Science Saturday: Depression and the Immune System

Did you know that immune changes are associated with Major Depressive Disorder? I certainly didn’t.

Lately, I’ve been fascinated by the research on depression and the immune system. Perhaps you’re more in-the-know about this topic than I am and this doesn’t surprise you, but I was shocked to learn that not only do there appear to be measurable changes to the immune system with Major Depressive Disorder, but there are numerous studies on it dating back decades. This isn’t a fringe area of research! Let’s take a look at what changes there are and what they mean for people with depression.

The Evidence: T Cells and Depression

flow-chart-of-types-of-leukocytes
bodytomy.com

T cells are a kind of lymphocyte, which are themselves a type of leukocyte, or white blood cell. Lymphocytes are involved in what’s called adaptive immunity; they use molecules on other cells – the body’s and invading pathogens – to recognize foreign material and defend against it. Kinds of lymphocytes include T cells, B cells, and Natural Killer cells. Different types of T cells perform different roles, such as “helper” cells (Th- cells), “regulatory” cells (Treg cells), and cytotoxic cells. CD4 and CD8 (which refer to markers on the cell surface) are the two main categories of T cells. CD4 T cells are mainly helper cells, and CD8 T cells are mainly cytotoxic, meaning they mount direct attacks against invaders.

Both main types of T cells, CD4 and CD8, have other molecules attached to their surfaces. Some are receptors that grant the cell access to infections; two such receptors are known as CXCR3 and CCR6. Antidepressant-free patients with MDD have been shown to have significantly lower expression of both receptors on both types of T cells. The same study also found a significant trend in MDD towards fewer Natural Killer cells, a finding that was corroborated in another study.

Research has shown that T cells have a neuroprotective quality. T cells migrating to the brain can reduce stress, promote neurogenesis (growth and development of nervous tissue), and reduce inflammation. Study after study have found inflammation, changes in immune cell composition, receptor alterations, and gene expression changes associated with Major Depressive Disorder.

Causes and Effects of MDD Immune Changes

All of these changes are fascinating in themselves, but are they the results of depression, causes of it, or some intermediary factor?

The Sickness Behavior Hypothesis

Some researchers view depression as a maladaptive result of what’s called “sickness behavior”. Sickness behavior is a vertebrate trait that, through behaviors like somnolence, anhedonia (loss of interest or pleasure), and reduced or no eating, conserve energy that can be directed towards fighting infection. Researchers have presented evidence that both sickness behavior and depression are mediated by pro-inflammatory cytokines– proteins that act in cell signaling roles. These two observations- depression and sickness behavior share symptoms as well as mediators- led to the following hypothesis. Depression is the alternate, maladaptive pathway of molecular processes that, on the other pathway, lead to sickness behavior. Under this hypothesis, the depression pathway leads to neurodegenerative changes that make repeated episodes more likely. Adding that to other research that shows a link between sickness behavior and major depression, and a fascinating picture emerges.

Sickness behavior and major depression do look remarkably alike in their symptoms, and we do know that major depression is often a lifelong illness.

Approximately 60% of people with MDD who experience a single depressive episode go on to have a second episode, and about 70% are likely to experience a third episode. Similarly, having had three episodes increases the chances to about 90% that a fourth episode will occur.

Functional Consequences

Biochemically, these changes are significant. Functionally, do they affect the people who have them? The answer may be yes. One study found a 59% increase in the risk of infection following one depressive episode. The increases weren’t linear, but the risk did go up again after the fourth episode. In addition, among college students, poor mental health is correlated with acute infectious illness.

Fortunately, treatment with antidepressants, if effective for depression, also returns T cell subsets to normal ratios. Differences in the subset ratios between those who responded to treatment and those who didn’t may help determine the chances of efficacy for a particular patient with antidepressant treatment.

 

time lapse photo of blue and red lights moving erratically

Science Saturday: Sensory Processing Disorder

Today’s topic is Sensory Processing Disorder. I didn’t have a specific question to answer, so I decided to make this post an overview of our current understanding of SPD. I’m particularly interested in this topic because I have Sensory Processing Disorder. I was diagnosed young and have had two rounds of occupational therapy, each several years apart. My knowledge of SPD centered around my own experience of it and what I’ve been taught in occupational therapy, so I was eager to dive into the literature and learn more.

Sensory Processing Disorder as a Diagnosis

SPD was first described as a construct by Ayres in 1964. At that time, it was known as Sensory Integration Dysfunction. Now, SPD has several subtypes, including Sensory Modulation Disorder.

Sensory Modulation Disorder

Three main categories compose SMD: sensory over-responsivity, under-responsivity, and sensory seeking.

Sensory Over-Responsivity (SOR) can be defined as:

…exaggerated responses to one or more types of sensory stimuli not perceived as threatening, harmful, or noxious by children and adults who are typically developing.

Analysis by different authors of data from a 2004 study that investigated the prevalence of SPD among kindergarten children in a Colorado school district found the prevalence of sensory over-responsivity to be between 2.8 and 6.4%.

Experiencing Sensory Under-Responsivity (SUR) might look like:

…quiet and passive, appearing to disregard stimulation by not responding…[they may have] inadequate body awareness, poor endurance, and movements that are not appropriately graded.

And lastly, sensory seeking, or Sensory Craving (SC), is “…craving sensory stimulation and appearing to be obsessed with obtaining additional sensory input.”

Sensory-Based Motor Disorder and Sensory Discrimination Disorder

The other two subtypes of SPD are Sensory-Based Motor Disorder, which includes dyspraxia and postural disorder, and Sensory Discrimination Disorder, which can affect one or more sensory systems. A diagnosis of Sensory Processing Disorder can include symptoms in each of the subtypes; in fact, it’s often a mishmash of seemingly contradictory symptoms that fit into different types.

SPD and its subtypes are included in the 2005 version of the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC:0-3R). However, it’s not included as its own disorder in the Diagnostic and Statistical Manual 5 (DSM-V), largely because of lack of research and no official consensus on its definition. Sensory symptoms are described in association with Autism Spectrum Disorder and ADHD, but SPD has remained a controversial diagnosis in some circles. Unfortunately, this could be preventing families and adults from getting help for their symptoms.

Neurological and Physiological Research

Fortunately, there is evidence supporting SPD as a valid diagnosis, which could lead to changes down the road. A 2013 study compared the brains of boys with and without SPD (sample size of 40) using diffusion tensor imaging. Significant differences in white matter microstructure were found in the posterior corpus callosum, corona radiata, and thalamic regions. This study used the cardiac vagal tone index to measure the physiologic reactivity of 15 children. The results were significant and showed that the kids with SPD had less effective vagal tone than kids without SPD. This indicates that people with Sensory Processing Disorder may have impaired parasympathetic functioning. I have no reason to doubt this result, I just wish the sample size were larger.

Not Significant?

I wanted to include this study, and as I read through it, I reached the part where they break it to you that the results were not statistically significant. Darn! (Remember when I said I was biased?) In any case, it’s still interesting, and this is part of what science is about; you can still learn something from insignificant results.

An EEG study with a sample size of 53 tested kids’ brain waves by introducing a “conditioning” stimulus followed by a “test” stimulus. The idea is that your brain becomes accustomed to stimuli that it deems safe, so the test stimulus elicits a smaller reaction than the conditioning stimulus. This is called sensory gating. As a group, the kids with sensory processing disorder showed less sensory gating than the comparison group (p= 0.04), but it wasn’t statistically significant when an adjusted alpha level was used. If the results are robust enough, it indicates that people with SPD don’t get conditioned by stimuli like people without SPD. Every instance of a startling stimulus produces the same reaction as the first one did.

Sensory Processing Disorder and Autism

The vast majority of people with Autism Spectrum Disorder (ASD) also have sensory challenges. Yet, not everyone with SPD also has ASD. Research is beginning to tease apart where the overlaps lie. Using the same imaging technique as in the study above, researchers found differences between the white matter in boys with autism and the white matter in boys with SPD alone. Compared to a control, both groups’ white matter differences overlapped in tracts thought to contribute to sensory processing. However, the boys with ASD had additional white matter differences in tracts linked to social processing. Other research suggests that assessing cognitive styles may be a good way to differentiate between Sensory Processing Disorder and Autism Spectrum Disorder.

Sensory Processing Disorder and Mental Health

If you’ve been keeping up with my blog (if not, welcome), you know that I have sensory processing disorder and depression. I stumbled upon a couple of studies that show correlations between sensory dysfunction and mental disorders. This one, for example, shows that both under-responsiveness and over-responsiveness correlate with depression and impulsivity. Another one suggests that under and over-responsiveness may be “trait” markers for people with major affective disorders. That last one seems like a stretch to me, but my own perception of those studies is that a.) perhaps there’s some neurological connection between the white matter changes of SPD and mental illnesses, and/or b.) it’s tough to live with SPD, leading many with the disorder to develop secondary disorders.

This is a complex topic, and I’d love to hear your thoughts. Let me know what you think in the comments.

Science Saturday: What are Automatic Thoughts?

We all have those sneaky thoughts that come unbidden when we make a mistake or are faced with a change. I don’t know a single person who hasn’t mentally beat themselves up over a perceived shortcoming. Often, it isn’t deserved. But when your automatic thoughts are that you deserve those thoughts, what do you do?

Types of Automatic Thoughts

First, some background. The Handbook of Social Psychology describes four types of automatic cognitive processes:

“Automaticity is granted if the perceiver lacks awareness of the process, does it with efficiency (i.e., with minimal use of cognitive resources), has no intention to do it, or cannot control it.”

Based on this definition, automatic thoughts include those about others, such as deeply held prejudices. It also includes the intrusive thoughts that characterize Obsessive Compulsive Disorder, but I’ll be focusing more on those automatic thoughts that don’t necessarily play a direct role in psychopathology. For example, self-referential thoughts like “I’m going to fail this exam. I always fail.” are the types of thoughts I’m talking about here.

Negative Automatic Thoughts

The most well-known measure in this area is the Automatic Thoughts Questionnaire (ATQ), a 30-item instrument developed in 1980. The ATQ contains statements like “I am a failure”, and asks participants to rate each statement on a scale representing the frequency with which they experience that thought. It’s a cross-validated questionnaire that’s been shown in several studies to correlate with depression and separate depressed from non-depressed individuals.

When presented with a distressing stimulus, previously depressed participants and people who have never been depressed experienced stronger belief in negative automatic thoughts. The researchers propose that cognitive reactivity is related to relapse and recurrence of depression.

Cognitive reactivity refers to the triggering of negative thought patterns by small declines in mood. The ability to resist slipping into negative cognitions seems to have a protective effect; inpatient surveys taken at two time points show that decreases in negative automatic thoughts are strongly correlated with reduced suicidal ideation.

Positive Automatic Thoughts

The relationship between negative automatic thoughts and depression and anxiety is well documented. We can infer that the lack of negative automatic thoughts has beneficial effects on mental health, but this still isn’t quite the same as the presence of positive automatic thoughts. However, research does support the assumption that positive thinking is related to positive mood. A variation of the ATQ was developed to measure positive automatic thoughts. It’s called the ATQ-P, and higher scores on it are strongly associated with lower levels of depression. A healthy balance of positive and negative thoughts appears to be weighted toward more positive than negative- a ratio of 0.62 to 0.38, to be exact (according to one study).

Where Exactly Do Automatic Thoughts Come From?

Understanding the present state of the science of cognition would take me a lot longer and several textbooks’ worth of information, so I’m not claiming to have a solid grip on this. In fact, how exactly our thoughts come to be is conceptualized in my mind as electricity zapping through convoluted tangles of long, mushy neurons. The transformation of those electrical signals into language and images is completely beyond my comprehension and, in my imagination, involves the universal translator from Star Trek.

Parahippocampal gyrus

limbic system

As far as I can tell, there are a couple of areas of the brain that are linked to automatic thoughts. One is the parahippocampal gyrus, a part of the limbic system.

Here’s a study that investigated the relationship between depression and brain tissue volume in the limbic system. Not gonna lie, my eyes glazed over a little when I read this:

“The voxel-based morphometry results showed that the GMV of the right parahippocampal gyrus and fusiform gyrus and the WMV of the right superior temporal pole increased with the severity of depression.”

Let’s break that down. A voxel is a value assigned to a three-dimensional grid. Think “pixel” but with volume. Voxel-based morphometry is a technique for assessing differences in brain volume. Brain scans are registered to a standard, voxel-based template, then each voxel is “smoothed” by averaging it with the values of the surrounding voxels. Finally, the image volume of each scan is compared to the other scans’ volumes and the differences between voxels are evaluated statistically. Basically, it’s a way to quickly compare lots of structural brain scans using computers.

The study with the jargon-filled results found that increases in the volume of grey and white matter in certain regions of the limbic system are associated with increasing severity of depression, as measured with the ATQ. So, negative automatic thoughts are associated with depression, and depression is associated with higher volume in the emotional center of the brain. That doesn’t necessarily mean that negative automatic thoughts are directly related to grey and white matter volume. Or does it?

Statistical tests showed that the combination of automatic thoughts and grey matter volume in the parahippocampal gyrus predicted depression measured by the ATQ and the Self-Rating Depression Scale. The automatic thoughts mediate the relationship between volume and depression. They also seem to mediate the relationship between neuroticism and depression.

Medial Prefrontal Cortex

The medial prefrontal cortex is not part of the limbic system. It’s located at the very front of your brain and is associated with the processing of social information. Hyperactivity in this region has been linked to neuroticism and self-generated thought. The tendency to worry and impose self-generated beliefs onto a reality that doesn’t match those beliefs sounds a lot like the automatic thoughts in the studies above. But it’s not all bad; the same hyperactivity and self-generated thoughts are also associated with creativity.

Combatting Negative Automatic Thoughts

Hopefully, you haven’t read all of that and decided that the next time someone tells you to be more positive you’ll just say “the grey matter in my parahippocampal gyrus says ‘no can do.'”

Cognitive behavioral therapy has been shown to result in reductions of automatic thoughts and dysfunctional attitudes associated with non-clinical depression. CBT makes use of behavioral experiments and automatic thought records. People perceive behavioral experiments to be more powerful than combatting automatic thoughts with logic alone, which could be because behavioral experiments function through emotion-based cognitive systems. Mindfulness has also been shown to reduce automatic thoughts, and it’s associated with increased life satisfaction.

I’m certainly not saying that the solution is just to “think positively”; then we’d be in a pot/kettle situation. There are, however, plenty of reasons to believe that we have the power to effect change in our own brains.

What helps you recognize negative automatic thoughts, and how do you practice self-compassion?

Science Saturday: How Does Nature Affect Mental Health?

I’m hoping to make this the first post in a series called “Science Saturdays” (now taking suggestions for a more creative name) where I dive into the research at the intersection of mental health and (fill in the blank). I dipped my toes into these waters with previous posts like “Pets and Mental Health“, “Can You ‘Grow Out Of’ Childhood OCD?“, and “What’s the Deal with MTHFR and Psychiatric Conditions?” My intention is to take an objective look at recent research, let it percolate through my noggin while I sift through the dozens of tabs I’ve amassed in Google Scholar, then report back with what I think are some important takeaways.


embroidery-of-wooden-fence-and-red-poppies

Here in the northern hemisphere, we’re perched on the cusp of spring, and boy, am I ready to get outside. I live in Colorado, and hiking is one of, if not the most, enjoyable ways I spend my time in the warmer months. I’ve been gazing longingly at the mountains, perusing dog backpacks (that’s backpacks for dogs to wear) on Amazon, and figuratively dusting off my trail map app in anticipation. It could just be that I’m particularly drawn to being outside because of my personality and upbringing, but I’ve recently come across some buzz surrounding the positive effects that nature has on our emotional and physical health. So, I figured, what better way to become even more entrenched in spring fever than to spend a few hours reading about the outdoors?

So Many Studies

Nearly every article I’ve read so far has referenced a study published in 1984 by RS Ulrich. The study looked at a group of 46 hospital patients, all of whom had their gallbladders removed and were monitored postoperatively. 23 patients stayed in rooms with views of trees, while the other 23 had views of a brick wall. The now classic study found that the patients who had views of trees recovered faster and required less pain medication than the other group of patients.

From what I can tell, the Ulrich study seems to have sparked an interest in, and an understanding of, how nature might benefit us. Countless subsequent studies have been conducted that suggest that exposure to nature reduces blood pressure and increases positive affect, promotes healthy composition of microbiota involved in immune functioning, and lowers mortality from circulatory disease. In terms of emotional health, nature is associated with reduced stress and decreased activation in an area of the prefrontal cortex associated with rumination and mental illness. Higher vegetation cover is associated with a lower prevalence of depression and anxiety. Even potted plants have been found to increase the quality of life for employees in office settings.

What’s in a Dose of Nature?

Nature has the power to make us feel better, but what is it about being outside that has this effect?

Species Richness and Biodiversity

“Nature is not biodiversity, nor a proxy for biodiversity, but certainly encompasses biodiversity.”

Sandifer et al., 2015

colored-pencil-drawing-of-western-meadowlark-perched-on-branch

Increasingly, researchers are investigating the relationship between biodiversity in green spaces and psychological benefits. Several studies have found significant associations between higher plant and bird diversity and positive mental effects. A 2007 study by Fuller et al. found a positive correlation between plant species richness and participants’ sense of identity and ability to reflect. The 312 participants were fairly accurate at assessing plant species richness, which muddies causality. The question then becomes: are the benefits derived from species richness or perceived species richness?

Here’s another study to elaborate on that distinction. Researchers here found that psychological benefits of nature exposure were correlated not with biodiversity, but with participants’ perception of biodiversity only. In this study, participants were apparently not at all good at estimating species richness, and it affected their experience of being outside, regardless of how many species were actually present.

Frequency and Duration

So it seems that the more varied and species-rich the environment, the better. But is glancing out a window now and then the same as going for a walk outside, psychologically? I’d say no, but that doesn’t mean that short exposures to nature don’t benefit us. After all, just a 40-second break to look at a green, plant-filled roof has been shown to improve attention and performance on cognitive tasks, as compared to a break of the same length with views of concrete roofs.

In a sample of over 1500 Australian respondents, longer duration of nature excursions is associated with decreased prevalence of depression and high blood pressure. More frequent visits to public green spaces are associated with a greater sense of social cohesion, which I imagine contributes positively to mental health in general.

Criticisms

Few studies on this topic take an epidemiological approach, leading some to point out that we have very little data on long-term, population-level health effects of nature exposure. Criticisms of some studies also include sample size, lack of adequate controls, and statistical rigor. However, the number of studies that demonstrate a correlation between nature exposure and psychological benefit vastly outweigh the number of studies that show no relationship. While this does not negate the weaknesses mentioned previously, it does seem to suggest that there is validity to the idea that nature is emotionally beneficial.

The Daffodils are Blooming

All the signs that winter is ending are here; the daffodils are blooming, more birds are singing, the neighbors are cleaning out their garage, and before spring really gets underway, Colorado is scheduled to get one or two more last-minute dumps of snow.

Speaking of, now that I’ve gotten myself extra excited to get outside and let my brain soak in the wonderful sights, sounds, and smells of spring, it’s time to prepare myself for tonight’s snowstorm.

Dear Spring, please hurry.