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.

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.

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