Melatonin – what will it do for you?

August 22, 2009

ResearchBlogging.orgIf you have chronic insomnia, but no octher psychiatric illnesses, will melatonin help you? This is the question addressed by a recent multi-center study by Geert Mayer and co-workers.

Chronic insomnia affects a large chunk of the population; papers cited by the authors have found a prevalence around 1 in 3 adults. It is a notoriously persistent condition and treatment is difficult. Many sleeping pills have unacceptable side effects (such as daytime drowsiness) and/or can only be used for short times. Behavioural interventions are difficult to sustain in the long run.

Hence the great interest in understanding how sleep is regulated, so that we can develop medications targeting the sleep cycle itself. Our circadian rhythms, i.e. the rhythms that tell us when it is morning, midday and night, are regulated by a brain area called the suprachiasmatic nucleus, where there is a collection of “clock cells”, that keep time in cycles of approximately 24 h. Another important component is melatonin secretion from the pineal gland, which synchronises the clock to the light/dark cycle of our environment. When it gets dark in the evening, melatonin secretion goes up.

Melatonin. Image from Wikipedia.

Melatonin. Image from Wikipedia.

So, why not give some extra melatonin 30 minutes before bedtime and see what happens to the sleep patterns? This is what Mayer et al did, with a placebo control group getting an identical-looking pill. Both groups kept doing it for 6 months, and the researchers recorded sleep patterns regularly as well as the subjective experiences of the patients, assessed by a questionnaire. Towards the end, they switched the treatment group over to placebo to see if there were any withdrawal symptoms. The drug they used was not melatonin itself but a synthetic compound called Ramelteon which binds to the same receptor.

What happened? Nothing, pretty much. The researchers monitored 20 different parameters, and found a statistically and clinically significant difference only in one: the latency to persistent sleep after going to bed. Patients on Ramelteon fell sleep faster. But they did not sleep better or longer. They did not have improved alertness or memory and they did not feel better in any way that the researchers asked for. On the other hand, there were just as many “adverse events” in the treatment and control groups, and no signs of withdrawal symptoms, so Ramelteon treatment seems not to be a risky business.

Now, it is necessary to exercise a bit of caution when interpreting a study that has many endpoints at the same time. The more endpoints you include, the higher is the likelihood that one of them will show a significant result purely out of chance. We should therefore be a little skeptical against the positive finding. Ramelteon seems to be in the league of making sacrifices to the god Hypnos – it doesn’t hurt, it could be a little expensive, and it’s not likely to help.

Hypnos (left) with his twin brother Thanatos (representing death). Painting by J W Waterhouse (1849-1917).

Hypnos (left) with his twin brother Thanatos (representing death). Painting by J W Waterhouse (1849-1917).

Melatonin could be great for some other uses that weren’t tested in this study – against jetlag, perhaps, or if you are having a manic episode and can’t sleep for that reason. The blogosphere’s number one chronobiologist Coturnix has an excellent overview post on sleep, including a bit on melatonin and its potential therapeutic uses.

Full reference:
Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, & Partinen M (2009). Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep, 32 (3), 351-60 PMID: 19294955

Do we need language to understand concepts?

July 14, 2009

AK doesn’t think so.

In another of his lengthy and well-researched posts, he argues that the understanding of more or less abstract concepts occurred in primates before a language based on words. This is based on a recent study of the mirror neurons in rhesus macaques. This research seems to indicate that rhesuses divide other rhesuses into two categories when the mirror neurons are activated: those within such a short distance that interaction is immediately possible, and those further away.

The post also includes an interesting reflection on how visual information is encoded in terms of a set of vectors in multidimensional space, suggesting that the same principle applies as a general form for representation in the brain.

In the process, AK also manages to discredit Plato’s idea that concepts are classes of things resembling an “ideal” concept that is by definition beyond our grasp. Instead, we construct concepts “bottom-up”, by grouping together objects and ideas that appear to us to have many similarities.

Implicit to AK’s argument is also the notion of a well-developed spatial modularity in the brain, with different areas encoding different concepts. While there is strong evidence for spatial modularity e.g. from split-brain experiments, showing that the two hemispheres can accurately identify and interact with objects independently of each other, it is very likely that at least some concepts are represented only by the concurrent activation of several areas in synchrony.

A prosthetic motivational system

April 13, 2009

Changing patients’ behaviours is one of the most challenging parts of medical practice. It is hard to overstate how much of our disease burden would simply disappear if people would not smoke, drink alcohol in moderation or not at all, exercise regularly and eat healthy food. Perhaps a third of current cancer morbidity would cease to be, and far more of the cardiovascular morbidity. Of course, people will die from something in the end, but the gain in terms of productive life years would be enormous.

The reason why it’s so difficult to change people’s behaviour is that the reward systems of our brains are such powerful regulators of what we do, and it’s frustratingly difficult for any physician to override the patient’s urge to have his next cigarrette.

When there’s an important problem in the world, there’s also a bunch of scientists trying to solve it. Taking control of our motivational systems could transform our societies in profound ways. Can it be done?

Yes, says Christopher Harris. He is an old friend of mine and a neuroscientist at the university of Sussex. He is personally leading a campaign for the use of deep brain implants to control our reward systems – iPlants, in his coinage.

Deep brain stimulation is a technique similar to the pacemaker. Electrodes are placed in a specific brain region, which can then be activated by passing current through the electrode.

The neuroanatomy of reward is very well known. A small group of nerve cells in the midbrain, when stimulated, release dopamine throughout the entire prefrontal cortex, which is our decision generator. Deep brain stimulation to control reward would be very similar to its application against Parkinson’s disease, in which dopamine signalling is impaired, leading to symptoms of the motor system. Thus, the technology is tried and tested in humans.

The human motivational system has been shaped over millions of years of evolution to a degree of robustness, which is why we find it so difficult to change. Sweet food is an instant reward for most people, as are alcohol and many drugs. The modern society has developed spectacular shortcuts to dopamine release, with the unfortunate effect of making many people’s lives less functional. Obesity and addiction are long-term scourges caused by the inability to resist short-term dopamine stimulation. Here is a technology that could change all that.

But who will push the button?

Improperly used, a system like this might make the patient a slave to the man with the remote control. And supposing that an accountable system can be put in place to prevent that, there is the problem of how, exactly, to connect stimulation to the desirable behaviour. Christopher suggests:

Physical exercise can be motivated by repeatedly delivering rewarding brain stimulation (RBS) whenever an animal runs on a treadmill[10] or lifts a weight[11]. iPlant-driven exercise programs would apply the same principle to humans, for example by delivering RBS whenever the user pulls a stroke on a rowing machine or when pressure-sensitive shoe hit the ground during running (see top image). Every exercise program must have a strict time-limit agreed on in collaboration with a physician.

The science and technology of the iPlant is described in some detail on Christopher’s own web page. Whether it will be tried or not is an open question, but it’s not science fiction. All the technology is there, and it works in laboratory rats.

Whether or not the iPlant will be tried, it is clear that our increasing understanding of the brain is driving remarkable advances in technology to modulate and control its function. If we manage these developments properly, we will be able to solve very many problems. But the iPlant also highlights that these advances will bring ethical issues with them of which the general public needs to be aware.

Christopher has put up a few video clips on this topic, more can be found on youtube or on his website.

Self-medication in a caterpillar

March 11, 2009

ResearchBlogging.orgSelf-medication among animals is sufficiently well studied to have a term of its own: zoopharmacognosy. Until now, such behaviour has mainly been observed among higher primates. Chimpanzees with intestinal parasites may seek out and eat shoots that are not part of their normal diet – indeed, that are toxic and make them look like they had just bitten deep in a slice of lemon. Sometimes, the same plants are used by local humans in traditional medicine.

Cool, right? But hardly rigorous. What we would really like to see in order to have good proof for the concept is an example of an animal eating a foodstuff whose medical properties can be proven, and furthermore only eating it in times of illness, and preferably suffering negative effects if they eat it when they are healthy.

A woolly bear caterpillar. Image from Wikipedia. NB: probably not the exact same species as in the study in question

A woolly bear caterpillar. Image from Wikipedia. NB: probably not the exact same species as in the study in question

Such a study has been published for the first time today, with a very surprising animal species as the protagonist: the woolly bear caterpillar. This is the larval stage of a moth of the Arctiidae family, which is apparently well known for its habits of communicating by ultrasonic sound waves, generated from a specialised organ.

Michael Singer and his co-authors have infected woolly bear caterpillars with an intestinal parasite and supplemented their diet with plants that contain substances called pyrrolizidine alkaloids (PA:s), but that are very nutrient-poor.

They found that infected larvae fared better if they ate the PA-containing plant-stuff, whereas uninfected larvae fared worse. Fewer parasites survived to reach maturity if they had access to PA. As a group, the caterpillars did not eat significantly more of the PA-food when they were infected, but there was a suggestive trend where the larvae with a greater infection load ate more PA.

In this case, the behaviour is clearly not socially learned, as it may be in the apes, but somehow coded into the neurological hardware of the caterpillar. Or rather, a subset of the caterpillars. If the parasites ceased to exist, the subpopulation most likely to eat PA-containing plants would be at a disadvantage since PA is toxic. Here is another instance of evolutionary dynamics creating a phenotype that is only advantageous in the face of an external threat – just like sickle-cell anemia in humans, which confers a measure of protection against malaria, and many other genetic diseases.

A 2005 Nature paper by the same authors showed that the peripheral taste nerve cells actually change their signalling in infected caterpillars and fire off more signals in response to PA. They speculate that the immunological response to infection is the direct cause of this change, which doesn’t even need to involve the neural cluster that resembles the caterpillar’s brain. From the perspective of information processing, this paper is a small triumph for those who try to find complex behaviours in relatively simple biological organisms.

Singer, M., Mace, K., & Bernays, E. (2009). Self-Medication as Adaptive Plasticity: Increased Ingestion of Plant Toxins by Parasitized Caterpillars PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004796

BOth Carl Zimmer at The Loom and Ed Yong at Not Exactly Rocket Science have written excellent posts on the same research.

Cells in context: when a single neuron makes the decision

February 23, 2009

The brain, our most magnificent organ, is among other things a generator of decisions. It routinely receives input, matches it against an internal representation about the exterior world, and adjusts our behavior in appropriate ways. (More often appropriate than not, that is.)

In our staggeringly complex human brains, it is impossible to pinpoint any decision to a single cell. Most researchers subscribe to a model where decisions in the brain are determined by the architecture and dynamics of the neural network, i.e. the synaptic connections, transmissions, and responses.

But what happens in a nerve system with less than our approx. 1014 connections? Brain sizes come in a huge continuum, ranging from 4-5 kg in the elephant, over approximately 1.3 kg in the human, down to invertebrates with only a few nerve cells in their entire bodies. Yet all these creatures share the ability to make decisions.

With diminishing complexity in the nervous system, the actual decision should become easier and easier to pinpoint, and eventually it might converge on a single cell. This is in fact what has been found in the Aplysia, a sea slug with a fairly simple and very well-characterised nervous system, and a common model organism in neuroscience. A neuron called B51 has been shown to make the decision to carry out feeding behaviour. Successful feeding is rewarded by dopaminergic signaling from the esophagus back to neuron B51. This is known in psychology as operant conditioning, meaning roughly that the organism learns from the consequences of its behavior.

A recent paper by Fred Lorenzetti and co-workers in the journal Neuron begins to shed light on how decision-making is carried out by neuron B51. Lorenzetti and his colleagues found that reward of the feeding behavior led to changes in the membrane structure of the neuron, reducing the threshold for firing and therefore making it more probable that feeding behavior will be initiated. They were also able to block the activities of a few intracellular proteins, and found two protein kinases that were crucial for operant conditioning to take place.

We can attribute meaning to these biochemical changes. In its context, a reduced firing threshold of neuron B51 probably means that there is a greater abundance of food in the environment. This piece of knowledge is a part of the internal representation of the outside world. And this particular cell possesses enough complexity to both carry this part of the internal representation and function as a decision generator on its own!

Of course, since the cell is part of the neural network this doesn’t mean that a network-centered view is any less correct or useful. The information processing of neuron B51 can only be made meaningful in the context of its neuronal connections. And it is not necessary to know, from a network-perspective, which specific changes in the cell that are underpinning the cell’s altered electrical activity. And finally, as a caveat, I should add that much is still unknown about the regulation of neuron B51. This model may well have to be questioned in the light of future evidence.

But this story illustrates three important things:

  • That a single cell can be capable of making decisions

  • That the internal workings underlying decision-making in the cell are attracting attention, although more from neurobiologists than from cell biologists.

  • That the decisions of single cells in multicellular organisms may require other cells to decode the decision and translate it into behavior, which means that the decision is only meaningful in that highly specific context.