Monday, December 2, 2013

The Neuroscience of Depression

I should begin by saying that the biological explanation for psychiatric disorders - IE: the "chemical imbalance" explanations - is certainly neuroscience. The roles of neurotransmitters such as dopamine and serotonin (the two most implicated in the imbalance theory) are certainly important factors in brain behaviour (and thus our behaviour) and are part of neuroscientific research. It's just that no exact biological marker has been found for any psychiatric disorder and the chemical imbalance theories have been discredited (having never really been proven in the first place) as well as now appearing overly simplistic. While neurotransmitters are a big part, there are many other factors involved in brain operations as well such as 
the connectome - IE: the crucial wiring between brain regions - electrical activity or brain waves, neuronal activity or lack thereof in specific regions, the concept of neuroplasticity (the constant growing and pruning back of the connections (dendrites and synapses) between neurons) and how neurons undergo tremendous change with just a single thought (a simplified synopsis of the information of that link can be found here) and so on. Neuroscience is deepening its understanding of the brain almost daily and enormous resources are now being poured into better understanding how it works. 

All of which leaves the chemical imbalance ideas - the bedrock of and the dominant paradigm of today's psychiatry - well in the dust. It was not a bad idea at the time but it's one that is decades out of date. That treatments based on these outdated notions are the front line treatment for all psychiatric disorders and are still heavily promoted by websites such as WebMD and the Mayo Clinic, not to mention mainstream media, is a tragedy that I had to personally find out and which costs the very lives or severely impacts the quality of life for tens of thousands of people (or even hundreds of thousands depending on how you quantify it). Discovering this tragedy and wanting to know why led me to studying neuroscience which has been my passion ever since. 

It is theoretically possible, by the way, to "tweak" certain human behaviours with artificial chemicals but today's current treatment model has been likened by 
renowned neurobiologist David Anderson to "adding oil to a car by pouring it all over the outside and hoping that some seeps into the right spot (the oil pan)". Current drug delivery methods, in other words, are unacceptably crude and cause too much collateral damage. That is if neurochemicals are alone responsible for complicated disorders such as schizophrenia, bipolar and major depressive disorder in the first place. My argument is that they're not. One of my problems with mainstream psychiatry is that they remain locked on a single facet of brain operations - neurotransmitters - and ignore almost all else, and this is always very dangerous in the world of medical science when lives are at stake. Which is why I study neuroscience in order to understand what's going on in the brain with our various disorders (my main interests are bipolar, major depression and schizophrenia).

What we'll look at today are some of the brain regions that appear to be involved in major depressive disorder and, we'll assume for today, the depressive phase of manic depression (or bipolar to some). [there is some confusion as to the difference between manic depression and bipolar disorder as the latter has been expanded to include what look an awful lot like schizophrenia symptoms and behaviour to me but we'll leave that for another day. When I refer to bipolar, I mean the classic manic-depression swings of mental states and brain functions.]

neuroimaging technology has its limits, enough research through the study of brain damage and the resultant specific human behavioural and ability changes, not to mention physical studies (as opposed to imaging studies) on animal brains, has been done for many decades to establish that individual brain regions are responsible for many behaviours and abilities in humans and animals and, more importantly to us, that specific stimulation to these regions can cause plastic changes and thus change or improve behaviours and habits. 

On Depression

In her book Mapping the Mind, Rita Carter describes clinical depression as:

singularly life diminishing. Its symptoms of despair, guilt, exhaustion, anxiety, pain and cognitive retardation often makes sufferers wish they were dead and one in  seven of those who are severely afflicted fulfill that desire through suicide.
 She goes on to say that:

depression is more than just a "mood" - it also brings on physical symptoms like fatigue, pain, sleep and appetite disturbances. Memory is affected and thinking is slowed. 

And then this:

Major depression is not a single disorder but a symptom of several different conditions, each of which probably has a slightly different brain abnormality at its root. The picture is still incomplete (do you hear that, psychiatric industry?), and brain imaging studies have shown that trying to pinpoint the exact mechanisms that are involved in mood disorders ("love" that term) is very difficult indeed. 

Now on to some of the brain regions that appear to be involved. 

First up is the Anterior Cingulate Cortex, or ACC. This is an older piece of cortical hardware and is more strongly connected to the limbic system where all the more ancient hardware exists and a great deal of traffic (urges, desires, wordless memories, among others) passes through the ACC. You can see its position and proximity to the limbic region here:

The ACC generates "self-willed" actions (such as they are) and plays a central part in creating the feeling of "agency" that goes along with self-willed behaviour. It also appears to be responsible for the feeling of "aliveness" we sense and which most people take for granted. Studies show conflicting information of over and under activation in depressed people in the ACC in people with depression and bipolar so some sort of discombobulation is happening there and this discombobulation will have a certain amount of affect in how we experience and sense "being alive". When we just cannot experience any zest for life, it appears that it is some sort of disfunction in the ACC that is responsible for this sensation. And mileage, as they say, would certainly vary as there would be no "one size fits all" for either how this region was endowed genetically or in how it was affected by environmental factors during its critical development period (which is true of all brain regions of course). Therefore, how this area was impacted along with how much "say" it gets in our moods would vary from person to person from mild to severe.

Other "dead" areas in depressed people include parts of the parietal and upper temporal lobes that are associated with attention, and particularly with attending to what's going on in the outside world. That feeling of being in our own little worlds we get when we're depressed isn't just our imagination, it's specific brain areas that are under or over activated, or perhaps we could say misdirected. The lateral prefrontal lobe is thought to hold sad memories in mind, and basic limbic system components the thalumus and amygdala are also "in the loop". 

As for that "power outage" that we feel, that complete lack of energy and/or interupted sleep patterns, here is some bleeding edge research that may give us valuable insight into what's going on there. This involves the Locus Ceoruleus, the major noradrenergic nucleus of the brain which gives rise to fibres innervating extensive areas throughout the neuraxis. The LC is a major awakeness-promoting nucleus. The pathways of the noradrenergic systems (transimitted via the neurochemical norepinephrine) are as thus:

Its location is in the brain stem which is as basic as brain hardware gets. Aside from routing through critical daily function areas such as the thalamus, amygdala, hippocampus and cerabellum, you can see its pathways go all through the neocortex as well (which is where all our higher brain functions reside). Any interruption in this ultra-key and fundamental system is going to throw our energy levels for a loop and greatly impact the energy levels in many of our basic and higher functions.

Norepinephrine also acts as a key hormone in our stress response system (AKA: fight or flight response) which sends along key quick energy boosts to all the various areas in your brain and body that need to respond quickly and energetically to a perceived threat. Constant stress then, often implicated in major depressive disorder and bipolar, would put this system under a major strain and, perhaps, just wear it out leaving us feeling drained and lethargic.

Update from August, 2014:

Since writing this piece I researched the "power outage" that often comes with an episode of bipolar depression and it appears that the key physiological problem involved is mitochondria dysfunction which I nicely lay out and explain in a three part series starting here. 

So what does all this mean? None of this is *the* answer to depression of course. And I don't expect anyone to memorize this and go around saying, to explain their depression, that their anterior who's-he-what's-it and locus thingy-me-bobber are out of wack. What I do hope is to give a better idea of what's going on with those of us so afflicted by major depressive disorder or bipolar depression and that it's not just a matter of the "suck it up, buttercup" bullshit advice that we always get. What's going on are major disruptions in both deep brain systems that are well, well beyond our conscious control, and areas of higher cognitive function, stuff that's beyond just "sucking it up" and "braving on" (though of course we do try to do those things anyway, with very limited result). If anyone can get over their depression with suck it up shiny-happy stuff, then guess what?! You didn't have major depressive disorder and certainly not bipolar depression. Lucky you! Not "strong", but lucky, pure and simple. 

And more importantly, what to do about all these discombobulated brain regions that are beyond our conscious control? Well, I'd be a bit of a you-know-what-hole if I didn't give some idea about what to do about it. And it just so happens that neuroscience has something to say about that as well. Stay tuned. 


Mapping the Mind  by Rita Carter

This paper at via my "brain bud", neuroscientist Mani. 

Glossary of terms:

Amygdala - the "seat of emotions". The amygdala is involved in almost all of our basic functions. All our outside data (brought in through the five senses) runs through the amygdala which both "tastes" it for emotional content and adds emotional content. It plays a very large role in all major psychiatric disorders. 

Thalamus - the thalamus is a large, dual lobe mass located in the limbic region (our basic sub-cortex group of hardware). It is involved in sensory perception and regulation of motor functions. As a regulator of sensory information, it also controls sleep and awake states of consciousness.

Hippocampus - is a key cog in memory forming and organization, and storage thereof. 

Cerebellum - a very, very basic bit of hardware common to all animals from the lizard on up. It's where where body movements are coordinated, where your abilities of balance and body posture are held and equilibrium is controlled


When I first started researching bipolar three and a half years ago, I came across a scholarly paper on hippocampal damage that showed a marked decrease in healthy tissue and an overall shrinkage in hippocampal volume in those with bipolar disorder. The study was carried out on suicide victims, meaning it was done through brain autopsies which further means that the results can be accepted as accurate as opposed to results from imaging scans on living subjects which may or may not be accurate.

Later, I came across other sources that showed the same results. I thought, "OK, there appears to be physical damage to the brain in bipolar disorder. That's interesting". I was in a very bad state back then, however - not to mention very, very confused, scared and upset (this was following my first psychosis driven suicide attempt) - so I didn't give it much further thought as I had, at that time, bigger fish to fry. 

Fast forward to this year, when I went into hyper-manic (no, I do not mean hypo-manic) research mode and I began studying neuroscience. I still didn't put much thought into those studies regarding the hippocampus as I was so involved in so many other avenues of research (1). I did try to find the original study I'd read three years earlier but couldn't find it (I do recall many of the details clearly, though, and that it was carried out at McGill University) so I let it drop. 

Fast forward a few more months to yesterday when I came across a video lecture by the highly, highly regarded 
Robert Sapolsky. (2) In the lecture, he was presenting the neurobiology of stress, neurodegeneration, and individual differences and BAM, guess what came up? Clear and specific damage to the hippocampus. Sapolsky showed indisputable and irrefutable linkage in excruciating detail between stress and a great deal of hippocampal damage. Furthermore, he showed how this occured in brains of those with major depression. And in what state to bipolar people spend most of their time? Depression. Severe long lasting and repetitive and cyclical depression. Finally, I had my smoking gun.

So what does this mean to us long term bipolar peeps? (I disclude those that have perhaps had only one cycle which may or may not - and a strong possibility of not - actually be "bipolar"). First, let's have a look at the hippocampus and its functions in our brains and thus ourselves. 

This is the hippocampus:

It's a major part of our limbic system and a very busy part of it indeed. That yellow nodule at the front of it is the amygdala, critical to so much of our emotional functions and regulation. It and the hippocampus, as one would expect from their immediate proximity to one another, very much work in cahoots. Much of our incoming sensory data routes through the amygdala (which will both sense it for emotional content and attach emotional content) which will then shuffle it off to the hippocampus for longer term storage. 

We are, 
as I've written before, our memories. By that, I don't just mean phone numbers, names, days at the beach, that special Christmas, your first kiss and so on, but critical procedural memories and all kinds of "data" that your brain needs in order to navigate you through life. It needs to file away all kinds of things in order for your brain to remember what to do when confronted with any given situation. Basically, it's all our experiences - good and bad - that we have gone through in life. Therefore, the hippocampus plays a major, major part in Who We Are and how we play our cards in life. It plays such an important role in the "filing system" of your brain, a filing system utterly crucial to how you live your life, it could be said that the hippocampus plays a great role in dealing your cards in life. Robust growth of the amygdala and hippocampus during infancy highlights the importance of this region for functional development (these two regions have been implicated in autism and Asperger's). In Alzheimer's and dementia, it is in the hippocampus that the damage first appears.

 So damage here is something to take very seriously. 

And the depressing news (sorry to be the bearer of bad news) is that this damage by all accounts is permanent. 

So what causes this damage in bipolar depression? In a word - stress. Stress plays such a huge role in schizophrenia, bipolar and major depression that I will have to devote a separate post to it - perhaps two - but I'll go over it briefly for now. 

Stress is part of our flight or fight response. In this mode, activated when we (our amygdala that is ... that's its job) perceive danger, the brain is flooded with stress hormones designed to a) shut down extraneous brain regions (including your frontal lobes ... facing a lion isn't the time to ponder life) in order to give energy priority to critical areas and b) deliver high octane fuel in the necessary brain regions and to your heart, lungs and major muscle groups. The evolutionary purpose of this was designed to run away from, for example, a lion and was meant to last minutes. In situations of acute danger, it's a life saver. When it gets locked on, as it so often does in today's wacky world, it is, literally, a killer. 

So before I get into all the detail of how all this works, what can we do about it? Obviously, if there's irreversible damage, there's no sense crying over spilled milk. The task then switches to minimizing any further damage.

Obviously, if you are "lucky" enough to have one of the disorders I listed, stress reduction is Job One for you. What's one of the best ways to reduce stress? Meditation (though there are others I'll get to in a post or two). That's meditation with a "t", baby, not medication with a "c". As I ever so briefly touched on in the 
previous post, there is just a crazy amount of bleeding edge science that shows the benefits of meditation at the synaptic, neuronal and wiring levels of the brain. Plus, as I mentioned, it's only been the most effective way of calming minds for 2,500 years. Meditation will calm the signals entering your amygdala and thus the input into your hippocampus. Calm those down, and you stop the release of stress hormones in their tracks.  

And besides meditation, sleep. I have a different long and detailed post on the neuroscience of sleep rumbling around in the bowels of my mind but briefly, just take my word for it - you really, really, really need your beauty sleep. Have trouble sleeping? Back to meditation. This was one of the first things I learned when I finally confronted my bipolar - I had to learn how to calm my ever racing mind and get more, and better, sleep. So I worked like hell at this. And it works. I learned some basic, very easy to do meditative techniques and my sleep duration and quality improved immeasurably. 

(1) When I say "research", I of course don't mean I go off to a fancy lab somewhere, wear a cool white smock, and poke around into brains and stuff. I just mean deep reading in science books, science journals, watching video lectures and so on in a very directed way.

(2) I am extremely wary of sources and will ruthlessly root out bullshit science, research papers and claims (just ask some of my online neuroscience buddies). So when I come across a new source, such as Sapolsky, I'll spend a day or two looking into him as much as possible and cross referencing his/her credentials. I'll get into the details of this another day, but there are way, way too many bullshit sources out there regarding neuropsychiatric disorders and the medicating thereof, bullshit that nearly cost me my life and the lives of very, very many other people. So I am utterly and absolutely ruthless about sources now. 

Sources and further reading:

Searching for the Mind by Jon Lieff

The Brain Book   by Rita Carter

The Willpower Instinct by Kelly McGonigal


  1. Good stuff -- conceptually well developed without leaving behind experiential grounding.

  2. As says,"People think depression is sadness,crying or dressing in black.But people are wrong.Depression is the constant feeling of being numb.You wake up in the morning just to go back to bed again."