A Hippo on Campus

Why parkin has scientists backing the future of Parkinson's research

2012-02-09T21:35:00.000+11:00

Back in the '80s the name Michael J. Fox was more or less interchangeable with that of Marty McFly, the effortlessly cool protagonist from the Back to the Future trilogy who introduced an entire generation of kids to hoverboards, self-lacing shoes and flux capacitors. Not to mention 'Johnny B Goode'. These days however Fox's name is more likely to have us thinking of his fight with Parkinson's disease, which he was diagnosed with back in 1991, or the advocacy work he does for his aptly named Michael J. Fox Foundation for Parkinson's Research. Looking at their mission statement you can't help but get the feeling that Fox has brought a little of Marty "nobody calls me chicken" McFly's fighting spirit to the Foundation as it dedicates itself to "finding a cure for Parkinson's disease through an aggressively funded research agenda". Whilst a cure remains allusive, recent research funded by the Foundation has resulted in a giant leap forward in our understanding of Parkinson's disease and suggests that the cure which Fox hopes will one day put him out of business may not be as far off as once thought.

It all starts in the basal ganglia

Clinically, Parkinson's disease (PD) is characterised by an array of motor symptoms including tremors, rigidity, slowness of movement (or bradykinesia) and gait and walking difficulties. Symptoms which are thought to result from neuronal degeneration within the substantia nigra, a small region of the basal ganglia which acts to produce and release the neurotransmitter dopamine. The basal ganglia is a highly organised group of structures located at the base of the forebrain which exerts a constant inhibitory effect on our various motor systems. An effect which helps to prevent our bodies from becoming inappropriately active. And that's where dopamine comes in. The dopamine, produced by the substantia nigra, acts to facilitate the release of the basal ganglia's inhibitory influence, and thus allows movement to occur. It might be easier to think of the motor system as a somewhat fused set of gears attached to a small motor. Despite the motor (motor system) being active the friction (basal ganglia) is too great to allow the gears to turn. The friction can however be overcome by spraying a small amount of lubricant (our dopamine in this analogy) onto the gears, thus whilst the dopamine doesn't actively turn the gears it acts to reduce the constant friction between the gears thus allowing the motor to initiate movement. Our brains work in much the same way, everything is able to work smoothly in the presence of our personal lubricant, dopamine (sounds wrong I know but stick with me here), however when sufficient levels of dopamine are not available, such as in Parkinson's disease, our ability to initiate and control our movements slowly grinds to a halt.

Like most neurodegenerative conditions, the neuronal loss associated with Parkinson's disease occurs due to a variety of factors, some of which are environmental whilst others are genetic. However, as is often the case, it is the rarer genetic forms of the disease which offer the greatest promise for therapeutic advancement in the field. Approximately one in 10 Parkinson's cases result from mutations in the parkin gene, a gene on chromosome six which encodes a component of the E3 ubiquitin ligase complex (for those of you playing at home). Normally this knowledge would result in the use of a mouse model of the disease, however parkin knockout mice show no signs of Parkinson's disease suggesting that parkin mutations act selectively on human nigral dopaminergic neurons. The selective nature of the parkin gene was, until recently, a major hurdle in Parkinson's research as the complexity of neuronal networks in the human brain make it incredibly difficult to study the genetic form of the disease. After all parkin-affected dopaminergic human neurons aren't something you can just grow in a lab. Or at least they weren't, until now.

Test tube neurons

That's right for the first time ever scientists have managed to generate human dopaminergic neurons from Parkinson's disease patients with parkin mutations. And what's more they made them from skin. Ok so to be more specific the researchers generated human induced pluripotent stem cells from dermal fibroblasts (skin cells), collected from two Parkinson's patients (both with parkin mutations) and two controls. The stem cells were subsequently used to generate the dopaminergic neurons some of which contained the parkin mutations and some of which did not. The generation of these mutant neurons allowed the researchers to finally observe parkin in action in its native habitat, and enabled them to see just how mutations in the gene were leading to neuronal damage. As it would turn out normal parkin acts to control the production of monoamine oxidase, or MAO for short, an enzyme which acts to catalyse dopamine oxidation. The production of MAO is normally tightly controlled to ensure that adequate levels of dopamine are being oxidised and our movements are able to all run smoothly. However when parkin mutations occur, the tight control of MAO production is lost and MAO is expressed at much higher levels. But what's the big deal? Surely there's nothing wrong with a bit of extra MAO floating around the place. After all it just means we'll have some MAO for a rainy day, right? Wrong. As it would happen MAO production is generally tightly controlled for a very good reason. It's toxic! Yep, at high levels MAO leads to the degeneration of our dopaminergic neurons as a result of oxidative stress. And no amount of shiraz-based anti-oxidants can do anything about it. But whilst shiraz may not work, it turns out that restoring control over MAO production does, as lead author Houbo Jiang and his team found that the early-stage damage could be reversed by delivering normal parkin back into the cells.

As well as providing insight into the role parkin plays in genetic forms of the disease, these findings also provide a novel target for future Parkinson's treatments. MAO production. Whilst one of the drugs currently on the market acts to inhibit MAO activity, there are no therapies which attempt to restore control over MAO production. At least not for the time being. So with the hope these findings seem to be injecting into the field of Parkinson's research, you can't help but get the feeling that if Marty McFly were reading this now he'd smile and say 'if only they knew, there's just a few short years to go'. And I for one am hoping he's right.

Sources

Jiang, H., Ren, Y., Yuen, E., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., Yan, Z., & Feng, J. (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells Nature Communications, 3 DOI: 10.1038/ncomms1669
Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, Blesa FJ, Guridi J, Marin C, & Rodriguez M (2008). Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society, 23 Suppl 3 PMID: 18781672

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'Michael J Fox as Marty McFly' sourced from Empire Online
'Cross section of mid brain' by Madhero88

This post was written by Andrew Watt for A Hippo on Campus.

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Taking the sacred path to decision making

2012-01-28T15:20:00.000+11:00

They say that when in polite company one should never discuss religion or politics. An old adage which is perhaps even more pertinent when you find yourself dining with boors. After all there are few topics of conversation with the innate ability to turn a soiree into a shouting match as those we hold sacred. Whether it be our views on life or what follows afterwards, there's just something about those consecrated concepts that doesn't allow any room for compromise. But what is about these fundamental beliefs that turn us into fundamentalists when they're challenged? Well as it would turn out the answer is all in our heads just, according to a recent study, in slightly different areas.

Trading the cow for some sacred beans

Sacred values are those fundamental values and beliefs which guide the decisions you make throughout your life. From your national identity to your political ideology, your religious persuasion, and maybe even your sports team of choice these values are defined by the fact that you wouldn't change them for all the gold in the world. Or at least not for $100. And that's precisely what participants in a recent study, investigating the neural networks of all that is sacrosanct, were asked to do. Researchers at Emory University used fMRI to observe the brains of 32 participants as they were shown statements ranging from the mundane ("You are a cat person") to those that were thought to tap into participant's sacred values ("You believe in god"). Each of the 62 statements had an opposing pair ("You are a dog person" and "You don't believe in god") and participants were told to select the statements which best reflected their views.

After they had made their selections the participants were given the opportunity to auction of their personal statements for an actual monetary reward, earning as much as $100 a statement providing they would sign a document disavowing their previous choices. Of course they were also given the option to not auction off their beliefs at all if they were deemed too valuable to sell, at least not for such a low value.

"If a person refused to take money to change a statement, then we considered that value to be personally sacred to them. But if they took money, then we considered that they had low integrity for that statement and that it wasn't sacred." Lead author, Gregory Berns says.

When Berns and co compared the fMRI results with the statements being viewed they found something very interesting. The statements tapping into the participant's sacred values resulted in significantly greater activation of the neural systems within the left temporoparietal junction and the left ventrolateral prefrontal cortex, and statements which the participants refused to oppose resulted in activation of the amygdala. Now I know what you're thinking. Aren't these the respective regions of the brain responsible for determining right vs wrong, semantic rule retrieval and emotional response? Yes they are, but to get a better idea of the significance of these results we should probably take a quick wander back through the laneways of virtue ethics.

Virtue ethics suggest that we all have two distinct paths by which we make our decisions: the deontological path and the utilitarian path. A deontological decision is one based on rights and wrongs with little or no empahsis placed on the pros and cons of the outcome. For example you may believe in god simply because you think it's the right thing to do. A utilitarian approach on the other hand would carefully weigh up the benefits of both choices before coming to their final decision, a decision which would be based on the greater benefit to the individual. So to continue the example whilst you think that the evidence for evolution is overwhelming you still believe in god because you don't really like not working Sunday's and there's no point risking being wrong and spending an eternity in hell. And that's more or less what the researchers found. Our decision making processes seem to take either a deontological pathway via the temporoparietal junction and the ventrolateral prefrontal cortex or a more utilitarian path via the inferior parietal lobules depending on whether they involve the activation of our sacred values.

Crossing the sacred divide

The results of this study provide the first neurobiological evidence that our failure to make trade-offs regarding our sacred values has a neural basis, not to mention the major implications it has regarding our understanding of the influences mediating cross-cultural human behaviour. However like any good study it is the questions raised rather than those answered which are of most interest. For example if the deontological pathway renders incentives moot what chance do we have of crossing the divide of political and religious opinion. And can values held sacred and processed deontologically ever be re-assessed in a utilitarian manner.

According to Bern "As culture changes, it affects our brains, and as our brains change, that affects our culture. You can't separate the two."

Whilst we don't have all the answers just yet, one thing is certainly clear; the era of cultural neuroscience is well on its way. In the meantime though when someone brings up politics at the dining table, it's probably easier to ask them what they know about virtue ethics, before you go ahead and tell them exactly what you're thinking.

Sources

Berns, G., Bell, E., Capra, C., Prietula, M., Moore, S., Anderson, B., Ginges, J., & Atran, S. (2011). The Price of Your Soul: Neural Evidence for the Non-Utilitarian Representation of Sacred Values SSRN Electronic Journal DOI: 10.2139/ssrn.1817982

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This post was written by Andrew Watt for A Hippo on Campus.

Happily dreaming of a slimmer waistline

2012-01-20T12:43:00.000+11:00

It's fairly easy to spot someone who hasn't had a great night's sleep. The bleary eyes. The birds-nest hair. Not to mention the constant growled demands to be left alone unless you come bearing coffee. When we find ourselves in this position it's fairly clear that those eight hours a night are important for our sanity. Very important indeed. So why is it that a lack of sleep can leave us feeling so lacklustre?

The wrong side of bed

You're probably well aware of the fact that sleep is one hell of an important pastime, after all it's intricately involved in such fundamental processes as memory consolidation and wound healing. Yet the first thing we seem to notice when we've missed out on that cathartic coma is the storm clouds brewing inside our heads. Yes a lack of sleep can turn even the most jolly Roger into Oscar the Grouch in no time, and a few short years ago researchers figured out why.

To do this the scientists conducting the study kept 13 participants awake for 35 straight hours before strapping them into an fMRI and showing them 100 images, which ranged from emotionally neutral to very upsetting. The resultant scans were compared to those obtained from participants who hadn't drawn the short straw, and were thus well rested, and showed that in the sleep deprived brain the disturbing images led to a pronounced activity spike in the centre for emotional reactions, the amygdala. So the distressing images were leading to more negative feelings in the sleep-deprived subjects, or as the researchers put it "without sleep, the brain had reverted back to more primative patterns of activity, in that it was unable to put emotional experiences into context and and produce controlled, appropriate responses". Tracing the patterns of activation back further showed them why. Instead of connecting to the prefrontal cortex, the site of logic and reason, the signals from the amygdala were actually connecting to the ancient emotional accelerator, known as the locus coeruleus. So rather than being rocked back and forth whilst being reassured that the images were just images, the amygdala was instead being pumped full of noradrenaline and ramped up into a veritable frenzy of emotional instability. And haven't we all been there... But just when you thought a bad night's sleep couldn't make you feel any worse, scientists have recently gone ahead and announced that it may also be making you fat.

Dreaming of a slimmer waistline

That's right new research suggests that it's not just your hypothalamus that has it in for your waistline, it's also your bed. Or more importantly what you're doing in it. The study, published in the Journal of Clinical Endocrinology and Metabolism, involved monitoring the neural activation of 12 normal-weight males while viewing images of high and low calorie food, the morning after either a solid 7 hours with the sandman or a "night of total sleep deprivation" (their words not mine). Yep, under strict instructions from Lionel Richie, participants were kept awake All. Night. Long. Watching TV, playing board games with the researchers and perhaps even dancing on the ceiling. All that can be certain is that the participants were running with the night (that's the last one I promise), with one exception. No food. All participants were given a standardised 700kcal dinner before bed on, both their sleep and sleep deprived nights in the lab and nothing else until just before the scans when they were given a glass of curdled milk. The fMRI results showed that a lack of sleep lead to significantly greater neural activation within the right anterior cingulate cortex despite a lack of differences in blood glucose levels. Interestingly higher activation of the anterior cingulate cortex, located within the frontal cortex, has been reported in obese individuals and is thought to be linked to enhanced perceptions of food-based rewards. So put simply if you are lacking sleep you'll see food, particularly high-calorie food, as being inherently more rewarding due to greater activation of your anterior cingulate cortex. And if we follow the authors further down this garden path we note that lack of sleep leads to a greater desire for food, which leads to us gaining weight, which leads to sleep apnoea, which leads to subsequent bad nights' of sleep. Which as you can see is a vicious, vicious cycle.

Waking up to alarming news

Now before you're left with the impression that these researchers are little more than sleep-depriving sadists perhaps we should have a quick look at some of the work they've been doing to help us all sleep that little bit better. Or wake up better as the case may be. Yes, those scientists of siestas have finally developed an alarm clock which will put our mornings of swatting at the snooze button to bed, once and for all. The clock, which you set to wake you up as normal, begins to monitor your brainwaves 90 seconds before the alarm is due to go off. If the clock notices that you are in the deeper stages of sleep (stages three and four) then it will quietly self-snooze and check in on you later, waking you up with a refreshing glow only when you re-enter the lighter sleep of stages one and two. Of course like all new technology this brain-scanning alarm clock will take some time to adjust to, after all the wait between your alarm time and the time you enter those lighter sleep stages might just result in you being late for work. Something which is sure to detract from that good night's sleep no matter how smoothly you were woken. And then there's the issue of the EEG cords. It's probably not every night that you hook your scalp up to your clock using electrodes. Then again maybe it is, I'm not here to judge.

Sources

Benedict, C., Brooks, S., O'Daly, O., Almen, M., Morell, A., Aberg, K., Gingnell, M., Schultes, B., Hallschmid, M., Broman, J., Larsson, E., & Schioth, H. (2012). Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study Journal of Clinical Endocrinology & Metabolism DOI: 10.1210/jc.2011-2759
Sylvia, J., Swittens, J., Komalavalli, R., Devi, C., & Manikandan, R. (2011). Alarm clock using sleep analysis International Journal of Biomedical Engineering and Technology, 7 (2) DOI: 10.1504/IJBET.2011.043176
Yoo SS, Gujar N, Hu P, Jolesz FA, & Walker MP (2007). The human emotional brain without sleep--a prefrontal amygdala disconnect. Current biology : CB, 17 (20) PMID: 17956744

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This post was written by Andrew Watt for A Hippo on Campus.

Why endorphins lead to a queue of men at the bar

2012-01-14T16:04:00.000+11:00

There's nothing quite like a stiff drink at the end of a long day to calm those shattered nerves. Whether it's a wine or a scotch, a gin and tonic or a vodka and orange, there's just something about the cortical balm that is alcohol that makes all our worries fade away. But what is it about this fermented solution that has us all at merlot? That leads us all to imbibe over 10 litres each year? Well according to a new study, published in Science Translational Medicine, it's the release of our own internal opioids, or endorphins, in the brain's pleasure centre which keeps us lining up at the bar.

Always a pleasure

That's right, opioids. Those psychoactive chemicals from which heroin's derived are also made inside your brain. In fact even as you read this your pituitary gland and hypothalamus are busy manufacturing and packaging these endogenous morphines. Ready to ship them off at a moments notice should you succumb to that bar of chocolate on the table or reach the denouement of a coital entanglement. Of course you could just as easily get your fix by going for a jog, afterall it's that exercise-induced release of endorphins which keeps those pavement-pounders out on the road, whatever the weather.

However, whilst both the pituitary and the hypothalamus are both involved in the production and release of endorphins, it's the hypothalamic neurons which are responsible for β-endorphins actions in the brain. β-endorphin exerts its effects through interactions with μ opioid receptors (MOR), which not-so-coincidentally are also the receptor of choice for members of the morphine family. Activation of MORs, via β-endorphin, results in the inhibition of GABA release, our major inhibitory neurotransmitter, and subsequent disinhibition of our dopaminergic pathways. Put simply β-endorphin release results in increased dopamine levels, hence all those warm fuzzy feelings we get after devouring a block of chocolate. But surely all this has been linked to alcohol before. After all the warm fuzzies from chocolate are nothing compared to those delivered by a capriosca. Well the simple truth is it has. Sort of. As it would turn out the role of endorphins in alcohol use have been known for a number of years it's just we've never been able to observe where it's all happening in humans. That is until now.

Endorphins orbiting the nucleus accumbens

In the study, 13 participants classified as heavy drinkers and 12 controls were injected with a radioactively tagged drug known as carfentanil, which due to it's opiate-like properties is able to bind to MORs. Once bound to the MORs the radioactive carfentanil emits radiation detectable by positron emission tomography (or PET imaging) thus allowing researchers to map the location of the MORs within the brain. Following the injections, the participants were given a gin and juice followed by a second injection of carfentanil (just to be sure) and a post-alcohol scan. By comparing the scans acquired before and after alcohol intake the researchers were able to determine the exact location in the brain where the endorphins were being released in response to alcohol.

As it would turn out alcohol intake led to the outpuring of endorphins in the nucleus accumbens and the orbitofrontal cortex in all participants. In fact the more endorphins that were released in the nucleus accumbens, widely regarded as the brain's pleasure centre, the greater the self-reported feelings of pleasure by the drinker. However perhaps of most interest to the researchers was the finding that the heavy drinkers reported feeling more intoxicated when higher levels of endorphins were released into their orbitofrontal cortices, a feeling which was not shared by the control participants. It is thought that the different responses to endorphin release in this area may provide clues as to why problem drinking is more likely to develop in some people instead of others. Or as lead author Jennifer Mitchell puts it “That greater feeling of reward might cause them to drink too much.”

These findings will no doubt aid in the development of new strategies targetting problem drinking. However, for those of us who aren't problem drinkers, or who merely have no problem drinking, the findings simply act to reinforce the notion that a glass of wine is just as effective as a long hard jog. After all they more or less result in the same thing, don't they.

Sources

Mitchell, J., O'Neil, J., Janabi, M., Marks, S., Jagust, W., & Fields, H. (2012). Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens Science Translational Medicine, 4 (116), 116-116 DOI: 10.1126/scitranslmed.3002902
Science Daily

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Harold Holt and Lyndon Johnson

This post was written by Andrew Watt for A Hippo on Campus.

Separating face from fiction with the fusiform gyrus

2012-01-11T01:00:00.000+11:00

"You've got a face, I've got a face. It's all gonna be alright." But is it Noel Fielding? Is it really? And how do you know it's a real face anyway? After all you might simply be looking at that rocky outcrop in the picture which bears resemblance to a face. Or maybe you're looking at a piece of toast branded with the face of Jesus or Erik Estrada. Alright so we can probably give Noel the benefit of the doubt when it comes to his ability to visually descriminate human faces from rocky outcrops and toast. After all we can all readily tell the difference between an actual face and something that just resembles a face. But how is it that we are able to do this? How does our brain help us to sort the face from the non-face?

Facing the facts on facial recognition

I guess to begin with we should probably take a quick look at how our brain helps us recognise faces in the first place. In short it's all thanks to a nifty little region of the temporal lobe known as the fusiform gyrus, or the fusiform face area (FFA). fMRI studies have consistently shown that when people are presented with facial images, major bilateral activation of the FFA occurs. Activation which is a great deal stronger than that produced by almost any other image. And it doesn't stop there. Like with a lot of cognitive / perceptual research a great deal of our knowledge and understanding stems from the investigation of individuals with acquired brain injury. And research into facial perception is no different. Damage to the FFA and surrounding areas results in a condition known as proposagnosia, which roughly translated means 'not knowing faces'. People with damage in the FFA have so much trouble perceiving faces that they are literally unable to pick their own face from a photographic line-up. Instead they rely on other stimuli such as clothing, voice and topics of conversation as clues to who it is they've been talking to for the past half-hour (it was probably that Noel Fielding fellow, they just kept banging on about faces).

Remarkably this ability to perceive and recognise faces is not limited to us humans, with almost every species of primate ever tested showing some level of facial recognition ability. In fact even sheep have the ability to spot a face in the herd. However the most remarkable finding regarding facial recognition has to go to a recent study involving golden paper wasps (Polistes fuscatus). In this study the authors found that the golden paper wasps, who themselves have clearly variable facial features, were better at learning to discriminate between images of other wasp faces, than they were at discriminating between images of caterpillars, which they prey on. Moreover these avant-garde arthropods were even able to discriminate between faces of wasps from other species. But hold on that doesn't necessarily mean that the wasps were using facial recognition to discriminate between the images. Surely it makes more sense that they were simply relying on basic pattern recognition of some kind. Well here's the kicker. The wasps uncanny ability to discriminate between faces was severely stunted when the images involved faces without antennae or faces which had simply been rearranged, thus suggesting that their ability to discriminate was based on facial recognition after all. But what about the faces in the rocks? Can they see those? Well probably not. After all they're only wasps. In fact there's a fair chance that pareidolia (the perception that a random stimulus is in some way significant) is a wholly human trait. But that's an argument best left for another day.

Vision or visage

For now let's get back to focussing on how to distinguish face from fiction. In a recent study, published in the Proceedings of the Royal Society B: Biological Sciences, researchers conducted fMRIs whilst presenting 36 participants with images ranging from nothing like faces to actual faces. As expected when the images of real faces were shown to the participants there was distinct bilateral activation of their fusiform area. Just not at the same time. The researchers found that not only did activation of the left fusiform gyrus precede that of it's right-sided counterpart but it also appeared to change only gradually as the images became more facelike. The right fusiform gyru on the other hand showed dramatically stronger activation to real faces when compared to any of the other images, regardless of their inherent facelike attributes. These findings were particularly exciting as the provided researchers with the first known example of the hemispheric separation of roles in high-level visual processing, something which was usually reserved for such cognitive functions as spatial perception and speech. But what exactly does it all mean? Well put simply, these findings suggest that when you see something resembling a face in some way your left fusiform gyrus activates as if to say "hey look a face!" to which your right gyrus responds "nah that's just a rock". And you know what he's probably right!

Sources

Cherian T, Singal G, & Sinha P (2012). Lateralization of face processing in the human brain. Proceedings. Biological sciences / The Royal Society PMID: 22217726
Katsnelson, A. (2011). Wasps clock faces like humans Nature DOI: 10.1038/nature.2011.9533 Meng M,
Leopold, D., & Rhodes, G. (2010). A comparative view of face perception. Journal of Comparative Psychology, 124 (3), 233-251 DOI: 10.1037/a0019460
Science Daily
Sheehan, M., & Tibbetts, E. (2011). Specialized Face Learning Is Associated with Individual Recognition in Paper Wasps Science, 334 (6060), 1272-1275 DOI: 10.1126/science.1211334

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Visage dans un rocher

This post was written by Andrew Watt for A Hippo on Campus.

Shocking discoveries at depress of a button

2012-01-06T17:27:00.000+11:00

"It's alive. ALIVE!" The mad scientist howls as his creation, well, comes to life. That potent mixture of neuronal connections and lightning are all it takes for the monster to arise once more. If you're anything like me, and since you're here I'll assume that you are, this iconic scene from Frankenstein will be the first thing your brain primes when somebody mentions electrodes in the brain. Or perhaps your hardwired to conjure up a more Hitchcock-esque scene involving electroshock therapy in action. Regardless of your imaginative leanings however, there's no denying that the notion of applying direct electrical stimulation to the brain, is once again back in the spotlight thanks to new research published in the Archives of General Psychiatry. But we'll get to that in a moment.

A truly shocking history

The idea of applying electricity directly to the human brain is by no means a new idea. In fact we've been doing it since way back in 1874, when Robert Bartholow first peeled back those cranial curtains to apply electrodes to the brain of Mary Rafferty, a woman with basal cell carcinoma (that's skin cancer for those playing at home). Bartholow found that the introduction of a small electrical current to the left hemisphere of Mary's brain resulted in visible muscular contractions in her right arm and leg, surprisingly all of which occurred with not so much as a headache. However when Bartholow, who in hindsight was perhaps a touch too excitable himself, decided to increase the current he was applying, Mary became distressed before succumbing to seizures and falling into a coma. Sadly, she died just four days later.

However despite this somewhat grim introduction, direct electrical stimulation (DES) of the brain had arrived, and at the hands of more reserved physicians of the time it was able to reveal some truly remarkable things. Perhaps the most famous research of the time was that performed by German neurosurgeon Fredor Krause, who used DES to map the motor cortex in the brains of patients with epilepsy, whilst trying to discover their epileptogenic sweet spots (or the regions of the cortex which were generating the seizures). Interestingly the use of electrodes to map epileptogenic regions is still in use today. In fact it's considered the "gold standard" method for cordoning off those epilepsy inducing sections before they can be carefully removed. Very carefully indeed. However it is not just epilepsy that has benefited from treatments involving DES, with neurological conditions from obsessive compulsive disorder to dystonia, Parkinson's to Tourette's also reaping the rewards. However it is the treatment of depression which has recently bought DES back into the limelight.

It's time we dove a little deeper

Thus far in this tale we have merely been skimming the surface of the applications that DES has in the clinic. The cortical surface as it were. So to gain a better understanding of the new research I was telling you about earlier, perhaps it's time we dove a little deeper. Deep down into our minds. Down to the subcallosal cingulate. It was here, in the subcallosal cingulate white matter, to be precise, that clinicians implanted deep brain stimulation (DBS) electrodes into 17 individuals with either bipolar disorder or major depressive disorder. The treatment involves the use of high-frequency electrical stimulation to a specific brain region, in this case bilaterally to the subcallosal cingulate. The implant, consisting of a thin wire electrode on each side of the brain, connects to a pulse generator, similar to a pacemaker, which is implanted into the patient's chest. Participants in the study initially received four weeks of single-blind stimulation from the implants, meaning they were never sure if the implant had been activated or not, followed by 24 weeks of active stimulation. After this 24 week period, three of the participants had gone into remission, meaning their depression had lifted, whilst seven participants were said to be responding well. More importantly though after two years of active stimulation a total of 92% of the participants were said to be responding to the treatment, with 58% of the participants enjoying the greener grass on the remission side. Most importantly however were the findings that none of the patients achieving remission experienced spontaneous relapse and the chronic treatment was safe and well-tolerated by those involved.

However the success of the study doesn't mean that everything is all rosy for the participants just yet. After years of social isolation they still face the challenge of reintegration back into society, which the authors are helping them through. Not to mention the hassle of constantly having to explain why they keep setting off those airport metal detectors. But one thing's for sure, despite these new found hurdles, there's little doubt that from now on they'll be greeting their days with a smile on their face just like the rest of us. Once we've all had our morning coffee that is.

Sources

Borchers S, Himmelbach M, Logothetis N, & Karnath HO (2011). Direct electrical stimulation of human cortex - the gold standard for mapping brain functions? Nature reviews. Neuroscience, 13 (1), 63-70 PMID: 22127300
Holtzheimer, P., Kelley, M., Gross, R., Filkowski, M., Garlow, S., Barrocas, A., Wint, D., Craighead, M., Kozarsky, J., Chismar, R., Moreines, J., Mewes, K., Posse, P., Gutman, D., & Mayberg, H. (2012). Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression Archives of General Psychiatry DOI: 10.1001/archgenpsychiatry.2011.1456

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This post was written by Andrew Watt for A Hippo on Campus.

Does this hypothalamus make me look fat?

2012-01-05T17:50:00.000+11:00

We've all had those moments in life when the mirror has been less than kind. When for whatever reason it's decided to add those few extra pounds when just weeks earlier we could have graced the cover of almost any magazine on offer. Or at the very least still fit into our jeans. And so the dieting begins. Caloric intake is restricted and a strict exercise regime is followed. Well maybe not strict, but walking is now done at a brisk pace rather than the meander of old. And then it happens. Like the tides retreating back to sea, our waistline begins to slowly subside. Until finally the top button on our jeans once again remains firmly in place. Life is good. For a month or so. And then. One day. Just like that. The pounds are back. Sound familiar?

So why is it that the weight always seem to find a way to get back into our lives? Were we not motivated enough? Did we not create a big enough support system? Or were all those years filled with cheese and wine just too hard to shake? Whilst it could be argued that any one of these factors may have played a role in it's return, it turns out that the main reason the fat is back, is all in our heads. That's right our brains are making us fat... Again. And here's the second blow. They're so keen to ensure that our biological saddle bags are packed and ready to go that they've developed not one, but two different methods of doing it. Two!

How our brains are making us fat...again.

To be fair it's not the entire brain which is behind this malevolent scheming, but a rather small, pearl-sized area known as the hypothalamus. But how does it do it? Well the first method in which the hypothalamus leads to weight regain is through the release of hormones. A recent Australian study investigated weight gain after dieting in 50 individuals with body mass indices (BMIs) ranging from 27 to 40 and an average weight of 95kg (or around 210lb for those preferring imperial). The researchers measured the levels of appetite-regulating hormones, such as leptin, ghrelin and gastric inhibitory polypeptide, before and after a 10-week low energy diet. As well as once more a year after the program had commenced. What they found was that following initial weight losses of around 13kg (or 29lb), the levels of appetite-regulating hormones coursing through the veins of the dieters had tweaked themselves to induce increased appetite. Making matters worse these hormones remained at their appetite increasing levels for at least a year, helping participants to put an average of 5kg (11lb) of weight back on.

Adding injury to insult

The second manner in which the hypothalamus appears to be conspiring to prevent our slender new bodies from becoming a permanent fixture involve, what some would call, more drastic measures. Not satisfied with its hormonal meddling, it would appear that the hypothalamus develops injuries in response to high fat diets (HFD). According to the study, published in the Journal of Clinical Investigation, both mice and rats, predisposed to obesity, showed evidence of hypothalamic inflammation within as little as 24 hours of being commenced on a HFD. The inflammatory response observed in the rodents' hypothalamic region, or more specifically the hypothalamic arcuate nucleus, were produced in response to neuronal injury, which were in turn thought to be induced by the consumption of the HFD. When the rats were taken off these diets, after only a few days, their injured hypothalamuses were able self-repair. When the HFDs were sustained however the neuronal injuries were also sustained.

Satisfied of their findings in rodents, the researchers turned their gaze toward their fellow humans, and performed MRIs on 34 participants. Just as in fat rats, the hypothalami of obese participants showed evidence of neuronal injury, with larger particpants showing greater areas of scarring.

No need to panic just yet

Now it should probably be noted that whilst startling these results don't actually prove cause and effect. Nor do they indicate how long a HFD can be consumed before damage becomes irreversible. So there's no need to put the chocolate down just yet.

The studies do however indicate that maybe it's time for us to change the way we approach the problem of obesity. Firstly there's little doubt that there will be a deluge of post-diet hormonal therapies popping up at pharmacy counters near you in the next few years. So begin preparing yourself for the horrendous ad campaigns that will no doubt accompany them. Secondly whilst our years of cheese and wine may suggest that it's too late for us to reverse any damage done, it's not for the kids. And with the knowledge that housework is a great way to burn calories, you might as well put the little rascals to work now. They'll thank you for it later. Well maybe.

Sources

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, & Proietto J (2011). Long-term persistence of hormonal adaptations to weight loss. The New England journal of medicine, 365 (17), 1597-604 PMID: 22029981
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, & Schwartz MW (2011). Obesity is associated with hypothalamic injury in rodents and humans. The Journal of clinical investigation PMID: 22201683

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This post was written by Andrew Watt for A Hippo on Campus.

Why men don't listen and women are great at maths

2012-01-04T16:34:00.000+11:00

Ask the average person on the street if men and women are wired differently and you'll more often than not get an affirmatory response. Not overly suprising given the knowledge that men are from Mars and women are from Venus. Am I right? But dive a little deeper and chances are you'll find that the vast majority of people would be relying heavily on deeply ingrained stereotypes, such as the "mythically superior 'multitasking’ abilities" of women or men who just don't listen, rather than on any scientifically verified information (although in fairness the bit about men not listening is probably true). Nonetheless, the fact that we rely on such stereotypes is not generally an issue, after all the human brain is a master at creating these categorical shortcuts in an effort to conserve its resources. However when these shortcuts are being used to endorse segregation in schools or distinct parenting styles based on gender, those of us who can spot the neuroscience from the neurononsense have a responsibility to take action.

Sum differences aren't what they seem

There is no denying that differences do actually exist between the male and female brain. For example whilst the global cerebral blood flow is higher in the female brain, the male brain is on average 11% larger and consists of a higher proportion of white matter than its female counterpart. However it can also be said that males are, on average, 9% taller and 18% heavier than females, thus suggests that the larger brain size is merely another representation of readily observable sexual dimorphism between men and women. Rather than an indication that the male brain is more suited to such non-emotive skills as spatial relations and mathematics. But if the differences in underlying neuronal connections between the sexes aren't to blame for the fact that over 70% of maths PhDs are men, who is? As it would turn out, we are. Or more specifically it's society's fault!

A recent study by husband and wife team Jonathon Kane and Janet Mertz investigated gender differences in mathematics performance and participation rates using scores from the internationally standardised OECD Program for International Student Assessment math test (2003 and 2009) and the Trends in International Mathematics and Science Study (2003 and 2007) . These data sets gave Kane and Mertz access to data from over 80 countries, with a 31-country overlap, and enabled them to rule out low-living standards, coeducational environments and innate variability among boys as potential causes for gender bias. Instead the study pointed to prevailing societal views and gender equity as the root of the problem. Maths pun intended.

Put simply the data showed that overall girls and boys performed equally well when it came to maths, so no evidence of biological variability there. But perhaps more importantly, both girls and boys from cultures with a higher level of gender equity performed better in the tests. Or as Kane puts it "Women doing better end up raising their kids better."

But if both boys and girls perform equally, what’swith the lack of female mathematicians? For starters, it would appear that thegender gap doesn’t rear its’ ugly head until the young women start thinking abouttheir future careers. Insert a steady drone of societal tut-tutting about womenand numbers in the background and it’s little wonder that most women choose a careeroutside of maths (and science and engineering). The gap is essentially formedby the self-fulfilling prophecy that is this stereotype. Women are told thatthey can’t do maths, so they don’t do maths. Thus the small numbers of women whochoose a career in maths act as proof that women can’t do maths. And so the farce continues.

From stereotype to societal change

On paper, getting women back in the maths class is as straightforward as giving them equal rights and equal pay before saying "Hey, turns out we're all great at maths." Sadly, in reality it's not quite so simple. Firstly, as it would turn out the aforementioned benefits which stereotypes bestow us regarding our cognitive resources ensure that they are deeply ingrained and so incredibly hard to shake. Secondly, any apparent differences between the genders, no matter how carefully reported, are often distorted and propagated by the media (see The Female Brain as a great example of such neurononsense or The Gender Delusion for an eloquent debunking of such myths). And they do this for the simple reason that biological gender differences fascinate us. And so they should.

As scientist, reporters, or simply those who know better (here's that responsibility to act I was talking about earlier) we cannot ignore the possibility that gender differences exist. Nor should we. We should continue to look for them through our proverbial microscopes with a fervour that verges on mania. But, to paraphrase Lise Eliot, we must also be mindful. Mindful to communicate the true magnitude and intricacy of these differences, in an effort to avoid more widespread misuse of such research.

Sources

Eliot, L. (2011). The Trouble with Sex Differences Neuron, 72 (6), 895-898 DOI: 10.1016/j.neuron.2011.12.001
Kane, J., & Mertz, J. (2012). Debunking Myths about Gender and Mathematics Performance Notices of the American Mathematical Society, 59 (01) DOI: 10.1090/S1088-9477-2012-00790-4

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Jesse Block and Eve Sully

This post was written by Andrew Watt for A Hippo on Campus.

A coffee a day keeps the adenosine at bay

2012-01-03T18:53:00.001+11:00

It's fair to say that for most of us the day doesn't truly begin until we can feel the warm lick of caffeine coursing through our veins. Be it an espresso, flat white, latte or low-fat, soy, double-shot, moccacino. Whatever your poison very little in our lives is ever achieved before that first cup of black magic has passed our lips.

However despite our love affair with this bitter alkaloid, the exact manner in which caffeine interacts with our brains has been largely misunderstood. That is until now.

Not your average stimulant

It should be said right from the start that caffeine is not your average stimulant. Unlike more illicit uppers such as amphetamines and MDMA which exert their effects by increasing noradrenaline levels, caffeine exerts its effects by blocking, or antagonising, adenosine receptors. When our brains switch on each morning and the neurons begin firing away they also begin to produce the neuronal by-product, Adenosine. Throughout the day, the neurons keep firing, adenosine levels keep rising and adenosine receptors throughout the CNS begin to monitor the action. Once a certain level of adenosine has been reached the receptors in your brain and spinal cord tell you that perhaps it's time to go to sleep. Or at least close your eyes for just a short while.

Enter caffeine. Whether from your coffee, your tea, your chocolate or your guarana, it flows into your body, heading straight for your adenosine receptors, or more specifically your adenylyl cyclase-modulating g protein-coupled A1 receptors. Once at the receptor it binds with great efficiency, due to its similarities with adenosine. However its differences mean that despite binding, caffeine doesn't actually activate the receptor and so no sleep signal is sent to the brain. So with caffeine acting like "a block of wood under one of the brain's primary brake pedals", the brain's natural stimulants, dopamine and glutamate, are left to do what they do best.

Of course we each have differing amounts of these natural stimulants floating around our heads at any given moment and so the effect of a coffee is somewhat variable from person to person and at different times of the day. The take home message is that coffee doesn't act to wake you up, but rather it acts to stop you from going to sleep. Which isn't quite the same thing, when you really think about it.

Next stop Hippo campus

Those of us who are regular partakers of the international psychoactive stimulant of choice know that coffee is so much more than just a drowse defying beverage. It is an elixir which increases our acuity and alertness. And it does this by acting on the hippocampus. Previous research has suggested that the inhibitory action of caffeine on the A1 receptors within the hippocampus, or more specifically the CA1 region, acts to evoke an enhancement in signal transmission between neurons, known as long-term potentiation (LTP). However a more recent study investigating the role of caffeine on the less well defined CA2 region, which just happens to contain the highest concentration of adenosine receptors, suggests that the role caffeine plays in our mental acuity might not be that simple.

The researchers found that excitatory post-synaptic currents were increased in the CA2 region, but not the CA1 region, of juvenile rats fed with caffeine for up to an hour after the caffeine was consumed. Furthermore when caffeine was added directly to naive slices of rat hippocampus, the increase in CA2 excitatory post-synaptic currents was measurable for up to three hours after the caffeine was applied. That is to say that caffeine was found to induce long-term potentiation through the CA2 region.

However the real interest of the article lies not in the fact that LTP was induced but rather in the manner in which caffeine acted to induce it. Within the CA1 region the induction of LTP is dependent on the activation of N-Methyl-D-aspartate, or NMDA, receptors and the consequential calcium dependent signalling pathway. As a result the addition of either an NMDA receptor antagonist or a calcium signalling inhibitor will act to prevent LTP in the CA1 region. However when added to the CA2 region neither the NMDA receptor antagonist nor the calcium signalling inhibitor had any effect on LTP. Instead LTP induction was found to involve the activation of the aforementioned adenylyl cyclase-modulating g protein which the A1 receptors are bound.

The results of this study hint towards 'a more complex signalling mechanism governing the consolidation of' LTP and helps to shed some light on the largely unknown role of the CA2 in normal brain function. Perhaps most importantly though is that it gives those of us addicted to our daily grind another excuse for that extra cup.

Source

Simons, S., Caruana, D., Zhao, M., & Dudek, S. (2011). Caffeine-induced synaptic potentiation in hippocampal CA2 neurons Nature Neuroscience, 15 (1), 23-25 DOI: 10.1038/nn.2962

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This post was written by Andrew Watt for A Hippo on Campus.

Craving predictability

2012-01-01T12:06:00.001+11:00

The thin blue curl of smoke dances into the night sky from Bogart's cigarette as their eyes meet. The film's black and white denouement is upon us but all they can see is that cigarette. They can almost taste it. They are the smokers and the recently ex-smokers whose neuronal circuitry is lighting up in anticipation of that next cigarette.

Some of them will acquiesce and slink off silently as the credits roll whilst others will shift uncomfortably in their seats and wait for the cravings to subside. Whatever action they take it will be of no suprise to the team of researchers at UCLA's Laboratory of Integrative Neuroimaging Technology, who have been using functional MRI techniques to observe the changes which arise in the brain during craving.

In the study, participants underwent fMRI scans whilst watching films designed to induce cravings, be neutral towards smoking, or simply watched no film at all. In all cases though they were instructed to fight their cravings.

The data produced by the scans was analysed and traditional machine learning methods were augmented by Markov processes in an effort to produce predictive algorithms. In essence, the researchers found that by observing the changes in the underlying neurocognitive structures of the participants, they were able to predict what film the participant's were watching, whether cravings were being induced and perhaps most importantly whether the cravings were being resisted.

"We detected whether people were watching and resisting cravings, indulging in them, or watching videos that were unrelated to smoking or cravings... Essentially, we were predicting and detecting what kind of videos people were watching and whether they were resisting their cravings." said Dr. Ariana Anderson, the study's lead author.

In layman's terms the algorithm produced worked much in the same way as Google does in predicting an entire search based on only a few words. So the algorithm would note that the activation of a particular neural network was indicative of the inducement of a strong craving for cigarettes.

Learning which neural networks are responsible for our cravings and urges gives researchers a clearer understanding of the obstacles that those of us with addictions face when our cravings surface. From coffee to cigarettes, chocolate to the illicit side of the spectrum, these machine learning methods may eventually provide a real-time biofeedback system capable of telling us when a craving is surfacing and how intense it may well be. These neural seismographs will give us a mechanism by which to train and suppress our cravings. Or perhaps they'll just tell us that the single shot latte just isn't going to cut it this morning. Better make it a double.

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Humphrey Bogart by Karsh

This post was written by Andrew Watt for A Hippo on Campus.

The Hippo in the Room

2011-12-30T16:21:00.000+11:00

"I used to think that my brain was the most wonderful organ in my body. Then I realised who was telling me this."

Equally I used to think that this quote was the most wonderful quote until I realised who was telling me this (Emo Philips. Not to be confused with Pee Wee Herman who is perhaps best remembered for his film work. And I mean that in the loosest possible way).

However regardless of the source the quote stands true. Our brains truly are amazing machines. Beguiling us with their wit, their wisdom and their insight and fooling us into thinking that nobody seems to have realised that on most occassions we don't actually know what we're talking about.And that's what this blog is all about. The proverbial Hippo in the room. The human brain.

It is an ode to the at times malevolent puppet master within us all. To the source of all our joys and all our frustrations. The 1200 odd grams of tightly folded neurons providing an electrically-charged pulsating link to the worlds both inside and outside our bodies. The masterpiece of neuronal origami that is the human brain.

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The Hippopotamus Polka

This post was written by Andrew Watt for A Hippo on Campus.

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