Smart Pills: Drugs to Boost Brain Power

One of the world's most commonly performed surgical procedures - cataract surgery - could soon be revolutionised with a laser. Stanford University scientist Daniel Palanker and his colleagues, writing in Science Translational Medicine, have developed a laser mapping and cutting technique to significantly improve the safety and success of lens replacement surgery, which up to one third of the developed world's population undergo in their lifetimes.

Cataracts occur when the lens, which sits at the front of the eye behind the cornea, becomes cloudy; this hinders the passage of light into the eye, impairing visual acuity, colour perception and making it especially difficult to see in low light conditions. Ophthalmic surgeons remedy the situation by first making an incision in the front part of the eye. They then painstakingly perform a technique called a capsulorhexis, which involves opening up a circular aperture in the capsular membrane that holds the damaged lens. This incision must be circular to avoid producing any "edges" that would be weak spots prone to rupture. When this is complete the lens is broken up, usually by ultrasound, and removed through the aperture. A replacement prosthetic lens is then inserted in its place. Although the the operation has an very high success rate, there are complications.

The trickiest step is performing the capsulorhexis, which relies entirely on the skill of the surgeon and his or her estimation of the "correct" placement of the incisions during the procedure. To remove this uncertainty, the Stanford team have designed a femtosecond laser-assisted technique that initially maps out the eye, performs the capsulorhexis procedure and also cuts up the lens into tiny fragments facilitating its removal. Using pig's eyes to hone the technique and then rabbits to test its safety, the new approach produced capsulorhexis results that were twice as strong as those performed free-hand by a surgeon, thus potentially reducing the risk of complications. The system was then tested on 50 patients - though not as a blind trial (!) - 30 of them in a cross-over study whereby one eye was treated via the traditional surgical technique, the other using the laser.

There were no negative outcomes, confirming the safety and effectiveness of the approach, the cuts made by laser were 50 times more precise than those made by hand and, although stastically not significant, the laser-treated individuals also had slightly better visual acuity afterwards.

Chris -   Also this week, the annual meeting of the Society for Neuroscience took place in San Diego, California; a nice sunny place.  This is actually the largest meeting of neuroscientists from around the world who meet to discuss their latest research and the progress they're making in understanding how the brain works.  Naked Scientist Smitha Mundasad was there for all the action and she's with us now to tell us what she got up to.  Hello, Smitha.

Smitha -   Hi, Chris.

Chris -   So the weather here, decidedly worse than California then?

Smitha -   It's so much nicer in California.

Chris -   So, a shame to be back, but what did you get up to?

Smitha -   Well, with over 30,000 neuroscientists in attendance, this year's Society for Neuroscience Conference in San Diego, was a hot bed of new research and exciting ideas.  One of the meeting's highlights was news that researchers have found a way for people to control computer cursors with their thoughts alone.  Using MRI machines connected to computers, scientists from the University of Pennsylvania School of Medicine had 14 participants think alternatively of two thoughts:  One, to think about playing tennis; and the other, to imagine going from room to room in a familiar place.  Analysing the brain activity from these two different scenarios, the researchers were able to show that the computers could distinguish two distinct patterns of brain activity for each thought.  While still in the MRI scanner, the participants were asked to use these thoughts to control the movement of a computer cursor on a screen.  This means that they had near instant feedback of how well they could control their own thoughts.  Lead author, Dr. Anna Rose Childress explains that how new approach could have major therapeutic implications, for example, in the treatment of addiction...

Anna -   Control of the screen cursor is a really good measure of how well a person can alternate their thoughts, between tennis and room by room.  The thoughts, of course, are completely arbitrary, but the act of controlling them and shifting them does require considerable attention and cognitive control.  For our patients, when they are in the real world and maintaining cognitive control while they're driving their car down the street in a cocaine neighbourhood, what they describe is that they will be intruded on by a brief vision of something cocaine related and they become derailed.  So we're going to be able to model that with this task.  We'll have people performing this task and be blipping in very brief cocaine images and be able to actually see the brain struggling to maintain control.  So it's a very sensitive probe for disrupted cognitive control in pathological conditions such as addiction for example.

Smitha -   Anna Rose Childress from the University of Pennsylvania. 

In other news from the conference, again combining the disciplines of computing and neuroscience, researchers have found a novel way to make blind mice see.  There's over 25 million people worldwide who suffer from degenerative diseases of the retina, often resulting in partial sight and blindness.  Photoreceptors on the retina normally receive light and then, with the help of retinal ganglion cells, this is converted into electrical impulses that can be understood by the brain.  But with many retinal diseases, these photoreceptors stop working.

Existing retinal prosthesis offer very limited hope.  Implanting electrodes into the retinal cells can allow people to make out spots of light or edges of objects, but very little in the way of real vision.  

But now, researchers at Weill Cornell Medical College in New York have taken a new approach.  By analysing the light input and then the corresponding neural output of the healthy mice retinal cells, they were actually able to mimic the way the retina converts light into electrical signals.  They've actually essentially cracked the neural code used by the brain.  This code can then be used to produce a much sharper, clearer image in mouse models.  The team hope to work with primates next and then humans very soon.  Lead author, Sheila Nirenberg, explains how her research differs from other approaches...

Sheila -   Our common analogy is that the patient's eye is like a digital camera with damaged pixels.  So the more of the pixels you replace, the better the picture you're going to get.  What our research shows is that there's another factor that's just as critical.  Not only do you need to stimulate large numbers of cells, but you also have to stimulate them with the code that the eye is sending to the brain.  This is because the camera analogy really only holds in part.  The eye does essentially take a picture, but then it goes much further.  It processes the picture.  It extracts information from it and then it converts that information into a code that the brain can read.  So, to make an effective prosthetic device, you've really got to have both these functions:  acquiring the picture and then converting the picture into a code that the brain can make use of, and I think we really have this now.  We have both of these components.

Smitha -   Sheila Nirenberg from Weill Cornell Medical College, New York.  

There was also good news for musicians at the Society for Neuroscience Conference.  Benjamin Zendel of the University of Toronto presented research that suggests that musicians may actually be protected from some of the age-related changes in the auditory cortex of the brain.  The researchers presented participants with complex sounds under two conditions:  One, where they were distracted by another activity and the other, where they were focused on the sounds.  During these experiments, the participant's brain activity was measured using EEG.  The brain activity patterns of older people with musical training were very similar to that of young people during the attentive listening task, but older non-musicians showed typical age-related changes.  Lead author, Benjamin Zendel...

Benjamin -   A lot of research has shown that musicians do better on many hearing tasks.  They have more acute hearing, they're better at making fine distinctions between sounds, and also the exact same things that change with age.  So as you get older, it's harder to make these fine distinctions between sound and that contributes to difficulty understanding speech in noisy environments like at a noisy restaurant or a noisy coffee shop, and so, the really exciting part of this research is that older musicians seem to maintain some of those abilities and it's reflected in changes in the auditory cortex.  That there are changes in the functional components of the auditory cortex in older musicians that make their brains effectively look like that of the younger adults.

Smitha -   So those piano lessons might have been a bit more valuable than I thought!  That was Benjamin Zendel from the University of Toronto.

Scientists have solved a long-standing mystery relating the structure of the placenta, the lifeline that connects mother and baby during embryonic development. For over 100 years anatomists have been scratching their heads trying to explain why, despite the function being the same for every animal, the placentae of different species were so dramatically different in structure.

Now two Durham University scientists, Isabella Capellini and Robert Barton, writing in the journal The American Naturalist, think they know why. Their study compared 109 different animal species, including humans, taking into account the size and length of gestation of each animal as well as the stuctures of their corresponding placentae. What they found is that the simpler the structure of the placenta, the longer the gestation. So animals like a human or an ape, which have relatively simple placentae comprising just "fingers" of foetal tissue projecting into the wall of the uterus to contact maternal blood, tend to have a longer gestation, while species like dogs and leopards, which have relatively short gestation times, have extremely complex and highly folded "labythine" placental structures.

This latter configuration provides a very high surface area through which nutrients can be picked up by the developing foetus, while the simpler stucture adopted by humans have a lower surface area and hence a more limited rate of nutrient provision to a baby, prolonging the gestation. Why this is important is that it reflects the metabolic cost of pregnancy and is probably a protective mechanism by which a mother controls the resource conflict between her needs and those of the developing baby. Now this relationship is understood, Robert Barton points out, "it will be interesting to track down the genes involved and this will inevitably have clinical consequences too, informing our understanding of pregnancy-related conditions like pre-eclampsia."

Chris -   This week, we're looking into brain boosting or so-called smart drugs.  Joining us to explain what they are and how they work is Cambridge University's Charlotte Housden.  Hello, Charlotte.

Charlotte -   Hello, Chris.  Hi.

Chris -   Welcome to the program.  What do we actually mean by cognition in the first place and a cognition boost?  What actually is this?

Charlotte -   Cognition can be thought of as a basic mental processing function that's essential for every day behaviour and activity; such as memory or attention.  And then these general areas of cognition can actually be divided up even further, so you've got different kinds of memory:  working memory, long term memory, and these are all associated with different areas of the brain.

Chris -   And how much do we understand about how the brain actually does those jobs in order to develop drugs that change them?  Or most of these drug interventions done blindly in terms of - we find something that works, so we use it.

Charlotte -   It's a mixture of those approaches actually so sometimes you have a drug and then we find it worked with a certain patient group, and that can tell you something about how the drug is working, that can open up doors on further potential treatments, and that's the more usual approach.  Or we can have a good idea around what's going on with a certain patient group and then go looking for drugs that would help them.

Chris -   Where are we with this at the moment when we're saying we have drugs?  We know people on campuses, in laboratories, in business board meeting are using these things because people have done studies published in pretty powerful journals where people are blindly and anonymously saying, "Yes, I'm using these things."  What's the scale of the use though, do you think?

Charlotte -   It's quite hard to say, but just as an indication of the use of these drugs by healthy people, the Cambridge University student newspaper did a survey last year and they interviewed a thousand students, and they found actually 10% of students admitted to using a drug to help them with their studies.  The reasons they gave were to improve concentration, and also, to enable them to have a work life balance.

Chris -   I'd quite like that!  But what are we classing as a drug?  Would they be answering, "I'm on a drug" if they said, "I had 15 cups of very strong coffee a day."

Charlotte -   Well, for the people who answered the survey in this particular case, we're just talking about actual drugs.  But it's interesting you brought up caffeine because actually, caffeine is a mild stimulant and is something that lots of people use to improve their cognitive ability.  It has been shown to improve memory and attention in people who are sleep-deprived, so it's a wake promoting drug that lots of people turn to.

Chris -   Although as one person put it to me, you're never quite clear whether it's just people getting relief from the side effects of caffeine deprivation, making them feel so much better that their performance improves, which I think is probably the case with me, compared with actually having some kind of tangible improvement on what your baseline would be.  People have presumably done that;  they've taken people who were not caffeine users and then put them on it and seen a demonstrable improvement.

Charlotte -   Yes.  So there have been double-blind studies with drugs such as caffeine, particularly in sleep-deprived people, it seems to have an effect.  So it seems that caffeine's cognitive enhancing effects are related to its wake promoting properties.  So caffeine would probably be best when you're feeling a bit tired.  But actually, if you're performing quite well, the effects might not be quite as big as if you were sleep-deprived.

Chris -   Well caffeine, that's common and lots of people use that quite legally - I'm one of them.  What about the other things that people use illicitly though?  What sort of drugs fit in to that category, that boost brain power?

Charlotte -   Well, there are other drugs which have originally been developed for use in patient populations.  So, from my point of view, I'm interested in investigating how drugs such as these can be used to help patients with cognitive impairments.  These drugs are being used by other people, and they include drugs such modafinil which is known as Provigil, which have been shown to improve cognition in healthy people.  And again, it was originally developed for use in patients with narcolepsy.  So again, it has wake promoting properties and it's also recently been licensed for use in shift work sleep disorder, so for people who aren't performing well because they're tired.

Chris -   So when you're taking these agents, the research you do, presumably what you do is to put people into a brain scanner and put them either on the agent or on a placebo and give them a trial to do some kind of cognitive workout in order to compare how the brain is performing under those conditions.  What does it do to the nervous system when you take these agents?  In what way is it achieving these beneficial effects?  I know you've said that it obviously wakes people up a bit, but is there something else beyond that?

Charlotte -   Okay, so if I use modafinil as an example, we've done cognitive tests with modafinil in Cambridge and we've found that modafinil in healthy people in Cambridge, healthy young adults with high intelligence, actually showed improvements on working memory and also response inhibition.  So that's the ability to stop yourself automatically responding to an appropriate stimuli, which is actually quite a useful cognitive skill.  

Chris -   So people become less distractible?

Charlotte -   Yes, in a way or less impulsive.  Modafinil seems to work through a few different neurotransmitter systems.  It doesn't just focus on one system, so something which lots of people might have heard of is dopamine.  It seems to bind very weakly to dopamine transporters so that increases throughout the brain.  It increases dopamine in a kind of tonic way rather than dopamine firing.  It's a diffused increase in dopamine and it also seems to affect noradrenalin glutamate systems.  And the way that modafinil actually makes people more alert is it helps more sensory information get to the prefrontal cortex which happens when you're feeling quite awake and the prefrontal cortex is a nerve of the brain that's really important for high level cognition, so we call them executive functions.  These are things that such as thinking flexibly, planning and problem solving, things that are quite high level.

Chris -   But the thing that strikes me is that if you take this agent and you get these effects, if they were beneficial, why wouldn't your brain already have those pathways and those levels of neurotransmitters normally?  Why should it be beneficial to enhance them in this way if it were good for you in the long run?

Charlotte -   Okay, so actually, we all have different levels of neurotransmitters in our brains.  Everybody has different levels and different levels are actually advantageous for different things, and actually, these drugs do work differently in different people.  That's something very important to keep in mind.  A drug that might enhance cognition in somebody may actually impair cognition in somebody else.  So, I talked about the prefrontal cortex being really important and actually, with dopamine in the prefrontal cortex, you want to kind of have an intermediate level of dopamine there, for you to be functioning at your best.  And some people have a naturally lower level of dopamine than others, so if they took a drug that improved dopamine, then the functions associated with the prefrontal cortex get better, such as working memory.  However, if you naturally have quite high levels of dopamine, you're a high functioning person, your memory is quite good, then actually, taking a drug like modafinil would actually make you perform worse on a working memory task.

Chris -   Or you might think you're performing better, presumably, do some students who take this stuff and it makes them wake up because of the action on other neurotransmitters, suffer a benefit in one regard, but a disbenefit in the other?

Charlotte -   It could potentially work like that.  So as I've said, modafinil works on a few different systems. Yyou could be seeing benefits in some areas and not others.  And actually, the amount of the drug that people take also influences that, so say for instance, another drug, methylphenidate which acts on dopamine systems.  When people with ADHD take this drug, their attention or levels go up as their dose increases, but actually, at high levels people become more impulsive.  So you've got to balance this out with the dose and it also depends on your individual genetic makeup as well.

Chris -   What about the long term effects, Charlotte?  Presumably, we haven't been using these agents for long enough to know about a lifetime's use of this in the workplace.  What will that do to my brain eventually?  Will I end up rotting out my brain, whereby I have to take this stuff, just to function normally?

Charlotte -   Yes, so that's an interesting concept.  It's quite difficult to know at the moment because we found it quite hard to get ethical approval to do studies in healthy people for long term use, just because if it is detrimental, then it's not very good to do that to people in your studies.  All of the drugs that people are using off-label, have been licensed for use and safe use in patient populations, so that's one thing.  There is a problem with long term use of drugs that are bought on the internet because actually, there's no guarantee that they're safe and actually, most internet sites will give you the drugs without a doctor's prescription.

Chris -   And that's where the students are getting it from, is it?

Charlotte -   There is different research saying different things, so yes, lots of people do get them off the internet and you don't need a doctor's prescription for that, which is quite worrying because you don't actually know what you're buying.  And there's also a problem with people selling drugs prescribed to them, to others, people obtaining drugs that are given to relatives or friends for their own cognitive impairments.

We put this to Charlotte Housden:

Charlotte - Okay, so the way I'm interpreting this is a "crutch" as being the potential for this seems to be addictive in some way or somebody become dependent on them. There is a concern that people might feel psychologically dependent on drugs because they lose confidence in themselves and they feel they need something extra in order to go on doing well. Furthermore with modafinil, an imaging study has actually shown that modafinil binds weakly to dopamine transporters in an area of the brain called the nucleus accumbens and other drugs which bind to this area have actually been shown to be addictive. But because it binds weakly, it's thought that the addictive potential is quite low, so people won't get addicted. But this is still something which could be a risk factor, and could affect some people. In terms of long term use, if you're using these drugs to help with exams, what happens afterwards and as we've already discussed, we haven't had the opportunity yet to look at long term use in healthy individuals. But it is a possibility that if somebody was taking a lot of some of these drugs over a long period of time, there might be some changes neurologically, but it's very difficult to say how this would transfer to behaviour.

We put this to Smitha Mundasad...

Smitha - I think that one's a little bit more difficult. I think that brings up a lot of issues. Who controls what you can download? Would you be able to download something from someone else's brain? I think we're a little bit far away from that, but there's a lot of progress in neuroscience, so it wouldn't surprise me if it happened...

Chris - I can quote meta-analyses of randomised control trials of St. John's Wort for major depression suggest that it is superior to placebo and it's similarly effective compared with conventional anti-depressant drugs and tends to have fewer side effects. St. John's Wort being a way of actually making your mood elevate. So it's a sort of natural anti-depressant. Although they do say in placebo control trials, trials from German speaking countries tend to report more favourable findings. So I guess the jury is out on that one.