Brain maturation continues for longer than previously thought - well up until age 30. That's according to two papers just out, which may be comforting for those lamenting the fact that they're nearing the big Three Oh.This challenges the widespread view that maturation is essentially complete by the end of adolescence, in the early to mid 20s.Petanjek et al show that the number of dendritic spines in the prefrontal cortex increases during childhood and then rapidly falls during puberty - which probably represents a kind of "pruning" process. That's nothing new, but they also found that the pruning doesn't stop when you hit 20. It continues, albeit gradually, up to 30 and beyond.This study looked at post-mortem brain samples taken from people who died at various different ages. Lebel and Beaulieu used diffusion MRI to examine healthy living brains. They scanned 103 people and everyone got at least 2 scans a few year years apart, so they could look at changes over time.They found that the fractional anisotropy (a measure of the "integrity") of different white matter tracts varies with age in a non-linear fashion. All tracts become stronger during childhood, and most peak at about 20. Then they start to weaken again. But not all of them - others, such as the cingulum, take longer to mature.Also, total white matter volume continues rising well up to age 30.Plus, there's a lot of individual variability. Some people's brains were still maturing well into their late 20s, even in white matter tracts that on average are mature by 20. Some of this will be noise in the data, but not all of it.These results also fit nicely with this paper from last year that looked at functional connectivity of brain activity.So, while most maturation does happen before and during adolescence, these results show that it's not a straightforward case of The Adolescent Brain turning suddenly into The Adult Brain when you hit 21, which point it solidifies into the final product,Lebel C, & Beaulieu C (2011). Longitudinal development of human brain wiring continues from childhood into adulthood. The Journal of Neuroscience, 31 (30), 10937-47 PMID: 21795544Petanjek, Z., Judas, M., Simic, G., Rasin, M., Uylings, H., Rakic, P., & Kostovic, I. (2011). Extraordinary neoteny of synaptic spines in the human prefrontal cortex Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1105108108... Read more »
Lebel C, & Beaulieu C. (2011) Longitudinal development of human brain wiring continues from childhood into adulthood. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(30), 10937-47. PMID: 21795544
Petanjek, Z., Judas, M., Simic, G., Rasin, M., Uylings, H., Rakic, P., & Kostovic, I. (2011) Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1105108108
When you drink alcohol and get drunk, are you getting drunk on alcohol?Well, obviously, you might think, and so did I. But it turns out that some people claim that the alcohol (ethanol) in drinks isn't the only thing responsible for their effects - they say that acetaldehyde may be important, perhaps even more so.South Korean researchers Kim et al report that it's acetaldehyde, rather than ethanol, which explains alcohol's immediate effects on cognitive and motor skills. During the metabolism of ethanol in the body, it's first converted into acetaldehyde, which then gets converted into acetate and excreted. Acetaldehyde build-up is popularly renowned as a cause of hangovers (although it's unclear how true this is), but could it also be involved in the acute effects?Kim et al gave 24 male volunteers a range of doses of ethanol (in the form of vodka and orange juice). Half of them carried a genetic variant (ALDH2*2) which impairs the breakdown of acetaldehyde in the body. About 50% of people of East Asian origin, e.g. Koreans, carry this variant, which is rare in other parts of the world.As expected, compared to the others, the ALDH2*2 carriers had much higher blood acetaldehyde levels after drinking alcohol, while there was little or no difference in their blood ethanol levels.Interestingly, though, the ALDH2*2 group also showed much more impairment of cognitive and motor skills, such as reaction time or a simulated driving task. On most measures, the non-carriers showed very little effect of alcohol, while the carriers were strongly affected, especially at high doses. Blood acetaldehyde was more strongly correlated with poor performance than blood alcohol was.So the authors concluded that:Acetaldehyde might be more important than alcohol in determining the effects on human psychomotor function and skills.So is acetaldehyde to blame when you spend half an hour trying and failing to unlock your front door after a hard nights drinking? Should we be breathalyzing drivers for it? Maybe: this is an interesting finding, and there's quite a lot of animal evidence that acetaldehyde has acute sedative, hypnotic and amnesic effects, amongst others.Still, there's another explanation for these results: maybe the ALDH2*2 carriers just weren't paying much attention to the tasks, because they felt ill, as ALDH2*2 carriers generally do after drinking, as a result of acetaldehyde build-up. No-one's going to be operating at peak performance if they're suffering the notorious flush reaction or "Asian glow", which includes skin flushing, nausea, headache, and increased pulse...Kim SW, Bae KY, Shin HY, Kim JM, Shin IS, Youn T, Kim J, Kim JK, & Yoon JS (2009). The Role of Acetaldehyde in Human Psychomotor Function: A Double-Blind Placebo-Controlled Crossover Study. Biological psychiatry PMID: 19914598... Read more »
Kim SW, Bae KY, Shin HY, Kim JM, Shin IS, Youn T, Kim J, Kim JK, & Yoon JS. (2009) The Role of Acetaldehyde in Human Psychomotor Function: A Double-Blind Placebo-Controlled Crossover Study. Biological psychiatry. PMID: 19914598
Via Dormivigilia, I came across a fascinating paper about a man who suffered from a severe lack of monoamine neurotransmitters (dopamine, serotonin etc.) as a result of a genetic mutation: Sleep and Rhythm Consequences of a Genetically Induced Loss of SerotoninNeuroskeptic readers will be familiar with monoamines. They're psychiatrists' favourite neurotransmitters, and are hence very popular amongst psych drug manufacturers. In particular, it's widely believed that serotonin is the brain's "happy chemical" and that clinical depression is caused by low serotonin while antidepressants work by boosting it.Critics charge that there is no evidence for any of this. My own opinion is that it's complicated, but that while there's certainly no simple relation between serotonin, antidepressants and mood, they are linked in some way. It's all rather mysterious, but then, the functions of serotonin in general are; despite 50 years of research, it's probably the least understood neurotransmitter.The new paper adds to the mystery, but also provides some important new data. Leu-Semenescu et al report on the case of a 28 year old man, with consanguineous parents, who suffers from a rare genetic disorder, sepiapterin reductase deficiency (SRD). SRD patients lack an enzyme which is involved, indirectly, in the production of the monoamines serotonin and dopamine, and also melatonin and noradrenaline which are produced from these two. SRD causes a severe (but not total) deficiency of these neurotransmitters.The most obvious symptoms of SRD are related to the lack of dopamine, and include poor coordination and weakness, very similar to Parkinson's Disease. An interesting feature of SRD is that these symptoms are mild in the morning, worsen during the day, and improve with sleep. Such diurnal variation is also a hallmark of severe depression, although in depression it's usually the other way around (better in the evening).The patient reported on in this paper suffered Parkinsonian symptoms from birth, until he was diagnosed with dystonia at age 5 and started on L-dopa to boost his dopamine levels. This immediately and dramatically reversed the problems.But his serotonin synthesis was still impaired, although doctors didn't realize this until age 27. As a result, Leu-Semenescu et al say, he suffered from a range of other, non-dopamine-related symptoms. These included increased appetite - he ate constantly, and was moderately obese - mild cognitive impairment, and disrupted sleep:The patient reported sleep problems since childhood. He would sleep 1 or 2 times every day since childhood and was awake during more than 2 hours most nights since adolescence. At the time of the first interview, the night sleep was irregular with a sleep onset at 22:00 and offset between 02:00 and 03:00. He often needed 1 or 2 spontaneous, long (2- to 5-h) naps during the daytime.After doctors did a genetic test and diagnosed STP, they treated him with 5HTP, a precursor to serotonin. The patient's sleep cycle immediately normalized, his appetite was reduced and his concentration and cognitive function improved (although that may have been because he was less tired). Here's his before and after hypnogram:Disruptions in sleep cycle and appetite are likewise common in clinical depression. The direction of the changes in depression varies: loss of appetite is common in the most severe "melancholic" depression, while increased appetite is seen in many other people.For sleep, both daytime sleepiness and night-time insomnia, especially waking up too early, can occur in depression. The most interesting parallel here is that people with depression often show a faster onset of REM (dreaming) sleep, which was also seen in this patient before 5HTP treatment. However, it's not clear what was due to serotonin and what was due to melatonin because melatonin is known to regulate sleep.Overall, though, the biggest finding here was a non-finding: this patient wasn't depressed, despite having much reduced serotonin levels. This is further evidence that serotonin isn't the "happy chemical" in any simple sense.On the other hand, the similarities between his symptoms and some of the symptoms of depression suggest that serotonin is doing something in that disorder. This fits with existing evidence from tryptophan depletion studies showing that low serotonin doesn't cause depression in most people, but does re-activate symptoms in people with a history of the disease. As I said, it's complicated...Smaranda Leu-Semenescu et al. (2010). Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin Sleep, 33 (03), 307-314... Read more »
Smaranda Leu-Semenescu et al. (2010) Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin. Sleep, 33(03), 307-314. info:/
Neuroskeptic readers will know that I'm a big fan of theories. Rather than just poking around (or scanning) the brain under different conditions and seeing what happens, it's always better to have a testable hypothesis.I just found a 2007 paper by Israeli computational neuroscientists Niv et al that puts forward a very interesting theory about dopamine. Dopamine is a neurotransmitter, and dopamine cells are known to fire in phasic bursts - short volleys of spikes over millisecond timescales - in response to something which is either pleasurable in itself, or something that you've learned is associated with pleasure. Dopamine is therefore thought to be involved in learning what to do in order to get pleasurable rewards.But baseline, tonic dopamine levels vary over longer periods as well. The function of this tonic dopamine firing, and its relationship, if any, to phasic dopamine signalling, is less clear. Niv et al's idea is that the tonic dopamine level represents the brain's estimate of the average availability of rewards in the environment, and that it therefore controls how "vigorously" we should do stuff.A high reward availability means that, in general, there's lots of stuff going on, lots of potential gains to be made. So if you're not out there getting some reward, you're missing out. In economic terms, the opportunity cost of not acting, or acting slowly, is high - so you need to hurry up. On the other hand, if there's only minor rewards available, you might as well take things nice and slow, to conserve your energy. Niv et al present a simple mathematical model in which a hypothetical rat must decide how often to press a lever in order to get food, and show that it accounts for the data from animal learning experiments.The distinction between phasic dopamine (a specific reward) vs. tonic dopamine (overall reward availability) is a bit like the distinction between fear vs. anxiety. Fear is what you feel when something scary, i.e. harmful, is right there in front of you. Anxiety is the sense that something harmful could be round the next corner.This theory accounts for the fact that if you give someone a drug that increases dopamine levels, such as amphetamine, they become hyperactive - they do more stuff, faster, or at least try to. That's why they call it speed. This happens to animals too. Yet this hyperactivity starts almost immediately, which means that it can't be a product of learning.It also rings true in human terms. The feeling that everything's incredibly important, and that everyday tasks are really exciting, is one of the main effects of amphetamine. Every speed addict will have a story about the time they stayed up all night cleaning every inch of their house or organizing their wardrobe. This can easily develop into the compulsive, pointless repetition of the same task over and over. People with bipolar disorder often report the same kind of thing during (hypo)mania.What controls tonic dopamine levels? A really brilliantly elegant answer would be: phasic dopamine. Maybe every time phasic dopamine levels spike in response to a reward (or something which you've learned to associate with a reward), some of the dopamine gets left over. If there's lots of phasic dopamine firing, which suggests that the availability of rewards is high, the tonic dopamine levels rise.Unfortunately, it's probably not that simple, as signals from different parts of the brain seem to alter tonic and phasic dopamine firing largely independently, and this would mean that tonic dopamine would only increase after a good few rewards, not pre-emptively, which seems unlikely. The truth is, we don't know what sets the dopamine tone, and we don't really know what it does; but Niv et al's account is the most convincing I've come across...Niv Y, Daw ND, Joel D, & Dayan P (2007). Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology, 191 (3), 507-20 PMID: 17031711... Read more »
Niv Y, Daw ND, Joel D, & Dayan P. (2007) Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology, 191(3), 507-20. PMID: 17031711
"It's pretty painless. Basically you just need to lie there and make sure you don't move your head".This is what I say to all the girls... who are taking part in my fMRI studies. Head movement is a big problem in fMRI. If your head moves, your brain moves and all fMRI analysis assumes that the brain is perfectly still. Although head movement correction is now a standard part of any analysis software, it's not perfect.It may be a particular problem in functional connectivity studies, which attempt to measure the degree to which different parts of the brain are "talking" to each other, in terms of correlated neural activity over time. These are extremely popular nowadays. It's even been claimed that this data may help us understand consciousness itself (although we've heard that before).A new paper offers some important words of caution. It shows that head motion affects estimates of functional connectivity. The more motion, the weaker the measured connectivity in long-range networks, while shorter range connections were stronger. Also, men tended to move more than women.The effect was small - head movement can't explain more than a small fraction of the variability in connectivity.The authors looked at 1,000 scans from healthy volunteers. They just had to lie in the scanner at rest. They looked at functional connectivity, using standard "motion correction" methods, and correlated it with head movement (which you can measure very accurately from the MRI images themselves.) Men tended to move more than women. Could this explain why women tend to have higher functional connectivity?Disconcertingly, head movement was associated with low long range / high short range connections, which is exactly what's been proposed to happen in autism (although in fairness, not all the evidence for this comes from fMRI).This clearly doesn't prove that the autism studies are all dodgy, but it's an issue. People with autism, and people with almost any mental or physical disorder, on average tend to move more than healthy controls.One caveat. Could it be that brain activity causes head movement, rather than the reverse? The authors don't consider this. Head movement must come from the brain, of course. Probably from the motor cortex. The fact that motor cortex functional connectivity was positively associated with movement does suggest a possible link.However, this paper still ought to make anyone who's using functional connectivity worry - at least a little.Head motion is a particularly insidious confound. It is insidious because it biases between-group studies often in the direction of the hypothesized difference....even though there is considerable variation that is not due to head motion, in any given instance, a between-group difference could be entirely due to motion. Van Dijk, K., Sabuncu, M., & Buckner, R. (2011). The Influence of Head Motion on Intrinsic Functional Connectivity MRI NeuroImage DOI: 10.1016/j.neuroimage.2011.07.044... Read more »
Van Dijk, K., Sabuncu, M., & Buckner, R. (2011) The Influence of Head Motion on Intrinsic Functional Connectivity MRI. NeuroImage. DOI: 10.1016/j.neuroimage.2011.07.044
Irving Kirsch, best known for that 2008 meta-analysis allegedly showing that "Prozac doesn't work", has hit the headlines again.This time it's a paper claiming that something does work. Actually Kirsch is only a minor author on the paper by Kaptchuck et al: Placebos without Deception.In essence, they asked whether a placebo treatment - a dummy pill with no active ingredients - works even if you know that it's a placebo. Conventional wisdom would say no, because the placebo effect is driven by the patient's belief in the effectiveness of the pill.Kaptchuck et al took 80 patients with Irritable Bowel Syndrome (IBS) and recruited them into a trial of "a novel mind-body management study of IBS". Half of the patients got no treatment at all. The other half got sugar pills, after having been told, truthfully, that the pills contained no active drugs but also having been told to expect improvement in a 15 minute briefing session on the grounds thatplacebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.Guess what? The placebo group did better than the no treatment group, or at least they reported that they did (all the outcomes were subjective). The article has been much blogged about, and you should read those posts for a more detailed and in some cases skeptical examination, but really, this is entirely unsurprising and doesn't challenge the conventional wisdom about placebos.The folks in this trial believed in the possibility that the pills would make them feel better. They just wouldn't have agreed to take part otherwise. And when those people got the treatment that they expected to work, they felt better. That's just the plain old placebo effect. We already know that the placebo effect is very strong in IBS, a disease which is, at least in many cases, psychosomatic.So the only really new result here is that there are people out there who'll believe that they'll experience improvement from sugar pills, if you give them a 15 minute briefing about the "mind-body self-healing" properties of those pills. That's an interesting addition to the record of human quirkiness, but it doesn't really tell us anything new about placebos.Kaptchuk, T., Friedlander, E., Kelley, J., Sanchez, M., Kokkotou, E., Singer, J., Kowalczykowski, M., Miller, F., Kirsch, I., & Lembo, A. (2010). Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome PLoS ONE, 5 (12) DOI: 10.1371/journal.pone.0015591... Read more »
Kaptchuk, T., Friedlander, E., Kelley, J., Sanchez, M., Kokkotou, E., Singer, J., Kowalczykowski, M., Miller, F., Kirsch, I., & Lembo, A. (2010) Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. PLoS ONE, 5(12). DOI: 10.1371/journal.pone.0015591
According to a new paper in the prestigous journal PNAS, High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China.The earthquake, you'll remember, happened on 12th May last year in central China. Over 60,000 people died. The authors of this paper took 44 earthquake survivors, and 32 control volunteers who had not experienced the disaster.The volunteers underwent a "resting state" fMRI scan; survivors were scanned between 13 and 25 days after the earthquake. Resting state fMRI is simply a scan conducted while lying in the scanner, not doing anything in particular. Previous work has shown that fMRI can be used to measure resting state neural activity in the form of low-frequency oscillations.The authors found differences in the resting state low-frequency activity (ALFF) between the trauma survivors and the controls. In survivors, resting state activity was increased in several areas:"The whole-brain analysis indicated that, vs. controls, survivors showed significantly increased ALFF in the left prefrontal cortex and the left precentral gyrus, extending medially to the left presupplementary motor area... [and] region of interest (ROI) analyses revealed significantly increased ALFF in bilateral insula and caudate and the left putamen in the survivor group..."They also reported correlations between resting activity in some of these areas and self-reported anxiety and depression symptoms in the survivors.Finally, survivors showed reduced functional connectivity between a wide range of areas ("a distributed network that included the bilateral amygdala, hippocampus, caudate, putamen, insula, anterior cingulate cortex, and cerebellum.") Functional connectivity analysis measures the correlation in activity across different areas of the brain - whether the areas tend to activate at the same time or not.Now - what does all this mean? And does it help us understand the brain?The fact that there are differences between the two groups is not very informative or surprising. "Resting state" neural activity presumably reflects whatever is going through a person's mind. Recent earthquake survivors are going to be thinking about rather different things compared to luckier people who didn't experience such trauma. It doesn't take a brain scan to tell you that, but that's all these scans really tell us.But these weren't just any differences - they were particular differences in particular brain regions. Does that make knowing about them more interesting and useful?Not as such, because we don't know what they represent, or what causes them. So living through an earthquake gives you "Increased ALFF in the left prefrontal cortex" - but what does that mean? It could mean almost anything. The left prefrontal cortex is a big chunk of the brain, and its functions probably include most complex cognitive processes. Ditto for the other areas mentioned.The authors link their findings to previous work with frankly vague statements such as "The increased regional activity and reduced functional connectivity in frontolimbic and striatal regions occurred in areas known to be important for emotion processing". But anatomically speaking, most of the brain is either "fronto-limbic" or "striatal", and almost everywhere is involved in "emotion processing" in one way or another.So I don't think we understand the brain much better for reading this paper. Further work, building on these results, might give insights. We might, say, learn that decreased connectivity between Regions X and Y is because trauma decreases serotonin levels, which prevents signals being communicated between these areas, which is why trauma victims can't use X to deliberately stop recalling traumatic memories, which is what Y does.I just made that up. But that's a theory which could be tested. Much of today's neuroimaging research doesn't involve testable theories - it is merely the exploratory search for neural differences between two groups. Neuroimaging technology is powerful, and more advanced techniques are always being developed. What with resting state, functional connectivity, pattern-classification analysis, and other fancy methods, the scope for finding differences between groups is enormous and growing. So I'm being rather unfair in criticizing this paper; there are hundreds like it. I picked this one because it was published last week in a good journal.Exploratory work can be useful as a starting point, but at least in my opinion, there is too much of it. If you want to understand the brain, as opposed to simply getting published papers to your name, you need a theory sooner or later. That's what science is about.Lui, S., Huang, X., Chen, L., Tang, H., Zhang, T., Li, X., Li, D., Kuang, W., Chan, R., Mechelli, A., Sweeney, J., & Gong, Q. (2009). High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0812751106... Read more »
Lui, S., Huang, X., Chen, L., Tang, H., Zhang, T., Li, X., Li, D., Kuang, W., Chan, R., Mechelli, A.... (2009) High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.0812751106
Absinthe is a spirit. It's very strong, and very green. But is it something more?I used to think so, until I came across this paper taking a skeptical look at the history and science of the drink, Padosch et al's Absinthism a fictitious 19th century syndrome with present impactAbsinthe is prepared by crushing and dissolving the herb wormwood in unflavoured neutral alcohol and then distilling the result; other herbs and spices are added later for taste and colour.It became extremely popular in the late 19th century, especially in France, but it developed a reputation as a dangerous and hallucinogenic drug. Overuse was said to cause insanity, "absinthism", much worse than regular alcoholism. Eventually, absinthe was banned in the USA and most but not all European countries.Much of the concern over absinthe came from animal experiments. Wormwood oil was found to cause hyperactivity and seizures in cats and rodents, whereas normal alcohol just made them drunk. But, Padosch et al explain, the relevance of these experiments to drinkers is unclear, because they involved high doses of pure wormwood extract, whereas absinthe is much more dilute. The fact that authors at the time used the word absinthe to refer to both the drink and the pure extract added to the confusion.It's now known that wormwood, or at least some varieties of it, contains thujone, which can indeed cause seizures, and death, due to being a GABA antagonist. Until a few years ago it was thought that old-style absinthe might have contained up to 260 mg of thujone per litre, a substantial dose.But that was based on the assumption that all of the thujone in the wormwood ended up in the drink prepared from it. Chemical analysis of actual absinthe has repeatedly found that it contains no more than about 6 mg/L thujone. The alcohol in absinthe would kill you long before you drank enough to get any other effects. As the saying goes, "the dose makes the poison", something that is easily forgotten.As Padosch et al point out, it's possible that there are other undiscovered psychoactive compounds in absinthe, or that long-term exposure to low doses of thujone does cause "absinthism". But there is no evidence for that so far. Rather, they say, absinthism was just chronic alcoholism, and absinthe was no more or less dangerous than any other spirit.I'm not sure why, but drinks seem to attract more than their fair share of urban myths. Amongst many others I've heard that the flakes of gold in Goldschläger cause cuts which let alcohol into your blood faster; Aftershock crystallizes in your stomach, so if you drink water the morning afterwards, you get drunk again; and that the little worm you get at the bottom of some tequilas apparently contains especially concentrated alcohol, or hallucinogens, or even cocaine maybe.Slightly more serious is the theory that drinking different kinds of drinks instead of sticking to just one gets you drunk faster, or gives you a worse hangover, or something, especially if you do it in a certain order. Almost everyone I know believes this, although in my drinking experience it's not true, but I'm not sure that it's completely bogus, as I have heard somewhat plausible explanations i.e. drinking spirits alongside beer leads to a concentration of alcohol in your stomach that's optimal for absorption into the bloodstream... maybe.Link: Not specifically related to this but The Poison Review is an excellent blog I've recently discovered all about poisons, toxins, drugs, and such fun stuff.Padosch SA, Lachenmeier DW, & Kröner LU (2006). Absinthism: a fictitious 19th century syndrome with present impact. Substance abuse treatment, prevention, and policy, 1 (1) PMID: 16722551... Read more »
Padosch SA, Lachenmeier DW, & Kröner LU. (2006) Absinthism: a fictitious 19th century syndrome with present impact. Substance abuse treatment, prevention, and policy, 1(1), 14. PMID: 16722551
When you smoke pot, you get stoned.Simple. But it's not really, because stoned can involve many different effects, depending upon the user's mental state, the situation, the variety and strength of the marijuana, and so forth. It can be pleasurable, or unpleasant. It can lead to relaxed contentment, or anxiety and panic. And it can feature hallucinations and alterations of thinking, some of which resemble psychotic symptoms.In Central nervous system effects of haloperidol on THC in healthy male volunteers, Liem-Moolenaar et al tested whether an antipsychotic drug would modify the psychoactive effects of Δ9-THC, the main active ingredient in marijuana. They took healthy male volunteers, who had moderate experience of smoking marijuana, and gave them inhaled THC. They were pretreated with 3 mg haloperidol, or placebo.They found that haloperidol reduced the "psychosis-like" aspects of the marijuana intoxication. However, it didn't reverse the effects of THC of cognitive performance, the sedative effects, or the user's feelings of "being high".This makes sense, if you agree with the theory that the psychosis-like effects of THC are related to dopamine. Like all antipsychotics, haloperidol blocks ... Read more »
Liem-Moolenaar, M., Te Beek, E., de Kam, M., Franson, K., Kahn, R., Hijman, R., Touw, D., & van Gerven, J. (2010) Central nervous system effects of haloperidol on THC in healthy male volunteers. Journal of Psychopharmacology. DOI: 10.1177/0269881109358200
A few months ago, I asked Why Do We Sleep?That post was about sleep researcher Jerry Siegel, who argues that sleep evolved as a state of "adaptive inactivity". According to this idea, animals sleep because otherwise we'd always be active, and constant activity is a waste of energy. Sleeping for a proportion of the time conserves calories, and also keeps us safe from nocturnal predators etc.Siegel's theory in what we might call minimalist. That's in contrast to other hypotheses which claim that sleep serves some kind of vital restorative biological function, or that it's important for memory formation, or whatever. It's a hotly debated topic.But Siegel wasn't the first sleep minimalist. J. Allan Hobson and Robert McCarley created a storm in 1977 with The Brain As A Dream State Generator; I read somewhere that it provoked more letters to the Editor in the American Journal of Psychiatry than any other paper in that journal.Hobson and McCarley's article was so controversial because they argued that dreams are essentially side-effects of brain activation. This was a direct attack on the Freudian view that we dream as a result of our subconscious desires, and that dreams have hidden meanings. Freudian psychoanalysis was incredibly influential in American psychiatry in the 1970s.Freud believed that dreams exist to fulfil our fantasies, often though not always sexual ones. We dream about what we'd like to do - except we don't dream about it directly, because we find much of our desires shameful, so our minds disguise the wishes behind layers of metaphor etc. "Steep inclines, ladders and stairs, and going up or down them, are symbolic representations of the sexual act..." Interpreting the symbolism of dreams can therefore shed light on the depths of the mind.Hobson and McCarley argued that during REM sleep, our brains are active in a similar way to when we are awake; many of the systems responsible for alertness are switched on, unlike during deep, dreamless, non-REM sleep. But of course during REM there is no sensory input (our eyes are closed), and also, we are paralysed: an inhibitory pathway blocks the spinal cord, preventing us from moving, except for our eyes - hence why it's Rapid Eye Movement sleep.Dreams are simply a result of the "awake-like" forebrain - the "higher" perceptual, cognitive and emotional areas - trying to make sense of the input that it's receiving as a result of waves of activation arising from the brainstem. A dream is the forebrain's "best guess" at making a meaningful story out of the assortment of sensations (mostly visual) and concepts activated by these periodic waves. There's no attempt to disguise the shameful parts; the bizarreness of dreams simply reflects the fact that the input is pretty much random.Hobson and McCarley proposed a complex physiological model in which the activation is driven by the giant cells of the pontine tegmentum. These cells fire in bursts according to a genetically hard-wired rhythm of excitation and inhibition.The details of this model are rather less important than the fact that it reduces dreaming to a neurological side effect. This doesn't mean that the REM state has no function; maybe it does, but whatever it is, the subjective experience of dreams serves no purpose.A lot has changed since 1977, but Hobson seems to have stuck by the basic tenets of this theory. A good recent review came out in Nature Neuroscience last year, REM sleep and dreaming. In this paper Hobson proposes that the function of REM sleep is to act as a kind of training system for the developing brain.The internally-generated signals that arise from the brainstem (now called PGO waves) during REM help the forebrain to learn how to process information. This explains why we spend more time in REM early in life; newborns have much more REM than adults; in the womb, we are in REM almost all the time. However, these are not dreams per se because children don't start reporting experiencing dreams until about the age of 5.Protoconscious REM sleep could therefore provide a virtual world model, complete with an emergent imaginary agent (the protoself) that moves (via fixed action patterns) through a fictive space (the internally engendered environment) and experiences strong emotion as it does so.This is a fascinating hypothesis, although very difficult to test, and it begs the question of how useful "training" based on random, meaningless input is.While Hobson's theory is minimalist in that it reduces dreams, at any rate in adulthood, to the status of a by-product, it doesn't leave them uninteresting. Freudian dream re-interpretation is probably ruled out ("That train represents your penis and that cat was your mother", etc.), but if dreams are our brains processing random noise, then they still provide an insight into how our brains process information. Dreams are our brains working away on their own, with the real world temporarily removed.Of course most dreams are not going to give up life-changing insights. A few months back I had a dream which was essentially a scene-for-scene replay of the horror movie Cloverfield. It was a good dream, scarier than the movie itself, because I didn't know it was a movie. But I think all it tells me is that I was paying attention when I watched Cloverfield.On the other hand, I have had several dreams that have made me realize important things about myself and my situation at the time. By paying attention to your dreams, you can work out how you really think, and feel, about things, what your preconceptions and preoccupations are. Sometimes.Hobson JA, & McCarley RW (1977). The brain as a dream state generator: an activation-synthesis hypothesis of the dream process. The American journal of psychiatry, 134 (12), 1335-48 PMID: 21570Hobson, J. (2009). REM sleep and dreaming: towards a theory of protoconsciousness Nature Reviews Neuroscience, 10 (11), 803-813 DOI: 10.1038/nrn2716... Read more »
Hobson JA, & McCarley RW. (1977) The brain as a dream state generator: an activation-synthesis hypothesis of the dream process. The American journal of psychiatry, 134(12), 1335-48. PMID: 21570
Hobson, J. (2009) REM sleep and dreaming: towards a theory of protoconsciousness. Nature Reviews Neuroscience, 10(11), 803-813. DOI: 10.1038/nrn2716
Wouldn't it be cool if you could measure brain activation with fMRI... right as it happens?You could lie there in the scanner and watch your brain light up. Then you could watch your brain light up some more in response to seeing your brain light up, and watch it light up even more upon seeing your brain light up in response to seeing itself light up... like putting your brain between two mirrors and getting an infinite tunnel of activations.Ok, that would probably get boring, eventually. But there'd be some useful applications too. Apart from the obvious research interest, it would allow you to attempt fMRI neurofeedback: training yourself to be able to activate or deactivate parts of your brain. Neurofeedback has a long (and controversial) history, but so far it's only been feasible using EEG because that's the only neuroimaging method that gives real-time results. EEG is unfortunately not very good at localizing activity to specific areas.Now MIT neuroscientists Hinds et al present a new way of doing right-now fMRI: Computing moment to moment BOLD activation for real-time neurofeedback. It's not in fact the first such method, but they argue that it's the only one that provides reliable, truly real-time signals.Essentially the approach is closely related to standard fMRI analysis processes, except instead of waiting for all of the data to come in before starting to analyze it, it incrementally estimates neural activation every time a new scan of the brain arrives, while accounting for various forms of noise. They first show that it works well on some simulated data, and then discuss the results of a real experiment in which 16 people were asked to alternately increase or decrease their own neural response to hearing the noise of the MRI scanner (they are very noisy). Neurofeedback was given by showing them a "thermometer" representing activity in their auditory cortex.The real-time estimates of activation turned out to be highly correlated with the estimates given by conventional analysis after the experiment was over - though we're not told how well people were able to use the neurofeedback to regulate their own brains.Unfortunately, we're not given all of the technical details of the method, so you won't be able to jump into the nearest scanner and look into your brain quite yet, though they do promise that "this method will be made publicly available as part of a real-time functional imaging software package."Hinds, O., Ghosh, S., Thompson, T., Yoo, J., Whitfield-Gabrieli, S., Triantafyllou, C., & Gabrieli, J. (2010). Computing moment to moment BOLD activation for real-time neurofeedback NeuroImage DOI: 10.1016/j.neuroimage.2010.07.060... Read more »
Hinds, O., Ghosh, S., Thompson, T., Yoo, J., Whitfield-Gabrieli, S., Triantafyllou, C., & Gabrieli, J. (2010) Computing moment to moment BOLD activation for real-time neurofeedback. NeuroImage. DOI: 10.1016/j.neuroimage.2010.07.060
Last month I wrote about how electrical stimulation of the hippocampus causes temporary amnesia - Zapping Memories Away.Now Toronto neurologists Laxton et al have tried to use deep brain stimulation (DBS) to improve memory in people with Alzheimer's disease. Progressive loss of memory is the best-known symptom of this disorder, and while some drugs are available, they provide partial relief at best.This study stems from a chance discovery by the same Toronto group. In 2008, they reported that stimulation of the hypothalamus caused vivid memory recollections a 50 year old man. In that case, the effect was entirely unintended and unexpected. The patient was being given DBS to try to curb his appetite (he weighed 420 pounds.) The hypothalamus is involved in regulating appetite, not memory - but the fornix, a nerve bundle that passes through that area, is. It's the main pathway connecting the hippocampus to the rest of the brain, and the hippocampus is vital for memory.In this new study, Laxton et al implanted electrodes to stimulate the fornix in 6 patients with mild (early-stage) Alzheimer's. What happened? The results, unfortunately, were quite messy. On average, the patients symptoms got worse over the course of the year. Alzheimer's is a progressive degenerative disease, so this is what you'd expect to happen without treatment. The authors say that the decline was a bit slower than you'd expect in these kinds of patients, but to be honest, it's impossible to tell because there was no control group.However, two patients did show memory improvements, and these were the same two who reported vivid recollections when the electrodes were first implanted (similar to the original obese guy):Two of the 6 patients reported stimulation induced experiential phenomena. Patient 2 reported having the sensation of being in her garden, tending to the plants on a sunny day... Patient 4 reported having the memory of being fishing on a boat on a wavy blue colored lake with his sons and catching a large green and white fish. On later questioning in both patients, these events were autobiographical, had actually occurred in the past, and were accurately reported according to the patient’s spouse.Also, the stimulation caused brain activation, generally switching "on" the areas that are turned "off" in Alzheimer's, and this lasted for a year (the length of the study so far). And there were no major side-effects. That's all good.Overall, these results are extremely interesting, but we don't know how well the treatment really works, and we won't know until someone does a randomized controlled trial with a longer follow-up period; something which is, unfortunately, true of a lot of the latest DBS studies.Link: The Neurocritic on the original 2008 paper.Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, & Lozano AM (2010). A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Annals of neurology PMID: 20687206... Read more »
Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS.... (2010) A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Annals of neurology. PMID: 20687206
A couple of months ago I pointed out that a Letter published in the American Journal of Psychiatry, critiquing a certain paper about antidepressants, made very similar points to the ones that I did in my blog post about the paper. The biggest difference was that my post came out 9 months sooner.Well, it's happened again. Except I was only 3 months ahead this time. Remember my post Clever New Scheme, criticizing a study which claimed to have found a brilliant way of deciding which antidepressant is right for someone, based on their brain activity?That post went up on July 21st. Yesterday, October 19th, a Letter was published by the journal that ran the original paper. Three months ago, I said -...there were two groups in this trial and they got entirely different sets of drugs. One group also got rEEG-based treatment personalization. That group did better, but that might have nothing to do with the rEEG......it would have been very simple to avoid this issue. Just give everyone rEEG, but shuffle the assignments in the control group, so that everyone was guided by someone else's EEG...This would be a genuinely controlled test of the personalized rEEG system, because both groups would get the same kinds of drugs... Second, it would allow the trial to be double-blind: in this study the investigators knew which group people were in, because it was obvious from the drug choice... Thirdly, it wouldn't have meant they had to exclude people whose rEEG recommended they get the same treatment that they would have got in the control group...Now Alexander C. Tsai says, in his Letter:DeBattista et al. chose a study design that conflates the effect of rEEG-guided pharmacotherapy with the effects of differing medication regimes...A more definitive study design would have been one in which study participants were randomized to receive rEEG-guided pharmacotherapy vs. sham rEEG-guided pharmacotherapy.Such a study design could have been genuinely double blinded,would not have required the inclusion of potential subjects whose rEEG treatment regimen was different from the control, and would be more likely to result in medication regimens that were balanced on average across the intervention vs. control arms.To be fair, he also makes a separate point questioning how meaningful the small between-group difference was.I'm mentioning this not because I want to show off, or to accuse Tsai of ripping me off, but because it's a good example of why people like Royce Murray are wrong. Murray recently wrote an editorial in the academic journal Analytical Chemistry, accusing blogging of being unreliable compared to proper, peer-reviewed science.Murray is certainly right that one could use a blog as a platform to push crap ideas, but one can also use peer reviewed papers to do that, and often it's bloggers who are the first to pick up on this when it happens.Tsai AC (2010). Unclear clinical significance of findings on the use of referenced-EEG-guided pharmacotherapy. Journal of psychiatric research PMID: 20943234... Read more »
Tsai AC. (2010) Unclear clinical significance of findings on the use of referenced-EEG-guided pharmacotherapy. Journal of psychiatric research. PMID: 20943234
A news feature in Nature asks whether placebo controls are always a good idea: Why Fake It?
The piece looks at experimental neurosurgical treatments for Parkinson's, such as "Spheramine". This consists of cultured human cells, which are implanted directly into the brain of the sufferer. The idea is that the cells will grow and help produce dopamine, which is deficient in Parkinson's.
Peggy Willocks, a 44 year old teacher, took part in a trial of the surgery in 2000. She says it helped stave off the symptoms for years, but the development of Spheramine was axed in 2008 after a controlled trial found it didn't work any better than a placebo.
The placebo was "sham surgery" i.e. putting the patient through a full surgical procedure, and making holes in their skull, but without doing anything to their brain.
It's cheap and easy to do a placebo controlled trial of a drug - all you need is a sugar pill. But with neurosurgery, it's clearly a lot more involved. A placebo has to be believable. Convincing sham surgery is expensive, time-consuming, and it has real risks, albeit small ones.
Is it ethical to put patients through that?
That, I think, can only be decided on a trial-by-trial basis. It depends on the likely benefits of the treatment, and whether the trial is scientifically sound. Obviously, it'd be wrong to do sham surgery as part of a flawed trial that won't tell us anything useful.
The Nature article, however, goes further than this, and suggests that placebo controlled trials may be unsuitable for testing these kinds of treatments, failing to detect a real benefit in some patients:
There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story. Some say, therefore, that sham controls are sinking the prospects of valuable drugs.
Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with [Roger Barker of Cambridge], says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.A patient advocate agrees:
According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.’”...Cohen [says] that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized. I'm not sure about this. If I had Parkinson's, I would certainly hate to miss out on the genuine cure because a trial had failed to recognize that it worked. But equally, I would not be happy to be given a rubbish treatment that would have failed a placebo controlled trial, but never got one, because of arguments like this.
Placebo controlled trials can fail to detect benefits if they are too short, too small, methodologically flawed, or whatever. Certainly, a trial can be placebo controlled, and still crap. But the answer is surely to do better trials, not no trials.
It may well be that we shouldn't rush to do placebo controlled trials until later in the development process, when the technique has been properly refined. But the history of medicine is littered with treatments that "we know work for some people" - that didn't.
Katsnelson, A. (2011). Experimental therapies for Parkinson's disease: Why fake it? Nature, 476 (7359), 142-144 DOI: 10.1038/476142a... Read more »
Katsnelson, A. (2011) Experimental therapies for Parkinson's disease: Why fake it?. Nature, 476(7359), 142-144. DOI: 10.1038/476142a
It's always nice when a local boy makes good in the big wide world. Many British neuroscientists and psychiatrists have been feeling rather proud this week following the enormous amount of attention given to Professor David Nutt, formerly the British government's chief adviser on illegal drugs.Formerly being the key word. Nutt was sacked (...write your own "nutsack" pun if you must) last Friday, prompting a remarkable amount of condemnation. Critics included the rest of his former organisation, the Advisory Council on the Misuse of Drugs (ACMD), and the Government's Science Minister. The UK's Chief Scientist also spoke in favour of Nutt's views. Journalists joined in the fun with headlines like "politicians are intoxicated by cowardice".Even Nature today ran a bluntly-worded editorial -"The sacking of a government adviser on drugs shows Britain's politicians can't cope with intelligent debate... the position of the Labour government and of the leading opposition party, the Conservatives, which vigorously supported Nutt's sacking, has no merit at all. It deals a significant blow both to the chances of an informed and reasoned debate over illegal drugs, and to the parties' own scientific credibility."They also have an interview with the man himself.*What happened? The short answer is a lecture Nutt gave on the 10th October, Estimating Drug Harms: A Risky Business? I'd recommend reading it (it's free). The Government's dismissal e-mail gave two reasons why he had to go - firstly, "Your recent comments have gone beyond [matters of evidence] and have been lobbying for a change of government policy" and secondly, "It is important that the government's messages on drugs are clear and as an advisor you do nothing to undermine public understanding of them."Many people believe that Nutt was fired because he argued for the liberalization of drug laws, or because he claimed that the harms of some illegal drugs, such as cannabis, are less severe than those of legal substances like tobacco and alcohol. On this view, the government's actions were "shooting the messenger", or dismissing an expert because they didn't like to hear to the facts. It seems to me, however, that the truth is a little more nuanced, and even more stupid.*Nutt's lecture, if you read the whole thing as opposed to the quotes in the media, is remarkably mild. For instance, at no point does he suggest that any drug which is currently illegal should be made legal. The changes he "lobbies for" are ones that the ACMD have already recommended, and this lobbying consists of nothing more than tentative criticism of the stated reasons for the rejection of the ACMD's advice. The ACMD is government's official expert body on illicit drugs, remember.The issue Nutt focusses on is the question of whether cannabis should be a "Class C" or a "Class B" illegal drug, B being "worse", and carrying stricter penalties. It was Class B until 2004, when it was made Class C. In 2007, the Government asked the ACMD to advise on whether it should be re-reclassified back up to Class B. This was in response to concerns about the impact of cannabis on mental health, specifically the possibility that it raises the risk of psychotic illnesses.The resulting ACMD report is available on the Government's website. They concluded that while cannabis use is certainly not harmless, "the harms caused by cannabis are not considered to be as serious as drugs in class B and therefore it should remain a class C drug."Despite this, the Government took the decision to reclassify cannabis as Class B. In his lecture Nutt criticizes this decision - slightly. Nutt quotes the Home Secretary as saying, in response to the ACMD's report -"Where there is a clear and serious problem [i.e. cannabis health problems], but doubt about the potential harm that will be caused, we must err on the side of caution and protect the public. I make no apology for that. I am not prepared to wait and see."Nutt describes this reasoning as -"the precautionary principle - if you’re not sure about a drug harm, rank it high... at first sight it might seem the obvious decision – why wouldn’t you take the precautionary principle? We know that drugs are harmful and that you can never evaluate a drug over the lifetime of a whole population, so we can never know whether, at some point in the future, a drug might lead to or cause more harm than it did early in its use."But he says, there's more to it than this. Firstly, we don't know anything about how classification affects drug use. The whole idea of upgrading cannabis to Class B to protect the public relies on the assumption that it will reduce drug use by deterring people from using it. But there is no empirical evidence as to whether this actually happens. As Nutt points out, stricter classification might equally well increase use by making it seem forbidden, and hence, cooler. (If you think that's implausible, you have forgotten what it is like to be 16.) We just don't know.Second, he says, the precautionary principle devalues the evidence and is thereby self-defeating because it means that people will not take any warnings about drug harms seriously - "[it] leads to a position where people really don’t know what the evidence is. They see the classification, they hear about evidence and they get mixed messages. There’s quite a lot of anecdotal evidence that public confidence in the scientific probity of government has been undermined in this kind of way." Can anyone really dispute this?Finally, he raises the MMR vaccine scare as an example of the precautionary principle ironically leading to concrete harms. Concerns were raised about the safety of a vaccine, on the basis of dubious science. As a result, vaccine coverage fell, and the incidence of measles, mumps and rubella in Britain rose for the first time in decades. The vaccine harmed no-one; these diseases do. We just don't know whether cannabis reclassification will have similar unintended consequences.That's what the Home Secretary described as "lobbying for a change of government policy". I wish all lobbyists were this reasonable.The Home Secretary's second charge against Nutt - "It is important that the government's messages on drugs are clear..." - is even more specious. Nutt's messages were the ACMD's messages, and as he points out, the only lack of clarity comes from the fact that the government and their own Advisory Council disagree with each other. This is hardly the ACMD's fault, and it's certainly not Nutt's fault for pointing it out.All of this is doubly ridiculous because of one easily-forgotten fact - cannabis was downgraded from Class B to Class C in 2004 by the present Labour Party government. Nutt's "lobbying" therefore consists of a recommendation that the government do something they themselves previously did. And if the government are worried about the clarity of their message, the fact that they themselves were saying that cannabis was benign enough to be a Class C drug just 5 years ago might be somewhat relevant.*... Read more »
Is there a gene for long life?Boston-based group Sebastiani et al say they've found not one but two, in RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans.They took 4 groups of "oldest old" people: from New England, Italy, and Japan, and American Ashkenazi Jews. All were aged 90 or more, and many of them were 100, centenarians. As control groups, they used random healthy people who weren't especially old. The total sample size was an impressive 2105 old vs. 3044 controls.On the basis of a pilot study, they chose to look at two candidate genes, ADARB1 and ADARB2. Both are involved in post-transcriptional RNA editing, one of the steps in the process by which genetic material, DNA, controls protein synthesis. It's something every cell in the body needs to do in order to function.What happened? Their abstract makes the exciting claim that18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study ... We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity.But read the whole paper and the picture is a little more complex. For ADARB1, they looked at 31 variants (SNPs). In the New England sample, which was the largest, 5 of them were statistically significantly more common in old people compared to the controls. However, none of these were significantly associated in any of the other samples, although for 3 of the 5 variants, there was some evidence of an effect in the same direction in the other samples.In ADARB2, out of 114 variants, 10 were significantly associated in the New England sample. Of these, 4 were independently significant in the Italian sample, and in the combined New England/Italian sample all 10 were still associated. But the Jewish and the Japanese samples showed a rather different picture: only 1 of the 10 associations was significant in the Jews, although several were weakly associated in the same direction, and in a pooled New England/Italian/Jewish analysis 9 were still significant. In the Japanese sample, one association was replicated but another variant was associated in the wrong direction.They also did some lab work and found that in nematode worms (C. Elegans), mutants lacking the worm equivalent of the ADARB1 and ADARB2 genes had a 50% reduced lifespan - 10 days, instead of the normal 20 - despite no obvious symptoms of illness. Hmm.I'm not quite sure what to make of this data. They looked at 4 separate, large samples, which is an excellent size by the standards of candidate gene association studies. The evidence implicating ADARB1 and (especially) ADARB2 variants in longevity is fairly convincing, although the most consistent effects came from the European-ancestry samples, suggesting that different things might be going on in other populations. This is the first research looking at these genes; ultimately, we won't know for sure until we get more. The worm data is a nice touch, but I'd like to see evidence from animals with a bit more similarity to humans, say mice.Still, suppose that these genes are associated with long life; suppose they they control the rate of the ageing process, protecting you from dying from "natural causes" too early. That doesn't mean that you'll live to an old age - it just makes it possible. If you get hit a truck or fall of a cliff, you're dead, anti-ageing genes or not.Frenchwoman Jeanne Calment, born 1875, died 1997, is the oldest person on record, at 122 years. But we'll never know whether someone with the genetic potential to outlive her died in WW2, or the Cultural Revolution, or just got hit by a truck. Calment presumably had the right genes, but she was also lucky.So a trait's being genetically heritable doesn't make it pre-ordained and immutable. IQ, for example, most likely has a heritability of around 50% - some people likely have a higher potential for intellectual achievement than others. But if you're born into an abusive family, or deep poverty, or you never get a chance to go to school, you may never reach that potential. There's always that truck.Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, & Perls TT (2009). RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PloS one, 4 (12) PMID: 20011587... Read more »
Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S.... (2009) RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PloS one, 4(12). PMID: 20011587
It's a cliché, but it's true - "schizophrenia genes" are the Holy Grail of modern psychiatry.Were they to be discovered, such genes would provide clues towards a better understanding of the biology of the disease, and that could lead directly to the development of better medications. It might also allow "genetic counselling" for parents concerned about their children's risk of schizophrenia.Perhaps most importantly for psychiatrists, the definitive identification of genes for a mental illness would provide cast-iron proof that psychiatric disorders are "real diseases", and that biological psychiatry is a branch of medicine like any other. Schizophrenia, generally thought of as the most purely "biological" of all mental disorders, is the best bet.With this in mind, let's look at three articles (1,2,3) published in Nature last month to much excited fanfare along the lines of 'Schizophrenia genes discovered!' All three were based on genome-wide association studies (GWAS). In a GWAS, you examine a huge number of genetic variants in the hope that some of them are associated with the disease or trait you're interested in. Several hundred thousand variants per study is standard at the moment. This is the genetic equivalent of trying to find the person responsible for a crime by fingerprinting everyone in town.The Nature papers were based on three seperate large GWAS projects - the SGENE-plus, the MGS, and the ICS. In total, there were over 8,000 schizophrenia patients and 19,000 healthy controls in these studies - enormous samples by the standards of human genetics research, and large enough that if there were any common genetic variants with even a modest effect on schizophrenia risk, they would probably have found them.What did they find? On the face of it, not much. The MGS(1) "did not produce genome-wide significant findings...power was adequate in the European-ancestry sample to detect very common risk alleles (30–60% frequency) with genotypic relative risks of approximately 1.3 ...The results indicate that there are few or no single common loci with such large effects on risk." In the SGENE-plus(2), likewise, "None of the markers gave P values smaller than our genome-wide significance threshold".The ISC study(3) did find one significantly associated variant in the Major Histocompatability Complex (MHC) region on chromosome 6. The MHC is known to be involved in immune function. When the data from all three studies were pooled together, several variants in the same region were also found to be significantly associated with schizophrenia.Somewhat confusingly, all three papers did this pooling, although they each did it in slightly different ways - the only area in which all three analyses found a result was the MHC region. The SGENE team's analysis, which was larger, also implicated two other, unrelated variants, which were not found in other two papers.To summarize, three very large studies found just one "schizophrenia gene" even after pooling their data. The variant, or possibly cluster of related ones, is presumably involved in the immune system. Although the authors of the Nature papers made much of this finding, the main news here is that there is at most one common variant which raises the relative risk of schizophrenia by even just 20%. Given that the baseline risk of schizophrenia is about 1%, there is at most one common gene which raises your risk to more than 1.2%. That's it.So, what does this mean? There are three possibilites. First, it could be that schizophrenia genes are not "common". This possibility is getting a lot of attention at the moment, thanks to a report from a few months back, Walsh et al, suggesting that some cases of schizophrenia are caused by just one rare, high-impact mutation, but a different mutation in each case. In other words, each case of schizophrenia could be genetically almost unique. GWAS studies would be unable to detect such effects.Second, there could be lots of common variants, each with an effect on risk so tiny that it wasn't found even in these three large projects. The only way to identify them would be to do even bigger studies. The ISC team's paper claims that this is true, on the basis of this graph: They took all of the variants which were more common in schizophrenics than in controls, even if they were only slightly more common, and totalled up the number of "slight risk" variants each person has.The graph shows that these "slight risk" markers were more common in people with schizophrenia from two entirely seperate studies, and are also more common in people with bipolar disorder, but were not associated with five medical illnesses like diabetes. This is an interesting result, but these variants must have such a tiny effect on risk that finding them would involve spending an awful lot of time (and money) for questionable benefit.The third and final possibility is that "schizophrenia" is just less genetic than most psychiatrists think, because the true causes of the disorder are not genetic, and/or because "schizophrenia" is an umbrella term for many different diseases with different causes. This possibility is not talked about much in respectable circles, but if genetics doesn't start giving solid results soon, it may be.Purcell, S., & et Al (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder Nature DOI: 10.1038/nature08185Shi, J., & et Al (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia Nature DOI: 10.1038/nature08192... Read more »
Purcell, S., & et Al. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. DOI: 10.1038/nature08185
Shi, J., & et Al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. DOI: 10.1038/nature08192
Deep-brain stimulation (DBS) is probably the most exciting emerging treatment in psychiatry. DBS is the use of high-frequency electrical current to alter the function of specific areas of the brain. Originally developed for Parkinson's disease, over the past five years DBS has been used experimentally in severe clinical depression, OCD, Tourette's syndrome, alcoholism, and more.Reports of the effects have frequently been remarkable, but there have been few scientifically rigorous studies, and the number of psychiatric patients treated to date is just dozens. So the true usefulness of the technique is unclear. How DBS works is also a mystery. Even the most basic questions - such as whether high-frequency stimulation switches the brain "on" or "off" - are still being debated.Recent data from rodents sheds some important light on the issue: Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. The authors took rats, and implanted DBS electrodes in the infralimbic cortex. This area is part of the vmPFC. It's believed to be the rat equivalent of the human region BA25, the subgenual cingulate cortex, which is the most common target for DBS in depression. The current settings (100 microA, 130 Hz, 90 microsec) were chosen to be similar to the ones used in humans.In a standard rat model of depression, the forced-swim test, infralimbic DBS exerted antidepressant-like effects. DBS was equally as effective as imipramine, a potent antidepressant, in terms of reducing "depression-like" behaviours, namely immobility.This is not all that surprising. Almost everything which treats depression in humans also reduces immobility in this test (along with few things which don't treat it). Much more interesting is what did and did not block the effects of DBS in these rats.First off, DBS worked even when the rat's infralimbic cortex had been destroyed by the toxin ibotenic acid. This strongly suggests that DBS does not work simply by activating the infralimbic cortex, even though this is where the electrodes were implanted.Crucially, infralimbic lesions did not have an antidepressant effect per se, which also rules out the theory that DBS works by inactivating this region. (Infralimbic lesions produced by other methods did have a mild antidepressant effect, but it was smaller than the effect of DBS. This may still be important, however.)What did block the effects of DBS was the depletion of serotonin (5HT). Serotonin is known to its friends as the brain's "happy chemical", although it's a bit more complicated than that. Most antidepressants target serotonin. And rats whose serotonin systems had been lesioned got no benefit from DBS in this study.So this suggests that DBS might work by affecting serotonin, and indeed, DBS turned out to greatly increase serotonin release, even in a distant part of the brain (the hippocampus). Interestingly this lasted for nearly two hours after the electrodes were switched off.Depletion of another neurotransmitter, noradrenaline, did not alter the effects of DBS.Overall, it seems that infralimbic DBS works by increasing serotonin release, but that this is not because it activates or inactivates the infralimbic cortex itself. Rather, nearby structures must be involved. The most likely explanation is that DBS affects nearby white-matter tracts carrying signals between other areas of the brain; the infralimbic cortex might just happen to be "by the roadside". Many researchers believe that this is how DBS works in humans, but this is the first hard evidence for this.Of course, evidence from rats is never all that hard when it comes to human mental illness. We need to know whether the same thing is true in people. As luck would have it, you can temporarily reduce human serotonin levels with a technique called acute tryptophan depletion This reverses the effects of antidepressants in many people. If this rat data is right, it should also temporarily reverse the benefits of DBS. Someone should do this experiment as soon as possible - I'd like to do it myself, but I'm British, and all the DBS research happens in America. Bah, humbug, old bean.There's a couple of others things to note here. In other behavioural tests, infralimbic DBS also had antidepressant-like effects: it seemed to reduce anxiety, and it made rats more resistant to the stress of having electrical shocks (although only slightly.) Finally, DBS in another region, the striatum, had no antidepressant effect at all. That's a bit odd because DBS of the striatum does seem to treat depression in humans - but the part of the striatum targeted here, the caudate-putamen, is quite separate to the one targeted in human depression, the nucleus accumbens.Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry DOI: ... Read more »
Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009) Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. Biological Psychiatry. DOI: 10.1016/j.biopsych.2009.08.025
Young children with autism prefer looking at geometric patterns over looking at other people. At least, some of them do. That's according to a new study - Preference for Geometric Patterns Early in Life As a Risk Factor for Autism.Pierce et al took 110 toddlers (age 14 to 42 months). Some of them had autism, some had "developmental delay" but not autism, and some were normally developing.The kids were shown a one-minute video clip. One half of the screen showed some kids doing yoga, while the other was a set of ever-changing complex patterns. A bit like a screensaver or a kaleidoscope. Eye-tracking apparatus was used to determine which side of the screen each child was looking at.What happened? Both the healthy control children, and the developmentally delayed children, showed a strong preference for the "social" stimuli - the yoga kids. However, the toddlers with an autism spectrum disorder showed a much wider range of preferences. 40% of them preferred the geometric patterns. Age wasn't a factor.Intuitively this makes sense because one of the classic features of autism is a fascination with moving shapes such as wheels, fans, and so on. The authors conclude thatA preference for geometric patterns early in life may be a novel and easily detectable early signature of infants and toddlers at risk for autism.But only a minority of the autism group showed this preference, remember. As you can see from the plot above, they spanned the whole range - and over half behaved entirely normally.There was no difference between the "social" and "geometrical" halves of the autism group on measures of autism symptoms or IQ, so it wasn't just that only "more severe" autism was associated with an abnormal preference.They re-tested many of the kids a couple of weeks later, and found a strong correlation between their preference on both occasions, suggesting that it is a real fondness for one over the other - rather than just random eye-wandering.So this is an interesting result, but it's not clear that it would be of much use for diagnosis.Pierce K, Conant D, Hazin R, Stoner R, & Desmond J (2010). Preference for Geometric Patterns Early in Life As a Risk Factor for Autism. Archives of general psychiatry PMID: 20819977... Read more »
Pierce K, Conant D, Hazin R, Stoner R, & Desmond J. (2010) Preference for Geometric Patterns Early in Life As a Risk Factor for Autism. Archives of general psychiatry. PMID: 20819977
Schizophrenia is generally thought of as the "most genetic" of all psychiatric disorders and in the past 10 years there have been heroic efforts to find the genes responsible for it, with not much success so far.A new study reminds us that there's more to it than genes alone: Social Risk or Genetic Liability for Psychosis? The authors decided to look at adopted children, because this is one of the best ways of disentangling genes and environment.If you find that the children of people with schizophrenia are at an increased risk of schizophrenia (they are), that doesn't tell you whether the risk is due to genetics, or environment, because we share both with our parents. Only in adoption is the link between genes and environment broken.Wicks et al looked at all of the kids born in Sweden and then adopted by another Swedish family, over several decades (births 1955-1984). To make sure genes and environment were independent, they excluded those who were adopted by their own relatives (i.e. grandparents), and those lived with their biological parents between the ages of 1 and 15. This is the kind of study you can only do in Scandinavia, because only those countries have accessible national records of adoptions and mental illness...What happened? Here's a little graph I whipped up:Brighter colors are adoptees at "genetic risk", defined as those with at least one biological parent who was hospitalized for a psychotic illness (including schizophrenia but also bipolar disorder.) The outcome measure was being hospitalized for a non-affective psychosis, meaning schizophrenia or similar conditions but not bipolar.As you can see, rates are much higher in those with a genetic risk, but were also higher in those adopted into a less favorable environment. Parental unemployment was worst, followed by single parenthood, which was also quite bad. Living in an apartment as opposed to a house, however, had only a tiny effect.Genetic and environmental risk also interacted. If a biological parent was mentally ill and your adopted parents were unemployed, that was really bad news.But hang on. Adoption studies have been criticized because children don't get adopted at random (there's a story behind every adoption, and it's rarely a happy one), and also adopting families are not picked at random - you're only allowed to adopt if you can convince the authorities that you're going to be good parents.So they also looked at the non-adopted population, i.e. everyone else in Sweden, over the same time period. The results were surprisingly similar. The hazard ratio (increased risk) in those with parental mental illness, but no adverse circumstances, was 4.5, the same as in the adoption study, 4.7.For environment, the ratio was 1.5 for unemployment, and slightly lower for the other two. This is a bit less than in the adoption study (2.0 for unemployment). And the two risks interacted, but much less than they did in the adoption sample.However, one big difference was that the total lifetime rate of illness was 1.8% in the adoptees and just 0.8% in the nonadoptees, despite much higher rates of unemployment etc. in the latter. Unfortunately, the authors don't discuss this odd result. It could be that adopted children have a higher risk of psychosis for whatever reason. But it could also be an artefact: rates of adoption massively declined between 1955 and 1984, so most of the adoptees were born earlier, i.e. they're older on average. That gives them more time in which to become ill.A few more random thoughts:This was Sweden. Sweden is very rich and compared to most other rich countries also very egalitarian with extremely high taxes and welfare spending. In other words, no-one in Sweden is really poor. So the effects of environment might be bigger in other countries.On the other hand this study may overestimate the risk due to environment, because it looked at hospitalizations, not illness per se. Supposing that poorer people are more likely to get hospitalized, this could mean that the true effect of environment on illness is lower than it appears.The outcome measure was hospitalization for "non-affective psychosis". Only 40% of this was diagnosed as "schizophrenia". The rest will have been some kind of similar illness which didn't meet the full criteria for schizophrenia (which are quite narrow, in particular, they require 6 months of symptoms).Parental bipolar disorder was counted as a family history. This does make sense because we know that bipolar disorder and schizophrenia often occur in the same families (and indeed they can be hard to tell apart, many people are diagnosed with both at different times.)Overall, though, this is a solid study and confirms that genes and environment are both relevant to psychosis. Unfortunately, almost all of the research money at the moment goes on genes, with studying environmental factors being unfashionable.Wicks S, Hjern A, & Dalman C (2010). Social Risk or Genetic Liability for Psychosis? A Study of Children Born in Sweden and Reared by Adoptive Parents. The American journal of psychiatry PMID: 20686186... Read more »
Wicks S, Hjern A, & Dalman C. (2010) Social Risk or Genetic Liability for Psychosis? A Study of Children Born in Sweden and Reared by Adoptive Parents. The American journal of psychiatry. PMID: 20686186
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