Saturday, November 3, 2018

Vacillating Disarray of the Memory Trace Theorists

In a February post entitled "Turmoil of the Baffled Engram Theorists," I discussed a Science News article that showed the theoretical disarray of engram theorists, scientists who speculate about a physical brain basis for human memories. Three scientific papers in recent years suggest that claims that human memories are stored in brains do not have a solid theoretical basis well-substantiated by experiments.

One paper was entitled “The mysteries of remote memory,” and was published in the Philosophical Transactions of the Royal Society B. Speaking of long-lasting memories, the authors told us that “our current knowledge of how such memories are stored in the brain and retrieved, as well as the dynamics of the circuits involved, remains scarce.” Using the term “engrams” to mean the hypothesis that there are cells in the brain that store memories, the authors state “what and where engrams are implicated in remote memory storage and how they change over time have received little experimental attention thus far.” The authors also frankly tell us that “From engrams to spines surprisingly little evidence exists in the literature on the grounds of remote information processing, maintenance and storage to account for the lifelong and persistent nature of the mnemonic signal.” This type of candor is a refreshing contrast from the click-bait hype about memory research that we get in the science news, where dubious studies using insufficient experimental groups are often trumpeted as scientific breakthroughs.

One of the ideas about a brain storage of memory is that memories get stored in dendritic spines, little bumps on dendrites. But this study found that dendritic spines in the hippocampus last for only about 30 days. And this study found that dendritic spines in the cortex of mice brains have a half-life of only 120 days. So such dendritic spines don't last enough to store memories that last for years. The “Mysteries of remote memory” paper mentions a study that found that studied the persistence of dendritic spines, and found a “near full erasure of the synaptic connectivity pattern within 15 days post-learning.” The paper says “these incongruent findings point to the need for an alternative explanation to spine dynamics for remote memory stability.” In other words, we can't explain dendritic spines as some physical basis for long-term memory. Referring to the often stated speculations that memories start out in the hippocampus and are transferred to the cortex, the paper states unequivocal experimental evidence in support of it is lacking.” The paper then spends some time talking about the very speculative possibility that DNA methylation has something to do with long-term memory, an idea for which there is no evidence. 

The overall impression we get from reading such a paper is one of uncertainty and disarray, as if no clear idea was emerging from brain studies on the long-term storage of memory. We get such an impression even more strongly from two other papers on this topic published in recent years. One is the 2016 paper “What Is Memory? The Present State of the Engram.” Very oddly for a scientific paper, the paper consists of ten sections, each written by a different author or authors. We get conflicting theories as to how a brain might store memories, with little agreement between the sections.

The 2017 paper here is entitled, "On the research of time past: the hunt for the substrate of memory." It is a portrait of memory theorists in disarray, presenting no one theory about how memory might be stored in a brain, and instead suggesting seven or more possibilities, none of which is plausible. The paper is all over the map in its speculations, like someone shooting a gun in all different directions.

The paper tells us on its sixth page that “Engram-labeling studies have shown that certain populations of neurons encode specific memories in mice.” This is not correct. The studies in question are typically small-sample studies with very low statistical power, in which there is a high chance of false alarms. In a typical such study, an experimenter will zap some small portion of a mouse's brain, and claim that he has elicited a fear memory stored in that part, producing a freezing effect in the mouse. But such freezing effects (which require subjective judgments) mean little, since it is known that there are many parts of a mouse's brain that can be stimulated to produce a freezing effect in a mouse.

The paper tells us on page 9 that “synaptic weight changes can now be excluded as a means of information storage.” But for many years neuroscientists have been pushing the very dubious dogma that memories are stored by changes in synaptic weights. As discussed here, this idea never made any sense, for there has never been a proven case of any information that was ever stored as changes in the weights of something, and also synapses are too volatile to store memories that last for decades, for reasons discussed later in this post. 

The authors then proceed to discuss a wide variety of possibilities for how memory might be stored in a brain.  These include the following (the quotes below in italics are from the paper):

Theory 1: “The particularly longlived proteins associated with DNA (i.e., nucleoporins and histones).” This is not a good option because a scientific paper tells us that the half-life of histones in the brain is only about 223 days, meaning that every 223 days half of the histone molecules will be replaced. So histones are not suitable for storing memories lasting decades.

Theory 2: “Some have suggested that DNA (or the epigenetic modifications on it) is the most suitable candidate for memory, being the cellular storage mechanism for other (lifelong) information.” For why this speculation is untenable, see the section entitled “Why Very Long-Term Memories Cannot Be Stored in the Cell Nucleus” in this post. Human DNA molecules have been exhaustively analyzed by multi-year projects such as the Human Genome Project and the ENCODE project, and no evidence has been found of human memories stored in DNA. See the "Why Long-Term Memories Cannot Be Stored in the DNA Methylome" section of this post for why DNA methylation is also an unsuitable possibility for memory storage. If DNA molecules stored memories, we would find that the DNA molecules in the brain of a dead person would vary a lot, with one DNA molecule in the brain being very different from another. Instead, all DNA molecules in the brain are basically the same, and are the same as DNA molecules in other parts of the body. 

Theory 3: “The late Roger Tsien recently proposed the notion that perineuronal nets, the extracellular matrices around neurons and synapses, provide the architecture for information.” Wikipedia tells us that these perineuronal nets are “composed of chondroitin sulfate proteoglycans,” but this paper tells us that the half-life of such molecules is only 10 days, making them unsuitable for a storage of memories lasting a lifetime. The idea behind this perneuronal nets speculation is that memory may be stored in a pattern of holes, like punch cards. The idea is absurd. IBM punchcards worked back in the 1960's because they worked with a punchcard reader which shined light through the punch cards. The brain has nothing like a punchcard reader to read information if it had information stored in such a way, and such a system only works with flat two-dimensional surfaces, not three-dimensional surfaces like that in the brain. There are two research papers that claim to have a result suggesting that perineuronal nets may be important in memory, but both do nothing to establish such a claim, because they both used fewer than 10 animals in some of their study groups (for a moderately reliable research result, 15 is the minimum number of animals per study group).

Theory 4: “Structures composed of short-lived components could constitute a long-term memory if the configurations were preserved by normal homeostatic replenishment.” To the contrary, there is certainly no “normal” bodily mechanism that might allow “structures composed of short-lived components” to store memories for decades.

Theory 5: “Other theories involve information storage or processing in microtubules, the long polarized helices of tubulin subunits that compose the cellular skeleton.” There is no evidence for such theories, and there is a good reason for rejecting them: the fact that there is high molecular turnover in microtubules. This paper tells us, “Neurons possess more stable microtubules compared to other cell types...These stable microtubules have half-lives of several hours and co-exist with dynamic microtubules with half-lives of several minutes.” So microtubules in the brain last less than a week, and are not any place that memories lasting decades could be stored.

Theory 6: “The physical connectivity within neural ensembles is a plausible new candidate substrate for memory information storage, with many merits, including robustness to insult, bioenergetic efficiency, stability of information storage in a potentially binary format, and a high capacity for informational content.” This is a completely different idea from all the previous things discussed, and the paper does not discuss it truthfully. Far from being a "plausible" idea having “many merits,” the idea has no merits. No one has any plausible idea as to how mere “physical connectivity” could be storing the complex things human remember. The paper refers us to the previously mentioned “What Is Memory? The Present State of the Engram” paper, but the sketch of the idea given in that paper does not present the idea in a coherent manner. We see a diagram showing what looks like a necklace of green beads as a representation of how "physical connectivity" could supposedly store information.  That's not a way to store complex information like humans learn. If there is “stability of information storage” in the connections between neurons, it is not the type of stability that would allow memories to be stored for years, let alone decades. The proteins in synapses have an average half-life of less than a week, and synapses themselves have a lifetime of less than a year. The research of Stettler suggests that synaptic connections do not last longer than about three months. In a paper he stated the following, referring to remodeling which would break any "connectivity pattern":

Depending on whether the population of boutons is homogeneous or not, the amount of bouton turnover (7% per week) has different implications for the stability of the synaptic connection network. If all boutons have the same replacement probability per unit time, synaptic connectivity would become largely remodeled after about 14 weeks.

A very important recent scientific paper is the paper “Synaptic Tenacity or Lack Thereof: Spontaneous Remodeling of Synapses.” The paper used the term “synaptic tenacity” for the idea that synapses (brain connections) are relatively stable. Making a devastating case against such a claim, the paper stated the following:

The aim of this Opinion is to discuss challenges to the notion of synaptic tenacity that come from general biological considerations and experimental findings. Such findings collectively suggest that synaptic tenacity is inherently limited, since synapses do change spontaneously and to a fairly large extent....It is probably unrealistic to expect that synapses maintain their particular contents and, by extension, their functional properties with pinpoint precision. This expectation is further challenged by the fact that synapses are not rigid structures but rather are dynamic assemblies of molecules (and organelles) that continuously migrate into, out of, and between neighboring assemblies through lateral diffusion, active trafficking, endocytosis, and exocytosis....Closer examination reveals, however, that properties of individual synapses, such as spine volume, presynaptic bouton volume, synaptic vesicle number, active zone (AZ) molecule content, and PSD protein content fluctuate considerably over these timescales....Imaging studies in primary culture indicate that synaptic configurations erode significantly over timescales of a few days....The findings summarized above indicate that synaptic tenacity is inherently limited or, using the terminology of Rumpel, Loewenstein, and others, that synapses are intrinsically ‘volatile’....When it comes to cognitive functions, long-term memory is one area where the notion of synaptic volatility raises perhaps some of the most challenging questions. In light of findings discussed in this Opinion article, and possibly others, age-old notions concerning relationships between histories of ‘elementary brain-processes’, connection strengths, and memory traces might need to be revisited; put differently (to paraphrase James, modern science might need to improve on this explanation.

The evidence presented by this “Spontaneous Remodeling of Synapses” paper is devastating evidence against the predominant theory of the brain storage of memories (that memories are stored by changes in synapse strength), and also Theory 6 mentioned above, that memories are stored by some “connectivity pattern” created by synaptic connections. Neither theory can be true if synapses have the kind of volatility described in the paper.

In a 2010 book two neuroscientists state that they are “profoundly skeptical” about the main theory of a physical storage of memory, but suggest that they have nothing like a substitute theory to offer:

We take up the question that will have been pressing on the minds of many readers ever since it became clear that we are profoundly skeptical about the hypothesis that the physical basis of memory is some form of synaptic plasticity, the only hypothesis that has ever been seriously considered by the neuroscience community. The obvious question is: Well, if it’s not synaptic plasticity, what is it? Here, we refuse to be drawn. We do not think we know what the mechanism of an addressable read/write memory is, and we have no faith in our ability to conjecture a correct answer.

I submit that the reason for such hesitancy is that there is no theory of a physical storage of memory that can stand up to careful scrutiny, no theory that can explain both memories that can form instantly and the fact that we can instantly retrieve memories of things learned or experienced long ago. Deprived of any credible neural explanation, we should conclude that human episodic and conceptual memory must be a spiritual or psychic or soul phenomenon, not a neural phenomenon.

One of the many reasons for rejecting claims that memories are stored in brains discussed at this site is the essentially instantaneous speed at which humans are able to remember very rarely recalled pieces of information. You say to me, “Dizzy Dean,” and I may in less than two seconds start saying, “eccentric St. Louis Cardinals pitcher, in the 1930's,” even though I haven't thought or read about Dizzy Dean in decades. How could a brain achieve this effect through reading just the right little spot where the information was stored, which would be like instantly finding a needle in a mountain-sized haystack, given a million little spots in the brain where a memory might be stored?

One major reason why it seems hard to believe that the brain could achieve instant recall is that neurons are slow. Information is passed around in a brain at the slow speed of about 100 meters per second, which is only the tiniest fraction of the speed at which electrical signals move about in a computer. Based on this fact we should consider a brain absolutely incapable of performing memory recall as quickly as humans do.

It is often claimed that the brain “makes up” for its slow speed of nerve transmission by being “massively parallel.” The claim that the brain is massively parallel is false. In the computer world, a computer system is massively parallel if it consists of multiple CPUs or central processing units, each of which is running a computer program. We know of nothing in the brain that acts like a computer CPU, nor do we know of anything like a program that the brain runs to compute. It is false to claim that each neuron is like its own CPU. Neurons do not run any program like a computer CPU does. So we cannot at all overcome the problem of low signal transmission speeds in the brain by claiming that the brain is “massively parallel.” It is true that the brain consists of many neurons working together, but that does not make the brain massively parallel. My television set has many transistors working together, but my television set is not massively parallel; and my arms have many cells working together, but that does not make my arms massively parallel. The brain does does not consist of multiple programs running together on multiple processors, and we don't even know of a single program running anywhere in the brain.

Let us imagine some weird group of conspiracy theorists who maintain that secret information from the World War II era is stored in the leaves lying about in modern Germany. If the theorists were to maintain that such information is written on individual leaves, you could easily show the absurdity of the theory by pointing out that leaves don't last much longer than a year. If the theorists were to maintain instead that it was the arrangements of the leaves that stored the information, with one type of leaf pile representing one thing and another type of leaf pile representing something else, you could also show the error of the theory by pointing out that leaf piles are unstable and ever-changing, being blown around by the wind. Similarly, the protein turnover, synaptic volatility and synaptic remodeling discussed in the "synaptic remodeling" paper above are constraining effects as powerful as the short lifetimes of leaves and the instability and impermanence of leaf piles. Anyone claiming that memories persist in synapses for 50 years is advancing a claim as unbelievable as the 50-year "leaf storage" claims of such conspiracy theorists. 

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