Hot Sex Prevents Breast Cancer

by Neuroskeptic in Neuroskeptic

Breast cancer is caused by sexual frustration. Women should ditch their unsexy husbands and find a real man to satisfy them if they want to reduce the risk of the disease. That's according to An Essay on Sexual Frustration as the Cause of Breast Cancer in Women: How Correlations and Cultural Blind Spots Conceal Causal Effects, a piece that was published today in The Breast Journal.Really -Endocrinological processes are important targets in breast cancer research. These processes are also important in human sexual behaviors. I hypothesize that these processes are capable of adjusting or distorting biological active forms of specific sex hormones depending on experienced sexual stimuli. These aberrantly metabolized sex hormones will ultimately lead to breast cancer....My thesis is that breast cancer is essentially caused by sexual frustration. The focus of this hypothesis is aimed at the (un)consciously experienced tension and sexual dissatisfaction between the chosen mate based on socio-economic, intellectual, ethnic or cultural motives and the nonchosen potential mate who has more appealing sexual incentive properties.In most western societies the improved economic independence of women has not changed to such a degree that long-term partners are chosen entirely according to sexual incentive properties. If the selected partner has no or weak sexual incentive properties for the other member of the couple, it is likely that sexual frustration will follow in the long run (6), which ultimately will cause breast cancer in some women...WHY HIGHER SOCIOECONOMIC GROUPS OF WOMEN ARE MORE AT RISK...higher socio-economic group of women pay more than average attention to the assets or status of the potential partner(7)....The chances of some women from higher socio-economic classes to find a sexually compatible mate are considerably reduced. This is due to an often self-imposed very limited range of potential partners. In this group of women, high status of the potential partner compensates for the acceptance of physically less attractive men (9)...HEIGHT AS RISK FACTOR IN BREAST CANCER...These women have a disadvantage because they have a smaller pool to choose from if they want a man they will not tower over. This increases the chances to settle for a sexually incompatible partner...BREAST CANCER RISK IN NUNS... There are 15 references, but they're all about sex, not cancer. Thus we get a citation to support the statement that "If the selected partner has no or weak sexual incentive properties for the other member of the couple, it is likely that sexual frustration will follow in the long run (6)", but not for the rather more controversial idea that disappointment in the bedroom somehow leads to malignant mutations in the DNA of cells of the mammary epithelium.Well except the line that "aberrantly metabolized sex hormones" are responsible, which is the scientific equivalent of waving your hands and saying "woo".How did this happen? The Breast Journal, so far as I can see, publishes lots of sensible research. It may not be a major journal but it's MEDLINE indexed and ranked 143/184 for impact in the field of oncology, which means there are 40 cancer journals in the world that have less impact than it. If I had published there, I'd be a bit miffed that my work was appearing in the same pages. Thankfully I haven't but as a scientist I'm still insulted that this has been published in a scientific journal, and will be appearing on the shelves of libraries around the world under the heading "science". Stuger, J. (2011). An Essay on Sexual Frustration as the Cause of Breast Cancer in Women: How Correlations and Cultural Blind Spots Conceal Causal Effects The Breast Journal DOI: 10.1111/j.1524-4741.2011.01206.x... Read more »

Antidepressants: Bad Drugs... Or Bad Patients?

by Neuroskeptic in Neuroskeptic

Why is it that modern trials of antidepressant drugs increasingly show no benefit of the drugs over placebo? This is the question asked by Cornell psychiatrists Brody et al in an American Journal of Psychiatry opinion piece.They suggest that maybe it's the patients fault:Participation that is induced by cash payments may lead subjects to exaggerate their symptoms [i.e. in order to get included into the trial]... Another contributing factor to high placebo response rates may be the extent to which the volunteers in antidepressant trials are really generalizable to patients in clinical practice. Since the initial antidepressant trials in the 1960s, participants have gone from being patients who were recruited primarily from inpatient psychiatric populations to outpatient volunteers who are often recruited by advertisements. At times, these symptomatic volunteers have participated in other trials. When we contact potential participants to schedule screening, they often ask to be reminded which trial we are screening for or mistake our research trial for a different protocol in which they recently participated. They then recount the tale of two "professional subjects" who claimed to be depressed and enrolled in two antidepressant trials simultaneously, without telling the researchers; it only came to light when someone involved in both studies spotted the duplicate names.I've been the victim of such nonsense myself, as have many of colleagues - it's a perennial watercooler topic. A few years ago I was running a study recruiting people who'd recovered from psychiatric illness. The main source of volunteers was online adverts.That study was a learning experience. What I learned is that House was right. We recruited about 20 people. No fewer than 3 turned out to have enrolled in other studies and lied about it. After I realized this I Googled the offender's names and two of them turned up in the crime pages of the local newspaper for various petty crimes.Another volunteer was left handed and, upon realizing that I was only recruiting right-handed people, discretely switched his pen to his right hand and then took 5 minutes trying to fill out a form with his off hand. He didn't make it in, but if I hadn't been paying attention he would have.So yes, it is a problem. However, it would have to be taking place on a massive scale for it to be having a significant effect on antidepressant trial results and this really seems pretty unlikely.In my view, the authors miss out on the real problem with recruiting depressed people through adverts:  depressed people don't tend to respond to adverts, because depressed people don't do anything. That's why they call it depression.Getting recruited into a modern clinical trial is actually quite a challenge. There are many pieces of paper to fill in, calls to return, appointments to attend. Turn up late to the screening visit, or otherwise make life difficult for the study staff, and you'll be marked down as "unreliable" and they'll find someone who plays by the rules. Modern trials are very expensive. The last thing a study sponsor wants is a volunteer who will end up forgetting to take their pills on time.Depression, unfortunately, makes you bad at doing things. You procrastinate, you forget, you put things off until too late, you have a change of heart and decide not to, you get cold feet, you can't be bothered... That goes for things as simple as cooking dinner in severe cases, let alone something as complicated as taking part in a trial.So while you wouldn't go looking for aquaphobic people in a swimming pool, I'm not sure we should be looking for depressed people through adverts.Brody B, Leon AC, and Kocsis JH (2011). Antidepressant clinical trials and subject recruitment: just who are symptomatic volunteers? The American journal of psychiatry, 168 (12), 1245-7 PMID: 22193668... Read more »

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

by Neuroskeptic in Neuroskeptic

Why do our eyes move during sleep?Here at Neuroskeptic we've already asked why do we sleep? and why do we dream? There are plenty of theories, but no clear answers to either of those questions.We don't even know the function of one of the most famous sleep phenomena, rapid eye movements (REMs). It's been known for decades that during certain phases of sleep, the eyes show a pattern of rapid flickering movements, and that this REM sleep is when most (but not all) dreams occur.But what are the eye movements?In a new paper, French sleep researcher Isabelle Arnulf sets out the case for the "scanning hypothesis". The idea is that REMs represent the dreamer "looking at" things in the dream, just like waking eye movements - at least much of the time.Some say that REMs are nothing to do with dreams, and it's just a coincidence that they tend to occur together. They may just be random, perhaps with the function of preventing the eyes from drying out during sleep, or maybe just a side-effect of sleeping brain activity with no function at all. A possible analogy: males usually get erections during REM sleep, even though most dreams have no sexual content.There's lots of evidence that seems to support a deflationist view of dreams. In humans and other mammals, foetuses have lots of REMs, even though they've never seen anything. Lab animals with the visual areas of the brain removed also continue to display REMs, albeit not as many of them, and people who've been blind since birth have REMs.Anaulf disagrees however, and discusses her work with the fascinating REM sleep behaviour disorder (RBD). RBD sufferers seemingly act out their dreams. Normally, we're paralyzed during REM by an inhibitory system which causes muscle relaxation during REM. The eyes are the exception, because they have a separate nerve pathway (which is also why some otherwise paralysed people can still communicate with their eyes). RBD can be a symptom of underlying neurological disease, such as Parkinson's, but it can also occur on its own.Anaulf's team studied 56 patients with RBD over 1 or 2 nights (Leclair-Visonneau 2010). They found that the behaviours were correlated with the onset of rapid eye movements, although 80% of the eye movements were not accompanied by any actions. What's more, out of 19 distinct behaviours (ranging from running away from lions, to strangling someone), 60% were associated with REMs, and of these 90% were in the same direction as the actions.This directional coherence between limb, head and eye movements during RBD suggests that, when present, REMs imitate the scanning of the dream scene. Because the REMs are similar in subjects with and without RBD, we suggest the extension of this concordance to normal REM sleep.They suggest, however, that it may not be that the eye movements are the result of the dream content, but just correlated with it. It's not that something happens on the left in the dream, and then in response, the eyes move to the left; rather it's that whatever pattern of neuronal activity causes the dream, also causes the corresponding eye movements.Either way it's an interesting idea, although it does rely on the assumption that RBD is a good model of normal sleep in this regard.Arnulf I (2011). The 'scanning hypothesis' of rapid eye movements during REM sleep: a review of the evidence. Archives italiennes de biologie, 149 (4) PMID: 22205589... Read more »

How Realistic is fMRI?

by Neuroskeptic in Neuroskeptic

How representative are fMRI experiments? Is "the brain" that we investigate with fMRI the same brain that we use outside the MRI scanner?A new paper from Bernhard Hommel and colleagues of Leiden in the Netherlands offers some important caveats. They looked to see what effect playing some recorded MRI scanner sounds had on people's ability to perform some simple cognitive tasks, while sitting outside the scanner.MRI is notoriously noisy. When you have an MRI scan you have to wear earplugs to protect against the sound but they only block out some of it. Opinions differ on whether the sound is pleasant or not. Personally I find the repetitive tick-tock rather soothing now, but then I've heard it many times over the years. First-timers can find it quite overwhelming.Anyway, Hommel et al found that while scanner noise had no overall effects on reaction time or accuracy, it actually improved performance on three measures of "cognitive control".For instance in a task in which participants had to respond to the colour of a circle by pressing the left or the right arrow key, they were slower to react when the circle appeared on the "wrong" side of the screen, i.e. on the left when the correct answer was the right arrow. This slowing of responses caused by a stimulus-response clash is called the Simon effect.The results showed that the Simon effect was reduced by noise. The same thing happened in two other studies: noise meant better performance.All of the noise effects were modest and the sample sizes were also quite small (14-18 per task, with everyone studied twice, noisy vs silent) but this paper joins a number of others raising questions about the representativeness of fMRI, with evidence that fMRI activates the brain and maybe even improves mood (although I doubt that last one). The authors' interpretation is that the noise made people pay more attention to the tasks, to compensate for the distraction, and that this means that fMRI studies may be biased in their measurements of cognitive control:Generalizing from fMRI findings to behavioral observations and vice versa seems to be more problematic than commonly thought, at least as far as control  processes are concerned. In a sense, then, investigating cognitive processes by means of  fMRI... is inevitably facing Heisenberg’s (1927) uncertainty principle, according to which the act of measurement can change what is being measured.To my mind the biggest weakness of this is that it only looked at noise. While scanners are noisy, that's not the only distracting thing about them: during an fMRI study you also have to lie down, in a small confined tube, and your only way to see the "screen" on which experimental stimuli are shown is indirectly via a small mirror which often doesn't give a good view.So ironically, I'm not sure how realistic this study is... Hommel, B., Fischer, R., Colzato, L., van den Wildenberg, W. and Cellini, C. (2011). The effect of fMRI (noise) on cognitive control. Journal of Experimental Psychology: Human Perception and Performance DOI: 10.1037/a0026353... Read more »

Scanning The Brain While Looking At Scans

by Neuroskeptic in Neuroskeptic

A new study investigated what goes on in the brain when doctors make a diagnosis.Radiologists use X-rays and other imaging techniques to diagnose diseases - but in this study, they went into the scanner themselves. Brazilian researchers Marcio Melo et al used fMRI to record neural activity while the radiologists were shown an array of chest X-rays.Some of the scans showed evidence of disease, which the doctors were required to diagnose. There were also two control conditions, in which the stimuli were still X-rays but with little pictures of either animals or letters embedded in them, instead of diseases.The image above shows how it worked. As well as pneumonia, one patient has a severe case of Alligator Lung, while the other looks like they've got the Influenza 'B' virus.Now, the point of all this was to compare the mental process of making a diagnosis to that of seeing an object. The idea is that a trained radiologist sees particular diseases in the scans, in the same way that anyone can see an alligator.Activity during diagnosis, object-recognition and letter naming was very similar (compared to doing nothing); this presumably represents the visual and language areas involved in looking at the image, recognizing what it is, and saying it out loud:There were some slight differences, with the left inferior frontal cortex and the posterior cingulate cortex being more activated by diagnosis than animals. But this difference disappeared after controlling for the number of different possible descriptions the radiologists reported thinking about for each image.The authors conclude thatThese results support the hypothesis that medical diagnoses based on prompt visual recognition of clinical signs and naming in everyday life are supported by similar brain systems.Which seems fair enough, although it's important to remember that the diagnoses in this study were quite easy ones. The mean response time was just 1.3 seconds and only 6% of those split-second diagnoses were wrong. Unfortunately diagnosis is not always that easy.Anyway, this study is all very well, but why stop at chest X-rays? Last year I speculated on the fun neuroscientists could have with a real-time fMRI machine:You could lie there in the scanner and watch your brain light up. Then you could watch your brain light up some more in response to seeing your brain light up...We really need to scan people while they're looking at brain scans. Only then will we be able to understand the neurological basis of being a neurologist, and find the brain's looking-at-a-blob blob.Melo M, Scarpin DJ, Amaro E Jr, Passos RB, Sato JR, Friston KJ, and Price CJ (2011). How doctors generate diagnostic hypotheses: a study of radiological diagnosis with functional magnetic resonance imaging. PloS ONE, 6 (12) PMID: 22194902... Read more »

An Objective Measure of Consciousness...?

by Neuroskeptic in Neuroskeptic

Could a puff of air in the eye offer a way to evaluate whether someone is conscious or not?Yes it could, say Cambridge's Tristan Bekinschtein and colleagues in a new paper about Sea slugs, subliminal pictures, and vegetative state patients.It's all about classical conditioning of the kind made famous by Pavlov. This is learning caused by the pairing of two stimuli, one of them unpleasant. So if I were to ring a little bell before, say, pepper spraying you, and I did that repeatedly, you would probably close your eyes whenever I rang that bell. Or just punch me, but you see the point.Anyway, the key is that there are two kinds of classical conditioning. In the unhelpfully named "delay" conditioning, the warning stimulus overlaps with the painful one. Like if I started ringing my bell, then kept ringing it while I sprayed you with my other hand. In other words, there is no delay between the two stimuli... I said it was badly named.By contrast in "trace", conditioning there is a delay - the warning stops shortly before the second stimulus. Bekinschtein et al argue that trace conditioning requires conciousness. While delay conditioning can occur without awareness of the link between the two stimuli, only conscious awareness can bridge the time gap in trace conditioning.In trace experiments (in which rather than pepper spray, the unpleasant stimulus is just a puff of air in the eye), people who, when asked, can't explain the relationship ("sound means puff") don't learn to blink when they hear the sound. But with delay conditioning, this "unconscious" conditioning can occur. Likewise, under anaesthesia, trace conditioning is lost.At first glance this looks like a piece of psychological trivia, but it could have literally life-or-death consequences. If trace conditioning is a measure of concious awareness then it could be used as a way of working out whether brain-injured people in a "coma" or "vegetative state" are aware or not.This paper is in fact a follow-up to the author's own 2009 study showing that some people in a vegetative state do show trace conditioning - and the ones who did were more likely to subsequently wake up. One snag is that the humble sea slug, Aplysia, can undergo trace conditioning, yet it is presumably not conscious, at least not in any recognizable senseBut Bekinschtein et al say that trace conditioning is a product of convergent evolution. Alplysia can do it and we can do it, but we use different means to the same end. Their argument is that while in Alpysia trace conditioning is known to be dependent on just a handful of individual neurons in the creature's tiny "brain", in humans it requires an intact hippocampus (containing millions of cells). People with hippocampal damage, who suffer amnesia, also can't do trace conditioning.That's a good point but does that mean such hippocampal patients aren't concious? That would be weird because, apart from the amnesia, they seem perfectly normal. Presumably they're just not concious of the relationship between things separated in time...Also, primitive pathways for conditioning might still exist in humans, able to reactivate under special conditions. They do acknowledge this with a discussion of experiments showing that trace conditioning in the absence of conscious awareness of the relationship can occur but only when the warning stimuli are "scary", like pictures of snakes. They say that with generic, neutral stimuli there is no good evidence of unconscious trace conditioning, but this seems like a fairly fine distinction.Ultimately, it's a very nice idea but only more studies on "unconscious" patients will tell us whether it's really able to measure consciousness in a useful way.Bekinschtein TA, Peeters M, Shalom D, and Sigman M (2011). Sea slugs, subliminal pictures, and vegetative state patients: boundaries of consciousness in classical conditioning. Frontiers in psychology, 2 PMID: 22164148... Read more »

Young, Canadian and on Antipsychotics

by Neuroskeptic in Neuroskeptic

Antipsychotic use in Canadian children and teens is rising dramatically - prescriptions more than doubled in just 4 years, from 2005 to 2009.That's according to a paper just out from Pringsheim et al. It's been known for a while that the same is true of the USA. The data reveal that the Canadian border is no barrier to the spread of antipsychotics.What's surprising is that while in the USA, some of these drugs are officially licensed for use in certain children and adolescent psychiatric disorders, in Canada all such use is off-label. That didn't stop there being nearly 700,000 youth prescriptions for an antipsychotic in 2009, in a country with a total population of 35 million - although bear in mind that this includes multiple prescriptions for the same person.The growth in antipsychotics is accounted for by the second-generation "atypical" antipsychotics. Risperidone (Risperdal) was the biggest success story accounting for well over half of the total. What's disturbing about this, as I've said before, is not so much the fact that these drugs are being used but the speed of the growth. It represents a fundamental shift in the way children and adolescent mental health problems are treated, one which has happenedUse of SSRI antidepressants and psychostimulants (mainly ADHD drug methylphenidate, Ritalin) also rose between 05 and 09, but only by about 40%. That means that there were more antipsychotic ... Read more »

"Mad Honey" Sex Is A Bad Idea

by Neuroskeptic in Neuroskeptic

A cautionary tale from Turkey - do not eat poison honey to try to spice up your sex life. "Mad honey" is honey made by bees from the nectar of toxic Rhododendron flowers. In places where wild Rhododendrons grow, including Turkey, it's a health hazard. The dangers of mad honey were known to the ancient Greeks and Romans, and it's reported that leaving tainted honeycombs in the path of invading armies was a popular military tactic.2000 years later, some people still haven't quite got the message. According to a case report from cardiologists Yarlioglues et al, a married couple deliberately ate some mad honey "for reasons of sexual performance".After eating one teaspoon per day for a week, they decided to crank it up a notch and ate a full tablespoon of the stuff. But their attempt to heighten their Turkish delight quickly turned sour, as they both suffered symptoms of confusion, chest pain, low blood pressure and slowed heartbeat. After presenting themselves to hospital, doctors discovered that they had both suffered an acute inferior myocardial infarction - a mild heart attack.It's not clear whether the sex was a contributing factor.The randy Rhododendron fans were lucky - following treatment, they both recovered. In fact, the authors say "To our knowledge, no fatal cases of mad-honey poisoning have been reported since ancient Roman times." However, it seems that some people are still willing to try their luck.The toxin in mad honey is gryanotoxin. It acts by potentiating the opening of sodium channels, which are found both in the heart and the brain. This may be why it produces a combination of cardiovascular and psychoactive effects.Mikail Yarlioglues et al (2011). Mad-Honey Sexual Activity and Acute Inferior Myocardial Infarctions in a Married Couple Texas Heart Institute Journal... Read more »

by Neuroskeptic in Neuroskeptic

Here's a paper - soon to appear in Psychological Science - which says that Most Reported Genetic Associations with General Intelligence Are Probably False PositivesThe authors tried to replicate published associations between particular genetic variants (SNPs) and IQ (specifically the g factor). They looked at three datasets, a total of about 10,000 people, and didn't confirm any of the 12 associations.As Razib Khan says in his post on this, "My hunch is that these results will be unsatisfying to many people." I'd go further and say that no-one will be happy with these.For those who believe that IQ is purely environmental and not genetic, any satisfaction they might feel will be short lived because these authors did replicate the recent finding that genetic variants explain about 50% of the variance in IQ. Looking at all SNPs together, there was a strong correlation between "genetic similarity" and similarity in IQ. That independently confirms what the much-criticized twin studies of IQ said - IQ is about 50% heritable.But for people who do believe in the genetics of intelligence, this shows us that we have no idea what the genes are, and that everything published so far has been pretty much for naught.There's another implication. We actually do know of many "IQ genes" in that we know genes that, when mutated, cause mental retardation (very low IQ).Now many researchers have hoped that if a certain gene causes you to have an IQ of, say, 50 when it's completely deleted by a mutation, then more subtle variants in that gene would have minor effects on IQ. Maybe a variant that reduces expression of the gene by 10% would knock off 5 IQ points.In other words, if big mutations cause big phenotypes, then small mutations in the same place ought to cause small phenotypes. It seems to make sense - but today's IQ literature shows that it's just not true.That's not just a problem for IQ though. Take autism or ADHD, we know that there are rare, severe mutations that cause these conditions. Many people are hoping that common variation in the same genes might also be interesting - but if IQ is anything to go by, it won't be.Perhaps this is not so surprising. Breaking your neck and becoming paraplegic is going to seriously impair your ability to play baseball. That doesn't mean that normal variation in baseballing skill has much to do with minor neck injuries.Chabris, C. F. et al (2011). Most Reported Genetic Associations with General Intelligence Are Probably False Positives Psychological Science... Read more »

Do Antidepressants Make Some People Worse?

by Neuroskeptic in Neuroskeptic

Antidepressants may help depression in some people but make it worse for others, according to a new paper.This is a tough one so bear with me.Gueorguieva, Mallinckrodt and Krystal re-analysed the data from a number of trials of duloxetine (Cymbalta) vs placebo. Most of the trials also had another antidepressant (an SSRI) as well. And the SSRIs and duloxetine seemed to be indistinguishable so from now on I'll just call it antidepressants vs. placebo as the authors did.People on placebo got, on average, moderately better over 8 weeks.People on antidepressants fell into two classes. The largest class got, on average, a lot better. But about 25% did poorly, staying just as depressed as before. This "nonresponder" group did much worse than the placebo group - again on average. Here you can see the mean "trajectories" of depression symptoms (HAMD scores) in the three groups:This raises the scary possibility that while antidepressants are helping some people, they're harming others. But hang on. It's complicated.First off, maybe this is all a statistical illusion. When the authors say that the people on drug fell into two classes, what they mean is that when you try to model the data according to a certain mathematical model, assuming either 1, 2, 3 or 4 underlying classes, the 2 class solution was the best fit. While for placebo a 1 class solution was best.We considered linear, quadratic, and cubic trends over time, with between 1 and 4 trajectory classes. We also considered piecewise models with a change point at 2 weeks, linear change before week 2, and quadratic change after week 2. The selection of the best model was based on the Schwartz-Bayesian information criterion and on the Lo-Mendell-Rubin (LMR) likelihood ratio test...That's nice... but they don't present the raw data. They don't tell us whether, looking at the individual trajectories of people on antidepressants, you'd actually see two classes. What I want is a graph of how likely people are to get better by a certain amount. If Gueorguieva et al are right, I want it to look like this i.e. bimodal -We're not shown this graph. I'll eat my hat if it does look like that, frankly, because if it did people would have noticed the bimodality in antidepressant trials ages ago. True, statistical models can tell us things that aren't obvious by inspection, so even if this isn't what the data look like, they might still be right. It could be that the two "peaks" are so broad, and there's so much random noise, that they blur into one.However, it's also true that you can fit an infinite number of models to any set of data and at some point you have to step back and say - am I making this more complicated than it needs to be?It could be that a 2-class model is better than a 1-class model for the people on antidepressants, but only because they're both crap, and really, every patient has a different, unpredictable trajectory which is poorly captured by such models.Let's assume however that this is true. What would it mean?Firstly, the fact that one class of people on antidepressants does worse than people on placebo doesn't mean that antidepressants are harming them. The authors miss this point, when they saythere are 2 trajectories for patients treated with antidepressants and 1 trajectory for patients treated with placebo [so] some patients would seem to be more effectively treated with placebo than with a serotonergic antidepressant.But that's fallacious. It treats a purely statistical entity as representing individual people. Suppose that what antidepressants do is to take people who, on placebo, would have improved a bit, and make them improve a bit more than they otherwise would have. You'd then end up with more people doing well, but also fewer people doing moderately because they'd have been "moved up" out of the middle ground. That "nudging people off the fence" could lead to a bimodal distribution and two distinct classes. But in this case the people doing badly would have done badly either way. The drug didn't make them do badly, it just made doing-badly into a class. On the other hand it's consistent with antidepressants doing real harm. We can't tell.We do know that other randomized controlled trials show very convincingly that in a small minority of people, mostly but not exclusively young people, antidepressants do worsen suicidal thoughts and behaviours. So it's plausible. But we just don't know yet.What worries me is that this paper is the latest in a series of attempts  to use, well, creative statistical approaches to antidepressant trial data. This one is nowhere near as dodgy as the Cherrypicker's Manifesto I discussed last year, but it cites that paper and others by the same group. The first sentence of the Abstract of this paper makes the intention clear:The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response.In other words, the reason clinical trials of new antidepressants often fail to show a benefit over placebo is not because the drugs are crap but because the statistics aren't subtle enough. And you can see where this is going: if only we could use statistical models to find the people who do benefit from antidepressants, and compare them to placebo, there'd be no problem... Gueorguieva R, Mallinckrodt C, and Krystal JH (2011). Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Archives of General Psychiatry, 68 (12), 1227-37 PMID: 22147842... Read more »

The Brain's High School Spot

by Neuroskeptic in Neuroskeptic

It's been known for a long time that electrical stimulation of the brain's temporal lobe can sometimes evoke vivid memories.The famous neurosurgeon Wilder Penfield first noticed this effect as part of his pioneering stimulation experiments, but he believed that it was both uncommon and haphazard with any given stimulation able to evoke any memory, more or less at random.A new paper, however, says different. Philadelphia's Joshua Jacobs et al report that they found a spot in the left temporal lobe of a male patient, stimulation of which evoked memories of the man's time at high school. The guy was in his 30s at the time, so these are quite distant memories.When it first happened, he is reported to have said: Iʼm, like, remembering stuff from, like, high school…. Why is this suddenly popping in my head?Repeated stimulation of the same electrode - but not nearby electrodes - caused other high school memories to emerge. Even more interestingly, when the same stimulating electrode was used to record activity during memory retrieval, the "high school spot" was found to be significantly less active when high school was being remembered, compared to when various other kinds of memories were being accessed.This graph shows that all kinds of memories evoked high-frequency activity in the high-school zone, but high-school memories did so less:No other electrode location caused the same effects (or indeed, any detectable memory effects), although as you can see on the image above, the electrode coverage was not huge. A little background: the guy had these electrodes in place because he suffered from epilepsy, resistant to medication, which was believed to originate in the temporal lobe. Temporal lobe epilepsy can cause memory phenomena rather like this, but this patient had never experienced that, and the electrically-evoked memories were experienced as entirely novel.It's a nice case report and it raises many questions. Why is the high-school spot less active during memory retrieval? That seems the wrong way around (I did a double-take to make sure I was reading it properly).And what would happen if you somehow disabled (or overactivated) this area, and asked him to remember a particular school memory? Would he draw a blank, or would he remember it but without the "high-school-ness"? What would that feel like?Either way, this case suggests that memories are stored in the brain "by topic", in the sense that "similar" memories are associated with nearby areas of the brain. At least sometimes. But then, why didn't nearby electrodes evoke other memories? If there's a high-school spot, why not a kindergarten spot, a my-first-job spot?Maybe those spots lay in areas with no electrode coverage... but the fact that many temporal electrodes didn't bring back any memories suggests that there's lots of cortex which isn't part of a "spot". Perhaps those areas are "spare", waiting to be used up? Clearly, he wasn't born with a high school spot. It must have emerged during high school. But in that case there had to be a "blank" area first. Jacobs J, Lega B, and Anderson C (2011). Explaining How Brain Stimulation Can Evoke Memories. Journal of cognitive neuroscience PMID: 22098266... Read more »

Scientific Databases - or Filters?

by Neuroskeptic in Neuroskeptic

A new online database called AutismKB offers a quick way to find the evidence linking genes to autism.You can read up on it in a paper describing the project.You can browse by chromosome or gene name, it includes data on all kinds of genetic variants from SNPs to CNVs and it gives each variant a score according to the strength of the evidence. I haven't had a chance to really tell how useful these scores are, but there's an option to create your own score based on how much weight you give different kinds of evidence. The dataset is huge although it doesn't seem to have been updated for a few months.Overall, it's a new tool and there's sure to be bugs to iron out, but it seems like it could be very useful. I do worry though that this kind of database encourages misleading ways of thinking about autism genetics.There are numerous genetic variants which have been strongly linked to autism, although none of them account for more a small proportion of cases because these variants are rare. But many (most, actually, is my impression) of them have also been observed in people with other symptoms ranging from ADHD to epilepsy to schizophrenia.So searching a database of "autism genes" could encourage you to think that these were only autism genes, which is far from true. Genetics, it is becoming increasingly clear, doesn't respect our current concepts of psychiatric illness or our academic specialities. There are few (if any) parts of the genome that can be neatly fenced off and declared exclusive to ADHD experts, schizophrenia researchers or whatever.But disease-specific databases encourage the illusion that they do exist. It's the same old problem of the filter bubble which many people have warned about in the context of general purpose search engines. Scientists have filter bubbles too.This is not of course a criticism of AutismKB in particular - the same goes for any similar "disease-gene" database. And to be fair AutismKB does provide links to a schizophrenia database, and a couple of others but you have to dig quite deep to get there. The "main page" of results for any given variant is pure autism.That's the whole problem with filter bubbles - they make it too easy to hear what you want to hear, compared to getting a new perspective, so you don't even think to look outside the filter.Xu LM, Li JR, Huang Y, Zhao M, Tang X, and Wei L (2011). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic acids research PMID: 22139918... Read more »

The Network of Mental Illness

by Neuroskeptic in Neuroskeptic

A provocative but problematic paper just out offers a new perspective on psychiatric symptoms.The basic idea is that rather than psychiatric disorders being entities, they are just bundles of symptoms which cause each other: ...symptoms are unlikely to be merely passive psychometric indicators of latent conditions; rather, they indicate properties with autonomous causal relevance. That is, when symptoms arise, they can cause other symptoms on their own. For instance, among the symptoms of MDE we find sleep deprivation and concentration problems, while GAD (generalized anxiety disorder) comprises irritability and fatigue. It is feasible that comorbidity between MDE and GAD arises from causal chains of directly related symptoms; e.g., sleep deprivation (MDE)→fatigue (MDE)→concentration problems (GAD)→irritability (GAD). The authors seem to have mixed up their labels in the middle there, but you see the drift. This symptom-based approach stands in contrast to the idea that psychiatric illnesses are underlying things which lead to some symptoms. So it's a challenge to the notion of underlying biological dysfunction (except maybe for specific symptoms) but it's equally incompatible with any theory of underlying psychological causes - there's no room for Freudian unconscious "complexes" here.So there's something very straightforward and un-mysterious about this model, which will either make it attractive or suspect, depending on whether you think human life is mysterious or not.What's the evidence? First, the authors do an analysis of the DSM-IV diagnostic manual in terms of symptoms. They take every symptom which is mentioned in at least one diagnosis. They found 439 symptoms in total, over 201 disorders, with many symptoms, such as insomnia, shared between lots of different "disorders".They then used network analysis to create a kind of graph where the "distance" between the nodes (symptoms) is based on the number of shared diagnoses. They found that while some symptoms are unique to just one disorder, there's a core of highly shared symptoms which form a "giant component"It's a very clever approach but I wonder what it really tells us. The DSM-IV is not data about mental illness. It's data about what we think about mental illness. Actually, it's not even that: it's data about what a particular set of people, at a particular time, were able to agree upon.DSM-V is coming soon, and before that we had DSM's I, II and III. What about them? Do they have a different network structure? I'd have thought they would, but we don't know.We've already seen the kinds of politics that lie behind the decision to include or exclude a diagnosis in the DSM. In the upcoming DSM-V they're seriously proposing to add a new diagnosis ("TDDD"), purely in order to stop people getting another diagnosis (childhood "bipolar").There is a lot of symptom overlap between TDDD and bipolar disorder. Because one was designed for the purpose of diverting patients from the other. But that doesn't tell us anything about real people with real symptoms. This is an extreme example and to be fair to the authors they do acknowledge some of these problems with the DSM, but still.The authors then show that the symptomatic closeness between DSM-IV disorders predicts the rates of comorbidity between those disorders, as measured in the American population survey the NCS-R. This is true even of disorders which don't share a common symptom but which are connected indirectly by a mutual friendship, as it were.Finally they show that a statistical model based on interacting symptoms can predict the prevalence of depression (10% per year according to the NCS-R survey) and GAD (3% per year). It does so much better than a random model in which symptoms randomly interact.However, I'm not convinced that all these show us that the symptom-network approach is the best model to explain the occurence of these disorders. It only shows us that it's a model that works better than a crazy random model. I'm also not sure that being able to model the NCS-R data is even a good thing, since these data are themselves of questionable validity.But it's a genuinely interesting approach and well worth following up.Borsboom D, Cramer AO, Schmittmann VD, Epskamp S, and Waldorp LJ (2011). The small world of psychopathology. PloS one, 6 (11) PMID: 22114671... Read more »

A Psychedelic Tale of Two Neurotransmitters

by Neuroskeptic in Neuroskeptic

An unexpected interaction between neurotransmitter systems may explain psychosis and hallucinations, according to a fascinating new paper.Serotonin (5HT) and glutamate are two neurotransmitters. Up until now, it was thought that they acted independently. A given neuron might have receptors for both serotonin and glutamate, but they didn't interact: serotonin would never affect the glutamate receptors, and vice versa.The new research overturns that view. Authors Miguel Fribourg and colleagues of Mount Sinai School of Medicine show, in a series of elegant experiments in mice, that different receptors can cluster together, forming a complex. The two receptors, serotonin's 5HT2A and glutamate's mGluR2, can talk to each other.However, this doesn't seem to happen under normal conditions. Serotonin and glutamate don't seem to trigger the receptor interaction, or at least not very much. Only certain drugs can do it. And this is where it gets really interesting.Psychedelic drugs, like LSD, have long been thought of as 5HT2A agonists, binding to the receptor and activating it. It turns out that this was only half right. They also inhibit mGluR2 transmission via the receptor complex. Serotonin itself is a 5HT2A agonist, but it doesn't do that. So psychedelics seem to be a kind of (for want of a better word) "superagonist".It also works in reverse. The antipsychotic drugs clozapine and risperidone are known as 5HT2A antagonists. But Fribourg et al show that they also activate the mGluR2 receptor.And the cross-talk can go in the other direction. Certain molecules that act on mGluR2 can either inhibit or promote 5HT2A. Unlike psychedelics and antipsychotics, these mGluR2 drugs have not been tested in humans yet. But these data predict that they will have psychedelic-like or antipsychotic-like effects, depending which way they work.The interaction turns out to be all about G proteins, which are part of the chain of transmitter substances that convey signals within the cell, in response to neurotransmitters outside it. Here's a chart showing the effects of various drugs on the balance between different G proteins: the LSD-like psychedelic DOI has the opposite effect from the antipsychotics clozapine and risperidone.This paper builds on a previous one from the same team showing that psychedelic 5HT2A "agonists" (like LSD and DOI) have different effects on G proteins from other, non-psychedelic agonists. That was interesting in itself but by adding glutamate to the picture, this new paper is really ground-breaking.This goes a long way to explaining one of the mysteries of serotonin which is this:  if 5HT2A agonists like LSD are psychedelic, why aren't antidepressants the same? Almost all antidepressants work by increasing extracellular 5HT levels. That ought to mean that they activate 5HT2A receptors (indirectly). This explains why not - 5HT alone doesn't promote the crucial 5HT2A-mGluR2 interaction.Taken together, these interesting results show clearly that 5HT2A and mGluR2 are hooking up and doing something exciting. Certainly in terms of how hallucinogens work.I'm less convinced that this can directly explain antipsychotic effects though. The problem is that while newer "atypical" antipsychotics act on 5HT2A, the older antipsychotics don't, and atypicals are at best only slightly more effective on average.What we don't yet know is whether this kind of complex receptor interactions can happen with other receptors. I'd have thought it unlikely that these two receptors were the only ones that could ever do it. The synapse looks like it's more complex than we could have imagined.Fribourg M, et al. (2011). Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs. Cell, 147 (5), 1011-23 PMID: 22118459... Read more »

Cognitive Behavioural Therapy vs. Psychoanalysis

by Neuroskeptic in Neuroskeptic

Clinical trials of cognitive behavioural psychotherapy (CBT) for depression are often of poor quality - and are no better than trials of the rival psychodynamic school.So says a new American Journal of Psychiatry paper that could prove controversial.CBT is widely perceived as having a better evidence base than other therapies. The "creation myth" of CBT (at least as I was taught it) is that it was invented by a psychoanalyst who got annoyed at the unscientific nature of psychodynamic i.e. Freudian-influenced therapy. CBT has always looked on clinical trials more favorably than the dynamic school. However, the authors of this meta-analysis found that while there are certainly lots of published CBT trials for depression, they're actually no better quality than the psychodynamic trials."Surprisingly" (their word), they found no difference between the CBT for depression trials, and the psychodynamic trials, on a rating score of trial methodology.Trials got better over time, but the two groups improved equally (see above). The mean score was 25.5 for CBT and 25.1 for dynamic, on a scale that goes from 0 to 48. Anything over 24 points is deemed acceptable but this is clearly an arbitrary cut-off.The RCTP-QRS scale is relatively new and it was developed by the people who wrote this paper (albeit with the input of other experts.) There's 24 items and each gets a score from 0 (bad) to 2 (good). Items are things like "Adaquate sample size", "Patients randomly assigned to group", etc.Worryingly, better CBT trials tended to find smaller benefits of CBT over the comparison treatment. The overall results showed that while CBT was clearly better than doing nothing, it was pretty much the same as antidepressants, and other psychotherapies, in adults with depression: The article follows one from the same group, Gerber et al, who reviewed the evidence for psychodynamic therapy in more detail. And last year, another team reported evidence of publication bias in psychotherapy trials. In this study, the authors report possible publication bias, but they don't go into detail.Overall this is interesting stuff, and a reminder that while CBT has the most evidence of any psychotherapy, this is not the same thing as saying that it has the best evidence...Nathan C. Thoma et al (2011). A Quality-Based Review of Randomized Controlled Trials of Cognitive-Behavioral Therapy for Depression: An Assessment and Metaregression American Journal of Psychiatry... Read more »

Beware Dead Fish Statistics

by Neuroskeptic in Neuroskeptic

An editorial in the Journal of Physiology offers some important notes on statistics.But even more importantly, it refers to a certain blog in the process:The Student’s t-test merely quantifies the ‘Lack of support’ for no effect. It is left to the user of the test to decide how convincing this lack might be. A further difficulty is evident in the repeated samples we show in Figure 2: one of those samples was quite improbable because the P-value was 0.03, which suggests a substantial lack of support, but that’s chance for you! A parody of this effect of multiple sampling, taken to extremes, can be found at http://neuroskeptic.blogspot.com/2009/09/fmri-gets-slap-in-face-with-dead-fish.htmlThis makes it the second academic paper to refer to this blog as far. Although I feel rather bad about this one, since the citation ought to have been to the original dead salmon brain scanning study by Craig Bennett. I just wrote about it.Actually, though, this editorial was published in five separate journals: The Journal of Physiology, Experimental Physiology, the British Journal of Pharmacology, Advances in Physiology Education, Microcirculation, and Clinical and Experimental Pharmacology and Physiology. Phew.In fact, you could say that this makes not two but six citations for Neuroskeptic now. Yes. Let's go with that. Anyway, after discussing the history of the ubiquitous Student's t-test - which was invented in a brewery - it reminds us that the p value you get from such a t-test doesn't tell you how likely it is that your results are "real".Rather, it tells you how often you'd get the result you did, if there was no effect and it was just random chance. That's a big difference. A p value of 0.01 doesn't mean your results are 99% likely to be real. It means that there's a 1% chance that you'd get them, by chance. But if you did say 100 experiments, or more likely, 100 statistical tests on the same data, then you'd expect to get at least one result with a p value of 0.01 purely by chance.In that case it would be silly to think that the finding was only 1% likely to be a fluke. Of course it could be true. But we'd have no particular reason to think so until we get some more data. This is what the dead salmon study was all about. This multiple comparisons issue is very old, but very important. Arguably the biggest problem in science today is that we're doing too many comparisons and only reporting the significant ones.Drummond GB, & Tom BD (2011). Statistics, probability, significance, likelihood: words mean what we define them to mean. British journal of pharmacology, 164 (6), 1573-6 PMID: 22022804... Read more »

A Dangerous Truth about Antidepressants

by Neuroskeptic in Neuroskeptic

An opinion piece by veteran psychiatrist and antidepressant drug researcher Sheldon Preskorn contains a remarkable historical note -“A dangerous idea!” That was the response after a presentation I gave to a small group of academic leaders with an interest in psychopharmacology [over 15 years ago].What evoked such a response? The acknowledgment that most currently available antidepressants specifically treat only one out of four patients with major depression based on the bulk of clinical trials data. There was no argument about the accuracy of this statement, but...some claim it is “dangerous” to admit that the specific response rate to most antidepressants is 20%–30% because such an acknowledgment might undermine the value of antidepressant treatment.By the "specific" response rate Preskorn means the number of depressed people who'll get better on antidepressants and who wouldn't have done so well on placebo. This rate is fairly low because, while most people get better on antidepressants, most of those improve on placebo as well.Preskorn rejects the view that it's dangerous to acknowledge this:...there are several problems with this reaction. First, it is hard to deny reality. The “placebo” response rate in antidepressant trials is arguably the most reproducible finding in psychiatry. Moreover, if available antidepressants were magic bullets, then polypharmacy would not be so common. Second, this reaction ignores the fact that antidepressants are tremendously valuable to the patients who specifically benefit from them... Every treatment in every area of medicine has limitations. Acknowledging that fact should galvanize us to action. Denial on the other hand perpetuates the status quo.Unfortunately, we're not told who these academic leaders were. I wonder if they included amongst their ranks some of the "key opinion leaders" in the field whose leadership proved rather less than ideal. The column is actually adapted from a 1996 article by Preskorn.Preskorn is right, of course, that denying the fact that antidepressants are only substantially better than placebo in a fraction of people who get diagnosed with "depression" is wrong, and also misses the point: because hundreds of millions of Americans have diagnosable depression (due to the loose definition of "depression"), even if they only helped 1% of them, they'd still help over a million people.But he doesn't mention that this approach was ultimately self-defeating. As a result of the failure to acknowledge that antidepressants are only helpful in some cases of depression (namely "severe" depression), these drugs became very widely used and - oh dear - people started saying that the drugs are being overused, and don't work in most people who take them.Whoever could have seen that coming.This has "devalued" antidepressants - and psychiatry itself - more than anything else has.Preskorn SH (2011). What Do the Terms "Drug-Specific Response/Remission Rate" and "Placebo" Really Mean? Journal of psychiatric practice, 17 (6), 420-424 PMID: 22108399... Read more »

The Gene That's "For" Nothing

by Neuroskeptic in Neuroskeptic

Scientists like to warn you not to talk about "the gene for" a particular disease or trait.I've done so in previous posts e.g. this one or this one.But such scalding is not always very effective. We like simple explanations, so we like to find simple connections between genes and phenotypes.Which is why a new paper is important. The authors, a large Turkish-American collaboration, found that mutations in a gene, WDR62, are associated with severe brain malformations in 9 patients. But what's interesting is that it doesn't cause any particular malformation.If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.As the authors put it, mutations in WDR62 causea wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're  different, they must have different genetic causes. They've just shown that this is wrong.So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.Bilgüvar K, et al (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467 (7312), 207-10 PMID: 20729831... Read more »

Was Evita Lobotomized?

by Neuroskeptic in Neuroskeptic

Eva Peron, or Evita, is perhaps the most famous woman in Latin American history. As the wife of Argentinian leader Juan Peron she was immensely popular. But she died at the age of just 33 from cervical cancer, after a two year struggle with the disease.A new paper makes the startling claim that Eva Peron may have received a prefrontal lobotomy in the months before her death. The lobotomy is best known as a treatment for mental disorders such as schizophrenia, but according to Nijensohn et al, Peron was given the operation as a kind of pain relief.The claim was first made in 2005 by Dr George Udvarhelyi, who worked as a neurosurgeon in Argentina before moving to John Hopkins in Baltimore. After his retirement, Udvarhelyi told the Baltimore Sun that he'd performed the operation.The authors of this paper checked out the claims against his unpublished memoirs. It turns out that they've just written Udvarhelyi's biography, and managed to slip in a plug for their book. Indeed, this paper could be seen as a plug. But anyway.The early 1950s were the golden age of lobotomy and it does seem plausible that if she had one, it would have been kept secret. But it seems that the only direct evidence is Udvarhelyi's testimony. The authors point to various facts that could be seen as consistent with it, like this memoir by a close friend:“The illness continued to advance. I visited her one afternoon andwas shown a notebook belonging to her brother Juancito. There was a drawing of Evita with her head criss-crossed by scissors. The sinister image suggested that she was either crazy or brain damaged. I found her very thin, quiet, and deeply introverted”But to be honest this is pretty weak. The authors also admit that in interviews with scholarly experts on Peron's illness, they were all surprised by the idea.They then point to postmortem X-rays of Peron's skull which were made public in 1955 to prove that her corpse hadn't been burned (long story). These, they suggest, show evidence of the kind of burr holes that were used to insert the lobotomy tools -And they say that a photo of her shortly before her death shows an "indentation at the coronal level" -Hmm. Not sure what to make of those. Ultimately though, the authors admit that the only way to know for sure would be to exhume Evita and study her skull, but this is unlikely to happen any time soon.Nijensohn DE, Savastano LE, Kaplan AD, & Laws ER Jr (2011). New Evidence of Prefrontal Lobotomy in the Last Months of the Illness of Eva Perón. World neurosurgery PMID: 22079825... Read more »