It’s official…

Well folks, I’ve finally been made legitimate.

No, I haven’t received my doctorate yet (that won’t be happening for awhile!) Instead my rogue bastardized blogging days are over – I’ve been made an official Nature Publishing Group blogger, writing for the Nature Education site Scitable. I’ll be blogging on all things brain and biology on the psychology group blog, Mind Read, with the fantastic Jordan Gaines of Gaines, on Brains. We’ll be posting weekly on the latest nerdy neuro papers and fascinating psychological phenomena – think similar Brain Study content but now on a legitimate platform.

As always though, Brain Study is dearest to my blogging heart, and I’ll be sure to post Mind Read pieces here, as well as trying out slightly “edgier” content perhaps not suitable for the corporate science blogosphere.

My first post is on one of my personal favorite topics, synesthesia, exploring Hearing, Touching and Tasting in Color. A sneak-peek with some insight into my own form is below:

I don’t know about you, but to me Wednesday is sun-shiney yellow. Tuesday is hunter green, Thursday purple-ish blue and Friday a deep red. Monday is white, a blank slate and a chance for a new week, whereas Saturday is sparkly black. Sunday is gray, the depressing slouch towards the beginning of the work-week, but also a convenient mix of Saturday and Monday.

This color-word association is not a figment of my imagination or an indication that I’m going crazy, but is instead a recognized neuropsychological phenomenon called synesthesia.

So please check out the new site, and let me know what you think!

Billions of dollars to map billions of neurons

A lot of money is being spent right now to ‘map the human brain’. In the last month, both the European Commission and U.S. president Barack Obama have pledged to give billions of dollars to fund two separate projects geared towards creating a working model of the human brain, all 100 billion neurons and 100,000 billion synapses.

The first, the Human Brain Project, is being spearheaded by Prof Henry Markram of École Polytechnique Fédérale de Lausanne. Together, with collaborators from 86 other European institutions, they aim to simulate the workings of the human brain using a giant super computer.

To achieve this, they will work to compile information about the activity of tons of individual neurons and neuronal circuits throughout the brain in a massive database. They then hope to integrate the biological actions of these neurons to create theoretical maps of different subsystems, and eventually, through the magic of computer simulation, a working model of the entire brain.

Similarly, the Brain Activity Map Project, or BAM! (exclamation added because it’s exciting), is a proposed initiative that would be organized through the United States’ National Institutes of Health and carried out in a number of universities and research institutes throughout the U.S. BAM will attempt to create a functional model of the brain – a ‘connectome’ – mapping its billions of neuronal connections and firing patterns. This would enable scientists to create both a ‘static’ and ‘active’ model of the brain, mapping the physical location and connections of these neurons, as well as how they work and fire together between and within different regions. At the moment, we have small snap-shots into some of these circuits but on only a fraction of the scale of the entire brain. This process would first be done on much smaller models, such as a fruit fly and a mouse, before working up to the complexities of a human brain version.

BAM proposes to create this model by measuring the activity of every single neuron in a circuit. At the moment, this is done using deep brain techniques, a highly invasive process that involves opening up the skull to implant electrodes onto individual cells to read and record their outputs. Understandably, this is only done in patients already undergoing brain surgery, and is a slow and expensive process. Thus, the first task of BAM would be to develop better techniques to acquire this information. Research into this field is already underway, and exciting proposals have included nanoparticles and lasers that could measure electrical outputs from these cells less invasively, or even using DNA to map neural connections.

Neither project has directly acknowledged the other, but it is thought that the recent announcement of the U.S. proposal is a response to the initial European scheme launched earlier this year. And while there are distinct differences between the two initiatives in how they will acquire and store the raw information, as well as how they plan to build their subsequent models, the two projects overlap significantly. Both have the potential to better illuminate how exactly the brain works, and each ultimately hopes to provide us with a clearer picture of not only normal brain functioning, but also what happens when these processes are disrupted. Scientists and doctors could then use computer models to simulate dysfunction involved in neurological or psychiatric disorders, such as Alzheimer’s or schizophrenia. This would also open up possibilities for investigating better treatment options, as well as drastically cutting down on the expense and risk currently involved in clinical drug trials for psychiatric and neurological disorders.

However, there is a long list of obstacles these projects must overcome before we get too excited, not the least of which are the 100,000,000,000,000 connections that need to be measured and modeled. That’s over one million times as many neurons as there were genes to map in the Human Genome Project, the closest approximation to the current endeavors. Additionally, while there was a clear end to the human genome, the ambition of making a human connectome is both much larger and much less well-defined. Indeed, neither proposal yet has a definitive end-goal, and no one is clear on what the final product will look like.

For the Human Brain Project, the collaboration of over 80 different labs across Europe will also be a significant challenge. By collaborating rather than competing, the capacity for productivity and innovation in this and future projects is far higher. However, it will be extremely difficult to manage differences in laboratory methods and communication, not to mention egos, between these institutions.

Another major concern for the American proposal is funding. With the financial crisis, fiscal cliff and federal sequestration of recent months, the U.S. economy (and Congress) do not have a very good track record at the moment. And it is hard to believe they are going to approve a multi-billion dollar project when they cannot even agree to continue funding for health care, education and military spending. Private companies including Google and Microsoft, as well as charities such as the Howard Hughes Medical Institute and Allen Institute for Brain Science have signed on to the project, but the bulk of funding will still have to be provided by government institutions.

In his State of the Union address, President Obama alluded to the Brain Activity Map Project, and tried to head-off the inevitable financial protests to it by invoking the Human Genome Project, which cost $2.7 billion to complete but has reportedly produced a return of $140 to every dollar spent. This was manifested through pharmaceutical and biotechnology developments, as well as subsequent start-up companies. This turnover has the potential to grow even further through future reductions in health care spending from medical developments, and the hope is that BAM will produce similar high returns. However, the question remains as to whether this investment could be better spent elsewhere, such as improving the medical system, research for drug treatment developments, or health education and prevention programs. Some in the scientific community are also worried that already limited funding to other fields of research will be slashed in order to subsidize the project.

Despite these concerns, it is undeniable that if these programs were to succeed they would be spectacular achievements in scientific research, not unakin to the discovery of the Higgs Boson or even the first space expeditions of the 1960s. Many believe that the human brain is the final frontier for medical research, and it will remain to be seen whether these brain-mapping projects will enable us to finally understand the wild and intricate workings of our own minds.

(Originally posted on King’s Review)

(And an updated version has been published on The Atlantic)

The second piece of chocolate

Imagine you have a piece of chocolate. Unwrap it, place it on your tongue. Savor its decadence as it melts in your mouth; relish the bitter and sweet coating your taste buds; indulge in its creamy texture. As the chocolate dissolves, signals are sent throughout your body. Chemicals are released, reinforcing its rewarding properties and preparing your body for the rush of sugar it is about to receive. You swallow. Immediately you want another piece.

The pleasure of eating is one of our most natural joys, be it savoring a perfectly cooked steak or delighting in that melt-in-your-mouth chocolate. But with the rise of obesity and related maladies – particularly cardiovascular disease, hypertension and type-II diabetes – such simple pleasures have been perverted, pathologized by experts and classed as a source of harm. With nearly 25% of English adults qualifying as obese, and with ensuing costs to the NHS reaching £5.1 billion each year, the UK is facing a self-induced public health pandemic. But how has this happened? And why can’t we all just put down that second piece of chocolate?

Added sugars have become the focus of widespread concern among doctors and researchers, their effects on our waistlines, livers, and even our brains, giving cause for alarm. Obesity specialist Dr. Robert Lustig has emerged as a crusader for the anti-sugar movement, contending that sugar, not fat, is behind the dramatic rise in ‘western diet’ conditions over the past 30 years. The problem stems from the way our bodies metabolize fructose – half of the refined sugar molecule, sucrose – as opposed to pure glucose, which makes up the other half and is found in foods like potatoes and white bread.

Glucose is metabolized by all cells in the body, whereas fructose is primarily processed by the liver. If the liver cannot adequately break down sugar into energy it is converted into fat, and the faster the body receives fructose, the more likely this is to happen. High fructose sugar solutions, like fizzy soft drinks, are particularly prone to this fat conversion, providing high volumes of fructose that reach the liver much more quickly. This inability to break down sugar and the subsequent rise in liver fat is believed to be at the root of insulin resistance, the main deficiency underlying type-II diabetes.

But regardless of doctors’ warnings and the evidence that increased sugar consumption leads to obesity, as well as liver and heart disease, our sugar intake continues to rise. This may be due to the seemingly addictive qualities of high-sugar foods themselves. For despite our best intentions to cut out the cake, doing so rivals quitting smoking in terms of difficulty. New research indicates that foods high in fat or sugar may qualify as addictive substances, causing similar neurochemical changes in the brain as drugs of abuse.

Researchers at Princeton University have demonstrated this phenomenon by intermittently exposing rats to a sucrose solution in addition to their regular food. After a month, rats began to show binge, craving and withdrawal-like behaviors for sucrose, self-administering extremely large quantities when it was available. Adaptations similar to those seen in cocaine-addicted animals emerged in the rats’ brains, with surges of dopamine released during a binge – a process linked to feelings of reward and novelty, and a key facet of drug addiction. An increase in craving was also seen in the test animals, demonstrated by greater sucrose-seeking when deprived of the solution, even in the face of punishment. Additionally, rats experienced withdrawal-like symptoms when the sugar was removed, exhibiting tremors, head-shakes and signs of anxiety and aggression. Such behavior is typically seen in animals going through opiate withdrawal, and is caused by the release of endogenous opioids in the brain by high-sugar foods, reinforcing their hedonic characteristics and creating a withdrawal effect when removed.

Given sugar’s apparently addictive properties, one proposed response to the obesity epidemic is to regulate its availability in much the same way as tobacco and alcohol. Labeling foods high in sugar and fat as ‘addictive’ could potentially remove the stigma attached to being overweight, re-characterising it as a complex medical condition rather than simply one of personal weakness and poor self-control. Furthermore, tougher regulations on the advertising and availability of junk food might help to reduce the proliferation of cheap high-fat/high-sugar snacks that has made diet control increasingly difficult. However, taking responsibility for diet out of the hands of individuals also diminishes personal accountability and the imperative for each of us to make positive food choices. The fast food industry certainly isn’t helping us to lose weight, but it’s also not forcing the food down our throats. Should we be trusted to control what we put into our bodies, or do we need someone to stop us from taking that second piece of chocolate?

*So this post is a bit cheeky. I originally wrote this as a submission for a writing competition, but seeing as how it was never published, I figured it made an apt piece in honor of New Year’s resolutions!

(Thanks to Paul Sagar for help in editing the original piece.)

A Thanksgiving ode to tryptophan

My favorite holiday is on Thursday. And while I can’t be at home in the States to celebrate, being an ex-pat at Thanksgiving does have its perks, as I get to attend multiple alternate feasts over the weekend. That means twice the stuffing, twice the cranberries, twice the turkey, twice the tryptophan.

Yes, tryptophan. That infamous amino acid we use to justify dozing off during our aunt’s vacation slideshow after the big meal. Tryptophan is an essential amino acid, a protein precursor that the body uses to build various chemical structures. This includes serotonin, one of the primary neurotransmitters in the brain that is involved in everything from decision-making to depression. Serotonin is also a precursor to melatonin, which is important in sleep and wakefulness and is where the tryptophan-tiredness link comes in. However, despite the popular neuro-myth, turkey is actually no higher in tryptophan concentration than other types of poultry. Numerous different plant and animal proteins provide us with our daily doses of tryptophan, with sunflower seeds, egg whites and soy beans having some of the highest concentrations of the amino acid. In fact, turkey comes in at a measly 10th on the list of tryptophan sources.

Instead, the relation between eating and sleeping seems to be more dependent on the amount of food consumed, rather than the type we eat. Insulin is released after every meal, particularly ones high in carbohydrates, and the more carbs consumed, the more insulin is produced. This increase then changes the chemical levels in our bloodstream, affecting the re-uptake and release of various amino acids. Ultimately these changes result in greater amounts of tryptophan crossing the blood-brain-barrier and being taken up into the brain. There the tryptophan is converted to serotonin, some of which is also metabolized into melatonin, causing our postprandial nap.

Tryptophan’s influence on serotonin levels doesn’t just affect sleep cycles. The link between depression and low serotonin levels is well established, and tryptophan supplements have been suggested as less invasive treatments for the disorder. Unfortunately these studies have been mostly unsuccessful to date, as mild modifications of tryptophan seem to have little to no effect on mood in most individuals. However, it is possible that people with low endogenous levels of tryptophan due to specific genetic profiles may be more susceptible to the chemical’s effect on mood, and current research is still ongoing in the matter.

So regardless of whether it’s turkey, stuffing or sweet potatoes you prefer, remember to load up your plate during Thanksgiving to get those happy drowsy effects later. It may just help you feel a little bit calmer, and prevent some of the Black Friday mayhem the next day.

More sexism in science

Following on my post the other week on Gender bias on both sides of scientific research, I want to draw attention to an incident that occurred at the annual Society for Neuroscience meeting last week in New Orleans. SFN is by far the largest neuroscience event every year, drawing over 30,000 attendees to come and revel in nerdy neuro madness for a week (think of it as a music festival for science geeks). With so many talks, poster sessions and symposiums, not to mention the sheer number of people, the conference can be overwhelming. But it is also overwhelmingly positive and exciting, allowing you the opportunity to check out new research, get new ideas, forge new relationships and collaborations, and, if you’re lucky, even meet your academic super-star crush (I’m looking at you David Eagleman).

However, one conference-goer decided that the quality of the researchers wasn’t quite up to his standards. Dr. Dario Maestripieri of the University of Chicago complained on Facebook that the cosmetic caliber of the female attendees was lacking this year, stating “there are…an unusually high concentration of unattractive women [at the conference]. The super model types are completely absent.” The comment, originally discovered and posted by Drug Monkey on his blog, went on to ask, “Are unattractive women particularly attracted to neuroscience? Are beautiful women particularly uninterested in the brain?”, and considerately topped it off with, “No offense to anyone…”

Fortunately many people did take offense to Maestripieri’s comments, including Dr. Janet Stemwedel who posted an eloquent rebuttal on Scientopia, which I highly recommend. Maestripieri’s overt sexism demeans female scientists, belittling them and insinuating that their value is only measured by their looks, not their research, intelligence or contributions to the field. And keep in mind that this comment was made at a professional scientific conference, where the emphasis should especially be on one’s intellect and creativity, not on beauty or breasts. The response to Maestripieri’s comments has been overwhelmingly negative, and a Wikipedia page about him has even been updated to mention the controversy. However, others still think his behavior was acceptable, writing it off as a joke and telling people to not take it so seriously. This is particularly problematic given the underlying gender bias we know to still exist in science. If we accept overt and covert discrimination against women in science we all lose out, not just women who are dissuaded from the field because of it, but everyone who might have benefited from their future work.

SFN ’12: Vulnerabilities for drug addiction

For anybody who’s in New Orleans for SFN this week, come by room 273 at 1pm today to learn about vulnerabilities for drug addiction. It’s an excellent nanosymposium set up by the fantastic Dr. Jenn Murray covering both human and preclincial studies into risk factors for addiction. The talks will include investigations into the classic predictive traits of impulsivity, anxiety and novelty-seeking, and they’ll also delve into environmental risk factors for addiction, such as maternal care and environmental stimulation.

I’ll be presenting first (so be there at 1pm sharp!) on my work on endophenotypes for addiction. This involves studying both dependent drug users and their non-dependent biological siblings, who share 50% of their genes and the same environment growing up, but who never developed any sort of drug or alcohol abuse. I’ll be looking specifically at cognitive control deficits and frontal cortex abnormalities in both of these groups compared to unrelated healthy control volunteers. There are some surprises in the results, so if you’re at SFN come by at 1pm to find out what they are!

Thought-controlled robot arms: Welcome to the future!

It’s the year 2012, and while we don’t all have jet packs or flying cars, there have been some pretty incredible scientific discoveries as of late. Two amazing studies in particular have come out involving advances in spinal cord injury rehabilitation. The first helped paralyzed rats to walk again, and in the second a tetraplegic woman used a thought-controlled robotic arm to take her first self-directed sip of coffee in 15 years.

The first study, published in Science by a Swiss research group, used rats to study physical rehabilitation in paraplegic animals. The researchers partially severed the spinal cords of a group of rats, paralyzing their hind-legs but crucially sparing some of the nerve tracts up to the brain. They then stimulated the spinal cords of these animals in the affected region with an electro-chemical current, hoping to excite the remaining nerve cells. The idea behind this is that if you can activate somatosensory signals (the sensations of touch and position of the body) in the affected limbs, you can help rewire the brain to potentially encourage firing of motor neurons as well.

Researchers also fitted the rats with a prosthetic harness that helped support the animals and placed them on a tiny treadmill, while simultaneously stimulating their injured spinal cords with the electro-chemical signal (the article has amazing videos of this here). By zapping the spine with this current and artificially moving the animals’ legs, it is possible that any lingering neurons involved in these motor and sensory regions will be stimulated, and possibly re-wire to facilitate further repair and improve locomotion. Sure enough, after just three weeks of this training program some of the animals were able to take steps voluntarily, and after six weeks all of the rats could walk with help from the stimulation. After two more weeks of training these formerly paralyzed rats were even able to go up stairs and jump over obstacles!

Confirming the researchers’ theory of assisted neurogenesis, the rats who had undergone the training program had significantly more new neurons and connections from the spinal cord to the motor area of the brain than animals who had not been trained.

In the second and even more fantastical study, two patients with tetraplegia (complete paralysis of the body) were able to self-direct a robotic arm using only their thoughts. Led by Dr. Leigh Hochberg at Brown University and published in the journal Nature, scientists implanted an electrode into the motor area of the paralyzed individuals’ brains. The patients practiced for months, training the computer chip to read their motor neurons’ signals by imagining moving their arms in various prescribed motions. The chip learned to decode the relevant firings from these cells, measuring the corresponding output from each neuron for the specified movement, and then used these signals to comunicate with a computer and direct a nearby robotic arm.

Starting with just simple point and touch actions, the patients trained the system on increasingly more difficult motions involving precise speed, force and direction. By the end of the study, the communication and interpretation of one of the patient’s thoughts was so well coordinated she was able to use the robotic arm to grasp a cup, raise it to her lips and drink through a straw (there are some pretty amazing images of this as well).

I’m going to repeat that: with the help of science and a microchip, this woman controlled a robot with her mind!

So while I’m still waiting for my jet pack, these studies are pretty exciting examples of advances in health-science research, showing just how far science has come and giving us a glimpse into the next generation of neuro-engineering. Welcome to the future.

A proposed shift in drug policy: From prevention to harm reduction

I recently finished Professor David Nutt’s new book, Drugs Without the Hot Air, on minimizing the harms of drug use, both legal and illegal. Professor Nutt’s tone is light and his writing is accessible to readers of all scientific backgrounds, but his message is an important one. He explores the history and culture surrounding many drugs of abuse, ranging from the popularization of caffeine and nicotine, to the original medicinal purposes for cocaine and heroin, to the widespread use of prescription stimulant drugs today. He also discusses previous governmental endeavors, both successful and unsuccessful, on limiting drug abuse. This includes the floundering War on Drugs waged by the United States since the Nixon administration, as well as the more effective reduction in tobacco use seen in the U.S. and U.K through smoking bans, higher taxation and tighter restrictions on marketing campaigns.

Professor Nutt also effectively explains the neurochemical mechanisms involved in many common drugs of abuse, again covering legal highs like alcohol and nicotine, as well as more commonly thought of addictive substances, such as cocaine and heroin, and newer experimental compounds like hallucinogens, ecstasy/MDMA and designer drugs. He goes on to articulate the harms and benefits associated with each of these substances, as well as why some of these chemicals are more addictive than others.

However, the real strength of Professor Nutt’s argument is in his rationale for sensible drug policy based on scientific results rather than political scare-mongering and media sensationalism. He cites his own extensive research on the varying degrees of harm caused both to the individual and society by different drugs of abuse, including his infamous comparison of the detriments associated with ecstasy use to those caused by horseback riding. His harm scale comprises assessments of the total amount of risk associated with each substance, including the potential for addiction and mental and physical impairment, as well as the damage caused to society through things like drug-associated crime and money spent on medical treatments and criminal containment.

Professor Nutt’s conclusions have caused sufficient controversy, as he claims that alcohol causes greater harm to both the individual and society than drugs like cannabis, MDMA and hallucinogens. Alcohol can be highly addictive, with users developing both physical and psychological dependence, and its use is associated with a number of severe mental and physical consequences, including death. Additionally, the harm caused to society through drunk-driving, alcohol-fueled assault and medical costs for aging users is severe. In comparison, hallucinogenic drugs have virtually no addictive properties, as they are slow-acting and cause a rapid increase in tolerance, meaning that immediate subsequent administration of the drug results in no increase in pleasure or effects. There are also virtually no hallucinogenic-related crimes reported, as these drugs typically increase feelings of empathy and tranquility rather than aggression. Finally, substances like cannabis and hallucinogens have very low risk for toxicity and cause few long-term physical or psychological side effects, particularly when used in moderation. Indeed, in many cases being charged with possession of the drug is far more detrimental to the individual and his or her future than consumption of the drug itself.

Thus, while labeling a drug ‘legal’ or ‘illegal’ has little bearing on its harmful or addictive tendencies, it does have far-reaching social and legal ramifications on the individual, as well as on the research opportunities and potential therapeutic applications of the substance. One such example is the surge in prescription drug use in the U.S., recently over-taking illicit highs as the most widely abused substance. Opiate-based narcotics like OxyContin can be highly lethal, particularly when combined with alcohol. They also have high potential for dependence, which is exacerbated when the drug is crushed up and snorted rather than taken orally. Different routes of drug administration can greatly affect the potential for abuse, with the faster the drug reaching the brain the greater the reward value associated with it. After all, everybody likes a little instant gratification. Injecting, smoking and snorting a substance all deliver the chemical to the brain within 60 seconds, whereas consuming a drug orally takes longer, as the chemical must be digested before it can reach the blood stream. As such, prescription pills of opiate-based pain killers have less abuse potential than heroin, which is most commonly smoked or injected. However, when these pills are crushed up and snorted their effects are much more rapid, and their potency and risk for abuse sky rockets.

The paradox lies in the fact that heroin, which is considered to be a more effective analgesic than morphine, is strictly banned, even for use in hospitals. However, substances that are nearly identical in chemical structure and abuse potential are legal and readily available to those with an ailing grandmother or friend whose wisdom teeth were recently removed. Of course this does not mean that these pain medications should be banned as well, but rather that there should be more careful restriction of these drugs. Similarly, substances such as medicinal marijuana, MDMA and hallucinogens could have beneficial therapeutic effects when used in clinical settings, such as for patients with a terminal illness or PTSD. However, because they are labeled ‘illegal’ any research on these substances is tightly restricted, and numerous people who may benefit from their use are unable to obtain them legally.

Therefore, one of the most important take-away messages of Drugs Without the Hot Air is that drug policy should be directed by scientific research and careful empirical evaluation of the benefits and harms of a substance, rather than a reactive emotional or moral response from politicians and the media.

(Thanks to Sam Greenbury for the gift of this book.)

I saw the (negative) sign: Problems with fMRI research

I feel the need to bring up an issue in neuroimaging research that has affected me directly, and I fear may apply to others as well.

While in the process of analyzing a large fMRI (functional magnetic resonance imaging) data-set, I made an error when setting up the contrasts. This was the first large independent imaging analysis I had attempted, and I was still learning my way around the software, programming language, and standard imaging parameters. My mistake was not a large one (I switched a 1 and -1 when entering the contrasts), however it resulted in an entirely different, but most importantly, still plausible output, and no one noticed any problems in my results.

Thankfully, the mistake was identified before the work was published, and we have since corrected and checked the analysis (numerous times!) to ensure no other errors were committed. However, it was an alarming experience for a graduate student like myself, just embarking on an exploration of the brain – an incredibly powerful machine that we barely understand, with revolutionary high-powered technology that I barely understand – that such a mistake could be so easily made and the resulting data so thoroughly justified. The areas identified in the analysis were all correct, there was nothing outlandish or even particularly unexpected in my results. But they were wrong.

Functional MRI is a game of location and magnitude. The anatomical analysis, looking for blobs in the brain that light up where we think they should, can be confirmed with pre-clinical animal models, as well as neuropsychology research in patients who have suffered localized brain damage and related loss of function. Areas involved in motor control and memory have been identified in such a manner, and these findings have been validated through imaging studies identifying activation in these same regions during performance of relevant tasks.

The question then remains as to the direction of this activation. Do individuals “over activate” or “under activate” this region? Are patients hyper- or hypo-responding compared to controls? FMRI studies typically compare activation during the target task to a baseline state to assess this directionality. Ideally, you should subtract neural activity levels during a similar but simpler process from the activation that occurs during your target cognitive function, and presumably the resulting difference in activity is the neurocognitive demand of the task.

An increase in activation compared to the baseline state, or compared to another group of participants – i.e. patients vs. controls, is interpreted as greater effort being exerted. This is typically seen as a good thing on cognitive tasks, indicating that the individual is working hard and activating the relevant regions to remember the word or exert self-control. However, if you become expert at these processes you typically exhibit a relative decrease in activation as the task becomes less demanding and requires less cognitive effort to perform. Therefore, if you are hypo-active it could be because you are not exerting enough effort and consequently under-performing on the task compared to those with greater activation. Or, conversely, you could be superior to others in performance, responding more efficiently and not requiring superfluous neural activity.

Essentially, directionality can be justified to validate either hypothesis of relative impairment. Patients are over-active compared to controls? They’re trying too hard, over-compensating for aberrant executive functioning or decreased activation elsewhere. Alternatively, if patients display less activity on a task they must be impaired in this region and under-performing accordingly.

Concerns about the over-interpretation of imaging results are nothing new, and Dr. Daniel Bor, along with a legion of other researchers in the neuroscience community, have tackled this issue far more eloquently and expertly than myself. My own experience, though, has taught me that we need greater accountability for the claims made from imaging studies. Even with an initially incorrect finding that resulted from a technical error, I was able to make a reasonable rationale for our results that was accepted as a plausible finding. FMRI is an invaluable and powerful tool that has opened up the brain like never before. However, there are a lot of mistakes that can be made and a lot of justifications of results that are over-stretched, making claims that can not be validated from the data. And this is assuming there are no errors in the analysis or original research design parameters!

I am particularly concerned about the existence of other papers where students and researchers have made similar mistakes to my own, but where the results seem plausible and so are accepted, despite the fact that they are incorrect. I would argue that learning by doing is the best way to truly master a technique, and I can guarantee that I will never make this same mistake again, but there does need to be better oversight, whether internally or externally, during the reporting of methods sections, as well as in the claims made while rationalizing results. Our window into the brain is a limited one, and subtle differences in task parameters, subject eligibility, and researcher bias can greatly influence study results, particularly when using tools sensitive to human error. Providing greater detail in online supplements on the exact methods, parameters, settings, and button presses used to generate an analysis could be one way to ensure greater accountability. Going one step further, opening up data-sets to a public forum after a certain grace period has passed, similar to practices in physics and mathematics disciplines, could engender greater oversight to these processes.

As for the directionality issue, the need to create a “story” with scientific data is a compelling, and I believe very important, aspect of reporting and explaining results. However, I think more of the fMRI literature needs to be based on actual behavioral impairment, rather than just differences in neural activity. Instead of basing papers around aberrant differences in activation, which may be due to statistical (or researcher) error, and developing rationalizing hypotheses to fit these data, analyses and discussions should be centered on differences in behavior and clinical evidence. For example, the search for biomarkers (biological differences in groups at risk for a disorder, often present before they display symptoms) is an important one that could help shed light on pre-clinical pathology. However, you will almost always find subtle differences between groups if you are looking for them, even when there is no overt dysfunction, and so these searches need to be directed by known impairments in the target patient groups. A similar issue has been raised in the medical literature, with high-tech scans revealing abnormalities in the body that do not cause any tangible impairments, but the treatment of which cause more harm than good! Instead of searching for differences in activation levels in the brain, we should be led by dysfunction that results from these changes. Just as psychiatric diagnoses from the DSM-IV are supposed to be directed by symptoms relating to pathology only if they cause significant harm or distress in the individual, speculations made about the results of imaging studies should be influenced by associated impairments in behavior and function, rather than red or blue blobs on the brain.

(Thanks to Dr. Jon Simons for his advice on this post.)

Frankenstein research methods in multiple sclerosis treatments

I recently attended a fascinating lecture by Cambridge neuroscientist Robin Franklin on progenitor cells (“neural stem cells”) and their treatment potential in neurodegenerative diseases, such as multiple sclerosis (MS). The progressive form of MS, which follows from the relapsing-remitting version, stems from a decreasing ability of oligodendrocyte cells and their crucial myelin sheaths to be regenerated after they are destroyed through the course of the disease. Dr. Franklin’s lab studies cell remyelination, specifically focusing on oligodendrocyte precursor cells (OPCs), which are a form of progenitor that can evolve into oligodendrocytes to replace the damaged cells and sheaths. However, as an individual ages, these cells have a greater difficulty differentiating and do not regenerate as efficiently, which is most likely the cause in the transition to the progressive form of the disease. Dr. Franklin’s lab has used parabiosis to study the effects of aging on progenitor cell differentiation, the amazing science fiction-esque research method of fusing two mice together (in this case young and old), enabling them to share blood flow. From this research, Dr. Franklin has provided the most compelling evidence to date that decreases in crucial blood proteins as an individual ages are behind the increasing disability in remyelination and disease progression.

But let’s take a step back and do some defining, as I’ve just introduced a lot of jargon in that first section. Until only the last few decades, it was commonly thought that brain structure was relatively stable through adulthood, the window of neurogeneration and plasticity closing after adolescence. However this myth has been debunked, and there has been a revival in research on neural plasticity in adulthood and its potential treatment implications for individuals suffering from stroke, traumatic brain injury, and neurodegenerative diseases.

Multiple sclerosis (MS) is a neurodegenerative disease that consists of the breakdown of myelin sheaths, the protective coatings that surround cell axons and make up white matter tracts, enabling more efficient signal transmission between cells. This is in contrast to other neurodegenerative diseases, such as Huntington’s or Parkinson’s disease, which stem from the death of gray matter neurons themselves. These myelin sheaths originate from oligodendrocyte cells, bizarre looking neurons that consist of a cell body and up to 80 projections of giant wrap-around sheaths coming out of each arm. These sheaths encase and protect neighboring cell axons, however in MS both the sheaths and the oligodendrocyte cells become damaged, eventually breaking apart and dying.

Fortunately, the brain contains its own version of stem cells, early stage neurons called progenitor cells that have the potential to develop into a variety of different types of mature neurons. These progenitor cells are particularly adept at evolving into oligodendrocytes, and thus in the early stages of MS these lost cells can be replaced relatively easily. This depletion-repletion process explains the relapsing-remitting course of the early stages of MS. However, as the disease progresses it becomes increasingly difficult for these oligodendrocytes to regenerate, stemming from an increasing inefficiency in differentiation of the progenitor cells. This turn of events seems to define the later stage of progressive MS, though why this decline occurs has been unclear.

Enter Dr. Franklin and his team of researchers. Published recently in Cell Stem Cell, Dr. Franklin’s group used parabiosis to determine that the decreasing efficiency of cell regeneration was caused by an increase in age. Comparing heterochronic (young and old mice joined together) with isochronic (young-to-young or old-to-old) pairs, researchers damaged the myelin in the spinal cord of the older animals using a local toxin injection, and measured subsequent levels of both oligodendrocyte precursor cells (OPCs) and oligodendrocytes themselves. After 14 days, the levels of OPCs in the older damaged mice in the heterochronic pairs was significantly greater than those in the older isochronic animals, and at 21 days the levels of mature oligodendrocytes in old heterochronic animals were equivalent to those in young isochronic pairs. Both of these results were associated with an overall increase in myelination in the damaged heterochronic-old animals as compared to the isochronic-old pairs.

This improvement in regeneration seems to stem from an increase in differentiation of the already existing progenitors in the old mice, rather than a pilfering of these cells from their young counterparts. Instead, by joining together the vascular systems of the young and old animals, the older mice were able to benefit from increased levels of proteins and cells, such as macrophages, that signal the need for differentiation in the progenitors, enabling them to once again trigger the transformation process into full-fledged oligodendrocytes.

In his talk, Dr. Franklin was quick to point out that this was not a therapeutic study, but that it instead shows a pharmacological approach towards regeneration of oligodendrocytes for remyelination in MS may be promising going forward. These results suggest that it is not an influx of new progenitor cells that is needed in older individuals, but instead an enhancement of the signalling cells that make these transformations possible. This would of course be a far easier clinical undertaking than surgically fusing together young and old patients, and provides one of the first bits of evidence for treatment options in actually repairing the damage caused by neurodegenerative diseases.