A new study was published today with results that contradict those found in the UCSF study that you've written about.
Human Hippocampal Neurogenesis Persists Throughout Aging
The Sorrells et al study is directly mentioned twice in this paper. The first claim is that the study failed to address medicaton and drug use, which impact adult hippocampal neurogenesis.
The density of doublecortin-positive (DCX+) cells were re- ported to decline from birth into the tenth decade of life (Knoth et al., 2010) in parallel with 14C-determined neuron turnover(Bergmann et al., 2015); however, medication and drug use, which affect AHN (Boldrini et al., 2014), were not addressed (Knoth et al., 2010; Sorrells et al., 2018; Spalding et al., 2013).
The second, more interesting claim is that the Sorrells et al study only looked at incredibly tiny slices of the dentate gyrus section of the hippocampus, and that the conditions of preservation for these samples likely impacted ability to detect neurogenesis.
Direct comparison between our data and Knoth’s data is not possible because they analyzed only three 5 µm sections per subject from portions of the hippocampus, treated tissue at 80◦C for 1 hr and at low pH to obtain deparaffinization and antigen retrieval, and assessed cell density without using stereology, which is the gold standard, given that cell density does not necessarily reflect total cell number (West and Gundersen, 1990). For the same reasons, we cannot compare our findings with those of a recent descriptive study that failed to detect DCX/PSA-NCAM+ cells in the DG from 15 subjects between 18 and 77 years of age (Sorrells et al., 2018)
According to this article in today's LA Times, the UCSF group responded to the study.
In an email statement, that group, which works out of developmental neuroscientist Arturo Alvarez-Buylla's lab, said that while they found the new study's evidence of declining blood vessel growth in the adult hippocampus interesting, they are not convinced that Boldrini and her colleagues found conclusive evidence of adult neurogenesis.
"Based on the representative images they present, the cells they call new neurons in the adult hippocampus are very different in shape and appearance from what would be considered a young neuron in other species, or what we have observed in humans in young children," they wrote.
They added that in their study, they looked not just at protein markers associated with different types of cells, as Boldrini and her team did, but also performed careful analysis of cell shape and structure using light and electron microscopes.
"That revealed that similarly labeled cells in our own adult brain samples proved to be neither young neurons nor neural progenitors, but rather non-neuronal glial cells expressing similar molecular markers," they wrote.
The times article continues to describe Boldrini's response, which touches upon the parts of her paper that I cited earlier.
Boldrini points out that the two groups were working with very different samples.
She and her team examined more than two dozen flash-frozen human brains, which were donated by families of the deceased at the time of death. The brains were immediately frozen and stored at minus-112 degrees Fahrenheit, which keeps the tissue from degrading.
The other research team received brain samples from hospitals in China, Spain and the U.S., and the brain tissue they examined had not been preserved in the same way. Boldrini said the chemicals that were used to fix the brains could have interfered with their ability to detect new neurons.
She also noted that while both groups were looking for signs of neurogenesis in the hippocampus region of the brain, her group had access to the entire hippocampus while the UCSF team was looking at thin slices of the tissue representing a small fraction of the brain.
I think there are many people who want believe neuroscience to be a robust field but at least since Vul et al's Voodoo Correlations in Social Neuroscience the evidence that the field isn't very robust seems to be good.
I think the more interesting question is why people want to believe that neuroscience is a robust field. I think it's due to a mistaken belief in the value of reductionism and an unfounded assumption that reductionism is a good way to go about understanding complex systems.
I've curated this post for these reasons:
My biggest hesitation in curating this post was:
In general I will try not to curate things I think people have already read (e.g. on SSC). I just think this is an important enough argument and that there aren't many people writing up models and data-points for when and where to trust different fields of science. Thanks for (cross)posting this!
I've cited this post loads of times as an example of how a whole area of science with lots of gears and bells and whistles turns out to be entirely false. I think it's a really valuable post from that perspective, and I'm really glad Scott wrote it.
There are some comments here suggesting the OP is not accurate, so I'll really appreciate anyone who has the time to independently review it and see whether they reach Scott's conclusions too.
I’m sure I’ve made some inexcusable mistakes somewhere in the process of writing this.
Found it. :P (Well, kind of.)
And if exercise has antidepressant effects in humans, then the claim that those effects are neurogenesis-mediated must be wrong too.
Apparently exercise correlates with less depression, but isn't causal. That is, depressed people tend to exercise less, but exercising more doesn't cause you to be less depressed.
Unrelated tangent thought: I'd really like to know if the huge correlation with lifespan/healthspan has the same issue. Like, I'm pretty sure VO2 Max is the metric we should be optimizing for, rather than a target weight or muscle mass. Like, once you control for excercise, weight is no longer a strong predictor of health/lifespan.
But maybe exercise has the same problem. If most people have a hard time doing callorie restriction, but can up their metabolism through exercise, then the only benefit of excercise might be avoiding a caloric surplus. Or maybe exercise isn't causal at all, but the sorts of people who exercise also do other things that help, or are just healthy enough to be able to exercise.
This seems real weird to me.
I do not have depression, but exercise seems to have an effect on my mood (and anecdotally appears to have similar affects on friends of mine, depressed or otherwise). Is part of the argument here that exercise doesn't have any reliable effect on mood? (i.e. I'm placeboing myself or not noticing that sometimes exercise doesn't affect my mood or does so negatively or something?).
Or just that it doesn't have any longterm effects on depression? (so a depressed person might feel a bit better via the same mechanism I do, but in a dimension that's different from "depression?")
Sorry; normally I try not to make claims like that without a citation, but I was on my phone at the time and couldn't find the source easily. But here it is:
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210112
It's a twin study with 5952 participants. Here's the highlight:
In genetically identical twin pairs, the twin who exercised more did not display fewer anxious and depressive symptoms than the co-twin who exercised less. Longitudinal analyses showed that increases in exercise participation did not predict decreases in anxious and depressive symptoms.
Conclusion Regular exercise is associated with reduced anxious and depressive symptoms in the population at large, but the association is not because of causal effects of exercise.
Maybe everyone's mood still goes up a little from exercise, due to endorphins or whatever? Like, I assume that people with depression can still experience runner's high, just like I'm pretty sure they can still experience a heroine high. Maybe it's numbed or less intense or something, I dono. But neither is going to cure their depression. Or, at least that's my interpretation. (Maybe a permanent heroine high would count as a cure, if it somehow didn't kill you?)
For whatever reason, they display about the same levels of depressive symptoms, regardless of exercise. But, I assume that those symptoms are somewhat independent of moment-to-moment mood, or how you feel about something in particular. So, it seems perfectly possible for the mood effects of exercise to be real, without conflicting with the study.
Personally, I don't think exercise itself has much effect on mood, aside from runner's high, which seems well-documented. Playing a game or sport definitely can, if you let yourself get really into it, but I think that's mostly independent of the physical exertion. But, all I have to back up this particular impression is personal subjective experience, and most of that has been doing fun things that also happened to involve physical activity.
Huh. I wonder if there is any kind of correlation among animals for neurogenesis, in the same way there is a correlation for lifetime-heartbeats.
Yep, crossposting creates a more natural shelling point for discussion on LessWrong, and a lot of people really dislike the context switch of link posts (I almost never click on them because they tend to violate my expectations, and are then also much less natural to quote from in the discussion).
It also makes the content of the post indexable in our search, and makes it possible for other users and the moderators to create sequences that include this post. And generally makes it easier for us to curate the post as part of the LessWrong canon.
Um, I think one or both of us is confused, so let me clarify what I meant:
I’m asking why this isn’t a link post while also still containing the full text of the post, just as it does now. (Like this post, for instance.) That would satisfy the “makes the content of the post indexable in our search” and the “makes it possible for other users and the moderators to create sequences that include this post” and the “easier to curate” desiderata.
The matter of the context switch is a UI issue; the way GW handles this issue is one solution, though there are others, no doubt.
As for the “natural Schelling point”, well, empirically… no, it really doesn’t, does it? Look at how many comments there are, here, and now look how many there are on SSC… perhaps you might consider adding a feature that allows you to transclude comments from certain sites, such as SSC and possibly other hand-picked blogs, into the LW comment sections of posts from said blogs that are cross-posted here—as I have done on my blog and on Naval Gazing (scroll down)?
Ah, yes. Looks like I misunderstood you. I agree that we should have some additional link to the original blogpost. I think it should be formatted slightly differently than a normal link post, since having "Link" in the title signals to users that they will have to leave the site to read the content, and that the content in the post is separate from the original article (i.e. has commentary on the linked article, instead of being an exact copy). We just haven't gotten around to making the UI for that. For now crossposting is indicated by the "SSC" tag visible on the frontpage.
(Re schelling point: I do think I was a bit unclear here. What I meant was "a natural schelling point for discussion of the SSC post, for people on LW, separate from SSC". I've generally found that there are just too many comments on SSC, with not enough tools to sort and filter them, with the average quality not being high enough, and with people being less familiar with the other material on LessWrong, so that it seems good to have a separate place to discuss the same posts with a different set of people and with different technology applied to them.)
(There isn't really much of a difference between the GW and LW2 implementation from the context switch perspective. Both require you to go to a different site to read the content, which seems quite hard to avoid, and is really the primary issue I am concerned with here. I like GWs implementation of making the link accessible from the frontpage, though that doesn't really have much to do with my worries about context-switching.)
I think it should be formatted slightly differently than a normal link post, since having “Link” in the title signals to users that they will have to leave the site to read the content.
Not that I necessarily disagree with this, but just want to note that there are already many posts on LW which are linkposts with text in them (in fact, I think this may actually be the majority of all linkposts; of the last 11 frontpage linkposts, for example, 6 contain text, while 5 are link-only posts); so what we take a “normal link post” to be—and consequently, what is the appropriate UI design for linkposts—should probably take that into account.
Yeah, I think the important distinction is "here is text that is commentary on the provided link" and "here is the text of the link". I think these two are the most important to distinguish from one another.
Agreed. Note, though, that even with that caveat, linkposts seem to be at least one-third text-containing.
Interesting. But not the question I'd like to see you take your best swing at. Why are we only able to utilize so little of our brain? That would be like successful nuclear fusion power. Actually engaging 100% of the human brain and controlling it would be a revolution on par with developing agriculture or industrialization. Who studies this, and how are they going about it?
[I am not a neuroscientist and apologize in advance for any errors in this article.]
Hey, let’s review the literature on adult neurogenesis! This’ll be really fun, promise.
Gage’s Neurogenesis In The Adult Brain, published in the Journal Of Neuroscience and cited 834 times, begins:
Subsequent investigation has found adult neurogenesis in all sorts of brain regions. Wikipedia notes that “In humans, new neurons are continually born throughout adulthood in two regions of the brain: the subgranular zone and the striatum”, but adds that “some authors (particularly Elizabeth Gould) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the neocortex”, and there’s also some research pointing to the cerebellum.
Some research has looked at the exact mechanism by which neurogenesis takes place; for example, in a paper in Nature cited 1581 times, Song et al determine that astroglia have an important role in promoting neurogenesis from FGF-2-dependent stem cells. Other research has tried to determine the rate; for example, Cameron et al (1609 citations) find that there is “a substantial pool of immature granule neurons” that may generate as many as 250,000 new cells per month. Still other research looks at the chemical regulators – a study by Lie et al, cited 1312 times, finds that Wnt3 signaling is involved.
(which is making you more nervous – the fact that I keep emphasizing how many citations these studies have, or the fact that one of the principal investigators is named “Lie”?)
But the most exciting research has been the work identifying the many important roles that neurogenesis plays in the adult brain – roles vital in understanding learning, memory, and disease.
Snyder et al (775 citations) finds “a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.” Dupret et al go further and find that “spatial relational memory requires hippcampal adult neurogenesis”. Aimone et al (633 citations) find “a possible role” for adult neurogenesis in explaining the “temporal clusters of long-term episodic memories seen in some human psychological studies”. And Jessberger et al (506 citations) finds a role in object recognition memory as well.
In terms of learning, one of the major studies was Gould et al in Nature Neuroscience (2207 citations) finding that Learning Enhances Adult Neurogenesis In The Hippocampal Formation. Lledo et al (1288 citations) find that neurogenesis plays a part in explaining the brain’s amazing plasticity, and is “highly modulated, revealing a plastic mechanism by which the brain’s performance can be optimized for a given environment”. Clemenson et al (17 citations) find that “from mice to humans”, enviromental enrichment improves neurogenesis, and this “may one day lead us to a way to enrich our own lives and enhance performance on hippocampal behaviors”.
But I’ve always been most interested in the link with depression. In 2000, Jacobs et al published Adult Brain Neurogenesis And Psychiatry: A Novel Theory Of Depression (961 citations). It’s important enough that I want to quote the whole abstract:
This theory got a boost from studies like Duman et al (522 citations), which found that antidepressant drugs like SSRIs upregulated neurogenesis – could this be their mechanism of action? And Ernst et al (327 citations) find that “there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis” – ie the antidepressant effects of exercise seem to work this way too. Electroconvulsive therapy, the most effective known treatment for depression? Works by promoting adult neurogenesis, at least according to Schloesser et al.
Is there anything that doesn’t have important neurogenesis-related effects? It would seem there is not. Sex, for example, “promotes adult neurogenesis in the hippocampus, despite an initial elevation in stress hormones” according to Leuner et al (124 citations). Drug addiction is modulated by neurogenesis. We need rock n’ roll to complete the triad, so here’s Music Faciliates The Neurogenesis, Regeneration, and Repair of Neurons.
A study in Nature Neuroscience that garnered over 3000 citations found that running increased neurogenesis. The popular science press was quick to notice. A slew of exercise-neurogenesis studies spawned articles like Psychology Today’s More Proof That Aerobic Exercise Can Make Your Brain Bigger. Dr. Perlmutter (“Empowering Neurologist!”) has a video about how you can Grow New Brain Cells Through Exercise. After this the pop sci world might have gotten a little carried away, until neurogenesis controls everything and is controlled by everything in turn. Slimland (of course there’s a site called Slimland) has a How To Grow New Brain Cells And Stimulate Neurogenesis page, suggesting you can “set yourself free and start flying” by removing toxins, eating a ketogenic diet, and meditating. Naturalstacks.com boasts 11 Proven Ways To Generate More Brain Cells, Improve Memory, And Boost Mood, which advises…really? Do you really want to know what it advises? Come on.
Also, growth mindset. Of course growth mindset. Carol Dweck’s Mindsetworks helpfully provides an infographic for teachers, urging them to tell their students that each time they set a goal or become motivated to learn a new skill, “a new neuron is formed through a process called neurogeneis” [sic].
So it’s no surprise that researchers in the area are calling adult neurogenesis “one of the most exciting and rapidly evolving areas of research in the field of neuroscience”.
II.
Fun fact: there’s no such thing as adult neurogenesis in humans.
At least, this is the conclusion of Sorrells et al, who have a new and impressive study in Nature. They look at “59 post-mortem and post-operative slices of the human hippocampus” and find “that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans.” Also, the subgranular zone, the supposed part of the brain where neurogenesis begins, isn’t even a real structure.
I am not a neuroscientist and am unqualified to evaluate it. But the Neuroskeptic blog, which I tend to trust in issues like this, thinks it’s legit and has been saying this for years. Ed Yong from The Atlantic has a really excellent review of the finding that interviews a lot of the major players on both sides and which I highly recommend. Both of these reinforce my feeling that the current study makes a really strong case.
I was kind of floored when I saw this, in a way that I hope I was able to replicate in you by preceding this with the literature review above. How do you get so many highly-cited papers speaking so confidently about every little sub-sub-detail of a phenomenon, if the phenomenon never existed in the first place?
As far as I can tell, this was entirely innocent, well-intentioned, and understandable. It happened like this:
Adult neurogenesis was discovered in rats. This was so surprising, and such a violation of established doctrine, that it quickly became one of the most-investigated areas in neuroscience. Hundreds of studies were done on rats to nail down every little detail of the process.
The work was extended to many other mammals, to the point where it seemed inevitable that it must be true of humans as well. This was difficult to test because the relevant studies involve dissecting brains, and there aren’t that many human brain specimens available with the necessary level of preservation. After a lot of work, a few people got a couple of brains, did some very complicated and contamination-prone tests, and found evidence of adult neurogenesis. This encouraged everyone to assume that the things they had discovered about rat neurogenesis were probably true in humans as well, even though they could never prove them directly because of the difficulty of human experimentation. Later some other researchers tried to replicate the complicated and contamination-prone tests and couldn’t find adult neurogenesis in humans, but everyone assumed they had just messed up some aspect of the complicated testing process.
And to complicate matters, everyone in the new study has been very careful to say they can’t prove with certainty that zero adult neurogenesis occurs – just that the levels are so low and hard to detect that they can’t possibly matter. Looking back on some past studies, it seems that “so low and hard to detect that they can’t possibly matter” was actually within their confidence intervals. So it may be that some team found some extremely tiny and irrelevant population of immature neurons in the brain, gave a confidence level that included that number, and then everyone just assumed we were talking about levels similar to the ones we saw in rats.
With real scientists taking not-entirely-sufficient care to distinguish rat from human results, the popular press felt licensed to totally ignore the distinction (did you even notice which of the studies in Part I were done on which species? Don’t worry, nobody else did either).
Meanwhile, synaptogenesis – the growth of new synapses from existing nerve cells – was getting linked to depression and all kinds of other things in a lot of interesting studies. When people started talking about neurogenesis’ role in depression, psychiatrists like me who have trouble keeping words ending with -genesis separate just sort of nodded and said “Oh, yeah, I heard about that” and didn’t give it the sort of scrutiny it deserved.
(I wonder if this is young-earth creationists’ problem too)
So it’s not like any one person made a spectacular mistake anywhere along the lines. Most of the studies done were in rats, and 100% correct. A few studies were done in humans, and may have gotten the wrong answer in a very difficult domain, while also hedging their bets and admitting they were trying something hard. It was only on a structural, field-wide level that all of this came together into people just assuming that adult human neurogenesis had to happen and be important.
…or at least, that’s the optimistic take on it. But I can’t help thinking – antidepressants work in humans, which suggests that the people who found neurogenesis was necessary for antidepressant effects must have just been plain wrong. And if exercise has antidepressant effects in humans, then the claim that those effects are neurogenesis-mediated must be wrong too. And, uh, humans form spatial and temporal memories, so unless we do this by a totally different mechanism than the ones rats use, people must have been wrong when they said neurogenesis was involved in that. ECT? Works in humans. Brain plasticity? Happens in humans. So maybe it would be better to say that the original claim that adult neurogenesis happens in humans seems innocent and understandable – but if the new study is true, that suggests that a lot of the followup claims must have been imaginary. Anything that focuses on a process that happens in humans and says “neurogenesis causes this” must not only be wrong to extend the results to humans, but must be under strong suspicion of being wrong even about rats, unless rat brains and human brains accomplish the same basic tasks through totally different mechanisms (eg antidepressants work on rats but for different reasons than in humans).
We know many scientific studies are false. But we usually find this out one-at-a-time. This – again, assuming the new study is true, which it might not be – is a massacre. It offers an unusually good chance for reflection.
And looking over the brutal aftermath, I’m struck by how prosocial a lot of the felled studies are. Neurogenesis shows you should exercise more! Neurogenesis shows antidepressants work! Neurogenesis shows we need more enriched environments! Neurogenesis proves growth mindset! I’m in favor of exercise and antidepressants and enriched environments, but this emphasizes how if we want to believe something, it will accrete a protective layer of positive studies whether it’s true or not.
I’m also struck by how many of the offending studies begin by repeating how dogmatic past neuroscientists were for not recognizing the existence of adult neurogenesis sooner. Remember Gage’s review above:
Or from Neurogenesis In Adult CNS: From Denial To Opportunities And Challenges For Therapy:
From Adult Human Neurogenesis: From Microscopy To Magnetic Resonance Imaging:
I’m bolding the word “dogma” because for some reason every article in this field uses it like a verbal tic. Washington University’s “Neuroscience For Kids” page feels compelled to use the word even though they don’t expect their readers to understand it:
I think Patient Zero in this use-of-the-word-dogma epidemic might be Neurogenesis In The Adult Brain: Death Of A Dogma, (880 citations) whose abstract says:
The dogma-concern isn’t totally wrong. Previous neuroscientists thought there wasn’t neurogenesis in rats, and there is. That was a legitimate mistake and one worth examining. But is it possible that the reaction to that mistake – a field-wide obsession with talking about how dogmatic you had to be to miss the obvious evidence of mammalian neurogenesis, and a desire never to repeat that mistake – contributed to the less-than-stellar effort to make sure neurogenesis was happening in humans? Heuristics work until they don’t. Those who fail to learn from history are doomed to repeat it, but those who learn too much from history are doomed to make the exact opposite mistake and accuse anyone who urges restraint of “failing to learn from history” and “dogmatism”. From the Virtues of Rationality:
Or maybe I’m just grasping for straws. But I feel like I have to grasp for something. I have nowhere near as much expertise as the actual neuroscientists writing about this result (and there are many). I’m sure I’ve made some inexcusable mistakes somewhere in the process of writing this. The reason I feel compelled to dabble in this subject anyway is that I don’t feel like anyone else is conveying the level of absolute terror we should be feeling right now. As far as I can tell, this is the most virulent outbreak of the replication crisis thus far. And it didn’t happen in a field like social psychology which everyone already knows is kind of iffy. It happened in neuroscience, with dramatic knock-on effects on medicine, psychology, and psychiatry.
I feel like every couple of months we get a result that could best be summed up as “no matter how bad you thought things were, they’re actually worse”. And then things turn out to be even worse than that. We can’t just become 100% certain things are arbitrarily bad – that would be making the same mistake as the neuroscientists who were overly eager to reject the no-neurogenesis dogma. But that means we always have to be ready for disappointment.
From the Neuroskeptic article:
Our total inability to ever change or get better in any way is what separates us from the animals. Inspiring!