NEUROPSYCHIATRY TAKES A SPIN ON THE WHEEL
The wheel of fire contains many parts. This essay has so far only touched on a few, though they are among some of the most important.
In BSSHM I discussed how the metabolic syndrome and sex hormone dysregulation are intertwined. Yet, it should hopefully now be clear that the wheel of fire at least also includes the sympathetic disease, which involves both HPA axis malfunction and neurosteroid exhaustion. It should also be clear that the wheel of fire includes hypothalamic-pituitary-thyroid dysregulation, both at the level of the axis itself as well as peripherally. And it should of course also be clear that all of these things are connected to and spin around an axis of chronic systemic inflammation.
I will now delve into how this fuller model explains some of the most common neurological and psychiatric diseases in the US and, in ever increasing prevalence, the world. As should become apparent, these neuropsychiatric diseases are intimately related to each other. And, as with so many other things, they both cause and are caused by the wheel of fire.
POST TRAUMATIC STRESS DISORDER
“War is hell.”
– William Tecumseh Sherman
Imagine that you are in the military. You get deployed to a far away country and experience something horrific in war.
Or imagine that, instead of a traumatic military experience, you spent your formative years under the tutelage of an abusive parent. Or, imagine being enmeshed in a dysfunctional and abusive relationship of another sort.
Now imagine that you have extricated yourself from these horrible scenarios. Yet, for one reason or another, brutal images and emotions bringing you back to that trauma stay with you.
And as time progresses, things get worse. You now experience perseverating conscious thoughts, subconscious reactions, and hypervigilant states that never go away. Fight or flight becomes an ever present reality.
It is like that feeling when you are speeding and see the blue lights from a police car behind you. You feel your heart skip a beat, only to see the blue lights pass you to arrest someone else. But even though you know that you are now safe, you still have that uneasy feeling in your stomach and your heart still races a little for about a minute. PTSD is like that, except that it is a thousand times worse and instead of lasting a minute it never goes away.
Thus what started as an acute or prolonged physical and/or psychological trauma has now turned into chronic fight or flight. There is now perpetual sympathetic activation. There is now a sympathetic disease.
Like everything in human physiology, the mechanisms by which this occurs are extraordinarily complicated and vary from person to person. But broad stroke explanations can be made that affect a majority of individuals with this affliction.
With PTSD, there is a near universal decrease in the amount of ALLO in the brain and serum. Cortisol can go up, or, as seen in the “exhaustion” phase, it can be low. Of course, this is complicated, as whether cortisol is elevated or depressed also has to do with the severity of the stress and how long it has been going on. Regardless, the drop in ALLO tends to be more pronounced than the drop in cortisol. DHEA also tends to get exhausted. Recall that DHEA and ALLO are essential for both activating GABA-A so as to cause relaxation, as well as attenuating the HPA axis. Therefore with exhaustion of DHEA and ALLO, overall brain activity increases and the HPA runs unchecked. Through a variety of mechanisms, not the least of which are cortisol regulation and HPA inflammation, sex hormone pathway becomes affected as well, leading to further dysregulation.
It is thus not surprising that individuals who suffer from PTSD are also much more likely to suffer from the metabolic syndrome and its many other associated diseases.
It is thus also not surprising that individuals who suffer from PTSD are also much more likely to suffer from sex hormone dysregulation and its many other associated diseases.
PTSD leads to multiple onramps to the wheel of fire. And, as may be easily seen, as the wheel of fire is also like a beltway, once on the wheel, it is often just a matter of time before one travels the full circle. The data shows that PTSD leads to the metabolic syndrome and sex hormone dysregulation relatively quickly and uniformly. And this is just the beginning.
TRAUMATIC BRAIN INJURY
Traumatic brain injury (TBI) is a complicated assortment of diseases. The brain is the most complex structure in the universe and trauma to any one part of it is technically a TBI. Thus, a mild concussion while playing soccer is a TBI, as is a gunshot wound through the temporal lobe, as is a blast injury incurred while serving in the military in Afghanistan. The nuances of TBI will of course therefore differ depending on the specific region of the brain injured, the severity of the injury, the baseline functioning of the brain prior to injury, the overall health of the individual, and numerous other factors. Again, this is complex.
My main goal of bringing up TBI when talking about the wheel of fire is not to give a comprehensive review of the pathophysiology and treatment of TBI, as even a massive textbook is insufficient to that task. Rather, it is to take a certain class of TBIs and relate them to PTSD and other neuropsychiatric disorders that involve the metabolic syndrome, sex hormone dysregulation, and sympathetic diseases. In other words, I want to begin to explore how many (and possibly most) cases of TBI lead to more onramps to the wheel of fire.
First, let’s look at some numbers.
The pituitary gland sits in a bony pit called the sella turcica, or turkish chair. It is very susceptible to injury from trauma. Not surprisingly then, somewhere around 30% of people with a TBI severe enough to see a physician have some sort of pituitary disorder. Recall that the pituitary controls the sex hormones and numerous other hormones at the behest of the hypothalamus. If the pituitary is damaged, then sex hormones become dysregulated, as do numerous other hormonal systems.
Yet, there is more going on than mere pituitary damage. While the pituitary is damaged around 30% (in at least some populations) of those with TBI, metabolic syndrome is markedly higher in those who have suffered TBI, even without overt pituitary damage. Why is this?
One of the possible reasons is that TBI typically causes widespread microscopic injuries throughout the brain. An example of this is diffuse axonal injury (DAI). While severe DAI can sometimes be seen on MRI, oftentimes the damage is so microscopic that it cannot. As DAI is a somewhat generalized injury, it of course will elicit somewhat generalized inflammation throughout the brain. Another term for this is neuroinflammation.
Recall how the body reacts when inflammation is present. When inflammation is present, the body acts like it is under attack. This is the sympathetic response. Fight or flight.
With severe TBI, the sympathetic response can become so severe that episodes of it are called “sympathetic storms“. Imagine all of those visceral reactions typified in PTSD, but much more severe. Sweating, severe tics and movement abnormalities, heart racing, blood pressure skyrocketing, and body temperature dangerously elevated. Oftentimes, this becomes so severe that it is life threatening.
But even when the TBI is not severe enough to cause a sympathetic storm, a milder version of elevated sympathetic activity due to neuroinflammation is usually present.
In fact, this milder version looks a lot like PTSD. If sympathetic storms are like a magnified PTSD, then PTSD is like mild, chronic sympathetic storms. And now we know that the pathophysiology behind the two are not that dissimilar. Neuroinflammation causes the sympathetic system to go out of control. The neurosteroids cannot keep up. Eventually, there is exhaustion of numerous systems that are supposed to keep the fight or flight response in check. This all causes a worsening of the metabolic syndrome and sex hormone regulation.
While there are many differences between PtSD and TBI, there are many more similarities. And while they create somewhat different onramps, they both frequently lead to the wheel of fire.
MAJOR DEPRESSIVE DISORDER, GENERALIZED ANXIETY DISORDER, AND RELATED DISEASES
“There is no point treating a depressed person as though she were just feeling sad, saying, ‘There now, hang on, you’ll get over it.’ Sadness is more or less like a head cold – with patience, it passes. Depression is like cancer.”
– Barbara Kingsolver, The Bean Trees
Imagine that you find yourself in a cubicle reminiscent to that of Innetek in 1999’s Office Space. You try to eat healthily but find yourself still eating food that is probably not the best health-wise. Your exposure to sunlight has declined precipitously since taking an office job. In order to destress at night, you end up Netflixing until you fall asleep. Working out at a gym sounds like a wonderful idea but it also is inconvenient and you have found that you really don’t have the energy for it.
Slowly, as time passes, you note that you cannot remember the last time you were really happy. You recall those days in your youth when you seemed carefree and able to truly enjoy things. But now things are different and that ability to relax and take pleasure no longer seem possible. Moreover, combined with all of this, there is an ever present sense of dread about things in general, and oftentimes about nothing in particular. Though sometimes particular triggers do set you off in a bad way.
Sleep becomes ever worse. Concentration becomes difficult. Interest in things fade. Muscles become tense.
This common progression describes the beginnings of major depressive disorder and generalized anxiety disorder. Like PTSD and every other psychiatric illness, however, these are incredibly complex and varied diseases. Their origins do not always follow the above narrative. Yet the story above is unfortunately all too common and getting worse.
Obesity, one of the most common manifestations of the metabolic syndrome, is intimately tied into depression, as are many of the other manifestations of the metabolic syndrome. An obese person is 55% more likely to present to the doctor with depression. Of course, this might make sense for the simple reason that having the metabolic syndrome and its associated health problems can make those suffering sad and even depressed.
Yet it is clear that there is more to it than this. Not only does obesity seem to cause depression, but depression causes obesity. Patients of normal weight who become depressed have a 58% greater chance of becoming obese than normal weight individuals who are not depressed.
And there is no singular mechanism as to why this is. Rather, there are many. Like PTSD, it is never exactly the same for each individual. That said, while there are a multitude of mechanisms that differ from person to person, there are also many commonalities between individuals and between mechanisms. Let’s look at a few of these commonalities.
One of the hallmarks of the metabolic syndrome is “insulin resistance”. There is clear evidence that individuals with chronic anxiety, particularly in the elderly, tend to have more insulin resistance (as measured by a test called HOMA-IR).
Insulin resistance in the brain is also associated with brain neuroinflammation. Recall that systemic inflammation is the axis of the wheel of fire. Like with PTSD, neuroinflammation is associated with both anxiety and depression.
Sex hormone dysregulation, in both men and women, appears to both cause and be caused by anxiety and depression. In fact, aberrant sex hormone levels appear to be the most common cause of anxiety and depression.
The thyroid gland is the master control mechanism of the body’s overall baseline metabolism. When the thyroid gland does not work well, or when thyroid hormone is not working correctly on its target tissues, depression and anxiety frequently develop. Of course, the thyroid gland is ultimately controlled by our friend, the hypothalamus. Thus, if the hypothalamus is inflamed or dysfunctional for another reason, the thyroid gland may also be affected.
On this note, it would behoove us to take a brief tangent and talk a little more about the thyroid hormone. The hypothalamic-pituitary-thyroid axis (HPT axis) parallels the HPA axis and is essential to understanding many of the complex relationships between various diseases. Yet, a comprehensive review of the subtleties of its function is beyond the scope of this essay. For the time being, it is important to at least understand the HPT axis is intimately related to the HPA axis, the metabolic syndrome, and systemic inflammation in general.
The interplay between the neurosteroids, the GABA-A receptor, and the HPA axis also appears to be fundamental to anxiety and depression. With major depressive disorder and pre-menstrual depressive disorder, there is a higher cortisol to DHEA ratio and frequently a higher cortisol to ALLO ratio. And it gets worse. The lower the DHEA and ALLO, the more predictive that the depression will last longer and get worse after the first episode.
Thus there are numerous mechanisms tying depression, anxiety, and similar diseases to the wheel of fire. And there are common sense reasons that these diseases are interrelated too, of course. If someone is depressed, he or she likely feels less motivated to exercise. “Comfort” food that is energy dense but nutrient poor might be ever more attractive. He or she might be more apt to hole themselves in their bedroom, isolating themselves from their friends and not seeing the particular wavelengths of sunlight requisite to activate the suprachiasmatic nucleus of the hypothalamus which would make them more likely to be happy and to think clearly. And since he or she no longer can think clearly, it becomes even harder to make the right decisions necessary to do some of the things that mitigate depression and anxiety’s destructive effects.
CHRONIC PAIN SYNDROMES
Imagine that you step over a curb the wrong way while crossing the street. The inside of a lumbar disk (the toothpaste consistency nucleus pulposus) herniates through the outer rings of the disk (the annulus fibrosus) and you get a searing pain in your upper buttock and down your legs that makes all other pains in this world seem like only prelude. Your doctor is not experienced with the most up to date methods for successfully treating this problem. You do not get the appropriate procedures, physical therapy, or medications. Unfortunately, because your pain is so severe, you have no choice but to give up exercise. Before long, you find yourself out of shape. Because you have lost muscle, you no longer have enough strength in your back to offload that herniated disk. Since you are having a hard time moving, your hamstrings and thoracic spine lose mobility. Arthritis starts to develop in other places in the spine thanks to now changed biomechanics. What started out as an acute injury has now progressed to a chronic pain syndrome.
You have now taken more onramps to the wheel of fire. Like PTSD, TBI, anxiety, and depression, there are numerous ways that chronic pain activates the wheel. Some of these are obvious though many others are rather subtle.
First, let’s talk about some of the more obvious mechanisms.
Severe pain hurts a lot. This is a tautology, but sometimes it behooves us doctors to remind ourselves how unpleasant severe pain really is. When someone hurts, it becomes tremendously more difficult to do all of the thing necessary to maintain a healthy, vibrant life. Recall the characteristics of the depressed and anxious person above. They are frequently the same behaviors that we are all wont to take when we hurt. We frequently want to be alone. We stay in bed. Highly palatable, highly processed, nutrient-poor food seems ever more attractive. It is nigh impossible to exercise. We stop seeing much sunlight. Our sleep is disrupted. Watching the Kardashians bicker and the 24 hour news cycle seem somewhat less onerous.
Not only do all these things frequently cause a downward spiral of eventually worse pain, but they also are a surefire recipe for getting the metabolic syndrome. Eat bad food. Don’t move. Get poor sleep. Never get sunshine. That’ll do it.
Thus it should be no surprise that chronic pain is tied to the metabolic syndrome, if only for common sense reasons.
These are some obvious mechanisms. Now let’s cover some of the more subtle ones.
The sensation of pain, both conscious and unconscious, strongly stimulates the fight or flight response. When pain continues unchecked, the HPA axis becomes dysregulated. Cortisol soars and DHEA, ALLO, and other neurosteroids cannot compensate. Eventually, physiological exhaustion kicks in. Cortisol declines somewhat, and DHEA and ALLO decline even more.
As cortisol plummets, generalized aches and pains start to ensue.
As HPA axis dysregulation and the metabolic syndrome kick in, the sex hormones also become affected. Chronic pain is strongly associated with sex hormone dysregulation and hopefully now it is evident that there are multiple reasons why this is. Visceral and subcutaneous adiposity tends to increase. Aromatase goes up. Systemic inflammation goes up. There is a greater preponderance now for increased damage to the initially injured area, as well as everywhere else in the body. And the wheel spins ever faster and brighter.
This picture of course looks very similar to the same pathophysiology behind depression and anxiety. And it is. Hence the extraordinarily high comorbidity of major depressive disorder and chronic pain. Fibromyalgia is a prototype of this interrelationship. Fibromyalgia is strongly associated with low cortisol, obesity, sleep disorders, and, of course, systemic inflammation. Thus, like everything else on the wheel of fire, one causes the other, which causes the one.
Lastly, there is another interesting phenomenon that occurs with chronic pain. While pain often starts with activation of nerves on the periphery, such as the skin or intervertebral disk, it is ultimately processed in the spinal cord and brain. Thus, one of the hallmarks of chronic pain is abnormalities within the central nervous system (CNS – or the brain and spinal cord). The term for this is “central pain syndrome”. There are a variety of mechanisms for how this happens, but most of these are beyond the scope of this essay. One that is very interesting and germane to neuroinflammation, however, is the idea that a lot of centrally-mediated pain is from gliopathies.
Glial cells are the support cells around the nerve cells in the brain and spinal cord. Some of them nourish the nerve cells (astrocytes), others act as a neural immune system (microglia), and others coat certain neural axons to help propagate nerve signals (oligodendrocytes). When the normally healthy relationship between glia and neurons becomes pathological, chronic pain can ensue. New research shows that this happens through a complicated web of events. However, a common theme among all of the mechanisms is an increase in inflammatory mediators.
Thus a CNS-wide increase in inflammation may occur whereby the support structures (glia) cause atypical growth and connections that ultimately adversely affect the neurons and the person as a whole.
But here’s the thing that is really fascinating. Notice how similar this is to what happens with the microscopic damage with TBI. There is generalized inflammation. The support structures change their physiology and microscopic anatomy almost as if they were damaged by an external event. This creates a positive feedback loop of inflammation and damage. Sympathetic activity increases. The metabolic syndrome worsens and the sex hormones become abnormal.
And since PTSD is like a mild TBI, notice how similar this is to PTSD. And how depression and anxiety also share common mechanisms with PTSD and TBI, and are frequently comorbid with chronic pain, notice how similar it is with these pathologies. They are all related, both symptomatically and mechanistically.
CHRONIC OPIOID USE
Imagine that, like the individual who herniates a disk, you do something that causes first acute, then chronic pain. For one reason or another you have been put on an opiate medication as your pain has become unbearable. Eventually you become tolerant to the medication, however, and it doesn’t work as well. Greater and greater doses are needed so that you can function and sleep.
Yet, as time progresses, you start to feel similar to the scenarios above. You lose interest in things. You have difficulty concentrating. Further, you notice that you seem to be losing muscle. You do not heal as well as you used to. New pains seem to be ever more common and severe.
Like PTSD, TBI, depression, anxiety, and chronic pain, chronic opioid use can create another onramp to the wheel of fire.
And like all of the other pathologies discussed in this post, there are multiple reasons for why this is. One reason is that chonic pain in and of itself, can lead to the metabolic syndrome, sex hormone dysregulation, and the sympathetic disease.
Another very common reason is that chronic opioid use lowers the sex hormones in both men and women.
The main mechanism by which opioids affect the sex hormones is by altering the pulsatile secretions of GnRH by the hypothalamus. When GnRH stops being released in a pulsatile way, LH and FSH are not released sufficiently by the pituitary and the more downstream sex hormones, like testosterone, estrodiol, and progesterone, are not released.
Recall from BSSHM that this is similar to how the metabolic syndrome diminishes GnRH secretion.
While chronic opioid use is more commonly associated with men and low testosterone, women are also profoundly affected. De Madelenna et al in their comprehensive review of the subject in a 2012 Pain Physician article give an excellent analysis of some common findings in women:
“Long-term opioid abuse or use is also a major cause of hypogonadism in women. In fact, opioids lead to a decline in LH, FSH, E2, testosterone and progesterone, thus affecting menstruation. Exogenous opioids were reported to have a drastic effect on the female menstrual cycle: after long-term intrathecal opioid administration, almost 70% of premenopausal women developed amenorrhea and 30% developed irregularities in menstruation. The profound inhibition of ovarian sex hormone and adrenal androgen production described among women chronically consuming sustained-action opioids was shown to have important consequences on menstrual flow and reduced fertility, but also was shown to significantly increase opioid-associated depression, osteoporosis, and hyperalgesia.”
This last sentence is key, as it shows that similar things happen to women as happen to men with chronic opioid use. Sex hormones drop. Fecundity and libido go down. That’s to be expected. But depression, osteoporosis, and hyperalgesia, or increased pain, goes up.
This means that in addition to all of the ways that chronic pain can make the wheel of fire spin, sex hormone dysfunction from chronic opioids can make it still worse.
Many of the most common neurological and psychiatric diseases are part of the wheel of fire. I have discussed a few here but this is by no means a complete list. As I wrote about in The Burden of Our Noblesse Oblige, other disorders, such as Alzheimer’s disease, seem to be intimately related to the metabolic syndrome. Even diseases such as Parkinson’s, which have a very strong genetic component, seem to be still made worse when aspects of the wheel of fire are present.
And even unrelated diseases, such as childhood epilepsy, nonetheless resemble aspects of the wheel of fire. Epilepsy is characterized by uncontrolled neuronal firing, neuroinflammation, and gliopathy. In Part 7, I will review some basic treatment modalities and it may be seen that there is considerable overlap with treating things like epilepsy, chronic pain, the metabolic syndrome, and other aspects of the wheel.
Next, in the penultimate post of this series, I am going to sum up this fuller (though of course, still incomplete) model of intersecting and mutually reinforcing positive feedback loop. Following this, in the final post, I will discuss how the model of the wheel of fire can aid with diagnosis, treatment, and in providing us with inspiration for future research.
This concludes part 5 of the Wheel of Fire: Neuropsychiatry Takes a Spin On The Wheel.