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Comments on neurobiology, neuroimaging, and psychiatry from a skeptical neuroscientist.

Neuroskeptic
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May 10, 2011
09:35 AM
883 views

There's no DNA in "Disease"

by Neuroskeptic in Neuroskeptic

Back when I was a mere first year biology student, the first thing we were taught was this:DNA makes RNA makes Protein.This is the Central Dogma of Molecular Biology, and it describes the intricate and beautiful process by which genes influence living things. The whole thing really is remarkable.Unfortunately, some people in psychiatry seem to have forgotten this. Reading some of the literature, you would think that:DNA makes DSM DiagnosesOr if you're feeling especially adventurous and concious of the fact that diagnoses are not necessarily real entitiesDNA makes Symptoms (which add up to make DSM Diagnoses)In fact, DNA has nothing to do with symptoms either, not directly. DNA makes proteins. Proteins interact with each other, and with all kinds of hormones and other signalling molecules, to control the growth and function of cells. Cells don't get symptoms. People get symptoms - and people are very complex systems made of billions of cells.So it would be extremely weird if a particular genetic variant only ever caused one specific disease. That would mean that, whenever you have that variant, and regardless of any other variants or environmental factors, it will always mess up cell function such that it causes the same ultimate symptoms.That does happen. There are lots of single-gene disorders - or to put it another way, single-disorder genes. But they may well be the exception. Rather, as Matthew State says in a short paper just out in Biological Psychiatry, the latest research suggests that genes that are linked to one psychiatric disorder are usually linked to lots of them, sometimes ones with quite different symptoms.I previously wrote about the case of "The ADHD Gene" that's actually a gene for lots of stuff including, sometimes, ADHD. State focusses on the example of the gene CNTNAP2, variants in which have been linked to (deep breath): epilepsy, mental retardation, autism, social anxiety, schizophrenia and Tourette's. Sometimes the same variant causes multiple different disorders in different people. Sometimes one variant causes one thing and protects against another, related, thing. Hmm.As State says, one possibility is that any given mutation always causes the same symptoms, it's just that our diagnostic categories are imperfect so the same symptoms get labelled as many different things. That's certainly true but as he points out, there's a more radical possibility: the same variant might cause genuinely different symptoms.mutations at single gene or locus may carry significant risks for truly divergent neurodevelopmental outcomes, neither demonstrating specificity for a clinically observable phenomenon nor conferring any reliable overlap among disparate behavioral phenotypes.How? Well, suppose there was a variant, "pinker", that codes for a fluorescent protein that makes half of your brain cells glow bright pink. By itself, that wouldn't cause symptoms. No-one would even know.Yet imagine another variant, "pinkophobe", that made cells refuse to communicate with pink cell. That wouldn't cause any symptoms either, by itself. But in conjunction with "pinker", where it would cause serious problems: half of your cells would be effectively out of action.But suppose you carried "pinker" and yet another variant, "welovepink", that made your cells respond much more strongly to pink cells. Then, you would have the opposite problem. Half of your cells would be super-responsivie to the other half, and that would probably cause epilepsy, amongst other things. You'd get symptoms, but they would be completely different symptoms from people who had "pinker" and "pinkophobe".So what symptoms does "pinker" cause? It doesn't cause symptoms. It's just a gene. The symptoms come much later. "pinker" would be associated with all kinds of stuff, even though it has a very specific role. It just codes for one protein. Genes are pretty simple folk. The complexity comes later.This is a silly example, but maybe not so far fetched after all. Neurons don't glow pink, but they do release neurotransmitters, and they don't have color preferences, but they do have receptors that respond to transmitters.State MW (2011). The Erosion of Phenotypic Specificity in Psychiatric Genetics: Emerging Lessons from CNTNAP2. Biological psychiatry, 69 (9), 816-7 PMID: 21497679... Read more »

State MW. (2011) The Erosion of Phenotypic Specificity in Psychiatric Genetics: Emerging Lessons from CNTNAP2. Biological psychiatry, 69(9), 816-7. PMID: 21497679

May 5, 2011
04:09 AM
870 views

Revenge Of The Depression Gene

by Neuroskeptic in Neuroskeptic

Last year, the world of psychiatric genetics was rocked by the news that a highly-studied gene, believed to be associated with depression, wasn't in fact linked to depression at all.The genetic variant was 5-HTTLPR. It's a length variant in the gene coding for the serotonin transporter protein (5HTT) which the target of antidepressants like Prozac. There are two flavors of this variant, short and long.Many studies have shown that the short ("s") variant is associated with a high risk of getting depression in response to stress - but then last year a large meta-analysis of all the evidence concluded that there was in reality no link. Bummer.Now another team of researchers have done a new analysis of the 5-HTTLPR & stress & depression data and they claim that there is a link after all: hooray! So who's right? I'm not sure, but the new paper raises many questions.The new paper puts together the results of all 54 studies which have looked at this gene in the context of depression, caused by any kind of stress. The authors were intentionally liberal in their inclusion criteria: studies in any population were OK, for example they included people with Parkinson's disease or heart disease.They say that this is the main difference between the present work and earlier meta-analyses that found no link. The famous 2010 paper, for example, only included 14 studies because they only considered certain kinds of stress.Anyway, the short variant is associated with depression after all, across all of the studies. They extracted the p values from the results of all previous studies, and took the average of those, weighted by the sample size. They found a very significant association: P=.00002.Here's all the results. Each square is a study, the further to the left, the more strongly they found an association. Bigger squares mean larger studies. As you can see, most studies found a link but the three largest studies - which were much larger than the others - found none. Hmm.In terms of specific kinds of stress, they found strong evidence that "specific stressors" (like medical illness), and childhood trauma, were associated with more depression in s-allele carriers. However, in the studies on "Stressful Life Events", which is a broad category meaning pretty much anything bad that happens, the evidence was weaker. The previous meta-analyses only considered these studies.Ultimately, I think this analysis should remind us that the issue of 5HTTLPR is still "open", but I have concerns about the dataset. The fact that larger studies seem less likely to be positive is a classic warning sign of publication bias.The authors do consider this and say that they calculate that there would have to be over 700 unpublished, negative studies out there, in order to make the overall data negative. They also find that you could ignore the smallest 45 studies and still find a result. But still. Something doesn't feel right. Maybe I just have the wrong 5HTTLPR variant.Karg K, Burmeister M, Shedden K, & Sen S (2011). The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation. Archives of general psychiatry, 68 (5), 444-54 PMID: 21199959... Read more »

Karg K, Burmeister M, Shedden K, & Sen S. (2011) The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation. Archives of general psychiatry, 68(5), 444-54. PMID: 21199959

May 3, 2011
04:27 PM
908 views

Psychiatry and Phrenology

by Neuroskeptic in Neuroskeptic

The notorious John P. "Most Published Research Findings Are False" Ioannidis has turned his baleful statistical gaze upon the literature on brain volume abnormalities in psychiatric disorders.Reports of regional volume differences in the brains of people with mental illness compared to healthy people have appeared in increasing numbers in recent years. Such studies have given plenty of positive results. People with depression have smaller hippocampi. The amygdala is bigger in people with autism. And so on.Ioannidis took a comprehensive look at this literature and he argues that it suffers from a fairly serious case of "excess significance bias" - essentially, that scientists are somehow biased towards reporting differences between patients and controls, and are not telling people about the times when there wasn't a difference. This could be because of publication bias, p-value fishing or other scientific sins.Scientists tend to call a difference between two groups significant if it has a p value of less than 0.05. This means that if there were no real difference, just some random noise, this result would be less than 5% likely to occur.However, there's many ways you could end up with a low (i.e. good) p value. You would get a significant result, even if the true difference was very small, if you do a big enough study. Even a small difference will be detected if you study enough people. On the other hand, when the true difference is huge, you might only need a small study to get the same p value.A power calculation is a way of specifying how likly a given study would be to detect a difference of a given size, based on the size of the study. These are usually used ahead of time to work out how big your upcoming study needs to be, assuming you know roughly how big the real effect you're interested in is going to be.Ioannidis turned this on its head and asked: assuming that the true difference in the brain volume is what the average of all the published studies says it is, how many of the published studies were big enough that they ought to have succesfully detected it?He found 41 seperate meta-analyses for different brain regions in various disorders. These were published in 8 papers - because each paper reported on multiple regions. He only looked at meta-analyses published in the past 4 years, but these analyses will themselves have included older work. This means that this paper is a kind of meta-meta-analysis. He didn't directly consider the raw brain scans at all.The meta-analyses found many significant volume differences - but in 29 of those 41, there was an excess of significant papers. Although, strangely, in 10/41 there were too few, and only in 2 were there the "right" number.For what it's worth, studies on schizophrenia and on relatives-of-people-with-schizophrenia showed the least evidence of this problem, while autism was terrible, with 4 times as many significant papers as expected by chance. I'm not sure this is worth much, though. We don't know if this tells us more about schizophrenia vs autism, or more about the researchers that study them.Anyway, this is an important study, and the inverse power calculation approach is certainly a useful one. It's not new, but it's not used as widely as it ought to be. It does make the assumption that the meta-analyses are "right" about the effect size, and then paradoxically concludes that they are biased. However, this means that the true bias is probably even bigger than this suggests.Unfortunately, this doesn't tell us which of the studies are wrong, so it's not directly useful for people researching mental illness. It tells us that there is something wrong with scientific publishing, however. Truth be told, I suspect that a similar picture would emerge if you did this kind of thing in many other fields of science. The only real solution, in my book, would be to require the pre-registration of scientific studies. Ioannidis actually advocates this at the end of the paper.Ioannidis JP (2011). Excess Significance Bias in the Literature on Brain Volume Abnormalities. Archives of general psychiatry PMID: 21464342... Read more »

Ioannidis JP. (2011) Excess Significance Bias in the Literature on Brain Volume Abnormalities. Archives of general psychiatry. PMID: 21464342

April 30, 2011
09:05 AM
930 views

The Neuro-Recession

by Neuroskeptic in Neuroskeptic

Everyone's favourite British psychopharmacologist David "Ecstasy Vs Horseriding" Nutt joins four other leading neuroscientists to discuss the impact of the financial crisis on neuroscience, in an article over at NR:N: Neuroscience in recession?It's interesting to get an international perspective. Susan Amara, President of the Society for Neuroscience, says that American scientists were encouraged by the surprise $10bn boost to NIH funds that made it into the 2009 economic stimulus package. But these funds are due to run out in 2012.Meanwhile, in Europe, some countries have slashed funding as part of their austerity programmes - Greece most of all - while the larger and richer nations like France and Germany have protected science. Japan has also opted against major cuts, so far, but with a massive deficit, researchers fear that the axe will fall in coming years.A repeated complaint is that biomedical research has faced a rate of inflation much higher than the rate experienced by the economy as a whole. Nutt says that if the overall inflation rate is 4% per year, the rate paid by scientists is more like 10%. As a result, even if nominal budgets are protected, the real budget will fall. The current British government has decided to keep nominal science funding flat, while cutting pretty much everything else, which is nice, but it still means falling real investment.So everyone pretty much agrees that there are cuts, and cuts are bad. OK. Where things get more interesting is in the debate over what this means for individual scientists. Susan Amara says that she fears that investigator-initiated "R01" grants are in danger. These are when a scientist gets an idea, writes it up as a proposal and says "Isn't this cool? Can we have some money to do it?"Amara warns that this kind of thing seems to be getting harder, while established, ongoing research programmes are being protected. But Tom Insel, head of the NIMH and, therefore, the guy with ultimate responsibility for these R01 grants, says the exact opposite. Insel claims that R01s are being protected in favour of the big programmes! "Where have we cut back in order to preserve R01 grants? ... We have reduced the budget of our intramural research programme."Who's right on this point? I'm not sure. Maybe US readers might be able to comment.The authors express particular worry that young neuroscientists (postdocs and PhD students) will suffer, either directly, as a result of not being able to find money, or indirectly in terms of poor morale and a sense that their talents might be better rewarded outside of science - leading to long-term harm to the next generation of neuroscientists.They offer some words of encouragement, though, saying that the pendulum will swing back towards more investment in the future. Until then, hang on as best you can, even if it means being willing to move to find work with a supervisor, or in a country, which does have good funding prospects...Amara SG, Grillner S, Insel T, Nutt D, & Tsumoto T (2011). Neuroscience in recession? Nature reviews. Neuroscience, 12 (5), 297-302 PMID: 21505517... Read more »

Amara SG, Grillner S, Insel T, Nutt D, & Tsumoto T. (2011) Neuroscience in recession?. Nature reviews. Neuroscience, 12(5), 297-302. PMID: 21505517

April 28, 2011
04:13 PM
968 views

The Schizophrenic Computer

by Neuroskeptic in Neuroskeptic

All over the world, inanimate objects are getting schizophrenia. Last week, it was a dish (full of neurons).Before that, it was a computer program. That's according to a paper, which appeared in Biological Psychiatry last month, although it involved no biology, called Using Computational Patients to Evaluate Illness Mechanisms in Schizophrenia.The authors set up a neural network model, called DISCERN, and trained it to "read" stories. The nuts and bolts are, we're reassured, not something that readers of Biological Psychiatry need to worry about: "Its details, many of which are not essential in understanding this study..."Anyway, it's basically a series of connectionist models. These are computer simulations of a large number of simple units, or nodes, which can have "activations" of varying strengths, and which have "connections" to other nodes. The model "learns" by modifying the strength of these connections according to some kind of simple learning rule.Connectionist models are a bit like brains, in other words. A bit. They're several orders of magnitude simpler than a real brain, in several different respects. Still, they can "learn" to do some quite complicated things. You can train them to recognise faces and stuff, which is not trivial.Anyway, DISCERN is a connectionist model of language, but it's not necessary a model of how the human brain actually learns language. Because we just have no idea how the human brain does that. We don't even know if our brain acts as a connectionist network at all, above the cellular level. Some cognitive scientists think it is, but others think that those guys are talking out of an orifice connected to their mouth, but not their mouth. Not in so many words you understand.So they set up this system and got it to learn 28 stories, each of which consisted of multiple sentences. Some of the stories were the autobiography of a doctor - "I was a doctor. I worked in New York. I liked my job. I was good doctor" - he was not a great communicator, clearly. Others were a story about gangster ("Tony was a gangster. Tony worked in Chicago..." etc.) The network had to read these stories and then recall them.The core of the study was that they tested to see what happened when they interfered with the program by introducing certain bugs - interfering with the activations or connections of nodes in particular parts of the model. They tried 8.They compared the computer's performance to that of 37 actual patients with schizophrenia (or the related schizoaffective disorder) who were tested on a similar task, compared to 20 healthy controls. When the human patients came to recall the stories they'd read, they tended to make more errors of particular kinds: mixing up who did what ("agent switching"), and adding stuff that wasn't in the story ("derailment").What they found was that DISCERN made the same kinds of errors when it was given 2 particular deficits, "working memory disconnection" and "hyperlearning". The other 6 deficits didn't cause the same pattern of findings. Hyperlearning was the best match.They comment thatA majority of three-parameter best-fit hyperlearning simulations also recurrently confused specific agents in personal stories (including the self-representation) with specific agents in crime stories (and vice versa) in a highly nonrandom fashion.Noteworthy was the high frequency of agent-slotting exchanges between the hospital boss, Joe, and the Mafia boss, Vito, and parallel confusions between the “I” self-reference and underling Mafia members, suggesting generalization of boss/underling relationships.Insofar as story scripts provide templates for assigning intentions to agents, a consequence of recurrent agent-slotting confusions could be assignment of intentions and roles to autobiographical characters (possibly including the self) that borrow from impersonal stories derived from culture or the media.Confusion between agent representations in autobiographical stories and those in culturally determined narratives could account for the bizarreness of fixed, self-referential delusions, e.g., a patient insisting that her father-in-law is Saddam Hussein or that she herself is the Virgin Mary.So if you believe it, they've just made a program that experiences schizophrenic-type paranoid delusions.It's fair to say that this is speculative. On the other hand, it's an interesting approach, and at least it's theory-based, rather than just an attempt to use ever more powerful genetic, neuroimaging and biological techniques to find differences between a patient group and a control group.Hoffman RE, Grasemann U, Gueorguieva R, Quinlan D, Lane D, & Miikkulainen R (2011). Using computational patients to evaluate illness mechanisms in schizophrenia. Biological psychiatry, 69 (10), 997-1005 PMID: 21397213... Read more »

Hoffman RE, Grasemann U, Gueorguieva R, Quinlan D, Lane D, & Miikkulainen R. (2011) Using computational patients to evaluate illness mechanisms in schizophrenia. Biological psychiatry, 69(10), 997-1005. PMID: 21397213

April 25, 2011
07:03 AM
943 views

Slipping Through Time In Autism

by Neuroskeptic in Neuroskeptic

Have you ever felt like you're reliving the past?Have you ever felt like you're reliving the past? A curious paper from Japan: ‘Time slip’ phenomenon in adolescents and adults with autism spectrum disorders. Have you ever felt like you're...OK, sorry. I'll stop that.The paper describes the cases of two young men with autism, who suffered from an unusual affliction - very vivid memories of a single past event. These recollections were so unpleasant that they led to outbursts of violence. In the first case, the event was somewhat traumatic in itself:Case 1, a male patient, was 16 years old at the time of his first visit to our hospital. He had not shown any delay in language development but had been isolated and unable to make friends since his infancy... He had been bullied by a classmate when he was in the 8th grade; thereafter he refused to go to school and began to stay indoors.One day, he clearly recalled the bullying incident that had occurred a few years earlier and re-experienced the feelings of fear and frustration as if he were once again experiencing that event. Thereafter, he often had similar experiences, even though he did not purposely intend to recall the event, and he became strongly distressed.He and his family stated that the recalled content was always the same. He thought that the distress could only be relieved by obtaining revenge on the boy who had bullied him, and he visited the boy’s house with a knife. He was subsequently admitted to the emergency ward of our hospital.This is not, perhaps, very surprising and sounds a bit like post-traumatic stress disorder. The second case, however, is more mysterious because the event that was remembered was, in itself, completely trivial - someone throwing away a cigarette end:Case 2, a male patient, was 27 years old at the time of his first visit. Since an early age, he had exhibited disturbed reciprocal sociality and did not have any close friendships. His interest was limited to collecting figures of comic characters. He began to be bullied during junior high school. He entered senior high school but quit during the second year. Thereafter, he tended to seclude himself at home.One day, he watched his neighbor discarding a cigarette butt in front of his home. Thereafter, he began to be annoyed by that memory. Almost every time he heard the voice of that neighbor or saw that man, he would leave his home and curse at the neighbor. His behavior became more violent and he eventually threatened the neighbor with a wooden sword.The authors end by saying that out of seven autistic patients who presented to their psychiatric emergency ward, no less than four of them experienced "time slips", though it's not clear how this was diagnosed and patients presenting to the emergency ward are a highly selected population - mostly people who have suddenly become violent or aggressive.The "time slip" phenomenon seems unknown outside of Japan. Google reveals that the only papers discussing it are Japanese. Is it something that only happens in Japan, like buru-sera? Are people with autism elsewhere experiencing this, and going unnoticed?Tochimoto S, Kurata K, & Munesue T (2011). 'Time slip' phenomenon in adolescents and adults with autism spectrum disorders: Case series. Psychiatry and clinical neurosciences PMID: 21489047... Read more »

Tochimoto S, Kurata K, & Munesue T. (2011) 'Time slip' phenomenon in adolescents and adults with autism spectrum disorders: Case series. Psychiatry and clinical neurosciences. PMID: 21489047

April 19, 2011
04:09 AM
824 views

Language Is General?

by Neuroskeptic in Neuroskeptic

So according to the authors of a paper in Nature:It suggests rather that language is part of not a specialised module distinct from the rest of cognition, but more part of broad human cognitive skills.The paper is Evolved structure of language shows lineage-specific trends in word-order universals. They found that the various grammatical rules governing the proper order of different words in a sentence changed over time, and crucially that there were no fixed associations between them: no correlations such that when one rule changed, another rule had to change at the same time.This, they say, is inconsistent with the currently dominant linguistic theory of "language universals" fixed by the structure of the human brain/mind. One of the authors has written an excellent explanation here and languagelog has a nice discussion here.Yet I'm not convinced that "broad human cognitive skills" can explain language. I'm not qualified to comment on the details of this study, but, I do know that the average 7 year old kid has effortlessly learned how to use at least one language, with the appropriate grammar, syntax, and a vocabulary of thousands of words.On the other hand, take my phone. My phone can't do that. It can, just about, take my voice and convert it into text. It gets it right most of the time. It has absolutely no idea what those words mean. All it can do is send them to Google and search for them.Speaking of Google, Google Translate is what you get when roomfuls of computers try to "do language". It's useful, it's cool, and it gets it more-or-less right most of the time. But the output it produces is stilted, often ungrammatical, and generally sounds nothing like a native speaker would ever produce.Let me repeat myself:Now my phone. My phone can do. It's just that text into voice can take me. Most of the time it gets to the right. It means what these words have absolutely no idea. It can be searched on Google for them is this. Speaking of Google, Translate Google is what you get when the language "not" show the state of the art computer trying to. It is useful to cool, but it is more or less right, most of the time. However, the output it generates is often ungrammatical exaggerated, what sounded like a native speaker so far generated in general.That's my last paragraph Google Translated to Japanese and right back. Hmm.On the other hand my phone can perform millions of arithmetical operations per second. The 7 year old probably takes a minute or two of hard effort to multiply two digits together. So who's got more "general cognitive ability"?To say that language is a manifestation of human "general" or "broad" cognition is to say that human general cognition is better at learning languages than it is at doing arithmetic: which rather begs the question of how "general" it is.This doesn't mean that language is a special module of the brain, or that there are "language universals" beyond the fact that they're all languages, though that seems like a pretty big one. But it would take very, very strong evidence to make me doubt that the existence of language is somehow built into the human brain.Dunn M, Greenhill SJ, Levinson SC, & Gray RD (2011). Evolved structure of language shows lineage-specific trends in word-order universals. Nature PMID: 21490599... Read more »

Dunn M, Greenhill SJ, Levinson SC, & Gray RD. (2011) Evolved structure of language shows lineage-specific trends in word-order universals. Nature. PMID: 21490599

April 18, 2011
02:18 PM
965 views

Schizophrenia In A Dish...?

by Neuroskeptic in Neuroskeptic

...or a storm in a teacup?According to a new paper just out in Nature from the prestigious Salk Institute, schizophrenia may be associated with differences in neural wiring which can be observed in a bunch of cells grown in the lab.The paper is here, and here's an open-access Nature news bit discussing it: Schizophrenia 'in a dish'. It's certainly an incredible piece of biology. They took fibroblasts, a cell found in the skin, from 4 patients with schizophrenia and 6 healthy controls.Using genetically modified viruses, they turned these cells into human induced pluripotent stem cells (hiPSCs), which have the ability to become any other type of cell in the human body. Then, they made those hiPSCs turn into neurons by putting them in a dish with various brain-related chemicals and culturing them for three months. Not entirely unlike those brains-in-a-vat that philosophers like to talk about...To test the connectivity of these cells, they then infected them with a modified rabies virus, after first infecting them yet another modified virus to make that work. Rabies can only spread from cell to cell via synapses between cells; they could spot the infected cells because the rabies was modified to carry a special fluorescent protein. So they could tell how many connections the neurons made.What they found was that cultures derived from schizophrenia patients made fewer connections:The distinct lack of red in the schizophrenia patient's dish shows that the rabies virus was less able to travel from cell to cell; the normal amount of green, yellow and blue shows that this wasn't just because it couldn't get into the cells in the first place.OK, that's extremely cool. But then it gets a bit tricky. They tried adding five different antipsychotic drugs to the dishes for 3 weeks. Four did nothing; one, loxapine, made the cells form more connections. But it's odd that it was loxapine, a drug with unremarkable efficacy, which did this; they also tried clozapine, the only antipsychotic which is verifiably more effective than any others, and it didn't.Loxapine is similar to (and metabolized to) amoxapine, an antidepressant; that's an issue, I would say, because we already know that antidepressants cause cells to sprout new connections. It would have been good to have used some antidepressants and some other medications as a control.They did a lot of other work, but the data are hard to interpret. The cells "mis-expressed" about 600 genes, but we're not hold how many genes they tested. 25% of them had been previously linked to schizophrenia, but you could say that of lots of genes: is that more than would be expected by chance alone?The patients were also unusual. Patient 1 suffered an onset of schizophrenia at age 6, and died by suicide aged 22; childhood-onset schizophrenia is extremely rare. Patients 2 and 3 were brother and sister; this means their data may not be independent, so there are (being conservative) only really 3 patients here.Overall it's a great idea, a technical tour-de-force, and I'm sure we'll be seeing much more work along these lines on schizophrenia and other neurological and psychiatric disorders. However, as it stands, schizophrenia remains mysterious.Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, & Gage FH (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature PMID: 21490598Callaway, E. (2011). Schizophrenia 'in a dish' Nature DOI: 10.1038/news.2011.232... Read more »

Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D.... (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature. PMID: 21490598

Callaway, E. (2011) Schizophrenia 'in a dish'. Nature. DOI: 10.1038/news.2011.232

April 13, 2011
01:49 PM
833 views

Who Gets Autism?

by Neuroskeptic in Neuroskeptic

According to a major new report from Australia, social and family factors associated with autism are associated with a lower risk of intellectual disability - and vice versa. But why?The paper is from Leonard et al and it's published in PLoS ONE, so it's open access if you want to take a peek. The authors used a database system in the state of Western Australia which allowed them to find out what happened to all of the babies born between 1984 and 1999 who were still alive as of 2005. There were 400,000 of them.The records included information on children diagnosed with either an autism spectrum disorder (ASD), intellectual disability aka mental retardation (ID), or both. They decided to only look at singleton births i.e. not twins or triplets.In total, 1,179 of the kids had a diagnosis of ASD. That's 0.3% or about 1 in 350, much lower than more recent estimates, but these more recent studies used very different methods. Just over 60% of these also had ID, which corresponds well to previous estimates.There were about 4,500 cases of ID without ASD in the sample, a rate of just over 1%; the great majority of these (90%) had mild-to-moderate ID. They excluded an additional 800 kids with ID associated with a "known biomedical condition" like Down's Syndrome.So what did they find? Well, a whole bunch, and it's all interesting. Bullet point time.Between 1984 to 1999, rates of ID without ASD fell and rates of ASD rose, although there was a curious sudden fall in the rates of ASD without ID just before the end of the study. In 1984, "mild-moderate ID" without autism was by far the most common diagnosis, with 10 times the rate of anything else. By 1999, it was exactly level with ASD+ID, and ASD without ID was close behind. Here's the graph; note the logarithmic scale:Boys had a much higher rate of autism than girls, especially when it came to autism without ID. This has been known for a long time.Second- and third- born children had a higher rate of ID, and a lower rate of ASD, compared to firstborns.Older mothers had children with more autism - both autism with and without ID, but the trend was bigger for autism with ID. But they had less ID. For fathers, the trend was the same and the effect was even bigger. Older parents are more likely to have autistic children but less likely to have kids with ID.Richer parents had a strongly reduced liklihood of ID. Rates of ASD with ID were completely flat, but rates of ASD without ID were raised in the richer groups, though it was not linear (the middle groups were highest. - and effect was small.)To summarize: the risk factors for autism were in most cases the exact opposite of those for ID. The more “advantaged” parental traits like being richer, and being older, were associated with more autism, but less ID. And as time went on, diagnosed rates of ASD rose while rates of ID fell (though only slightly for severe ID).Why is this? The simplest explanation would be that there are many children out there for whom it's not easy to determine whether they have ASD or ID. Which diagnosis any such child gets would then depend on cultural and sociological factors - broadly speaking, whether clinicians are willing to give (and parents willing to accept) one or the other.The authors note that autism has become a less stigmatized condition in Australia recently. Nowdays, they say, a diagnosis of ASD may be preferable to a diagnosis of "just" "plain old" ID, in terms of access to financial support amongst other things. However, it is also harder to get a diagnosis of ASD, as it requires you to go through a more extensive and complex series of assessments.Clearly some parents will be better able to achieve this than others. In other countries, like South Korea, autism is still one of the most stigmatized conditions of childhood, and we'd expect that there, the trend would be reversed.The authors also note the theory that autism rates are rising because of some kind of environmental toxin causing brain damage, like mercury or vaccinations. However, as they point out, this would probably cause more of all neurological/behavioural disorders, including ID; at the least it wouldn't reduce the rates of any.These data clearly show that rates of ID fell almost exactly in parallel with rates of ASD rising, in Western Australia over this 15 year period. What will the vaccine-vexed folks over at Age of Autism make of this study, one wonders?Leonard H, Glasson E, Nassar N, Whitehouse A, Bebbington A, Bourke J, Jacoby P, Dixon G, Malacova E, Bower C, & Stanley F (2011). Autism and intellectual disability are differentially related to sociodemographic background at birth. PloS one, 6 (3) PMID: 21479223... Read more »

Leonard H, Glasson E, Nassar N, Whitehouse A, Bebbington A, Bourke J, Jacoby P, Dixon G, Malacova E, Bower C.... (2011) Autism and intellectual disability are differentially related to sociodemographic background at birth. PloS one, 6(3). PMID: 21479223

April 12, 2011
04:16 AM
501 views

First Fish, Now Cheese, Get Scanned

by Neuroskeptic in Neuroskeptic

Here at Neuroskeptic we have closely followed the development of fMRI scanning on fish.But a new study has taken it to the next level by scanning... some cheese.OK, this is not quite true. The study used NMR spectroscopy to analyze the chemistry of some cheeses, in order to measure the effects of different kinds of probiotic bacteria on the composition of the cheese. NMR is the same technology as MRI, and indeed you can use an MRI scanner to gather NMR spectra.In fact, NMR is Nuclear Magnetic Resonance and MRI is Magnetic Resonance Imaging; it was originally called NMRI, but they dropped the "N" because people didn't like the idea of being scanned by a "nuclear" machine. However, this study didn't actually involve putting cheese into an MRI scanner.But the important point is that they could have done it by doing that. And if you did that, what with the salmon and now the cheese, you could get a nice MRI-based meal going. All we need is for someone to scan some vegetables, some herbs, and a slice of lemon, and we'd have a delicious dataset. Mmm.How to cook it? Well, it's actually possible to heat stuff up with an MRI scanner. When scanning people, you set it up to make sure this doesn't happen, but the average fMRI experiment still causes mild heating. It's unavoidable.I'm not sure what the maximum possible heating effect of an average MRI scanner would be. I doubt anyone has gone out of their way to try and maximize it, but maybe someone ought to look into it. Think of the possibilites.You've just finished a hard day's scanning and you're really hungry, but the microwave at the MRI building is broken. Not to worry! Just pop your fillet of salmon in probiotic cheese sauce in the magnet, and scan it 'till it's done. You could inspect the images and the chemical composition of the meal before you eat it, to make sure it's just right.Just make sure you don't use a steel saucepan...Rodrigues D, Santos CH, Rocha-Santos TA, Gomes AM, Goodfellow BJ, & Freitas AC (2011). Metabolic Profiling of Potential Probiotic or Synbiotic Cheeses by Nuclear Magnetic Resonance (NMR) Spectroscopy. Journal of agricultural and food chemistry PMID: 21443163... Read more »

Rodrigues D, Santos CH, Rocha-Santos TA, Gomes AM, Goodfellow BJ, & Freitas AC. (2011) Metabolic Profiling of Potential Probiotic or Synbiotic Cheeses by Nuclear Magnetic Resonance (NMR) Spectroscopy. Journal of agricultural and food chemistry. PMID: 21443163

April 1, 2011
02:51 AM
819 views

Women Are Better Connected... Neurally

by Neuroskeptic in Neuroskeptic

Note: Please ignore the early draft of this post that I accidentally posted earlier because I'm stupid.The search for differences between the brains of men and women has a long and rather confusing history. Any structural differences are small, and their significance is controversial. The one rock-solid finding is that men's brains are slightly bigger on average. Then again, men are slightly bigger on average in general.A new paper just out from Tomasi and Volkow (of cell-phones-affect-brain fame) offers, on the face of it, extremely strong evidence for a gender difference in the brain, not in structure but in function: Gender Differences in Brain Functional Connectivity Density.Here's the headline pic:They used resting-state "functional connectivity" (though see here for why this term may be misleading) fMRI in men and women. This essentially means that they put people in the MRI scanner, told them to just lie there and relax, and measured the degree to which activity in different parts of the brain was correlated to activity in every other part. They had a whopping 561 brains in total, though they didn't scan everyone themselves: they downloaded the data from here.As you can see the results were highly consistent around the world. In both men and women, the main "connectivity hub" was an area called the ventral precuneus. This is interesting in itself although not a new finding as the precuneus has long been known to be involved in resting-state networks. However, the degree of connectivity was higher in women than in men 14% higher, in fact.The method they used, which they've dubbed "Local Functional Connectivity Density Mapping", is apparantly a fast way of calculating the degree to which each part of the brain is functionally related to each other part.You could do this by taking every single voxel and correlating it with every other voxel, for every single person, but this would take forever unless you had a supercomputer. LFCDM is, they say, a short-cut. I'm not really qualified to judge whether it's a valid one, but it looks solid.Also, men's brains were on average bigger, but interestingly they show that women had, relative to brain size, more grey matter than men. Here's the data (I'm not sure about the color scheme...)So what does the functional connectivity finding mean? It could mean anything, or nothing. You could interpret the highly interconnected female brain as an explanation for why women are more holistic, better at multi-tasking, and more in touch with their emotions than men with their fragmented faculties. Or whatever.Or you could say, that that's sexist rubbish, and all this means is that men and women on average are thinking about different things when they lie in MRI scanners. We already now that resting-state functional connectivity centred on the precuneus is suppressed whenever your attention is directed towards an external "task".That's not a fault of this research, which is excellent as far as it goes and certainly raises lots of interesting questions about functional connectivity. But we don't know what it means quite yet.Tomasi D, & Volkow ND (2011). Gender differences in brain functional connectivity density. Human brain mapping PMID: 21425398... Read more »

Tomasi D, & Volkow ND. (2011) Gender differences in brain functional connectivity density. Human brain mapping. PMID: 21425398

March 30, 2011
11:41 AM
897 views

Neuroskeptic Irreverent and Sometimes Profane, Study Finds

by Neuroskeptic in Neuroskeptic

I was most surprised and honored to find out this morning that the Annals of Neurology has declared Neuroskeptic to beIrreverent, sometimes profane, and can skirt the boundaries of good taste. Nonetheless, Neuroskeptic covers a rich mixture of important, engaging, or amusing topics focusing on the basic and clinical neurosciences, and does so in a data-driven, user-friendly, and comment-enabled format. Neuroskeptic is only one of a number of increasingly used web sites and blogs dedicated to promoting public education, rational discourse, and a healthy dose of skepticism around important issues in the neurosciences...No really: Scientific literacy and the media. They also list a small number of other neuroblogs, although they leave out many outstanding ones including the blog that most inspired this one, and that everyone confuses me with, The Neurocritic.Anyway, the editorial goes on to note that:Last April, a series of sensationalist stories reporting the “creation of life” and a newfound capability to “play God” appeared in the national media following the demonstration that synthetic DNA could transform a mycoplasma species from one to another subtype(ref). This represented a tour de force of DNA synthesis, but probably only a modest step forward for the science of genetic engineering.In response, President Obama directed his Presidential Commission for the Study of Bioethical Issues to prepare a comprehensive advisory report to help frame policies about synthetic biology(ref). The Commission noted that sensationalist headlines may attract readers to scientific topics but do a terrible disservice by promoting “claims that fail to convey accurately to the public the current state of the field, the implications of research results, and the limits of scientists' present knowledge and abilities.” The Presidential Commission recommended creating a well-funded, interactive website... to monitor claims about new scientific discoveries and technologies.Ideally, such a site would be only part of a wider effort to promote scientific literacy and critical thinking across all segments of society... In the coming years, scientific innovation is certain to play an increasingly large role in the global economy... The public discourse on these and related matters needs to be rational, evidence-based, and accurate.Broadly speaking, this is why I write this blog, because it is indeed extremely important. Well, ok, the real reason is that it gives me an excuse to make funny pictures with MS Paint (someone accused me of using Photoshop to do those once - no, that would be too advanced). However, if a few people understand neuroscience a bit better in the process, I can live with that...Hauser, S., & Johnston, S. (2011). Scientific literacy and the media Annals of Neurology, 69 (3) DOI: 10.1002/ana.22410... Read more »

Hauser, S., & Johnston, S. (2011) Scientific literacy and the media. Annals of Neurology, 69(3). DOI: 10.1002/ana.22410

March 26, 2011
06:50 AM
884 views

Fake Clinical Trial - Real Problems

by Neuroskeptic in Neuroskeptic

Here at Neuroskeptic we've seen our fair share of dubious clinical trials over the years, but the Indian Journal of Psychiatry has just published one which really takes the biscuit, because it was completely made up.Luckily, the trial is actually a rather neat spoof paper, written for educational purposes to highlight bad practices in the design and writing up of clinical trials. It's accompanied by a serious piece which analyzes these problems. They're both open access so you can take a look.The sham study is ostensibly a trial of a new antidepressant, "placeboxetine", compared to an older drug for depression - but it was really written by one of the Editors of the journal via "Common shortcomings in manuscripts submitted to the Indian Journal of Psychiatry were collated into a single manuscript". These shortcomings are certainly not limited to Indian papers.The problems included:No placebo group. This is extremely common in trials comparing two drugs, so it's "accepted practice", but it's still a bad thing.The "placeboxetine" was given at a higher dose, relative to its dose range, than the comparison drug but they don't say why.Side effects are reported but they don't explain how these were assessed. If you specifically ask about them you find a lot more than if you rely on patients to spontaneously complain.Subtle, but important, issues with the statistics, such as reliance on t-tests over more appropriate methods.The trial had some unusual features for a depression trial - with no explanation. Most patients were males in their 20s, while the norm is for about 65% females and an average age in the 40s; very few people dropped out; very few people who were screened were excluded, whereas most trials exclude loads of people for all kinds of reasons.The effectiveness of both drugs was remarkably high (75% cure rate over 6 weeks - better than any treatment, drug or therapy, would be expected to show.) Yet they don't mention this.It was badly written. The title in particular was far too long and clumsy.It turns out that the trial was sponsored by the fictional pharmaceutical company, and was probably conducted to help get placeboxetine sold in India - but we only find this out in the small print at the end.Hot pink and white is not a good color scheme for your graphs, or for anything except marshmallows. (I may have added this myself.)Overall I think this kind of thing is extremely valuable. The author's final comments, however, are a bit questionable. He advises people running clinical trials to base their research protocol, and their paper, on previously published studies of a similar nature published in good journals. Unfortunately, even leading journals publish stuff which suffers from some of these problems...Andrade C (2011). A 6-week, multicentre, randomized controlled clinical trial to evaluate the safety and efficacy of placeboxetine hydrochloride in the treatment of major depressive disorder in an Indian setting. Indian journal of psychiatry, 53 (1), 69-72 PMID: 21431013Andrade C (2011). Placeboxetine for major depressive disorder: Researcher, author, reader, and reviewer perspectives on randomized controlled trials. Indian journal of psychiatry, 53 (1), 73-6 PMID: 21431014... Read more »

Andrade C. (2011) A 6-week, multicentre, randomized controlled clinical trial to evaluate the safety and efficacy of placeboxetine hydrochloride in the treatment of major depressive disorder in an Indian setting. Indian journal of psychiatry, 53(1), 69-72. PMID: 21431013

Andrade C. (2011) Placeboxetine for major depressive disorder: Researcher, author, reader, and reviewer perspectives on randomized controlled trials. Indian journal of psychiatry, 53(1), 73-6. PMID: 21431014

March 24, 2011
04:20 PM
950 views

A Stroke Of Good Fortune Cures OCD?

by Neuroskeptic in Neuroskeptic

A 45 year old female teacher had a history of severe obsessive-compulsive disorder, along with other problems including ADHD. Her daughter, and many other people in her family, had suffered the same problems and in a few cases had Tourette's Syndrome.But all that changed - when she suffered a stroke. This is according to a brief case report from Drs. Diamond and Ondo of Texas:[she] had a long history of constant intrusive and obsessive thoughts that interrupted her daily activities and sleep. She had constant unfounded fears that something bad would happen to her family and had persistent violent thoughts of using knives to harm family members. She would check the door locks up to 15 times a day. In addition to her OCD symptoms, she had ... inattention, poor concentration, and difficulty sitting still.She had never been treated for the OCD, despite how it interfered with her life, because she feared losing her job as a teacher if she sought psychiatric help. But then... Nine months before approaching us, she developed the acute onset of paresthesia [weird sensations] and weakness in the left upper extremity and face, associated with slurred speech. Initially, she was unable to lift her arm against gravity. These are classic signs of a stroke, but it was a very mild one, because the symptoms only lasted a few minutes and were pretty much gone even before she arrived at the emergency room. She made a full recovery. More than a full recovery in fact:Within weeks of her stroke, she realized that her obsessive and intrusive thoughts, fears, rituals, and impulsive behavior had completely resolved. In addition, there was some improvement in her temperament. There was no improvement in attention or concentration. Owing to her improvement in neuropsychiatric symptoms, she strongly felt that her stroke was beneficial. These benefits have persisted for 24 months.Most medical case reports concern patients who died, or got really sick, in a particularly interesting fashion, but this one has a happy ending. Strokes can be devastating, of course, although people also make full recoveries - it all depends on the severity of the stroke, and whether they get prompt treatment.There have been a few other cases of brain damage which brought unexpectedly beneficial effects. In Vietnam veterans, for example, people with damage to the vmPFC due to combat trauma seemed to be protected from depression.Whether the stroke really cured her, or whether it was some kind of psychological "placebo" effect, we'll never know. It's hard to see why a stroke would have a placebo effect, but on the other hand, an MRI scan revealed that the stroke occured in an area of the brain - the right frontoparietal cortex - which is fairly low down on the list of "OCD-ish" areas.The authors make some vague comments about "modulation of the cortical–subcortical circuits" but this is really the neuroscientific equivalent of saying "We guess it did something", because the entire brain is made of cortical-subcortical circuits, given that the cortex is at the top and everything else is, by definition, the sub-cortex. It's quite possible. But we really can't tell.Diamond A, & Ondo WG (2011). Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience PMID: 21426244... Read more »

Diamond A, & Ondo WG. (2011) Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience. PMID: 21426244

March 20, 2011
02:52 PM
949 views

Depressed or Bereaved? (Part 2)

by Neuroskeptic in Neuroskeptic

In Part 1, I discussed a paper by Jerome Wakefield examining the issue of where to draw the line between normal grief and clinical depression.The line moved in the American Psychiatric Association's DSM diagnostic system when the previous DSM-III edition was replaced by the current DSM-IV. Specifically, the "bereavement exclusion" was made narrower.The bereavement exclusion says that you shouldn't diagnose depression in someone whose "depressive" symptoms are a result of grief - unless they're particularly severe or prolonged when you should. DSM-IV lowered the bar for "severe" and "prolonged", thus making grief more likely to be classed as depression. Wakefield argued that the change made things worse.But DSM-V is on its way soon. The draft was put up online in 2010, and it turns out that depression is to have no bereavement exclusion at all. Grief can be diagnosed as depression in exactly the same way as depressive symptoms which come out of the blue.The draft itself offered just one sentence by way of justification for this. However, big cheese psychiatrist Kenneth S. Kendler recently posted a brief note defending the decision. Wakefield has just published a rather longer paper in response.Wakefield starts off with a bit of scholarly kung-fu. Kendler says that the precursors to the modern DSM, the 1972 Feighner and 1975 RDC criteria, didn't have a bereavement clause for depression either. But they did - albeit not in the criteria themselves, but in the accompanying how-to manuals; the criteria themselves weren't meant to be self-contained, unlike the DSM. Ouch! And so on.Kendler's sole substantive argument against the exclusion is that it is "not logically defensible" to exclude depression induced by bereavement, if we don't have a similar provision for depression following other severe loss or traumatic events, like becoming unemployed or being diagnosed with cancer.Wakefield responds that, yes, he has long made exactly that point, and that in his view we should take the context into account, rather than just looking at the symptoms, in grief and many other cases. However, as he points out, it is better to do this for one class of events (bereavement), than for none at all. He quotes Emerson's famous warning that "A foolish consistency is the hobgoblin of little minds". It's better to be partly right, than consistently wrong.Personally, I'm sympathetic to Wakefield's argument that the bereavement exclusion should be extended to cover non-bereavement events, but I'm also concerned that this could lead to underdiagnosis if it relied too much on self-report.The problem is that depression usually feels like it's been caused by something that's happened, but this doesn't mean it was; one of the most insidious features of depression is that it makes things seem much worse than they actually are, so it seems like the depression is an appropriate reaction to real difficulties, when to anyone else, or to yourself looking back on it after recovery, it was completely out of proportion. So it's a tricky one.Anyway, back to bereavement; Kendler curiously ends up by agreeing that there ought to be a bereavement clause - in practice. He says that just because someone meets criteria for depression does not mean we have to treat them:...diagnosis in psychiatry as in the rest of medicine provides the possibility but by no means the requirement that treatment be initiated ... a good psychiatrist, on seeing an individual with major depression after bereavement, would start with a diagnostic evaluation.If the criteria for major depression are met, then he or she would then have the opportunity to assess whether a conservative watch and wait approach is indicated or whether, because of suicidal ideation, major role impairment or a substantial clinical worsening the benefits of treatment outweigh the limitations.The final sentence is lifted almost word for word from the current bereavement clause, so this seems to be an admission that the exclusion is, after all, valid, as part of the clinical decision-making process, rather than the diagnostic system.OK, but as Wakefield points out, why misdiagnose people if you can help it? It seems to be tempting fate. Kendler says that a "good psychiatrist" wouldn't treat normal, uncomplicated bereavement as depression. But what about the bad ones? Why on earth would you deliberately make your system such that good psychiatrists would ignore it?More importantly, scrapping the bereavement criterion would render the whole concept of Major Depression meaningless. Almost everyone suffers grief at some point in their lives. Already, 40% of people meet criteria for depression by age 32, and that's with a bereavement exclusion.Scrap it and, I don't know, 80% will meet criteria by that age - so the criteria will be useless as a guide to identifying the people who actually have depression as opposed to the ones who have just suffered grief. We're already not far off that point, but this would really take the biscuit.Wakefield JC (2011) Should Uncomplicated Bereavement-Related Depression Be Reclassified as a Disorder in the DSM-5? The Journal of nervous and mental disease, 199 (3), 203-8 PMID: 21346493... Read more »

Wakefield JC. (2011) Should Uncomplicated Bereavement-Related Depression Be Reclassified as a Disorder in the DSM-5?: Response to Kenneth S. Kendler's Statement Defending the Proposal to Eliminate the Bereavement Exclusion. The Journal of nervous and mental disease, 199(3), 203-8. PMID: 21346493

March 18, 2011
10:26 AM
908 views

A Look Inside A Brain

by Neuroskeptic in Neuroskeptic

A remarkable paper just out in Nature has revealed images of the brain's structure and function in unprecedented detail: Network anatomy and in vivo physiology of visual cortical neurons.Harvard Medical School researchers Bock et al took a mouse - just one - and used two forms of microscopy to investigate a small patch of it's primary visual cortex, the area which receives input from the eyes.First, they used two-photon calcium imaging to look at the functional properties of individual cells. They displayed various kinds of patterns in front of the mouse's eyes, and looked to see which cells lit up, using a special dye which become fluorescent in the presence of calcium, which rises inside cells when they fire.Having done that they took the same chunk of cortex (a rough cube of about 0.4 mm on each side) and used electron microscopy to see it in its entirety. This was the tricky part. Electron microscopy only works if the sample is first cut into extremely thin slices. Each of the 1,200 slices took 20 minutes to image so in total they spent "several months" to get it all done, using a home-made device consisting of 4 high-resolution digital cameras that fed the information to an image processing system.In total, they acquired 36 terabytes of electron microscope images, and after processing it all they ended up with a 3D picture of 10 million megapixels. My phone has a 16 GB internal storage and a 5 megapixel camera, so in order to get this data I would have to take 2 million photos, and it would take about 2000 phones to store them. There isn't an app for that...yet.The end result was some very pretty pictures, and amazing movies. Oh, and also, some science - they were able to compare the functional properties of brain cells to their actual physical wiring diagram. This, in the broadest sense, is what all neuroscientists are trying to do, in one form or another; Bock et al, however, went out and did it directly.They were able to test an important hypothesis, namely that in the visual cortex, pyrimidal cells (the main cortical cell type) project to inhibitory GABA interneurons in a manner which doesn't depend on their orientation-selectivity - whether they respond most strongly to seeing vertical lines, horizontal lines, diagonal ones, etc. Bock et al found that this seemed to be true: pyrimidal cells synapsed onto whichever GABA cells happened to be nearest to them, regardless of their orientation-selectivity.Still, it took them several months to image an area containing just 1,000 neurons. The mouse cortex has 4 million, and the human cortex has 11,000 million, so this is a tiny fraction of the whole brain, and the small size of the area meant that they were only able to examine short-range connections between neighboring cells, not long-range wiring. So this is early days, but it's clearly an extremely exciting technique and is sure to open the way to major advances in the future.Link: Also blogged at Brains Lab.Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, & Reid RC (2011). Network anatomy and in vivo physiology of visual cortical neurons. Nature, 471 (7337), 177-82 PMID: 21390124... Read more »

Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, & Reid RC. (2011) Network anatomy and in vivo physiology of visual cortical neurons. Nature, 471(7337), 177-82. PMID: 21390124

March 15, 2011
04:09 AM
853 views

Neural Correlates of 80s Hip Hop

by Neuroskeptic in Neuroskeptic

A ground-breaking new study reveals the neurological basis of seminal East Coast hip-hop pioneers Run-D.M.C.The study is Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study, and it actually has nothing to do with hip-hop, but it does have one of the best study acronyms I have ever seen.RUN DMC stands for the "Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study".Or maybe it does relate to rapping. Because the paper is about verbal memory, and if there's one thing a rapper needs, it's a good memory for words, otherwise they'd forget their lyrics and... OK no, it doesn't relate to hip-hop.It is however a very nice piece of research. They took no fewer than 503 elderly people - making this by far the single biggest neuroimaging study I have ever read. They used DTI to measure the quality of white-matter tracts in the brain and correlated this with verbal memory function. DTI is an extremely clever technique which allows you to measure the integrity of white matter pathways.The theory behind the study is that in elderly people, white matter often shows degeneration. This is thought to be caused by vascular disease - problems with the blood flow to the brain, such as cerebral small-vessel disease which means, essentially, a series of mild strokes, which often go unnoticed at the time, but they build up to cause brain damage, specifically white matter disruption.The symptoms of this are extremely varied and can range from cognitive and memory impairment, to depression, to motor problems (clumsiness), all depending on where in the brain it happens.All of the people in this study had cerebral small-vessel disease as defined on the basis of symptoms and the presence of visible white matter lesions on the basic MRI scan. The authors found that the integrity of the white matter tracts in the area of the hippocampus, as measured with DTI, correlated with performance on a simple word learning task:The healthier the hippocampal white matter, the better people did on the task. This makes sense as the hippocampus is a well known memory centre. This is only a correlation, and doesn't prove that the hippocampal damage caused the memory problems, but it seems entirely plausible. The authors controlled for things like age, gender, and the size of the hippocampus, as far as possible.Should we all be worried about our white matter when we get older? Quite possibly - but luckily, the risk factors for vascular disease are quite well understood, and many of them are things you can change by having a healthy lifestyle.Smoking is bad news, as are hypertension (high blood pressure), obesity, and high cholesterol. Diabetes is also a risk factor. So you should quit smoking, eat well, and ensure that you're getting tested and if necessary treated for hypertension and diabetes. All of which, of course, is a good idea from the point of view of general health as well.van Norden AG, de Laat KF, Fick I, van Uden IW, van Oudheusden LJ, Gons RA, Norris DG, Zwiers MP, Kessels RP, & de Leeuw FE (2011). Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study. Human brain mapping PMID: 21391278... Read more »

van Norden AG, de Laat KF, Fick I, van Uden IW, van Oudheusden LJ, Gons RA, Norris DG, Zwiers MP, Kessels RP, & de Leeuw FE. (2011) Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study. Human brain mapping. PMID: 21391278

March 10, 2011
02:20 PM
893 views

Depressed Or Bereaved? (Part 1)

by Neuroskeptic in Neuroskeptic

My cat died on Tuesday. She may have been a manipulative psychopath, but she was a likeable one. She was 18.On that note, here's a paper about bereavement.It's been recognized since forever that clinical depression is similar, in many ways, to the experience of grief. Freud wrote about it in 1917, and it was an ancient idea even then. So psychiatrists have long thought that symptoms, which would indicate depression in someone who wasn't bereaved, can be quite normal and healthy as a response to the loss of a loved one. You can't go around diagnosing depression purely on the basis of the symptoms, out of context.On the other hand, sometimes grief does become pathological - it triggers depression. So equally, you can't just decide to never diagnose depression in the bereaved. How do you tell the difference between "normal" and "complicated" grief, though? This is where opinions differ.Jerome Wakefield (of Loss of Sadness fame) and colleagues compared two methods. They looked at the NCS survey of the American population, and took everyone who'd suffered a possible depressive episode following bereavement. There were 156 of these.They then divided these cases into "complicated" grief (depression) vs "uncomplicated" grief, first using the older DSM-III-R criteria, and then with the current DSM-IV ones. Both have a bereavement exclusion for the depression criteria - don't diagnose depression if it's bereavement - but they also have criteria for complicated grief which is depression, exclusions to the exclusion.The systems differ in two major ways: the older criteria were ambiguous but at the time, they were generally interpreted to mean that you needed to have two features out of a possible five; prolonged duration was one of the list and anything over 12 months was considered "prolonged". In DSM-IV, however, you only need one criterion, and anything over 2 months is prolonged.What happened? DSM-IV classified many more cases as complicated than the older criteria - 80% vs 45%. That's no surprise there because the criteria are obviously a lot broader. But which was better? In order to evaluate them, they compared the "complicated" vs "normal" episodes on six hallmarks of clinical depression - melancholic features, seeking medical treatment, etc.They found that "complicated" cases were more severe under both criteria but the difference was much more clear cut using DSM-III-R.Wakefield et al are not saying that the DSM-III-R criteria were perfect. However, it was better at identifying the severe cases than the DSM-IV, which is worrying because DSM-IV was meant to be an improvement on the old system.Hang on though. DSM-V is coming soon. Are they planning to put things back to how they were, or invent an even better system? No. They're planning to, er, get rid of the bereavement criteria altogether and treat bereavement just like non-bereavement. Seriously. In other words they are planning to diagnose depression purely on the basis of the symptoms, out of context.Which is so crazy that Wakefield has written another paper all about it (he's been busy recently), which I'm going to cover in an upcoming post. So stay tuned.Wakefield JC, Schmitz MF, & Baer JC (2011). Did narrowing the major depression bereavement exclusion from DSM-III-R to DSM-IV increase validity? The Journal of nervous and mental disease, 199 (2), 66-73 PMID: 21278534... Read more »

Wakefield JC, Schmitz MF, & Baer JC. (2011) Did narrowing the major depression bereavement exclusion from DSM-III-R to DSM-IV increase validity?: evidence from the National Comorbidity Survey. The Journal of nervous and mental disease, 199(2), 66-73. PMID: 21278534

March 6, 2011
06:27 AM
933 views

Paxil: The Whole Truth?

by Neuroskeptic in Neuroskeptic

Paroxetine, aka Paxil aka Seroxat, is an SSRI antidepressant.Like other SSRIs, its reputation has see-sawed over time. Hailed as miracle drugs in the 1990s and promoted for everything from depression to "separation anxiety" in dogs, they fell from grace over the past decade.First, concerns emerged over withdrawal symptoms and suicidality especially in young people. Then more recently their antidepressant efficacy came into serious question. Paroxetine has arguably the worst image of all SSRIs, although whether it's much different to the rest is unclear.Now a new paper claims to provide a definitive assessment of the safety and efficacy of paroxetine in adults (age 18+). The lead authors are from GlaxoSmithKline, who invented paroxetine. So it's no surprise that the text paints GSK and their product in a favourable light, but the data warrant a close look and the results are rather interesting - and complicated.They took all of the placebo-controlled trials on paroxetine for any psychiatric disorder - because it wasn't just trialled in depression, but also in PTSD, anxiety, and more. They excluded studies with fewer than 30 people; this makes sense though it's somewhat arbitrary, why not 40 or 20? Anyway, they ended up with 61 trials.First they looked at suicide. In a nutshell paroxetine increased suicidal "behaviour or ideation" in younger patients (age 25 or below) relative to placebo, whether or not they were being treated for depression. In older patients, it only increased suicidality in the depression trials, and the effect was smaller. I've put a red dot where paroxetine was worse than placebo; this doesn't mean the effect was "statistically significant", but the numbers are so small that this is fairly meaningless. Just look at the numbers.This is not very new. It's been accepted for a while that broadly the same applies when you look at trials of other antidepressants. Whether this causes extra suicides in the real world is a big question.When it comes to efficacy, however, we find some rather startling info that's not been presented together in one article before, to my knowledge. Here's a graph showing the effect of paroxetine over-and-above placebo in all the different disorders, expressed as a proportion of the improvement seen in the placebo group.Now I should point out that I just made this measure up. It's not ideal. If the placebo response is very small, then a tiny drug effect will seem large by comparison, even if what this really means is that neither drug nor placebo do any good.However the flip side of that coin is that it controls for the fact that rating scales for different disorders might be just more likely to show change than others. The d score is a more widely used standardized measure of effect size - though it has its own shortcomings - and I'd like to know those, but the data they provide don't allow us to easily calculate it. You could do it from the GSK database but it would take ages.Anyway as you can see paroxetine was better, relative to placebo, against PTSD, PMDD, obsessive-compulsive disorder, and social anxiety, than it was against depression measured with the "gold-standard" HAMD scale! In fact the only thing it was worse against was Generalized Anxiety Disorder. Using the alternative MADRS depression scale, the antidepressant effect was bigger, but still small compared to OCD and social anxiety.This is rather remarkable. Everyone calls paroxetine "an antidepressant", yet at least in one important sense it works better against OCD and social anxiety than it does against depression!In fact, is paroxetine an antidepressant at all? It works better on MADRS and very poorly on the HAMD; is this because the HAMD is a better scale of depression, and the MADRS actually measures anxiety or OCD symptoms?That's a lovely neat theory... but in fact the HAMD-17 has two questions about anxiety, scoring 0-4 points each, so you can score up to 8 (or 12 if you count "hypochondriasis", which is basically health anxiety, so you probably should), out of a total maximum of 52. The MADRS has one anxiety item with a max score of 6 on a total of 60. So the HAMD is more "anxious" than the MADRS.This is more than just a curiosity. Paroxetine's antidepressant effect was tiny in those aged 25 or under on the HAMD - treatment just 9% of the placebo effect - but on the MADRS in the same age group, the benefit was 35%! So what is the HAMD measuring and why is it different to the MADRS?Honestly, it's hard to tell because the Hamilton scale is so messy. It measures depression and the other distressing symptoms which commonly go along with it. The idea, I think, was that it was meant to be a scale of the patient's overall clinical severity - how seriously they were suffering - rather than a measure of depression per se.Which is fine. Except that most modern trials carefully exclude anyone with "comorbid" symptoms like anxiety, and on the other hand, recruit people with symptoms quite different to the depressed inpatients that Dr Max Hamilton would have seen when he invented the scale in 1960.Yet 50 years later the HAMD17, unmodified, is still the standard scale. It's been repeatedly shown to be multi-factorial (it doesn't measure one thing), no-one even agrees on how to interpret it, and a "new scale", the HAMD6, which consists of simply chucking out 11 questions and keeping the 6 that actually measure depression, has been shown to be better. Yet everyone still uses the HAMD17 because everyone else does.... Read more »

Carpenter DJ, Fong R, Kraus JE, Davies JT, Moore C, & Thase ME. (2011) Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials. The Journal of clinical psychiatry. PMID: 21367354

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