Episode 191: Francisco Gonzalez-Lima discusses methylene blue & noninvasive human brain stimulation

Welcome to Stem Talk. STEM Talk. Stem Tal Stem Plant Talk. STEM Talk Talk. Stem Talk. Welcome to STEM Talk, where we introduce you to fascinating people who passionately inhabit the scientific and technical frontiers of our society. Hi, I'm your host, Don Carnegis, and joining me to introduce today's podcast is the man behind the curtain, Dr. Ken Ford, IHMC's founder and chief executive officer emeritus, who is

is also the chairman of the Double Secret Selection Committee that selects all the guests who appear on STEM Talk. Hello, Don. Great to be here. So today we have Doctor Francisco Gonzalez Lima. A behavioral neuroscientist at the University of Texas at Austin, and he and his colleagues at the Gonzalez Lima lab are recognized as world leaders for their research on the relationships between brain energy metabolism, memory, and neurobehavioral disorders.

Francisco was our guest five years ago on episodes 106 and 107 of STEM Talk. In episode 106, Francisco talked about his work on brain metabolic mapping and Alzheimer's disease. In episode one oh seven. We discussed Francisco's research on methylene blue and near infrared light as therapies for cognitive disorders.

So since those 2020 interviews, Francisco and his colleagues at the Gonzalez-Lima Lab have produced dozens of other papers and studies that have advanced their work on transcranial lasers, memory enhancement, neuroprotection, and neurocognitive disorders.

And the lab's most recent research has focused on the beneficial neurocognitive and emotional effects of non-invasive human brain stimulation in healthy, aging, and also mentally ill populations. And this research primarily uses transcranial infrared laser stimulation and also multimodal imaging, which we're gonna talk about in today's interview.

But before we jump into our conversation with Francisco, we have a bit of housekeeping to take care of. First a big thank you to everyone who has subscribed to STEM Talk. And extra thanks to all of you who have left those wonderful five star reviews. If you're new to the show and you like what you hear, please consider subscribing. And if you enjoyed today's episode,

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Talk at ihmc.us to claim your very own official STEM Talk t-shirt. And that is proof that the Double Secret Selection Committee does, in fact, exist. Today, our winning review comes from Rafa M. Carlos, a nutritionist from Portugal. It reads I really enjoy your show. As a nutritionist from Portugal, I have found many of your episodes featuring discussions on ketogenic diets, such as those with Dominic Dagasino.

Jeff Vullick, Stephen Kunane, and others especially valuable. They have truly helped me consolidate my knowledge and gain confidence in applying a ketogenic diet. Both in my own life and with many of my patients, particularly those with psychiatric disorders and other health issues. These conversations also gave me the confidence to pursue a PhD in sports physiology at the Human Ketogenic Faculty in Portugal, allowing me to deepen my study of nutritional ketosis.

Whether through diet or through supplementation. genuinely inspired by your many interviews, not only those focused on the ketogenic field, and that's it. Thank you for the excellent work you do. Well, that is amazing and what a wonderful note, Rafa. Thank you so much. And also thank you to all of our other STEM Talk listeners who've helped STEM Talk become such a great success. Okay, and now on to today's conversation with Dr. Francisco Gonzalez-Lima. Stem talk. Stem talk.

Hi, welcome to STEM Talk. I'm your host, Don Carnegas, and joining us today is Francisco Gonzalez Lima. Francisco, welcome back to the podcast. Thank you. Glad to be here. And also joining us is Ken Ford. Hello, Don. And hello, Francisco. Hello.

So Francisco, it's been five years since we last had you on STEM Talk and you and your lab have definitely continued to be very productive over this past five years. Lots of new research directions and lots of publications. So we're first wondering, have you been sleeping at the office to get this much work done? I hope I had uh more time to sleep. Let's put it that way.

I understand that you recently started to collaborate with your sister, and that sounds like uh pretty neat and pretty unusual. She has a PhD in computational and applied mathematics. Can you tell us about this uh fledgling collaboration? Yes, uh thank you for asking. It's been a dream of mine to be able to collaborate with her. We were always uh sort of running in parallel lines, but uh finally we found a point of uh contact and that is

in some of the studies that we're doing that we have interventions. We have people that respond better to the interventions than others. For example with this transcranial stimulation using uh infrared light. And one of the things that she specializes in her research is uh machine learning AI applications. And therefore, what we have been doing together is uh using her tools to try to classify high and low responders.

to various interventions that we're doing in the lab. And uh she was able to spend one semester with us uh here in Austin, Texas, and now she's back and she's a professor of mathematics at the University of Puerto Rico. That sounds like a great opportunity to collaborate with your sister and to have her actually there physically for a semester really unusual and and really great. Yeah, and her name is uh Maria Gonzalez Lima.

So Francisco, although you and your team have been very productive as we talked about, we also understand that you've hit a few roadblocks. books and you have several papers up for review, but the review process is kind of slow right now, and this is true not only for you and your lab but also just for about everybody. So what's going on in your view?

Well that's question in which I would have to do some speculation, but what seems to be happening uh to me in my field of uh behavioral neuroscience but also colleagues in all All kinds of areas uh that I have talked to, including my sister in mathematics, computational sciences, chemistry, physics. is there is a like a traffic jam

of papers are being submitted to journals, in particular what you may refer to as uh Western journals. And uh Nearly all of these uh papers that are forming the jam are coming from the same country, China. And these papers, uh, the majority of them uh do not contribute any original data. They are just uh reviews, systematic reviews. Sometimes uh meta analysis And uh from our review of these papers, uh, because we are constantly every day I receive requests to review these papers.

They are primarily uh AI generated. And uh this created uh traffic jam. There are not enough reviewers. Uh one of the journals uh in psychiatry, the editorial office told me They had requested hundred and two different reviewers uh for one of our papers and everybody was too busy for for doing that. Some other journal editors that I know, they have told me the same. And they don't know how to handle this. It's uh for lack of a better word, it's like a cyber attack.

uh on the Western journals. Yes it's on the other hand it's sort of a denial of service attack. You know, if you're familiar with in uh in cyber there's a thing called denial of service where you essentially just bombard a server with requests. They don't have to be anything particularly malicious, but it will tie everything up. And uh it's a it's a well known cyber method.

Yeah, you are uh right on target. That's exactly what's happening. Uh it is just occupying all of the resources from these editorial offices and reviewers, and on the other hand, I get invitations uh nearly daily from uh new Chinese journals to submit my papers uh on then with uh free of charge and all kinds of perks. So having a background, as you know, uh having been born in Cuba, communist country, I cannot imagine that this is not a government orchestrated situation.

and it's really affecting our communication of scientific knowledge, at least in the Western world. I hope uh this is gonna be transient, but uh it's just continues to progress. And we're seeing more and more of these papers. Some of them are just paraphrasing of some of uh all the papers that have been published. Including mine. Mm-hmm. Yes, we have this uh problem at a very large scale at the national AI conference.

where you know you just get a tremendous flood of papers and many of them are AI generated and as you said they're um paraphrased not by the human but by the AI itself, which often doesn't include references. to other people's work. It it's just whole paragraphs are lifted and sometimes not even paraphrased. But it it's an amazing problem. The j journal system is under duress.

from not just from this phenomenon, but from many others. You know, the the system itself that we've used for a long time for communicating scientific knowledge is really starting to strain. Mm-hmm. Yes. So in a way, I'm glad that you're doing this podcast because there is a need to communicate to the public scientific information and there are a lot of competing now uh sources of information.

So speaking of getting original research out there, so back in our twenty twenty interview, we talked a lot about your research on methylene blue. And historically it's been used primarily to treat met hemoglobinemia, which is a condition where blood cannot effectively deliver oxygen.

But we've now had considerable research that demonstrates the potential of methylene blue to also enhance things like memory and cognitive function. And despite considerable research showing the many benefits of methylene blue, you still got a lot of you get a lot of questions about its safety.

And I suspect that's because there remain misconceptions about methylene blue. And I know that a common question that you get is whether methylene blue in low doses affects microbiota. So h how do you respond to that question? Yes, uh one one of the issues there, uh yes, there are a number of myths that have been building up. Unfortunately anyone can give an opinion and nowadays uh can

be amplified by uh social media. And the only way to really uh address that that question from a rigorous scientific point of view was to do uh animal studies. And this is and this was done. So animal studies were done uh using rodents in which uh you would provide different levels or doses of methylene blue over a very broad range, about one hundred times from the low to the high doses. And in those studies the microbiota was analyzed very systematically.

and all of the findings were negative. None of these doses that were tried in animals for uh many weeks uh resulted in any change to the microbiota as compared to the control animals. And one interesting thing is that the only positive finding of those studies were that the animals performed better in the memory tasks that they were given.

So some unfortunately some gastroenterologists and other people are just jumping to conclusions that uh because a high doses, very high doses, methylene blue can be a pro oxidant that this will uh somehow impair the microbiota. But the only uh evidence available shows that this is not the case. There are other safety concerns. Another one that I found that is a little bit perplexing to me, but it's part of a new trend.

is that Methylen Blue cannot be beneficial because it is a synthetic chemical. And only natural products can provide benefits, uh supplements or through dietary manifestation. And this is something that really denies the fact that the same people who are saying this are using cellphones, internet, AI, they are uh pasteizing Their dairy products. In other words, there are all of these human made uh STEM applications in our life.

And in terms of health, they are y using synthetic antibiotics if they have an infection. They are also using synthetic analgesics uh to control pain. So but somehow Now uh methylene blue because it was the first synthetic chemical used in the history of medicine, is uh now being questioned because it's not a natural compound. And those sane people would not be eager to ingest arsenic, which is quite natural but not healthy. Uh you are entirely right. And uh or cyanide, uh for that matter.

which is the m the the most classic poison and methylene blue in the emergency room is uh the most effective antidote for cyanide poisoning. or carbon monoxide poisoning or other natural products like uh rothanon that is uh organic pesticide. So people have to understand that uh whether something is natural, synthetic is not uh enough to classify as uh being beneficial or harmful.

So what are some of the other misconceptions about methylene blue that you are sometimes asked about or that spring to mind in this discussion? Yes, uh Ken. Uh one common misconception is about the dosing. It is not really scientifically appropriate to r talk about methyl and brew properties or actions. just referring to methylene blue in general, because low and high doses of methylene blue produce opposite effects. This uh biphasic uh dose response or

More commonly referred to as a horbisis or hormetic dose response. It is the norm, not the exception. in uh most uh compounds are used for pharmaceutical purposes. In other words, uh at uh low doses they may have a beneficial effects, but at high doses uh they may be harmful. And for example You mentioned uh meth hemoglobinemia, which is uh now one of the most uh common uh indications for the use of methylene blue in the emergency room at uh low uh doses.

Methylene blue rescues people from methemoglobinemia actually being able to rescue them from dying from this uh problem that prevents the transport of oxygen through in their blood, in their hemoglobin. However, if you give a high dose of methylene blue, you produce meth hemoglobinemia. So the same compound at low and high doses have the opposite effects. So one common uh complaint is uh oh uh methylene blue inhibits uh nitric oxide or nitric oxide synthesis.

Again, what dose of methylene blue does that? It is only the very high doses that produce that effect. And these are s uh findings are usually coming from uh in vitro studies in which uh these concentrations are not entirely equivalent to what happens uh with methylene blue is on board in the

in the circulation o of a of a living uh organism. In that respect, uh then people uh uh are afraid to take it because oh because uh I hear nitric oxide is a good thing and this inhibits it, therefore I shouldn't take that. Again, both uh situations are oversimplifications of what's really happening. And this is very commonly amplified and repeated in the social media.

And unfortunately, uh physicians are echoing uh some of these uh concerns and even our our own FDA, Food and Drug Administration has uh yelded to similar concerns when they came up with labels of warning not to use any serotoninergic drugs in conjunction with methylene blue. Well the low doses of methylene blue has really no interaction. with these uh serotonergy compounds. And there is absolutely no scientific evidence to demonstrate that. if you're taking medellum blue at oral

Low doses. There's just no documentation. And the experiments that have been done in animals show this doesn't happen. uh however there's been uh some cases that prompted this uh warning in which uh people w that were undergoing surgery in their neck to remove the parathyroid glands in a procedure in order to identify the parathyroids as compared to the surrounding. fat tissue they will uh literally put methylene blue liquid on the open wood and and then watch and then put more and then watch.

and see what part of the tissue absorbs the methylene blue. And this of course is absorbed by the more act metabolically active cells and not the uh adipose tissue cells, the fat cells.

and then surgeons who have been using these techniques for many years then to identify and remove the abnormal parathyroids that are uh overactive. However, When this procedure is done, one thing that happens they don't have a good control of what the dosing is of the methylene blue that is being directly put in into the wound and They have never had any problem with this except uh that they were having people who were under anesthesia.

And also taking serotonergic drugs, in particular so called SSRIs, selective serotonin rail take inhibitors for use as uh antidepressants, even though they are not very effective. They are uh consumed chronically uh for uh in people. uh nowadays. And Only those cases were enough for the uh FDA to s to give this warning. However, for example, Canada made this uh made a warning Much earlier than the FDA, but it was specific to those conditions in which people were anesthetized.

they were also having these other drugs on board and the amount that were uh being used in the open wood exceeded these uh low doses. So these are examples uh of safety concerns that are not really founded on uh scientific evidence. but uh misinterpretations or extrapolations. Mm-hmm. That's a very good point. And uh for our listeners to follow up on this, I'm sure they're wondering, some of them at least

are wondering, given that we're talking about low doses and safe doses in humans, what seems to be the range, you know, the the range of a uh a relatively or very safe dose in a human? Yes, uh the range that have been tested. is are the ones that we can talk about, but but they're always uh lower than five milligrams per kilogram of body weight. if we just want an acute use of methylene blue low dose, one can go up to four milligrams per kilogram. But for the chronic oral use, uh

For a cognitive enhancement, you can use uh much lower doses, uh less than one milligram per kilogram. We find zero point five. to zero point three milligrams per kilogram are sufficient. And the important point also is that this can be personalized, can be adjusted for each individual because when you take a dose of a low dose of methylene blue, you're gonna screet nearly all of the pattern compound through the urine

and you can see that your urine becomes a discolor. So this can be used for two in two ways. One, to see whether you are ingesting enough of methylene blue that it will be visible. In terms of discoloration of the urine. And number two was to see how long the compound is excreted from your own body. So that you know how long it's circulating and having an effect, for example, in in the mitochondrial respiration, which is our focus.

And there are some people that uh will take uh a small dose, like I mentioned zero point five or one milligram per kilogram, and then they will continue for four or five days uh urinating with this color urine. And the discolored urine you have to be observant because if you're well hydrated your urine is fairly transparent, it's clear. But if you are not well hydrated your y urine becomes uh yellow, jellowish jellow. It could be dark jellow. In some people you can even reach uh uh light brown.

So the color of the discoloration will be different. If you have transparent, clear urine, it will look bluish. If you have a jellow uh type of uh urine excretion, then it will it will look like green. But the important thing is that you can tell if after let's say four days uh you no longer are screening it that it's already out out of your system. And then you can take the next dose.

So one rule of thumb that I say for personalizing this is If you do this a couple of times and you see that it's a trick. uh four days, the last uh time that you see the excretion of urine with discoloration, well, the next time you take methylene blue can be after three days from the prior time. And that way you're o always gonna have uh levels of methylene blue circulating. We know in great detail this so-called pharmacokinetics of methylene blue, but the fact that it's visible.

It really helps uh people to tell. whether they have it on board or they already have uh excreted it. And uh then they can't uh personalize it. As you grow older, for example, your renal excretion becomes a little more compromised than when you were younger. And of course there are people that have issues with the urinary tract that will make it harder for them to excrete any compound including methylene blue. So those things by looking at the urine you can tell.

And that way is the best way to do it that is specific to you and how long the compound is uh in your system. Yes, it's kind of neat that uh you have a color code automatically available. Imagine if this were the case with other kinds of uh supplements and drugs that people ingest. It would be quite a colorful world, but uh it's it's it's really interesting that it this comes along with its own sort of indicator.

You're right. That is a very useful and in the past one of the main uh uses of methylene blue in this country was uh for urinary tract infections that were recurrent. And uh this application has been replaced now by the use of uh antibiotic. Basically no physician in the US will prescribe methylene blue for an urinary tract infection.

They will give you a round of antibiotics. But in some cases, like older people, especially older women, they suffer from recurrent urinary tract infections. And they go through a round of antibiotics, they get better. But then soon after they get another infection and they have to go through another round. And these rounds are very debilitating. And for example, they do affect the microbiota, these uh rounds of antibiotics for uh many, many days.

And methylene blue was very effective. Uh it was available over the counter, and people were taking higher doses than what I just told you. They were taking a sixty-five milligram uh tablet. Uh three times a day. So it's uh it is uh very safe, but the idea was to build up enough amount inside the bladder in these people that have this problem, which are usually people this older or uh uh individuals that are not screeting at the same rate that they should and sometimes they are not uh also

hydrating the cells. So the urine stays for too long in the bladder and creates an environment. appropriate for growth. In some of those individuals they also have uh

high sugar levels and this also contributes to bacterial growth. But in any case, uh methane blue was very effective and I know now a group of physicians are usually referred to themselves as integrated uh uh medical doctors that uh are using it for that purpose for urinary tract infections that are recurrent especially in uh older uh population.

Yes, um quite a few do. Um I mean uh it's I have um several friends that fit the category you just described and uh uh their physician has indeed uh recommended it for that purpose. Wonderful news. Yeah, it is uh it is amazing how uh methyl and blue uh can be uh used for uh so many different applications.

There was an article published a few months ago titled Beyond Plat. How methylene blue and ketones address vascular hypometabolism in Alzheimer's disease. I thought the article did a good job of summarizing your research As well as some of the work of Stephen Cunane. Uh Stephen works on ketones as an alternative view for brain's energy needs. He was our guest on episode fifty-nine of STEM Talk. What are your thoughts generally speaking on this art?

Yes, I agree. I thought that was a good summary of uh not only the findings but the concepts uh behind where programme of research for uh several decades now.

in in a nutshell uh we found in Alzheimer's brains that hypometabolism was a major problem and that this uh was unrelated to some of the other variables that have been historically blamed for the Alzheimer's dementia and specifically examine fresh frozen tissue post mortem and by that I mean uh tissue that was available uh within three hours and We were able to identify that this mitochondrial enzyme, cytochrome oxidase, also called cytochrome C oxidase.

was the key metabolic change that was producing the hypometabolism that you could detect, for example, with functional neuroimaging using FTG PET. or using cerebral blood flow uh imaging or using fMRI TR spin labeling, every available technique has shown this uh hypometabolism in the brains of Alzheimer's patients. However, what is underneath this uh change is what interests us.

And we found this a long time ago. Uh this was found over twenty years ago by our our group was a PhD dissertation of one of my trainees. published in the journal of neuroscience and it took us to spend a summer collecting uh brains at the Sun City in Arizona where retired people donate their brains. And we had a unique opportunity as soon as they were declared death, uh, to go and quickly extract their brains and also to use brains, uh frozen brains from the uh brain bank.

No nowhere else in the world there was such uh facilities or this was a unique uh study for us. But the question was then now we know that this Mitochondrial enzyme is impaired, and that this impairment increases with the progression of the disease.

how can we act on it? Is there anything that we can do about it? And for a long time I wasn't unable to do anything. So I started uh my interest with methylene blue because methylene blue was the first and only way that I could uh modify such crumb oxidate. and upregulate the M side. So Methylen Blue was in low concentrations. It forms an equilibrium inside mitochondria.

that it we we call it a redox equilibrium between the oxidized and the reduced form and this allows the cycling of electrons to this uh electron transport in which satochromoxidase is the terminal rate limiting M sign. And then uh these electrons are taken by oxygen and in the process with phospholylate adenosine to produce uh adenosine triphosphate or ATP. So that process was what allow us to focus on methylene blue.

and has a has a beneficial intervention in terms of uh energy metabolism in the brain. And uh from there on then I have to do all the studies uh in the animals in Bebo. and eventually uh we did uh the human studies. And in the meantime we were also looking for other compounds or other ways

to facilitate this mitochondrial function and that's how we ended up with the other two uh approaches. One of them is this uh photobiomodulation that I can talk about uh a little bit more later But the other one was uh using ketones. or ketogenesis or to produce so-called ketosis. And in that approach You're taking advantage of a parallel route.

to generate energy that doesn't depend, for example, on the use of uh sugar, glucose, which is the main uh fuel that the brain uses for doing this process of oxidative fossilization. So I wrote a paper some years back, uh ten years back or so, saying, well, if we could combine those three strategies.

uh we'll be able to target mitochondrial dysfunction and by doing that improve cognitive function, not only in individuals with neurocognitive disorders, but generally speaking in any uh healthy individuals. And since then we have been trying this in humans. I have spent m most of the time after the initial work with Methylen Blue focusing on the photobiomodulation.

And it's only recently that now I have built a team that we're gonna work also with uh ketones and uh and hopefully combine these approaches in a synergistic manner.

Yeah, this is really fascinating research and we're gonna switch for a second to talk a little bit about that photobiomodulation as as you've noted, which Specifically you've been working on transcranial infrared laser stimulation, which is a non-invasive method for neuroprotection and cognitive enhancement.

And you've written two chapters on this research, one of which appeared in the second edition of the Oxford Handbook on Transcranial Stimulation. And this is a really good chapter that gave an overview of what transcranial infrared laser stimulation is. is and then also how it can be an effective intervention. And then the other chapter that you wrote is in a book on augmentation of brain functions that was based on some presentations that you did in Switzerland.

And both chapters did a great job summarizing a lot of the work that you've been doing on photobiomodulation. So, Francisco, we will make sure that we include links to these two chapters in our show notes, but can you give our listeners a brief overview of what you covered in these chapters? Yes, uh in brief we were explaining the how photobiomodulation can do something similar. Not the same but similar to what methylene blue was doing in relationship to cytochromo oxidase.

It turns out cytochrome oxidase, like the name implies, cytomine cells, chrome color, is the enzymatic complex. that gives color to the inside of the cell. In uh in in uh more technical words, is the major photo asector or photon asector intracellularly.

Taking advantage of that uh property of cytochromo oxidase then uh we were very impressed by some in vitro work that was done by a colleague of mine, Margaret Won Reilly, uh using uh retinal cells in vitro and showing For example, if you put toxins that affect the mitochondria and would result in the generation of this uh neuronal type, you could prevent that, you could rescue them by having photobomodulation that was absorbed by these cytochrom oxidase and accelerated the

production of oxygen and other downstream changes. That allows the sales to fight back the stock chains and remain alive and viable. So one of my trainees. And MD PhD doctor Julio Rojas He did the PhD in my lab in neuroscience, working out uh an in Bible model. In other words, trying these uh in living animals. And in one of the chapters uh we provide the data the first time we we did this.

was also in the retina. The reason we selected the retina was that we were sure that then the light would be able to get to those cells. in those uh days we were not completely sure how much light would penetrate uh through the head, how we should do this uh parametrically. So targeting the retina through the eye was uh the best way

to use the eye as a model of the brain and to make sure that our intervention was gonna get there. So we published the findings in uh the journal Neuroscience in uh two thousand and eight. was the first study showing this in vivo neuroprotective action of photovolomodulation. And in the process of doing this, uh we found that

Indeed, going through the head in rats we could affect the brain, we could measure directly cytochromo oxide activity histochemically. We could also measure with oxygen sensors in vivo. And we were really encouraged by these findings, and then started the process of us translating this into humans. And like the second part of one of the chapters about augmentation of brain functions reports over a decade of studies that we have with humans uh using transgranial infrared uh lasers.

So transcrania referring that we are applying this to the forehead. Why the forehead? Because there is no hair. the same way that we have on the scalp. Hair contains melanin, the general pigment that we use in the body for all kinds of pigmentation. and most uh wavelengths of light in the visible spectrum are absorbed by melanin in very high amount. So the light that we use is actually invisible, it's infrared light.

And if we use the forehead, we don't have to worry about dosing because there is minimal interference uh with the melanin on the skin. It's not a problem. It is uh the one in the hair. And what resulted from these studies was the first I think the first one was published in uh twenty thirteen.

in neuroscience, the uh official journal of the International Brain Research Organization, and it demonstrated for the first time in a control study that transcranial infrared light Targeting the prefrontal cortex through the forehead could result in improvement in cognitive and emotional functions. And then we continue doing this different kinds of testing.

in different paradigms and demonstrating that one could improve working memory. It's a type of short term memory. Like uh if you go out of your house and you wonder whether you lock the door or not. That would be a working memory type of action. And also things like sustain attention or vigilance.

All the phenomena that are referred to as executive function, where you are engaged in problem solving, all the phenomena we call category learning. The common denominator of all of these cognitive tasks that we use. was that they were strongly based or influenced by the prefrontal cortex. And what we were doing with the transcranial infrared laser was providing photons that were absorbed by cytochrome oxidase

in a process that I refer to as a photo oxidation. It's an interaction between the absorption of the photon and the emission of an electron cytochrome oxidase into oxygen. similar to what uh Albert Einstein in the nineteen thirties described as the uh photoelectric emission phenomenon which was believed to be happening only in some metal.

But this is actually happening and can happen in the mitochondria with these electron transport complexes because they are specialized for moving electrons and oxygen is the ultimate electron acceptor. So if you provide photons, photons take the place of electrons in the electron transport and then move electrons uh to oxygen. And the that reduces oxygen to water and that f is coupled with oxidative phosphorylation for the production of ATP, that is the chemical that we're using for energy.

And not only that, some of this uh oxygen that normally is not fully reduced can create uh reactive oxygen species. And by facilitating this process one also reduces the amount of this, for example, superoxide, this reactive oxygen species to a minimum only at the very beginning of the process.

that can be used as a signalling mechanism, but not uh afterwards. So photobiomodulation in humans and we have done so far well over a thousand participants in these studies from young uh people to people as old as ninety years old, and we have never found any adverse reactions or there being any any reports. Of a side effect. and it takes only eight minutes of a simulation.

to see significant changes that you can measure directly using optical methods uh We developed in collaboration with uh bioengineers a way to measure the changes in concentration of uh oxidized cytochromo oxidase in people through the forehead while we were doing this uh stimulation. And also you can measure changes in oxygenated and deoxygenated hemoglobin using more standard technique.

And so you can validate that you have a target engagement, you can see the enzyme Becoming oxidized by the photons, and you can see that that tissue becomes more oxygenated. And that increasing oxygenation to the prefrontal cortex is what is driving this series of events. That makes you more cognitively efficient and that allows you to perform better in this cognitive challenge test.

Really interesting. In in twenty twenty three A workshop on photobiomodulation was organized and convened by the Director of the National Institute on Aging, as well as several NIH lab directors of the The invited participants included what NIH regarded as the leading experts in photobiomodulation.

You and the other researchers who attended the workshop produced a paper that did a nice job of describing photobiomodulation therapy and its therapeutic potential across different biological processes. The paper actually has a really clever title, at least I think so, Light Buckets and Laser Beams, Mechanisms and Applications of Photobiomodulation Therapy. Can you talk about the significance of this article and what you liked about it?

That paper I think was a landmark paper based on a landmark workshop for a couple of reasons. One that was an initiative taken by the National Institute of Health, NIH in particular, the director of that National Institute of Energy, and this is indication.

major funding agency in the US showing an interest in this uh process of photobomodulation. And the second point was that they did the homework and collected the experts on the field For example, when when I talk about some of the studies that were done in vitro or studies that were done in the retina.

and our in vivo studies, so the the whole range of studies that were done that uh especially uh relevant to the interest of in in aging, that is a condition where we have a cognitive decline and a number of other uh changes, for example, in the cardiovascular system. And uh I would say the third unique situation was in addition to these leading experts

we have NIH uh lab directors who have been testing photobiomodulation on their own. In other words, they were not just taking our reports for granted. They were doing these with their own uh animal models, primarily studies using mice.

that are uh used in a very large way uh at the NIH labs. And not many, all of these uh uh studies that they were doing intramurally had not been published. So it was something that gave us an opportunity, the people working in photovoltaic, to see what these other people who were highly skeptical were doing.

And to witness the results. Uh most of them still uh not published, so I cannot comment on on on many of them, but they were really impressed. I was really impressed. These animals not only brain functions, But with the whole body photobal modulation, they were able to improve. Cardiovascular functions in ways that make animals that were all uh look like uh mature john much younger animals.

Measurements were taken over one hundred different measures, for example, just focusing on cardiovascular phenomena on these animals, in addition to complete uh chemical batteries. And everything pointed to improve In all of these parameters including. the animals living longer to the point that with certain protocols, by the time all of the control animals had died, none of the animals that were uh getting mo photobombulation starting at at mid

had die of aging. So this was uh really impressive for uh us to see these older people uh come to the field However, it's taking a long time for that information to come out. I presume there may have been some some resistance to some of this, but uh I have no way of knowing. What we did publish was uh each one of the individuals who participated, I should say, with substantive findings.

provided then a description of those to facilitate the mechanisms and applications of this photobow modulation. And I did most of the part that had to do with this mitochondrial mechanisms and also the ones that have to do with these uh neurocognitive improvements. But uh the work continues and the expectation was that this NIH uh scientists and uh administrators were going to solicit

uh applications requests for proposals in this area, but uh so far that hasn't happened. So we are waiting to see whether it will happen or not. In the meantime, In addition to this paper, another important mainstream acknowledgement of photobiomodulation was that the FDA approved the use of photobiomodulation for the first Intervention known.

and stop neurodegeneration. And that was uh using photovomulation like in our first in vivo study through the eyes to target aging related uh macular degeneration. which is a neurodegenerative process. So in a way that uh and I uh it was a company who uh invested in putting a device that you only look through your eyes because that's what the FDA prefers, a device that is uh very uh

specific to a condition. However, it's the same thing that we were using with the animals without having them look into the eyes. with a specific device. And that is already approved and there's a company I uh that is the one that they uh they actually the company the the original company is uh in the UK, but they create the one in the US uh for that specific application. And I uh predict that the the hopefully that other device makers uh will likewise go through that process.

Fortunately the majority of these uh suppliers are not doing that. They are just uh making uh inexpensive, especially uh LED based, light emitting diode based devices that do not really have the parameters and adequate uh that are adequate for for really doing any beneficial effect.

STEM Talk is an educational service of the Florida Institute for and machine cognition, a not-for-profit research organization investigating a broad range of topics aimed at understanding and extending human cognition. Locomotion, health span, resilience, and performance. I'm sure our listeners are wondering if there are any commercially available devices that you believe have substantial utility in general?

Well, uh those that were approved by the FDA definitely for that condition. And it's being a moving target because we had our original lasers, the one that we use in the majority of our studies, were made commercially in Dallas. It was uh the two owners of that small business where uh one was uh medical doctor and the other one was uh his uh brother engineer, who used to be uh nuclear submarine engineer in the US.

And they put together the best quality devices that were the ones that we ended up using for the human studies. And importantly, their device were clear, safe for use with humans. And the physician had a clinic in Dallas where he was using these, but primarily for the application of improving circulation. and pain relief in a very uh wide range of intensity. Just to give you an idea, for the forehead we use uh 3.4, 3.5 uh watts.

in our lasers and for some of his applications for pain relief like back pain or carpetonal syndrome pain, which eventually was approved by the FDA, they were using up to eighteen or twenty watts in this same device. So for the forehead and the brain, you actually do not need much in terms of uh the intensity or power of these uh lasers. They went out of business and Fortunately one of our trainees uh here

at the University of Texas at Austin. Somebody who's uh received two PhDs from our uh university, one in uh computer science and the second one in uh computer and electrical engineering. Uh he decided uh I was his co advisor for the second one and he decided to build his devices after he graduated and made a small company in Austin that is the one that we're using as a source supplier

for our uh current studies and some of the ones that are in the pipeline uh waiting to be published. And I anticipate that there will be another uh former trainee from the university that will also do uh uh similar kinds of devices. So unfortunately those are the ones that we have tested in our lab, are the ones that are have been done

two hour specifications and they are the only ones that I can provide uh any confidence that will be effective. Yes, and I I think it's fine if you would like to mention the name of the company. So I think the the company from the former trainee, Dr. Li Da Huang, originally from Taiwan, he is uh called Saiton Pro. And uh is based here in Austin. And uh he's uh had several devices, not just the lasers, but also with LEDs.

And we're using all these devices for in different experiments and have validated that they are doing the same as our previous uh one. The LED ones are uh It took us a while to also be able to use LEDs because there were not commercially available LEDs that could do what our lasers were doing. And uh however uh a few years ago a Japanese company was uh making those infrared lasers that were the same wavelength and power

characteristics and nearly monochromatic light emission that we were able to incorporate. Now the advantage of using these LEDs is that uh you don't have to have any concern about lasers. The only concerns about this uh Very low level lasers that we're using was if you were to put them in your eyes and directly look at them because they were invisible, your pupil would not constrict.

and you may have too much of the light uh going through. So people have to always use gaggles that prevent that particular wavelength from going through their eyes when we did experiments. But with the LEDs uh that produce diffuse light, uh that is not a problem. And uh in fact uh you can uh put it directly on over your eyes. for beneficial effects uh on the retina. And uh just like the FDA approved uh device.

Very interesting. And uh if it's helpful to the startup, we can put a link to their website in the show notes uh if you think that's helpful to them. Y well yeah, that former trainee probably uh will be very happy with that.

So you mentioned mitochondrial dysfunction several times and mitochondria are a topic of great interest here at IHMC and mitochondria lab here as well. It's quite good. And as many of our listeners know, mitochondrial dysfunction is thought to play a central role in a range of neurodegenerative disorders, particularly Parkinson's but others too. And you've written about this.

and you've written about t how targeted stimulation of mitochondrial function with photobiomodulation or low light therapy is a sound and yet largely underexplored area for neurocognitive enhancement and protection from neural degeneration. So could you talk a little bit about how mitochondrial dysfunction is believed to play a central role in neural G generation? You you mentioned it briefly, but if you could talk about that a little bit.

Yes, uh one of the things uh that happened when mitochondria cannot use oxygen to produce energy in the form of ATP, our neurons cannot sustain the regular activities. Neurons are the most highly dependent cells in our body on mitochondrial function. Some other cells types they may have other biochemical processes that can be used in parallel or as alternative. to generate energy. But neurons really for all practical purposes, they relied only on mitochondrial respiration.

This is not the same as uh other brain cells like the glial cells that are also very important, but uh they can also uh use uh alternate ways to gain energy. So from the point of view number one of obtaining energy and neurons uh really do not store Energy. It is almost as if for neurons to function, they have to be plugging to their energy source. So if you unplug that energy source, it's just like unplugging a lamp. in front of you and then and then the lamp uh lights stop.

We mentioned before the uh for example cyanide. The cyanide acts on that cytochrom oxidase, it uh binds to the catalytic side, that is the site where normally oxygen will go. And this side is chemically. the same compound that the one in hemoglobin is called a hem group that has an iron in the center. So many poisons like cyanide or I mention also uh carbon monoxide will enter that catalytic site and prevent the enzyme then to catalyze the reaction of uh

converting oxygen into water that is the one coupled with the ATP production. So when that process doesn't happen, that is enough. for neurons to atrophy and degenerate just uh due to this uh lack of uh energy metabolism. There is another process, and cells uh do this in many different ways. One way I can illustrate is when this uh oxide of phosphorylation is compromised.

the permeability of the membranes in the mitochondria change and then some small compounds inside the mitochondria, for example, in this that I talk about the electron transport chain. The one that carries an electron to cytochrome oxidase is called cytochrome C, not to be confused with cytochrome C oxidase, which is a large enzymatic complex.

This is a very small protein that carries an electron from Uh cytochrome oxide is also called complex four of the electron transport, so it carries it from complex three To complex four. Well, if that membrane permeability changes in mitochondria because of that process gets compromised, that cytochrome C permeates out of mitochondria. And when cytochrome C permeates out, this is called a signal for cell death. It's also called an apoptotic signal.

So we have a built in mechanism that if we don't have enough energy in production happening in mitochondria, the mitochondria will signal the cell to To self destruct by the release of these mitochondrial proteins, cytochrome C, the little one. So this is a direct way to link cell death with mitochondrial phones. There are also some other indirect ways mitochondria in order to get oxygen, they need delivery.

from the circulatory system. So there is a so-called neurovascular coupling in which the primary is the demand for oxygen by matochondly respiration. And when mitochondria respiration then accelerates, uh one thing that happens is that you consume more oxygen so locally in that in those mitochondria oxygen levels start going down and down. When that happens.

The same enzymes, cytochromo mitochondrial cytochromoxidase, switches from reducing uh oxygen to water of which there is little oxygen to work with to catalyzing the reaction of using nitrate to produce nitric oxide, another gas Well that nitric oxide. acts as a vasodilator in the local microvasculature. And that change then allows more blood, more oxygenated blood to reach that area where those mitochondria reach.

tissues like the cortical tissues in our brain around synaptic contacts need uh to produce more energy. So this is a constant process and then It can operate in the in the in the opposite direction, so it can slow down the mitochondrial function, the nitric oxide. by occupying that catalytic site of the cytochromo oxidase. But it is a continuous we we physiologically continuously are adjusting. If there is enough oxygen, we reduce it.

with cytrochrom oxidase. If there's not enough Saltochrome oxidase catalyzes reaction of more nitric oxide, we get vasodilation, we get more oxygen to through the circulation. bound to uh hemoglobin. And we can measure these things in vivo. We can measure oxygenated and deoxygenated hemoglobin uh from these uh brain regions that we're uh stimulating.

So it is possible to see these uh hemodynamic processes. Uh unfortunately I have to say there is a caveat here that a lot of work uh is done in mitochondria is done in bitroom. And when you have a situation in vitro, all of this scenario that I just presented to you doesn't happen. So you can learn certain things at that level, but you cannot really learn what is happening in this neurovascular coupling that is operating in a living organism, in particular a living brain.

And uh this has led to some apparent conflicts or for example, believing that some mitochondrial process was not affected by photobomodulation because it doesn't happen in Bruce. Well, it shouldn't happen in vitro if it works the way it uh that I'm talking. And one of them is for example just measuring the amount of cytochrome C that becomes oxidized by donating that electron to cytochrome oxidate.

And that is not an appropriate way to measure what the cytochromox is functioning, even though it's a standard way to measure chemically or with a spectrophotometry, because the photons are being absorbed directly. by cytochromoxid bypassing that step. and and then pushing the electrons, uh the the photons are producing the photoelectric emission.

directly to the LC and so in that paper that we were talking about uh light buckets and laser beams, you see a presentation of that apparent conflict by one of the contributors. that I uh challenge uh during that workshop. And uh unfortunately to be able to integrate different levels of analysis is not not always uh straightforward and can lead to this apparent discrepancies.

Yes, you can certainly imagine that would be the case in this instance. I mean I think it's fortunate that you were there to challenge that, because otherwise it would go unnoticed. Yes, and and and then uh it just adds confusion uh to the feel if you don't look at the details of what's going on in the different studies. Right. The study itself is right.

But uh the conditions are not the ones that are happening in in vivo. So in in reality our focus then has moved, even though at the beginning we did in in vitro and and cultures cell culture. It it is always to test this uh in vivo in living uh animals and humans. Yes. Uh so that's way one of uh My heroes, Dr. Louis Sokoloff, the former director of the Laboratory for Cerebral Metabolism at NIH. uh used to say something in in Latin in vivo veritas yeah in in life truth

And that's a motto I uh follow in my lab. Even though at the beginning we have to know, you know, baby step. and and see how the systems work in a more uh simplified manner. But uh if you keep insisting that that's just how it works in the living organism, you're just not reaching the truth. Agree.

Well that was really interesting and you know we've talked about the potential of photobiomodulation as applied to neurodegenerative disorders, but could you also talk about the possibility of counteracting some broader sort of general undesirable aspects of aging beyond uh Parkinson's or Alzheimer's or other neurodegenerative disorders, but other aspects of age.

Yes, uh one of the advantages of uh doing the photobomodulation and seeing the beneficial effects is that clearly they are not necessarily linked. to impacting specific processes that may be happening, for example, in Parkinson's disease or Alzheimer's disease. They are uh acting on a more general process that involves mitochondrial physiology. So this mitochondrial physiology is present all the time in the living organism, so in uh ha but as we aged.

Mitochondrial function becomes more compromised. This is uh something that's been known for a long time. The mitochondrial theory of aging, if you wanna call it that way. Whenever some of these mitochondria are having difficulties in their machinery, they tend to divide more often than the other ones that don't have the same issues. And when that happens as time goes by, you're creating mosaics of different mitochondrial lines.

and the lines are reproducing the more are the ones that have more defects. So as we grow older, our neurons for the most part are not replaced. So we are living with the same ones that we were born with. So they contain more and more of this inef inefficient mitochondria, and this is uh believed to be one of the contributions to this uh general biological aging processes.

This is manifested at the behavioral level by having a cognitive decline. It is usually in healthy elderly notice uh with what is referred to as a subjective. Memory concern or subjective cognitive concern, and that people realize that they are forgetting uh things. The first things that that happened from a aging point of view uh affect shorter term memories like the one I mentioned, working memory, like remembering where your car keys were a minute ago, or if you just lock the door.

a few minutes ago before you're moving out, uh and these are prefrontal base. In other words, the prefrontal cortex, which is the last one to mature in the human brain. is the first one to start showing difficulties uh as we grow older from the point of view of uh cognitive behavioral changes. And these affects not only higher order so-called functions like problem solving, but uh memory is the one that uh working memory is the one that uh shows up first.

So you can intervene at that point. That was one of the studies that that we did. That wasn't a large enough study to be conclusive. Uh we only had a dozen participants. And we can demonstrate that uh doing this uh once a week for five weeks to have significant changes in your working memory. and sustain attention in an older population.

We also did other measurements like uh looking at carotid ultrasounds to assess their level of perfusion to the brain. And we also used MRI, FMRI to look at uh changes uh directly. However, the important point is that this can be done in healthy aging. As long as your mitochondria is still responding to being able to produce this process of oxidative phosphorylation. This process is going to be facilitated by adding this light.

And one of the reasons is that uh this enzyme, for example, cytochrome uh C oxidase, is what is called an inducible enzyme. What that means is that if you increase your energy demand the enzyme will put into process a mechanism to increase its concentration to increase its copy numbers inside mitochondria. And this is a mechanism that operates at many different temporal levels Some of them are very quick. For example, the M sign may be right in place, this so called

an intra membrane enzyme that goes in the inner membranes of the mitochondria. And the enzyme may have, for example, all of the ten subunits that are or synthesized in the nucleus in place. And may have two out of the three subunits that come from the mitochondria DNA. But it needs another one to finish the to become what is called the holo enzyme, the one that is functional.

So if you demand more oxygen consumption from brain tissue or muscle tissue I can use as an example as well, then it will quickly add this other one. subunit that is missing and become a holo enzyme that is able to do the catalytic uh reaction. of reducing oxygen to water. But sometimes you're missing not one, but missing two, three, and so on, and I can go on and therefore the process will take longer and longer.

We can see in animal experiments, we can directly look at the tissue, within half an hour, you can see dramatic changes, either increasing or decreasing the enzyme. Let me give you an example with uh uh an enzyme that is also inducible. In our liver, uh we have this so-called cytochrome system, the same, same name, uh over there, the most famous.

The toxifying one is called Cytochrome P four fifty. And uh If you uh drink alcohol uh on one day, the next day, you're gonna have more of this detoxifying enzyme available to you to detoxify that alcohol. because that first exposure to it not only make the enzyme do the detoxification, but it also induce more production of that enzyme. They we d we have the same for example in muscles, skeletal muscles, let's say, when we do exercise, when we do exercise, if we reach a point.

This is the point of you are breathing, let's say you are running in a treadmill, and you reach a point where you need more oxygen and you start breathing faster and faster and you breathe and breathe, but it doesn't get any better. It's because the rate limiting is not the amount of oxygen. The amount of oxygen is in the air around to you is available. It is this enzyme that will use oxygen in this mitochondria respiration that uh is all already occupied. You cannot accelerate the rate anymore.

but then you come the next day after you've done this and you'll be able to do more. because the en sign have been induced, you have more of it available. And this process can continue. So some people refer to this as neuroplasticity in the overall context of of a neuron, but it's something that applies to all of the cells that have mitochondria. this uh and these inducible enzymes are present in other situations as well. So the system has the ability to upregulate itself.

And these can be used in healthy people to optimize their performance. In other words, just like uh by exercising you can optimize your athletic performance. like photobiomodulation, that you uh accelerate uh oxygen consumption and have a longer lasting effect by this enzymatic induction, then you can also improve your cognitive performance.

And therefore this has applications in all kinds of situations, not only health related But individuals uh that are performing all kinds of tasks that for example, I mentioned at the beginning, uh you can improve sustained attention or vigilance. That's necessary in many situations that have individuals. that will benefit from improving their vigilance, not to mention working memory that is the one that is affected by aging more readily.

So I think this provides some examples and uh the ones that I mentioned were the ones that we had tested and uh shown that can be modified. by this transgranial infrared laser. What we're doing now is uh trying to see whether we can get the same effects instead of having a weekly laser intervention, having a daily intervention with the LEDs at home. so it's more convenient for people to use it and we can use

less light, making it uh even safer. And we know from animal studies that this is we call uh uh dose fractionation or fractionated dosing that is also effective. In other words, you don't give the whole dose in in one session, but you do daily sessions. And uh so we haven't published some of these studies uh on the duration of action and those responses, but uh that's what we're doing uh at the time.

That makes a lot of sense to me and it certainly seems promising direction for further investigation. Yeah, absolutely.

So as you mentioned earlier, transcranial infrared laser stimulation facilitates prefrontal energy metabolism and oxygenation and This produces cognitive enhancing effects that you described earlier this year in a paper that was titled Augmenting Internet Based Cognitive Behavioral Therapy for a Major Depressive Disorder. with transcranial infrared laser stimulation.

So this was the first study to investigate whether transcranial infrared laser stimulation would augment the antidepressant effects of internet based cognitive behavioral therapy. Really interesting. So can you walk us through this study and what you learned? Yes, uh this is uh one of the what I believe a a good example of how this tool of photobiomodulation could be used for diseases that involve cognitive decline. And the there are certain conditions

that I I think uh I look for when deciding how to apply this. For example, in the case of depression, we know the prefrontal cortex is a major player in the depressive disorder. So that's at the level of uh the neuroanatomy. But also at the level of mitochondrial function, we know that there is a hypometabolism that can be traced to mitochondrial respiration in the prefrontal cortex of people who are depressed.

There are some other areas of the brain a little separate from where we target that the opposite phenomenon is happening, that you have like a hyper metabolic area. For example, in the case of depression, that's a an area that is part of a limbic system that is responsible for this rumination that you have of these negative thoughts and emotions. ma le prefrontali, le anterior prefrontali regioni sono hypometaboliche.

So when you have these uh two situations then I add a third element that I think really improves this approach. For something like a mental disorder. And that is leading the prefrontal cortex in this case into an active state that is favorable to counteract what. the disease is doing. In the case of this study, what we were doing was uh then combining so called cognitive behavioral therapy. Uh one unique thing was that it was uh self administered uh through the internet using your phone.

So you we could monitor what what was happening, but they could uh do this So this results in in a in an improvement, but that improvement is not enough for uh reducing the depression synthesis. But you reach a certain point that the people that are improving, let's say they improve about ten percent over two weeks, because they are now in that improving condition.

Now we provide uh together the photobiomodulation. And it is uh sufficient just to to do it once, but we did it once a week uh for for example, in this case uh six weeks. and we tested them uh all along. And what we were doing was facilitating that process of then rehabilitating this uh prefrontal function by providing more energy to the system.

And that's the int what I call the intelligent way to use uh photobiomodulation in these uh diseases, though just simply as uh just having some people just receive the photobiomodulation and they're doing uh nothing in particular. that uh may not work and in fact we have tested that directly in the case of the operation. If uh you just provide the photobowel modulation and you don't do anything to get the prefrontal cortex. operating in a way that is antagonizing the mood the negative mood

then the photobomulation you're providing energy to a system that is not moving in the right direction. And we have demonstrated that now with two different forms of cognitive uh therapy that the one in this paper was uh cognitive behavioral therapy with on another one called attention bias modification. That is uh when uh people are depressed they look at a glass of of water that has

water all the way to the middle part of the glass and they say, well the glass is half full. And another person who doesn't have depression may say the glass is half

Excuse me, I say the half empty. Uh the other one will say it's uh half full. In other words, it's a negate it's a an attention to the negative aspects of of everything. Uh it's something However trying to we we have ways to try to modify this uh through uh that that people don't know that they're modifying this, but they don't work that effectively. But when we combine them with the photobowel modulation to provide energy to that prefrontal cortex,

then that learning that is going on is facilitated and they can improve. So this paper had that distinction. Of being the first one that is on in uh work control study in the case of cognitive behavioral therapy. And I hope that.

Some of my competitors that I uh use in photobommodation for depression, they just They just stimulate the patients or have them do this every day at home but they don't really are trying to put this uh region, in particular this prefrontal region, in working in the right direction so that they can benefit from this addition of uh energy to the system.

The results of that study certainly do seem promising and as you reflect on it, uh what do you see as the most exciting potential next research steps that you'd like to take uh to further this progress? Yes. Well I wanna try it in diseases, conditions that uh fulfill those elements that I mentioned, in other words that the prefrontal cortex uh has a important, major role to play in the particular function that we're looking at.

And that there is mitochondrial respiration involvement, which is the molecular target that we are uh addressing with this uh photoboom modulation. and in which we can see, for example, compromise cognitive and mood at the behavioural level. And uh for example, uh the other study that we published recently was with uh bipolar disorder. In the case of bipolar disorder it fulfills those requirements.

Uh one of the things that happened in individuals with bipolar disorder is that as they grow older, for example, they have a much larger cognitive decline than individuals of compatible age that do not have bipolar disorder. So right now, the treatment of bipolar disorder focuses on the mood stabilization, so-called mood stabilizing drugs. are very effective. There are some issues like compliance, but the mood can be stabilized. However, they are not addressing this cognitive decline.

And this is going to decline result from the compromise of this prefrontal cortex and the hypometabolic state in which it's... Mitochondrial are operating. So in that study we found we we use uh remitted bipolar disorder participants, meaning that their mood was stabilized. We had to test this every week. psychiatrists will will have to verify that this was the case. It was very uh and we will be taking uh fMRIs every week, uh following these people uh weekly for again a period of six weeks.

and also doing battery of uh neurocognitive testing. So it was very difficult study, so we had to lower the number of uh subjects. However, it it uh proved the concept that uh we could facilitate their cognitive improvement in in a population where this is not being addressed by any type of uh medication or intervention. Right, that's a very tough ailment. Uh yeah. I have a former colleague that suffers from that and uh any progress in that direction would certainly help a lot of people.

Yes, uh that's uh one that we want to extend that initial study to uh larger scale and of course Now we don't need to uh do this every week, fMRIs which are very costly, and taxing for these uh populations of people. that they have to come to the lab and undergo these procedures. So that's uh one that that I plan. I have a really good uh colleague, the director of the uh center for bipolar studies here at uh university.

uh doctor uh George Almeida is my collaborator in that and his team. For all of these studies I l I look for collaborators that are experts on the particular uh condition that I'm trying to target. That's why uh And I did that for for depression also with Doctor Chris Beavers who is uh All this research is on unipolar depression in adults, the population that we use. So the other one that we uh just submitted for publication that maybe is part of that traffic jam somewhere, is on uh ADSD.

So, in that population, it fulfills these characteristics of a dysfunctional hypometabolic prefrontal cortex. that is leading to this impulsivity, the inability to inhibit behavioral responses. And in that study that hasn't been published yet, uh we show that we can significantly control the impulsivity in ADSD patients.

And we did uh a lot of uh this studied uh that involved uh hundreds of participants, both uh with and without ADST. And it's gonna be the dissertation of one of my graduate students. ご視聴ありがとうございました first two studies uh we combine in one paper will come out uh soon and we follow up we're gonna follow up uh that with uh more uh uh protocols that are more suitable for longer lasting type of interventions.

And in the pipeline I uh have the fortune of had many millions of dollars uh given to our group for studying uh autism, what is we normally referred to as autistic uh spectrum disorder. And uh we're just starting those studies and recruiting uh people. Again, because we found we convinced ourselves there was a prefrontal component, a significant prefrontal component, and mitochondrial respiration was involved.

And some of these phenomena that is happening can be also influenced through the prefrontal cortex. The prefrontal cortex is the CEO. of the brain, just like uh Dr. uh Kent Ford is the CEO of your institute. So it has the uh capability to influence just about all other areas of the brain. There is no other area of the brain that has more interaction with the rest of the brain. So providing this energy to that CEO prefrontal part of the brain actually helped orchestrate widespread network.

Not just a local effect on the mitochondria there in the tissue, but because these areas communicate with each other forming this network. Uh we have that we have shown this in both animals and humans now. You can have these uh widespread uh effects on on networks are participating in this uh more complex cognitive and emotional function.

So that's a direction that that we're gonna continue following. And hopefully we'll have donors and foundations that will see it uh our way and not just uh fun things that are just uh Unfortunately, there is a belief that many saints are simpler than and that they just can be dealt with let's say at the genetic molecular level but in our hands we think that this approach can already produce benefit even if we do these things in parallel with these other approaches.

It's very interesting and it seems like you're been very busy but you're also have a fruitful path in front of you with more opportunities ahead. Yeah, I I hope so and I hope when the public uh knows what's happening and again there are many people who are motivated for a technique in which there is no medication or surgical intervention involved that has shown a really good safety profile.

And that presumably they can have an inexpensive device uh eventually available that they can take home and benefit from these. But again, uh we have to do it in an intelligent way, that is uh we have to combine the photobowel modulation with an approach that is getting the brain in the direction that we want it to go. And then we're gonna feed it with this source of metabolic energy.

Have you ever looked at photobiomodulation, perhaps in combination with something like transcutaneous vagal nerve stimulation? No, but I have a new postdoc in my lab that is working on that area and he wants me to try this. In fact, One thing that we can try is actually using the laser to stimulate the vagus nerve transcutaneally in the neck, uh and and see how that compares to the electrical form of stimulation.

One of the big differences between the electrical and the optical or stimulation or photonic stimulation is photons are absorbed by the tissue. So they are constrained, they don't spread out. Either they are absorbed or they're reflected back out of the tissue. In the case of electricity, it tends to propagate throughout the body. So the two techniques do not work in the same way. When you apply electricity, you essentially

an electrical field to where neurons are, you you're pushing them in a particular direction and that direction is costly. In other words, there's gonna be an energy expenditure. When you uh deliver the photons you're facilitating the energy in the system, but you're not pushing them in any particular direction. So that that's why you have to provide that uh that guidance that uh with with another cognitive therap therapy or

uh for example, or mood stabilizing therapy. In fact, uh we found uh synergism in the bipolar study with patients who were most stabilized but that it inc it included, in addition to the mood stabilizing drug, it included a particular type of antipsychotic medication, Qai Tipping, that is known to facilitate prefrontal metabolism, which is a phenomenon that is really not pay attention to in psychiatry. In other words, they use drugs

based primarily on neurotransmitters, neuromodulator uh considerations. But they don't uh really I don't know if they don't care or they don't study how they affect uh energy metabolism or mitochondrial metabolism. And it turns out that some do in a beneficial ways and others uh do not uh seem to have much of an effect and others uh negatively affect mitochondrial respiration.

So we find that the if you have on board, the one that also facilitates mitochondrial respiration in the prefrontal cortex, like this uh particular one, uh guitepin, then those individuals uh are high responders. to our intervention. Whereas the o the ones that uh are with uh drugs that uh actually interfere with mitochondria respiration then they become low responders. Yeah makes sense.

And uh this is something that is uh entirely new, the idea of uh understanding mitochondrial respiration, mitochondrial function. in the context of psychopharmacology. I think we need a new kind of a metabolic psychopharmacology. And this uh technique, this combination actually helps to point to that.

Yes, very interesting. And back to my uh a question about transcutaneous uh vagal nerve stimulation coupled with photobiomodulation. We have some colleagues here that are interested in that and been thinking of potential research targets there. Episode one seventy nine with JP Erico. uh would be something that the post your postdoc might enjoy listening to. It's all about vagus nerve stimulation. Uh he's the inventor of a lot of those devices

Some of which we've used in research for DOD and uh that would be relevant. And then Kevin Tracy also I don't remember the episode, but he does the implantable vagal nerve stimulus. Yes. One of the questions uh that I have, uh as you know, I have a PhD in anatomy and neurobiology, so I I I'm concerned The vagus nerve in that part of the neck, it is uh wrapping around the carotid artery. So when you stimulate that electrically, I did my

dissertation with uh electrophysiology, you're gonna affect uh not only the vagus nerve, you're gonna affect the the carotid. And that may have an impact on your circulation to the brain. And some of the effects that we are ascribing to the vagus nerve may or may not be also the result of this action on the carotid circulation. And this is something that I haven't seen uh disentangled and it's probably not gonna be able to uh

It probably be very difficult to disentangle, but I think there'll probably likely be uh hemodynamic responses that are unrelated to the vagus itself, but are related to the carotid artery. And it is something that often happens in fields that you're focusing on only uh part of the picture. So that's one thing that we're gonna try to see

whether we c can do s things in a clever way to try to disentangle the separate contributions from these two structures in the neck that are associated uh anatomically. I think that disentanglement will be tricky. Yes. But if it's uh if the benefits are there, we just need to understand it and not try to control that. Uh but uh I am sure that both Could potentially be beneficial, especially in the older population. A major problem

is uh the vascular supply to the brain. So that could be a population where that part of the of the stimulation will be very relevant. By by the way, mitochondria still respond really well in the older people and we demonstrated this in animals and humans. And the reason is that uh it's basically you start with a lower baseline in the older individuals.

and then you can increase this metabolic resp respiration to a larger degree than in a healthy young individual which is already near asymptote or ceiling. in terms of this metabolic capacity. So sometimes those things can work in favor. However, it is very difficult to improve the cerebral blood flow. And the medications that we have, for example, to control uh hypertension, they they don't help. No, I'm sure. And sometimes uh side effects they have things like uh depression.

because they they compromise some of this uh uh supply to these uh highly demanding regions like this uh cortical region. So yeah, there are many challenges out there and I'm uh very uh fortunate that we have a a really good group and that we are always in collaboration with others for the particular topics that we address.

I think that's a great way you approach it. Rather than develop sort of a second tier expertise on some topic, you partner with the people who are really, really good at it. and then bring your expertise to the table and that strikes me as a better way of going than some folks.

I understand that you've been thinking about easing yourself a little bit away or a little bit out of animal studies and having more focus on human studies and frankly I certainly encourage that transition and it uh aligns very strongly with our approach here at IHM C when we have work that really does require animal work, we usually partner

for another entity to do that work and we do the human part. So I'm I really support your perspective. Uh what kind of uh human trials are you thinking of next? Yeah, the next one uh we're gonna do we're gonna follow up on the ADST with repeated treatment. So we're gonna see whether we can have they have a longer lasting impact on impulsivity and memory and some

Some uh cognitive measures that we're doing with this population. And we're doing a very large clinical trial, just starting out recruiting. uh with the autistic spectrum disorder. My goal is to have two hundred and eighty participants half of them, I mean, they will be randomized to the cham condition or the active photobound modulation condition. And I w are gonna have three cohorts, children, adolescents and adults.

So that's the next focus that we have is on the autism study and I have a lot of our effort uh focus on that, the majority of our effort It's very challenging. We again have to partner with uh experts, for example, in autistic children. How do we deal with autistic children? How can we create an environment for them to cooperate in the lab? We realize things uh

there are practicalities like what is called level three autism that is a very severe. Uh well they they won't let you put any anything on their body or uh follow the instructions or There are some of them that have very serious comorbidities, neurodevelopmental defects. And so we cannot do all uh in e everyone in the spectrum with this technique. So we ha we have learned and uh we are collaborating then to to

And also we understood phenomena that are related. Like at the beginning of the talk I talked about the microbiota. Well now we we're uh doing uh stool samples where we're measuring the microbiota. in this particular out autistic population because they do have really uh important interaction between the gut and the brain. The deficits are bilateral and they influence each other.

And so we are going to study and hopefully pioneer doing interventions that will affect uh the microbiota using photobiomodulation. And uh we are in the process of doing that. Really? With the institutional review board uh to do all of these things and uh uh having to upgrade facilities and create biosafety facilities for doing some of these uh bio specimens and so on.

And uh it's taking time and effort, but uh we we are still doing it. And in a couple of months I'm going to be uh seventy years old. And uh I plan to continue doing this uh at least for the next twenty years. Wow. I hope you're using uh all of your best techniques on yourself. Yeah, only as needed.

So as always Francisco, we absolutely enjoy chatting with you and after hearing you just now talk about your future research and your would you say twenty more years of research? I think we should plan on having you back on some talk in another five years and keep that a regular pattern. So if that works for you, it works for us.

Uh five years, I think. More recent years. Yeah, yeah, we'll do three years. Three years sounds good. Because at the rate he's going, he'll have lots of exciting things to tell us about in three years. Let's hope so. Uh I hope not to have another uh But uh thank you very much. I I really appreciate the opportunity to communicate with you and to be able to amplify this uh through your media. Uh we we enjoy it very much and thank you for coming on STEM Talk. STEM Talk STEM STEM Talk

Well Kent, as you know, much of my research career has been devoted to studying as well as better understanding therapies that can protect the brain. So I really enjoyed today's discussion with Francisco. He and his colleagues have been so productive over the past five years since we last talked. And it was a great idea to have him back on the show.

The potential of photobiomodulation and transcranial infrared stimulation to become applications used not only for neurodegenerative disorders, but also as therapies to counteract neurocognitive issues that arise from aging. This is both promising and frankly really exciting work.

So this is where I just go ahead and raise my hand in strong agreement with you, Ken. Uh so again, we're super excited to have this discussion with Francisco. This is Don Carnegie signing off. And this is Ken Ford saying goodbye until we meet again on STEM talk. Thank you for listening to STEM Talk. We want this podcast to be discovered by others, so please to iTunes to rate the podcast and perhaps even write a review. More information about

Our website, stemtalk.us. There, you can also find more information about the guests we interview.