Network (DMN). The DMN has two cortical “node” areas (collection of nerve cells) located near the midline (middle) of the brain. One is the mPFC (in the frontal lobes) and the second is the precuneus (in the parietal lobes, behind the frontal lobes). These cortical nodes are “active” when a person is daydreaming or sleeping. However, in order for executive function to take place, these two nodes (mPFC and precuneus) must down-regulate (de-activate) simultaneously. This must occur, in order to permit up-regulation (activation) of other parts of the frontal lobes, such as the dorsolateral prefrontal cortex (dlPFC) on the sides of the frontal lobes, in order to perform executive functions.

However, after TBI, the “nodes” of the DMN are often dysfunctional and cannot “turn off” or down-regulate, simultaneously. Thus, they prevent up-regulation of the dlPFC parts of the frontal lobes which are necessary for executive function and normal brain function. Poor cellular function in the mPFC following TBI can have devastating effects on cognition, including poor executive function. One goal in using tPBM to treat chronic TBI cases is to deliver NIR photons to poorly functioning cells in the cortical “nodes” of the DMN – especially the mPFC and precuneus. The mPFC location, at the center front hairline area on the forehead, makes it an especially vulnerable place for head impact and brain damage.

Additional brain dysfunction related to TBI

In TBI there is often twisting and shearing of the white matter axons, due to the angular force of the head trauma. This type of brain damage is also present after exposure to the blast from an improvised explosive device (IED) that exploded within 100 yards of someone. Ultimately (based on animal studies), this blast wave produces poor mitochondrial function in the nerve cells. Furthermore, there is low production of ATP, as well as lower cerebral blood flow to that part of the brain.

Can a brain with TBI benefit from transcranial photobiomodulation?

After tPBM application of NIR photons to the damaged brain areas, the ATP levels are expected to increase, as well as local blood flow to the area due to release of nitric oxide. Several research labs have shown increased, local cerebral blood flow after tPBM (Schiffer et al., 2009; Nawashiro et al., 2012; Naeser, Ho, Martin et al., 2012; Ho, Martin, Yee et al., 2016; Hipskind et al., 2019; Chao, 2019).

Thus, following tPBM treatments, there is increased cerebral blood flow near the areas treated. Furthermore, the damaged cells begin to function more normally, with increased production of ATP. Our research has observed that in chronic TBI cases after a series of 18 red/NIR tPBM treatments (3 times per week, six weeks), post-testing scores showed significant improvements in executive function and verbal memory, as well as reduced symptoms of PTSD (Naeser, Zafonte et al., 2014; Naeser, Martin, Ho et al., 2016; Naeser, Saltmarche et al., 2011). These improvements were present at 1 week after the final, 18th, tPBM treatment. Also, there was additional improvement 1 month and 2 months later, without any intervening tPBM treatments, in these chronic TBI cases.

How the use of transcranial photobiomodulation is different for TBI and stroke?

In TBI, there is damage to both sides of the brain, due to the twisting and shearing of the axons during the TBI event. In stroke patients, however, there is usually brain damage to only one side of the brain, where the stroke occurred. Thus, in TBI cases we apply the tPBM to both sides of the head. However, in stroke cases, we apply tPBM to only the side of the head where the stroke occurred – i.e., where the compromised/hypoxic cells are located. (Naeser, Ho, Martin, et al., 2012; Ho, Martin, Yee et al., 2016; Naeser, Ho, Martin et al., PMLS in press.)

Q: Based on your research work, what do you view as the most promising areas for photobiomodulation applications?

Our early studies with tPBM have observed significant improvements in brain disorders including TBI, PTSD, dementia/Alzheimer’s Disease, possible, chronic traumatic encephalopathy (CTE) in athletes who have suffered repetitive head impacts, and stroke. Results for tPBM with TBI/PTSD were reviewed above (Naeser et al., 2011; 2014; 2016). In our study with five mild to moderately severe dementia patients treated in Toronto, after 12 weeks of tPBM treatments, there were significant improvements on the Mini-Mental State Exam (MMSE), p<0.003) and on the Alzheimer’s Disease Assessment Scale for Cognition (ADAS-cog) (p<0.023) as tested once, within a week after the final tPBM treatment. All transcranial photobiomodulation treatments were stopped at the end of the 12-week treatment series (weeks 13 to 16).

After that 4-week, no-treatment period, there was decline from the previous gains. This suggests that continued tPBM treatments, including transcranial LED (tLED) at-home treatments, would be appropriate to consider, when treating patients with a progressive, neurodegenerative disease.

Case studies: Using tPBM to treat retired athletes, possibly developing CTE

We have recently had the opportunity to work with a few retired, professional football players, ages 57 and 65, who may be developing symptoms of the progressive neurodegenerative disease, CTE. Both responded well to a 6-week, In-Office tLED treatment series. Improvements were in executive function and verbal memory. In addition, there were reduced emotional outbursts (symptoms of PTSD), less depression and better sleep. These improvements were present for both retired football players, at one week and at one month after completing the 18th, In-Office tPBM treatment. The red/NIR tLED treatments were administered to the left and right sides of the head, as well as to the midline cortical “node” areas of the DMN, including mPFC and precuneus (Naeser, Martin, Ho et al., International Brain Injury Association, IBIA, Meeting, Toronto, March 2019).

At-home transcranial photobiomodulation treatment for TBI with possible CTE.
Applying NIR LED light to the brain’s Default Mode Network.

Additional, follow-up data are available for the first football player. At two months after the final In-Office tLED treatment, his initial gains wore off. His emotional outbursts, depression, poor sleep and worsening executive function and verbal memory returned. He then obtained his own transcranial LED device, where the diodes were pulsed at 40 Hz (Neuro Gamma). This football player treated himself at home three times per week, for three months. He also used a red-light, 633nm, intranasal LED device.

What is the Neuro Gamma tPBM device?

The Neuro Gamma device is designed to deliver NIR photons primarily, only to the cortical “node” areas of the Default Mode Network. These include the mPFC, precuneus, left and right intraparietal sulcus areas/angular gyrus areas. There is also a single NIR diode used in the nose (intranasal PBM). Presumably, this intranasal PBM delivers photons to the olfactory bulbs located on the orbito-frontal cortex (behind the eyebrows). There are neural connections from the olfactory bulbs to the hippocampus areas, important for memory.

This retired, professional football player returned to our office after three months of using the transcranial NIR home treatments. In these treatments he applied NIR to the cortical “nodes” of the Default Mode Network. Additionally, he used a red-light intranasal LED. His initial gains then returned, or were even better. He has continued the LED treatments at home. He uses only the At-Home, tLED treatment program – the NIR Neuro Gamma device. This device is pulsed at 40 Hz, applied to the cortical “nodes” of the DMN, including the NIR intranasal nose-clip, which is part of the Neuro Gamma; plus a red-light, 633nm, intranasal nose-clip device. The At-home LED treatments have now been on-going for 14 months. He reports that he continues to do well.

What do MRI scans show before and after the tPBM treatments? 

In addition, this retired, professional football player participated in some MRI brain imaging studies before and after the In-Office, and At-Home, tPBM series. A specific type of brain MRI scan, resting-state functional-connectivity MRI, was obtained. This football player showed increased “functional connectivity” between cortical regions of interest in the left and right hemispheres of the brain, as well as within only the left hemisphere, and within only the right hemisphere. This occurred at one week and at one month after the initial In-Office tLED treatment series was finished. However, the improved functional connectivity in cortical brain regions fell off, after three months of no tLED treatments. Furthermore, there was again increased functional connectivity (especially within the left hemisphere) after three months of the At-Home tPBM treatments (Martin, Ho, Bogdanova et al., 2018).

Thus, when working with someone who is potentially developing a progressive neurodegenerative disease, it appears that additional, long-term tLED treatments may be important, in order to maintain any gains made.

What do findings from the current studies and early research using tPBM suggest?

The tLED treatment devices used with the five dementia cases (Saltmarche, Naeser et al., 2017); and with the first, retired professional football player during his At-Home tLED treatments, both applied NIR, 810nm photons to only the cortical node areas of the Default Mode Network – an intrinsic neural network in the brain. The DMN is dysfunctional in dementia/Alzheimer’s disease (Greicius, Srivasta, Reiss et al., 2004).

Alzheimer’s Disease is associated with amyloid-beta and tau abnormal protein deposits located in “nodes” of the DMN. CTE, however, is associated with unique tau abnormal protein deposits located in deep sulci (grooves) of brain cortex, especially near blood vessels (McKee et al., 2009). There are four stages to this progressive neurodegenerative disease, and eventually, the entire brain cortex has tau deposits.

Our early research suggests that treating only the cortical “node” areas of the Default Mode Network (critical for executive function and verbal memory) may be indicated for specific progressive, neurodegenerative disorders. Future tPBM research which includes fMRI brain scans will be important.

Additional areas for application for transcranial photobiomodulation

In addition to the brain disorders for which we have some early tPBM data, there are other disorders where potential for improvements with tPBM exist. Two of them are with children – autism spectrum disorder (ASD) and Down Syndrome (DS). In each of these disorders there is dysfunction in the Default Mode Network (DMN), and in the language network, in the left hemisphere. Children with ASD and DS have problems with language development. Treatment of midline, cortical nodes of the DMN (mPFC and precuneus), as well as treatment of the left hemisphere language areas (Broca’s area, Wernicke’s area and other left perisylvian language areas) might be helpful in these disorders.

Those with Down Syndrome also suffer from amyloid-beta, abnormal protein deposits that build up in the brain by age 60. At that time these individuals have developed dementia/Alzheimer’s Disease. Delay or reduced severity of this late-stage dementia might be possible by using tPBM pulsed at 40 Hz. In mice genetically altered to develop Alzheimer’s Disease (Iaccarino et al., 2016), the 40 Hz pulse rate reduced the amounts of amyloid-beta and tau. This occurred only in visual cortex, because the pulsed light was shown only to the eyes. The pulse rate of 40 Hz increased the phagocytosis effect of microglia in the brain.

The midline cortical node areas of the DMN, in combination with tLED placements over the language areas in the left hemisphere, might be a reasonable approach. The treatment may be more effective if started at a young age. These are reasonable areas for future tPBM research.

Other disorders where tPBM could be helpful include Parkinson’s Disease (PD) and Multiple Sclerosis (MS). Research in these areas is underway. John Mitrofanis, PhD, University of Sydney, Australia, is working with PD; and Jeri-Anne Lyons, PhD, University of Wisconsin, Milwaukee, is studying MS.

Millions suffering from TBI and Alzheimer’s Disease need help

In just the US, there are currently 5 million cases with TBI sequelae and 5.8 million cases with Alzheimer’s Disease. If tPBM clinical trials are successful, then tPBM intervention for these disorders could have a large, beneficial impact. It could potentially help to reduce symptom severity in possibly millions of people.

 

Full Disclosure, Conflict of Interest Statement:
The research lab of Margaret Naeser, PhD, located at the VA Boston Healthcare System receives research funding from the Vielight Inc. There is no personal conflict of interest for her or her staff.