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

Neuroskeptic
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  • March 17, 2010
  • 05:32 AM
  • 25 views

Mmm... Food-Induced Seizures

by Neuroskeptic in Neuroskeptic

In a tasty new paper, British neurologists Kate El Bouzidi et al report on the case of a woman who suffered epileptic seizures whenever she saw, or tasted, food:A 44-year-old right-handed woman was walking in the Scottish highlands. Upon unwrapping her lunch, she had a focal seizure with witnessed onset on the right side of the face and secondary generalization... She was airlifted to hospital. Three weeks later, the smell of food triggered another seizure and she was admitted to the neurology unit...Even hospital fare was able to provoke the attacks:The next morning, the patient had a simple partial seizure after eating a spoonful of porridge. Thereafter, most meals triggered seizures, as did other food-related stimuli such as being offered a piece of cake, seeing her visitors pass around food at her bedside, and smelling the hospital dinner trolley.Anti-convulsant drugs failed to control the seizures. An MRI scan revealed an abnormal mass and electrode recordings from the surface of the brain confirmed that the seizure activity was starting nearby. The mass was surgically removed - it turned out to have been a grade IV glioblastoma cancer - which put an end to the seizures, although sadly we're told that the surgery was "subtotal" i.e. they weren't able to remove the tumour entirely.The authors note that eating-induced seizures have been reported hundreds of times, most commonly in India and Sri Lanka, curiously enough, but this is the first known case in which merely seeing or thinking about food was also a trigger. Why it happens is a mystery: presumably, neural activation in response to the taste or smell of food somehow spills over into the epileptic focus... but the details are sketchy.In this case, seizures were specifically triggered by food-related stimuli in the context of hunger. The finding of a seizure focus in the left frontal operculum, adjacent to the tumor, is consistent with the hypothesis that activation of this region by appetite triggered seizure activity that then propagated to the surrounding cortex and was manifest clinically as a motor seizure.El Bouzidi K, Duncan S, Whittle IR, & Butler CR (2010). Lesional reflex epilepsy associated with the thought of food. Neurology, 74 (7), 610-2 PMID: 20157165... Read more »

El Bouzidi K, Duncan S, Whittle IR, & Butler CR. (2010) Lesional reflex epilepsy associated with the thought of food. Neurology, 74(7), 610-2. PMID: 20157165  

  • March 15, 2010
  • 05:52 AM
  • 64 views

How to Stop Smoking

by Neuroskeptic in Neuroskeptic

1. Don't smoke.2. See 1.This is essentially what Simon Chapman and Ross MacKenzie suggest in a provocative PloS Medicine paper, The Global Research Neglect of Unassisted Smoking Cessation: Causes and Consequences.Their point is deceptively simple: there is lots of research looking at drugs and other treatments to help people quit smoking tobacco, but little attention is paid to people who quit without any help, despite the fact that the majority (up to 75%) of quitters do just that. This is good news for the pharmaceutical industry and others who sell smoking-cessation aids, but it's not clear that it's good for public health.As they put it,despite the pharmaceutical industry’s efforts to promote pharmacologically mediated cessation and numerous clinical trials demonstrating the efficacy of pharmacotherapy, the most common method used by most people who have successfully topped smoking remains unassisted cessation ... Tobacco use, like other substance use, has become increasingly pathologised as a treatable condition as knowledge about the neurobiology, genetics, and pharmacology of addiction develops. Meanwhile, the massive decline in smoking that occurred before the advent of cessation treatment is often forgotten.Debates over drugs, or other treatments, tend to revolve around the question of whether they work: is this drug better than placebo for this disorder? Chapman and MacKenzie point out that even to frame an issue in these terms is to concede a lot to the medical or pathological approach, which may not be a good idea. Before asking, do the drugs work? We should ask, what have drugs got to do with this?Their argument is not that drugs never help people to quit; nor are they saying that tobacco isn't addictive, or that there is no neurobiology of addiction. Rather, they are saying that the biology is only one aspect of the story. The importance of drugs (and other stop-smoking aids like CBT), and the difficulty of quitting, is systematically exaggerated by the medical literature...Of the 662 papers [about "smoking cessation" published in 2007 or 2008], 511 were studies of cessation interventions. The other 118 were mainly studies of the prevalence of smoking cessation in whole or special populations. Of the intervention papers, 467 (91.4%) reported the effects of assisted cessation and 44 (8.6%) described the impact of unassisted cessation (Figure 1).... Of the papers describing cessation trends, correlates, and predictors in populations, only 13 (11%) contained any data on unassisted cessation.And although pharmaceutical industry funding of research plays a part in this, the fact that medical science tends to focus on treatments rather than on untreated individuals is unsurprising since this is fundamentally how science works:Most tobacco control research is undertaken by individuals trained in positivist scientific traditions. Hierarchies of evidence give experimental evidence more importance than observational evidence; meta-analyses of randomized controlled trials are given the most weight. Cessation studies that focus on discrete proximal variables such as specific cessation interventions provide ‘‘harder’’ causal evidence than those that focus on distal, complex, and interactive influences that coalesce across a smoker’s lifetime to end in cessation.Overall, it's an excellent paper and well worth a read in full (it's short and it's open access). Of course, it is itself only one side of the story and many in the tobacco control community will find it controversial. But I think Chapman and MacKenzie's is a point that needs to be made, and point applies to other areas of medicine, especially, although not exclusively, to mental health. This week, British social care charity Together told us thatSix out of ten of people have had at least one time in their life where they have found it difficult to cope mentally... stress (70%), anxiety (59%) and depression (55%) were the three most common difficulties encountered by the publicWhich was not still not quite as good as rivals Turning Point who last month saidThree quarters of people in the UK experience depression occasionally or regularly yet only a third seek helpThese were opinion surveys, not real peer-reviewed science, but they might as well have been: the best available science says that if you go and ask people, 50-70% of the population report suffering at least one diagnosable DSM-IV mental disorder in their lifetime, and that the majority receive no treatment at all. This leads to papers in major journals such as this one warning that "Depression Care in the United States" is "Too Little for Too Few."But we don't know whether these tens of millions of cases of untreated "mental illness" should be treated, because there is basically no research looking at what happens to such people without treatment. On the other hand, the very fact that they aren't treated, and yet manage to hold down jobs, relationships and so forth, suggests that the situation is not so bad.Of course we must never forget that depression and anxiety can be crippling diseases, but fortunately, such cases are at least comparatively rare. By using the word "depression" to cover everything from waking-up-at-4-am-in-a-suicidal-panic-melancholia to feeling-a-bit-miserable-because-something-bad-just-happened, it's easy to forget that while clinical depression is a serious matter, feeling a bit miserable is normal and resolves without any help 99% of the time. Even though there are no published scientific studies proving this, because it's not the kind of thing scientists study.Incidentally, this issue is a good reminder that there's no one big bad conspiracy behind everything. With smoking, Big Tobacco find themselves in direct opposition to Big Pharma, like in From Dusk Till Dawn when the psychopaths fight the vampires. With depression, the people who are quickest to decry the widespread use of antidepressants often seem to be the ones who are most keen on the idea that depression is common and under-treated, perhaps because it allows them to recommend their own favorite psychotherapy. Big Pharma hands the baton to Big Couch in the race to medicalize life.Chapman S, & MacKenzie R (2010). The global research neglect of unassisted smoking cessation: causes and consequences. PLoS medicine, 7 (2) PMID: 20161722... Read more »

  • March 10, 2010
  • 05:10 PM
  • 66 views

Can We Rely on fMRI?

by Neuroskeptic in Neuroskeptic

Craig Bennett (of Prefrontal.org) and Michael Miller, of dead fish brain scan fame, have a new paper out: How reliable are the results from functional magnetic resonance imaging?Tal over at the [citation needed] blog has an excellent in-depth discussion of the paper, and Mind Hacks has a good summary, but here's my take on what it all means in practical terms.Suppose you scan someone's brain while they're looking at a picture of a cat. You find that certain parts of their brain are activated to a certain degree by looking at the cat, compared to when they're just lying there with no picture. You happily publish your results as showing The Neural Correlates of Cat Perception.If you then scanned that person again while they were looking at the same cat, you'd presumably hope that exact same parts of the brain would light up to the same degree as they did the first time. After all, you claim to have found The Neural Correlates of Cat Perception, not just any old random junk.If you did find a perfect overlap in the area and the degree of activation that would be an example of 100% test-retest reliability. In their paper, Bennett and Miller review the evidence on the test-retest reliability of fMRI studies. They found 63 of them. On average, they found that the reliability of fMRI falls quite far short of perfection: the areas activated (clusters) had a mean Dice overlap of 0.476, while the strength of activation was correlated with a mean ICC of 0.50.But those numbers, taken out of context, do not mean very much. Indeed, what is a Dice overlap? You'll have to read the whole paper to find out, but even when you do, they still don't mean that much. I suspect this is why Bennett and Miller don't mention them in the Abstract of the paper, and in fact they don't spend more than a few lines discussing them at all.A Dice overlap of 0.476 and an ICC of 0.50 are what you get if average over all of the studies that anyone's done looking at the test-retest reliability of any particular fMRI experiment. But different fMRI experiments have different reliabilities. Saying that the average reliability of fMRI is 0.5 is rather like saying that the mean velocity of a human being is 0.3 km per hour. That's probably about right, averaging over everyone in the world, including those who are asleep in bed and those who are flying on airplanes - but it's not very useful. Some people are moving faster than others, and some scans are more reliable than others.Most of this paper is not concerned with "how reliable fMRI is", but rather, with how to make any given scanning experiment more reliable. And this is an important thing to write about, because even the most optimistic cognitive neuroscientist would agree that many fMRI results are not especially reliable, and as Bennett and Miller say, reliability matters for lots of reasons:Scientific truth. While it is a simple statement that can be taken straight out of anundergraduate research methods course, an important point must be made about reliability in research studies: it is the foundation on which scientific knowledge is based. Without reliable, reproducible results no study can effectively contribute to scientific knowledge.... if a researcher obtains a different set of results today than they did yesterday, what has really been discovered?Clinical and Diagnostic Applications. The longitudinal assessment of changes in regional brain activity is becoming increasingly important for the diagnosis and treatment of clinical disorders...Evidentiary Applications. The results from functional imaging are increasingly being submitted as evidence into the United States legal system...Scientific Collaboration. A final pragmatic dimension of fMRI reliability is the ability to share data between researchers...So what determines the reliability of any given fMRI study? Lots of things. Some of them are inherent to the nature of the brain, and are not really things we can change: activation in response to basic perceptual and motor tasks is probably always going to be more reliable than activation related to "higher" functions like emotions.But there are lots of things we can change. Although it's rarely obvious from the final results, researchers make dozens of choices when designing and analyzing an fMRI experiment, many of which can at least potentially have a big impact on the reliability of their findings. Bennett and Miller cover lots of them:voxel size... repetition time (TR), echo time (TE), bandwidth, slice gap, and k-space trajectory... spatial realignment of the EPI data can have a dramatic effect on lowering movement-related variance ... Recent algorithms can also help remove remaining signal variability due to magnetic susceptibility induced by movement... simply increasing the number of fMRI runs improved the reliability of their results from ICC = 0.26 to ICC = 0.58. That is quite a large jump for an additional ten or fifteen minutes of scanning...The details get extremely technical, but then, fMRI is a technology, so that's only to be expected. When you do an fMRI scan you're using a superconducting magnet to image human neural activity by measuring the quantum spin properties of protons. It doesn't get much more technical.Perhaps the central problem with modern neuroimaging research is that it's all too easy for researchers to write off the important experimental design issues as "merely" technicalities, and just put some people in a scanner using the default scan sequence and see what happens. This is something few fMRI users are entirely innocent of, and I'm certainly not, but it is a serious problem. As Bennett and Miller point out, the devil is in the technical details.The generation of highly reliable results requires that sources of error be minimized across a wide array of factors. An issue within any single factor can significantly reduce reliability. Problems with the scanner, a poorly designed task, or an improper analysis method could each be extremely detrimental. Conversely, elimination of all such issues is necessary for high reliability. A well maintained scanner, well designed tasks, and effective analysis techniques are all prerequisites for reliable results.Bennett CM, Miller MB. (2010). How reliable are the results from functional magnetic resonance imaging? Annals of the New York Academy of Sciences... Read more »

Bennett CM, Miller MB. (2010) How reliable are the results from functional magnetic resonance imaging?. Annals of the New York Academy of Sciences. info:/

  • March 8, 2010
  • 03:45 PM
  • 148 views

Life Without Serotonin

by Neuroskeptic in Neuroskeptic

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:/

  • March 2, 2010
  • 02:52 PM
  • 106 views

Is Your Brain A Communist?

by Neuroskeptic in Neuroskeptic

Capitalists beware. No less a journal than Nature has just published a paper proving conclusively that the human brain is a Communist, and that it's plotting the overthrow of the bourgeois order and its replacement by the revolutionary Dictatorship of the Proletariat even as we speak.Kind of. The article, Neural evidence for inequality-averse social preferences, doesn't mention the C word, but it does claim to have found evidence that people's brains display more egalitarianism than people themselves admit to.Tricomi et al took 20 pairs of men. At the start of the study, both men got a $30 payment, but one member of each pair was then randomly chosen to get a $50 bonus. Thus, one guy was "rich", while the other was "poor". Both men then had fMRI scans, during which they were offered various sums of money and saw their partner being offered money too. They rated how "appealing" these money transfers were on a 10 point scale.What happened? Unsurprisingly both "rich" and "poor" said that they were pleased at the prospect of getting more cash for themselves, the poor somewhat more so, but people also had opinions about payments to the other guy:the low-pay group disliked falling farther behind the high-pay group (‘disadvantageous inequality aversion’), because they rated positive transfers to the high-pay participants negatively, even though these transfers had no effect on their own earnings. Conversely, the high-pay group seemed to value transfers [to the poor person] that closed the gap between their earnings and those of the low-pay group (‘advantageous inequality aversion’)What about the brain? When people received money for themselves, activity in the ventromedial prefrontal cortex (vmPFC) and the ventral striatum correlated with the size of their gain.However, when presented with a payment to the other person, these areas seemed to be rather egalitarian. Activity rose in rich people when their poor colleagues got money. In fact, it was greater in that case than when they got money themselves, which means the "rich" people's neural activity was more egalitarian than their subjective ratings were. Whereas in "poor" people, the vmPFC and the ventral striatum only responded to getting money, not to seeing the rich getting even richer.The authors conclude that thisindicates that basic reward structures in the brain may reflect even stronger equity considerations than is necessarily expressed or acted on at the behavioural level... Our results provide direct neurobiological evidence in support of the existence of inequality-averse social preferences in the human brain.Notice that this is essentially a claim about psychology, not neuroscience, even though the authors used neuroimaging in this study. They started out by assuming some neuroscience - in this case, that activity in the vmPFC and the ventral striatum indicates reward i.e. pleasure or liking - and then used this to investigate psychology, in this case, the idea that people value equality per se, as opposed to the alternative idea, that "dislike for unequal outcomes could also be explained by concerns for social image or reciprocity, which do not require a direct aversion towards inequality."This is known as reverse inference, i.e. inference from data about the brain to theories about the mind. It's very common in neuroimaging papers - we've all done it - but it is problematic. In this case, the problem is that the argument relies on the idea that activity in the vmPFC and ventral striatum is evidence for liking.But while there's certainly plenty of evidence that these areas are activated by reward, and the authors confirmed that activity here correlated with monetary gain, that doesn't mean that they only respond to reward. They could also respond to other things. For example, there's evidence that the vmPFC is also activated by looking at angry and sad faces.Or to put it another way: seeing someone you find attractive makes your pupils dilate. If you were to be confronted by a lion, your pupils would dilate. Fortunately, that doesn't mean you find lions attractive - because fear also causes pupil dilation.So while Tricomi et al argue that people, or brains, like equality, on the basis of these results, I remain to be fully convinced. As Russell Poldrack noted in 2006caution should be exercised in the use of reverse inference... In my opinion, reverse inference should be viewed as another tool (albeit an imperfect one) with which to advance our understanding of the mind and brain. In particular, reverse inferences can suggest novel hypotheses that can then be tested in subsequent experiments.Tricomi E, Rangel A, Camerer CF, & O'Doherty JP (2010). Neural evidence for inequality-averse social preferences. Nature, 463 (7284), 1089-91 PMID: 20182511... Read more »

Tricomi E, Rangel A, Camerer CF, & O'Doherty JP. (2010) Neural evidence for inequality-averse social preferences. Nature, 463(7284), 1089-91. PMID: 20182511  

  • February 27, 2010
  • 07:42 AM
  • 80 views

The Decline and Fall of the Cannabinoid Antagonists

by Neuroskeptic in Neuroskeptic

Cannabinoid Receptor, Type 1 (CB1) antagonists were supposed to be the next big thing.They're weight loss drugs, and with obesity rates rising and the diet craze showing no signs of abating, that's a large and growing market (...sorry). They worked, at least in the short term, and they were at least as effective as existing pills. They may even have had health benefits over and above promoting weight loss, such as improving blood fat and sugar levels through metabolic effects.It all started off well. Rimonabant, manufactured by Sanofi, was the first CB1 antagonist to become available for human use: it hit the European market in 2006, as Acomplia. Four large clinical trials showed convincingly that it helped people lose weight. Rival drug companies were hard at work developing other CB1 antagonists, and inverse agonists (similar, but even more potent). The "bants" included Merck's taranabant, Pfizer's otenabant, and more.Even more excitingly, there were indications that CB1 antagonists could do more than help people lose weight: they might also be useful in helping people quit smoking, alcohol or drugs. The animal evidence that CB1 antagonists did this was strong. Human trials were underway. Optimists saw rimonabant and related drugs as offering something unprecedented: self-control in a pill, abstinence on demand.*But it ended in tears, literally. Rimonabant was pulled from the European market in late 2008; it was never approved in the USA at all. After rimonabant was withdrawn, drug companies abandoned the development of other CB1 antagonists.The problem was that they made people depressed. In several large clinical trials of rimonabant it raised the risk of suffering depression and other psychiatric problems, like anxiety and irritability, compared to placebo. The reported rates of these symptoms ranged from a few % up to over 40% depending upon the population, but there have been no trials (except very small ones) in which these effects weren't seen. This means that CB1 antagonists cause depression rather more consistently than antidepressants treat it.Merck have just released the data from a trial of taranabant: A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients. It makes a fitting epitaph to the CB1 antagonists. They gave taranabant, at a range of doses, or placebo, to overweight people to go alongside diet and exercise to help them lose weight. The results were extremely similar to those seen with rimonabant; the drug worked:But there were side effects. Alongside things like nausea, vomiting, and sweating, about 35% of people taking high doses of taranabant reported "psychiatric disorders". 20% of people on placebo also did, so this is not quite as bad as it first appears, but it's still striking, especially since a number of people on high doses of taranabant reported suicidal thoughts or behaviours...Suicidal ideation was reported in three patients in the taranabant 6-mg group in year 1 and in one patient in the 4-mg group in year 2. There was one suicide attempt reported in a patient with a previous history of suicide attempts in the 6/2-mg group while the patient was receiving 2-mg, and one episode of suicidal behavior reported in a patient in the 6/2-mg group while the patient was receiving 6-mg. There were no completed suicides. The adjudication of possibly suicide-related adverse experiences during years 1 and 2 indicated an increased incidence of suicidality in the taranabant groups...This is the kind of thing that gives drug companies nightmares, especially today, in the post-SSRI lawsuits era. This is why rimonabant was removed from the EU market in 2008 and why it was never approved in the US.*Safety concerns have plagued weight loss medications for decades. The problem is not that they don't work: plenty of drugs cause weight loss, at least for as long as you keep taking them. But unfortunately, there's always a 'but'.Fenfluramine worked, but it caused heart valve defects, and was banned. Sibutramine works, but it's just been suspended from the European market due to concerns over heart disease (a different kind). Amphetamine-like stimulants such as phentermine work, but they're addictive and liable to abuse. What with rimonabant and sibutramine are gone, the only weight-loss drug approved for use in Europe is orlistat, which seems to be safe, but has some very unpleasant side effects...Still, CB1 antagonists have a unique mechanism of action: they block the CB1 receptor, which is what gets activated by the cannabinoid ingredients in marijuana, and also the brain's own cannabinoids neurotransmitters (endocannabinoids). The past five years has seen a huge amount of research showing that the CB1 receptor is involved in everything from memory and emotion to motivation, pain sensation and hormone secretion. We recently learned that there are even CB1 receptors on the tongue that regulate taste.CB1 is able to do all this because it's found almost everywhere in the brain. To simplify, but only a little, the endocannabinoid system is a general feedback mechanism, which allows cells on the receiving end of neural transmission to "talk back" to the neuron sending them signals; if they're receiving lots of input, they tell the cell sending the signals to quiet down. In other words, endocannabinoids regulate the release of just about every other neurotransmitter. To be honest, given how important the system is in the brain, it's surprising that depression and anxiety are the biggest problems with CB1 antagonists.For all that, we still don't know why they cause psychiatric symptoms, although a number of mechanisms have been suggested. Hopefully, someone will work this out sooner or later, since that would add an important piece to the puzzle of what goes on in the brain during depression...... Read more »

  • February 24, 2010
  • 07:21 AM
  • 70 views

More on Deep Brain Stimulation for OCD

by Neuroskeptic in Neuroskeptic

Over the past few years, deep brain stimulation (DBS) has emerged as a promising treatment for severe psychiatric disorders that haven't responded to conventional approaches. A new paper from the University of Florida reports on a trial of DBS in obsessive-compulsive disorder (OCD), and unlike most DBS studies, it was placebo-controlled: Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder.Six patients were implanted with electrodes in the "ventral capsule/ventral striatum" (VC/VS). This area has previously been used as a DBS target for OCD. The original reason for choosing to implant electrodes in this region was that it's long been known that destroying the anterior limb of the internal capsule (capsulotomy) alleviates OCD symptoms in many cases, especially if the ventral (lower) part is removed.Did it work? Yes, but not for everyone. Out of the 6 patients who entered the trial, all of whom were extremely ill despite having tried multiple medications and psychotherapy, 4 (66%) eventually responded well. The other 2 unfortunately got little or no benefit over the 12 month trial period.The study had a double-blind, placebo-controlled phase: the patients weren't told when the DBS electrodes were going to be switched on. As the graphs show, in the 3 patients who were randomly selected to have them switched on early, 2 responded pretty much immediately, while in the 3 patients whose electrodes were left off, none responded until they were turned on 30 days later, although the response at this point was fairly gradual.One person (S1), who responded very well initially, suddenly relapsed about a year later. Upon investigation, it turned out that the battery powering their electrodes had worn out, although no-one knew this until the OCD symptoms returned, so this can't have been a placebo effect. They recovered after getting a new battery.Overall there are few surprises here. These results confirm what we already knew about DBS: it works in many people, but not all, with response rates of around 60%; When it works, it works very well; but sometimes the effects take weeks or months to become fully apparent. This could be either because DBS starts some gradual process of change in the brain which takes time to work; or it could be that it often takes a long time to find the right stimulation parameters (voltage, frequency, etc.) which provide a good response, since this has to be done by trial-and-error. Most likely, it's a bit of both.What I found most interesting was that the VC/VS stimulation didn't just treat people's obsessions and compulsions. It also had a mood-improving effect, and crucially, it sounds as though mood was the first thing to improve, with OCD symptoms following days or weeks later:Finding the optimal settings for an individual subject proved challenging...unlike other experiences with DBS, there is not a clear positive symptom (e.g., tremor improvement) to gauge settings. In this study... the goal was to select parameters that produced some benefit in mood or anxiety symptoms acutely, with minimal side effects.and mood was the first thing that got worse when the DBS was accidentally turned off for whatever reason:Worsening in mood or increased anxiety were typically the first symptoms reported following battery depletion or inadvertent inactivation by metal detectors. Other signs of depression, such as diminished energy or interest, also emerged within days of device interruption... Exacerbation of OCD symptoms generally lagged the emergence of affective or anxiety symptoms.And in fact, four people experienced temporary hypomania, i.e. abnormally elevated mood, which is usually seen in bipolar disorder, although none of the patients in this study had a history of bipolar. People also commonly reported increased alertness, motivation, and difficulty falling asleep.This all fits with the fact that VC/VS stimulation has been used as a DBS target for clinical depression, as well as for OCD. Indeed, this suggests that DBS probably works in essentially the same way in both conditions. The drugs that are used to treat OCD are all antidepressants - specifically serotonin-based ones - so this makes sense too.With luck, research on DBS in animals and humans will finally allow us to understand the neural basis of mood states like depression, and mania - something which, despite decades of research on drugs like antidepressants and mood stabilizers, is still deeply mysterious...Goodman, W., Foote, K., Greenberg, B., Ricciuti, N., Bauer, R., Ward, H., Shapira, N., Wu, S., Hill, C., & Rasmussen, S. (2010). Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder: Pilot Study Using a Blinded, Staggered-Onset Design Biological Psychiatry, 67 (6), 535-542 DOI: 10.1016/j.biopsych.2009.11.028... Read more »

  • February 19, 2010
  • 12:03 PM
  • 117 views

Drunk on Alcohol?

by Neuroskeptic in Neuroskeptic

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 »

  • February 17, 2010
  • 11:07 AM
  • 62 views

The Case of the Missing Retrovirus

by Neuroskeptic in Neuroskeptic

In October 2009, a team led by Vincent C. Lombardi of the Whittemore Peterson Institute reported the presence of a recently discovered virus, XMRV, in 67% of the blood samples from 101 American patients with chronic fatigue syndrome (CFS). XMRV had previously been linked to some cases of prostate cancer.This sparked intense interest amongst many people and much discussion. But in January this year, Erlwein et al reported that they did not find any evidence of XMRV in the blood of 186 British CFS patients (my post).Now, a second British study has appeared, and the results are also negative. The paper is Groom et al's Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. They found no XMRV in 170 British CFS patients or 395 healthy controls. VirologyBlog has an excellent summary of the latest paper.In order to help people interested in this topic, I've put together a quick summary of all the data on XMRV infection in humans. If I've left anything out or made any mistakes, let me know in the comments. I'll try to keep this list up to date with every new publication - because there are sure to be plenty more.Overall, the most striking thing about these results is the national differences. XMRV has been detected in 67% of American CFS patients, in 10-25% of American prostate cancer cases, and in 3-4% of healthy Americans. By contrast, in Germany, Britain and Ireland, it's only been detected in 2 Germans, out of a grand total of 1288 European people who have been tested so far using a variety of methods. The situation elsewhere is unclear; one study claimed to detect XMRV in 1.5% of healthy Japanese blood donors but this is unpublished, and the methodology is unclear.Other than that, it's not clear what's going on here, and it seems to me that it would be premature to conclude anything about XMRV and CFS (or, indeed, cancer) at this stage.*Published Papers - CFS1. Lombardi et al 2009Patients: "CDC Fukuda Criteria and the 2003 Canadian Consensus Criteria... presenting with severe disability... their diagnosis of CFS is based upon prolonged disabling fatigue ... cognitive deficits and reproducible immunological abnormalities ... impaired exercise performance with extremely low VO2 max measured on stress testing."Origin: USAMethod A: PCR of DNA from PBMCsResult: 68 of 101 patients (67%), 8 of 218 controls (3.7%)Method B: PBMC reactivity to anti-MLVp30Gag antibodiesResult: 19 of 30 patients (63%), 0 of 16 controls (0%)Method C: Plasma immunoreactivity to SFFV-EnvResult: 9 out of 18 patients with XMRV, 0 out of 7 controls2. Erlwein et al 2010Patients: CDC Fukeda criteria "markedly unwell. Few were working, and 19% were members of patient support groups for CFS/ME... The levels of fatigue in this sample were high ... as were levels of disability"Origin: London, UKMethod: PCR of DNA from whole bloodResult: 0 out of 186 patients (0%)3. Groom et al 2010Patients: CDC Fukeda criteriaOrigin: Bristol, Dorset, London, Birmingham, Norfolk and Epsom, UKMethod A: PCR of gDNA from PBMCsResult: 0 of 48 patients (0%)Method B: PCR of gDNA, cDNA, or both from PBMCsResult: 0 out of 142 patients (0%), and 157 controls (0%)Method C: Serum immunoreactivity to XMRVResult: 1 out of 160 patients; 25 out of 395 controls; but positives were not considered specific to XMRV, as they also reacted to and neutralized other viruses.Published Papers - Prostate Cancer4. Urisman et al 2006Patients: Familial Prostate CancerOrigin: Cleveland, USAMethod: PCR on tumor cell DNAResult: 9 of 86 (10.4%); associated with R462Q QQ genotype5. Schlaberg et al 2009Patients: Prostate CancerOrigin: Columbia University Medical Center, USAMethod A: PCR on tumor cell DNAResults: 14/223 prostate cancer patients (6.2%), 2/101 non-cancer prostate controls (2.0%). Not associated with R462Q QQ genot... Read more »

Harriet Groom, et al. (2010) Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. info:/

  • February 12, 2010
  • 05:19 PM
  • 114 views

Dope, Dope, Dopamine

by Neuroskeptic in Neuroskeptic

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  

  • February 10, 2010
  • 04:56 AM
  • 96 views

Are We All Homeopaths Now?

by Neuroskeptic in Neuroskeptic

There are two main kinds of Complementary and Alternative Medicine (CAM) - the ones that involve actually doing stuff, and the ones that don't.Things like herbal medicine, chiropractic, and acupuncture could plausibly make someone better, as more than just a placebo, given what we know about physics and chemistry, because they involve physically acting on the body. I don't claim to know whether they do in fact work, but in theory, they could.Other CAM techniques, however, are just magic. Homeopathy is the best example of this: it cannot work, except as a placebo, unless our understanding of nature is fundamentally wrong. The "active ingredient" in a homeopathic remedy is diluted in water to the point where not a single molecule of it remains (and then diluted more, for good measure). If some mystical "essence" or "energy" can somehow survive in water despite dilution then, logically, all water must contain the essence of pretty much everything. It literally involves nothing beyond sugar pills and waterBut there's one useful thing about homeopathy: it shines a light on the rest of modern medical science, or rather, it holds up a mirror to it. Unfortunately, the reflection is not as pretty as you'd hope.These two graphs come from a paper by Shang et al, Are the clinical effects of homoeopathy placebo effects?, which was a major meta-analysis of 110 randomized, placebo-controlled trials (RCTs) of homeopathy. It was published in The Lancet in 2005.Shang et al 2005 was bad news for homeopathy, because it concluded that "[the meta-analysis] is compatible with the notion that the clinical effects of homoeopathy are placebo effects." - i.e., homeopathy doesn't work. Since its publication the paper has been hotly criticized by homeopaths, and defended by skeptics, with the skeptics generally being right. But it was bad news for conventional medicine too.These two graphs are funnel plots. Each dot represents a published RCT. Dots to the left of the vertical line are trials where the 'active treatment' did better than the placebo control; the further left, the better. The higher up the dot is, the more "precise" the results of the trial, i.e. the less variability there was in the results. They may not look like much, but they're terrifying.The top funnel plot shows the 110 published RCTs of homeopathy for various illnesses. The bottom one shows 110 RCTs of "proper" medical treatments, for the same diseases, that Shang et al picked out as comparisons. You'll notice that the two plots look rather similar - there's a lot of spread, but most of the dots are to the left of the vertical line, meaning that the treatments were better than the placebos. Quite a lot are very far to the left, meaning the treatment worked really well. Very few are on the right.But homeopathic treatments, by definition, are placebos - they're literally sugar pills. So any trial of homeopathy should have an equal chance of finding it to be better than placebo, or worse. Placebos are placebos. It should be a coin toss, 50/50. In fact, Shang et al found only about 20 trials showing homeopathic placebos to be worse than placebo placebos, and 90 finding they were better.How can this be? Either homeopathy works, in which case we need to rewrite physics and chemistry, or there is something very wrong with the published literature. I find it easier to believe the latter. But then how could the published literature be so wrong?Almost certainly the answer is publication bias, broadly speaking. If people do a trial and don't get the result they want, they generally either don't write it up for publication; or if they try to, it doesn't get published. Related to this is selective outcome bias: they pick out and write up only those results that do match what they wanted; or they pick out statistical techniques to get the result they wanted, etc.The plot for homeopathy RCTs is what you get when people study a treatment that doesn't work, but that they believe does work, and publish their findings in a biased way. But the plot for "real" medicines looks disturbingly like that.In other words, the whole clinical trial literature - all of those RCTs and meta-analyses, published in respectable journals, the ones we rely on to determine what treatment decisions doctors make - could be produced even if all of our treatments were no better than placebos. Like I said, terrifying.I should stress that this doesn't mean that real medicines are no better than placebos. Shang et al's results are also what you'd see if there's no publication bias in conventional medicine, and the treatments work really well. (The evidence for positive effects in the "real medicine" trials was also somewhat stronger than in the homeopathy trials - the dots were further left - which is reassuring, but the difference was pretty small.) The problem though is that we can't tell - at least not on the basis of the clinical trial literature.Luckily, there's an answer - mandatory registration of clinical trials. Medical journals or, ideally, governments, can require researchers to publicly announce the details of each trial, and how they plan to analyze the results, before the trial takes place, and require that the final results are made public. The USA has had such a system in place, backed by law, since 2007, and most major medical journals now demand registration.Sadly, biases still seem to be happening in registered trials. But this doesn't mean the system doesn't work, it just means it should be more strictly enforced, and extended to other countries and, I'd argue, beyond just clinical trials. Either that, or we might as well take up homeopathy.... Read more »

  • February 7, 2010
  • 06:35 AM
  • 84 views

Beware The Clam of Forgetfulness

by Neuroskeptic in Neuroskeptic

Every day, PubCrawler emails to tell me about the latest papers that match various search terms. It means I never miss a relevant paper, but it also means I get told about an awful lot of irrelevant ones. Sometimes though, the title alone grabs my attention and demands a read. Such as yesterday's Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans. Shellfish causing amnesia?It turns out that there's a neurotoxin, domoic acid, which can indeed cause brain damage including memory loss. It's produced by certain algae, and can accumulate inside shellfish, especially mussels.Domoic acid is responsible for amnesic shellfish poisoning, which struck a cluster of over 100 people in Canada in 1987; 4 died, and several others suffered permanent neurological symptoms, including epilepsy and most notoriously, anterograde amnesia, the inability to form new memories.Autopsies revealed prominent damage to the hippocampus and nearby temporal lobe areas. Domoic acid victims were therefore very similar to Henry Molaison (HM), the most famous amnesia sufferer, whose memory loss was caused by the surgical removal of the same areas.Domoic acid is related to kainic acid, which neuroscientists will have heard of: it's widely used in epilepsy research to give animals seizures, amongst other things. Both are excitotoxins - they kill neurons by over-activating them, which opens ion channels allowing calcium to enter the cell and reach toxic levels. They're able to do this because of their chemical similarity to glutamate, the brain's most common neurotransmitter (and the one that the drug ketamine antagonizes).Since 1987, there have been no further cases in humans, thanks to shellfish harvesting regulations. Marine animals and birds continue to suffer however, especially sea lions, although interestingly, sharks seem to be immune despite having the same glutamate receptors as mammals.Overall, this is one more reason I'm glad to be a vegetarian. Although, that said, there are some equally nasty neurotoxins in plants...Kumar KP, Kumar SP, & Nair GA (2009). Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans. Journal of environmental biology / Academy of Environmental Biology, India, 30 (3), 319-25 PMID: 20120452... Read more »

Kumar KP, Kumar SP, & Nair GA. (2009) Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans. Journal of environmental biology / Academy of Environmental Biology, India, 30(3), 319-25. PMID: 20120452  

  • February 3, 2010
  • 07:05 AM
  • 74 views

Imaging the Brain Better, Faster,Thinner

by Neuroskeptic in Neuroskeptic

A lot of the studies that I cast my Neuroskeptical eye over are related to functional magnetic resonance imaging (fMRI).This is because, in my opinion, quite a lot of today's fMRI work suffers from methodological flaws. But that's not to say that all fMRI work is suspect, or, worse, that there's something inherently unscientific about fMRI as such. fMRI's a tool, an amazing one in a lot of ways, but like any tool it needs to be used well. Along with others, I've criticized various aspects of recent fMRI practice, but only because it's frustrating to see such a powerful tool not being used to its full potential.So I was very pleased by a recent paper by Sabatinelli et al, The Timing of Emotional Discrimination in Human Amygdala and Ventral Visual Cortex. The authors set out to test a hypothesis - that seeing an emotionally charged picture would activate the amygdala and the inferotemporal cortex (IT) before activating the extrastriate occipital cortex.This is what should happen according to an influential model of how the brain processes emotionally meaningful information; the theory goes that the amygdala is part of a rapid "emotion detector" pathway, which responds faster than the standard visual perceptual system. You see that it's scary before you see what it is, in other words.To test the prediction, they scanned a single 5mm slice of the brain - see above - which cut through all of the regions of interest given the hypothesis. Most fMRI studies image the whole brain, but because scanning takes time, this produces one whole-brain image every 2 or 3 seconds.Sabatinelli et al's single slice approach gave them 10 scans/second, which was crucial given that they were concerned with detecting which parts of the brain activated first. They scanned people while showing them a series of pictures. Some were boring images with no emotional impact, some were "positive" (i.e. porn), and others were "negative" (bloody pictures of mutilation).The results are on the left. All images activated the visual system more than a blank screen did, unsurprisingly. Both kinds of "emotional" pictures activated the amygdala, IT, and more than the boring ones did (the green line), which is reassuring, since if they didn't, the basic assumptions of the experiment would be in question. And crucially, the emotional vs. non-emotional difference occurred about up to 1s earlier in the amygdala and the IT than in the mOcc (extrastriate occipital cortex), in line with the original predictions.In itself, this doesn't prove the "rapid emotion pathway" model, but it's an important piece of supporting evidence. It's also a great example of the flexibility of fMRI; while it's often thought of as a way to detect where neural activation happens, as opposed to when, with the right scanning parameters, it doesn't have to be that way. Although there's an unavoidable time lag in the BOLD response that fMRI measures - the response peaks about 5 seconds after the brain cells actually fire - this doesn't stop you from investigating the relative timing of activation in different areas, as in this study.The key was that Sabatinelli et al had a specific hypothesis and designed their experiment to test it, as opposed to just scanning people under some conditions and looking to see which parts of the brain lit up - fishing for blobs, as it's known. fMRI is a very powerful tool for blob-fishing, unfortunately. But it's also a powerful tool for doing more informative science.Sabatinelli D, Lang PJ, Bradley MM, Costa VD, & Keil A (2009). The timing of emotional discrimination in human amygdala and ventral visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29 (47), 14864-8 PMID: 19940182... Read more »

Sabatinelli D, Lang PJ, Bradley MM, Costa VD, & Keil A. (2009) The timing of emotional discrimination in human amygdala and ventral visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(47), 14864-8. PMID: 19940182  

  • January 30, 2010
  • 05:12 PM
  • 119 views

Is Depression Undertreated?

by Neuroskeptic in Neuroskeptic

Neuroskeptic readers will be familiar with the idea that too many people are being treated for mental illness. But not everyone agrees. Many people argue that common mental illnesses, such as depression, are undertreated. Take, for example, a paper just out in the esteemed Archives of General Psychiatry: Depression Care in the United States: Too Little for Too Few.The authors looked at the results of three large (total N=15,762) surveys designed to measure the prevalence of mental illness in American adults. I've described how these surveys are conducted before: they took a randomly selected representative sample of Americans, and asked them a standardized series of questions (the CIDI interview) about their mood and emotions, in order to try to diagnose mental illness. The interviewers, while trained, were not clinicians.What did they find? The rate of people experiencing Major Depressive Disorder (MDD), as defined in DSM-IV, in the past year, was 8.3%. When they examined ethnicity, this ranged from 6.7% in African Americans to 11.8% in Puerto Ricans. The average severity of the depression was roughly the same in all ethnic groups.Of those with MDD, 51% reported that they'd had treatment in the past year, either antidepressants, psychotherapy, or both. This ranged from 53% for Whites down to just 29% of Caribbean Blacks and 33% of Mexican Americans. Therapy was somewhat more popular than drugs in all ethnic groups, although a lot of people used both. However, few of the treatments were classed as "guideline-concordant", i.e. long enough to do any good, which they defined asuse of an antidepressant for at least 60 days with supervision by a psychiatrist, or other prescribing clinician, for at least 4 visits in the past year. For psychotherapy...having at least 4 visits to a mental health professional in the past year lasting on average for at least 30 minutes each.Only 21% of depressed people were getting such treatment, even though these strike me as very lenient guidelines, especially in the case of psychotherapy - how much good is 2 hours per year doing to do?*So depression's undertreated. Too little, for too few. But this rests on an assumption: that we should treat Major Depressive Disorder.That might not seem like an assumption, but assumptions generally don't. It seems like common sense, almost a tautology - it's a disorder, of course we should treat it! Yet it's not so simple. DSM-IV criteria for MDD require you to have 5 or more out of a list of 9 symptoms, including either depressed mood or a loss of interest in activities, lasting at least 2 weeks, and causing significant distress or impairment in social, occupational, or other important areas of functioning.Fair enough. That's quite useful as a way of ensuring that psychiatrists in different countries are talking about the same thing when they talk about depression. But to think that depression is undertreated because only half of people meeting DSM-IV criteria for Major Depressive Disorder are being treated, is to put absolute faith in DSM-IV as a guide to who to treat. This is not what the DSM was meant to be, and there's no evidence it works for that purpose.Is it really true that people with 5 symptoms need help, and those with 4 don't? Why not 6, or all 9? Why 2 weeks - why not 3 weeks, or 3 months? It's not as if there are loads of studies showing that treating people who have 5 symptoms for 2 weeks, and not treating people who don't, is the best strategy. I'm not aware of any such research.This is not to say that any other criteria would be better than DSM-IV as guides to treatment, or that there is anything identifiably wrong with the DSM-IV criteria (although there is evidence that antidepressants are not useful in people with relatively "mild" MDD). The point is that doctors don't strictly apply textbook criteria when diagnosing and treating mental illness; they also use clinical judgement.I don't know any psychiatrist who would prescribe treatment for someone solely on the basis that they met DSM-IV criteria for MDD. They would also want to know about the severity of the symptoms, whether they're related to any stresses or life events, how far they're "out of character" for that individual, etc. In general, they would deploy their training and experience to try to judge whether this person would benefit from treatment. This is why the DSM-IV carries a cautionary statement that "The proper use of these criteria requires specialized clinical training that provides both a body of knowledge and clinical skills."So, it's far from clear that we should be treating everyone who answers interview questions in such a way that they meet DSM-IV criteria for Major Depressive Disorder. That's an assumption.This isn't to say that everyone who needs depression treatment gets it. Sadly, there are many sufferers who would benefit from help and don't get any, or don't get it as early as they should. We need to do more to help such people. In this respect, depression is undertreated, although it's hard to know the extent of the problem. Yet it's quite possible that depression is also overtreated at the same time.H/T Thanks to The Neurocritic for drawing my attention to this paper.Gonzalez, H., Vega, W., Williams, D., Tarraf, W., West, B., & Neighbors, H. (2010). Depression Care in the United States: Too Little for Too Few Archives of General Psychiatry, 67 (1), 37-46 DOI: 10.1001/archgenpsychiatry.2009.168... Read more »

Gonzalez, H., Vega, W., Williams, D., Tarraf, W., West, B., & Neighbors, H. (2010) Depression Care in the United States: Too Little for Too Few. Archives of General Psychiatry, 67(1), 37-46. DOI: 10.1001/archgenpsychiatry.2009.168  

  • January 28, 2010
  • 02:33 PM
  • 121 views

The British Media's "Blonde Moment"

by Neuroskeptic in Neuroskeptic

Ten days ago, the Sunday Times - Britain's "newspaper of record" - recorded thatBlonde women born to be warrior princessesWomen with fair hair are more aggressive and determined to get their own way than brunettes or redheads, according to a study by the University of California... “We expected blondes to feel more entitled than other young women — this is southern California, the natural habitat of the privileged blonde,” said Aaron Sell, who led the study...Well who'da thought it. Other sources repeated the story. The problem is, it was all made up. The study in question had nothing to do with blondes, or indeed hair at all. As originally reported over at Neuroworld, Dr. Aaron Sell, the lead author, denies saying the things he is quoted as saying in the article. His response -Journalistic ethics requires, at a minimum, that you remove from this article all references to me, and to the research I and my collaborators have conducted. This article consists almost entirely of empirical claims and quotes about blonde women that Mr. Harlow fabricated, and then attributed to me. Please take the article offline immediately. Once your investigation is completed, please issue a retraction...The Times has done neither - the article's still online. According to Dr. Sell, what happened was that journalist John Harlow noticed the paper, which is about, amongst other things, physical attractiveness and anger. Harlow, whose recent output includes "Brad Pitt and Angelina Jolie no more" and that incisive piece of reportage, "Sandra Bullock overtakes Streep in dash for awards glory", wrote to Sell saying that he was writing an article about blondes, and asking whether Sell's data was relevant.Sell hadn't considered hair color in his research, but he reanalyzed his data on Harlow's request. He found no association between blondness and personality, which is not surprising because it's hair we're talking about. Harlow, apparently unhappy with this, wrote the article anyway, simply making up various claims about blondes and attributing them to Sell and his paper, backed up with some fake quotes.That's what Sell says, anyway. Maybe the Times dispute it, but since they haven't responded in any way, I guess we have to assume they agree. Science blogger Satoshi Kanazawa commented that "by American standards, all British newspapers are tabloids because they don’t distinguish between what is true and what they make up. " You can see his point. But I think the problem is especially serious when it comes to science journalism.A journalist who faked an interview with a politician would be sacked on the spot - so noone would even consider doing that. Scientists, apparently, are fair game. The standard of British journalism in general may not be fantastic, but what appears on the "Science" pages is bad even by the standards of the rest, as Neuroskeptic readers know. To be fair to other journalists, Harlow's article is even worse than average. But it's not unique - a couple of years ago the Guardian ran a front-page story about autism research which was also largely made-up.*In all the excitement over the Times, though, the paper itself hasn't attracted much discussion. What Sell et al actually found was that in men, physical strength (as measured by ability to lift weights, etc.) correlates with the tendency to get angry, and feelings of entitlement. And in both men and women, perceived physical attractiveness was also correlated with angriness and entitlement. Specifically, the men and women were University of California students.What does this mean? Sell et al describe their results as empirical proof of the "recalibrational theory" of anger. This is the idea that evolution provided us with anger to make other people treat us better, because early humans who got angry reaped benefits from it -The function of anger is to orchestrate behavior in the angry individual that creates incentives in the target of the anger to recalibrate upwards the weight he or she puts on the welfare of the angry individual.In essence: we get mad when we think that someone's not giving our interests the weight they deserve. Anger signals to the offender that if they don't pay the proper respect, we'll make them sorry, so they'd better fall into line... or else.Sell et al say that the recalibrational theory predicts that people with more power to make others sorry - people with "formidability" - should get angry more easily, because their formidability means that they're likely to triumph if things came to blows (either literally or metaphorically).They further say that in men, physical strength is an important part of formidability, while in women, attractiveness is more important. While men have the muscles, women have the babies, at least if they're fertile, so having a hot (a signal of fertility according to some accounts) woman, decide not to sleep with you is the ultimate evolutionary defeat for any male who wants to propagate his DNA, which, according to evolutionary psychology, is all of us -males will tend to preempt and hence monopolize ... Read more »

Sell A, Tooby J, & Cosmides L. (2009) Formidability and the logic of human anger. Proceedings of the National Academy of Sciences of the United States of America, 106(35), 15073-8. PMID: 19666613  

  • January 26, 2010
  • 09:15 AM
  • 146 views

The Grid in Your Head

by Neuroskeptic in Neuroskeptic

According to a lovely new Nature paper combining fMRI imaging with animal experiments, the human brain encodes spatial information in the form of of a hexagonal grid - Evidence for grid cells in a human memory network.If you've ever played Chinese checkers, you'll know what a hex grid is. It's already known that in rats, the entorhinal cortex of the brain contains "grid cells", each of which fires according to where in a certain place the rat is. The diagram above left shows how one example grid cell fires more often when the rat is in certain places in a 1m x 1m box.Doeller et al wanted to test whether grid cells exist in humans, but being unable to just stick electrodes in people's heads, they made use of two useful facts about rat grid cells. First, the orientation of the grid is fixed in all the cells in each particular rat, although each cell prefers different locations, i.e. the "grids" are offset, but not rotated. Second, grid cells fire faster when the animal is walking or running in a direction which corresponds to "along the lines" of their brain's internal grid - especially when the movement is rapid.So, if our brains do contain grid cells, our entorhinal cortex should be more active overall when we're moving along the lines of our grids, as opposed to across them. Bearing in mind that there are three axes, and that you could either "forward" or "backward" along each one, that makes 6 directions, so the grid cell theory predicts that entorhinal cortex activity should correlate with direction of motion with "6-way directional symmetry", like this:Doeller et al used fMRI to measure neural activity while 42 volunteers "walked" around a computer-generated landscape on a screen, and looked for areas where activity had the pattern above. Lo and behold, the entorhinal cortex did indeed show this pattern of activity in most volunteers. As a control, they looked for areas showing 4, 5, 7 or 8- fold directional symmetry, and didn't find any.Doeller et al point out that they haven't directly proven the existence of grid cells in humans - in theory, these results could also indicate the presence of another type of cell which encodes direction with 6-way directional symmetry. But this is a great piece of research, and a nice example of using neuroimaging to test neurobiological theories, as opposed to just going hunting for blobs of activation without knowing what to look for, which I've criticized before.Doeller, C., Barry, C., & Burgess, N. (2010). Evidence for grid cells in a human memory network Nature DOI: 10.1038/nature08704... Read more »

  • January 24, 2010
  • 03:28 PM
  • 214 views

A "Severe" Warning for Psychiatry

by Neuroskeptic in Neuroskeptic

Imagine there was a nasty disease that affected 1 in 100 people. And imagine that someone invented a drug which treated it reasonably well. Good work, surely.Now imagine that, for some reason, people decided that 10% of the population need to be taking this drug, instead of 1%. So sales of the drug sky-rocket. Eventually some clever person comes along and asks "This is one of the biggest selling drugs in the world - but does it work?" They look into it, and find that it doesn't work very well at all. For about 9 out of 10 people, it's completely useless! What a crap drug.*Back to reality. According to accepted DSM-IV diagnostic criteria, close to 50% of people suffer from a mental illness at some point; a large fraction of this being depression. 10% of Americans took antidepressants last year according to the best estimates.Guess what? Clever people have started asking "Antidepressants are amongst the biggest selling drugs in the world - but do they work?" And the answer is - not very well. The latest such claim came from Fournier et al and appeared in JAMA a couple of weeks ago: Antidepressant Drug Effects and Depression Severity.These researchers re-analysed the data from six clinical trials testing antidepressants against placebo pills. The drugs were the tricyclic imipramine and the newer SSRI paroxetine. The total sample size was a respectable 718, and most trials lasted 8 weeks, which is longer than average for this kind of study. Here's what they found -Grey circles are people on antidepressants, white circles people on placebo. What this shows is that the more severe the patient's depression, the more they get better - when they're given either drugs or placebos. However, because the improvement on antidepressants rises more steeply, the benefit of antidepressants versus placebos correlates with severity. The thin blue line marks the minimum severity for which the average effect of the drugs over placebo was "clinically significant" according to NICE criteria.*So, this study says that antidepressants work better in more severe depression. This is not a new claim - Kirsch et al (2008) famously found the same thing, and long before that so did Khan et al (2002). However this new analysis has some advantages over previous ones. First, Fournier et al looked at what happened to each patient individually, whereas the previous studies found that in trials where the patients were more severely depressed, on average, antidepressants worked better.Second, the patients in this analysis spanned a wide range of severity scores, from 10 points on the Hamilton Scale to nearly 40. In Kirsch et al almost all the trials had average severities in the narrow range of 22 to 29. Finally, none of the trials in the new paper used a placebo washout period. These are meant to exclude people from the trial if they improve "too well" during an initial week or so of placebo pills. In theory, they bias trials against finding large placebo effects; it's not clear they actually work, but either way, it's good to know it wasn't a factor.*Overall, the evidence all seems to point to the idea that people with more serious clinical depression respond better to antidepressants vs. placebos in clinical trials. The exact details are debatable, there's the issue of whether antidepressant clinical trials are realistic, and the question of how clinically effective antidepressants are is also controversial, but I'm not aware of any studies which have contradicted this central claim.But when you start to think about, this is a very odd result. Fournier et al say thatThe general pattern of results reported in this work is not surprising. As early as the 1950s, researchers conducting controlled investigations of treatments for a wide variety of medical and psychiatric conditions described a phenomenon whereby patients with higher levels of severity showed greater differential (i.e., specific) benefit from the active treatments.and refer to a couple of papers from the 1960s. But I must admit that I do find this very surprising. We don't wait until someone's nearly dead from a bacterial infection before we give them antibiotics, we give them early, when the disease is still mild. Doctors unfortunately don't tell people "Good news! You've got advanced-stage cancer - just the kind where drugs work best." Why is depression so different?Look a little closer, and a possible answer emerges. Severity, in all of these studies, was measured using the Hamilton Rating Scale for Depression (HAMD). The HAMD has 17 items, and each asks whether you're suffering from certain symptoms; the more symptoms you have, and the more pronounced they are, the higher your total score. You get 1 point if you have "occasional difficulty falling asleep", 2 points for "nightly difficulty falling asleep", 4 points for "Hand wringing, nail biting, hair-pulling, biting of lips". Here's the whole thing.The HAMD was designed in 1960 by a psychiatrist, Max Hamilton, and it was originally intended for use by staff at psychiatric hospitals for use on depressed inpatients. So it's not a measure of severity per se: it's a measure of how well your symptoms match those considered to be characteristic of severe depression in 1960.Western psychiatry's concept of depression has changed greatly since then; for one thing, this was 20 years before the DSM-III criteria of depression were published, which form the basis for today's DSM-IV criteria. A quick comparison of the DSM-IV alongside the HAMD reveals a lot of differences. It's quite possible to meet DSM-IV criteria for "Major Depressive Disorder" yet score low on the HAMD.Which brings us back to the imaginary scenario at the start of this post. My personal interpretation of results like those of Fournier et al is this: antidepressants treat classical clinical depression, of the kind that psychiatrists in 1960 would have recognized. This is the kind of depression that they were originally used for, after all, because the first antidepressants arrived in 1953.Yet in recent years "clinical depression" has become a much broader term. Many people attribute this to marketing on the part of pharmaceutical companies. Whatever the cause, it's almost certain that many people are now being prescribed antidepressants for emotional and personal issues which wouldn't have been considered medical illnesses until quite recently. Antidepressants also ha... Read more »

Fournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010) Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis. JAMA: The Journal of the American Medical Association, 303(1), 47-53. DOI: 10.1001/jama.2009.1943  

  • January 22, 2010
  • 06:32 PM
  • 165 views

Brain Scanning Software Showdown

by Neuroskeptic in Neuroskeptic

You've just finished doing some research using fMRI to measure brain activity. You designed the study, recruited the volunteers, and did all the scans. Phew. Is that it? Can you publish the findings yet?Unfortunately, no. You still need to do the analysis, and this is often the most trickiest stage. The raw data produced during an fMRI experiment are meaningless - in most cases, each scan will give you a few hundred almost-identical grey pictures of the person's brain. Making sense of them requires some complex statistical analysis.The very first step is choosing which software to use. Just as some people swear by Firefox while others prefer Internet Explorer for browsing the web, neuroscientists have various options to choose from in terms of image analysis software. Everyone's got a favourite. In Britain, the most popular are FSL (developed at Oxford) and SPM (London), while in the USA BrainVoyager sees a lot of use.These three all do pretty much the same thing, give or take a few minor technical differences, so which one you use ultimately makes little difference. But just as there's more than one way to skin a cat, there's more than one way to analyze a brain. A paper from Fusar-Poli et al compares the results you get with SPM to the results obtained using XBAM, a program which uses a quite different statistical approach.Here's what happened, according to SPM, when 15 volunteers looked at pictures of faces expressing the emotion of fear, and their brain activity was compared to when they were just looking at a boring "X" on the screen (I think - either that it's compared to looking at neutral faces; the paper isn't clear, but given the size of the blobs I doubt it's that.)Various bits of the brain were more activated by the scared face pics, as you can see by the huge, fiery blobs. The activation is mostly at the back of the brain, in occipital cortex areas which deal with vision, which is as you'd expect. The cerebellum was also strongly activated, which is a bit less expected.Now, here's what happens if you analyze exactly the same data using XBAM, setting the statistical threshold at the same level (i.e. in theory being no more or less "strict") -You get the same visual system blobs, but you also see activation in a number of other areas. Or as Fusar-Poli et al put it -Analysis using both programs revealed that during the processing of emotional faces, as compared to the baseline stimulus, there was an increased activation in the visual areas (occipital, fusiform and lingual gyri), in the cerebellum, in the parietal cortex [etc] ... Conversely, the temporal regions, insula and putamen were found to be activated using the XBAM analysis software only.*This begs two questions: why the difference, and which way is right?The difference must be a product of the different methods used. SPM uses a technique called statistical parametric mapping (hence the name) based on the assumption of normality. FSL and BrainVoyager do too. XBAM, on the other hand, differs from more orthodox software in a number of other ways; the most basic difference is that it uses non-parametric statistics but this document lists no less than five major innovations -"not to assume normality but to use permutation testing to construct the null distribution used to make inference about the probability of an "activation" under the null hypothesis.""recognizing the existence of correlation in the residuals after fitting a statistical model to the data."using "a mixed effects analysis of group level fMRI data by taking into account both intra and inter subject variances."using "3D cluster level statistics based on cluster mass (the sum of all the statistical values in the cluster) rather than cluster area (number of voxels)."using "a wavelet-based time series permutation approach that permitted the handling of complex noise processes in fMRI data rather than simple stationary autocorrelation."Phew. Which combination of these are responsible for the difference is impossible to say.The biggest question, though, is: should we all be using XBAM? Is it "better" than SPM? This is where things get tricky. The truth is that there's no right way to statistically analyze any data, let alone fMRI data. There are lots of wrong ways, but even if you avoid making any mistakes, there are still various options as to which statistical methods to use, and which method you use depends on which assumptions you're making. XBAM rests of different assumptions from SPM.Whether XBAM's assumptions are more appropriate than those of SPM is a difficult question. The people who wrote XBAM think so, and they're very smart people. But so are the people who wrote SPM. The point is, it's a very complex issue, the mathematical details of which go far beyond the understanding of most fMRI users (myself included).My worry about this paper is that the average Joe Neuroscientist will decide that, because XBAM produces more activation than SPM, it must be "better". The authors are careful not to say this, but for fMRI researchers working in the publish-or-perish world of modern science, and whose greatest fear is that they'll run an analysis and end up with no blobs at all, the temptation to think "the more blobs the merrier" is a powerful one.Fusar-Poli, P., Bhattacharyya, S., Allen, P., Crippa, J., Borgwardt, S., Martin-Santos, R., Seal, M., O’Carroll, C., Atakan, Z., & Zuardi, A. (2010). Effect of image analysis software on neurofunctional activation during processing of emotional human faces Journal of Clinical Neuroscience DOI: 10.1016/j.jocn.2009.06.027... Read more »

Fusar-Poli, P., Bhattacharyya, S., Allen, P., Crippa, J., Borgwardt, S., Martin-Santos, R., Seal, M., O’Carroll, C., Atakan, Z., & Zuardi, A. (2010) Effect of image analysis software on neurofunctional activation during processing of emotional human faces. Journal of Clinical Neuroscience. DOI: 10.1016/j.jocn.2009.06.027  

  • January 20, 2010
  • 10:45 AM
  • 144 views

The Sweet Taste of Cannabinoids

by Neuroskeptic in Neuroskeptic

Every stoner knows about the munchies, the fondness for junk food that comes with smoking marijuana. Movies have been made about it.It's not just that being on drugs makes you like eating: stimulants, like cocaine and amphetamine, decrease appetite. The munchies are something specific to marijuana. But why?New research from a Japanese team reveals that marijuana directly affects the cells in the taste buds which detect sweet flavors - Endocannabinoids selectively enhance sweet taste.Yoshida et al studied mice, and recorded the electrical signals from the chorda tympani (CT), which carries taste information from the tongue to the brain.They found that injecting the mice with two chemicals, 2AG and AEA, markedly increased the strength of the signals produced in response to sweet tastes - such as sugar, or the sweetener saccharine. However, neither had any effect on the strength of the response to other flavors, like salty, bitter, or sour. Mice given endocannabinoids were also more eager to eat and drink sweet things, which confirms previous findings.2-AG and AEA are both endocannabinoids, an important class of neurotransmitters. Marijuana's main active ingredient, Δ9-THC, works by mimicking the action of endocannabinoids. Although Δ9-THC wasn't tested in this study, it's extremely likely that it has the same effects as 2-AG and AEA.In follow-up experiments, Yoshida et al found that endocannabinoids enhance sweet taste responses by acting on cannabinoid type 1 (CB1) receptors on the tongue's sweet taste cells themselves. In fact, over half of the sweet receptor cells expressed CB1 receptors!This is an important finding, because CB1 receptors are already known to regulate the pleasurable response to sweet foods (amongst other things) in the brain. These new data don't challenge this, but suggest that CB1 also modulates the most basic aspects of sweet taste perception. The munchies are probably caused by Δ9-THC acting at multiple levels of nervous system.This paper also sheds light on the question of how CB1 antagonists work. Given that drugs which activate CB1 make people eat more, it would make sense if CB1 blockers made people eat less, and therefore lose weight, a kind of anti-munchies effect. And indeed they do. Which is why rimonabant, a CB1 antagonist, was released onto the market in 2006 as a weight loss drug.It worked pretty well, although unfortunately it also it caused clinical depression in some people, so it was banned in Europe in 2008 and was never approved in the USA for the same reason. The depression caused by rimonabant was almost certainly due to its ability to block CB1 receptors in the brain, but Yoshida et al's findings suggest that a CB1 antagonist which didn't enter the brain, but only affects peripheral nerves like the taste buds, might be able to make people less fond of sweet foods without causing the same side-effects. Who knows - in a few years you might even be able to buy CB1 antagonist chewing gum to help you stick to your diet...Yoshida, R., Ohkuri, T., Jyotaki, M., Yasuo, T., Horio, N., Yasumatsu, K., Sanematsu, K., Shigemura, N., Yamamoto, T., Margolskee, R., & Ninomiya, Y. (2009). Endocannabinoids selectively enhance sweet taste Proceedings of the National Academy of Sciences, 107 (2), 935-939 DOI: 10.1073/pnas.0912048107... Read more »

Yoshida, R., Ohkuri, T., Jyotaki, M., Yasuo, T., Horio, N., Yasumatsu, K., Sanematsu, K., Shigemura, N., Yamamoto, T., Margolskee, R.... (2009) Endocannabinoids selectively enhance sweet taste. Proceedings of the National Academy of Sciences, 107(2), 935-939. DOI: 10.1073/pnas.0912048107  

  • January 14, 2010
  • 08:25 AM
  • 134 views

A Brief History of Bipolar Kids

by Neuroskeptic in Neuroskeptic

Can children get bipolar disorder?It depends who you ask. It's "controversial". Some say that, like schizophrenia, bipolar strikes in adolescence or after, and that pre-pubertal onset is extraordinarily rare. Others say that kids can be, and often are, bipolar, but their symptoms may differ from the ones seen in adults. You know a 20 year old's manic when they stay up for 3 days straight writing a book about how God's chosen them to save the world. A 10 year old, though, is more likely to show irritability and mood swings. Critics say that this isn't evidence of bipolar, it's evidence of... irritability and mood swings.But what's not always appreciated is how new the concept of pediatric bipolar as a common disorder is, and how specific it is to American psychiatry. Here are a few graphs I put together to illustrate this, based on numbers of scientific publications.First up, when did people start talking about it? Here's the number of PubMed hits for pediatric bipolar each year. As you can see, it was rarely talked about before the year 2000, after which its popularity shot up rapidly; it seems to have plateaued now, but it's hard to tell.In fact, the true trend is even more dramatic, because many of the early hits were not about psychiatry at all. For example, in 1999, 5 of the 10 were nothing to do with manic-depression. One was about the growth pattern of a certain kind of bacteria (they're "bipolar", because they have two poles of growth.)Is the post-2000 spike just a reflection of the fact that people are publishing more papers about bipolar in general? No. Here's a graph showing pediatric bipolar hits as a fraction of all "bipolar disorder" hits for that year. It's been rising for a while and it's now 5%.Where are these publications coming from? America. Taking the first two pages of PubMed hits for pediatric bipolar, and excluding the non-psychiatric ones, 30 are from the USA, and just 4 are from elsewhere. For "bipolar disorder", it's 13 vs. 25. (This is in terms of the affiliation listed for the primary authors of the study.)What about paediatric bipolar, the British spelling? It's almost unheard of. There are only 53 PubMed hits in total, as against 564 for pediatric bipolar. Of the first 20 hits, 9 are non-psychiatric, and 3 are from an Australian journal, criticizing the American concept of pediatric bipolar!It's remarkable that the monthly British Journal of Psychiatry has never published a paper about "pediatric bipolar" or "paediatric bipolar": if you search their archives you get just 5 hits, and they are all in the references section! The monthly American Journal of Psychiatry has published 37 papers mentioning "pediatric bipolar", of which 25 are not just in the references, and 10 are in the titles.So, at least in terms of the literature, pediatric bipolar is overwhelmingly a 21st century American phenomenon. It barely existed before 2000, and it barely exists elsewhere. This corresponds to what some non-American psychiatrists have observed. In The Paediatric Bipolar Hypothesis: The View from Australia and New Zealand, Australian psychiatrists Peter Parry, Gareth Furber and Stephen Allison point out thatTraditionally, bipolar affective disorder has been considered rare in children and uncommon in adolescence ... However paediatric bipolar disorder (PBD) has become a topical issue in child and adolescent psychiatry over the last decade, driven by research in the USA. The proponents of PBD are concerned that the traditional approach to bipolar disorder in children and adolescents is missing a large number of distressed children, whose course of bipolar illness could be ameliorated or attenuated by early treatment.Pediatric bipolar has certainly become more common as a diagnosis in the USA recently - a 40-fold increase in 12 years up to 2003:The number of visits to primary care physicians in the under 20 age group where the diagnosis was bipolar disorder increased from 0.01% in 1994/5 to 0.44% in 2002/3Whereas elsewhere, it's still regarded as incredibly uncommon...Soutullo et al. reported that none of the 2,500 children 10 years or younger referred to the Royal Manchester Children's Hospital ... had a diagnosis of mania or bipolar disorder ... A more recent German survey revealed German child and adolescent psychiatrists were largely holding to a traditional stance as only 8% claimed to have diagnosed a pre-pubertal child with bipolar disorder.Parry, Furber and Allison then present the results of a survey of 199 child and adolescent psychiatrists in Australia and New Zealand.The majority of participants (53.4%) said they had never seen a case of pre-pubertal bipolar disorder, whilst a further 28.5% estimated they'd seen only 1 or 2 cases. Only 35 participants (18.2%) estimated having seen 3 or more cases of pre-pubertal bipolar disorder. ... Most participants (83.1%) were of the opinion that bipolar disorder in pre-pubertal children was either "very rare (Of course this is just a survey, but the results are striking.Peter Parry reports as a conflict-of-interest that he's a member of Healthy Skepticism, who are, in their own words, in the business of "Improving health by reducing harm from misleading drug promotion". I'm sure neither he nor I need to spell out why drug companies might conceivably have an interest in promoting the concept of pediatric bipolar disorder, given the wide range of drugs available for bipolar adults...... Read more »

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