Drunk Rats Could Overturn Neurological Orthodoxy

A form of brain abnormality long regarded as permanent is, in fact, sometimes reversible, according to an unassuming little paper with big implications.

Here's the key data: some rats were given a lot of alcohol for four days (the "binge"), and then allowed to sober up for a week. Before, during and after their rodent Spring Break, they had brain scans. And these revealed something remarkable - the size of the rats' lateral ventricles increased during the binge, but later returned to normal.

Control rats, given lots of sugar instead of alcohol, did not show these changes.

This is really pretty surprising. The ventricles are simply fluid-filled holes in the brain. Increased ventricular size is generally regarded as a sign that the brain is shrinking - less brain, bigger holes - and if the brain is shrinking that must be because cells are dying or at least getting smaller. So bigger ventricles is bad.

Or so we thought... but this study shows that it might not always be true: alcohol reversibly increases ventricular volume over a timescale of days. It does so, the authors say, essentially by drying brain tissue out; like most things, if you dry the brain out, it gets smaller (and the ventricles get bigger) but when the water comes back to the tissues, it expands again.

As you can see here in Figure 2...

Maybe. I admit that just eyeballing this, it looks more like the ventricles are getting brighter, rather than bigger, but I'm not familiar with the details of water scanning. Maybe some readers will know more about it.

If it's true, this is big - maybe it's not just high doses of alcohol that does this. Maybe other drugs or factors can shrink or expand, the ventricles, or even other areas, purely by acting on tissue water regulation, rather than by anything more 'interesting'.

Take the various claims that some psychiatric drugs boost brain volume while others decrease it, just for starters...could they be headed for a watery grave?

Of course, this is in mice - and it might not translate to humans... we need to find out, and I for one am keen to apply for a grant. Here's my draft:

Participants: 8 healthy-livered neuroscientists.
Materials: 1 MRI scanner, 1 crate Jack Daniels.
Methods: Subjects will confer to pick a Designated Operator, who will remain sober. If no volunteers for this role are forthcoming, selection will be randomized by Bottle Spinning. All other participants will consume Jack Daniels ad libitum, and take turns being scanned. Once all Jack Daniels is depleted, participants will continue to be scanned until fully sobered up (defined as when they can successfully spell "amygdalohippocampal").
Instructions to Participants: i) what happens in the magnet, stays in the magnet. ii) If you 'dirty' the scanner, you clean it up. iii) Bottle caps are not MRI safe!

Er... seriously though, someone should check.

Zahr NM, Mayer D, Rohlfing T, Orduna J, Luong R, Sullivan EV, and Pfefferbaum A (2013). A mechanism of rapidly reversible cerebral ventricular enlargement independent of tissue atrophy. Neuropsychopharmacology  PMID: 23306181

The Case Of The Missing Parasites

Collembola or "Springtails" are a common group of bugs - they're technically not insects although much like them - found all over the world.

There's no evidence that these critters are parasites for humans - except for one strange scientific report claiming to have found Collembola body parts in skin scrapings from people diagnosed with delusional parasitosis - a psychiatric disorder characterised by the belief that one is infested with parasites.

According to said 2004 paper by Altschuler et al, these patients are not delusional after all. This paper has been popular in the delusional parasitosis community.

However, insect expert Matan Shelomi says that Altschuler et al's best photo of the so-called Springtails was probably Photoshopped. He explains that in the only pic to clearly show anything resembling a 'bug' (there were many others, but none look convincing), the raw microscope image shows nothing but a blurry blob.

Altschuler et al claimed to have enhanced the contrast, but when Matan did that, there was still no visible critter. However, in the published image, a rather sinister bug is clearly seen. How did it get there?

Either the image contrast was somehow selectively enhanced just for the 'bug' part - which, of course, presumes that the bug was there, and is quite invalid - or more likely,

The level of detail present in Altschuler et al.’s enhanced image, particularly in the areas of the legs and a very odd pair of stripes along the abdomen, does not appear when contrast is applied equally. Such detail, however, can easily be created using functions such as Burn, Dodge, and Colorize on Photoshop®,when applied to select portions of the image manually as if via paintbrush.

However, Shelomi says, even if such fraud is proven, there may be nothing anyone can do: the journal the original paper was published in has since folded, so it would be impossible to retract it, and the author runs an independent non-profit and is hence not subject to scientific misconduct regulations.

Thanks very much to @benmeg for sending me a copy of this paper.

Shelomi M (2012). Evidence of Photo Manipulation in a Delusional Parasitosis Paper. The Journal of parasitology PMID: 23198757

Publication Bias in Animal Research

Publication bias has historically been thought of mostly in the context of clinical trials. But I have been banging on for the past 4 years about how it's a problem for more 'basic' science as well.

I'm not alone in my concerns as an interesting new paper reveals: Publication Bias in Laboratory Animal Research. The authors surveyed the approximately 3,000 Dutch scientists involved in research on laboratory animals. The response rate was about 20%.

When asked how much animal research ends up being published, university researchers estimated about half, but industrial scientists put it at only about 10% - which, if true, suggests that publication bias in Pharma animal work is extremely serious.

In terms of solutions, the survey considered two ideas which Neuroskeptic readers will be familiar with - public pre-registration of studies:

Mandatory anonymous publication of research protocols of all ethics-approved animal research experiments in a publicly available database

and also open access to all data:

Mandatory anonymous publication of a brief structured form in a publicly available database, that gave main results or explained why an experiment could not be completed

On average the surveyed researchers felt that these measures would aid scientific progress; improve the validity of the literature; and prevent wasteful duplication of effort - but they also worried that it would increase bureaucracy.

Now, bureaucracy is second only to bias on my list of Things I Hate About Science, so I share their concern - but I really think registration wouldn't have to involve any extra paperwork. In many cases, it could be implemented simply by making existing data public.

For instance, grant applications, and requests for ethical approval, already contain detailed a priori protocols in most cases. They could so easily be published (perhaps with certain details removed for confidentiality reasons) and turned into a powerful weapon against publication bias.

Having said that though - it easily could end up being needlessly complicated and obstructive, as so much of the scientific process unfortunately is today. It will all depend on how it's implemented.

This is why I think it's so important that, as scientists, we reform science ourselves, and get it right, rather than leaving it to the bureaucrats, who won't.

Ter Riet G, Korevaar DA, Leenaars M, Sterk PJ, Van Noorden CJ, Bouter LM, Lutter R, Elferink RP, and Hooft L (2012). Publication bias in laboratory animal research: a survey on magnitude, drivers, consequences and potential solutions. PloS one, 7 (9) PMID: 22957028

Brains In A Dish Need Sleep Too?

All animals sleep, but despite decades of research, neuroscientists still have no clear answer as to why. Now a dramatic new study reveals that sleep may be a fundamental state that even brain cells growing in a dish need.

Swiss neuroscientists Valerie Hinard and colleagues cultured mouse cortical neurons in dishes equipped with arrays of electrodes. This allowed them to record the electrical activity produced by the growing 'brain'. They also measured the expression of different genes in the neurons, and compared these to gene expression in real mouse brains.

They found that while cultures of neurons started out fired randomly, after about 10 days, the cultures entered a state of synchronized periodic firing, with the whole population of cells firing together in slow cycles of activity - with a frequency of 1 cycle every 5 to 15 seconds. This is extremely slow - by contrast the "slow waves" characteristic of animal sleep cycle about 30 times faster - but the authors say that such ultra-slow waves have been seen in sleeping animals too.

But the dishes could be 'woken up' by adding a mixture of neurotransmitters, which abolished the burst cycles. They reappeared about 24 hours later. Gene expression changes in the cells in the 'sleep' and 'wake' state were significantly correlated with changes seen in real mice deprived of sleep.

Finally - and this might end up being the most important bit - the authors compared the biochemistry of the 'sleep deprived' dishes to the 'well rested' ones. They found remarkably few major changes, but they did observe a significant increase in the levels of lysolipids.

Lysolipids are breakdown products of phospholipids, which make up the membranes of all living cells. When present in membranes, lysolipids can act as 'detergents', distorting their structure. That's bad. These results suggest that sleep might serve to prevent the build up of lysolipids. If that pans out, it would mean that the function of sleep is very primitive, a fundamental biological necessity for any connected network of neurons, even what amounts to a random medley thrown together on a plate.

This study used cultured mouse neurons, but it's possible to grow human brain cells in a dish too. The obvious next step will be to check if human neurons exhibit the same sleep/wake-like states - and whether the very slow synchronized firing is really like human sleep. If so, could this help understand insomnia? Narcolepsy? Maybe even jetlag?

It's also got implications for all other brain-in-a-dish research. Scientists may literally need to ensure that their dishes get enough sleep in future studies.

It's all very exciting. I don't study sleep in my own research, but I try to keep up with the literature as I find it very interesting. I've covered various aspects of sleep neuroscience previously. So while I'm no expert, this seems to me like truly groundbreaking stuff, and potentially a "game changer" for the whole of neuroscience.

Hinard V, Mikhail C, Pradervand S, Curie T, Houtkooper RH, Auwerx J, Franken P, and Tafti M (2012). Key electrophysiological, molecular, and metabolic signatures of sleep and wakefulness revealed in primary cortical cultures. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (36), 12506-17 PMID: 22956841

That Antidepressants In Water Cause Autism Study

Oh dear. The newspapers this morning are reporting that

Autism 'could be triggered by very low doses of anti-depressants or other chemicals found in water supply'

Here's the study. Young fish were exposed to a combination of three drugs, two antidepressants and an epilepsy med, for 18 days.

First off, this study was tiny with an effective sample size of just 6. Three tanks of fish got exposed to the drugs, and three control tanks didn't. There were multiple fish per tank, five in fact, but those are not five independent observations, because they shared a tank. That's just tiny for a drug trial, or any scientific study really.

Next, the drug doses were much higher than in the water supply. Levels of fluoxetine (Prozac) were 700 times higher than observed in drinking water, for carbamazapine it was 400 times higher. And that's based on the authors' figures for drinking water which they admit are "the highest observed concentrations from various systems". The authors defend this by saying that in drinking water there will be other related compounds, on top of the drugs themselves, adding up to a higher dose. OK - but 400, 700 times higher? We've no idea if that's realistic. They don't justify this number.

What did the drugs actually do to the fish? After 18 days of exposure to the drugs, the fish - juvenile fathead minnows - had their brains removed and the expression levels of various genes measured using a genetic microarray.

The drugged minnows had significantly increased expression of a set of 324 genes dubbed "autism genes" ("autism_ideopathic" in the paper.) I'm not going to get into the question of whether these really are autism genes in humans, or whether fish brains are a good of model of humans. Those are hard issues. But what's easy to see is that while this set of genes were apparantly increased, so were many others. It was not specific to 'autism genes'.

The autism genes were upregulated by an average factor of +1.621... but this was only slightly more than the "Parkinson's Disease genes" at +1.56 and the "Multiple Sclerosis" ones at +1.375. Meanwhile, "Bipolar Disorder" genes were down by -1.172. So if antidepressants in the water are causing autism, they're probably also causing (or preventing!) a lot of other problems too.

The authors note that only three of the gene sets were statistically significantly altered, but that doesn't mean those sets were special, this is the fallacy of treating differences in significance levels as evidence of significant differences.

Of 10 more specific "autism gene" sets that they also examined (in the same fish), all were increased by various amounts (+1.050 to +1.537), some of which were significant - but one of those was a set of genes previously reported decreased in autistics, not increased (it was the "synapse" genes from this study).

What these changes in gene expression mean is anyone's guess. Given the small sample size they could be just noise. If not, all they really show is that levels of psychoactive medications that are quite low, but much higher than in drinking water, have affect the brains of fish. We don't know what that effect means, for the fish, let alone humans.

Early life antidepressant exposure might cause autism. I don't know. Stranger things have happened. We know that fetal anticonvulsant exposure can do it but that's when mothers are actually taking the pills. It's one giant leap from that to traces in drinking water. It's the difference between falling off your chair and falling off the Empire State Building.

Michael A. Thomas, and Rebecca D. Klaper (2012). Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic Autism PLoS ONE

The Wriggling Brain

What do we mean when we talk about "the brain"?

Easy, right? It's this:

Certainly, this is the image that comes to my mind.

But this is not an image of a brain. It's an image of a dead brain.

In a living brain, all kinds of interesting things are happening. Things we literally can't begin to imagine. Because these are hard to visualize, they can't enter the mental picture.

To picture the living brain as just a yellowy lump is like picturing Wikipedia as a disc. It's accurate as far as it goes, but it misses the whole point. You could download Wikipedia onto a BluRay disc, and then you could describe that disc as "Wikipedia" and you wouldn't be wrong, but Wikipedia is much more than a silver circle.

It doesn't help much that we know that there's more to the living brain than a yellowy lump. Yes, most of us know that the living brain is somehow responsible for thought, feeling, perception, and consciousness.

But we have no idea of how it does so, we don't have any feel for this relationship. We agree with the idea that brain = mind, but that's just an abstract equation. Just as most of us know that e=mc2, but only physicists understand it.

All this leads to philosophical problems. Wittgenstein wrote:

Look at a stone and imagine it having sensations. - One says to oneself: How could one so much as get the idea of ascribing a sensation to a thing? One might as well ascribe it to a number! - And now look at a wriggling fly and at once these difficulties vanish and pain seems able to get a foothold here.

What he meant is that we only feel that we can ascribe pain (or any "internal" mental state or event) to something which is behaving "externally".

Now in most cases, that's fine. Most inanimate objects really don't have mental states. But brains do. The brain, we feel, is inanimate; it's just a yellowy lump. By itself the brain is like Wittgenstein's stone - it seems.

So, we feel, the brain itself can't really have mental states, only walking, talking, behaving people can, like wriggling flies. Except we know on an abstract level that brains do have mental states; so we tie ourselves into philosophical knots about "brains" and "persons", asking whether a person is more or less or the same as a brain, and so on.

The whole problem could be removed, I think, if instead of a yellowy lump, we could picture the living brain in all its active complexity; if we could talk about "the brain", not as an inanimate object, but as the most animate thing in the world.

In the brain there are hundreds of billions of cells, and each one is a hive of movement - not visible to the naked eye or even to a microscope, but the movement of ions and neurotransmitters and ultimately information.

I think many philosophical puzzles would lose their edge if we could somehow get a feel for all that; if we could replace the accurate, but misleading, yellowy lump picture of "the brain" with one that captures the complexity and dynamism of the thing: a city, a hive of insects, a vast machine.

Dolphins who Dream of Whales

Once in a while you come across a paper that can only be described as lovely. This is one: Do dolphins rehearse show-stimuli when at rest?

Five dolphins lived in a certain aquarium in France. Every day, they put on shows for people - jumping around, that kind of thing. One day the aquarium started playing a 20-minute clip of "intro music" for the show. This consisted of various oceanic sounds including sea birds, dolphin noises and some whale-song.

What happened next was amazing. About a month about they brought in the intro sounds, the researchers noticed some odd sounds coming from the dolphins, late at night. It turned out that the dolphins had started making whale noises.

They only did this at night, mostly between 1 am and 3 am, when they were resting, possibly even sleeping. No-one trained them to do this. The "atypical vocalizations" were much lower than the dolphin's normal whistles, and also lasted longer.

Unfortunately, it wasn't possible to tell how many of the dolphins did this.

The authors recorded the dolphin's whale impressions with an underwater microphone, and played them back to a sample of 20 biologists, who weren't told the hypothesis of the study. Many of them thought they were whale-song, especially when the clips were slowed down to half-speed, dolphin's voices being "higher" than whales'.

Why the dolphins did this is a mystery. All of them had been born in captivity, so they'd never encountered a real whale. One theory is that they were mentally rehearsing the events of the day to come. Maybe they were even dreaming about them and "talking in their sleep" - although this is unclear, because it's not known whether dolphins dream; don't exactly sleep in the same way we do.

The paper's open access and it even comes with some audio clips of the dolphins, although unless you're familiar with what they sound like normally these aren't very meaningful.

Kremers D, Jaramillo MB, Böye M, Lemasson A, & Hausberger M (2011). Do dolphins rehearse show-stimuli when at rest? Delayed matching of auditory memory. Frontiers in Psychology, 2 PMID: 22232611

What're You Lookin' At (When You Dream)?

Why do our eyes move during sleep?

Here at Neuroskeptic we've already asked why do we sleep? and why do we dream? There are plenty of theories, but no clear answers to either of those questions.

We don't even know the function of one of the most famous sleep phenomena, rapid eye movements (REMs). It's been known for decades that during certain phases of sleep, the eyes show a pattern of rapid flickering movements, and that this REM sleep is when most (but not all) dreams occur.

But what are the eye movements?

In a new paper, French sleep researcher Isabelle Arnulf sets out the case for the "scanning hypothesis". The idea is that REMs represent the dreamer "looking at" things in the dream, just like waking eye movements - at least much of the time.

Some say that REMs are nothing to do with dreams, and it's just a coincidence that they tend to occur together. They may just be random, perhaps with the function of preventing the eyes from drying out during sleep, or maybe just a side-effect of sleeping brain activity with no function at all. A possible analogy: males usually get erections during REM sleep, even though most dreams have no sexual content.

There's lots of evidence that seems to support a deflationist view of dreams. In humans and other mammals, foetuses have lots of REMs, even though they've never seen anything. Lab animals with the visual areas of the brain removed also continue to display REMs, albeit not as many of them, and people who've been blind since birth have REMs.

Anaulf disagrees however, and discusses her work with the fascinating REM sleep behaviour disorder (RBD). RBD sufferers seemingly act out their dreams. Normally, we're paralyzed during REM by an inhibitory system which causes muscle relaxation during REM. The eyes are the exception, because they have a separate nerve pathway (which is also why some otherwise paralysed people can still communicate with their eyes). RBD can be a symptom of underlying neurological disease, such as Parkinson's, but it can also occur on its own.

Anaulf's team studied 56 patients with RBD over 1 or 2 nights (Leclair-Visonneau 2010). They found that the behaviours were correlated with the onset of rapid eye movements, although 80% of the eye movements were not accompanied by any actions. What's more, out of 19 distinct behaviours (ranging from running away from lions, to strangling someone), 60% were associated with REMs, and of these 90% were in the same direction as the actions.

This directional coherence between limb, head and eye movements during RBD suggests that, when present, REMs imitate the scanning of the dream scene. Because the REMs are similar in subjects with and without RBD, we suggest the extension of this concordance to normal REM sleep.

They suggest, however, that it may not be that the eye movements are the result of the dream content, but just correlated with it. It's not that something happens on the left in the dream, and then in response, the eyes move to the left; rather it's that whatever pattern of neuronal activity causes the dream, also causes the corresponding eye movements.

Either way it's an interesting idea, although it does rely on the assumption that RBD is a good model of normal sleep in this regard.

Arnulf I (2011). The 'scanning hypothesis' of rapid eye movements during REM sleep: a review of the evidence. Archives italiennes de biologie, 149 (4) PMID: 22205589

An Objective Measure of Consciousness...?

Could a puff of air in the eye offer a way to evaluate whether someone is conscious or not?

Yes it could, say Cambridge's Tristan Bekinschtein and colleagues in a new paper about Sea slugs, subliminal pictures, and vegetative state patients.

It's all about classical conditioning of the kind made famous by Pavlov. This is learning caused by the pairing of two stimuli, one of them somehow meaningful (usually unpleasant). So if I were to ring a little bell before, say, pepper spraying you, and I did that repeatedly, you would probably close your eyes whenever I rang that bell. Or just punch me, but you see the point.

Anyway, the key is that there are two kinds of classical conditioning. In the unhelpfully named "delay" conditioning, the warning stimulus overlaps with the painful one. Like if I started ringing my bell, then kept ringing it while I sprayed you with my other hand. In other words, there is no delay between the two stimuli... I said it was badly named.

By contrast in "trace", conditioning there is a delay - the warning stops shortly before the second stimulus. Bekinschtein et al argue that trace conditioning requires conciousness. While delay conditioning can occur without awareness of the link between the two stimuli, only conscious awareness can bridge the time gap in trace conditioning.

In trace experiments (in which rather than pepper spray, the unpleasant stimulus is just a puff of air in the eye), people who, when asked, can't explain the relationship ("sound means puff") don't learn to blink when they hear the sound. But with delay conditioning, this "unconscious" conditioning can occur. Likewise, under anaesthesia, trace conditioning is lost.

At first glance this looks like a piece of psychological trivia, but it could have literally life-or-death consequences. If trace conditioning is a measure of concious awareness then it could be used as a way of working out whether brain-injured people in a "coma" or "vegetative state" are aware or not.

This paper is in fact a follow-up to the author's own 2009 study showing that some people in a vegetative state do show trace conditioning - and the ones who did were more likely to subsequently wake up.

One snag is that the humble sea slug, Aplysia, can undergo trace conditioning, yet it is presumably not conscious, at least not in any recognizable sense.

But Bekinschtein et al say that trace conditioning is a product of convergent evolution. Alplysia can do it and we can do it, but we use different means to the same end. Their argument is that while in Alpysia trace conditioning is known to be dependent on just a handful of individual neurons in the creature's tiny "brain", in humans it requires an intact hippocampus (containing millions of cells). People with hippocampal damage, who suffer amnesia, also can't do trace conditioning.

That's a good point but does that mean such hippocampal patients aren't conscious? That would be weird because, apart from the amnesia, they seem perfectly normal. Presumably they're just not conscious of the relationship between things separated in time...

Also, primitive pathways for conditioning might still exist in humans, able to reactivate under special conditions. They do acknowledge this with a discussion of experiments showing that trace conditioning in the absence of conscious awareness of the relationship can occur but only when the warning stimuli are "scary", like pictures of snakes. They say that with generic, neutral stimuli there is no good evidence of unconscious trace conditioning, but this seems like a fairly fine distinction.


Ultimately, it's a very nice idea but only more studies on "unconscious" patients will tell us whether it's really able to measure consciousness in a useful way.

Bekinschtein TA, Peeters M, Shalom D, and Sigman M (2011). Sea slugs, subliminal pictures, and vegetative state patients: boundaries of consciousness in classical conditioning. Frontiers in psychology, 2 PMID: 22164148

The Real "Contagion" Virus

Seen Contagion yet?

It's pretty scary. A new epidemic disease comes out of nowhere and starts killing everyone. It infects the brain - victims suffer seizures, or fall into a coma, and die. It spreads like wildfire. Humanity's only hope lies in Lawrence Fishburne and Kate Winslet.

Luckily, that's fiction. But only just.

In the movie, the killer bug is called "MEV-1", but it might as well have been called the Nipah virus, because it was closely based on a real disease of the same name. So much so that this post about Nipah contains movie spoilers.

The Nipah Virus came to the world's attention in late 1998. There was an outbreak of a severe fever accompanied in many cases by encephalitis (viral infection of the brain) in Malaysia and Singapore. 276 patients were recorded. 40% of them died.

In the initial outbreak, there was probably no person-to-person transmission of the virus. Rather, only people who came into contact with Malaysian pigs - mainly farmers and butchers - caught the disease. Over a million pigs were culled in 1999 to try and contain the outbreak, and this seemed to be effective.

But since then, there have been several other smaller Nipah outbreaks in Asia, one almost every year in fact. In some of these, person to person transmission has been detected, notably in Bangladesh and India. The fatality rate in these more recent outbreaks has also been higher (70-90%). Luckily, unlike in the movie, it doesn't seem to be very contagious - so far. Most years have seen only 10 or 12 cases. But who knows what the future holds?

The virus is distantly related to measles, but is much more severe. Symptoms can begin anywhere from 4 days to 2 months after infection, but generally within 1 to 2 weeks. More recent outbreaks seem to have a shorter incubation period. The symptoms include fever, headache, vomiting, seizures, muscular jerks, and altered consciousness (confusion, coma).

Even after the initial infection is over, a minority of patients (4-8%) later suffer a relapse encephalitis. The virus seems able to remain dormant in the body before re-emerging to infect the brain again. Survivors may suffer neurological problems such as epilepsy, movement disorders, fatigue, and others. This is especially common following relapse encephalitis.

Where did it come from? It turns out that various strains of Nipah-like viruses are common in certain bats that inhabit various Asian countries, specifically fruit bats of the Pteropus genus, aka "flying foxes". The bats don't get sick, but infected bats are highly contagious, excreting the virus in their urine.

The virus seems to have made the leap into humans not once but several times, from different kinds of bats. Each outbreak could represent a new crossover event. Often there was an intermediate animal host, such as the domestic pigs in Malaysia .

Nipah is a classic zoonotic disease - it jumps from animals to humans. Zoonoses are scary for two reasons. They're new to humans, so humans haven't had a chance to develop immunity. And they may be especially deadly, because they haven't evolved not to be deadly to us.

Viruses and bacteria don't actually want to kill you. They want you alive, so that you can keeping breathing, walking, having sex, and otherwise spreading them. So pathogens tend to evolve to be less lethal to their primary hosts. Unfortunately, that's only good news if you are the primary host, and in the case of zoonoses, we're not. Bats don't get sick, but we do.

Lo, M., & Rota, P. (2008). The emergence of Nipah virus, a highly pathogenic paramyxovirus Journal of Clinical Virology, 43 (4), 396-400 DOI: 10.1016/j.jcv.2008.08.007

Is Sleep Brain Defragmentation?

After a period of heavy use, hard disks tend to get 'fragmented'. Data gets written all over random parts of the disk, and it gets inefficient to keep track of it all.


That's why you need to run a defragmentation program occasionally. Ideally, you do this overnight, while you're asleep, so it doesn't stop you from using the computer.

A new paper from some Stanford neuroscientists argues that the function of sleep is to reorganize neural connections - a bit like a disk defrag for the brain - although it's also a bit like compressing files to make more room, and a bit like a system reset: Synaptic plasticity in sleep: learning, homeostasis and disease

The basic idea is simple. While you're awake, you're having experiences, and your brain is forming memories. Memory formation involves a process called long-term potentiation (LTP) which is essentially the strengthening of synaptic connections between nerve cells.

Yet if LTP is strengthening synapses, and we're learning all our lives, wouldn't the synapses eventually hit a limit? Couldn't they max out, so that they could never get any stronger?

Worse, the synapses that strengthen during memory are primarily glutamate synapses - and these are dangerous. Glutamate is a common neurotransmitter, and it's even a flavouring, but it's also a toxin.

Too much glutamate damages the very cells that receive the messages. Rather like how sound is useful for communication, but stand next to a pneumatic drill for an hour, and you'll go deaf.

So, if our brains were constantly forming stronger glutamate synapses, we might eventually run into serious problems. This is why we sleep, according to the new paper. Indeed, sleep deprivation is harmful to health, and this theory would explain why.


The authors argue that during deep, dreamless slow-wave sleep (SWS), the brain is essentially removing the "extra" synaptic strength formed during the previous day. But it does so in a way that preserves the memories. A bit like how defragmentation reorganizes the hard disk to increase efficiency, without losing data.

One possible mechanism is 'synaptic scaling'. When some of the inputs onto a given cell become stronger, all of the synapses on that cell could weaken. This would preserve the relative strength of the different inputs while keeping the total inputs constant. It's known that synaptic scaling happens in the brain, although it's not clear whether it has anything to do with sleep.

There are other theories of the restorative function of sleep, but this one seems pretty plausible. It stands in contrast to the idea that sleep is purely a form of inactivity designed to save energy, rather than being important in itself.

What this paper doesn't explain, and doesn't try to, is dreaming, REM sleep, which is very different to slow-wave sleep. REM is not required for life, so long as you get SWS, and some animals don't have REM, but they all have SWS, although in some animals, only one side of the brain has it at a time.

So it makes sense, but what's the evidence? There's quite a bit - but, it all comes from very simple animals, like flies and fish.

The pictures above show that, in various parts of the brain of the fruit fly, measures of synaptic strength are increased in flies that have been awake for some time, compared to recently rested ones. In general, synapses increase during the wake cycle and then return to baseline during sleep.

There's similar evidence from fish. But the authors admit that no-one has yet shown that the same is true of any mammals - let alone humans.

I'd say that this is important, because the fly brain is literally a million times smaller than ours. Synaptic overgrowth could be a more serious problem for a fly because they just have fewer neurons to play with. Sleep may have evolved to prune extra connections in primitive brains, and then shifted to playing a very different role in ours.

Wang G, Grone B, Colas D, Appelbaum L, & Mourrain P (2011). Synaptic plasticity in sleep: learning, homeostasis and disease. Trends in Neurosciences PMID: 21840068

Brain-Modifying Drugs

What if there was a drug that didn't just affect the levels of chemicals in your brain, it turned off genes in your brain? That possibility - either exciting or sinister depending on how you look at it - could be remarkably close, according to a report just out from a Spanish group.

The authors took an antidepressant, sertraline, and chemically welded it to a small interfering RNA (siRNA). A siRNA is kind of like a pair of genetic handcuffs. It selectively blocks the expression of a particular gene, by binding to and interfering with RNA messengers. In this case, the target was the serotonin 5HT1A receptor.

The authors injected their molecule into the brains of some mice. The sertraline was there to target the siRNA at specific cell types. Sertraline works by binding to and blocking the serotonin transporter (SERT), and this is only expressed on cells that release serotonin; so only these cells were subject to the 5HT1A silencing.

The idea is that this receptor acts as a kind of automatic off-switch for these cells, making them reduce their firing in response to their own output, to keep them from firing too fast. There's a theory that this feedback can be a bad thing, because it stops antidepressants from being able to boost serotonin levels very much, although this is debated.

Anyway, it worked. The treated mice showed a strong and selective reduction in the density of the 5HT1A receptor in the target area (the Raphe nuclei containing serotonin cells), but not in the rest of the brain.

Note that this isn't genetic modification as such. The gene wasn't deleted, it was just silenced, temporarily one hopes; the effect persisted for at least 3 days, but they didn't investigate just how long it lasted.

That's remarkable enough, but what's more, it also worked when they administered the drug via the intranasal route. In many siRNA experiments, the payload is injected directly into the brain. That's fine for lab mice, but not very practical for humans. Intranasal administration, however, is popular and easy.

So siRNA-sertraline, and who knows what other drugs built along these lines, may be closer to being ready for human consumption than anyone would have predicted. However... the mouse's brain is a lot closer to its nose than the human brain is, so it might not go quite as smoothly.

The mind boggles at the potential. If you could selectively alter the gene expression of selective neurons, you could do things to the brain that are currently impossible. Existing drugs hit the whole brain, yet there are many reasons why you'd prefer to only affect certain areas. And editing gene expression would allow much more detailed control over those cells than is currently possible.

Currently available drugs are shotguns and sledgehammers. These approaches could provide sniper rifles and scalpels. But whether it will prove to be safe remains to be seen. I certainly wouldn't want to be first one to snort this particular drug.

Bortolozzi, A., Castañé, A., Semakova, J., Santana, N., Alvarado, G., Cortés, R., Ferrés-Coy, A., Fernández, G., Carmona, M., Toth, M., Perales, J., Montefeltro, A., & Artigas, F. (2011). Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects Molecular Psychiatry DOI: 10.1038/mp.2011.92

Ban These Sick Ape-Man Frankensteins

According to a new report, urgent action is required to stop scientists creating a monstrous race of apes with fully functional human brains (just as Christine O'Donnell warned us about those mice), thus causing Planet Of The Apes to come true.

OK, that's not quite what the Academy of Medical Sciences said. But judging from most of the media coverage, you might think it was.

The report is actually about "Animals containing human material" and it notes that under British law, experiments of this kind are covered by generic animal research rules, but there are no special animal-human regulations.

Should there be?

I think there should be. We as a society allow experiments on animals or animal embryos that we don't allow on humans, even on human embyros. Clearly, we need to decide what we're going to do about organisms that have both human and animal DNA, or whatever. This doesn't mean restricting it - to clear up the rules could also facilitate such research, by making it explicit what is allowed.

However, we should tread carefully here. This is an area where our intuitions can lead us astray.

Although we have absolutely no idea how to make an animal-human "hybrid", or even whether it's possible at all, the very idea of it has many people worried. It's probably a case of the uncanny valley and lots of cultural baggage (Planet of the Apes et al).

So, for whatever reason, we have a hang-up about making monstrous ape-men. Fair enough. So long as we remember that this is entirely hypothetical, and that it might, for all we know, be literally impossible.

Yet other things in this debate are very real. Over-zealous regulation of research could easily end up delaying, say, a cure for Alzheimer's for, say, 10 years. That would be dooming tens of millions of people to suffering and death.

The problem is, that's hard to picture. It's hard to imagine how bad Alzheimer's is unless you have personal experience. Even if you do, it's hard to multiply that badness by ten million anonymous, hypothetical people. "One ape-man is a tragedy; a million deaths is a statistic".

Delaying science is easy to do (for politicians), and hard to picture why it's bad. Whereas "a monstrous ape-man" is the exact opposite. Easy to imagine - just look at the media interest in this story - yet nowhere close to being reality.

This is a problem. The human mind and the way we think about these issues is a problem. Even when that mind is safely inside a nice normal human skull.

What Did Marc Hauser Do?

Marc Hauser, the cognitive psychologist who's been under scrutiny over a case of scientific misconduct since August last year (see past posts), has resigned from Harvard University.


He'd already been suspended from teaching, but until this announcement, it looked as though he might be able to hang on and resume his research, which focussed on the evolution of language and morality. Not any more. Hauser says he's quitting the field that made him famous:

“While on leave over the past year, I have begun doing some extremely interesting and rewarding work focusing on the educational needs of at-risk teenagers. I have also been offered some exciting opportunities in the private sector,” Hauser wrote in a resignation letter to the dean, dated July 7. “While I may return to teaching and research in the years to come, I look forward to focusing my energies in the coming year on these new and interesting challenges.”

So that's the end of the Hauser controversy, then?

Not really. The problem is, we still don't know what actually happened. It's hard for anyone to draw a line under this and move on, as Hauser seems to be doing.

Harvard have been reluctant to reveal any more than the barest details of the case. When the allegations first appeared, they set up an internal investigation. In August 2010 this concluded that Hauser was "soley responsible" for 8 cases of scientific misconduct.

But no-one - outside Harvard's investigative committee - knows what they were. He's been found guilty, and he's been punished, but no-one knows the crimes or the evidence against him.

Am I alone in finding this situation unsatisfactory?

Marc Hauser has published hundreds of scientific papers as well as various books. Only a small number of papers were implicated in the misconduct allegations. But to scientifically evaluate the rest of Hauser's work, we need to know what happened - and how easy the misconduct was to detect.

It makes a big difference, for example, whether the misconduct was the kind of thing that could have been going on, leaving no trace, for many years prior to this.

The lack of firm facts has led to discussion of the case being dominated by rumours and speculation. In October last year, for example, a newspaper published an article claiming that the case against Hauser might not be as strong as it first seemed.

This led to a rebuttal by Gerry Altman, then Editor of Cognition, a journal from which Hauser retracted a paper. Altman said that based on the information he had, Hauser was indeed guilty. But he admitted that he was going on what the Harvard investigation told him; he had not had access to the full data.

When Harvard found Hauser guilty, the Dean of his Faculty justified their secrecy:

The work of the investigating committee as well as its final report are considered confidential to protect both the individuals who made the allegations and those who assisted in the investigation.

Our investigative process will not succeed if individuals do not have complete confidence that their identities can be protected throughout the process and after the findings are reported to the appropriate agencies.

Furthermore, when the allegations concern research involving federal funding, funding agency regulations govern our processes ... For example, federal regulations impose an ongoing obligation to protect the identities of those who provided assistance to the investigation.

However, while this is certainly important, I don't see why it would prevent Harvard from releasing the conclusions of the report. They don't need to name the people who gave evidence against Hauser - but they do need to spell out what he did, and what they think he didn't do, so that the scientific community can come to their own conclusions as to the validity of the rest of Hauser's work.

In his letter, the Dean closed by saying that Harvard were going to

form a faculty committee this fall to reaffirm or recommend changes to the communication and confidentiality practices associated with the conclusion of cases involving allegations of professional misconduct.

I hope so.

New Brain Cells: Torrent, or Trickle?

An important paper just out asks, Could adult hippocampal neurogenesis be relevant for human behavior?

Neuroscientists, and the media, are very excited by hippocampal neurogenesis - the ongoing creation of new neurons in an area called the dentate gyrus of the hippocampus. This is because it was thought, for a long time, that no new neurons were created in the adult brain. It turned out that this was wrong.

There's lots of exciting suggestive evidence that the process is involved in learning and memory, responses to stress, depression, and the action of antidepressants, to name just a few, although this is controversial.

However, there's a big question which has rarely been considered: how much neurogenesis are we talking about? Are there enough new cells that it would be realistic for them to be doing important stuff, or is it just a little trickle?

The most common source of skepticism toward a functional role for adult neurogenesis is the perception that too few new neurons are added in adulthood to have a significant impact. Interestingly, this concern, while valid, is usually raised informally and rarely in the scientific literature. Very few studies have addressed this issue...

The new paper reviews the evidence. Firstly, they point out that in the hippocampus, there's a group of cells called dentate gyrus granule cells which are unusual in that activity in just a few of these cells can have big downstream consequences. And these are the cells that new born neurons turn into.

Each granule cell contacts only 10–15 CA3 pyramidal cells...a single granule cell is able to trigger firing in downstream CA3 targets...Because of this “detonator” action...a single granule neuron can potentially have a large impact despite representing only a tiny fraction of the population.

So new cells may play an important role. But exactly how many are there? They re-analyze data from their own lab in rats, and, making a few assumptions, arrive at the following rough estimate: in 3 month old rats, there are 650k "young" cells less than 8 weeks old; even in 2 year old rats (ancient, for a rat) there are 50k.

This is enough to have a big impact downstream:

Since there are approximately 500,000 CA3 pyramidal cells, and each granule cell contacts 11–15 pyramidal cells, this suggests that even in the oldest animals, each CA3 pyramidal cell could receive a direct contact from a young granule cell

That's all in rats, though. What about humans? It's hard to tell. The problem is that the best way to assess the rate of neurogenesis is to inject a drug called BrdU and then study the brain post-mortem. Unfortunately, this drug can cause cancer so you can't just give it to people for the purposes of science. The only time it's used in humans is (ironically) to help detect cancer.

However, one study did manage to look at BrdU staining in the hippocampus, using people who'd been injected with BrdU for cancer (not brain cancer) and then died. This study found, the authors say, rates of neurogeneis at least as high as in rats, considering the low dose of BrdU, the fact that the patients were old, and stressed (by having cancer).

They admit that this is just one study, and comparing doses between rats and humans is inexact. They nonetheless conclude:

Are these numbers potentially sufficient to exert a functional impact in humans? We feel that the answer to this question is an overwhelming "yes".

Snyder JS, & Cameron HA (2011). Could adult hippocampal neurogenesis be relevant for human behavior? Behavioural brain research PMID: 21736900

The Partly Asleep Brain

Some animals - such as dolphins and whales - are able to "sleep with half their brain". One side of the brain goes into sleep-mode activity while the other remains awake.


But a remarkable new study has revealed that something similar may happen in humans as well - every night.

The research used a combination of scalp EEG, and electrodes planted inside the brain, to record brain activity from 5 people undergoing surgery to help cure severe epilepsy. The subjects were then allowed to go to sleep for the night, while recording took place.

As expected, after falling asleep, the EEG showed delta wave activity - strong, slow waves of electrical activity (0.5 to 4 Hz) which are typical of deep, dreamless "slow wave sleep".

However, the electrodes inside the brain told a different story. While they recorded delta waves most of the time, they also showed that there were episodes, lasting from a few seconds to up to 2 minutes, in which the motor cortex suddenly went into "waking mode". Delta waves disappeared, and were replaced with fast, unpredictable activity.

This image shows one episode, lasting just 5 seconds. The hotter the color, the more activity in a particular frequency. The higher the band, the higher the frequency. This shows a clear burst of high frequency activity in the motor cortex. The other parts of the brain showed the opposite effect - even stronger slow wave activity - at the same time.

Another area, the dorsolateral prefrontal cortex, also showed this phenomenon occasionally, but it was much less common than in the motor cortex.

There's a few caveats. These patients had severe epilepsy, and they were taking anti-convulsant drugs. This wouldn't obviously create the effects seen here, but we can't rule it out. Still, these results are intriguing.

They challenge the view of slow wave sleep as a "whole brain" phenomenon. We've known for a while that this isn't true of animals, and in people with certain sleep disorders, but this is first demonstration in healthy humans.

It may help to explain the mysterious fact that, although slow wave sleep is often referred to as "dreamless", there are consistent reports that people woken up from this phase of sleep do report dreaming (or at least thinking) about things.

While episodic arousal of the motor cortex probably wouldn't explain this per se, if the same thing happens in the visual cortex or other sensory areas, it might create dreams.

Nobili L, Ferrara M, Moroni F, De Gennaro L, Russo GL, Campus C, Cardinale F, & De Carli F (2011). Dissociated wake-like and sleep-like electro-cortical activity during sleep. NeuroImage PMID: 21718789

Gamma Waves: The Brain's Clock, Or Neural Noise?

Gamma waves are very hot at the moment.


Gamma band activity is a term for electrical oscillations recorded from the brain that have a frequency of over 25 Hz. In most brains, a peak frequency of about 40 Hz is seen. This makes gamma waves the fastest brain waves.

If you believe some recent claims, gamma waves are the answer to all the mysteries of life and the universe. They're said to underlie the symptoms of schizophrenia and autism, and they've been invoked to answer deep questions such as the binding problem and maybe conciousness itself. You can even buy a Nintendo game that promises to boost them.

A new paper from Burns et al casts doubt on all of these grand claims. Gamma-based theories of brain function all assume that gamma waves act a bit like a clock, with a consistent rhythm of about 40 Hz. Activity of about 40 Hz is indeed observed in brain recordings but is that just because the brain is randomly generating all kinds of signals, and only the 40 Hz ones "get through"?

To put it another way, imagine that you got a letter in the mail at 9 am every morning. That could be because someone is sending you one letter each day like clockwork. But it could also be that loads of people are sending you letters at random times, and your mailman only has room in his sack to deliver one each morning.

Here's the key data, recorded using electrodes implanted into the brains of two male macaque monkeys:


This shows that the monkey data closely resemble what you'd expect if gamma activity were filtered noise, and are not what you'd see if it were a more meaningful "clock". The "triangle" on the graph shows the number of bursts of a given frequency and duration.
The data also show that the phase of the gamma activity isn't consistent, which it would be if it were clocklike. In fact, the phases change entirely randomly.

So if gamma is just "filtered noise", what's the "filter"? Why 40 Hz, not 80 or 4000? Probably because this is just the maximum frequency at which neurons can fire. It takes a certain finite amount of time for cells to communicate with each other: a silicon chip can get a clock speed of many billions of hertz, but a cell just physically can't.

There's a catch, though. These monkeys were asleep, anaesthetized with the powerful opiate sufentanil. This is a good choice of drug: unlike most other sedatives and anaesthetics, you wouldn't expect an opiate to directly affect gamma oscillations. But still. If you believe that coherent gamma waves are the key to high-level concious experience, as many do, you might not expect to see much of that in the primary visual cortex in asleep animals.

However, this is clearly a very important issue, and it's not the first gamma-skeptic paper. In 2008, Yuval-Greenberg et al reported that many attempts to measure gamma activity using EEG were contaminated by electrical activity from scalp muscles. Rather than coming from the brain, the "gamma" activity reflected nothing more than tiny eye movements. The implications are still being debated.

This paper attacks the gamma hypothesis from a completely different angle, saying that even the "real" gamma in the brain, may be nothing more interesting than filtered noise.

Burns SP, Xing D, & Shapley RM (2011). Is gamma-band activity in the local field potential of v1 cortex a "clock" or filtered noise? The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (26), 9658-64 PMID: 21715631