Wednesday, May 13, 2015

Bipolar, the Brain and Energy - Part Two

Okay, in this follow up to the Part One of Bipolar, the Brain and Energy, let's look a little more about what's going in the brain, the body and what we experience as energy. 

While I initially researched this series specifically regarding bipolar disorder, I want to say that what we will learn here does not only apply to bipolar disorder. Bipolar is particularly bad for burning out the brain and body at the micro cellular level, but since originally researching for and writing this piece in the spring of 2014, I've since seen and learned that people who are suffering from or have recently suffered a severe psychiatric episode, such as severe depression, anxiety and panic attacks accompanied by unusually long periods of sleep deprivation also very often suffer from debilitating fatigue. So there is lots to be learned here for anyone, I believe.

First off, let's understand what an energy consumer the brain is to begin with. Though it represents less than 2% of our body weight, our 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 as food). All to that little three pound organ between your ears. 

Now that's in a 
normally operating brain. Bipolar brains, however, are far from "normal", which is not in any way to sound 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, enormous amounts of research bear this out. This isn't a great brain scan but it serves well enough here to illustrate the point. 

At 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, but briefly, hypomania is "mania lite", a much milder form of a manic episode). 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). 

Now note the brain wide lack of activity recorded in depressive brains. This will make much more sense when we learn more about the role mitochondria plays in all cell functions but particularly in brain cell functions (which we will look at in more detail in Part Three). 

Not only is the brain more fired up, but it won't shut off. In the manic episode I experienced at the start of 2013 and which led to the state I now find myself in, I went thirty-five straight days with virtually no sleep. That's five straight weeks of maybe an hour's nap per day. I've read reports of even longer manic episodes. 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 and ideas during this time are going to be happening at a breathtaking pace (though not all necessarily for the good).

All of this means not only way above average numbers of neurons, neuronal regions 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 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 acute crisis, for example, it will shut down parts of the frontal cortex (where all kinds of higher human functions such as emotional regulation, judgment, risk evaluation among others usually take 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 years ago early in my exploration of what exactly bipolar is: "Whatever mania is, and I am scouring the earth looking for the neuroscience to this, it is energy at its core"
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 Part One of this series (albeit very briefly), mitochondria manufactures energy in all the cells in our body and brain. There is considerable evidence for the idea that mitochondria and the neurons' energy are particularly at risk for damage in psychiatric disorders or even perhaps that our mitochondria being prone to damage is the very source or core to may pychiatric disorders

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 indefinitely. 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. This would not only go a long ways to explaining the "crash" following a manic episode, but also in explaining the often debilitating fatigue. And while this does not fully explain the long term debilitating fatigue that some bipolar patients (though not all) suffer through, from all my research and using myself and my own case over the past three years, I will argue firmly that it is perhaps the biggest factor. There are other important factors as well that can lead to the post mania crash but those are something I'll have to get to in a separate piece.

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. We looked at dopamine's roles in moods and behaviours in this neurochemical in focus piece
 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 largely why anti-psychotics are almost always prescribed (anti-psychotics are dopamine blockers at the synaptic level). 

The "wakefulness" neurotransmitter norepinephrine almost certainly plays a large role in manic phases as would high levels of adrenaline and other stress response system neurobiology

These and other factors 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 or the insomnia that often comes with depressive and anxiety disorders?
Bad news. I'll not get into this too deeply here but as I've written elsewhere, sleep is also a critical factor in both neuronal and overall proper brain 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. Those waste products are 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 for laypeople and clinicians alike by Robert Sapolsky lectures and books. While the stress response system is a complicated piece of business (and what isn't in the brain?), the triggering of symptoms and the microscopic neurological damage found in psychiatric disorders 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) and other individual differences, 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, impaired memory) 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 one of the papers I came across when researching for this series

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 has done an enormous amount of work on glucocorticoids that very firmly establishes that not only will chronic stress loads lead to chronically elevated levels of GCs but also his work (and that of many others) documents the cascading amounts of damage they will have in neuronal circuitry and neurons.

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 greatly damage and impair mitochondria's mechanisms for converting various substances into energy, which again is what we're going to see manifested as the physical and mental lethargy and fatigue of the bipolar depressive cycle. And as I stated at the top of this piece, I can now see and have come across enormous amounts of supporting evidence that this mitochondrial damage will be present following many severe depressive and/or anxiety episodes. 

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 can draw some strong inferences. We can take take "subject A", the clinically well observed (and experienced by myself) 
chronic and debilitating fatigue of bipolar depression, add that to our now deeper understanding of mitochondria's vital role in producing the mental and physical energy we need to properly function day to day, and then add these two to what appears to be growing evidence for mitochondrial function being damaged or compromised by both being over taxed during manic phases and/or periods of severe sleep deprivation and 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 (led by the above mentioned Professor Berk). The nature of this research is to test a special cocktail of nutrients meant to boost mitochondrial function

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 in the body and brain. 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 and other Neuropsychiatric Disorders:

So what does stress have to do with bipolar disorder and other neuropsychiatric disorders? 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 and other psychiatric disorder episodes, but more importantly, what to do about it.

And in better 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). As well, we'll see what a major role chronic and acute stress plays in many psychiatric disorders and why recovery is so difficult. 

The roles of the stress response system has long been a major focus of my research and reading and I'll be getting to that in a series that I hope to have completed soon. 

Please continue to Part Three of the series

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