Thursday, April 17, 2014

Dear CNRS: That mouse study did not "confirm" the neurobiological origin of ADHD in humans

Late last week the French National Centre for Scientific Research (CNRS - the acronym is based on the French translation) put out a press release describing a study conducted through a collaboration between several of its researchers and scientists from The University of Strasbourg. CNRS is a large (30,000+ employees), government-run research institution in France. It is the largest research organization in Europe, and is responsible for about 1/2 of the French scientific papers published annually.

The study in question, conducted by Mathis et al., investigated the role of a brain region called the superior colliculus in disorders of attention. The superior colliculus, also known as the tectum, is part of the brainstem. It is strongly connected to the visual system and is thought to play an important role in redirecting attention to important stimuli in the environment. For example, imagine you are sitting in your favorite coffee shop quietly reading a book, when someone in a gorilla suit barges in and runs through the middle of the room. You would likely be surprised and you would, somewhat reflexively, direct your attention towards the spectacle. This rapid shift in attention would be associated with activity in your superior colliculus.

It has been proposed that individuals who suffer from disorders like attention-deficit hyperactivity disorder (ADHD) may experience increased activity in the superior colliculus, which causes rapid, uncontrolled shifts of attention. Mathis et al. investigated the role of the tectum in attention using mice with a genetic abnormality that makes the superior colliculus hypersensitive.

The researchers exposed mice with this defect to a series of behavioral tests. They found that the mice performed normally on tests of visual acuity, movement, and sensory processing. However, the mice seemed to be less wary than control mice of entering areas of bright light (usually something mice avoid as open spaces make them vulnerable to attacks from natural predators). Additionally, the mice performed worse on a task that required them to inhibit impulses. These abnormalities in behavior were associated with increased levels of the neurotransmitter norepinephrine in the superior colliculus.

The authors of the study mention that their work supports the hypothesis that superior colliculus overstimulation is a contributing factor in ADHD. I have no qualms with the verbiage used in the paper, but CNRS's press release about the study is titled "Confirmation of the neurobiological origin of attention-deficit disorder" and they state in the article: 
"A study, carried out on mice, has just confirmed the neurobiologial origin of attention-deficit disorder (ADD)..."
When it comes to psychiatric disorders without a clearly defined molecular mechanism (which is almost all of them), it is improbable that a finding in mice can confirm anything in humans. Our understanding ADHD in humans is limited. We have no objective diagnostic criteria; instead we base diagnosis on observable and self-reported symptoms.

If our understanding of a disorder in humans is based primarily on symptomatology (as opposed to the underlying pathophysiology), then it makes the results of experiments that use animals to model the disorder more difficult to interpret. For, if we don't know what molecular changes we can expect to see as a correlate of the disease (e.g. senile plaques in Alzheimer's), then we are resigned to trying to match symptoms of mice with symptoms of men. In this type of situation where we don't know the true pathophysiology, we can never be sure that the symptoms we are seeing in mice and those we are seeing in men have an analogous biological origin.

Thus, when it comes to psychiatric disorders, translating directly from animals to humans is difficult. In the case of ADHD, because the biological origins of the disorder are still mostly unknown, animal models can be used as a means to explore the neurobiology of a similar manifestation of symptoms in the animal. They can't, however, be used to "confirm" anything about the human disorder. In this case, CNRS drastically overstated the importance of the study. Of course, the wording used by CNRS in their initial press release was also found on dozens of other media outlets after they picked up the story.

Do I doubt that ADHD has a neurobiological origin? No. But the study by Mathis et al. did not confirm that it does. CNRS, as an institution of science, should be more careful about the claims they make in their communications with the public.

Mathis, C., Savier, E., Bott, J., Clesse, D., Bevins, N., Sage-Ciocca, D., Geiger, K., Gillet, A., Laux-Biehlmann, A., Goumon, Y., Lacaud, A., Lelièvre, V., Kelche, C., Cassel, J., Pfrieger, F., & Reber, M. (2014). Defective response inhibition and collicular noradrenaline enrichment in mice with duplicated retinotopic map in the superior colliculus Brain Structure and Function DOI: 10.1007/s00429-014-0745-5

Saturday, April 12, 2014

Early brain development and heat shock proteins

The brain development of a fetus is really an amazing thing. The first sign of an incipient nervous system emerges during the third week of development; it is simply a thickened layer of tissue called the neural plate. After about 5 more days, the neural plate has formed an indentation called the neural groove, and the sides of the neural groove have curled up and begun to fuse together (see pic to the right). This will form the neural tube, which will eventually become the brain and spinal cord. By around 10 weeks, all of the major structures of the brain are discernible, even if they are not yet fully mature. So, in a matter of two months, the framework for the human brain is built from scratch. If that doesn't put you in awe of nature, nothing will.

Although the process of neural development is amazing, it is also very sensitive. There are indications that a number of environmental exposures during prenatal development may increase the risk of disorders like autism, schizophrenia, and epilepsy. Some of these dangerous environmental exposures are well known (e.g. alcohol consumption during pregnancy increasing the risk of developing fetal alcohol syndrome). However, there are a number of other factors whose detrimental effects on fetal neural development are still debated or have not yet been fully elucidated. For example, the effects on a fetus of substances like phthalates (plasticizers that are likely found in a number of products throughout your home), bisphenol A (another substance used in the production of plastics - found frequently in food and drink containers), and even tobacco smoke, are still being investigated. But a pregnancy free from exposure to any potentially harmful substances doesn't guarantee normal neural development. Even factors that are natural and more difficult to control, like maternal infection during pregnancy, are suspected of being detrimental in some cases.

To complicate the issue even further, it is difficult to predict who will be affected by these environmental insults and who will not. It seems that there may be a genetic susceptibility to neurodevelopmental damage that causes a particular exposure to be detrimental to one fetus, while it may not have a major impact on another with a different genetic makeup. This complication, however, also provides an opportunity to learn more about the etiology of neurodevelopmental disorders. For, if we can learn what mechanism is failing in the fetus who is affected, but functioning in the fetus who is not, then our understanding of the origin of these disorders will be drastically improved.

In a paper published last week in Neuron, Hashimoto-Torii et al. approached the problem from this angle and examined the role of heat shock proteins in neurodevelopmental problems. Heat shock proteins are peptides whose expression is increased during times of stress. They earned their name when it was discovered in the early 1960s that high levels of heat increased their expression in Drosophila (fruit flies). Since, it has been learned that heat shock protein expression is increased during all sorts of stress, including infection, starvation, hypoxia (lack of oxygen), and exposure to toxins like alcohol. Thus, some also refer to heat shock proteins as stress proteins.

To investigate the role of heat shock proteins in neurodevelopmental disorders, Hashimoto-Torii et al. exposed mouse embryos to three different types of environmental insults. They injected pregnant mice with either alcohol, methylmercury, or a seizure-inducing drug. Then, they looked to see how the brains of the embryos reacted. As they hypothesized, they saw a significant increase in the expression of a transcription factor (heat shock factor 1 or HSF1) that promotes the production of heat shock proteins.

When the researchers investigated the effects of prenatal exposure to the insults listed above in mice who lacked an HSF1 gene (HSF1 knockout mice), they saw that the exposed moms had smaller litters than control mice. The mice that were born, however, also displayed malformations consistent with neurodevelopmental damage, greater susceptibility to seizures after birth, and reduced brain size. The reduction in brain volume seemed to be due to decreased neurogenesis after the insult.

To make a clearer connection between heat shock protein activation and human disease, the researchers exposed stem cells derived from schizophrenic patients to methylmercury and alcohol, and compared the response of the "schizophrenic cells" to the response of cells from non-schizophrenic (control) patients. They didn't see an overall difference in heat shock protein expression between the two types of cells, but they did see significant variability in expression among the schizophrenic cells. In other words, both schizophrenic and control cells increased expression of heat shock protein after an insult, but some of the schizophrenic cells appeared to increase expression more or less than others. The control cells all displayed a relatively similar increase in expression. This suggests that there may be an abnormal response involving heat shock proteins in individuals with a certain genetic predisposition; perhaps this abnormal response makes the individual more susceptible to disrupted neurodevelopment.

Thus, the study by Hashimoto-Torii et al. points to heat shock proteins as a potential culprit behind what goes wrong in early brain development to lead to psychiatric disorders like schizophrenia and autism. More research will need to be done, however, to verify this role for heat shock proteins. And, even if future research supports this finding, it is likely that heat shock proteins are still only part of the puzzle. But the puzzle is complex, and so we will need to add many of these little pieces before we can begin to comprehend the whole picture.

Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., Ju, M., Ishii, S., Chao, S., Brennand, K., Gage, F., & Rakic, P. (2014). Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders Neuron DOI: 10.1016/j.neuron.2014.03.002

Wednesday, April 9, 2014

Why do I procrastinate? I'll figure it out later

If you are a chronic procrastinator, you're not alone. Habitual procrastination plagues around 15-20% of adults and 50% of college students. In a chronic procrastinator, repeated failure to efficiently complete important tasks can lead to lower feelings of self-worth. In certain contexts, it can also result in very tangible penalties. For example, a survey in 2002 found that 29% of American tax-payers procrastinated on their taxes, resulting in errors due to rushed filing that cost an average of $400 per person. More importantly, we tend to procrastinate when it comes to medical care (both preventive and therapeutic), which can involve very real costs to our well-being.

Why is the urge to procrastinate so strong? It sometimes seems that we are compelled to procrastinate by a force that is disproportionate to the small reward we may get from putting off a task we're not looking forward to. According to Gustavson et al., the authors of a study published last week in Psychological Science, a predisposition to procrastinate may have its roots in our genes.

Previous research has suggested a potential link between a tendency to procrastinate and an impulsive nature. Gustavson et al. explored this possible connection by observing the traits of procrastination and impulsivity in a group of 181 identical and 166 fraternal twins. Because identical twins share 100% of their genes and fraternal twins only share around 50% of their genes, if a trait is shared by identical twins more frequently than it is by fraternal twins, it suggests the trait has a significant genetic basis (for more on twin studies see this post).

The investigators reported a significant correlation between procrastination and impulsivity (r = .65). The group also reported that their genetic model determined that procrastination and impulsivity were perfectly correlated (r = 1.0), suggesting that the genetic influences on procrastination and impulsivity are completely shared. In other words, according to this study, there are no genetic influences on procrastination that aren't also affecting impulsivity.

But why would these two traits be associated with one another? Procrastination involves putting things off, while impulsivity involves doing them on a whim. Gustavson et al. suggest that both procrastination and impulsivity involve a failure in goal management and a deficit in the ability to guide behavior effectively using goals. The authors refer to a hypothesis proposed by procrastination researcher Piers Steel that suggests impulsivity may have been adaptive to our ancient ancestors when survival depended more on thinking and acting quickly. In today's much safer world, however, planning for events yet to come has superceded impulsivity in terms of importance.

Thus, like many of our other bad habits, procrastination may have its roots in a behavior that was at one point adaptive and is now outdated. So, if it feels like your desire to procrastinate is driven by a force much stronger than your willpower, it may be so. If Gustavson et al. are correct, the impetus for procrastination lies in genetic programming that dates back to the Pleistocene era.

Gustavson, D., Miyake, A., Hewitt, J., & Friedman, N. (2014). Genetic Relations Among Procrastination, Impulsivity, and Goal-Management Ability: Implications for the Evolutionary Origin of Procrastination Psychological Science DOI: 10.1177/0956797614526260

Monday, April 7, 2014

Is ketamine really a plausible treatment for depression?

Last week, a publication in the Journal of Psychopharmacology made international news by reporting that patients with treatment-resistant depression (TRD) showed improvement after being given the dissociative hallucinogenic drug ketamine. Ketamine, which is traditionally used as an anesthetic in humans and other animals, is probably better known for its use as a party drug (in this context it is often called "special K"). However, a growing body of evidence has begun to suggest that ketamine may be effective (at least in the short-term) in treating depression.

I'm a bit surprised by the headlines prompted by this recent publication, though, for a number of reasons. The study, conducted by a group of scientists at Oxford, didn't really present any groundbreaking--or extremely convincing--data. The group explored the effects of ketamine infusions over a period of three weeks. Similar protocols of ketamine administration have been tested in the past (with similar results). However, the recently-published study had some shortcomings that make it a bit less convincing than some prior ketamine studies. First, there was no control group. All patients received ketamine and, although 29% of the participants showed improvement (a modest effect but relevant because these patients experienced little benefit from other treatments in the past), there is not a group whom their improvement can be compared to in order to gauge the true effects of the drug. Additionally, this was an open-label study, which means that the investigators and patients all knew that ketamine was being administered. In other words, there was no possibility that a placebo might be given. This could create expectancy effects in the patients and investigators, making the need for a control group all the more important.

The investigators were aware of these shortcomings in the study design; they initiated the study as an exploratory venture. They were interested in knowing how ketamine infusions over a prolonged period affected memory when patients also continued to take other antidepressant medications. So, they were mostly concerned with examining safety and effects on memory (they did not observe any detrimental effects on memory), not with assessing the benefit of the treatment.

But the fact remains that, despite the headlines, this study was not a huge advancement in depression research or even research into the use of ketamine to treat TRD. There is some intrigue (especially in the media) surrounding the use of ketamine as an antidepressant because of its notoriety as a taboo recreational substance. I assume this is why a relatively minor study was reported on in major media outlets across the world.

Ketamine is also an intriguing treatment for depression in the eyes of scientists, but its abuse status has nothing to do with that. It's interesting because ketamine is thought to work as an antagonist at receptors for glutamate called NMDA receptors. Since hypotheses regarding the mechanism of depression have historically focused on monoamines like serotonin, ketamine's unique (although as yet not fully elucidated) mechanism suggests there may be other valid approaches to treating depression.

However, any publicly-available ketamine treatment is at best far off and at worst improbable. 29% (the same percentage that saw a benefit) of the participants in the Oxford experiment withdrew, either due to lack of perceived benefit or adverse reactions. The adverse reactions ranged from anxiety and panic to a vasovagal reaction that caused a "reduced level of consciousness" and lasted for 10 minutes. Two of the patients vomiting during infusions. So, although the reported improvements in a minority of patients are dramatic, there are also significant adverse effects that would make treatment undesirable for other patients. Additionally, very little is known known about the potential long-term effects of ketamine treatment; there are some indications ketamine has the potential to be neurotoxic.

Ketamine may have a role to play in helping us to understand depression. But right now it is very unclear if this drug will ever be of real use in treating patients with TRD on a large scale. So, these media reports about the excitement surrounding ketamine should be taken with a grain of salt.

Diamond, P., Farmery, A., Atkinson, S., Haldar, J., Williams, N., Cowen, P., Geddes, J., & McShane, R. (2014). Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic Journal of Psychopharmacology DOI: 10.1177/0269881114527361

Friday, April 4, 2014

Is your biological clock ticking? Maybe you should ignore it

As I've transitioned into middle age, I've gotten used to seeing my Facebook feed filled with baby pictures, descriptions of charming family outings, and adorable quotations from the mouths of toddlers. If I knew nothing about what it were like to have a child (mine is just finishing up the terrible twos), I would assume from scrolling through these perfectly tailored social media portraits of others' lives that having kids is a non-stop fun-filled procession of treasured moments. Of course, this perspective is not confined to my Facebook news feed. It's common knowledge that children make us happier and help us to feel more fulfilled.

This is one of many instances, however, where research and folk wisdom don't mesh. In fact, when studies have compared the happiness of those with children to the happiness of those without children, they have often found that having children is associated with lower life satisfaction. A recent publication looked at data from close to 1.8 million Americans and over a million other respondents throughout the world. What the researchers (a psychologist and an economist--both from Princeton) found generally supported the idea that those who have children are not as happy as those who do not.

There are many explanations for such a finding other than the hypothesis that kids make us miserable. For example, although the survey data used by the Princeton researchers indicated lower life satisfaction in people with children, people with children also experienced less physical pain, felt they had more enjoyment in their lives, earned higher incomes, were better educated, and were healthier. On the other hand, they experienced more stress, worry, and anger. Thus, it may be that having children generates its share of highs and lows, causing us periods of intense stress and upset that are relieved by the enjoyment we get from spending time with our kids. Most parents would probably agree with this statement to some extent.

Regardless, if the data indicates that people with kids are--in a best case scenario--no happier than those without, then where do we get this idea that having kids will make us happier? And why, when we talk to people with kids (or see their posts on Facebook), are we given the distinct impression that a life without children is somehow...lacking?

Survival of the Fittest

The answer to this conundrum may involve evolution. Of course, because having children is the only way to directly pass on one's genetic lineage, then the act of having children causes the propagation of a genetic makeup that may predispose someone to look favorably upon having children. In other words, if there were genes that affected someone's personality in such a way that they loathed the idea of having children, then those genes wouldn't last very long in the population because the reluctance of those who possessed them to have children would naturally limit their propagation.

Although genes that predispose one for parenthood may be part of the answer to this puzzle, there also may be a role for another unit of transmission: the meme. The term meme was coined by Richard Dawkins in his revolutionary book about genetics called The Selfish Gene. A meme is an idea. The idea can be represented by a cultural norm, a style, a behavior, or anything else that can be spread from person to person and generation to generation. Just like genes, however, memes are subject to natural selection.

For example, the rock group Bad English recorded a song 25 years ago called "When I See You Smile." You may or may not remember this song depending on your age and how often you listened to top-40 music in 1989. Here's a link to the video if you care to refresh your memory and/or reminisce. Bad English's song could be considered to have moderately good "fitness" as a meme. It was an idea that enjoyed brief popularity, and at the height of its popularity a significant percentage of the world's English-speaking population was aware of its existence (and maybe even sung along once or twice). However, I don't expect anyone will be singing it 100 years from now.

In contrast, the lyrics to Auld Lang Syne came from a Robert Burns poem written way back in 1788. Over 225 years later, the song is known in many countries throughout the world and sung regularly at events like the beginning of the new year or any other occasion that signals the end of a period of time (e.g. funerals, graduations). The song is easy to remember, has a meaning (the symbolism of endings and beginnings) that resonates with people regardless of their culture, and is sung to a tune that is easy to reproduce. Auld Lang Syne is an extremely "fit" meme.

Although songs may be somewhat trivial examples of memes (contrasted with examples like organized religion or language), the difference between the longevity of these two songs suggests that some memes seem to be better at replicating than others. With that in mind, lets turn back to the idea that having children is an enriching experience. There isn't a much better way for a meme to ensure its survival than if holding it as a belief makes people more likely to engage in behavior that will lead to its own propagation. Believing in the idea that children bring happiness makes one more likely to have children. Those offspring then provide another set of impressionable minds who are readily convinced by their child-having parents and grandparents that children are the greatest source of joy in the world. And the meme continues to spread.

Genes don't necessarily have to promote health to allow them to continue to be propagated, but they have to have some quality that promotes their own transmission. Memes work the same way. They don't need to be accurate ideas, but there has to be something driving their dissemination. Could it be that our belief in the wonder of childbearing is simply due to the success of this meme in promoting its own transmission?

It's possible. As Daniel Gilbert discusses in his investigation of the errors we commit in deciding what will make us happy, Stumbling On Happiness, it would not be the first meme that led us astray. For example, the meme that great wealth leads to happiness continues to thrive throughout much of the world.  Evidence suggests, however, that once one has enough money to ensure one's basic needs are provided for, additional money does little to contribute to one's satisfaction.

So, if you're childless and experiencing pangs of jealousy over the seemingly perfect family photos your friends are posting to Facebook, remember that the research suggests your friends aren't as happy as they look in those photos. And maybe you don't have children because you just haven't been suckered into the mass delusion that children will make your life complete.

Deaton, A., & Stone, A. (2014). Evaluative and hedonic wellbeing among those with and without children at home Proceedings of the National Academy of Sciences, 111 (4), 1328-1333 DOI: 10.1073/pnas.1311600111