"Strong evidence"? "The neurogenesis-depression hypothesis confirmed"? Schweeet!!!

July 13, 2011

I admit I got a little excited when I saw a Twitt RT’d earlier today from Noah Gray.

Soon to be in press: Strong evidence supporting the neurogenesis-depression hypothesis, from @jsnsndr: http://j.mp/qn6fyD

I’m sort of vaguely aware and following a literature that is trying to establish a causal link between depression and alterations in hippocampal neurogenesis, proliferation and general plasticity based on creating new, functioning cells.

This is generally a non-human literature, typically in mouse models and….highly correlative.

With respect to this latter, the state of the art for a long time has been to treat markers of neurogenesis (there are many stages and concepts here which I’ll glomp under one heading. Follow the link in the tweet to the Functional Neurogenesis blog for all your background reading) as dependent variables to be reported. Not manipulated. This is, perhaps obviously, the case for any post-mortem human brain analysis but also for many animal models to date. In essence, you do some thing to the animal and then look at the markers afterward. Then you report whether neurogenesis is up, down or unchanged. So far so good. But this approach doesn’t quite get at the question of causality which is important if we think that altering the effects on neurogenesis (say by a drug or behavioral therapy*) would have a beneficial effect on the affective disorder itself. It could, after all, be a result of depression with no causal role.

There is also a question of whether a given animal model is a valid representation of a human affective disorder. Here we can think about issues of predictability- does it matter, for example, what the mouse model looks like if the ability to predict what anti-depression, anti-anxiety or anti-mania drugs will work (ultimately) in the clinic is high? Of course not…if your goal is drug development.

If you goal is understanding the neurobiological underpinnings of the human disease, well, you want to be careful.

My take on the current state of the nonhuman models of depression is that we are not yet at the point where we have high confidence in calling any model “depression”. They are models, they have various points of high correspondence to human illness but they also have limitations. They are, in cases, highly predictive of drugs which will ultimately prove useful in the clinical setting.

So I confess that when I see a scientist (Noah Gray is, after all, a scientist by training even if he currently inhabits an Editor job) tweet “strong evidence”, well, I’m looking for some coolio stuff.

Following the link to the post on Functional Neurogenesis, I found the post title to include the word “confirmed”! yay, let’s read!!!!

So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice).

“in mice”. Fuck.

Okay, so let’s scratch the “strong evidence” and the “neurogenesis-depression hypothesis confirmed stuff” for now.

Pretty cool paper, by the sounds of it. Again, from my distinctly nonspecialist position, this is the next step. Manipulations of the neurogenesis processes as independent variables to provide stronger evidence that there is a causal relationship. Between these processes and a behavioral or physiological phenotype. I can’t really say where this all fits into the “first demonstration” or “best demonstration” or “critical demonstration” picture so as to give you a valance for exactly how cool it is. But I do recognize that these approaches are the next place the field needs to go to better establish that the neurogenesis-depression hypothesis could be “confirmed”.

Me, until the state of animal models are better and more convincingly established, I want to see data in human subjects before I am willing to concede either “confirmation” or “strong evidence”.

__
ps. Do take a read over the Functional Neurogenesis blog. It is really quite good and this area of neuroscience is fun. Many of you may still labor under the old belief that the adult brain doesn’t grow new neurons and can’t repair itself. It’s no liver, but the brain does have some capacity to generate new neurons.

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No Responses Yet to “"Strong evidence"? "The neurogenesis-depression hypothesis confirmed"? Schweeet!!!”

  1. Jason Snyder Says:

    Nice summary of the field (and it’s problems). The title of my post may be a bit much, but I couldn’t resist having some fun with it. Indeed, the neurogenesis-depression hypothesis may never be “confirmed” if depression is taken to be purely a human phenomenon. And will we ever be able to do the studies of neurogenesis in humans that are needed to say that it’s functionally important? So for now I guess I/we have to be willing to settle for making “the neurogenesis-depression hypothesis *could* be confirmed” a bit more of a reality.

    Hey, while on the topic, if anyone out there wants to help out on the “human relevance” aspect of all this and ingest some BrdU (labels newborn cells, no toxic side effect PROMISE!) in the name of science, let me know.

    Like

  2. Noah Gray Says:

    As Jason mentions, this is a nice, brief review of the biology involved, but you essentially set up a straw man with regards to the rest of the post by nitpicking the wording of a 140-character tweet. Jason’s blog post *clearly* states that it is in rodents, as you proved above with your quotation. Yet you decided to lecture on how scientists should define “strong evidence” and regarding the burden of proof you would need to put up the “Mission Accomplished” banner.

    Rest assured that Jason, myself and the whole of the neurogenesis community (who reviewed and will read this paper) will never consider the hypothesis proven as law based only on data from animals. Mostly because nobody said that in the first place.

    Like

  3. David Kroll Says:

    New T-shirt: “The Brain. It’s No Liver.”

    Like

  4. Dr Becca Says:

    I thought it was pretty clear that Jason was joking when he used the word “confirmed.” I mean, what (quality) scientist ever claims in earnest that their work confirms much of anything? Even the most convincing of studies are more likely to use qualified language like “suggests,” “evidence for,” “indicates,” etc.

    Like

  5. DrugMonkey Says:

    My objection to “confirmed” in the heading to a blogpost which describes the necessary particulars is several orders of magnitude less that my objection to the journalistic excess of a Twitt. Until y’all explain how that was just a joke or snark, that is….

    Like


  6. my objection to the journalistic excess of a Twitt

    Wait. You mean this is all about what some fuckewadde tweetered??? Jeezus motherfucke, holmes, get a fucken grippe on yourself!

    Like

  7. FmsRse12 Says:

    how is depression defined in mice??….

    Like

  8. DrugMonkey Says:

    If you clicked through to the post you would find for that particular study:

    increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia.

    Like

  9. Noah Gray Says:

    If this really is all about the wording of the tweet above, you have undermined a good portion of your post here. The arguments and rhetoric you use to paint all with the same brush may be good for blog traffic, but frankly, it’s pretty tiresome. “Strong evidence” supporting this theory *is* available in the upcoming paper. In Google+, where I would have had more room, clearly “in rodents” would have been easy to add. Alas, it was a tweet. Yet after clicking through, one is immediately met with the notion that this work was in mice (actually, I can’t believe I am having to type and explain this; boggles the mind, doesn’t it dear reader??) Headlines often lack all the details, I’m afraid to tell you. WHICH IS WHY ALL CRITICAL INFORMATION IS PROMPTLY OFFERED TO MAKE SURE THERE ARE NO MISUNDERSTANDINGS. Your post, in retrospect, is only really justified had rodents never been mentioned at all in the source.

    Anyway, I’d love to discuss these issues further at the SfN meeting since blog comments are such a poor replacement for real social interaction. You’ll be there, right? I’ll be there the whole time. Would prefer to introduce you to an actual editor, not just the dim, two-dimensional strawman you love to whack on this here web log. But I’ll understand if you can’t make it.

    Like


  10. […] article: “Strong evidence”? “The neurogenesis-depression hypothesis … This entry was posted in depression and tagged browser, browser-privacy, depression, […]

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  11. Make sure you d00ds bring seconds!

    Like

  12. drugmonkey Says:

    We disagree that a mouse model constitutes “strong evidence” for any hypothesis that depression (as in the human disorder) is caused by alterations in neurogenesis, Noah. If you really believe the “strong evidence” claim you made then I suppose I need to back off the part of my critique that attributed your word choice to a reflexive tendency for overexaggeration of any given paper or finding. Unfortunately this simultaneously lowers my opinion of your scientific acumen, but I’m sure that worries you not.

    Like

  13. Isis the Scientist Says:

    Rodents don’t give strong evidence of shit for dick about anything. They certainly can offer support for a mechanism, but if you are hanging your hat on evidence from rodents, you’re a dumbass.

    Hmmm…this sounds like a CPP-length blog post.

    Like

  14. David Says:

    The results in any one paper are not strong (certainly not convincing) evidence for almost anything, let alone the idea that neurogenesis participates either in the pathophysiology of clinical depression and/or its treatment. One could argue that the results in this paper – ONLY WHEN taken along with of the heap of previous results – is strong-“ish” evidence.

    That said, I think there is something much more important than “strong” evidence. It’s convergent evidence. When data from multiple species, derived using multiple approaches, all point in the same direction, you’re onto something. Here, the concerns of several posters are right. The evidence outside of rodents is very limited. That doesn’t mean it’s wrong. It just means those studies have to be completed before we can claim strong/convergent/convincing evidence.

    Like

  15. Dr Becca Says:

    I’d love to discuss these issues further at the SfN meeting since blog comments are such a poor replacement for real social interaction.

    So I guess Tideliar and I should pick a venue for our BANTER party based on availability of a boxing ring?

    Like

  16. drugmonkey Says:

    The evidence outside of rodents is very limited. That doesn’t mean it’s wrong. It just means those studies have to be completed before we can claim strong/convergent/convincing evidence.

    Precisely. However let us not lose sight of the fact that irresponsible discussion of any given paper as if it is some ultimate proof of something, nails down an airtight case, etc does active harm to the public perception of the conduct of science.

    Others much more thoughtful than my self have waxed eloquent on why this is a problem. For me it boils down to the problem of continually raising a level of expectation in the lay reader that is inevitably disappointed. This then makes the lay reader extremely suspicious of new findings and unable to learn to integrate ongoing progress in a meaningful way. Too much of this and the lay public concludes that science is all just bullshit anyway and why should they take any of it seriously. Facts are not facts, just a matter of opinion….even in science? well then why should we think the facts and reality have any meaning for, say, our public policy decisions.

    all for the want of a horseshoe nail….

    Like

  17. Noah Gray Says:

    I don’t understand how the point continues to be missed. Research is done in animals or cell culture or whatever model to reveal which theories or ideas have enough merit or clout to actually be considered for the pains and efforts of exploring it further in humans. Human studies are complicated, sensitive, expensive and, depending on the study, dangerous. Having strong evidence in a model system to support an idea is important in order to pursue great ideas further where it really counts.

    All of the above comments are arguing semantics. It’s laughable to think that nobody in this thread either uses model systems, or has never felt like their data has strongly-demonstrated any particular connection.

    I repeatedly make the point you discuss above regarding the danger of disappointing the lay reader when I give talks, so we’re on the same page there. Do you really want to be that poor of an analyst and base your opinion of my scientific acumen over a single tweet? You must know that headline writing is typically only a handful of words. One makes a point and then is sure to explain the nuances in the body. That is precisely what was done here. One can’t control whether the lay public reads any particular essay discussing science, but that is the hope and shame on the reader if they don’t.

    I repeat my invitation to have a discussion regarding this at SfN. I just need you to tell me when. I really do believe this would be fruitful. I take accusations over my expertise and credibility very seriously, as I know you do too. This is particularly true when you use a public forum to question my ability to do my job. Let’s make sure your readers know exactly what you are talking about when you offer slanderous opinions of Nature editors. Or let’s make sure that they know you are more-willing to make snap-judgments and generalize based on your pre-conceived motions of how things work, without actually seeking to confirm those opinions. Your choice. When would you like to meet. My schedule is wide open.

    Like

  18. Isis the Scientist Says:

    I see little point in a face to face meeting. Can’t a highly credible in print editor articulate his point in writing? Especially an expert like a nature editor?

    Like

  19. Isis the Scientist Says:

    I amend my previosu statement. If you’ll take smack him with your glove and challenge him to a duel for challenging your honor, I would support your need to meet at SfN to handle this matter further.

    Like

  20. PsyguyLA Says:

    This is fascinating stuff…in my lab we are undertaking studies with ketamine (investigational) and ECT, used to treat depression in humans and both potent inducers of neurogenesis (possibly), and applying multimodal advanced neuroimaging methods (MRS in particular (to look for a neurogenesis marker) but also rsMRI, ASL, DTI inter alia.) Subjects will be stratified according to current inflammatory load, history of childhood trauma, and duration of current depressive episode. Additional genetic microarray and peripheral bioinflammatory marker assays will be applied.

    However, as for BrdU use in humans…it’s mutagenic, teratogenic and cytotoxic, so would likely not pass human IRB or IBC panels, which is why we’re going with neuroimaging (at high field strengths.)

    Like

  21. FmsRse12 Says:

    “increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia.”

    maybe I missed something but if a mouse is in novel environment after acute stress chances are he is gonna avoid food….and also if you force him to swim he will be in despair…..after all this he may avoid sucrose …..

    Like

  22. brooksphd Says:

    FmsRse12 – these data are in comparison to baseline/control data of the rodent reaction to novel stimuli etc. So yes, you can tell the difference.

    Like

  23. brooksphd Says:

    Oh, and Tideliar informs me he’ll be bringing his mouthguard and gloves to the meeting just in case. He knows a good gym just the other side of the Potomac in NOVA y’all can meet for your “discussion” at. Furthermore, he agrees to referee…

    Like


  24. […] dear friend Drugmonkey has an interesting post up on some new data on the “neurogenesis-depression hypothesis.” Whatever the balls that means. You all know how I feel about the brain. Drugmonkey writres […]

    Like

  25. becca Says:

    “You must know that headline writing is typically only a handful of words. One makes a point and then is sure to explain the nuances in the body. That is precisely what was done here. One can’t control whether the lay public reads any particular essay discussing science, but that is the hope and shame on the reader if they don’t. ”
    One of my committee members told me after my defense “you should never assume that the reader will read”. Seriously, he literally said that. I almost didn’t get my PhD because I made the crazy assumption the reader would read. LET THAT BE A LESSON TO YOU ALL!

    “slanderous opinions of Nature editors”
    If it’s in print, wouldn’t it be libelous?
    /pedantic twittery

    “If you’ll take smack him with your glove and challenge him to a duel for challenging your honor,”
    Or at least steal his hat. Or throw a boston cream pie in his face. Or something equally entertaining. But pics or it didn’t happen.

    All that aside- DM, listen carefully:
    headlines : stories :: advertisements : products
    Think about how egregiously wrong something must be to win a suit for ‘false advertising’. The headline is to entice you to read the story, and occasionally to give writers a chance to make awful, terrible, horrible puns. That’s it. It is NOT a summary of the story. Any expectation on your part that a headline function like the title of a scientific paper, or worse yet like a fucking English 101 “thesis statement” is pure DM-generated BS. Nobody views news headlines as The Truth.

    Like

  26. daedalus2u Says:

    A lack of neurogenesis is not the cause of depression.

    I have a poster accepted at the SfN where I will explain what is. 😉

    I would be happy to have extensive discussions on it too.

    Like

  27. Isis the Scientist Says:

    If you can get between DM and Noah’s battle to the death in the poster aisles, I hope you’ll get your opportunity to explain it to him.

    Like

  28. DrugMonkey Says:

    A review of animal models of depression used in drug discovery may be of interest to some readers of this discussion.

    Like


  29. […] at Scientific American have great summaries of the findings and their significance. And the Drugmonkey blog attacks the question of whether or not a depression study in mice can be relevant for […]

    Like

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    Like

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