Okay, in this follow up to the first part on mitochondria and bipolar fatigue, let's look a little more about what's going in the brain with bipolar and energy.
First off, let's understand what an energy consumer the brain is to begin with. Your brain will consume twenty percent of all your body's total energy. Yes, you heard that right - twenty percent. That's approximately twenty percent of the oxygen that your lungs put into your bloodstream and about twenty percent of the nutritional energy that enters your bloodstream through the foods you eat (we'll get to this another time, but trust me, you want to pay a whole lot more attention to what you put into your body). All to that little three pound organ between your ears.
Now that's in a normally operating brain. Bipolar brains are far from "normal". I don't, by the way mean that to be in any way disparaging, but it's just a fact (albeit not a widely known or precisely understood fact); bipolar brains operate differently than that of the general population.
Bipolar brains tend to activate far more brain regions much more intensely when manic than non-bipolar brains. While I can personally attest to this, brain scans also bear this out.
The top is a normal control subject, the middle a hypomanic brain and the bottom depressed. The brighter yellow or red the region is, the more activated it is.
It is hard to understate just how active a manic or hypomanic brain is (I'll leave distinguishing between those two for another time). And again, without having experienced it, it is utterly beyond what anyone with a 'normal' brain can fathom. It really does feel like your brain is lit up like a blast furnace. Your brain feels like, and is running on all eight cylinders (usually, as we'll see, the brain actually limits the number of "cylinders" running at any one time). Massive amounts of neuronal real estate is fired up, regions that would not normally operate all at once (not all of this "fired up neuronal activity" is for the good, but again, for another time).
Not only is the brain more fired up, but it won't shut off. I once went thirty-five straight days with virtually no sleep. I've read reports of even longer stretches. Long periods of very little or no sleep is a hallmark of mania or hypomania (this, it must be clear, is not the same as insomnia and restless inability to sleep). Thoughts during this time are going to be happening at a breathtaking pace (not all necessarily for the good, either).
All of this means not only way above average numbers of neurons and various circuitry are activated, but for much longer durations than nature ever intended. In just a single thought there is an enormous amount of activity and energy requirements so one can well imagine how much demand there is being put on energy during manic phases. And here's the thing with brains: they are evolved to be highly efficient in energy conservation. Generally, a brain will only "bring on board" a limited amount of regions at any one time (other than for perhaps for brief bursts) for the simple reason of conserving energy. In times of crisis, for example, it will shut down parts of the frontal cortex (where deeper thought usually takes place) and fire up other regions (or put them on higher alert). It does this to make the most efficient and conservative use of available energy not only for the brain, but throughout the body.
In other words, it simply has not evolved to run at the energy outputs seen during manic/hypomanic phases for that long.
I have long considered bipolar disorder to be largely a disorder of brain energy allocation. I wrote this: "Whatever mania is - and as I said, I am scouring the earth looking for the neuroscience to this - it is energy at its core" in a post last December explaining bipolar disorder so it's nice to see serious researchers coming to the same conclusion:
"Bipolar disorder seems to be a disorder of energy; too little in depression and too much in mania," said Professor Michael Berk, who is leading the study. "This suggests that if we can usefully target energy, we might help depression in bipolar disorder"
[Professor Berk is leading the study cited below]
Energy is not in infinite supply. It does not just materialize out of thin air. As we saw in the previous post (albeit very briefly), mitochondria manufactures energy in all the cells in our body and brain. I personally believe, mitochondria and the neurons' energy are particularly at risk for damage (there's too much background to get into as to why I believe that but I can assure you it is a very well founded idea).
Mitochondria depends on numerous factors to manufacture that energy and when demand is high, those factors are not going to be able to keep up forever. That's just kind of cellular biology 101.
So just for starters, with high energy demands during a manic phase, those supplies are just simply going to be exhausted (in the literal sense of "running out") at some point. This is easily observable (and likely easier to understand) in muscle cells - put them under demand for too long, and they will burn out and you'll literally not be able to move a muscle.
So without going into a lot of long scientific explanation, I think we can fairly understand that aspect of the cyclical nature of bipolar - the brain simply, just like a cellular structure such as a muscle, needs recovery time after a high demand period. But this does not fully explain the long term debilitating fatigue that some bipolar patients (though not all) suffer through.
Now I have to remind that there is no single one thing going on in bipolar disorder and I don't mean to suggest that energy and mitochondria is the end all to be all in understanding and treating bipolar; it's just one piece of a very complex puzzle. Certainly dopamine is a major factor. I've written elsewhere a small amount on the huge role dopamine plays in all human behaviour and dopamine has long been thought to play a major role in bipolar. Dopamine, just briefly, is greatly involved in what controls our motivations and drives (and also is widely implicated in many addictions, such as compulsive gambling). When manic, our motivations and drives are on hyper-drive and the role of dopamine in this is why anti-psychotics are almost always prescribed (anti-psychotics are dopamine blockers at the synaptic level).
The "wakefulness" neurotransmitter norepinephrine is also thought to play a large role (which I touched on here).
These and other factors (that I hope to explore in more detail one day) are part of what gets manic brains so fired up. And these high energy demands are just part of what's going to burn out the cellular energy factories, mitochondria.
But there's more.
That sleep the brain doesn't get when manic? Bad news. I'll not get into this too deeply here but as I've written elsewhere, sleep is very critical to neuronal function. Briefly though, it has to do with neurons needing the down time of sleep for basic housekeeping such as "waste disposal". This is more cellular biology 101 - cells take in substances to produce energy, that process produces waste byproducts that have to be removed. That waste is toxic when build-up occurs. There is much research to suggest that neurons (along with all other cells in your body for that matter) need the sleeping state in which to perform this waste disposal and rid neurons of hazardous waste build up (I bet you never thought of it that way before, did you?).
But there's more yet and the news gets worse.
Mitochondria and Stress:
There is massive amounts of literature on the relation between stress and neuropsychiatric disorders so I can only hope to summarize this very briefly for now. There are also great bodies of literature on stress and cellular damage throughout the body, perhaps best summarized by Robert Sapolsky's lectures and books. While the stress response system is a complicated piece of business (and what isn't in the brain?), it more or less boils down to the effects the stress hormone glucocorticoid has on various brain systems and components.
Chronic stress - which essentially means chronically elevated levels of glucocorticoids - is really bad news for all of your health. While what particular part of your bodily systems it effects will be determined by genetics (a rather large subject in itself that we'll leave for perhaps another day), in the brain it's going to cause DNA to be changed this way or that, cellular damage, compromised immune systems, neuronal death (particularly in the hippocampus - hello, Alzheimer's and dementia) and, to get to today's topic, damage to mitochondria.
To get a bit of an understanding of the role of GCs (glucocorticoids) and mitochondria, we'll look at this excerpt from this paper:
Such work suggests that, under physiological conditions, GCs enhance (my emphasis - BGE) mitochondrial functions to provide cells with more energy for coping and adapting to acute challenges.
So far, so good. This is what all the literature on GCs will show - short term gains in times of, as they put it, "acute challenges". Which in evolutionary historical terms (IE: what our brains and bodies are most evolved/adapted for), means escaping a tiger attack or vigorously hunting for food. These are short term crisis situations though.
Further now from the excerpt:
However, chronic stress may lead to chronically elevated levels of GCs, which in turn may reduce cell functioning via the interaction between GRs/Bcl-2 and mitochondria. The decrease in proper cell function may contribute to the pathophysiology of several stress related mental health disorders, including major depression.
Sapolsky's work takes most of the "may lead to" out of that equation and establishes it almost without question as will lead to chronically elevated levels of GCs while furthermore documenting the cascading amounts of damage they will have in neuronal circuitry and neurons (which I summarized in an earlier post).
So what that latter excerpt is saying, in layman's language, is that chronic exposure to GCs will go past the short term energy boost and instead - pardon my French - fuck up mitochondria's mechanisms for converting various substances into energy.
How bad this damage may be and how repairable it may or may not be are matters of ongoing research and study. For now though, I think we have to take "subject A" - the well observed (and experienced by moi) aspect of bipolar depression - the chronic and debilitating fatigue, add it to our now deeper understanding of mitochondria's vital role in producing the mental and physical energy we experience and need and then add these two to what appears to be growing evidence for that role being damaged or compromised by chronically elevated levels of GCs and make a conclusion that damaged mitochondria are in large part responsible for the fatigue suffered by many people with bipolar depression and major depressive disorder (and, some literature suggests, schizophrenia).
There are other factors in the lethargy and lack of motivation experienced during depressive phases - and I will get to those in other posts - but for understanding the worst of the fatigue, I do think we have our smoking gun.
But I always like to include multiple sources, so there's more. The role of mitochondria dysfunction is becoming more widely known and is the subject of more and more research. A reader of this blog brought the following research to my attention. This is from a university group in Australia and New Zealand. The nature of this research is to test a special cocktail of nutrients meant to boost mitochondrial function, an outline of which can be found here.
What I found of interest is support for the theory that stress is the source of damage to mitochondrial functioning and furthermore, this is the basis for bipolar fatigue.
There is a growing body of evidence supporting the presence of oxidative stress states in bipolar disorder. With high levels of oxidative stress comes mitochondrial dysfunction.
Oxidative stress is outside my body of reading so I'll leave an understanding of that to what appears to be a well written and sourced entry in Wikipedia. (I don't like relying on Wikipedia for a source but often it really does summarize various bodies of research as well as anywhere). While I cannot claim an understanding of the exact mechanisms of oxidative stress (gads, yet more reading for my 'to-read' list), it does appear to me that oxidative stress damage (and the world of anti-oxidants to combat it) is different than GC stress damage.
So to summarize, mitochondria are responsible for all cellular energy generation. Their functionality comes under attack in bipolar, it would appear, via four possible means:
- plain exhaustion (again, in the literal sense of supplies running out) due to chronic overuse during manic phases (in the brain, this is just as in any over-taxed cell that simply shuts down due to overuse).
- build up of toxic cellular waste products as a result of lack of sleep during manic phases
- grave, long term damage due to chronically elevated levels of glucocorticoids which comes from chronic stress (which will arise from a wide variety of sources both within the brain of a bipolar person and from external stressors)
- oxidative stress damage
Stress and Bipolar Disorder:
So what does stress have to do with bipolar disorder? Well, almost everything. And in better understanding what stress is and how it affects brain components, we can better understand not only what triggers bipolar episodes, but more importantly, what to do about it.
And in understanding the role of stress - or the stress response system - we'll better understand why some people get hammered more by the down cycles of bipolar and why some develop the debilitating chronic fatigue well documented to plague many people who are bipolar (and is the main reason, IMO, it IS a disorder for many).
But that is a longish subject and will have to wait for the next installment.
Academic publications, books and university lectures of Robert Sapolsky
Searching for the Mind with Jon Lieff (which was recently named one of the most comprehensive sources of neuroscience information on the web)
Mapping the Mind by Rita Carter
The Willpower Instinct by Kelly McGonigal
Numerous academic research articles supplied to me via neuroscience acquaintances linking acute stressful events or chronic stress to neuropsychiatric disorders which, while not represented in detail here, laid the groundwork for establishing stress as a key factor in not only triggering psychiatric episodes (schizophrenia, bipolar, various forms of depression, anxiety, ADHD among others) but also in determining their long term outcomes.
Please continue to Part Three of the series.