Chapter 6: What Happens inside People’s Brains when they’re Depressed?

Table of Contents

There have been studies showing a change in brain activity when mood shifts, but there is now also research showing a change in brain shape that appears to be associated with severe mood disorders. The brain shrinks, or rather, certain parts of it do. One of those parts is called the hippocampus. This part is associated with making and being able to recall memories. If mood symptoms are severe or go on very long, the hippocampus shrinks. This chapter shows you the evidence that this shrinkage really occurs. The same process appears also to be occurring in frontal lobes as well, though not elsewhere in the brain. This brain shrinkage, called “atrophy”, has long been associated with Alzheimer’s dementia; but lately it has also been associated with obesity, and even with back pain, and very clearly with depression. The good news is that treatments can reverse this shrinkage, at least to a significant extent.

Here is the problem, described in the next 4 chapters, and the hoped-for results of treatment, detailed in Chapter 11:

Cellular Connections During Mood Disorders
Cellular Connections During Mood Disorders

Results of Effective Treatments
Results of Effective Treatments
(Most of the images in these chapters, including these two, are used by courtesy of Dr. Husseini Manji; please do not copy them)

Link to Chapter 7: Why do some parts of the brain atrophy during major depression?


The pictures above and the next six chapters, present the work of many brain scientists, including especially Dr. Husseini Manji, former Chief of the Laboratory of Molecular Pathology at the National Institutes of Mental Health.


Periodically some of us doctors have the privilege of hearing Dr. Manji summarize the rapidly growing story of how mood changes and brain changes interact, and how our treatments affect these shifts. He has graciously agreed to a “translation” of his 2004 version of this presentation, for people who do not spend their lives studying molecules and brain cells. Many of the images in the next 6 chapters are his. Indeed the concept that brain shape change is involved in the very nature of mood disorders; and the possibility of treatments developed from understanding the molecules involved in this process — these are the result, in large part, of his efforts and those of his research team at the NIMH (isn’t that a great way to see your tax dollars working?)

When you are done with this whole story here, in the last chapter I’ll link you to an interview with Dr. Manji where he summarizes all the work presented here and expands on its application to patients.

Introduction to the next six chapters

When mood shifts, some parts of the brain change their activity. However, here we’re going to look not at brain activity, but at very size and shape of the brain itself, as mood changes occur. In other words, we’ll be looking not at what the software is doing, but at the hardware itself. Surprisingly, in the last 5 years it has become clear that changes in chemicals like serotonin are only a tiny part of the story. Instead, research attention is now focused on changes in genes and proteins that control the size and sometimes even the life or death of cells involved in mood.

The focus in these next 6 chapters will be on brain changes in depression. Other conditions like bipolar disorder will be included where possible, particularly in the section on how medications work.

We’ll start by looking at what happens if depression arrives and stays a long time: unremitting depression”, we could call it. Unfortunately, there is now very good evidence that what happens is brain shrinkage, in several important regions of the brain (although, come to think of it, there aren’t too many regions of the brain we’d call unimportant, are there?). These include the frontal lobes and older, more central structures called the hippocampi, which are involved in memory as well as mood (picture coming up).

Hippocampal atrophy (shrinkage) with depression

The hippocampi are easy to measure for size, so much of this research focuses there, though the story so far looks very similar for the frontal lobes.

Here’s one study that showed smaller hippocampi in patients who remained depressed for several yearsSheline:


Notice that for depression lasting less than 1000 days — about 3 years — patients with depression don’t seem to have lost much volume. But those patients whose depression lasted longer had smaller hippocampi.

What is this “hippocampus” thing, anyway? In addition to playing a role in emotion, it’s also a part of the brain that is associated with the process of making new memories. Alzheimer’s disease leads to severe hippocampal shrinkage, and thus severe problems with memory. In the diagram below, you can see the left one, very near the middle of the brain, outlined in purple. For more pictures which will help you understand just where this structure is, see the Brain Tour about the hippocampus.


The hippocampus has also been shown to be smaller in patients who have had bipolar disorder for a long time.DeickenAgain we see the pattern of increased volume loss with increasing duration of illness:


But in some people, it does not take years and years for this to happen. When mood problems hit early, in childhood, they are often more severe than the forms which hit later in life. It appears that severe mood symptoms are more likely to cause this kind of hippocampal shrinkage. And sure enough, the same shrinkage has been shown in kidsMacMaster and in another condition which often has severe mood symptoms, so-called “borderline personality disorder”.Driessen

Until recently there was still some doubt as to whether this shrinkage is really associated with the mood problem, but two 2004 re-examinations of the research to date concluded that this phenomenon, called hippocampal atrophy, is for real. Videbech, Campbell These re-examinations are called “meta-analysis” studies, as they gather up multiple previous studies and pool the results. Generally these meta-analyses are thought to present even more reliable results, so the fact that there are two such reports on brain size in depression lends increased confidence to this whole atrophy story here. Just to impress you with the number of studies it takes to reach this degree of certainty, here is a list from Dr. Manji’s presentation on this subject. I know you can’t read the names, but just look at the sheer number of them:


Frontal lobes atrophy too

The hippocampus gets lots of attention for this shrinkage. But as noted above, another part of the brain may also shrink during depression: the frontal lobes. Though they are much bigger than the hippocampus, they are studied less often in regard to this shrinkage process, in part because their size makes them harder to evaluate as precisely as the hippocampus, and in part because rats have hippocampi, but they don’t have big frontal lobes like us, so frontal lobe changes cannot be studied except in humans — who are in general much harder to study than rats! But in studies that have looked at brain shrinkage in both areas, the frontal lobe seems to be undergoing the same changes as the hippocampus. Since the frontal lobes are directly involved in managing emotional reactions, as well as focusing attention (as well as a whole lot of other tasks), shrinking frontal lobes is just as important as shrinking hippocampi. So keep in mind that it is not just the hippocampi involved in this process.

Before we jump to the next chapter, to look at just how this shrinkage seems to happen (then later we’ll look at why), here are two interesting recent additions to this atrophy story. Both made national news — thus I heard of them in that famous journal of medicine, my local Corvallis Gazette-Times!

People with many years of back pain were studied by team of neurologists. They found that such patients had 5-10% less brain matter, particularly in the frontal lobes, than those without the history of back pain.Apkarian The other new report found an association between obesity and temporal lobe atrophy (the lobe, you will recall, where the hippocampus is located).Gustafson

These studies each report only an “association”: increased rates of atrophy noted in people with back pain, or with obesity. This leaves open the possibility that some third variable might be causing both the atrophy and the back pain, or the obesity. We’re going to look shortly (chapter 8) at the stress hormone cortisol, which is now clearly implicated in causing depression. It can also cause obesity. And it might easily be increased in people with chronic back pain. Perhaps stress hormones, or perhaps even depression itself, is the common variable that might connect back pain, or obesity, with brain shrinkage? This represents a very new way of thinking about mental health matters, you see? We might see here a way in which mood disorders could be directly involved in medical problems which have not traditionally been the territory of “mental health” types (for example, note that none of the authors of these two recent studies are psychiatrists, but rather neurologists, radiologists, and family medicine doc’s).

The point here is that “brain atrophy” is becoming popular! People are starting to look for it in places where it might not have been expected. Perhaps the story you’re reading here, about how stress causes depression and atrophy, particularly in people with two short Serotonin Transporter alleles, may be part of the explanation for some of these other observations as well. Perhaps “mental health” will get a boost from this increased recognition of the importance of brain shape changes.

Now let’s take a look at the current understanding of just how these shape changes are occurring in depression.

On to Chapter 7: Why do some parts of the brain atrophy during major depression?

(updated 12/2014)

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