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Our future, our universe, and other weighty topics

Monday, November 22, 2021

A Hailed "Breakthrough" May Be the Same Old Schlock

Behold the modern beast that is online science news reporting.  To understand it, we must understand its financial dynamics. Major websites have learned the following fundamental formula, which applies to any web page containing ads:

                         Page Views = Cash Income

The reason for this is that major websites make money from online ads. So the more people view a web page giving some hyped-up science story, the more money the website makes. This means that science reporting sites have a tremendous financial incentive to hype and exaggerate science stories. If they have a link saying, “Borderline results from new neuron study,” they may make only two dollars from that story. But if they have a story saying, “Astonishing breakthrough unveils the brain secret of memory,” they may make five hundred dollars from that story. With such a situation, it is no wonder that the hyping and exaggeration of scientific research is at epidemic levels.

There is a rule of thumb you can follow as a general guideline: the more ads you see on a page reporting scientific results, the more suspicious you should be that you are reading some hyped-up clickbait.  Using that rule we should be very suspicious indeed of a recent story on www.statnews.com, one with the untrue title "Using optogenetics, scientists pinpoint the location and timing of memory formation in mice."  The page devoted to giving this story has no less than four online ads. 

Here is the opening of the story, ending in an unjustified claim, and describing what the author fails to see is a very defective method for testing memory in mice:

"A mouse finds itself in a box it’s seen before; inside, its white walls are bright and clean. Then, a door opens. On the other side, a dark chamber awaits. The mouse should be afraid. Stepping into the shadows means certain shock — 50 hertz to the paws, a zap the animal was unfortunate enough to have experienced just the day before. But when the door slides open this time, there is no freezing, no added caution. The mouse walks right in. ZAP. The memory of this place, of this shock, of these bad feelings had been erased overnight by a team of neuroscientists at four leading research institutions in Japan using lasers, a virus, and a fluorescent protein normally produced in the body of sea anemones. Their work, published Thursday in Science, pinpoints for the first time the precise timing and location of minute brain changes that underlie the formation and consolidation of new memories."

We read above a description of scientists using one of the silliest methods used by neuroscientists: trying to determine whether a rodent is feeling fear based on some subjective and unreliable judgment about "freezing behavior" in which an animal supposedly stops moving because it is afraid. Trying to determine fear in an animal by judging "freezing behavior" is unreliable, and makes no sense. Many times in my life I suddenly saw a house mouse that caused me or someone else to shreik, and I never once saw a mouse freeze. Instead, they seem invariably to flee rather than to freeze. So what sense does it make to assume that the degree of non-movement ("freezing") of a rodent should be interpreted as a measurement of fear?  Moreover, judgments of the degree of "freezing behavior" in mice are too subjective and unreliable. 

Fear causes a sudden increase in heart rate in rodents, so measuring a rodent's heart rate is a simple and reliable way of measuring fear in a rodent.  A scientific study showed that heart rates of rodents dramatically shoot up instantly from 500 beats per minute to 700 beats per minute when the rodent is subjected to the fear-inducing stimuli of an air puff or a platform shaking. But rodent heart rate measurements seem to be never used in neuroscience rodent experiments about memory.  Why are the researchers relying on unreliable judgments of "freezing behavior" rather than a far-more-reliable measurement of heart rate, when determining whether fear is produced by recall? 

The Stat News story (written by a writer with a bachelor's degree in biology and a master's degree in journalism) is a typical example of "gee whiz" science journalism in which dubious triumphal claims are uncritically parroted or amplified.  The author repeats a legend that Steve Ramirez implanted a memory in a mouse. Read here for a 2016 post I wrote debunking such a claim reported in a 2013 paper. 

The Stat News story then repeats another groundless legend spread by neuroscientists, the legend that study of so-called "long-term potentiation" has shed some light on how memories are created. We read this:

"One way that scientists think that happens is through something called long-term potentiation. All the sights and sounds and smells and emotions associated with a given experience cause certain neurons to fire. And when they do, it leads to enduring changes in those cells and in cells nearby — they sprout protrusions that help transmit electrical signals and make more connections with nearby neurons."

What is misleadingly called “long-term potentiation” or LTP is a not-very-long-lasting effect by which certain types of high-frequency stimulation (such as stimulation by electrodes) produces an increase in synaptic strength.  The problem is that so-called long-term potentiation is actually a very short-term phenomenon. A 2013 paper states that so-called long-term potentiation is really very short-lived:

"LTP always decays and usually does so rapidly. Its rate of decay is measured in hours or days (for review, see Abraham 2003). Even with extended 'training,' a decay to baseline levels is observed within days to a week."

So-called long-term potentiation is no more long-term than a suntan. The use of the term "long-term potentiation" for such an effect is deceptive, particularly when it is suggested that so-called "long-term potentiation" might have something to do with explaining memories that can last for 50 years or longer. 

The new Japanese study is all based on equating so-called "long-term potentiation" with memory, and since this so-called "long-term potentiation" is very short-lived, we can be rather sure that nothing has been done to explain how brains could form or store permanent memories.  Besides this and the reliance on unreliable "freezing behavior" judgments mentioned above, there are other reasons why we should suspect the new Japanese study is just another example of the same old schlock, yet another example of Questionable Research Practices by neuroscientists. 

The link here goes to the paper, but it is hidden behind a paywall; and I can't find a preprint on the main biology preprint server.  But the page does have two links I can use, one a link allowing you to download Materials and Methods information.  When I use that link I see figures such as Figure S5 (which tells us some of the sample sizes used for the experiments, which were numbers such as 6 mice, 8 mice and 10 mice) and Figure S10 (which mentions a sample size  of only 6 mice).  These sample sizes are way too small for a reliable result to be claimed. As a general rule, we should suspect that a  neuroscience experiment has produced a mere false alarm whenever it fails to use at least 15 animals per study group.  Some of the study group sizes were less than half the size that should be used for a reliable result. 

It is well known that it is very easy to get misleading false alarm results whenever too-small sample sizes are used.  Here's an example.  Suppose there are twenty researchers who ask five friends whether a flipped coin will be heads or tails.  Probably one of them purely by chance will report that all five of his friends correctly predicted the results. But that's just a false alarm effect. Change the experiment so that each experimenter asks fifteen of his friends to predict the coin flips, and very probably not a single researcher will report that all of them guessed correctly. 

There is a standard way for a serious researcher to calculate whether he has used a sample size sufficient to get a result that is very probably not a false alarm. The standard method is to do what is called a sample size calculation.  When I use the "MDAR Reproducibility Checklist" link on the page giving the abstract for the Japanese researchers,  I see this confession:

"No statistical method was used to determine sample size. Sample sizes are similar for those used in the field."

Oops, our researchers failed to calculate how large a sample size they should use.  That's like a rocket engineer failing to calculate whether his moon rocket will land on the moon or crash into it. Given the kind of sample sizes mentioned in one of their documents (6 mice, 8 mice and 10 mice), we should assume the Japanese researchers used way too small a sample size to get a moderately persuasive result.  Their claim that their sample sizes are "similar for those used in the field" should do nothing to restore our trust. In experimental rodent research there has for a very long time been a gigantic failure of experimenters to use adequate sample sizes, with inadequate sample sizes being more of a rule than an exception. 

A neuroscience experiment researcher who confesses to failing to calculate how large a sample size should be used is like a man standing in public with his pants pulled down. Such researchers know that good research practice mandates calculating how large a sample size is needed to show a robust result, and using at least such a sample size. The failure of most neuroscience experimental  researchers to follow such a practice is a huge ongoing scandal of modern neuroscience. 

The paper by the Japanese researchers begins by making an unbelievable claim, stating, "Episodic memory is initially encoded in the hippocampus and later transferred to other brain regions for long-term storage." To the contrary, data in the leading scientific paper on this topic indicates that no such thing is true. I refer to the paper "Memory Outcome after Selective Amygdalohippocampectomy: A Study in 140 Patients with Temporal Lobe Epilepsy." That paper gives memory scores for 140 patients who almost all had the hippocampus removed to stop seizures.  Using the term "en bloc" which means "in its entirety" and the term "resected" which means "cut out," the paper states, "The hippocampus and the parahippocampal gyrus were usually resected en bloc."  The paper refers us to another paper  describing the surgeries, and that paper tells us that hippocampectomy (surgical removal of the hippocampus) was performed in almost all of the patients. 

The "Memory Outcome after Selective Amygdalohippocampectomy" paper does not use the word "amnesia" to describe the results. That paper gives memory scores that merely show only a modest decline in memory performance.  The paper states, "Nonverbal memory performance is slightly impaired preoperatively in both groups, with no apparent worsening attributable to surgery."  In fact, Table 3 of the paper informs us that a lack of any significant change in memory performance after removal of the hippocampus was far more common than a decline in memory performance, and that a substantial number of the patients improved their memory performance after their hippocampus was removed. 

Consequently there is no scientific warrant for the Japanese researchers claiming that "episodic memory is initially encoded in the hippocampus."  We know that humans can typically remember pretty well after removal of the hippocampus.  And when scientists make claims about memories being encoded in the brain, they are bluffing.  No one has any understanding of how learned information could be encoded into neural states or synapse states. The job of neurally encoding all of the different things people learn would require an army of genes dedicated to such a task, and there is no sign that such genes exist. A neural encoding of memories would leave fingerprints of representation all over the place in the brain, and no such fingerprints exist. The complete lack of any substantial and credible theory of neural memory encoding (and the lack of evidence for a neural encoding of memories) are two of the biggest reasons for rejecting all claims that memories are stored in brains. Read here for many others. 

lack of evidence for neural memory encoding

Why did the scientists make this strange claim that "e
pisodic memory is initially encoded in the hippocampus and later transferred to other brain regions for long-term storage"?  Is it because anyone has seen a memory moving from one part of the brain to another? Not at all. No one has actually observed a memory stored in a brain, nor has anyone seen a memory moving around in the brain. 

The reason why neuroscientists make such a claim is mainly that internally the hippocampus is extremely unstable.  In the hippocampus the things called dendritic spines (hypothesized to be related to memory) last for only about 30 days. Almost nowhere in the brain is there more internal instability and dendritic spine turnover.  Not wishing to claim that memories are stored permanently in this brain place of such very high instability, neuroscientists have resorted to telling the ridiculous tall tale that first memories appear in the hippocampus and then magically migrate to the cortex.  Such a tale is futile, because the cortex is almost as unstable as the hippocampus. A study found that the half-life of dendritic spines in the cortex is only 120 days. So the tall tale of memories moving from the hippocampus to the cortex is kind of a "out of the fire into the frying pan" kind of story.  Humans can reliably remember things for fifty years, so you don't solve the instability problem by imagining that memories migrate to a cortex where dendritic spines and synapses don't last for years. As for the proteins that make up such dendritic spines and synapses, they have average lifetimes of only a few weeks or less. Such numbers indicate that the brain cannot be the storage place of memories that can last for 50 years. 

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