More on the legacy of HM; or, journalists behaving badly

Well that was fast. The book excerpt on HM and Corkin has gone over like a lead balloon. Here are some excerpts of a statement by Jim DiCarlo, head of BCS at MIT:

1. Allegation that research records were or would be destroyed or shredded.

We believe that no records were destroyed and, to the contrary, that Professor Corkin worked in her final days to organize and preserve all records. Even as her health failed (she had advanced cancer and was receiving chemotherapy), she instructed her assistant to continue to organize, label, and maintain all records related to Henry Molaison. The records currently remain within our department.

2. Allegation that the finding of an additional lesion in left orbitofrontal cortex was suppressed.

The public record is clear that Professor Corkin communicated this discovery of an additional lesion in Mr. Molaison to both scientific and public audiences. This factual evidence is contradictory to any allegation of the suppression of a finding.

3. Allegation that there was something inappropriate in the selection of Tom Mooney as Mr. Molaison’s guardian.

Mr. Dittrich identifies some individuals who were genetically closer to Mr. Molaison than Mrs. Herrick or her son, but it is our understanding that this family took in Mr. Molaison and his mother, and took care of Mr. Molaison for many years. Mr. Mooney was appointed conservator by the local court after a valid legal process, which included providing notice of a hearing and appointment of counsel to Mr. Molaison.

So: no research records destroyed, no attempt to suppress the lesion, nothing inappropriate about asking a very-extended family member that had already been taking care of HM for many years to be his conservator.

It will be interesting to see the re-rebuttal. Assuming that the author recorded the conversation, he would have a direct quote from Corkin saying she would shred the documents. And assuming that the author has the e-mails and paper revisions, you would Corkin attempting to delete the lesion data from the initial versions of the paper – unless the author has totally taken that out of context.

I would love to hear from the fact-checkers at the publishing house…

Update – from the comments below, Neuroskeptic points to the re-rebuttal from the author of the original piece. Basically sums up my ‘interesting’ statement above which is: they have sources and evidence for all of the assertions (such as recordings, etc).

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The legacy of HM; or, scientists behaving badly

There is a book about Henry Molaison (HM) that will be coming out tomorrow and it is already causing a bit of a fuss in the scientific community. There is an excerpt in the New York Times Magazine which investigates how the lead researcher (Corkin) dealt with her authority, especially after HM passed away. It kind of has to be read to be believed:

…Despite what she said during the meeting, Corkin’s central problem with the paper, the one she pushed back on hardest, wasn’t Annese’s chatty writing style. Instead she was concerned with something Annese had discovered in Henry’s brain.

Specifically, Annese’s analysis had revealed a previously unreported lesion in Henry’s frontal lobe. The lesion was in the left hemisphere and appeared to have been caused by a man-made object…As one of the paper’s anonymous peer reviewers pointed out, “much of the neuropsychological literature on H.M. has made the case that so-­called frontal function was intact.”

When Corkin sent Annese her revisions of his paper, she deleted all references to the newly discovered frontal lesion. In a note to Annese, she explained that “the frontal lobe lesion does not appear on either the in situ scans [the M.R.I. scans made while the brain was still in Henry’s skull] or the fresh brain photos” and that “any consideration of it would be highly misleading.” Annese responded with a series of images from in situ M.R.I. scans that, contrary to Corkin’s assertions, gave clear views of the lesion.

The paper has since been published here. Here is the (fairly clear) lesion which can also be seen in old (1991-92) MRIs:

HM frontal lobes

Then it turns out that the ‘next of kin’ that became his conservator, donating HMs brain and consenting to further experiments, was not only chosen by Corkin but also was not remotely his next of kin.

Eventually, over the phone, Mooney told me that he and Henry were third cousins, very distant relations.

I asked Corkin whether she was aware that when Mooney became Henry’s conservator, one of Henry’s first cousins, Frank Molaison, was living nearby — his actual next of kin — and had not been consulted. I mentioned that his name should have made him particularly easy to find.

“I was not aware of his existence,” she said.

I asked whether she had ever done any genealogical research at all into the man she had studied for almost a half-­century.

“No,” she said.

I had tracked down and spoken with Henry’s closest living relatives, and some were surprised and disturbed to learn about the things Corkin and her colleagues did with their cousin while he was alive and about the fight over his brain that took place after his death.

I asked Corkin why she arranged for Mooney to apply to become Henry’s conservator in the first place. I knew that for more than a decade before Mooney was named Henry’s conservator, Henry himself had been the only one signing the consent forms for his experiments.

“I just wanted another level of security,” Corkin said. “Another person who was not amnesiac and who had Henry’s best interests at heart.”

I asked what she meant by “security.” Security from what?

“For Henry,” she said. “For M.I.T.”

And what were M.I.T.’s vulnerabilities?

“I don’t know,” she said. “I’d have to ask our lawyers that.”

Someone posted HM’s informed consent form, which claims that HM’s close relatives had passed away which is…clearly not true if his cousin by the same surname lived nearby.

And hey, the whole thing only gets worse (emphasis added):

Me: Right. And what’s going to happen to the files themselves?

(She paused for several seconds.)

Corkin: Shredded.

Me: Shredded? Why would they be shredded?

Corkin: Nobody’s gonna look at them.

Me: Really? I can’t imagine shredding the files of the most important research subject in history. Why would you do that?

Corkin: Well, you can’t just take one test on one day and draw conclusions about it. That’s a very dangerous thing to do.

Me: Yeah, but your files would be comprehensive. They would span decades.

Corkin: Yeah, well, the tests are gone. The test data. The data sheets are gone. Because the stuff is published. Most of it is published. Or a lot of it is published.

Me: But not all of it.

Corkin: Well, the things that aren’t published are, you know, experiments that just didn’t … [another long pause] go right. Didn’t. You know, there was a problem. He had a seizure or something like that.

And on and on. Read the article in full, it is pretty mindblowing (and full of great gossip). Neuroskeptic wrote a review of the full book earlier in the summer which has some other interesting morsels.

As written, a charitable reading of the article is that Corkin did not want to try too hard to wrestle with the ethics of her experiments on this man’s life, wanted to willfully ignore any complicating evidence, and saw no need for others to look at her data. Charitably.

Update

Some push back on the article from a couple of groups. First is Earl Miller and 200 neuroscientists (who?) with the following letter to the NYT:

“We are a community of scientists who are disturbed by a recent New York Times Magazine article (“The Brain That Couldn’t Remember”), which describes Professor Suzanne Corkin’s research in what we believe are biased and misleading ways. A number of complex issues that occur in research with humans, from differing interpretations of data among collaborators to the proper disposition of confidential data, are presented in a way so as to call into question Professor Suzanne Corkin’s integrity. These assertions are contrary to everything we have known about her as a scientist, colleague, and friend. Professor Corkin dedicated her life to using the methods of neuropsychology to illuminate how the brain gives rise to the mind, especially how different regions of the human brain support different aspects of memory. Her scientific contributions went far beyond her work with the amnesic patient HM (whose well being she protected for decades), with major contributions to understanding clinical disorders such as Alzheimer’s and Parkinson’s disease. She was a highly accomplished scientist, an inspiring teacher, a beloved mentor to students and faculty, and a champion of women in science. While her recent passing is a great loss to our field, her passion and commitment continue to inspire all of us. We only regret that she is not able to respond herself.”

Second is Jenni Ogden who reviews the book in Psychology Today. It puts the above in more context but I don’t see it really rebutting any of the key points.

I am hearing on twitter that Corkin did not, in fact, shred documents but do not understand how that jives with the above direct quotation. “A full rebuttal” is on its way.

Fun brain fact: 13 spikes per second is too much energy

spike-energy

I will admit I have never thought about the question: how many spikes is your brain emitting every second? And how many could it emit? Lucy notwithstanding, it is probably something less than ‘all of them’. Beyond the obvious “that is called epilepsy”, there is also an unappreciated metabolic constraint. Spiking is costly! How much could the brain spike?

Screen Shot 2016-07-30 at 10.58.09 AMLet’s think about how we can estimate this. First you have to know how much energy a single spike would ‘cost’ the brain. Every spike is the result of an ebb and flow of sodium and potassium (et al) ions through the pores in the cell. The net result is an unbalancing of these ions which need to be actively pumped out. Additionally, every spike is caused by EPSPs which also require the neuron to expend energy. A spike traveling down the axons is costly. Exocytosis and endocytosis of neurotransmitters requires energy. Sum these all up and you can get some energy requirement: precisely how much energy you need in order to sustain a single spike. In terms of ATP, the unit of energy in biology, we get something on the order of 2.4 * 10^9 molecules of ATP needed for each one!

Once we estimate this, we can ask how much energy the brain consumes as a whole. PET scans are able to estimate the amount of glucose the brain is consuming, and this turns out to be about 77 mg/min, or 34 mg/min for the neocortex (meaning neocortex alone uses 44% of the brain’s energy!). Converting to ATP, we get about 3.4 * 10^21 molecules of ATP per minute. Finally, we do a bit of division and we can guess that cortex is emitting 3,360,000,000 spikes per second – so each neuron is spiking only once every six seconds!

Screen Shot 2016-07-30 at 11.12.30 AMHow high could we push this spike rate? If the cortex was spiking at a measly 1.8 Hz, it would use more energy than the whole brain. If it were spiking at 13 Hz, it would use more energy than the whole body!

Just from metabolic constraints we can ask how sparse the activity in the brain is. Simply put, as the average spike rate in ‘active’ neurons goes up, the number of neurons that the brain can support goes down. If neurons were to fire a single spike in a single second, then only 0.1-1% of neurons could be active at all.

Not every neuron is the same, though. Neurons aren’t just chattering away at each other but are actually trying to communicate something, each in their own special way. Some are especially chatty in their attempts to shut down the signaling of other cells and spike really quickly. These are given the imaginative name of “fast spiking interneurons”. One fancy feature of these fast spikers is that they have very narrow action potentials in order to maximize how fast they can go.

Screen Shot 2016-07-30 at 11.23.26 AM

But this ability comes with a cost: energy. In order to end each spike quickly, the cell has very quick and powerful potassium channels that drive the membrane potential down. Look at the figure just below. In the second row, you can see a model of the sodium and potassium currents. There is so much more going on when the spike is narrower (right) than when it is broad (left). This means that these cells not only fire more, but each time they do that they consume more energy.
spikeenergyestimate

If these neurons are firing so much, and using so much energy, how little must the other neurons be spiking? Does the average spike rate for non-fast spikers go down from 0.16Hz to 0.016Hz? Does the number of active excitatory cells go from maybe 0.5% all the way to 0.05%?

References

Lennie, P. (2003). The Cost of Cortical Computation Current Biology, 13 (6), 493-497 DOI: 10.1016/S0960-9822(03)00135-0

Hasenstaub, A., Otte, S., Callaway, E., & Sejnowski, T. (2010). Metabolic cost as a unifying principle governing neuronal biophysics Proceedings of the National Academy of Sciences, 107 (27), 12329-12334 DOI: 10.1073/pnas.0914886107

On the connectome

Via Twitter, MnkyMnd thinks this should be required reading for every scientist:

In that Empire, the Art of Cartography attained such Perfection that the map of a single Province occupied the entirety of a City, and the map of the Empire, the entirety of a Province. In time, those Unconscionable Maps no longer satisfied, and the Cartographers Guilds struck a Map of the Empire whose size was that of the Empire, and which coincided point for point with it. The following Generations, who were not so fond of the Study of Cartography as their Forebears had been, saw that that vast map was Useless, and not without some Pitilessness was it, that they delivered it up to the Inclemencies of Sun and Winters. In the Deserts of the West, still today, there are Tattered Ruins of that Map, inhabited by Animals and Beggars; in all the Land there is no other Relic of the Disciplines of Geography.

On Exactitude in Science (Borges, 1946)

Should small labs do fMRI experiments?

Over at Wiring The Brain, Kevin Mitchell asks whether it is worth it for small labs to do fMRI:

For psychiatric conditions like autism or schizophrenia I don’t know of any such “findings” that have held up. We still have no diagnostic or prognostic imaging markers, or any other biomarkers for that matter, that have either yielded robust insights into underlying pathogenic mechanisms or been applicable in the clinic.

A number of people suggested that if neuroimaging studies were expected to have larger samples and to also include replication samples, then only very large labs would be able to afford to carry them out. What would the small labs do? How would they keep their graduate students busy and train them?

I have to say I have absolutely no sympathy for that argument at all, especially when it comes to allocating funding. We don’t have a right to be funded just so we can be busy. If a particular experiment requires a certain sample size to detect an effect size in the expected and reasonable range, then it should not be carried out without such a sample. And if it is an exploratory study, then it should have a replication sample built in from the start – it should not be left to the field to determine whether the finding is real or not….Such studies just pollute the literature with false positives.

At the end of the day, you are doing rigorous science or you are not.

I do have a silly little theory – which I keep meaning to write up – on the economics of science. In some cases, it may be worth doing underpowered studies as a cost-effective way to generate hypotheses. However, this depends on the cost of the experiment – and fMRI seems to fall way too far into the “too expensive per data point” field to be worth it.

Commentary on a comment

If you want to see a masterclass in dissecting a paper, go read Tal Yarkoni’s discussion of “The dACC is selective for pain“:

That conclusion rests almost entirely on inspection of meta-analytic results produced by Neurosynth, an automated framework for large-scale synthesis of results from thousands of published fMRI studies. And while I’ll be the first to admit that I know very little about the anterior cingulate cortex, I am probably the world’s foremost expert on Neurosynth*—because I created it.

…The basic argument L&E make is simple, and largely hangs on the following observation about Neurosynth data: when we look for activation in the dorsal ACC (dACC) in various “reverse inference” brain maps on Neurosynth, the dominant associate is the term “pain”…The blue outline in panel A is the anatomical boundary of dACC; the colorful stuff in B is the Neurosynth map for ‘dACC’…As you can see, the two don’t converge all that closely. Much of the Neurosynth map sits squarely inside preSMA territory rather than in dACC proper…That said, L&E should also have known better, because they were among the first authors to ascribe a strong functional role to a region of dorsal ACC that wasn’t really dACC at all… Much of the ongoing debate over what the putative role of dACC is traces back directly to this paper.

…Localization issues aside, L&E clearly do have a point when they note that there appears to be a relatively strong association between the posterior dACC and pain. Of course, it’s not a novel point…Of course, L&E go beyond the claims made in Yarkoni et al (2011)—and what the Neurosynth page for pain reveals—in that they claim not only that pain is preferentially associated with dACC, but that “the clearest account of dACC function is that it is selectively involved in pain-related processes.”…Perhaps the most obvious problem with the claim is that it’s largely based on comparison of pain with just three other groups of terms, reflecting executive function, cognitive conflict, and salience**. This is, on its face, puzzling evidence for the claim that the dACC is pain-selective.

etc. etc. Traditionally, this type of critique would slowly be drafted as a short rebuttal to PNAS. But isn’t this better? Look how deep the critique is, look how well everything is defined and explained. And what is stopping the authors from directly interacting with the author of the critique to really get at the problem? The only thing left is some way for pubmed or Google Scholar to link these directly to the paper.

Go read the whole thing and be learned.

Recording thousands of cells like it’s nobody’s business

Is this what the world is now? Recording thousands of cells per paper? After the 14000 neuron magnum opus from Markram, comes a paper from Jiang et al recording 11000 neurons. When your paper is tossing off bombs like:

We performed simultaneous octuple whole-cell recordings in acute slices prepared from the primary visual cortex (area V1)

and figures like:

octuple recordings

you know you are doing something right. How much do you think this cost compared to the Blue Brain project? (Seriously: I have no sense of the scale of the costs for BBP, nor this.)

I will try to read this more closely later, but I will leave you with the abstract and some neural network candy for now:

Since the work of Ramón y Cajal in the late 19th and early 20th centuries, neuroscientists have speculated that a complete understanding of neuronal cell types and their connections is key to explaining complex brain functions. However, a complete census of the constituent cell types and their wiring diagram in mature neocortex remains elusive. By combining octuple whole-cell recordings with an optimized avidin-biotin-peroxidase staining technique, we carried out a morphological and electrophysiological census of neuronal types in layers 1, 2/3, and 5 of mature neocortex and mapped the connectivity between more than 11,000 pairs of identified neurons. We categorized 15 types of interneurons, and each exhibited a characteristic pattern of connectivity with other interneuron types and pyramidal cells. The essential connectivity structure of the neocortical microcircuit could be captured by only a few connectivity motifs.

NN candy

Read it here.

Is everything we know about Phineas Gage wrong?

How many of the stories we tell about Gage are wrong? Well, a metal rod did fly through the guy’s skull but:

The day after his accident, a local newspaper misstated the diameter of the rod. A small error, but an omen of much worse to come…Within a few days, however, his health deteriorated. His face puffed up, his brain swelled, and he started raving, at one point demanding that someone find his pants so he could go outside. His brain developed a fungal infection and he lapsed into a coma… 

[T]here’s no record of what Gage did in the months after the accident—and we know even less about what his conduct was like. Harlow’s case report fails to include any sort of timeline explaining when Gage’s psychological symptoms emerged and whether any of them got better or worse over time. Even the specific details of Gage’s behavior seem, on a closer reading, ambiguous, even cryptic. For instance, Harlow mentions Gage’s sudden “animal propensities” and, later, “animal passions.” Sounds impressive, but what does that mean? An excessive appetite, strong sexual urges, howling at the moon?

People butcher history all the time, of course, for various reasons. But something distinct seems to have happened with Gage. Macmillan calls it “scientific license.” “When you look at the stories told about Phineas,” he says, “you get the impression that [scientists] are indulging in something like poetic license—to make the story more vivid, to make it fit in with their preconceptions.”

Apparently there’s a minor industry in academia devoted to modeling rods being blown through people’s skulls. And this author is not impressed with Antonio Damasio.

In the end, I think Gage is a proxy for the idea that changes in the brain can cause changes in behavior: it’s hard to emotionally grasp that we’re controlled by a squishy thing in our skull until you have ‘seen it’.

MRI now for dopamine?

The Jasanoff lab has been working on improving MRI for a while, using such cool terms as ‘molecular fMRI’. They are really attempting to push the technology by designing molecular agents to help with the imaging. For instance, they have sensors that can respond to kinase activity or to amines like dopamine.

MRI works by sending powerful magnetic fields at a tissue such as the brain, and measuring the time it takes for molecules in this tissue to ‘relax’ to its previous state. In order to detect molecules such as dopamine, they modified magnetized proteins to bind specifically to those molecules. The relaxation occurs in a specific ‘communication channel’ called T1, as opposed to the T2 ‘channel’ that is used to detect changes in blood flow for fMRI. Since the proteins have different relaxation times depending on whether they are bound or unbound, MRI can be used to measure when there is more or less dopamine in the tissue.

Although I’ve been hearing about these sensors for a few years (the dopamine one came out in a paper four years ago, the kinase one six), I hadn’t seen a paper that really used them until now. The Jasanoff lab has now shown that if you stimulate the nerves that release dopamine, their sensors can indeed detect it. Problem is: they have to inject the sensor directly into the brain. This means, first of all, that they probably aren’t able to measure dopamine activity across the whole brain using this technique. I’m not sure, but I imagine they can image the level of the sensor that is at any given point? But that level is going to affect the signal that they get. Further, someone suggested that because the sensor is large and polar, it’s not going to cross the blood-brain barrier so it’s not a plausible way to image dopamine release in humans. The field will just have to stick with PET imaging for now.

Finally, a personal complaint: they kept claiming they were measuring ‘phasic’ activity of the dopamine (ie, transient). Although they were stimulating the dopamine neurons phasically, I didn’t see any control to measure the tonic level of dopamine! I’m not sure I would have allowed them to get away with that if I were a reviewer. Still, it’s a cool technique that has a lot of potential in the years ahead. It should be exciting to see how it gets developed.

Unrelated, but the Jasanoff lab page claims they are doing MRI in flies. In flies! But I can’t find any papers that do this; anyone know about that?

‘Primitive’ cardiovascular systems

A 520-million year old cardiovascular system:

It was both modern and unsophisticated. A simple, tubelike heart was buried in the creature’s belly—or thorax—and shot single blood vessels into the 20 or so segments of its primitive body. In contrast, x-ray scans of the specimen revealed profoundly intricate channels in the head and neck. The brain was well supplied with looping blood vessels, which extended branches into the arthropod’s alienlike eyestalks and antennae and rivaled the complexity of today’s crustaceans.

The study of cardiovasculature is actually extremely important to understanding neuroscience. There is a complicated apparatus in the brain designed to interact with the vasculature in order to get ATP (energy), etc. Though a commenter (Ginny Freeman) notes:

The “heart” was NOT buried in the “creature’s belly”. It’s a crustacean, for heaven’s sake! Crustaceans like all arthropods have a DORSAL circulatory system.

Here is the original paper.