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by Neuroskeptic in Neuroskeptic
Nature Neuroscience has a nice little report about a new resource that should prove useful for neuroscientists - an anatomic gene expression atlas of the adult mouse brain.The atlas is freely available at http://mouse.brain-map.org/agea, courtesy of the Allen Foundation. It's a map of the entire adult mouse brain including data on the expression levels of 4,376 genes. You can click on a point in the brain and see which areas have a similar pattern of gene expression:The hotter the colour, the more correlated is the gene expression profile in that point vs. your selected region. This allows one to see the different regions of the brain defined not just anatomically, but genomically - fancy. Here I've clicked on a point in the cortex and this shows that other points in the cortex tend to have the same pattern of gene expression. That's hardly surprising, of course.This is the kind of thing that will be invaluable for some neuroscientists, and not much use to most others, but it's a source of pretty pictures for everyone - and it's an example of the power of this kind of database. The genomic atlas is derived from the Allen Brain Atlas which allows you to see where in the brain any given gene is expressed. See also BrainMAP.org for a modest attempt to do the same thing for functional neuroimaging.Lydia Ng, Amy Bernard, Chris Lau, Caroline C Overly, Hong-Wei Dong, Chihchau Kuan, Sayan Pathak, Susan M Sunkin, Chinh Dang, Jason W Bohland, Hemant Bokil, Partha P Mitra, Luis Puelles, John Hohmann, David J Anderson, Ed S Lein, Allan R Jones, Michael Hawrylycz (2009). An anatomic gene expression atlas of the adult mouse brain Nature Neuroscience, 12 (3), 356-362 DOI: 10.1038/nn.2281... Read more »
Lydia Ng, Amy Bernard, Chris Lau, Caroline C Overly, Hong-Wei Dong, Chihchau Kuan, Sayan Pathak, Susan M Sunkin, Chinh Dang, Jason W Bohland.... (2009) An anatomic gene expression atlas of the adult mouse brain. Nature Neuroscience, 12(3), 356-362. DOI: 10.1038/nn.2281
by Neuroskeptic in Neuroskeptic
There's been a glut of face-based science lately. There was the first American face transplant (the second if you count the ill-fated Travolta/Cage one...) Then an Atlanta group allegedly found that chimpanzees have a part of the brain specialized for recognizing the faces of their fellow chimps.As I'll explain, this would be extremely important if true. This research is just the latest chapter in a long and contentious debate going back many years - a debate which, believe it or not, may hold the answer to Life, the Universe, and Everything! I'll get onto that later.The human brain may, or may not, have regions which are "hard-wired" specifically for the visual processing of faces; the question of whether it does is generally known as the "Are Faces Special?" debate.(*) The majority of neuroscientists today would say that yes, they are, and that yes, we do have at least one such face area. I agree with this, but the debate's not yet ever - although as usual the reporting on this study glosses over such complexities.On the face of it (ha), the evidence for specialized processing of faces in the human brain is very strong. We're very good at distinguishing and recognizing faces, despite the fact that they are all extremely similar - and when faces are shown upside-down, we are much worse at dealing with them. This suggests, to most people, that we have a specialized capacity for processing faces.Following certain brain lesions, some patients lose their ability to recognize faces, a condition known as prosopagnosia. This most commonly follows damage to a part of the temporal lobe of the brain called the fusiform gyrus. Prosopagnosics may be able to identify and recognize other kinds of objects, but they just can't "get" faces. (Prosopagnosia can also be congenital i.e. present from birth). To a prosopagnosic, every face is as inscrutable as upside-down faces are to the rest of us.Meanwhile, neuroimaging has consistently shown a small portion of the aforementioned fusiform gyrus on the right side, dubbed the "fusiform face area (FFA)", is more activated when people are looking at pictures of faces than when they are looking at inanimate objects, other body parts, or pictures of faces which have been scrambled up so as to no longer look like faces.So all of the evidence seems to mesh together ("converge") splendidly: there's a face area in the human brain, located in the Fusiform Face Area, which is responsible for our unusually good face-processing abilities. Hurrah. However, there's a parade-raining alternative view, namely that faces are not special, we are only good at processing them because we have so much experience doing so, and the FFA's role lies in detecting the differences between similar objects about which we have learned to be highly familiar - faces being just one example.The details of this debate are fairly bewildering. For what it's worth, the "expertise" account has always seemed rather contrived to me and expertise theorists seem to be on the defensive against the more confident and plausible "specialist" neuroscientists. But that's just my opinion. For an excellent overview of the neuroscience of faces see here; for a skeptical view of the Fusiform Face Area see this; for skepticism of the skepticism here.Anyway, into this debate stepped Lisa Parr et. al. who used 18F-flurodeoxyglucose PET imaging to measure neural activity in five adult chimpanzees. Their goal was to see whether chimps possess a Fusiform Face Area or not. Chimps, unlike "lower" monkeys, are good at recognizing chimp (and human) faces. The five luckless chimps had to perform two tasks, one of which involved visually "matching" pictures of chimp faces in order to earn Kool-Aid. The other control task involved the same procedure but with matching non-face pictures ("Clip Art").Subjects have been trained to control the movements of a cursor on the computer screen by manipulating the joystick ... At the beginning of a trial, a single image (the sample) appears on the computer screen on a black background. ... After this, the sample clears the screen and two comparison images appear on the monitor ... One of these comparisons matches the sample (the target), and the other (the foil) is a different image from the same category, either another face or another clip art object. ... Subjects must contact the image that matches the sample by contacting it with the joystick-controlled cursor.Compared to the control Clip Art task, the chimp's brains were more active during the face task in a wide range of areas. The most "face-selective" area was the "Dorsal primary motor/medial parietal cortex (Left)" which has nothing to do with faces, vision, or any of that kind of stuff. The authors try to put a brave face on this (emphasis mine)...The first [whole brain] analysis revealed numerous brain regions that showed greater metabolic activity during the face-matching task when compared directly to the object-matching ... [including] the posterior superior temporal sulcus (STS) and orbitofrontal cortex ... These regions comprise part of the distributed cortical network for face processing in humans. Notably absent from this analysis was activity in the fusiform gyrus, the primary region where face-selective activity is found in humans when the comparable analysis is used....but this is clearly a disappointing result. No chimp FFA found. Yet this is hardly surprising, considering that there were only five subjects in this experiment, and there's obviously a big difference between a human volunteer, and a chimpanzee who's spent years being experimented on, is locked in a cage, is highly trained on the computerized task, and who is doing the experiment for Kool-Aid.(**) The absence of evidence in this experiment is not evidence of absence.All was not lost, however, because the authors then did a different analysis, looking for individual voxels (small parts of the brain) which were "face selective" or "object selective". (I suspect this was a post-hoc analysis, a naughty practice which I have warned about before, but here it's arguably OK). Short story - they found a lot of such voxels, most of them in areas which are nothing to do with faces or vision, but there were quite a few in the fusiform gyrus, which is where you might expect them to be based on human work (see above.) But honestly, neuroimaging data is noisy enough at the best of times and with just five subjects it's virtually impossible to draw any conclusions. A human PET study with n=5 would never get published; by the standards of chimp research n=5 is big because chimps are much harder to work with. Personally, I'm just glad I don't work with chimps.What about Life, the Universe, and Everything? Well, the "Are Faces Special" debate is relevant to such cosmic questions (almost), because it's one aspect of the great "modularity" debate, which is basically psychologists and neuroscientists debating the existence of human nature. If humans are genetically programmed to have a part of the brain (a "module") specialized for processing faces, presumably this is because we evolved to do so. If so, then this makes it very plausible that other parts of our brains evolved for such specialist purposes, and this implies that our minds work in certain ways because of evolution (i.e Evolutionary Psychology) and that human nature is largely fixed.On the other hand, if faces aren't special, maybe nothing is - maybe there is no such thing as human nature and all our behavior is learned by experience. That would imply that culture and history are much more important than biology in understanding human life, and that with sufficient political and social advancement anything is possible! Wow. That's the importance of neuroscience. At least, that's what neuroscientists will tell you when they want you to give them money or buy their books...(*) If you're at a cognitive neuroscience conference and feel like a slap in the face, try opening a conversation with a pretty young grad student with the line "I don't know if faces are special, babe, but yours is".(**) Although given the state of some undergrads, the differences might not always be in the human's favor.L PARR, E HECHT, S BARKS, T PREUSS, J VOTAW (2008). Face Processing in the Chimpanzee Brain Current Biology DOI: 10.1016/j.cub.2008.11.048... Read more »
L PARR, E HECHT, S BARKS, T PREUSS, & J VOTAW. (2008) Face Processing in the Chimpanzee Brain. Current Biology. DOI: 10.1016/j.cub.2008.11.048
by Neuroskeptic in Neuroskeptic
Are you addicted to Starcraft? Do you want to get off Battle.net and on a psychoactive drug?Well, South Korean psychiatrists Han et al report that Bupropion sustained release treatment decreases craving for video games and cue-induced brain activity in patients with Internet video game addiction.They took 11 people with "Internet Game Addiction" - the game being Starcraft, this being South Korea - and gave them the drug bupropion (Wellbutrin), an antidepressant that's also used in drug addiction and smoking cessation. These guys (because, predictably, they were all guys) were seriously hooked, playing on average at least 4 hours per day.Six were absent from school because of playing Internet video game in Internet cafes for more than 2 months. Two IAGs had been divorced because of excessive Internet use at night.They helpfully summarize Starcraft for the layperson:As a military leader for one of three species, players must gather resources for training and expanding their species’ forces. Utilizing various strategies and alliances with other species, players attempt to lead their own species to victory.Which is all true, but it doesn't quite communicate the sheer obsessiveness that's require to win this game. As Penny Arcade said "it is OCD masquerading as recreation", and that's coming from someone who literally plays video games for a living.Anyway, apparently the drug worked:After 6 weeks of bupropion SR treatment in the IAG group, there were significant decreases in terms of craving for playing StarCraft (23.6%), total playing game time (35.4%), and Internet Addiction Scale scores (15.4%)They also did some fMRI and found that the addict's brains responded more strongly to pictures of Zerglings than did control people, and that the drug reduced activity a bit. But there was no placebo group, so we have no idea whether this was the drug or not.Sadly, the point is moot, because Starcraft II has just come out, and it's more addictive than ever. I'm off to try and optimize my Terran build order, and by God I will get those 10 marines out in the first 5 minutes if it takes me all night...Han DH, Hwang JW, & Renshaw PF (2010). Bupropion sustained release treatment decreases craving for video games and cue-induced brain activity in patients with Internet video game addiction. Experimental and clinical psychopharmacology, 18 (4), 297-304 PMID: 20695685... Read more »
Han DH, Hwang JW, & Renshaw PF. (2010) Bupropion sustained release treatment decreases craving for video games and cue-induced brain activity in patients with Internet video game addiction. Experimental and clinical psychopharmacology, 18(4), 297-304. PMID: 20695685
by Neuroskeptic in Neuroskeptic
During the development of the brain, young neurones need to form connections with other cells. But equally important, they need to avoid making connections with themselves.Unfortunately, the chance of this happening is rather high. As a neurone grows and branches out in all directions, many of the branches will inevitably come into contact with others from the same cell. They're right next to each other.So, how do brains achieve self-avoidance? The answer, according to a new Nature paper building on previous work, is a clever mechanism involving a single protein, Dscam1. The DNA code which produces it contains three sections (exons), which can each vary in several ways. There are 12 variants of exon 4, 48 of exon 6, and 33 of exon 9.That means that Dscam1 can end up in 12 x 48 x 33 = 19,008 different configurations (isoforms). It's as if whenever the protein is formed, it rolls a 12 sided dice, a 48 sided dice, and a 33 sided dice, and then ends up signalling the result. The diagram illustrates this nicely. The clever part is that each developing neurone expresses only a few isoforms, entirely at random.If a growing neuronal branch encounters another branch with the same Dscam1 isoform, the two identical proteins interact and the branches repel each other. Because every part of any given cell expresses the same "fingerprint", this produces self-avoidance. But the chance that another neighbouring cell will have the same protein is very small. There are billions of neurones in the brain, so many will share the same protein, but the chance of a cell encountering another nearby with the identical fingerprint is tiny.In this paper, the authors genetically engineered fruit flies (Drosophila) so that they had fewer than the normal 19,008 Dscam1 variants. (Previous work suggests that the system is similar in mammals.) Flies with 4,752 variants developed normally, but with only 1,152, problems arose: neurones got repelled from other nearby neurones because they shared the same protein. With 576, 24, or 12 isoforms, the problem became progressively worse, as the chance of two cells having the same isoform rose.So, in order to avoid tying themselves in knots, brains need somewhere between about one thousand and five thousand Dscam1 variants. It's an elegant solution to the problem of neurite self-avoidance, and a lovely example of evolution at work.Hattori D, Chen Y, Matthews BJ, Salwinski L, Sabatti C, Grueber WB, & Zipursky SL (2009). Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature, 461 (7264), 644-8 PMID: 19794492... Read more »
Hattori D, Chen Y, Matthews BJ, Salwinski L, Sabatti C, Grueber WB, & Zipursky SL. (2009) Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature, 461(7264), 644-8. PMID: 19794492
by Neuroskeptic in Neuroskeptic
Via Mind Hacks, we learn about the case of Francisco Lacerda, a University of Stockholm academic who's been threatened with legal action by the sinister-sounding Nemesysco company. Nemesysco sell software which, they claim, can detect deception and emotions by analyzing the sound of people's voices - lie detection, in other words. (In fact it turns out that it can also be used to detect love, or at least, so they say - see below...)The legal dispute surrounds a 2007 paper authored by Lacerda and Anders Erikkson, entitled Charlatanry in Forensic Speech Science: A Problem to be Taken Seriously. It was originally published in The International Journal of Speech, Language and the Law, but was taken down from the journal's website following Nemesysco's threats. However, the full text is still available on scribd.To be fair to Nemesysco, you can see why they took offence. The paper is unusually lively for an academic article. Here are some of the best bitsContrary to the claims of sophistication...the LVA [Nemesysco's "Layered Voice Analysis" system] is a very simple program written in Visual Basic. The entire program code, published in the patent documents, comprises no more than 500 lines of code... there is really nothing in the program that requires any mathematical insights beyond very basic secondary school mathematics... we initially intended to use the code published in the patent documents to make a running copy of the program, but the code is rather messy and not particularly well structured and we decided it would not be worth the time and effort to clean up the code in order to convert it into a running program.In fact, in parts the thing reads more like a blog post or an op-ed than a scientific paper - no bad thing, of course. Even Lacerda admits that "The article had a journalistic tone and was rather provocatively written. We wanted to prove that the technology behind the lie detector is a scam." It's also not entirely clear why Nemesysco, who claim no specific scientific credentials, are a fit subject for an academic journal. (Other voice analysis companies who mis-read scientific papers in support of their claims seem a more obvious target.)Still, Erikkson and Lacerda make an excellent case against Nemesysco. They point out that, according to the patent documents, Nemesysco's "LVA" system does nothing more than apply a simplistic analysis to the amplitude waveform of the speech, involving counting the number of "thorns" (sharp peaks or throughs) and "plateaus" (flat bits):As they point out, the number of these things will depend upon, amongst other factors, the quality of the audio recording and digitizating process: a better sound recording with a higher sampling rate (more "dots" on the graph above) will inevitably have more thorns and plateausThe number of thorns and plateaus...depends crucially on the sampling rate, amplitude resolution, and the threshold values defined in the programEven setting aside these issues, the fundamental point is that there is absolutely no reason to think that the number of thorns and plateaus in the speech waveform has any relation to whether someone is lying, under emotional stress, or whatever. This makes the LVA system even less plausible than the older "Voice Stress Analysis" (VSA) method of vocal lie detection, which Erikkson and Lacerda also discuss. There is at least some theoretical basis in physiology for that system, although a very very shaky one. LVA doesn't even have that - or at least none has been provided - so when Nemesysco claim thatThe SENSE technology can detect the following emotional and cognitive states: Excitement Level: Each of us becomes excited (or depressed) from time to time. SENSE compares the presence of the Micro-High-frequencies of each sample to the basic profile to measure the excitement level in each vocal segment. Confusion Level: Is your subject sure about what he or she is saying? SENSE technology measures and compares the tiny delays in your subject's voice to assess how certain he or she is. Stress Level: Stress is physiologically defined as the body's reaction to a threat, either by fighting the threat, or by fleeing. However, during a spoken conversation neither option may be available. The conflict caused by this dissonance affects the micro-low-frequencies in the voice during speech. Thinking Level: How much is your subject trying to find answers? Might he or she be "inventing" stories? S.O.S: (Say Or Stop) - Is your subject hesitating to tell you something? Concentration Level: Extreme concentration might indicate deception. Anticipation Level: Is your subject anticipating your responses according to what he or she is telling you? Embarrassment Level: Is your subject feeling comfortable, or does he feel some level of embarrassment regarding what he or she is saying? Arousal Level: What triggers arousal in the subject? Is he or she interested in you? Aroused by certain visuals? This new detection can be used both for personal use for issues of romance, or professionally for therapy relating to sex-offenders. Deep Emotions: What long-standing emotions does your subject experience? Is he or she "excited" or "uncertain" in general? SENSE's "Deep" Technology: Is your subject thinking about a single topic when speaking, or are there several layers (i.e., background issues, something that may be bothering him or her, planning, etc.) SENSE technology can detect brain activity operating at a pre-conscious level.and yet nowhere on their website is there any hint of evidence for any of this, skepticism is justified. Amongst many other things, it's unlikely that even if we each have a vocal pattern associated with, say, arousal, (not implausible), the same pattern would be present in the voice of men, women, people of different ages, and so forth. People just aren't that alike, as any psychologist or neuroscientist knows. Even direct measures of brain activity during very simple cognitive tasks vary greatly between individuals. The chance that any kind of analysis of the voice could reveal such complex information about an individual without their compliance is remote.Almost certainly, Nemesysco's analysis provides no useful information about the speaker as such, but as Erikkson and Lacerda suggest, it probably "works" through two psychological mechanisms. Firstly, the fact that if someone believes that their voice is being analyzed, they may tend to be more truthful because they think that lies will be detected. Secondly, the fact that the voice analysis user is able to interpret the output - e.g. "speaker stressed, concentrating hard" - in terms of what they already know about the speaker. Anyone might be stressed and concentrating hard during almost any conversation, so it always "fits".Still, if you don't believe me, and you want to try out LVA for yourself, you can - and you don't have to be a cop or a spy. Nemesysco are now marketing their technology directly to consumers in the form of the Love Detector. The Love Detector is available as a Skype plug-in for just $29, and it allows you to know whether the object of your affections feels the same way about you, all from the sound of their voice.Love Detector was originally designed with young singles in mind, or anyone searching for "the ONE". If you are currently looking for love, starting to date someone, or just have that unmistakable feeling, and you want to make sure it's mutual, Love Detector is the tool for you. If you are in a long-term relationship or even married, this version of Love Detector offers a "Relationship Selector" option designed to meet your needs as well.There is even, apparantly, a free online version. If the mood strikes, maybe I'll try it out. Watch this space. And lock up your daughters (or at least unplug their microphones...)Anders Eriksson, Francisco Lacerda (2008). Charlatanry in forensic speech science: A problem to be taken seriously International Journal of Speech Language and the Law, 14 (2) DOI: 10.1558/ijsll.2007.14.2.169... Read more »
Anders Eriksson, & Francisco Lacerda. (2008) Charlatanry in forensic speech science: A problem to be taken seriously. International Journal of Speech Language and the Law, 14(2). DOI: 10.1558/ijsll.2007.14.2.169
by Neuroskeptic in Neuroskeptic
The brain is a tightly regulated system. Levels of neurotransmitters, for example, are regulated by reuptake proteins, which move transmitters from outside the cell to inside, where they are inactive. This means that after cells release a neurotransmitter, such as dopamine, it is rapidly taken back up again.Interestingly, however, the levels of the reuptake protiens themselves are variable and can change in response to various things. If dopamine levels rise, for example, nearby cells rapidly increase the number of dopamine transporters (DAT), thus helping to reduce dopamine levels again. This happens when DAT proteins waiting dormant within nerve cells are sent to the surface (the cell membrane) in response to increased dopamine levels.This much is fairly well known, but a lovely experiment from a University of Michigan team has revealed just how fast the process is. (Dopamine and Amphetamine Rapidly Increase Dopamine Transporter Trafficking to the Surface: Live-Cell Imaging Using Total Internal Reflection Fluorescence Microscopy).The authors used a form of light microscopy which allows the membrane of a single cell to be imaged. They created cells genetically engineered to have dopamine transporter protein (DAT) which glows, because it was linked to Green Fluorescent Protein. This allowed them to view changes in the level of DAT on the surface of the cells, in real time, in living cells.They found that adding dopamine caused DAT levels to rise astonishly fast - within just a few seconds. Amphetamine, a drug which acts on the DAT, had the same effect. However, cocaine, a drug which blocks DAT, prevented this effect.They've even made a video so that you can see the dopamine transporters bubbling up on the surface of a single cell. Watch it (if you have academic access) - it beats 99% of YouTube.This is a fascinating result, and it underlines the fact that nothing in the brain is ever straightforward. For example, most people will tell you that amphetamine and cocaine both have stimulant effects by "increasing dopamine levels" - cocaine by blocking dopamine reuptake and amphetamine by causing the dopamine transporter to actually go into reverse and start releasing dopamine. But this result suggests that amphetamine also increases membrane dopamine transporter levels. That could have any number of indirect effects. Then again over longer time-scales (minutes), amphetamine reduces the DAT levels. That could have indirect effects too...It's also worth bearing in mind that although this experiment involved the dopamine transpoter, other reuptake proteins like the serotonin transporter might well be regulated in the same way, which could have big implications for antidepressant action...Furman, C., Chen, R., Guptaroy, B., Zhang, M., Holz, R., & Gnegy, M. (2009). Dopamine and Amphetamine Rapidly Increase Dopamine Transporter Trafficking to the Surface: Live-Cell Imaging Using Total Internal Reflection Fluorescence Microscopy Journal of Neuroscience, 29 (10), 3328-3336 DOI: 10.1523/JNEUROSCI.5386-08.2009... Read more »
Furman, C., Chen, R., Guptaroy, B., Zhang, M., Holz, R., & Gnegy, M. (2009) Dopamine and Amphetamine Rapidly Increase Dopamine Transporter Trafficking to the Surface: Live-Cell Imaging Using Total Internal Reflection Fluorescence Microscopy. Journal of Neuroscience, 29(10), 3328-3336. DOI: 10.1523/JNEUROSCI.5386-08.2009
Furman, C., Chen, R., Guptaroy, B., Zhang, M., Holz, R., & Gnegy, M. (2009) Dopamine and Amphetamine Rapidly Increase Dopamine Transporter Trafficking to the Surface: Live-Cell Imaging Using Total Internal Reflection Fluorescence Microscopy. Journal of Neuroscience, 29(10), 3328-3336. DOI: 10.1523/JNEUROSCI.5386-08.2009
by Neuroskeptic in Neuroskeptic
Which is more dangerous, taking ecstasy or riding a horse?This is the question that got Professor David Nutt, a British psychiatrist, into a spot of political bother. Nutt is the Editor of the academic Journal of Psychopharmacology. He recently published a brief and provocative editorial called "Equasy".Equasy is a fun read with a serious message. (It's open access so you can read the whole thing - I recommend it.) Nutt points out that the way in which we think about the harms of illegal drugs, such as ecstasy, is unlike the way in which we think about other dangerous things such as horseriding - or "equasy" as he dubs it:The drug debate takes place without reference to other causes of harm in society, which tends to give drugs a different, more worrying, status. In this article, I share experience of another harmful addiction I have called equasy...He goes on to describe some of the injuries, including brain damage, that you can get from falling off horses. After arguing that horseriding is in some ways comparable to ecstasy in terms of its dangerousness he concludes:Perhaps this illustrates the need to offer a new approach to considering what underlies society’s tolerance of potentially harmful activities and how this evolves over time (e.g. fox hunting, cigarette smoking). A debate on the wider issues of how harms are tolerated by society and policy makers can only help to generate a broad based and therefore more relevant harm assessment process that could cut through the current ill-informed debate about the drug harms? The use of rational evidence for the assessment of the harms of drugs will be one step forward to the development of a credible drugs strategy.Or, in other words, we need to ask why we are more concerned about the harms of illicit drugs than we are the harms of, say, sports. No-one ever suggests that the existence of sporting injuries means that we ought to ban sports. Even if it turns out that on an hour-by-hour basis, you're more likely to die riding a horse than dancing on ecstasy (quite possible), no-one would think to ban riding and legalize E. But why not?This attitude raises the critical question of why society tolerates –indeed encourages – certain forms of potentially harmful behaviour but not others, such as drug use.Which is an extremely good question. It remains a good question even if it turns out that horse-riding is much safer than ecstasy. These are just the two examples that Nutt happened to pick, presumably because it allowed him to make that cheeky pun. Comparing the harms of such different activities is fraught with pitfalls anyway - are we talking about the harms of pure MDMA, or street ecstasy? Do we include people injured by horses indirectly (e.g. due to road accidents?)Yet the whole point is that no-one even tries to do this. The dangerousness of drugs is treated as quite different to the dangerousness of sports and other such activies. The media indeed seem to have a particular interest in the harms of ecstasy - at least according to a paper cited by Nutt, Forsyth (2001), which claims that deaths from ecstasy in Scotland were much more likely to get newspaper coverage than deaths from paracetemol, Valium, and even other illegal drugs. It's not clear why this is. Indeed, when you make the point explicitly, as Nutt did, it looks rather silly. Why shouldn't we treat taking ecstasy as a recreational activity like horse-riding? That's something to think about.Professor Nutt is well known in psychopharmacology circles both for his scientific contributions and for his outspoken views. These cover drug policy as well as other aspects of psychiatry - for one thing, he's strongly pro-antidepressants (see another provocative editorial of his here.)As recently-appointed Chairman of the Advisory Council on the Misuse of Drugs - "an independent expert body that advises government on drug related issues in the UK" - Nutt might be thought to have some degree of influence. (He wrote the article before he became chairman). Sadly not, it appears, for as soon as the Government realized what he'd written he got a dressing down from British Home Secretary Jacqui Smith - Ooo-er:For me that makes light of a serious problem, trivialises the dangers of drugs, shows insensitivity to the families of victims of ecstasy and sends the wrong message to young people about the dangers of drugs.I'm not sure how many parents of ecstasy victims read the Journal of Psychopharmacology, but I can't see how anyone could be offended by the Equasy article. Except perhaps people who enjoy hunting foxes while riding horses (Nutt compares this to drug-fuelled violence). Nutt's editorial was intended to point out that discussion over drugs is often irrational, and to call for a serious, evidence-based debate. It is not really about ecstasy, or horses, but about the way in which we conceptualize drugs and their harms. Clearly, that's just a step too far.D. Nutt (2008). Equasy -- An overlooked addiction with implications for the current debate on drug harms Journal of Psychopharmacology, 23 (1), 3-5 DOI: 10.1177/0269881108099672... Read more »
D. Nutt. (2008) Equasy -- An overlooked addiction with implications for the current debate on drug harms. Journal of Psychopharmacology, 23(1), 3-5. DOI: 10.1177/0269881108099672
D. Nutt. (2008) Equasy -- An overlooked addiction with implications for the current debate on drug harms. Journal of Psychopharmacology, 23(1), 3-5. DOI: 10.1177/0269881108099672
by Neuroskeptic in Neuroskeptic
In the last couple of weeks we've seen not one but two reports about "reading minds" through brain imaging. First, two Canadian scientists claimed to be able to tell which flavor of drink you prefer (Decoding subjective preference from single-trial near-infrared spectroscopy signals). Then a pair of Nashville neuroimagers said that they could tell which of two pictures you were thinking about through fMRI (Decoding reveals the contents of visual working memory in early visual areas); you can read more about this one here. Can it be true? And if so, how does it work?Although this kind of "mind reading" with brain scanners strikes us as exciting and mysterious, it would be much more surprising if it turned out to be impossible. That would mean that Descartes was right (probably). There's nothing surprising about the fact that mental states can be read using physical measurements, such as fMRI. If you prefer one thing to another, something must be going on in your brain to make that happen. Likewise if you're thinking about a certain picture, activity somewhere in your brain must be responsible.But how do we find the activity that's associated with a certain mental state? It's actually pretty straightforward - in the sense that it relies upon brute computational force rather than sophisticated neurobiological theories. The trick is data-mining, which I've written about before. Essentially, you take a huge set of measurements of brain activity, and search through them in order to find those which are related to the mental state of interest.The goal in other words is pattern classification: the search for some pattern of neural activity which is correlated with, say, enjoying a certain drink, or thinking about a bunch of horizontal lines. To find such a pattern, you measure activity over an area of the brain while people are in two different mental states: you then search for some set of variables which differ between these two states.If this succeeds, you can end up with an algorithm - a "pattern classifier" - which can take a set of activity signals and tell you which mental state it is associated with. Or if you want to be a bit more sensationalist: it can read minds! But importantly, just because it works doesn't mean that anyone knows how it works.Here's a pic from the first paper showing the neural activity associated with preferring two different drinks (actually pictures of drinks on a screen, not real drinks.) X's are the activity measured when the person preferred the first out of two drinks, and O's are when they preferred the second. The 2D "space" represents activity levels in two different measures of neural activity. A spot in the top left corner means that "Feature 2" activity was high while "Feature 1" activity was low.You can see that the X's and the O's tend to be in different parts of the space - X's tend to be in the top left and O's in the bottom right. That's not a hard-and-fast rule but it's true most of the time. So if you drew an imaginary line down the middle you could do a pretty good job of distinguishing between the X's and the O's. This is what a pattern classifier does. It searches through a huge set of pictures like this and looks for the ones where you can draw such a line.The second paper uses what's in essence a similar method to discriminate between the neural activity in the visual areas of the brain associated with remembering two different pictures. Indeed, the technique is fast becoming very popular with neuroimagers. (One attractive thing about it is that you can point a pattern classifier at some data that you collected for entirely seperate reasons - two publications for the price of one...) But this doesn't mean that we can read your mind. We just have computer programs that can do it for us - and only if they are are specially (and often time-consumingly) "trained" to discriminate between two very specific states of mind.Being able to put someone in an MRI scanner and work out what they are thinking straight off the bat is a neuroimager's pipe dream and will remain so for a good while yet.Sheena Luu, Tom Chau (2009). Decoding subjective preference from single-trial near-infrared spectroscopy signals Journal of Neural Engineering, 6 (1) DOI: 10.1088/1741-2560/6/1/016003Stephanie Harrison, Frank Tong (2009). Decoding reveals the contents of visual working memory in early visual areas Nature... Read more »
Sheena Luu, & Tom Chau. (2009) Decoding subjective preference from single-trial near-infrared spectroscopy signals. Journal of Neural Engineering, 6(1), 16003. DOI: 10.1088/1741-2560/6/1/016003
Stephanie Harrison, Frank Tong. (2009) Decoding reveals the contents of visual working memory in early visual areas. Nature. DOI: http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature07832.html
by Neuroskeptic in Neuroskeptic
One of the most blogged-about psychology papers of 2008 was Weisberg et. al.'s The Seductive Allure of Neuroscience Explanations.As most of you probably already know, Weisberg et. al. set out to test whether adding an impressive-sounding, but completely irrelevant, sentence about neuroscience to explanations for common aspects of human behaviour made people more likely to accept those explanations as good ones. As they noted in their Introduction:Although it is hardly mysterious that members of the public should find psychological research fascinating, this fascination seems particularly acute for findings that were obtained using a neuropsychological measure. Indeed, one can hardly open a newspaper’s science section without seeing a report on a neuroscience discovery or on a new application of neuroscience findings to economics, politics, or law. Research on nonneural cognitive psychology does not seem to pique the public’s interest in the same way, even though the two fields are concerned with similar questions.They found that the pointless neuroscience made people rate bad psychological "explanations" as being better. The bad psychological explanations were simply descriptions of the phenomena in need of explanation (something like "People like dogs because they have a preference for domestic canines"). Without the neuroscience, people could tell that the bad explanations were bad, compared to other, good explanations. The neuroscience blinded them to this. This confusion was equally present in "normal" volunteers and in cognitive neuroscience students, although cognitive neuroscience experts (PhDs and professors) seemed to be immune.But is this really true?This kind of research - which claims to provide hard, scientific evidence for the existence of a commonly believed in psychological phenomenon, usually some annoyingly irrational human quirk - is dangerous; it should always be read with extra care. The danger is that the results can seem so obviously true ("Well of course!") and so important ("How many times have I complained about this?") that the methodological strengths and weaknesses of the study go unnoticed. People see a peer-reviewed paper which seemingly confirms the existence of one of their pet peeves, and they believe it - becoming even more peeved in the process.(*)In this case, the peeve is obvious: the popular media certainly seem to inordinately keen on neuroimaging studies, and often seem to throw in pictures of brain scans and references to brain regions just to make their story seem more exciting. The number of people who confuse neural localization with explanation is depressing. Those not involved in cognitive neuroscience must find this rather frustrating. Even neuroimagers roll their eyes at it (although some may be secretly glad of it!)So Weisberg et al. struck a chord with most readers, including most of the potentially skeptical ones - which is exactly why it needs to be read very carefully critiqued. Personally, having done so, I think that it's an excellent paper, but the data presented only allow fairly modest conclusions to be drawn, so far. The authors have not shown that neuroscience, specifically, is seductive or alluring.Most fundamentally, the explanations including the dodgy neuroscience differed from the non-neurosciencey explanations in more than just neuroscience. Most obviously, they were longer, which may have made them seem "better" to the untrained, or bored, eye; indeed the authors themselves cite a paper, Kikas (2003), in which the length of explanations altered how people perceived them. Secondly, the explanations with added neuroscience were more "complex" - they included two separate "explanations", a psychological one and a neuroscience one. This complexity, rather than the presence of neuroscience per se, might have contributed to their impressiveness.Perhaps the authors should have used three conditions - psychology, "double psychology" (with additional psychological explanations or technical terminology), and neuroscience (with additional neuroscience). As it stands, the authors have strictly shown is that longer, more jargon-filled explanations are rated as better - which is an interesting finding, but is not necessarily specific to neuroscience.In their discussion (and to their credit) the authors fully acknowledge these points (emphasis mine)Other kinds of information besides neuroscience could have similar effects. We focused the current experiments on neuroscience because it provides a particularly fertile testing ground, due to its current stature both in psychological research and in the popular press. However, we believe that our results are not necessarily limited to neuroscience or even to psychology. Rather, people may be responding to some more general property of the neuroscience information that encouraged them to find the explanations in the With Neuroscience condition more satisfying.But this is rather a large caveat. If all the authors have shown is that people can be "Blinded with Science" (yes...like the song) in a non-specific manner, that has little to do with neuroscience. The authors go on to discuss various interesting, and plausible, theories about what might make seemingly "scientific" explanations seductive, and why neuroscience might be especially prone to this - but they are, as they acknowledge, just speculations. At this stage, we don't know, and we don't know how important this effect is in the real world, when people are reading newspapers and looking at pictures of brain scans.Secondly, the group differences - between the "normal people", the neuroscience students, and the neuroscience experts - are hard to interpret. There were 81 normal people, mean age 20, but we don't know who they were or how they were recruited - were they students, internet users, the authors' friends? (10 of them didn't give their age and for 2 gender was "unreported" -?) We don't know whether their level of education, their interests, or values were different from the cognitive neuroscience students in the second group (mean age 20), who may likewise have been different in terms of education, intelligence and beliefs from the expert neuroscientists in the third group (mean age 27). Maybe such personal factors, rather than neuroscience knowledge, explained the group similarities and differences?Finally, the effects seen in this paper were, on the face of it, small - people rated the explanations on a 7 point scale from -3 (bad) to +3 (excellent), but the mean scores were all between -1 and +1. The dodgy neuroscience added about 1 point on a 7 point scale of satisfactoriness. Is that "a lot" or "a little"? It's impossible to say.All of that said - this is still a great paper, and the point of this post is not to criticize or "debunk" Weisberg et. al.'s excellent work. If you haven't read their paper, you should read it, in full, right now, and I'm looking forward to further stuff from the same group. What I'm trying to do is to warn against another kind of seductive allure, probably the oldest and most dangerous of all - the allure of that which confirms what we already thought we knew.(*)Or do they? Or is this just one of my pet peeves? Maybe I need to do an experiment about the allure of psychology papers confirming the allure of psychologist's pet peeves...Deena Skolnick Weisberg, Frank C. Keil, Joshua Goodstein, Elizabeth Rawson, Jeremy R. Gray (2008). The Seductive Allure of Neuroscience Explanations Journal of Cognitive Neuroscience, 20 (3), 470-477 DOI: 10.1162/jocn.2008.20040... Read more »
Deena Skolnick Weisberg, Frank C. Keil, Joshua Goodstein, Elizabeth Rawson, & Jeremy R. Gray. (2008) The Seductive Allure of Neuroscience Explanations. Journal of Cognitive Neuroscience, 20(3), 470-477. DOI: 10.1162/jocn.2008.20040
by Neuroskeptic in Neuroskeptic
Neuroskeptic has warned before of the pitfalls of candidate gene association studies. With small sample sizes and multiple comparisons, false positive results are all too common, especially in behavioural genetics. Yet it's not all bad. The renowned Klaus-Peter Lesch and colleagues have just produced a paper which is a cut above the rest. They report on an association between a promoter region polymorphism in the gene NOS1 and "impulsive" traits.NOS1 codes for the enzyme nitric oxide synthase 1, which is expressed in neurones and makes nitric oxide (Nitrogen monoxide, NO). NO is a small molecule with various roles in animals, most famously the ability to induce erections - Viagra works by enhancing this effect. NO is also known to act as a neurotransmitter, with widespread but poorly understood functions in the brain. It's therefore plausible that altered nitric oxide synthase function could affect behaviour, and several animal studies suggest that indeed it does.The new paper, published in the Archives of General Psychiatry, reports on the characterization of a functional variant in the human NOS1 gene, and its association with behaviour in several large human samples. The polymorphism, which Lesch et. al. previously discovered and called NOS1 Ex1f VNTR, is a Variable Number Tandem Repeat in a promoter region of DNA. It can be either "short" (S) or "long" (L) (although note that these are arbitrary categories, since the length of the region varies along a range.)The authors first established that Ex1f is a functional (biologically meaningful) variant, by showing that shorter forms of the Ex1f promoter are less active than the longer forms in vitro (see graphs). They then examined human brain tissue from post-mortem samples and found that the short/long polymorphism was associated with signficant differences in the expression of a large number of proteins. Although most of the proteins in question were nothing to do with NO, this shows that the polymorphism does something, which is a start (many don't).They then report on the association between the short form of the gene and what they call "impulsivity". Here's the exciting bit:In two seperate control samples of normal German adults (most of whom) were screened to exclude psychiatric disorders (n=640 and 1314), 21 and 20% carried two copies of the short allele (SS). I've helpfully highlighted that in green above. Then, in samples of German people who displayed various forms of impulsive behaviour, the SS genotype was more common: in 383 adults with ADHD (28% SS), 189 adults who had attempted suicide (25% SS), and adults with "Cluster B" personality disorders 26% SS, but not those with "Cluster C" disorders representing anxious traits. Also, in a sample of 182 criminals referred to a forensic psychiatry unit, those who had been assessed as "violent" were more likely to carry the SS genotype than those not (p=0.04). In a nutshell, SS is bad. There was a negative result in a family-wise association study in childhood ADHD, however.As if that weren't enough data, in 1099 healthy volunteers, those carrying the S allele scored lower on the "Conscientiousness" factor of the NEO personality questionnaire than LL people, although the difference was only significant in women. Low conscientiousness could be seen as impulsiveness - although note that there are 5 personality factors on the NEO and the authors presumably checked for a genetic effect on all 5, so that's at least 5 comparisons.Finally, they managed to work a bit of neuroimaging into the paper in the form of an EEG study in which SS subjects showed a greater posteriorization of the "no-go" centroid during a continuous performance task. The no-go centroid is an electrical signal which occurs in the brain during inhibition of an action; the authors claim that the fact that this signal occured further back in the brain in SS subjects points "toward impaired function of the medial prefrontal cortex in these subjects, which probably underlies an improper cognitive control of initiated responses resulting in impulsive behaviors", but to be honest, that's very optimistic. What, if anything, this finding means is unclear.Still, despite a couple of dodgy bits, the paper as a whole offers pretty good evidence that the NOS1 Ex1f variant is functional and influences personality. This is the first report linking NOS1 to behaviour in humans, although since the paper includes data from a number of different samples, it's more than just preliminary evidence. On the other hand, nothing in this field should be considered a fact until the exact effect in question has been replicated by independent researchers - at least, that's my rule of thumb.The nature of the effect (the associated phenotype) is also unclear. The authors interpret it as increased "impulsivity", but that's a vague concept. Impulsivity in all situations? Only in social situations? Only when stressed? We don't know. Also, the authors seem to have only looked for assocations with impulsive conditions. Were someone to look for an association with, say, depression, or schizophrenia, they might well find one, in which case this might be best seen as a resilience gene rather than an impulsivity one. No doubt someone will be doing such a study as we speak, so hopefully, we'll know soon.History note: Klaus-Peter Lesch first attained fame as the lead author on the first paper associating the 5HTTLPR variant with personality. In the 12 years since this polymorphism has attracted more attention than any other in the field of behavioural genetics with several hundred papers at last count. So if that's anything to go by, we'll be hearing a lot more about NOS1. Stay tuned.Andreas Reif, MD; Christian P. Jacob, MD; Dan Rujescu, MD; Sabine Herterich, PhD; Sebastian Lang, MD;, Lise Gutknecht, PhD; Christina G. Baehne, Dipl-Psych; Alexander Strobel, PhD; Christine M. Freitag, MD;, Ina Giegling, MD; Marcel Romanos, MD; Annette Hartmann, MD; Michael Rösler, MD; Tobias J. Renner, MD;, Andreas J. Fallgatter, MD; Wolfgang Retz, MD; Ann-Christine Ehlis, PhD; Klaus-Peter Lesch, MD (2009). Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans Archives of General Psychiatry, 66 (1), 41-50... Read more »
Andreas Reif, MD; Christian P. Jacob, MD; Dan Rujescu, MD; Sabine Herterich, PhD; Sebastian Lang, MD;, Lise Gutknecht, PhD; Christina G. Baehne, Dipl-Psych; Alexander Strobel, PhD; Christine M. Freitag, MD;, Ina Giegling, MD; Marcel Romanos, MD; Annette Hartmann, MD; Michael Rösler, MD; Tobias J. Renner, MD;, & Andreas J. Fallgatter, MD; Wolfgang Retz, MD; Ann-Christine Ehlis, PhD; Klaus-Peter Lesch, MD. (2009) Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans. Archives of General Psychiatry, 66(1), 41-50. DOI: http://archpsyc.ama-assn.org/cgi/content/short/66/1/41
by Neuroskeptic in Neuroskeptic
Just when you thought it was safe to compute a correlatation between a behavioural measure and a cluster mean BOLD change...The fMRI voodoo correlations controversy isn't over. Ed Vul and collegues have just responded to their critics in a new article (pdf). The critics appear to have scored at least one victory, however, since the original paper has now been renamed. So it's goodbye to "Voodoo Correlations in Social Neuroscience" - now it's "Puzzlingly high correlations in fMRI studies of emotion, personality and social cognition" by Vul et. al. 2009. Not quite as catchy, but then, that's the point...Just in case you need reminding of the story so far: A couple of months ago, MIT grad student Ed Vul and co-authors released a pre-publication manuscript, then titled Voodoo Correlations in Social Neuroscience. This paper reviewed the findings of a number of fMRI studies which reported linear correlations between regional brain activity and some kind of measure of personality. Vul et. al. argued that many (but by no means all) of these correlations were in fact erroneous, with the reported correlations being much higher than the true ones. Vul et. al. alleged that the problem arose due to a flaw in the statistical analysis used, the "non-independence error". For my non-technical explanation of the issue, see my previous post, or go read the original paper (it really doesn't require much knowledge of statistics).Vul's paper attracted a lot of praise and also a lot of criticism, both in the blogosphere and in the academic literature. Many complained that it was sensationalistic and anti-fMRI. Others embraced it for the same reasons. My view was that while the paper's style was certainly journalistic, and while many of those who praised the paper did so for the wrong reasons, the core argument was both valid and important. While not representing a radical challenge to social neuroscience or fMRI in general, Vul et. al. draws attention to a widespread and potentially serious technical issue with the analysis of fMRI data, one which all neuroscientists should be aware of.That's still my opinion. Vul et. al.'s response to their critics is a clearly worded and convincing defense. Interestingly, their defense is in many ways just a clarificiation of the argument. This is appropriate, because I think the argument is pretty much just common sense once it is correctly understood. As far as I can see the only valid defence against it is to say that a particular paper did not in fact commit the error - while not disputing that the error itself is a problem. Vul et. al. say that to their knowledge no accused papers have turned out to be innocent - although I'm sure we haven't heard the last of that.Vul et. al. also now make explicit something which wasn't very clear in their original paper, namely that the original paper made accusations of two completely seperate errors. One, the non-independence error, is common but probably less serious than the second, the "Forman error", which is pretty much fatal. Fortunately, so far, only two papers are known to have fallen prey to the Forman error - although there could be more. Go read the article for more details on what could be Vul's next bombshell...EDWARD VUL, CHRISTINE HARRIS, PIOTR WINKIELMAN, AND, & HAROLD PASHLER (2009). Reply to comments on “Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition” Perspectives in Psychological Science... Read more »
EDWARD VUL, CHRISTINE HARRIS, PIOTR WINKIELMAN, AND, & HAROLD PASHLER. (2009) Reply to comments on “Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition”. Perspectives in Psychological Science.
by Neuroskeptic in Neuroskeptic
A while back, I wrote about an important paper which cast doubt on the "neurogenesis hypothesis" of antidepressant drug action, which I summarized as...the proposal that antidepressants work by promoting the survival and proliferation of new neurones in certain areas of the brain - the "neurogenesis hypothesis". Neurogenesis, the birth of new cells from stem cells, occurs in a couple of very specific regions of the adult brain, including the elaborately named subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Many experiments on animals have shown that chronic stress, and injections of the "stress hormone" corticosterone, can suppress neurogenesis, while a wide range of antidepressants block this effect of stress and promote neurogenesis. (Other evidence shows that antidepressants probably do this by inducing the expression of neurotrophic signalling proteins, like BDNF.)It's a popular theory at the moment, not least because it's the only real alternative to the older, much-maligned and certainly incomplete monoamine hypothesis of antidepressants. But the neurogenesis hypothesis has problems of its own. A new paper claims to add to what seems like a growing list of counter-examples: Ageing abolishes the effects of fluoxetine on neurogenesis.The researchers, Couillard-Despres et. al. from the University of Regensburg in Germany, found that fluoxetine (Prozac) enhances hippocampal neurogenesis in mice - as expected - but found in addition that this only holds true in young mice. In middle-aged and older mice, there was no such effect. That's a new finding, and a very important one.More specifically, the (male) mice were given injections of Prozac for two weeks each. Compared to mice given placebo injections, the mice on Prozac showedincreased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age).For mice, 100 days old corresponds to a human age of about 20 years; 200 days is 35 and 400 days is 65 years. The graph here shows the number of BrdU-labelled cells in the dentate gyrus, a measure of neural progenitor cell survival. As you can see, although Prozac robustly increased BrdU+ cell counts in the 100 day old mice, this effect was much less prominent (although perhaps still present a bit?) in the older mice.It's already well known that hippocampal neurogenesis is age dependent. Young animals (and people) have lots of new neurones being generated, but the rate progressively and inevitably declines with age. This has always been a problem for the simple hypothesis that reduced neurogenesis causes depression, because if that were the case, we'd all be paralyzed by despair by the age of 50. Despite this, it remained plausible that antidepressants worked by increasing neurogenesis, but this new evidence suggests otherwise.Or does it? What if it turns out that fluoxetine has no antidepressant-like effects in old rodents? In that case, the neurogenesis hypothesis would be supported, not weakened, by this evidence. The author's of the paper don't even consider this possibility, which is a little odd. They do note that antidepressants are effective in older people with depression, but given that this is a paper about mice that's not the same thing. Someone needs to find out whether Prozac has anti-depressant-like effects in the same kind of old mice as those used in this study. If so, the neurogenesis hypothesis will be looking pretty fragile.This should also serve as a reminder that lab mice are animals, not research robots. They get old, like the rest of us, and research done only on young mice, or male mice, or a certain breed of mice, may not be applicable to others. I have two cats: if you stroke the grey one on the belly, she'll purr contentedly. But if you foolishly assume that the tabby one is the same, you'll get bitten pretty quickly...S Couillard-Despres, C Wuertinger, M Kandasamy, M Caioni, K Stadler, R Aigner, U Bogdahn, L Aigner (2009). Ageing abolishes the effects of fluoxetine on neurogenesis Molecular Psychiatry DOI: 10.1038/mp.2008.147... Read more »
S Couillard-Despres, C Wuertinger, M Kandasamy, M Caioni, K Stadler, R Aigner, U Bogdahn, & L Aigner. (2009) Ageing abolishes the effects of fluoxetine on neurogenesis. Molecular Psychiatry. DOI: 10.1038/mp.2008.147
by Neuroskeptic in Neuroskeptic
Saturday saw the Guardian on fine form with a classic piece of bad neuro-journalism which made it all the way onto the front page: Psychologists find gene that helps you look on the bright side of lifeThose unfortunate enough to lack the 'brightside gene' are more likely to suffer from mental health problems such as depression What the research actually found was nothing to do with looking on the bright side of anything, and was nothing to do with depression either. In fact, it suggests that the gene in question doesn't cause mental health problems. So the headlines are a little misleading, then.The study comes from Elaine Fox and colleagues from the University of Essex.* They took 111 people, presumably students, and got them to do a "dot-probe" task. Performance on this task was related to the genotype of the 5HTTLPR polymorphism, a variant in the gene which encodes for the serotonin transporter protein. Serotonin is "the brain's main feelgood chemical" as the Guardian put it... except it isn't, although it does have something to do with mood.What's a "dot probe" task? It's a test which has become popular amongst all kinds of psychologists over the past 10 years or so, having first been used in 1986 by Colin MacLeod et. al. The task involves pressing a button whenever a "probe" - a little dot - appears on a screen. The goal is to press the button as quickly as possible, as soon as the dot appears.The twist is that as well as the dots, there are other things on the screen. In the 1986 version of the test these were words, while in this experiment they were colour pictures. Some of the images were pleasant: smiling faces, flowers, and other nice things. Some were unpleasant - scary dogs, bloody injuries, etc. And some were neutral objects, like furniture.Pairs of these pictures appeared on the screen for a short time (half a second) immediately before each dot appeared, one on the left of the screen and one on the right. The key is that the dot appeared in the same place as one of the pictures.The task operates under the assumption that if the viewer's attention is grabbed by one of the pictures, they are likely to be faster to respond to seeing the dot when it appears in the same place as that picture, because they will already be focused on that area of the screen. If, for example, people are on average faster to detect the dot when it appears in the same place as the nice pictures as opposed to the horrible ones, this is described as indicating a "positive attentional bias" i.e. an unconscious tendency to pay attention to pleasant pictures.Unfortunately, now that you know what a dot probe task is, you can't take part in any psychology experiments which uses one, because once you know how it's supposed to work there's no point in doing it. Sorry. But on the bright side, you now officially know more about psychology than The Economist, whose write-up of this experiment was even worse than the Guardian's. They managed to misunderstand the point of the dot-probe task as well as sensationalizing it (it's not about "distraction", it's about selective attention-grabbing).Anyway, that's the task, and the study found that carriers of two "long" variants of the 5HTTLPR gene showed a strong attention bias towards nice pictures and away from nasty ones, while other people showed no biases. Statistically, the result was highly significant, so let's assume it's true. What does it mean? You could take it to mean that carriers of two long variants were more optimistic in that they tend to pay attention to the good stuff. On the other hand you could equally well say they're so squeamish and wussy that they can't bear to look at the bad stuff and have to avert their eyes from it.And what's this got to do with depression? Well to cut a very long story short the gene in question has been previously linked to depression and also to personality traits such as "neuroticism" - being anxious, worried and generally miserable (see this paper). But in this study they found no such association with neuroticism. Despite the fact that it was a report of this association which got everyone interested in the 5HTTLPR variant in the first place back in 1996! Brilliantly, they spin their negative finding as a good thing -The fact that our genotype groups were matched on a range of self-report measures, including neuroticism can be seen as a major strength.Hope springs eternal. Overall, while this paper is a fine contribution to the psychology literature on the dot-probe task (and the results genuinely do seem to be very significant - there's probably something going on here) it's got nothing to do with optimism and little to do with anything that the average newspaper reader cares about. Luckily, we have journalists to make science interesting on the cheap and on the quick - at the cost of accuracy. There's a lot of really interesting, really thought-provoking popular science writing to be done about the dot-probe, and about the 5HTTLRP gene. But none of it has yet made it into the British papers.[BPSDB]*Fox, my PubMed search reveals, also does work on so-called "electromagnetic sensitivity". The upshot of her work is that lots of people sincerely believe that signals from mobile phones and other sources make them feel unwell, but actually, it's all the placebo effect. Now that really is something that everyone should find fascinating - much more so than this study, anyway.Elaine Fox, Anna Ridgewell and Chris Ashwin (2009). Looking on the bright side: biased attention and the human serotonin transporter gene Proc. R. Soc. B... Read more »
Elaine Fox, Anna Ridgewell and Chris Ashwin. (2009) Looking on the bright side: biased attention and the human serotonin transporter gene. Proc. R. Soc. B.
by Neuroskeptic in Neuroskeptic
Bloggers were amused by the Daily Mail's latest crap science article - a scary cancer story about research that hadn't even been done yet. The article is about a study to be conducted by University of Leicester scientists, which will investigate whether coffee intake by pregnant women is correlated with DNA changes in babies, similar to those seen in leukemia. In other words: coffee-drinking might be associated with some molecular changes which might point to a risk of leukemia. We should ban the stuff, clearly.What did scare me though was this line:Previous research has shown that caffeine damages DNA, cutting cells’ ability to fight off cancer triggers such as radiation.Hold on, caffeine is genotoxic? That would be pretty worrying. It wouldn't mean that coffee causes cancer, but it would make it highly plausible. But does caffeine in fact damage DNA? That might sound like a simple question to answer. Sadly not. It turns out that caffeine is one of the most researched chemicals in all of genotoxicology, and after over 1000 studies there's no consensus on what, if anything, it does to DNA. The story is remarkably complex and has all the good elements of a scientific intrigue. This review by Steven D'Ambrosio , for example, convincingly argues that:A number of [genotoxic] effects have been observed [in the lab]. However, they usually appear after very high doses ( 1 mM) of caffeine in combination with genotoxins, and are usually specific to certain cell types and/or cellular parameters. Humans, on the other hand, consume much less caffeine in the diet...thus, it is difficult to implicate caffeine, even at the highest levels of dietary consumption, as a genotoxin to humans.That's a relief. But right at the end we find that "This work was supported by the National Coffee Association"! If the author was in the pocket of Big Java, how can we trust him? Was he being bribed, perhaps with sacks of top-grade Columbian beans...? There's good evidence that high concentrations of caffeine interfere with DNA repair processes, and that it can therefore enhance the DNA damage produced by other genotoxic agents such as radiation. But most of these experiments used caffeine concentrations hundreds of times higher than most coffee-drinkers are likely to experience. And there's little epidemiological evidence of any association between coffee drinking and cancer; what evidence there is seems to suggest that coffee might even protect against various cancers...Still, one comforting lesson from all this is that it's not just neuroscience in which seemingly simple questions (like is there are an area of the brain for recognizing faces?) can turn out to be much more complicated than one might hope...S Dambrosio (1994). Evaluation of the Genotoxicity Data on Caffeine Regulatory Toxicology and Pharmacology, 19 (3), 243-281 DOI: 10.1006/rtph.1994.1023... Read more »
S Dambrosio. (1994) Evaluation of the Genotoxicity Data on Caffeine. Regulatory Toxicology and Pharmacology, 19(3), 243-281. DOI: 10.1006/rtph.1994.1023
by Neuroskeptic in Neuroskeptic
See also Lessons from the Placebo Gene. Also, if you like this kind of thing, see my other fMRI-curmudgeonry(1, 2)The life of a neurocurmudgeon is a hard one, but once in a while, fate smiles upon us. This article in the Daily Telegraph neatly embodies several of the mistakes that people make about the brain, all in one bite-size portion.The article is about a recent fMRI study published in the Journal of Psychiatric Research. 22 healthy Stanford student volunteers (half of them male) played a "video game" while being scanned. The game wasn't an actual game like Left 4 Dead(*), but rather a kind of very primitive cross between Pong and Risk, designed specifically for the purposes of the experiment:Balls appeared on one-half of the screen from the side at 40 pixel/s, and 10 balls were constantly on the screen at any given time. One’s own space was defined as the space behind the wall and opposite side to where the balls appeared. The ball disappeared whenever clicked by the subject. Anytime a ball hit the wall before it could be clicked, the ball was removed and the wall moved at 20 pixel/s, making the space narrower. Anytime all the balls were at least 100 pixels apart from the wall ... the wall moved such that the space became wider.Essentially they had to click on balls to stop them moving a line. This may not sound like much fun, but the author's justification for using this task was that it allowed them to have a control condition in which the instructions and were the same (click on the balls) but there was no "success" or "failure" because the line defining the "territory" was always fixed. That's actually a pretty good idea. The students did the task 40 times during the scan for 24s at a time, alternating between the two conditions, "no success" (line fixed) and "game with success/failure" (line moves).The results: While men & women were equally good at clicking balls, men were more successful at gaining "territory" than the women. In both genders, doing the task vs. just resting in the scanner activated various visual and motor-related areas - no surprise. Playing the game vs. doing the control task in which there was no success or failure produced more activation in a handful of areas but only "at a more liberal threshold" i.e. this activation was not statistically reliable. A region-of-interest analysis found activation in the left nucleus accumbens and right orbitofrontal cortex, which are "reward-related" areas. In males, the game-specific activation was greater than in females in the right nucleus accumbens, the orbitofrontal cortex, and the right amygdala.These areas are indeed "neural circuitries involved in reward and addiction" as the authors put it, but they're also activated whenever you experience anything pleasant or enjoyable, such as drinking water when you're thirsty. Water is not known to be addictive. So whether this study is relevant to video-game "addiction" is anyone's guess. As far as I can tell, all it shows is that men are more interested in simple, repetitive, abstract video games. But that's hardly news: in 2007 there was an International Pac-Man Championship with 30,000 entrants; the top 10 competitors were all male. (If anything in that last sentence surprises you, you haven't spent enough time on the internet.)Anyway, that's the study. This is what the Telegraph made of it:Playing on computer consoles activates parts of the male brain which are linked to rewarding feelings and addiction, scans have shown. The more opponents they vanquish and points they score, the more stimulated this region becomes. In contrast, these parts of women's brains are much less likely to be triggered by sessions on the Sony PlayStation, Nintendo Wii or Xbox. Well, not quite. No opponents were vanquished and no Wii's were played. But so far this is just another fMRI study that attracted the attention of a journalist who knew how to spin a good story. Readers of Neuroskeptic will know this is not uncommon. However, it doesn't end there. Here's the really instructive bit:Professor Allan Reiss of the Centre for Interdisciplinary Brain Sciences Research at Stanford University, California, who led the research, said that women understood computer games just as well as men but did not have the same neurological drive to win."These gender differences may help explain why males are more attracted to, and more likely to become 'hooked' on video games than females," he said."I think it's fair to say that males tend to be more intrinsically territorial. It doesn't take a genius to figure out who historically are the conquerors and tyrants of our species – they're the males."Most of the computer games that are really popular with males are territory and aggression-type games."Now this is a theory - men like video games because we're intrinsically drawn to competition, conquest and territory-grabbing. This may or may not be true; personally, in the light of what I know of history and anthropology, I suspect it is, but even if you disagree, you can see that this is an important theory: it makes a big difference whether it's true or not.However, the fMRI results have nothing to do with this theory. They neither support nor refute it, and nor could they; this experiment is essentially irrelevant to the theory in question. Prof. Allan Reiss is simply stating his personal opinions about human nature - however intelligent & informed these opinions may be. (Just to be clear, it's quite possible that Reiss didn't expect to be quoted in the way he was; he may have, not unreasonably, thought that he was just giving his informal opinion.) The Telegraph's sub-headline?Men's passion for computer games stems from a deep-rooted urge to conquer, according to researchThere are some lessons here.1. If you want to know about something, study it.If you want to learn about human behaviour, study human behaviour. Stanley Milgram discovered important things about behaviour; if he had never even heard about the brain, it wouldn't have stopped him from doing that.Neuroscience can tell us about how behaviour happens. We get thirsty when we haven't drunk water for a while. Neuroscience, and only neuroscience, will tell you how. Some people get depressed or manic. One day, I hope, neuroscience will tell us the complete story of how - maybe mania will turn out to be caused by hyper-stimulation of a certain dopamine receptor - and we'll be able to stop it happening with some pill with a 100% success rate.However, neuroscience can't tell you what human behaviour is: it cannot describe behaviour, it can only explain it. People know about thirst and depression and mania long before they knew anything about the brain. More importantly, and more subtly, neuroscience can only explain behaviour in the "how" sense; only rarely can it tell you why behaviour is the way that it is.If someone is behaving in a certain way because of brain damage or disease, that's one of these rare cases. In that case "damage to area X caused by disease Y" is "why". But in most cases, it's not. To say that men like video games because their reward systems are more sensitive to video games is not a "why" explanation. It's a "how" explanation, and it leaves completely open the question of why the male brain is more sensitive to video games. The answer might be "innate biological differences due to evolution", or it might be "sexist upbringing", or "paternalistic culture", or anything else.(This is often overlooked in discussions about psychiatry. Some people object to the idea that clinical depression is a neuro-chemical state, pointing out that depression can be caused by stress, rejection and other events in life. This is confused; there is no reason why stress or rejection could not cause a state of low serotonin. By extension, saying that someone has "low serotonin" always leaves open the question of why.)2. Brains are people tooThis leads on to a more subtle point. Some people understand the difference between how and why explanations, but feel that if the "how" is something to do with the brain, the "why" must be to do with the brain too. They look at brain scans showing that people behave in a certain way because their brain is a certain way (e.g. men like games because their reward system is more activated by games), and they think that there must be a "biological" explanation for why this is.There might be, but there might not be. Brains are alive; they see and hear; they think; they talk; they feel. Your brain does everything you do, because you are "your" brain. The astonishing thing about brains is that they are both material, biological objects, and concious, living people, at the same time.Your brain is not your liver, which is only affected by chemical and biological influences, like hormones, toxins, and bacteria. Your liver doesn't care whether you're a Christian or a Muslim, it cares about whether you drink alcohol. Your brain does care about your religion because some pattern of connections in your brain gives you the religion that you have.Brain scans, by confronting us with the biological, material nature of the brain, make us look for biological, material why explanations. We forget that the brain might be the way it is because of cultural or historical or psychological or sociological or economic factors, because we forget that brains are people. We tend to think of people as being something beyond and above their brains. Ironically, it's this primitive dualism that leads to the most crude materialistic explanations for human behaviour.3. Beware neuro-fetishistsThere's a doctoral thesis in "Science Studies" to be written about how it came to happen, but that we fetishize the brain is obvious. For much of the 20th century, psychology was seen in the same way. Freud joined Nietschze, Marx and Heidegger in the ranks of Germanic names that literary theorists and lefty intellectuals loved to drop.Then the bottom fell out of psychoanalysis, Prozac and fMRI arrived and the Decade of the Brain was upon us. Today, neuroscience is the new psychology - or perhaps psychology is becoming a branch of neuroscience. (If I asked you to depict psychology visually, you'd probably draw a brain - if you do a Google image search for "psychology", 10 out of the 21 front page hits depict either a brain or a head; this might not surprise you but it would have seemed odd 50 years ago.) There's a presumption that neuroscience is key to answering both how and why questions about the mind.Neuroscience is now hot, but what people are mostly interested in are psychological and philosophical questions. People care about The Big Questions like -"Is there life after death? Do we have free will? Is human nature fixed? Are men smarter/more aggressive/more promiscuous/better drivers than women? Why do people become criminals/geniuses/mad?"These are good questions - but neuroscience has little to say about them, because they're not questions about the brain. They're questions for philosophers, or geneticists, or psychologists. No brain scan is going to tell you whether men are better drivers than women. It might tell you something about the processes by which make decisions while driving, but only a neuroscientist is likely to find that interesting.P.S It turns out that people were saying similar things about this research back in Feburary. A blogger who writes about research on video games (neat) wrote about it way back then. So why did the Telegraph decide to resurrect the story as if it were new? That's just another one of life's mysteries.[BPSDB](*) Which is so awesome.F HOEFT, C WATSON, S KESLER, K BETTINGER, A REISS (2008). Gender differences in the mesocorticolimbic system during computer game-play Journal of Psychiatric Research, 42 (4), 253-258 DOI: 10.1016/j.jpsychires.2007.11.010... Read more »
F HOEFT, C WATSON, S KESLER, K BETTINGER, & A REISS. (2008) Gender differences in the mesocorticolimbic system during computer game-play. Journal of Psychiatric Research, 42(4), 253-258. DOI: 10.1016/j.jpsychires.2007.11.010
by Neuroskeptic in Neuroskeptic
Brain damage - it's not much fun when it's your brain, but for science, it's often good news. While neuroimaging can find the neural correlates of mental processes - areas of the brain which become active during the experience of an emotion, say - lesion studies are often necessary to establish the direction of causality. Just because somewhere in the brain is activated during the experience of fear, for example, doesn't mean that this area is responsible for our feelings of fright; it might just happen to be lighting up as a side effect. Neuroimaging can't tell the difference, but if someone suffers damage to some part of the brain and then becomes fearless, it becomes possible to establish which parts do what. Localizing a function to a certain region of the brain is not the same as understanding it, of course, but it's a start.The main problem with lesion studies is that there aren't enough of them. Because of those pesky ethical considerations, you can't just go around poking holes in people's brains - you have to wait until damage occurs naturally. In many interesting parts of the brain, localized damage is frustratingly uncommon.Yet good things come to those who wait. The Journal of Neuroscience have just published a landmark lesion study by Koenigs et. al.(*) who studied two separate, large groups of people who had suffered brain damage to a range of areas - Vietnam veterans with combat head injuries, and Iowa citizens who had suffered tumors, strokes, and other medical conditions. In both samples they measured symptoms of depression and attempted to correlate them with the location of the lesions.They succeeded. In both samples, patients who had suffered damage to the ventro-medial prefrontal cortex (vmPFC), which sits a few inches behind the center of the forehead, seemed to be protected against depression. Compared to people who had suffered lesions to all of the other parts of the brain, people with vmPFC damage on both sides of the brain were rated as having fewer depressive symptoms, both according to their own report and the observations of the experimenters. In particular, they reported being almost completely free of emotional or subjective symptoms such as feelings of guilt, sadness, or self-dislike. For illustration, they describe the incredible (and ironic) case of a woman with a self-inflicted vmPFC lesion:We identified one patient in the Iowa registry who represents an intriguing case of an apparent alleviation of severe depression after a bilateral vmPFC lesion. ... per secondary report the patient was being treated for depression when she attempted suicide 11 years ago by means of a gunshot to the head. The gunshot destroyed most of ventral PFC, including vmPFC bilaterally, but left intact most of dorsal PFC. The patient’s neuropsychologist, neurosurgeon, and long-term boyfriend all remarked that her depression was markedly diminished after the brain injury (boyfriend, speaking 16 months after the injury: “no sign of depression whatsoever since the accident”; neuropsychologist: “she never shows distress, worry, or anger”).Overall, these results are exciting, but unsurprising - the vmPFC is commonly thought of as being involved in emotion and emotional decision making; Antonio Damasio famously inferred this from the case of Phineas Gage, who after losing his medial prefrontal cortex to an iron rod, became impulsive, reckless, and unconcerned for himself or others. It's not difficult to see that someone with such characteristics might be resistant to such emotional difficulties as depression, or, say, post-traumatic stress - and indeed Koenigs et. al. previously reported that such lesions also protect against PTSD in combat veterans.Fascinatingly, old-fashioned psychosurgery frequently ended up destroying much the same areas of the brain; the desired result, sometimes achieved, was a patient who no longer cared or worried about anything - which was thought preferable to someone paralyzed by despair or anxiety. The point is that the vmPFC is not specifically a "depression area of the brain" - although these results suggest that it is necessary for the experience of depression, it is probably also responsible for a broad range of other emotions, and patients lacking a vmPFC clearly lack more than just sadness. (If there is a "depression area", which is possible, my money's on the subgenual cingulate cortex.)The paper also reported that damage to another part of the brain, the dorsal prefrontal cortex (bilateral), seemed to cause depression - however, there were only 5 patients with this kind of damage, of whom 2 were clinically depressed, so it's harder to interpret this result:The proportion of individuals meeting DSM-IV criteria for "current" MDD was significantly greater for the dorsal PFC lesion group (2 of 5) than for the non-PFC lesion group (1 of 101; p = 0.005) or non-brain-damaged group (0 of 54; p = 0.006). Thus, bilateral dorsal PFC lesions were associated with a relatively high prevalence of subsequent major depression.A few things to note: Case histories are anecdotes, not data - and the brain of the woman described above is extensively abnormal; CT scans, not for the squeamish. The total number of vmPFC patients here was just twenty. This is the largest group of these patients studied so far, because this kind of injury is very rare, but this is still a smallish sample. Most importantly, levels of depression in the control groups in this study were fairly low. The vmPFC group showed essentially zero depressive symptoms, but even the control patients only showed mild symptoms on average, and only a couple of them were diagnosed with actual clinical depression. So the between-group differences were, while statistically significant, modest.(*) Annoyingly, pretty much every paper from Mike Koenigs is a landmark lesion study. It's always the same lesion patients. Not that this is a major problem, I'm just annoyed that he gets to study them and not me.M. Koenigs, E. D. Huey, M. Calamia, V. Raymont, D. Tranel, J. Grafman (2008). Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression Journal of Neuroscience, 28 (47), 12341-12348 DOI: 10.1523/JNEUROSCI.2324-08.2008... Read more »
M. Koenigs, E. D. Huey, M. Calamia, V. Raymont, D. Tranel, & J. Grafman. (2008) Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression. Journal of Neuroscience, 28(47), 12341-12348. DOI: 10.1523/JNEUROSCI.2324-08.2008
by Neuroskeptic in Neuroskeptic
A cautionary tale from Turkey - do not eat poison honey to try to spice up your sex life. "Mad honey" is honey made by bees from the nectar of toxic Rhododendron flowers. In places where wild Rhododendrons grow, including Turkey, it's a health hazard. The dangers of mad honey were known to the ancient Greeks and Romans, and it's reported that leaving tainted honeycombs in the path of invading armies was a popular military tactic.2000 years later, some people still haven't quite got the message. According to a case report from cardiologists Yarlioglues et al, a married couple deliberately ate some mad honey "for reasons of sexual performance".After eating one teaspoon per day for a week, they decided to crank it up a notch and ate a full tablespoon of the stuff. But their attempt to heighten their Turkish delight quickly turned sour, as they both suffered symptoms of confusion, chest pain, low blood pressure and slowed heartbeat. After presenting themselves to hospital, doctors discovered that they had both suffered an acute inferior myocardial infarction - a mild heart attack.It's not clear whether the sex was a contributing factor.The randy Rhododendron fans were lucky - following treatment, they both recovered. In fact, the authors say "To our knowledge, no fatal cases of mad-honey poisoning have been reported since ancient Roman times." However, it seems that some people are still willing to try their luck.The toxin in mad honey is gryanotoxin. It acts by potentiating the opening of sodium channels, which are found both in the heart and the brain. This may be why it produces a combination of cardiovascular and psychoactive effects.Mikail Yarlioglues et al (2011). Mad-Honey Sexual Activity and Acute Inferior Myocardial Infarctions in a Married Couple Texas Heart Institute Journal... Read more »
Mikail Yarlioglues et al. (2011) Mad-Honey Sexual Activity and Acute Inferior Myocardial Infarctions in a Married Couple. Texas Heart Institute Journal. info:/
by Neuroskeptic in Neuroskeptic
A foundation is offering to fund research into novel psychiatric medications, we read in the latest Nature Neuroscience:The Broad Institute in Cambridge, Massachusetts has launched an initiative called ‘PsychHTS’ inviting scientists with ideas and data suggesting novel mechanisms contributing to psychiatric disease to apply for access to the Broad’s infrastructure and expertise for high throughput screening (HTS) of chemical compound libraries.HTS is a clever technique for discovering new drugs, based on the crude but effective principle of trying hundreds of thousands of different chemicals until you find one which works, by using machines to automatically run the experiments (“assays”) extremely quickly. Hence, “high throughput”. It’s pretty cool.The Stanley Medical Research Institute wants to use HTS to find new psychiatric drugs. There have been no truly new drugs in psychiatry for a long time: there are dozens of different antidepressants, for example, but they all work (if and when they work) by increasing brain monoamine levels, just like the very first antidepressants, iproniazid and imipramine, discovered in the early 1950s. The same is true of antipsychotics, which all block dopamine D2 receptors, just like the very first, chlorpromazine.So new drugs for the mind would be great. But how are you going to find them by doing experiments in test-tubes, even if you have 50,000 test-tubes? The mind doesn’t fit in a test-tube. Here’s where the proposal gets a bit iffy:Readouts may be anything from classical enzymatic reactions ... up to subcellular changes captured by automated high-content imaging. ... ‘Hits’—compounds that affect the assay results in a way that indicates potential usefulness in a psychiatric research context—are automatically retested at several concentrations...So, the idea is that potential new drugs will be found by measuring how they affect certain cellular processes or chemical pathways. But which ones? Until we know what cellular or protein or enzymatic changes underlie mental illness, we won’t know what to look for. And the whole problem is that we don’t know much about that – if we did we’d have lots of new drugs already.The article suggests only one route to finding truly novel mechanisms – genetics. In the past few years, there have been many genetic studies trying to find genes which cause mental illnesses. Some of them have identified risk genes which seem to imply new biological pathways. For example, the current orthodoxy is that schizophrenia is caused by abnormalities in the brain’s dopamine system. But the gene most strongly implicated in schizophrenia is called “neuregulin-1”, and it has nothing to do with dopamine. That’s interesting but unfortunately -Recent genetic studies have indeed suggested new targets, but the identification of specific genetic risk factors remains elusive. The genetic results are themselves variable, often have small effect sizes and need independent replication.In other words, the genetics evidence is so patchy, that using it as a basis for finding new drugs is like building a house on very shaky foundations. It might stand. But if the genetic links turn out to be spurious, all the subsequent research will have been in vain.Personally, while I welcome any truly groundbreaking work in psychiatry, I would rather people spend time and money doing better research on the drugs we already have.Nature Neuroscience Editorial (2009). Mining chemistry for psychiatry Nature Neuroscience, 12 (7), 809-809 DOI: 10.1038/nn0709-809... Read more »
Editorial. (2009) Mining chemistry for psychiatry. Nature Neuroscience, 12(7), 809-809. DOI: 10.1038/nn0709-809
by Neuroskeptic in Neuroskeptic
The latest issue of Neuropsychopharmacology is chock full of goodies - not only one of the first ever controlled trials of medical marijuana, but also a surprise gem from an American-Israeli collaboration, called A Data Mining Approach to In Vivo Classification of Psychopharmacological Drugs. Yet despite being an excellent paper, it raises some worrying questions about what is and isn't science.In a nutshell, the authors sought to discover a way of efficiently determining what a drug does. There are several broad classes of psychoactive drugs, such as stimulants, e.g. cocaine, and opioids, e.g. morphine. If you want to find out whether an unknown drug has opioid-like painkilling effects, for example, you have to test for them specifically - e.g. by measuring how the drug alters a mouse's pain threshold in a test called the Hot Plate test (guess what that involves.) If you want to test whether the same compound has antidepressant effects, you would have to do a different test entirely, like the Porsolt test. And so on.The authors tried - and claim to have succeeded - to find a way of detecting the effects of drugs in a single, simple test. The test involved putting a mouse onto an empty circular platform (an "open field") and just allowing it to run around for an hour. A camera records the movements of the mouse, and a computer analyzes the video to give the mouse's position every 1/30th of a second. The result is a series of numbers showing the path which the mouse took around the area.The clever bit follows: from this path data, one can derive various other numbers - for example, the mouse's velocity, acceleration, and direction of movement relative to the wall of the platform, at any given point in time. An hour of a mouse's life can be broken down into a veritable mountain of data (especially since there are 30 x 60 seconds x 60 minutes = 108,000 time points.)The authors then used a technique called data mining to discover patterns in this data which could be useful in discovering drugs. Data mining is nothing complicated - it essentially means taking a lot of data and searching it all for anything interesting. In this case, they injected mice with various doses of various different drugs from three different classes - stimulants, opioids, and "psychotomimetics" such as phencyclidine (angel dust) and ketamine. They recorded their movement over the course of an hour and analyzed it to get 10 numbers ("attributes") at each of the 108,000 time points. They then considered the combination of up to 4 different attributes simultaneously in a procedure they call (and have no doubt patented as) "Pattern Array Analysis".The single-attribute pattern coded P{*,*,3,*,*,*,*,*,*,*} is defined only by the third bin (40-60 cm/s) of the third attribute (speed), ie the animal is moving moderately fast... as more attributes are added to the definition of a pattern it becomes more and more specific, eg the four-attribute pattern P{*,*,1,2,*,1,5,*,*,*} means moving very slowly while slightly decelerating in the direction of the arena wall but turning sharply away from it.They then took every one of this huge number of possible "behaviour patterns" (there were 73,042), measured how many times each mouse did each one over the course of the hour, and worked out which patterns became more or less common after giving each of the different drugs. They ended up with this:This is a plot with 73,042 dots on it. Each dot represents a pattern of mouse movement behaviour. Dots further to the right represent behaviours which are more common, while dots higher up represent behaviours the frequency of which is most significantly different between mice given opioids and mice given other drugs (or no drugs). Most of the dots are low down the plot, showing that the opioids had little effect on them. But the dot with an arrow pointing at it represents a behaviour which is both common, and much, much less common in mice injected with opioids; in fact the significance p value of the difference is below 0.00000000000001 (that's 15 zeroes).What is this behaviour? It's P{*,*,*,*,4,*,*,*,*,*} (‘moderately positive jerk’), meaning that the mouse's acceleration was increasing at a certain point in time (for those who know calculus: the second derivative of speed was positive & quite high). So, give a mouse morphine, and you can be pretty sure that its acceleration won't be increasing very often. Hmm. A similar procedure was performed for the other two classes of drugs. Now, what on earth does that mean? Why do opioids suppress the ‘moderately positive jerk’? No-one knows - and the odd thing is that we don't need to know. Once we've identified the pattern of behaviour to look for, we could use it to determine whether drugs have opioid-like activity, even if you haven't got any idea why it works. And it does work - the authors report that by looking for the right behaviours, they could successfully classify a range of other drugs, including a couple of mystery drugs for which the person running the experiment didn't know what they were. This plot shows the success rate; the three classes of drugs are in different colours, and they clearly occupy three distinct regions of the "space", the two dimensions of which are frequency of two different patterns of behaviour. Overall, this is a very impressive paper, and the practical implications are potentially very great - soon, it might be possible to tell what effects a newly designed drug has, all in a single mouse test. This could greatly speed up, and reduce the cost, of drug discovery. For drug companies, it could be very useful indeed.But is it "science"? This paper doesn't really add to our understanding of the world - all it does is tell us that a seriously obscure aspect of mouse movement, 'moderately positive jerk’, is altered by opioids. This is a potentially useful fact, especially if you're a drug company, but it's a completely uninterpretable one - it doesn't help us to explain, or understand, anything about mice, or opioids, or anything. It's not a theory or a hypothesis, and it will probably never give rise to one. It's just an isolated, brute fact. This is the kind of "science" that the most hard-core logical positivist would be happy with.And this kind of thing is becoming popular in neuroscience. Essentially similar techniques are becoming widely used in fMRI data analysis. Here's a diagram from another paper from 2007 reporting on a method of using genetic algorithms to data-mine MEG data (a way of recording changes in the magnetic field surrounding the brain) to discover patterns which could be used to diagnose various neurological and psychiatric illnesses. It works:It's an elegant technique and it's a nice result. But again, no-one has any idea what this diagram really "means" and almost certainly no-one never will. The fact that the schizophrenia patients and the Alzheimer's disease patients occupy different areas of this imaginary 2D "space" defined by two complex variables somehow derived from a huge mountain of numbers is potentially useful, if you want to diagnose a disease, but it tells you absolutely nothing about that disease. It's like going to a witch-doctor and asking if someone is ill; she's always right, but if you ask her how she knows, she just says "By magic".Data mining's cool, but when it's done like this, it's not science...Neri Kafkafi, Daniel Yekutieli, Greg I Elmer (2008). A Data Mining Approach to In Vivo Classification of Psychopharmacological Drugs Neuropsychopharmacology, 34 (3), 607-623 DOI: 10.1038/npp.2008.103Apostolos P Georgopoulos, Elissaios Karageorgiou, Arthur C Leuthold, Scott M Lewis, Joshua K Lynch, Aurelio A Alonso, Zaheer Aslam, Adam F Carpenter, Angeliki Georgopoulos, Laura S Hemmy, Ioannis G Koutlas, Frederick J P Langheim, J Riley McCarten, Susan E McPherson, José V Pardo, Patricia J Pardo, Gareth J Parry, Susan J Rottunda, Barbara M Segal, Scott R Sponheim, John J Stanwyck, Massoud Stephane, Joseph J Westermeyer (2007). Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders Journal of Neural Engineering, 4 (4), 349-355 DOI: 10.1088/1741-2560/4/4/001... Read more »
Neri Kafkafi, Daniel Yekutieli, & Greg I Elmer. (2008) A Data Mining Approach to In Vivo Classification of Psychopharmacological Drugs. Neuropsychopharmacology, 34(3), 607-623. DOI: 10.1038/npp.2008.103
Apostolos P Georgopoulos, Elissaios Karageorgiou, Arthur C Leuthold, Scott M Lewis, Joshua K Lynch, Aurelio A Alonso, Zaheer Aslam, Adam F Carpenter, Angeliki Georgopoulos, Laura S Hemmy.... (2007) Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders. Journal of Neural Engineering, 4(4), 349-355. DOI: 10.1088/1741-2560/4/4/001
by Neuroskeptic in Neuroskeptic
Or so says Oliver James(*) on this BBC radio show in which he also says things like "I absolutely embraces the credit crunch with both arms".Oliver James is a British psychologist best known for his theory of "Affluenza". This is his term for unhappiness and mental illness caused, he thinks, by an obsession with money, status and possessions. Affluenza, James thinks, is especially prevanlent in English-speaking countries, because we're more into free-market capitalism than the people of mainland Europe. In fact, he regularly makes the claim that we in Britain, the U.S., Australia etc. are today twice as likely to be mentally ill as "the Europeans", rates of mental illness having surged due to Reagan/Thatcher free market policies.Were this true, it would be incredibly important. Certainly important enough to justify writing three books about it and seemingly endless articles for the Guardian. But is it true? Well, this is Neuroskeptic, so you can probably guess. Also, bear in mind that James is someone who is on record as thinking that[The Tears for Fears song] Mad World. With the chilling line "The dreams in which I'm dying are the best I've ever had", in some respects it is up there with TS Eliot's Prufrock as a poetic account of bourgeois despair.Obviously poetic taste is entirely subjective etc., but honestly.Anyway, where did James get the twice-as-bad-as-Europe (or, in some articles, three times as bad) idea from? He says the World Health Organization. Presumably he is referring to one of the World Health Organization's World Mental Health Surveys, such as the analysus presented in this JAMA paper.At first glance, you can see what he means. This paper reports that the % of people reporting suffering from at least one mental illness over the last year was far higher in the US (26.4%) than in say Italy (8.2%), or Nigeria (4.7%). But on closer inspection, even this data includes some incongruous numbers. Why is Beijing (9.1%) twice as bad as Shanghai (4.3%)? Worse, why does France have a rate of 18.4% while across the border in Germany it's just 9.1%? Are the French twice as materialistic as the Germans? The answer, of course, is that these numbers are more complicated than they appear. In fact, if you believe those figures at face value, you are...well, you're probably Oliver James.These numbers come from structured interviews, conducted by trained lay researchers, of a random sample of the population. In other words, some guy asked some random people a series of fairly personal questions, reading them off a list, and if they said "Yes" to questions like "Have you ever in your life had a period lasting several days or longer when most of the day you felt sad, empty or depressed?" they might get a tick for "depression". We know this because the interviews used the WHO-CIDI screening questionaire, the first part of which is here.As part of my own research, I have been that guy asking the questions (in a slightly different context). At some point I'll write about this in more detail, but suffice to say that it's hard to trying to retrospectively diagnose mental illness in someone you've never met before. The potential for denial, mis-remembering, malingering, forgetting or just plain failure to understand the questions is enormous, although it doesn't come across in the final data, which looks lovely and neat.The authors of the JAMA paper are well aware of this which is why they're skeptical of the apparantly large cross-national differences. In fact, most of their comment section consists of caveats to that effect. Just a few (edited, emphasis mine - see the full paper for more, it's free):An important limitation of theWMH surveys is their wide variation in response rate. In addition, some of the surveys had response rates below normally accepted standards [i.e. many people refused to participate]... performance of the WMH-CIDI could be worse in other parts of the world either because the concepts and phrases used to describe mental syndromes are less consonant with cultural concepts than in developed Western countries [almost certainly they are] or because absence of a tradition of free speech and anonymous public opinion surveying causes greater reluctance to admit emotional or substance-abuse problems than in developed Western countries. [again, almost certainly, and Europeans are generally more reserved than Americans in this regard.] ... some patterns in the data (eg, the much lower estimated rate of alcoholism in Ukraine than expected from administrative data documenting an important role of alcoholism in mortality in that country) raise concerns about differential validity.There's another, more fundamental problem with this data. On any meaningful criterion of "mental illness", a society in which 25% people were mentally ill in any given year would probably collapse. The WHO survey, however, is based on the DSM-IV criteria of mental illness. These are are increasingly regarded as very broad; for example, DSM-IV does not distinguish between feeling miserable & down for two weeks because your boyfriend leaves you, and spending a month in bed hardly eating for no apparant reason. Both are classed as "depression", and hence a "mental illness", although 50 years ago, only the second would have been considered a disease. For someone who styles himself a rebel in the mould of R. D. Laing, it's baffling that James accepts the American Psychiatric Association's dubious criteria.What other data could we look at? Ideally, we want a measure of mental illness which is meaningful, objective and unambigious. Well, there aren't any, but suicide rates might be the next best thing - they're nice hard numbers which are difficult to fudge (although in cultures in which suicide is strongly taboo, suicides may be reported as deaths from other causes.) Although not everyone who commits suicide is mentally ill, it is fair to say that if Britain really were twice as unhappy as the rest of Europe, we would have a relatively high suicide rate.What's the data? Well, according to Chishti et. al. (2003) Suicide Mortality in the European Union, we don't.In fact suicide rates in the UK are boringly middle of the road. They're higher than in places like Greece and Spain, but well below rates in France, Sweden and Germany. Suicide rates are not a direct measure of rates of mental illness, because not everyone who commits suicide is mentally ill, and the rate of succesful suicide depends upon access to lethal means. But does this data look compatible with James's claim that rates of "mental illness" are twice as high in Britain as on "the Continent"? - or indeed with James's implicit assumption that "the Continent" is monolithic?What's odd is that James clearly knows a bit about suicide, or at least he does now, because just today he wrote a remarkably sensible article about suicide statistics for the Guardian. So he really ought to know better.Drug sales are another nice, hard number. Of course, medication rates do not equal illness rates - in any field of medicine, but especially psychiatry. Doctors in some countries may be more willing to use drugs, or patients may be more willing to take them. With that in mind, the fact that population-adjusted (source, also here) British sales of antidepressants drugs are twice those of Ireland and Italy, equal to those of Spain, and half those of France, Norway and Sweden does not necessarily mean very much. But it hardly supports James's theory either.Interestingly, although James holds up Denmark as an example of the kind of happy, "unselfish capitalism" that we should aspire to, the Danes take 50% more antidepressants than we do! (They also have a much higher suicide rate.) True, sales of anxiety drugs and sleeping pills are relatively high in the UK, but still less than Denmark's. Most interestingly, sales of antipsychotics are very low in the UK - roughly the same as in Germany and Italy but less than a quarter of the sales in Ireland and Finland!So cheer up, Anglos. We're not twice as sad as the French. More likely, we are just more open about talking our problems in the interests of scientific research. However, the French, to their credit, didn't give the world Oliver James.(*) This is Oliver James, psychologist. Not to be confused with: Oliver James, heartthrob actor; Oliver James, Fleet Foxes song, and Oliver James, Ltd.The WHO World Mental Health Survey Consortium (2004). Prevalence, Severity, and Unmet Need for Treatment of Mental Disorders in the World Health Organization World Mental Health Surveys JAMA: The Journal of the American Medical Association, 291 (21), 2581-2590 DOI: 10.1001/jama.291.21.2581... Read more »
The WHO World Mental Health Survey Consortium. (2004) Prevalence, Severity, and Unmet Need for Treatment of Mental Disorders in the World Health Organization World Mental Health Surveys. JAMA: The Journal of the American Medical Association, 291(21), 2581-2590. DOI: 10.1001/jama.291.21.2581
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