The impairment of memory consolidation in psychiatric patients

Genzel L, Ali E, Dresler M, Steiger A, & Tesfaye M (2010). Sleep-dependent memory consolidation of a new task is inhibited in psychiatric patients. Journal of psychiatric research PMID: 20869069


Just a little update, since I've been slacking lately.

The authors looked at schizophrenic and depressive Ethiopian patients given a sequential finger tapping task (a motor task used often in sleep research because the timing can be measured and for the simplicity of the task). The all participants were, notably, keyboard naive - and so everyone learning the tapping task weren't used to the feeling of keys under their fingers. Trials 1-12 of the task were done on day 1, 6 more trials (13-18) on day 2, and 6 more (19-24) on day 3.

The good: the authors do clearly show an increase in performance (measured in number of correctly tapped sequences in 30 seconds) for healthy participants. So far, in line with prior studies. Now, schizophrenic patients and depressive patients do not show an increase in performance with sleep - suggesting something's going on (and I suspect it lies in the patterns of synaptogenesis that underlie sleep which have been suggested in depression and schizophrenia - but that's my speculation).



The not-so-good: The authors infer between trials one and six an increase in performance in healthy controls that they claim does not exist in the psychiatric patients. They show a nice box and whisker, and spit out the p-values, but they seem to run into the problem again that "not being able to rule out the null" (in this case, the difference between trials one and six for the psychiatric patients was not significant). Remember: just because you can't rule it out doesn't mean the null is true either. It could just as well mean you have a lot of variability and an underpowered study - which, with small ns like this, is particularly problematic.

In any case, interesting from a sleep perspective, and probably just as much so to those who deal in the neural mechanisms that underlie psychiatric disorders.

Big ideas in sleep: Borbély's Two Process Model

I think I'm sticking with sleep for now. I enjoy it, and I'm familiar with the literature a little better than other sub-fields. I may even try to volunteer in a sleep/circ lab the following semesters(!). In any case, I won't pretend to be an expert either... Definitely not, and I really don't want to step on anyone's toes. But sleep is FUN for me, so that's what I'm doing. For now. Unless I find another hobby. Undergraduates are allowed to do that, right?

ON TO THE PAPER!

We've got lined up for you one of the biggest, bestest papers in sleep research ever published - or at least I think so anyway - and it's pretty easy to find a .pdf even without a subscription to a journal service, because tons of courses have used this paper as part of their required readings.


Borbély, A., & Achermann, P. (1999). Sleep Homeostasis and Models of Sleep Regulation Journal of Biological Rhythms, 14 (6), 559-570 DOI: 10.1177/074873099129000894



Now, to make this clear, Borbély wasn't unveiling this model with this paper - he had worked on it long before, and this particular paper is among the long line of papers on the model. This one, though, is a well-consolidated version of the work.

So to make clear definitions: we're saying that sleep regulation is homeostatic in the sense that there is a baseline measure of some sort, and the organism exhibits a "pressure" to return to that baseline. What's being measured in the baseline in the case of sleep will soon be apparent.

This is what sleep looks like:



The top chart shows stages of sleep over time, from wake, to stages 1-4 and REM sleep. Keep in mind here, all this stuff has been common knowledge for a while - early on, sleep goes through the stages, from shallow to deep; most of the deep sleep is in the early part of the bout, whereas REM starts to happen in 90-120 minute epicycles (ultradian cycles) later in the bout.

The bottom chart is where the interesting stuff for Borbély is, mostly - the frequency of slow wave oscillations throughout the night. (If you've ever seen a sleep study, this is what they're looking at with the EEG-cap). Slow wave oscillations are strongest in the deeper stages of sleep (3 & 4), hence their name as "slow wave sleep" - REM lacks slow wave activity altogether.



This is again more evidence showing slow wave density - a spectral power density graph. The baseline (the perfectly straight horizontal line) on the left is the fourth cycle of sleep. Basically, what's going on here is showing that there's more slow wave activity earlier in sleep - inferable from the previous image - and that slow wave activity drops off and is less dense later in the sleep bout.

The right side shows averages across whole nights, with 40 hours of sleep deprivation and the following three bouts of sleep. The baseline is the third night, and the point here is just greater density in the night(s) immediately following the deprivation.

So for the homeostatic model - we see that deprivation drives up slow wave density. And further, we see that slow wave density is highest earlier in the night. So we have the suggestion that we can measure sleep "pressure" by the density of this slow wave activity. A few more figures cover this in detail (and I thoroughly encourage anyone interested to read the full paper), but basically longer sleep debt increases slow wave density - continued sleep drives it down.

Glancing over a lot of interesting research, but to get to the important point of it all, we have the point that sleep is homeostatically regulated. But there's another factor, and this one I'm not going to cover quite as thoroughly, because many before me have done it much better. Circacian processes are the cyclic processes with a period of about 24 hours, give or take a little bit of variation. Circadian processes are also important in sleep/wake, and part of Borbély's insight is working this well into the mix.



This, in essence, is Borbély's two-process model. Process S is the aforementioned sleep process - the tendency of slow wave activity to build up over the night, and drop off. There's a cool bit of math there in the drop-off during sleep (the hashed out area) - it's a logrithmic cliff (if I'm not mistaken), so similar in structure to, say, Newton's Law of Cooling for any physicists or chemists out there - the higher the starting point, the faster it drops. Process C is the circadian process, with the bar under the chart showing time of day in a 24 hour cycle. The distance between the S and C lines is the pressure for the organism to sleep - explaining, in a sort, why you're a little less tired mid-day after a marathon wake session, even going longer without sleep. [I just edited this to fix it - I mistakenly noted that the distance was indicative of slow wave density, which is actually JUST associated with Process S. Forgive my late night typing errors.]

This paper does throw out a couple of nice little springboards, too - Borbély leaves with a consideration of neurochemical factors, as well as a little chart suggesting that the process may be use-dependent rather than simply a factor of time. But I'll probably get to that another day. For now, enjoy Borbély's two stage model!

This is your brain on sleep... fakin' it.

So I've talked a little bit about sleep and memory formation prior, and it's actually a fun topic for me. So I'm running with it.

Now, there's a lot more in the field of normal memory, and I'll get to that eventually, but there's always a fun side-field to memory research - FALSE memories. In other words, you just KNOW it happened... except it didn't. You made it up. Except you didn't really make it up intentionally, but for whatever reason, it didn't happen but you think it did. And then your head hurts.

This is false memory, for the most part. It's a big field, and a lot of theories behind it, like the idea that we tend to remember generalizations more than we care to admit, and a lot of the detail-filling-in is reconstruction. This at least the generally accepted form, in brief, as to what happens (although I can't say I experience this a lot, because I just forget everything anyway).

Anyway, the most common paradigm in false memory research is the Deese-Roediger-McDermott paradigm (DRM) - basically, throw a bunch of words at someone with a 'theme' and people will be SO SO SURE that you said the word that fits the theme. For example, in the paper the authors use the wordlist door, glass, pane, shade, ledge, sill, house, open, curtain and then with that, there is a pretty high chance that the participant will report having heard the word window... even though you said no such thing. (In the DRM, these words are the 'critical words'.) The original research with the list showed that a 2-day delay produced HIGHER levels of false recall than true recall.

Payne, J., Schacter, D., Propper, R., Huang, L., Wamsley, E., Tucker, M., Walker, M., & Stickgold, R. (2009). The role of sleep in false memory formation Neurobiology of Learning and Memory, 92 (3), 327-334 DOI: 10.1016/j.nlm.2009.03.007



So, subjects here: 101 WEIRD Merrimack college sophomores, repeated with 84 WEIRD Harvard college sophomores. (Actually, we don't know that they're sophomores... that's me making up information.) Give them eight DRM wordlists. Two long-term groups - study at 9 AM and repeat at 9 PM, and study at 9 PM and repeat at 9 AM - and two short-term groups - study at either 9 AM or 9 PM and repeat 20 minutes later. The latter was a baseline, mainly to see if there were circadian effects (this is HARD to control for well, though, in sleep/memory research, and I don't think anyone has ever done it very effectively because it's practically confounded by nature).

Anyway, what did they get?

The sleep group had better recall. No big surprise - they remembered about six more words on average (out of the 96 total - 8 groups of 12 words each). Both groups had similar intrusions (non-critical words 'remembered'), but the sleep group showed on average one more critical word recalled. Because of the similarity in intrusions, but difference in critical words, the authors suggest that the false critical words aren't simply a by-product of having more overall recalls.

There's two more parts to the experiment, trying ever so more to zoom in on what's going on. A second experiment found a negative correlation with the amount of slow wave sleep and recall rates, but no significant difference in the number of critical words recalled - this experiment was smaller, and thus greater variance, and there's only eight critical words after all. Part 3 was a nap study, and the authors see (significant) greater critical word recall in the sleep groups compared against the no-sleepers, without a significant effect in the true-recalls or intrusions.

Question on part 3 - The authors conclude that slow wave sleep preferentially favors critical recall over true recall. But on what basis? Well, that critical recall between sleep/no-sleep was above significance threshold, tested against the null, but not for true recall. But wouldn't you want to be comparing the differences against each other, and then look for significance? Granted, looking at the graphs, it should pass that test - the recall measures look almost identical for the sleep/no-sleep peeps, but really... methinks you did the wrong test. I enjoy the enthusiasm in running multiple experiments, and I think their data probably do support their tentative conclusion from 3... but they didn't test it right, unless I happened to misread it.

So the authors suggest that a big part of the DRM's success in getting false critical words is that in the delay, there is sleep. Fair enough. And it's actually a good paper to show that sleep and memory work is hard, and results can be confusing and seem to run counter to each other sometimes (although this is often an effect of the constructions we use to 'divide' types of memory.

Medical students + Sleep deprivation = Plagiarism?

Say it ain't so!

Dr. Free-Ride notes the diminished moral capacity of students applying for medical residencies.

Days later, Allison pulls out a study showing worsened moral reasoning of sleep deprived military officers.

Coincidence? I think not!

vos Savant revisited

In PLoS Biology, Cirelli and Tononi visit the same argument in an essay that's worded much better than my own. Read it here.

Hippocampal ripples and memory consolidation

So the vos Savant post got me thinking... I'm kind of comfortable talking about sleep (or at least, comfortable enough to get in trouble, I'm sure), and would love to make a few more posts on it. And, hey, why the hell not? I'm sure some of my friends would like to see what I read, and why not start making occasional research posts out of it? Who knows; if even one or two readers get something out of it, this whole thing is definitely worthwhile. If not, at least I get to work things out myself.

So, I present one of my favorite papers in recent history:

Girardeau, G., Benchenane, K., Wiener, S., Buzsáki, G., & Zugaro, M. (2009). Selective suppression of hippocampal ripples impairs spatial memory Nature Neuroscience, 12 (10), 1222-1223 DOI: 10.1038/nn.2384

It's a short, short paper, with an online supplement; a lot of publications in the glamour journals are shorter than I feel they should be, because there's a lot of backstory that this article could go into. However, all the relevant citations are there, and I can at least do a quick zip through those. There's a really nice narrative to all this, I promise.

So let's start WAAAAY back in the 1980s. Gregory Buszaki was working away in his lab on memory consolidation and saw these little ripple events from electrode recordings in mice during sleep. In a 1989 commentary piece, he laid out his theory in full. The short version: exploratory (mostly waking) behavior saw certain activation patterns in pyramidal cells in the CA3 region. During quiescence and slow wave sleep, sharp-wave ripples, or population bursts, in the pyramidal cells of the CA3 region of the hippocampus were potentiating post-synaptic regions in the CA1 region; in more plain-speak, the CA1 neurons, which were active in exploration, were now "priming" the CA3 neurons.



(See the mousey hippocampus. See it SPIKE! Original image from the Buszaki 1988 paper.)

I'm probably doing a minor disservice to summarize Buszaki's model that shortly (it's a great big 20 page paper, after all, and a wonderful one at that; if you're big into the neuroscience of memory, it's a must-read), but the narrative must continue! We've still got a few stops in history to make.

So, moving right along, we go to William Skaggs in 2007. He was looking for the same thing in macaques. The catch? Well... their brains are a little bit bigger than mouse brains, so getting deep brain recordings is usually a challenge. Having not worked with primates before, I can only sympathize with the sort of difficulties they pose. Noisy data, few subjects, and generally undisciplined behavior... all seen in this paper. But he got the same spikes in the same region, spiking on rest behavior after a memory intensive task. The article doesn't show much except "Oh, we see the same in primates! Awesome!"

And step up another year to 2008, a paper by Nikolai Axmacher. We have humans this time!

Now, we can't exactly throw electrodes into deep-brain areas of humans for purely experimental reasons - his participants were epileptic patients, and his recordings were from electrodes implanted for therapeutic purposes. Further, the fact that we saw them in humans had been established, but he took it a step further. He had participants doing a visual memory task - Show participants a series of pictures, let them rest for an hour (preferably napping) while recording, then show them old pictures mixed with new. "Is this new or old?" Record correct answers.

So what did he find? The more sharp-wave ripples he saw, the better that person performed on the new/old task. This sort of thing had been measured in rats back in Buszaki's lab, but to find that the same observation held for humans? Woohoo!

And now back to mice. See, all the prior studies have a minor flaw from a strictly empiricist standpoint - they were all purely correlative. Sure, we can match how many of these show to an increase in performance... but there's nothing selective about that. It could be a side-effect of something upstream, perhaps.

So NOW we're to the Girardeau paper. Girardeau's team used a radial arm maze, three times a day with three baited arms. Rats were given either until they got all three correct arms or time was up, then after the training period were put in a flowerpot in the middle of the maze to rest for an hour.

(See, I wasn't kidding about the flowerpot.)

Now, for the really cool part: Girardeau's team had a method of suppressing the synchronous neuronal firing of the sharp wave ripples. Delivering a small shock to the relevant area disrupted the ripple-events, and didn't otherwise disturb the little whiskered ones! So there were three groups - one didn't even have have any shocks delivered, one group delivered shocks when ripples were observed (suppressing ripples), and one group had a delayed shock (giving shocks, but conserving ripple events). The latter two are shown in the above figure. This was during that one hour period following training.



And what did Girardeau's team find? EXACTLY what Buszaki's model twenty years ago would have predicted. The no-shock and delay-shock little ones performed exactly the same being re-tested in the maze; the disrupting-shock/ripple-suppressed group performed worse, with more errors. And keep in mind, these ripple events weren't disrupted for all sleep, just one hour following training. And sleep architecture (the large-scale electrical patterns associated with sleep and sleep stages) was conserved even in the ripple-suppressed group, so it wasn't any change in the sleep architecture, either! Girardeau's team is pretty thorough on covering bases, with the checks on sleep architecture, checking that motion wasn't stereotyped (in other words, establishing spatial rather than motor memory as the "strategy" used by the rats).

I can't even imagine how that must have been for Buszaki, to see his model play out so beautifully. The whole narrative picture here I've actually doubted at times, because it plays out too well. Getting a picture that pretty is usually a Bad Thing - someone's fudging something somewhere. Sometimes, though, it does happen, as it seems to have done so here.



Sources:
Axmacher, N., Elger, C., & Fell, J. (2008). Ripples in the medial temporal lobe are relevant for human memory consolidation Brain, 131 (7), 1806-1817 DOI: 10.1093/brain/awn103

BUZSAKI, G. (1989). Two-stage model of memory trace formation: A role for “noisy” brain states Neuroscience, 31 (3), 551-570 DOI: 10.1016/0306-4522(89)90423-5

Girardeau, G., Benchenane, K., Wiener, S., Buzsáki, G., & Zugaro, M. (2009). Selective suppression of hippocampal ripples impairs spatial memory Nature Neuroscience, 12 (10), 1222-1223 DOI: 10.1038/nn.2384

Skaggs, W., McNaughton, B., Permenter, M., Archibeque, M., Vogt, J., Amaral, D., & Barnes, C. (2007). EEG Sharp Waves and Sparse Ensemble Unit Activity in the Macaque Hippocampus Journal of Neurophysiology, 98 (2), 898-910 DOI: 10.1152/jn.00401.2007

In which Marilyn vos Savant misrepresents sleep

As I lazily looked through my Sunday newspaper (complete with Parade insert), I took the liberty of completing the Numbrix puzzle. In the less than five minutes it took to finish the puzzle, I look just above it to read the Ask Marilyn column. I generally disregard advice and question columns, but I'm aware of Marilyn vos Savant's reputation as a "smart person"(tm) and see the question "Do all animals sleep?".

The reply? "No..."

"Okay," I think, "perhaps she's going to qualify this statement with a rather detailed behavioral definition." (Siegel published a review in Trends in Neuroscience that would agree with the general view, although he's much more careful than vos Savant.)

Well, not exactly. She admits to a behavioral definition, but not a detailed one. And her reply irks me ever so slightly. I'll admit, I've had little respect for her since she decried Andrew Wiles' proof of Fermat's Last Theorem invalid on the basis that it was non-Euclidean. So I suspect my irritation is partly a result of bias, but that doesn't make her reply any more true or correct.

Let's break down her reply:

She begins by noting that she's not including rest or reduced activity - a fair caveat, and a better statement than what follows, although a bit off. I'll let that much slide. But by most accounts, normal rest still is marked by a rather low arousal threshold (similar to the arousal threshold for an obviously vigilant animal). Sleep, not so much. One of the more common operational definitions of sleep in non-mammals is this reduced arousal threshold. This was the point of a recent study in Nature (2008) by Raizen et al., determining that lethargus in C. elegans (the flatworm) was a sleep-like state. For those familiar with the nervous structural changes associated with sleep in animals, it's worth noting that this sleep-like state preceded each new stage of development.

She then cites tuna, and seems to be correct in oxygen demands and water movement over gills (as far as I can tell, since it's not the point of calling her out on this), using the fact of required motion to refute that tuna enter a sleep-like state. The first problem to note here is that sleep is generally not defined by motion or lack thereof in all but the most loose definitions involving mammals. Evidence continues to suggest that sleep is primarily a nervous phenomenon, and the prior mentioned arousal thresholds are sometimes more promising measures. This has been observed in zebrafish (Yokogawa et al., 2007) as well as a rebound of this increased arousal threshold period when deprived it by electrical stimulation.

This same pattern (increased arousal threshold with rebound) is even seen in insects, with the best studied example being Drosophila melanogaster (the fruit fly, a favorite of geneticists since Thomas Hunt Morgan).

Lastly, vos Savant cites what is one of the most unusual mammals in terms of sleep patterns - dolphins. The claim is that dolphins rest half their brain at a time, and are otherwise vigilant. The claim is, at its base, true: dolphin sleep is often unihemispheric. However, I don't think vos Savant can use a mammal, with robust EEG characteristics of sleep, as an example of not-sleep at all. Dolphins are a favorite of sleep researchers actually because of their unihemispheric deprivation potential. I don't think I've ever seen a researcher ever call what dolphins do "not-sleep". As noted earlier, total immobility is not the case for cetaceans... but it's not the case for almost anything aquatic. However, even in cetaceans, reduced activity is associated with sleep, and the extent of activity in captivity is circling the perimeter of the enclosure with minimal echolocation activity (Lyamin et al., 2001). (Note on the paper: the novel research is concerned mostly with gray whales, but the paper is openly accessible and covers dolphins in the introduction.)

So Marilyn is right in a narrow sense - animal sleep is not totally equivalent to human sleep. But of course not! And yet, there is still enough uniformity for researchers to at least call states in animals from dolphins to flies to the simple flatworm as at least "sleep-like". Considering sleep as a nervous phenomenon is likely the most useful characterization of sleep, and considering it as such sweeps away Marilyn's critiques. So it's strictly, yet vacuously true that animals don't undergo human-like sleep. At the same time, it's missing a lot of truth. She constrains herself by her definition from the beginning (not a very good definition, either), and in doing so does a disservice to the concept of sleep in general.

Sources:

Hendricks JC, Finn SM, Panckeri KA, Chavkin J, Williams JA, Sehgal A, & Pack AI. (2000) Rest in Drosophila Is a Sleep-like State. Neuron 25(1):129-138 doi:10.1016/S0896-6273(00)80877-6

Lyamin, Manger, Mukhametov, Siegel & Shpak. (2001) Rest and activity states in a gray whale. Journal of Sleep Research 9(3):261-267. doi:10.1046/j.1365-2869.2000.00212.x

Raizen DM, Zimmerman JE, Maycock MH, Ta UD, You Y-j, Sundaram MV & Pack AI. (2008) Lethargus is a Caenorhabditis elegans sleep-like state. Nature 451:569-572 doi:10.1038/nature06535

Yokogawa T, Marin W, Faraco J, Pézeron G, Appelbaum L, et al. (2007) Characterization of Sleep in Zebrafish and Insomnia in Hypocretin Receptor Mutants. PLoS Biol 5(10): e277. doi:10.1371/journal.pbio.0050277