Physiology behind the Magic Light Helmet for Alzheimer's

There have been a number of different blogs about the Magic Light Helmet for Alzheimer’s. Respectful Insolence and again! (Must be Orac's self-identification with blinking LED based intelligence boosting schemes ;), Science Based Medicine.

This is a more elaborate explanation of the quick comment I made at Science Based Medicine. My explanation is based on my understanding of the cause of Alzheimer's (which is not one of the common explanations (all of which I am quite skeptical of (in other words I think they are wrong)). I see Alzheimer's as being strictly due to low NO which then causes low ATP (via sGC), and invokes ischemic preconditioning (IP). The low perfusion is secondary to the low NO. Ischemic preconditioning can be mediated by oxidative stress in multiple ways. Normally IP is thought of as a good thing because it does reduce damage during ischemia. IP is invoked by brief periods of ischemia and after it is invoked organisms can survive periods of ischemia that would have been fatal. IP is a low ATP state, and it is also a low ATP consuming state. If organisms could be in the low ATP consuming status of the IP state long term, they would have evolved to do so. Spending less ATP on basal metabolism means more ATP for reproduction. Organisms haven't evolved to do so, which means there must be something incompatible with life and/or reproduction from being in the IP state long term. Neurons don't divide, so there must be something incompatible with long term survival for neurons to be on the IP state long term. I discuss more details of why accumulation of amyloid is a major outcome in Alzheimer’s below.

I am assuming that this Magic Light Helmet actually has physiological effects beyond the placebo effect. It might not. The placebo effect is mediated through NO, and all disorders associated with low NO are very susceptible to being improved by the placebo effect. That would include Alzheimer's. I will use the analogy of an internal combustion engine a lot. Not because it is an especially good analogy, but because it is easy to understand how bypassing the very simple controls of an engine to get “better performance” could easily shorten its lifetime by orders of magnitude. What does bypassing the extremely complex control system of the brain do? Most of which is completely unknown (but is likely already disrupted for that brain to have Alzheimer’s in the first place)? It is extremely unlikely (virtually inconceivable) that bypassing the normal control system of the brain would only have benign effects.

We know that Alzheimer's is not caused by a "deficiency" of light at 1072 nM. This Magic Light Helmet is not replacing some physiological need that is missing in Alzheimer's. The fundamental problem of Alzheimer's is low ATP supply (discussed below). Since the brain does not have photosynthetic centers to capture the energy of light at 1072 nM and convert that energy into ATP, any change in ATP supply can occur only via changing the regulation of existing ATP production systems via mechanisms susceptible to light at 1072 nM. Since physiology didn't evolve to be physiologically regulated by an external source of 1072 nM light these lights must be doing something else, something that is non-physiologic. Even if there are physiological receptors of 1072 nM light, they would be for sensory purposes (maybe setting day/night biorhythms?) and the levels used in the magic light helmet are many orders of magnitude greater, and narrow band rather than broad band natural sources (sunlight or fire).

If this NIR light does do "something", it pretty much has to be via modulation of kinetics of either free radical reactions, decay of "excited transition states" in activated molecules, or in photodissociation of things from other things (such as NO from cytochrome c oxidase). There could easily be hundreds of things that are being affected, none of which are well understood. Or it might just be placebo.

There are at least 4 main regions which might be important and which I will discuss, by far the most important is ATP production in mitochondria and I spend most of my time on that. Synthesis of compounds by the cytochrome P450 enzymes, catecholamine metabolism and acetylcholinesterase activity might be important too. There might be others, but these are 4 important ones, changes in any of them could conceivably be consistent with the "data" that a handful of non-blinded observers noticed improvement in 6 weeks of use. Although I will be discussing these somewhat separately, they are not separate. Physiology doesn't divide what it does into neat little orthogonal and independent boxes. In physiology everything is coupled to everything else. There is no evolutionary driving force to keep things separate or modular. There are only evolutionary driving forces for survival, and for economy (so more resources are available for reproduction).

ATP production

In neurons virtually all ATP is made by mitochondria through oxidation of substrates, lactate, ketone bodies, small acids such as acetate, aspartate. Mitochondria are small organelles that have a few thousand proteins, 13 of which are coded for by mitochondrial DNA, all the others are coded by nuclear DNA. Mitochondria have 2 lipid membranes, inside the inner one is where the DNA is and the protein manufacture stuff (the mitochondria matrix) and the enzymes of the citrate cycle and most everything that mitochondria do. Mitochondria work by generating an electrical potential and a pH gradient across that inner membrane. The different respiration complexes take electrons and protons from chemical compounds and extract energy from the chemical reactions as those electrons and protons are moved across the membrane and store that energy in the electrical and pH gradient. In the terminal enzyme, cytochrome c oxidase those electrons are gathered and 4 of them are simultaneously put onto O2 along with 4 protons making two molecules of water. Doing so many things all at once is a “tricky” and complicated thing for an enzyme to do. That energy gradient is then used to make ATP.

The 13 proteins are all parts of the respiration chain, usually the part containing the active site. All animals (except for a few invertebrates) have these same 13 proteins coded in their mitochondria. Plants have a few extra. These proteins are all large and quite hydrophobic. Why these (and only these) proteins are coded in mitochondria is not understood. I think it has to do with regulation of mitochondria, some of which has to be local to each mitochondrion and sometimes that regulation means turning off part of the respiration chain and then turning it back on. One mechanism might be destroying the protein and then making the protein again. In most cells mitochondria are close to the nucleus so that proteins can be made from DNA in the nucleus and then transported to mitochondria (in principle, whether this happens or not is unknown). In neurons that can't happen because the distance between the cell body (where the nuclear DNA is and the protein synthesis capacity) and mitochondria can be inches or even a meter in motor neurons. There simply isn't time for a signal to propagate from mitochondria to the cell body, trigger protein synthesis and then transport proteins out to mitochondria in need of them. If protein synthesis is needed for control of mitochondria, that synthesis must occur locally using locally available DNA.

If neurons are deprived of substrates, O2 and organic compounds, disruption of neuronal function (unconsciousness) occurs in seconds.

NIR does cause the photodissociation of “poisons” from cytochrome c oxidase. This is discussed in terms of NO in a recent article in Nature. They get the basic chemistry right, however they get the implications of how NO fits in physiology wrong. The problem is not too much NO, the problem is too little. One of the papers cited by the Nature article epitomizes much of what is misunderstood in the NO field (but the author is quite senior, so I won't link to the article). NO and superoxide can form peroxynitrite, however superoxide from mitochondria is confined to the mitochondria matrix, there are 2 lipid membranes the superoxide has to go through before it can get to the cytosol. Both of those lipid membranes have ~10x higher NO levels than the cytoplasm (NO partitions into lipid ~10x over aqueous). NO reacts with superoxide at near diffusion limited kinetics. It is completely implausible to me that superoxide could get out of the mitochondria matrix. Particularly when the mitochondrial potential (~140 mV) is going to keep the negatively charged superoxide inside. When peroxynitrite forms in the mitochondria inner matrix, it is consumed by cytochrome c oxidase, or decomposes generating NO2 (which is also a signaling molecule).

NO and superoxide only form peroxynitrite at near stoichiometric ratios. When NO or superoxide is in excess that doesn't happen. A much better conceptualization of what happens when NO and superoxide are generated in cells is by Wink et al. They make a very important (and correct) statement

"We demonstrate that the primary consequence of [superoxide] O2- generation concomitant with NO production is not the toxicity associated with the formation of higher nitrogen oxides, but rather the resultant phenotypic cellular changes that occur because of limiting the bioavailability of NO and H2O2."

This is precisely correct. The problem of oxidative stress is not the presence of nitrating NOx species, the problem is not enough NO. The problem of nitrated proteins in neurodegenerative diseases is from not enough NO, not from too much.

Of course what is a "poison" in one circumstance may be an absolutely necessary regulatory pathway in another. Normally cytochrome c oxidase is tonally inhibited by NO, which blocks O2 from binding and is the major regulatory pathway by which mitochondria regulate their O2 consumption. If you look at figure 1, you can see that in the absence of NO, mitochondria consume O2 down to ~5 microMolar. The solubility of O2 in plasma (assume same as in cytoplasm) at 1 atmosphere is 23 cm3/L (at 38 C) or about 1.1 mM/L. 5 micromolar O2 is then a partial pressure of about 0.0045 atm or 3.42 Torr.

The only reason mitochondria can regulate their O2 consumption is because NO "poisons" cytochrome c oxidase and inhibits O2 consumption. Remove that inhibition and mitochondria consume O2 to very low partial pressure, well below what is the "normal" basal O2 level at the location of the mitochondria. At "rest", the O2 flux to a mitochondrion in the heart is 1. The O2 consumption by that mitochondrion can increase by 10x. The flux of O2 from the blood vessel to the mitochondrion is purely passive down a concentration gradient. For the flux to go up 10x, either the gradient has to go up 10x, or the distance has to go down by 10x because the concentration at the blood vessel stays the same. For the gradient to go up by 10x, the concentration at the mitochondrion has to go down, and go down a lot, by a factor of 10x. It has to go down while the mitochondrion is increasing its O2 consumption by 10x. The specific O2 consumption by that mitochondrion, moles O2/mg protein/Torr O2 has to go up by a factor of ~100. This is only achieved by removing the "poisoning" of cytochrome c oxidase by NO during the “at rest” condition.

With NO blocking cytochrome c oxidase, the electron respiration chain becomes fully reduced and O2 can pick up electrons from complex III, forming superoxide. This superoxide is vectorally produced in the inner matrix, where MnSOD dismutates it at near diffusion controlled kinetics. NO also reacts with superoxide at near diffusion controlled kinetics and it is the destruction of NO by superoxide generated by too great a reduction of the respiration chain that lowers the NO level and disinhibits cytochrome c oxidase so that O2 can consume electrons (and be reduced to water).

If this light does dissociate NO from cytochrome c oxidase it would cause the respiration chain to become more oxidized and would reduce the quantity of superoxide formed. This would increase NO levels and upregulate ATP levels via sGC.

An analogy by looking at the regulation of an engine would be to consider that the “throttle” “poisons” the engine so that the engine does not run at 100% full throttle 100% of the time. What the Magic Light Helmet might be doing is bypassing the normal mitochondria regulation, an effect analogous to jury rigging a separate wire to the carburetor to bypass the normal controls. If you had only one mitochondrion to control, perhaps external control might work. Each cell has many thousands, if not millions of mitochondria. If they are not working together and sharing the load, some are working harder than others, consuming O2 that others could consume, generating non-physiological O2 gradients perhaps generating non-physiological gradients in ATP, or in other substrates consumed by mitochondria. A better analogy would be to think of it as a power grid, with millions of engines connected together. Removing the throttles on some of them might improve the total power production of the grid, until those engines running at 100% full power 100% of the time start to fail, or until the idle engines (those that are not doing anything) get shut down. Of course if the engines running at 100% full throttle were uniformly distributed it might work out. If they were only the ones within 50 miles of the ocean (analogous to limited light transmission in the brain), the non-uniform distribution might set up instabilities in power flow leading to roving brownouts or blackouts or even grid failures. Maybe not too bad for a carbureted engine, but what if they are fuel injected? What if your jury-rigged control bypass only delivered extra fuel to some cylinders and not others? Do you start getting bad vibration? Do you start getting bad fuel-air mixtures? Too rich in some and too lean in others? If you were as ignorant about engines as we are about physiology it would be easy to do serious damage due to ignorance. Of course the more ignorant you are, the more difficult it is to tell just how ignorant you are.

A figure that shows the mitochondria respiration chain is here. There is control mediated all along the respiration chain. Exactly how the respiration chain is regulated under what conditions in which tissue compartments under what normal and abnormal circumstances is a good question that all of the senior researchers working in the field would like to understand. This particular paper is about nitration of proteins in mitochondria under conditions of hypoxia and denitration when that hypoxia is removed. This nitration and denitration occurs rapidly and reproducibly. It is likely some sort of control mechanism for controlling each of the proteins that get nitrated and denitrated. The nitration is likely mediated via NO reacting with superoxide and forming peroxynitrite, or forming NO2, both of which can nitrate proteins. Precisely how that happens is unknown. Virtually all the nitration is on tyrosines which are in specific parts of the enzymes that are so regulated. Tyrosine gets nitrated more than other things because it is aromatic (has a benzene ring in it) and the pendant groups on that benzene ring direct agents that do nitration to specific carbons on that benzene ring. Tyrosine also tends to form tyrosyl radicals, that has an unpaired electron distributed on the aromatic ring (which stabilizes it somewhat). Tyrosyl radicals are much more reactive than tyrosine. It may be (actually is quite likely) that formation of tyrosyl radicals and then quenching of that radical by something else is likely part of a regulatory system.

Low ATP caused by low NO hypothesis of Alzheimer's

One of the most consistent symptoms of Alzheimer's is a reduction in brain metabolism. Amyloid (and all the other protein aggregates of the neurodegenerative disorders) is normally cleared by ATP powered proteases in the proteasome, or during autophagy (which requires an ATP powered pH gradient). My hypothesis of Alzheimer's is that the buildup of amyloid is a natural compensatory mechanism to cope with there being not enough ATP. There are simply more important things to use ATP for (when there is not enough) than to use it to get rid of amyloid (or to make new mitochondria). If the ATP setpoint is too low, my hypothesis is that ATP conservation pathways are invoked (which include not getting rid of amyloid) as in ischemic preconditioning. I discuss this in my blog on fevers and autism . Getting rid of garbage is something that can always be put off "a little bit longer" if there is something better to do. I think that Alzheimer's happens when that heuristic is taken a bit too far.

Just about every other physiological function inside neurons is more important than getting rid of amyloid. Nerve conduction is a lot more important. If your nerves are not conducting properly, a bear could catch and eat you. Keeping nerves alive is more important too. Amyloid buildup causes essentially no problems for quite a while, months, even years. My mother and both her parents died with advanced Alzheimer's, so I am not being flip, I know what it can do. But that the brain can function so well and for so long with such a serious decline in metabolism is quite remarkable to me. One of the things that has helped me in my research is that I inherited my mother's low nitric oxide physiology, so I experienced quite dramatic changes when I corrected it (I appreciate that my experiences are anecdotes).

The Magic Light Helmet might work in the short term for people who already have low ATP. I would be very concerned how it modifies the normal regulatory pathway(s) by which the number of mitochondria per neuron is regulated. My research indicates that regulation involves formation of long lived NOx species which accumulate in mitochondria and which release NO during autophagy and then trigger appropriate mitochondria biogenesis. I think those long lived NOx species include nitrated proteins, which derive only from the combination of NO and superoxide. The formation of superoxide by mitochondria under metabolic “stress” is then the signal by which the cell “measures” the metabolic stress of the mitochondria it has, and then infers how many it needs to make. In a neuron that number can be different by 3 or more orders of magnitude depending on the length of the axons.

In the rat CNS, mitochondria lifetime is on the order of a month. How long it is in humans is unknown. It might be somewhat longer, but likely not more than an order of magnitude. The turnover time for mitochondria might be inferable from the progression rates of some neurodegenerative diseases. If we assume that a neurodegenerative disease affects mitochondria biogenesis, and is not acutely toxic to mitochondria, then the minimum course of that disease might reflect mitochondria turnover. ALS tends to have a course longer than a certain minimum length. A more stringent criteria might be the woman who received an acute toxic dose of dimethyl mercury but had no symptoms for 5 months and was dead at 7 months post exposure. Her symptoms were consistent with neurodegeneration. If the mercury had acutely poisoned mitochondria her death would have been much sooner. If it only poisoned mitochondria biogenesis, then her survival to 5 and 7 months might reflect how long her inventory of mitochondria at exposure could sustain neuronal activity. In any case, a treatment for Alzheimer’s has to extend beyond several mitochondria lifetimes to be considered an effective treatment.

The Magic Light Helmet might slow the progression of Alzheimer’s for a while by operating existing mitochondria in a way that generates less superoxide. But that would likely compromise the regulation of mitochondria by superoxide. Mitochondria regulation by superoxide includes regulation of O2 consumption under normoxia and hypoxia, and very likely includes regulation of mitochondria number. The progression of Alzheimer’s could greatly accelerate at some future time when mitochondria wear out faster than they are replaced.

A (poor) analogy would be to suppose that one had a car with 100,000 miles on it, and it is starting to run not as well as it used to. A salesman says he can "fix" the car by installing nitrous oxide injection and by adding nitromethane to the fuel. Sure enough when you do that, the car "runs" better than it ever has. But if the car had been nursed along gently, it could have easily gone 150,000 miles, but with nitromethane it only goes 100,500. That is why long term trials with the proper endpoints (i.e. death) are most appropriate for terminal conditions like Alzheimer's. Four weeks is too short. I imagine that the right dose of cocaine or amphetamine might produce "improvement" in Alzheimer's for 4 weeks but would accelerate decline and hasten death.

On the Science Based Medicine blog, neurocritic made a comment about the result reported on the very rapid improvement of Alzheimer's on enterocept injection (into the spine). I see this as consistent with the low NO hypothesis of Alzheimer's with NO being what regulates the acute functional connectivity in the brain. I replied to neurocritic in this comment.

Dysregulation of cytochrome P450 metabolism

Cytochrome c oxidase is not the only heme enzyme inhibited by NO. All the cytochrome P450 enzyme are too. Many of them are active in the brain. How is changing the operating point of all of those enzymes going to change things? Very complexly, and very likely not in only benign ways.

There are about 60 cytochrome P450 enzymes, which synthesize such things as steroids, cholesterol via a reaction cycle that generates superoxide. Normally the P450 enzymes generate significant superoxide which is vectorally produced to the inside of the microsomes the enzyme is active in. Microsomes normally have superoxide dismutase and catalase inside them. Testosterone synthesis is known to be inhibited by NO.

Dysregulation of catecholamine metabolism

I bring up catecholamine metabolism because many aspects of it are also quite involved with free radical chemistry and so would likely be susceptible to disruption by NIR. Parkinson’s disease has some similarities to Alzheimer’s (it is characterized by buildup of protein inclusions too, but of a different composition). Dopamine pathways are highly involved in feelings of wellbeing. Parkinson’s disease-like symptoms can be reliably induced by killing certain nerves associated with the dopamine pathways. The usual experimental mechanism is with a compound that damages mitochondria (MPTP) in those neurons, causing their death via oxidative stress and ATP depletion.

Dysregulation of acetylcholinesterase metabolism

NIR does affect the activity of acetylcholinesterase enzymes in red blood cells (abstract only). Not surprisingly, the effect is complex with low levels reducing it and higher levels increasing it. Which is the Magic Light Helmet doing? Neither or some of both?

Acetylcholinesterase inhibitors are used to treat Alzheimer’s. There is a treatment effect, and the treatment effect is dose dependant, but the treatment effect is small. There does seem to be an association of increased executive function with increased inhibition of acetylcholinesterase.

If the Magic Light Helmet is inhibiting acetylcholinesterase, it is doing so in a spatially non-uniform manner. It might even be increasing activity in some parts of the brain and decreasing it in others. Because some nerve cells are larger than the region where the light has a single flux (and hence a single dose-response), some cells might experience both increased and decreased acetylcholinesterase activity but in different regions.

Expression of acetylcholinesterase is ultimately regulated in the cell body because that is where the DNA is that codes for it. If one axon of a nerve has it inhibited and one has it enhanced, how does the cell decide how much to make? What does that do to the actual operation and long term regulation of those two different axons? It would be extremely unlikely that the nerve cells most in need of having their acetylcholinesterase enzyme activity modified by the Magic Light Helmet were located in the regions of the brain where that could actually happen.

Safety

With no understanding of the mechanism there is no basis for saying if it is safe or not.

They claim it works, but offer no physiological explanation. They have a 6 week open label trial, but with no controls and no blinding of patients or investigators. All of physiology is non-linear. You can’t extrapolate from known conditions to unknown conditions when the underlying phenomena are non-linear (and unknown). The lifetime of mitochondria is likely longer than 6 weeks. Adverse effects might not show up during that time.

What concerns me most about this device is that the investigators don't seem to be asking the right questions about what it is actually doing, if it is doing anything. Rushing to human testing is (in my opinion) quite premature with something with little to no understanding behind it. This could easily be a situation where anecdotes were used instead of actual clinical trials and people become seriously injured.

Summary:

In summary, I have presented several plausible (but speculative) physiological mechanisms by which the Magic Light Helmet could have actual physiological effects. In none of these mechanisms does the Magic Light Helmet produce an effect that is representative of actual physiological needs that the brain has. The Magic Light Helmet doesn't regulate anything by any mechanism that is known or understood.

If it does any of those things it is likely to do so indiscriminately. There is nothing "magic" about 1072 nM, these investigators looked at a handful of wavelengths (where LEDs are available for cheap). Something like that might have a short term positive effect but is very likely to be very bad in the longer term. Physiology is too complex and too coupled to simply whack away at it indiscriminately and make it "better".