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Classifying yin and yang using MRI

Zad Chow writes:

I wanted to pass along this study I found a while back that aimed to see whether there was any possible signal in an ancient Chinese theory of depression that classifies major depressive disorder into “yin” and “yang” subtypes. The authors write the following,

The “Yin and Yang” theory is a fundamental concept of traditional Chinese Medicine (TCM). The theory differentiates MDD patients into two subtypes, Yin and Yang, based on their somatic symptoms, which had empirically been used for the delivery of effective treatment in East Asia. Nonetheless, neural processes underlying Yin and Yang types in MDD are poorly understood. In this study, we aim to provide physiological evidence using functional magnetic resonance imaging (fMRI) to identify altered resting-state brain activity associated with Yin and Yang types in drug-naïve MDD patients.

They didn’t really have much prior evidence to go on with this study, so a lot of the analyses seemed exploratory,

The aim of this exploratory study is to provide physiological evidence, using functional magnetic resonance imaging (fMRI), to identify altered resting-state brain activity associated with Yin and Yang types in drug-naïve MDD patients. Previous studies using functional connectivity (FC) method of resting-sate fMRI demonstrated altered inter- and intral-regional brain connectivity, including local functional connectivity in the medial prefrontal cortex and frontoparietal hypoconnectivity in MDD brains (14, 15). As proposed in Drysdale’s work (8), differential brain function at resting-state may be a useful physiological marker to identify specific subpopulation of MDD patients. Thus, we hypothesize that resting-state brain activity and FC in MDD patients with Yin type are altered when compared to those with Yang type. To test this hypothesis, we examined resting-state functional activities across the entire brain in MDD patients in both Yin and Yang groups as well as matched healthy controls.

The authors ended up finding a few differences that were corrected for using the AlphaSims approach (a method to correct for multiple comparisons in fMRI studies) and a few exploratory comparisons that weren’t corrected for because those were considered exploratory. The authors state,

To the best of our knowledge, this is the first study demonstrating [emphasis added] biological differences in brain function associated with Yin and Yang types characterized by somatic symptoms.

I think the conclusions the authors draw here are fairly interesting because it seems there wasn’t that much evidence to go on with this theory besides ancient Chinese traditions. They acknowledge that a lot of the study is exploratory, but they’re able to say so confidently that they’ve demonstrated biological differences between participants that are classified as “yin” and those classified as “yang”.

I personally believe that subtypes of depression likely do exist. We’ve had some interesting discoveries using data-driven clustering (which is a method that obviously has problems of its own) and it would be in our best interest to discover accurate subgroups so we could tailor therapies for them, but the idea of depressed patients being classified as yin and yang doesn’t seem to sound very realistic to me.

And the conclusions of studies like this, even when correcting for multiple comparisons (which I know you think is unnecessary when using multilevel modeling), make me incredibly skeptical of fMRI studies. Would love to hear your thoughts.

My reply: I took a very quick look at the article. It seems that there are 48 people in the study, and it’s not clear at all how we are supposed to draw conclusions based on the general population. The groups identified as “yin” and “yang” are different in systematic ways—something about somatic symptoms and responses to a questionnaire—so you’d expect to see some differences in other measures too. But, again, I don’t know what this really tells us about people not in the group.

The point of the study can’t be just to demonstrate that the two groups are different. We already knew they were different in some systematic ways, even before doing a single MRI scan. The real question is what are the systematic differences. And, for that, statistical significance is not so useful.

I guess they could consider a preregistered replication. But I share your concern, as it does seem like a bit of a fishing expedition. And I don’t think the researchers would have much of a motivation to do a replication study, as the potential losses from a failed replication are greater than the potential gains from a successful replication.

Just to be clear: I know nothing about yin and yang and I only skimmed the article, I did not read it carefully. So I’m just giving my general impression, which is that I’d be cautious about generalizing beyond these 48 people in the particular setting of the study.

38 Comments

  1. Ed Hagen says:

    I just wrote a blog post why most Major Depression is probably not a brain disorder:

    https://grasshoppermouse.github.io/2018/12/16/seven-reasons-why-major-depression-is-probably-not-a-brain-disorder/

    #7 Points out that MD is thoroughly confounded with sadness and adversity, facts that are ignored by every imaging or other biomarker study on MD that I’ve ever seen.

    • Martha (Smith) says:

      Thanks for the link. Case very well argued.

    • Andrew says:

      Ed:

      I see what you’re saying but it doesn’t seem to capture the whole story. Yes, bad things happen to people and cause depression, but it also does seem that some people are prone to depression and that does seem like a latent characteristic of a person.

      • Ed Hagen says:

        That’s partially captured in the figure in #3 that shows that folks who are higher on neuroticism are at greater risk of depression for a given level of “contextual threat.” There are other risk factors too. Female sex is a major one. And that same figure give a bit of insight into the sex difference: note that at low levels of threat that women are at higher risk of depression than men (controlling for neuroticism), but at higher levels of threat the risk of depression is pretty similar between the sexes. Childhood adversity also seems to predispose to depression in adulthood. None of this is compelling evidence that depression is a brain disorder, though.

        • Curious says:

          Ed:

          Are you claiming that major depression occurs somewhere besides in the brain? You appear to be arguing that the absence of evidence is in fact evidence. Do I have that right?

          • Ed Hagen says:

            No. I’m arguing that the many brain differences between depressed and non-depressed are not, in and of themselves, evidence of brain *dysfunction* (more specifically, they are not evidence that depression is a brain dysfunction). Given the design of all such studies that I’ve seen, the differences could be, e.g., aspects of the neurobiological basis of sadness, or functional brain responses to adversity (beyond sadness and low mood), or non-functional neurobiological consequences of adversity that are unrelated to depressed mood.

            • Curious says:

              Ed:

              You have now changed your argument from *disorder* to *dysfunction*. What is the difference? Is there a physiological difference between *disorder* and *dysfunction*? Is there are cognitive difference? Is there a serotonin reuptake inhibitor difference? Must the difference be apparent on an MRI for it to be a *dysfunction* rather than a *disorder*?

    • Nate says:

      I am not clear on the logic here. Of course, people who face more adverse events are more likely to become depressed, but how does that separate the psychological components of MDD from the brain-based, biological ones?

      A good counter-example would be PTSD. To be diagnosed with PTSD, it is necessary to first be exposed to a traumatic event. However, arguably everyone experiences trauma at some point in life, yet the prevalence rates for PTSD are not so high (~6-7% lifetime). Further, we know that there are brain abnormalities (particularly in the hippocampus) that predict development of PTSD given traumatic experiences, and the persistent hypervigilance and stress that follows PTSD tends to do further damage to areas of the brain associated with memory and executive functioning. Clearly, the brain can both: (1) be pre-disposed (i.e. nature), and (2) be negatively impacted through environmental insults (i.e. nurture).

      Similar arguments can be made for MDD, although MDD is much easier to diagnose given that one only needs to experience a single depressive episode (which explains the high prevalence rates). All that being said, why argue for only nature or only nurture for MDD? The brain is not separate from everything that happens to it, and claiming that MDD is not brain-based seems naïve when you make such a statement. When there is so much evidence on both sides, it is likely both (e.g., What about the effects of SSRIs and SNRIs? What about about electroconvulsive therapies in extreme cases of depression? The list goes on…).

      • Ed Hagen says:

        Nate,

        I never argued that MD, or any other psychological state, was not brain-based. On the contrary, they are all brain-based, whether functional, dysfunctional, or non-functional. As I said in my blog post:

        “Differences in subjective experiences must be caused by physical differences in the brain. Indeed, if there weren’t biochemical and neurophysiological changes underlying MD this would be a shocking finding that would shake our materialist conception of the brain to its core.”

        In the case of MD, I’m instead saying that this fallacious circular argument is pervasive:

        MD is *assumed* to be a disorder > there are genuine brain differences between those with, and without, MD > because MD is assumed to be a disorder, these brain differences are characterized as “deficits” > therefore MD is a disorder!

        • Curious says:

          Like all areas of medicine where the causal processes are not well understood, crude methods are used to identify and describe something. Whether it is a problem depends on what is done with these crude descriptions. When used to deny people employment, they are problematic. When used to help people recover from trauma, they are useful.

        • Nate says:

          It’s pretty clear then that you are arguing over the definition of the term “disorder”, rather than whether MDD is a brain-based disease.

          To me, the problem with your position is in making the claim that MDD only follows adversity—this is completely overstated and not even supported by the data in your post. Practically every psychological disorder is far more likely to develop after an “adverse” event (e.g. diathesis stress models), but this by no means suggests that there are not biological factors that predispose someone to developing a disorder given the right environmental context. Twin studies show this very clearly.

    • Jacob C Kesinger says:

      So there’s a lot of things I could say about this article of yours, but I’ll restrain myself and just say that it’s full of special pleading and cherry picking and outright reckons.

      (Actually I lied, I’ll also say that if you have people in your life whom are important to you who are being or have been treated for clinical depression, please consider listening to them about their lived experiences; if you do not have such people please consider the possibility that you do and they do not trust you enough to have told you).

  2. Ed Hagen says:

    Sorry, I was treating disorder and dysfunction as synonyms in the above. But to be precise, I favor the “harmful dysfunction” concept of “disorder”:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174594/

    Under this concept, dysfunction is necessary for disorder, but not sufficient, because to be a disorder, the dysfunction must also be “harmful”.

    • Curious says:

      If an inability to live one’s life normally is not considered harmful — then what would be considered harmful?

      • Ed Hagen says:

        I’m not disputing that depression can be harmful, but lots of things that are not dysfunctions are harmful, e.g., aggression, jealousy, and even physical pain. The physical pain mechanisms of a person with terminal cancer are not malfunctioning (the dysfunction is instead in the cancer cells), but the pain is nevertheless quite harmful in that situation because there is nothing to be done about the cancer, yet the consequent physical pain prevents the person from doing all the things they still need to do. In another example from Wakefield, illiteracy is harmful in our society, but never having learned to read is not a brain dysfunction.

        To be a disorder, a condition must be both harmful *and* a biological dysfunction.

        • Curious says:

          Then give me an example of a disorder.

          • Curious says:

            Here is a DSM-5 definition quoted from a Psychology Today article:

            https://www.psychologytoday.com/us/blog/rethinking-mental-health/201307/the-new-definition-mental-disorder

            Then, under pressure by skeptics as to the whether this definition made any sense whatsoever, they redefined non-existing mental disorders this new way in the recently released DSM-5:

            “A mental disorder is a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. Mental disorders are usually associated with significant distress in social, occupational, or other important activities. An expectable or culturally approved response to a common stressor or loss, such as the death of a loved one, is not a mental disorder. Socially deviant behavior (e.g., political, religious, or sexual) and conflicts that are primarily between the individual and society are not mental disorders unless the deviance or conflict results from a dysfunction in the individual, as described above.”

            On what basis can you argue that Major Depression does not fall under this definition?

            • Curious says:

              The article makes a very poorly drawn analogy between human attempts to explain the unknown and attempts to describe, label, and code a specific type of human suffering. These are not the same processes.

              I grabbed the article because it was the first that came up with the DSM definition of mental disorder.

            • Anonymous says:

              “On what basis can you argue that Major Depression does not fall under this definition?”

              This part:

              “… that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning”

              is very debatable for Major Depression (MD), to say the least. That was a key point of my blog post. MD is caused by adversity, it is diagnosed with symptoms, like sad or depressed mood, that are almost certainly functional responses to adversity, and for most sufferers it has a time course of a few months to about 1 year, which seems pretty reasonable following the experience of moderate-to-severe adversity. Where is the evidence of dysfunction that is so overwhelming that virtually all mental researchers take it as axiomatic that MD is a disorder?

              • Curious says:

                I am not quite following why your desire to minimize the other symptoms and experiences that are far beyond “sad or depressed mood”.

                You are using the term functional from an normative perspective when in fact functional is from an organismic perspective relative to the demands of modern life. It is not simply that it is “to be expected”. It is that the person cannot function within the demands of their life. You appear to be confusing that term.

                https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/clinical-depression/faq-20057770

                What does the term “clinical depression” mean?
                Answer From Daniel K. Hall-Flavin, M.D.
                Depression ranges in seriousness from mild, temporary episodes of sadness to severe, persistent depression. Clinical depression is the more-severe form of depression, also known as major depression or major depressive disorder. It isn’t the same as depression caused by a loss, such as the death of a loved one, or a medical condition, such as a thyroid disorder.

                To diagnose clinical depression, many doctors use the symptom criteria for major depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association.

                Signs and symptoms of clinical depression may include:

                Feelings of sadness, tearfulness, emptiness or hopelessness
                Angry outbursts, irritability or frustration, even over small matters
                Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
                Sleep disturbances, including insomnia or sleeping too much
                Tiredness and lack of energy, so even small tasks take extra effort
                Reduced appetite and weight loss or increased cravings for food and weight gain
                Anxiety, agitation or restlessness
                Slowed thinking, speaking or body movements
                Feelings of worthlessness or guilt, fixating on past failures or self-blame
                Trouble thinking, concentrating, making decisions and remembering things
                Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
                Unexplained physical problems, such as back pain or headaches
                Symptoms are usually severe enough to cause noticeable problems in relationships with others or in day-to-day activities, such as work, school or social activities.

                Clinical depression can affect people of any age, including children. However, clinical depression symptoms, even if severe, usually improve with psychological counseling, antidepressant medications or a combination of the two.

              • Ed Hagen says:

                The blog swallowed my name. The above comment is mine.

          • Ed Hagen says:

            Infectious disease, cancer, heart attack, Parkinson’s, dementia.

            • Curious says:

              So you are arguing that there is no such thing as a mental disorder? Just as the Psychology Today article is?

              • Curious says:

                Ed:

                You appear to dislike the term “disorder”. What would you prefer to label the experience that is currently described as Major Depression?

              • Curious says:

                Whether the cause of the experience is genetic or environmental is irrelevant to the experience and the ability to diagnose such experience as a disorder. You allow for infection and heart disease to both be categorized as a disorder — but not major depression. What is the relevant difference?

              • Ed Hagen says:

                No, I am emphatically not arguing that there is no such thing as a mental disorder. All functions, including brain functions, can dysfunction. In my blog post I included many examples of mental disorders, such as schizophrenia, autism, intellectual disabilities, bipolar, Alzheimer’s and other dementias, and Parkinson’s.

                And to respond to your comments below:

                I like the term “disorder”, defined as a harmful dysfunction. I’m arguing that for most MD in the community, there is little compelling evidence of dysfunction, whereas for heart disease, there is compelling evidence of dysfunction (one or more components of the cardiovascular system is failing to perform its function, leading to an eventual failure of the system to adequately circulate blood). For infectious disease, pathogens are interfering with one or more physiological functions (i.e., causing dysfunction). In pneumonia, for example, an infection of the lungs interferes with breathing and oxygen absorption (dysfunctions).

              • Curious says:

                Ed:

                You are redefining “disorder” to fit your idiosyncratic belief.

                You are arguing that because we do not understand the brain better and our methods of examining it are still crude that this is justification to declassify Major Depression as a disorder (i.e., the lack of evidence as evidence).

            • Grumpofus III says:

              You are being ridiculous. Framing the question in those terms you are losing everything that’s important in it. Obviously depression is different from cancer! For heavens sake!

    • Curious says:

      Ed:

      to return to your earlier point:

      I will agree that the clear onset for psychological disorders, including major depression, are not clearly demarcated and often appear to be the extreme end of a “normal” reaction, but that is likely because there are only a small number of negative emotions to choose from and people who have not experienced major depression have no reference from which to intuit a difference in experience. Whether a physical change occurs to the brain during major depression is an interesting question and one worth study, but quite beside the point of whether the patient is experiencing dysfunction in their brain. They obviously are or they would not even present as such.

      Mood is a function of physiology. Depression is a function of physiology. All human experience is a function of physiology. Does torture result in depression? Yes. To your point, it overrides any individual variation in resilience that may exist. Does continued harassment and racial injustice do the same on a lesser scale? Yes.

      As someone who has experienced both depression due to losing loved ones and major depression instigated by other adverse events, I can tell you unequivocally that there is a massive experiential difference between the two. It is virtually impossible to convey the true experience of sustained major depression to someone who has not also experienced it.

      • Ed Hagen says:

        Curious,

        “As someone who has experienced both depression due to losing loved ones and major depression instigated by other adverse events, I can tell you unequivocally that there is a massive experiential difference between the two. It is virtually impossible to convey the true experience of sustained major depression to someone who has not also experienced it.”

        I actually don’t doubt that there are qualitative differences in experiences of sadness, grief, and MD, which I also admit undercuts my argument to some extent.

        Let me make two points. First, differences in subjective experiences, in and of themselves, don’t provide much evidence for dysfunction. There are many different negative emotions, such as anger, jealousy, sadness, and grief, all caused by some kind of “adversity,” broadly construed. The fact that the experience of jealousy is different from the experience of sadness does not indicate that one is functional and the other is dysfunctional.

        Second, when it comes to depression, there is a considerable body of literature debating whether it is a dimensional or categorical phenomenon. In the blog post I cited this study:

        http://psycnet.apa.org/record/2005-15138-022

        which concluded that depression is dimensional. But I’m still very open to the idea that MD also has aspects that are qualitatively different from sadness or grief. I would argue, however, that those categorical differences are functional differences. This is a topic for a future blog post, though.

        • Curious says:

          Subjective experiences is the ENTIRETY of depression — dismissing this will get us no closer to reality. There is no other experience. Whether one is functional is also a subjective experience and relative to individual life requirements. Diagnosis takes place via careful questions from a diagnostician — that we do not have a chemical test to diagnose the experience does not change the experience.

          I think dimensionality does not capture depression in the way crude measures of personality are thought to be dimensional, but that it is closer to a sequence of conditional symptoms that are necessary but insufficient until essentially reaching a point of inability to function.

      • Ed Hagen says:

        Curious,

        I’m responding to these comments down here because the blog limits nested comments:

        “You are redefining “disorder” to fit your idiosyncratic belief.”

        It’s not my redefinition, it’s Jerry Wakefield’s. As for it being idiosyncratic, his original publication on the “harmful dysfunction” illness concept has over 1300 citations:

        https://scholar.google.com/citations?user=NkiWM10AAAAJ&hl=en&oi=sra

        At a minimum, it has generated a lot of debate, and it’s influence can easily be seen in the DSM-5 definition (Wakefield was heavily involved in the debate over DSM-5), and so it probably doesn’t serve to be characterized as idiosyncratic at this point. But it is still debated, true.

        “You are arguing that because we do not understand the brain better and our methods of examining it are still crude that this is justification to declassify Major Depression as a disorder (i.e., the lack of evidence as evidence).”

        Actually, I argued in my blog post that the claim that MD is a disorder should “instead be treated as a testable hypothesis.”

        • Curious says:

          If you are arguing that bereavement is indeed a diagnosable form of depression, then I agree. If you are arguing — because bereavement is not distinguishable from other forms of depression, these other forms should not be considered diagnosable depression then the argument is backwards.

        • Curious says:

          Fair enough. It was Wakefield’s idosyncratic belief that has generated a confused argument.

      • Ed Hagen says:

        Curious,

        Responding down here again to your comment above:

        “Depression ranges in seriousness from mild, temporary episodes of sadness to severe, persistent depression. Clinical depression is the more-severe form of depression, also known as major depression or major depressive disorder. It isn’t the same as depression caused by a loss, such as the death of a loved one”

        That is incorrect. Google DSM-5 and the “bereavement exclusion” for much more on this. Here is one key study:

        https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.2008.07111757

        “Conclusion: The similarities between bereavement-related depression and depression related to other stressful life events substantially outweigh their differences. These results question the validity of the bereavement exclusion for the diagnosis of major depression.”

  3. Martha (Smith) says:

    Having a name for something doesn’t mean you understand what it is.

    For example, I’d often start a class (with calculus as a prerequisite) by asking “What is the integral?” A lot of students said, “Area” (to which I’d typically respond by bringing up the method of finding distance traveled by integrating speed). Virtually none gave anything like a definition.

    See also https://fs.blog/2015/01/richard-feynman-knowing-something/

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