Sequencing Neanderthals

Just out now in Cell is a wonderful article on the full sequence of mitochondria DNA from the Neanderthal. The paper is already receiving much interest in the media, and Nature has a news story somewhat misleadingly entitled “First complete Neanderthal genome sequenced“.

Using very rigorous methods for extracting DNA material from the Vindija Cave in Croatia and keeping it clean from (human) contamination, the researchers were able to analyze 35 samples. The paper abstract basically tells the main findings:

A complete mitochondrial (mt) genome sequence was reconstructed from a 38,000 year-old Neandertal individual with 8341 mtDNA sequences identified among 4.8 Gb of DNA generated from ∼0.3 g of bone. Analysis of the assembled sequence unequivocally establishes that the Neandertal mtDNA falls outside the variation of extant human mtDNAs, and allows an estimate of the divergence date between the two mtDNA lineages of 660,000 ± 140,000 years. Of the 13 proteins encoded in the mtDNA, subunit 2 of cytochrome c oxidase of the mitochondrial electron transport chain has experienced the largest number of amino acid substitutions in human ancestors since the separation from Neandertals. There is evidence that purifying selection in the Neandertal mtDNA was reduced compared with other primate lineages, suggesting that the effective population size of Neandertals was small.

But even more interesting is that a month ago, I unexpectedly met one of the co-authors on this paper. Michael Egholm had entered my wife’s gallery for a brief visit to check out her famous microscopy paintings. While it took me some time to understand who he was, and who he worked with (such as Svante Pääbo), our conversation continued after he’d left for the US. Luckily to you English-only readers, Egholm has spent too many years to feel comfortable writing science in his native Danish. He sent me the submitted manuscript with the following comment:

The somewhat simplistic grand purpose of the Neanderthal project is to figure out what makes us human - presumably our unique brain function.  By comparing the Neanderthal sequence with Chimpanzee and Human we can ideally pin point areas on the genome that has undergone rapid evolution the last 660K years (the new split time determined in the paper). It is generally accepted that something dramatic happened within the last 100K years or so which eventually let to the exodus from Africa and population of the rest of the world along with the extinction of other hominoids.  So with the Neanderthal genome we’re on the safe side but a lot closer than our divergence from Chimpanzee (est. at 6M years).  Obviously, we will be blind in areas of the Neanderthal genome that have undergone evolution since the split from modern humans.

The mitochondrial genome is an obvious first milestone in the project because of its overrepresentation and because it does not undergo recombination the analysis is a lot simpler with respect to split time etc.  Anyways, there is one big surprise and/or coincidence in the 13 proteins that are coded for by the mtDNA in that we find one gene with 4 ns changes - this is exactly what we had hoped for and while highly statistically significant within the context of the 13 proteins of the mtDNA it is not within the context of 20K+ genes.

How’s that for an explanation?

-Thomas

Brainless economics no more

Does economics need brain science? This is the aim of a recent article in the Economist. Throughout the history of economics, major advances have sometimes come from areas outside of the core discipline. Just as similar developments in other scientific disciplines. This includes the influence from psychology, which has demonstrated that decisions are not made through the rational, overt weighing of alternatives before consciously choosing the right option. Rather, choices are influenced by context, internal states, unconscious processes, emotions, and a whole host of less (or different form of) rational processes.

Today, few seriously think that homo economicus, or the rational man view, is the best model of human decision making. Nevertheless, such assumptions haunt several economic models, most often in implicit ways. One may, of course, say that the unconscious and emotional processes that influence preferences and decisions are built on some kind of rationality. Indeed, they are the remains of adaptive strategies throughout human and mammalian phylogeny.

But this begs the question of the rational man idea. Human preferences and decisions are the result of both overt and covert processes in the mind and brain. What drives our decisions and indeed our behaviours in general are the result of a convergence of several parallel processes of perceptual, emotional, cognitive and social processes. Conscious as well as unconscious kinds. Models of decision making are currently lacking the full implementation of such multidimensional factors, and in particular the temporal aspect of this.

Cognitive neuroscience has thus been suggested as a means to improve this, by applying both the insights from its own research, as well as in direct testing of ideas from economics. This branch, often referred to as neuroeconomics, but also decision neuroscience, has received a lion’s share of attention both within academia and in the media. And, not surprisingly, many economists are sceptic.

And they should be! In present-day pop-science culture, showing a brain image — or better, a brain activation image — is an exceptional way of getting attention, and give the impression of scientific rigour. But going beyond the brain blobs, it becomes harder to know exactly how much news there is  in the image. So let’s say that you find that regions x, y and z show increased activation when performing behaviour B. Interesting, right? This is what makes many people fascinated (simplified). “Yeah, they found that this region called orbitofrontal cortex was activated when people expected a reward”. But if you ask yourself or that person: “so what?” what is your answer? What is really the most valuable information in this?

Looking at blobs are, of course not sufficient. But it may be one of the underlying causes of the scepticism and criticism that neuroeconomics has received. There are too many just so stories (or so what stories). Blobs don’t tell stories or hint at causal relations, not even why the brain is important. This is covered briefly in The Economist article:

The fiercest attack on neuroeconomics, and indeed behavioural economics, has come from two economists at Princeton University, Faruk Gul and Wolfgang Pesendorfer. In an article in 2005, “The Case for Mindless Economics” (PDF), they argued that neuroscience could not transform economics because what goes on inside the brain is irrelevant to the discipline. What matters are the decisions people take—in the jargon, their “revealed preferences”—not the process by which they reach them. For the purposes of understanding how society copes with the consequences of those decisions, the assumption of rational utility-maximisation works just fine.

It’s funny to note that this article by Gul and Pesendorfer was published online long before it seems to have hit the presses. And what a smear! Don’t we always want the best possible model with the most available details? But the main claim — that what goes on in the brain is irrelevant to economics — is actually a widespread idea. And to some extent, rightfully so!

Neuroimaging results are not self-evident. It needs to be explained. And it needs to be related to existing knowledge about the brain. Consequently, we need to move beyond the blobology fascination and look into causal relationships, and ultimately how this affects behaviour. Neuroscience has the tools to provide this. For example, if we look at the brain during a decision making task, we learn that one may be able to define specific sub-processes that occur before and during the decision behaviour. According to the oft-cited 2007 Neuron study by Knutson et al. (PDF) we may distinguish between preference formation, valuation, and decision making. Already during the viewing of a product, activation in the nucleus accumbens was positively related to purchase behaviour (occuring several seconds later). Product price that exceeded that of an expected price lead to increased activation in the insula, and was negatively related to purchase behaviour. Among many other factors in this study, it neatly illustrates that decision making (the end product) can be disentangled into relevant sub-processes. And this information is unavailable unless you use neuroimaging.

Furthermore, knowing brain substrates and time-frames allows us to alter behaviour. If an identified region — say the amygdala — is implemented in pathological gambling, we may assume that altering the function of this region may also influence the (undesired) behaviour. Since the amygdala is largely serotonergic, applying medication that increase or decrease the levels of serotonin may affect gambling behaviour. And indeed, this is what research indicates.

This, neuroeconomics should be expected to allow us to probe into the detailed processes that lead to decision behaviour. Knowing the where and when (and why) of the brain during decision making is also going to allow us to affect the causal mechanisms. In effect, neuroeconomics is already today proving its’ effect. And researchers such as Gul and Pesendorfer should pay heed to the discipline. But we — and they — need to go way beyond the blobology so often offered in this arena. Cognitive neuroscience has the tremendous power to influence a whole range of theories of the mind — from psychology and paedagogics to economics and politology. But in order for it to succeed, the science needs to be closely accompanied by valid explanations and less sensationalism.

-Thomas

Sway — irrational desires and errors

Just noticed this very attractive title by the Brafman brothers- The book, Sway – the irresistable pull of irrational behavior, “will challenge your every thought”, according to a NY Times review. And it gets similarly good reviews from other prominent people, like Michael Shermer, the author of the recent book The mind of the market, which I blogged about recently.

I found a couple of good videos on this book that’s good to share:

A longer version with more nuances can be seen here:

So after this, you get the idea: unconscious, automatic thought patterns act out and cause irrational behaviours, sometimes at the worst possible time and place.The questions raised are, of course, interesting and important. Why do we sometimes make horrific decisions, despite having all the information available to make better ones? Why do prominent people, like George W. Bush, suffer from loss aversion, leading to billions of dollars spent and thousands of lives lost? Because it’s “too late” to pull out? Because the pain of acknowledging defeat, error or insufficiency is bigger than the benefit of sparing yet more money and lives?

Other examples can be found at the Wall Street, military, aircraft captains, and even yourself. Maybe even on a daily basis. Taken together, the examples presented in these videos and the book demonstrate that we are all susceptible to make these kinds of errors. The next and better step is, of course, to identify these errors in ourselves (and others) and act upon them in time. Coaching, anyone?

I guess I should read the book, if the publishers will send me the book

-Thomas

A neuroeconomic framework

In a recent review article in Nature Reviews Neuroscience, Antonio Rangel, Colin Camerer and Read Montague suggest a framework for neuroeconomic research. Indeed, the very core of its idea is simple, but not simplistic. After reading the article, I think it will provide a useful reference for future research into neuroeconomics, aka value-based decision making. I’ve made a copy of the model here for you to see:

The caption reads:

Basic computations involved in making a choice. Value-based decision making can be broken down into five basic processes: first, the construction of a representation of the decision problem, which entails identifying internal and external states as well as potential courses of action; second, the valuation of the different actions under consideration; third, the selection of one of the actions on the basis of their valuations; fourth, after implementing the decision the brain needs to measure the desirability of the outcomes that follow; and finally, the outcome evaluation is used to update the other processes to improve the quality of future decisions.

In my own emerging work on this arena, I am trying to combine this with recent advances cognitive neuroscience. First, the advances in imaging genetics, i.e., the knowledge and study of how genetic variance leads to specific changes in neurotransmission, which in turn may affect cognition, emotion and behaviour. Second, the advances in the cognitive neuroscience of ageing, i.e, the relationship between age-related changes in brain structures and functions, and mental alterations.

Briefly put, in a just submitted manuscript, I suggest that the Rangel-Camerer-Montague framework can serve as a model for looking at genotype and age effects. This leads us to three advances: first, it provides a better way to illustrate and understand the minute details of the preference and decision making systems. Second, it serves as a demonstration that individual (and intra-individual) differences must be taken into account. The “economic agent” is not a homogenous subject, but an agent that differs from person to person and with persons over time. Finally, it may also serve as a framework for identifying potential ways to induce alterations in the systems, e.g., through medical intervention. More on this story later, given that the manuscript is accepted For now, here’s an illustration of how genotype (exemplified through COMT, MAO-A and 5-HT) and age effects may expand the model. Of course, this is only scratching the surface, but I hope you’ll see what I mean.

This is an extended version of the Rangel-Camerer-Montague model. Within each processing node, two dimensions are added, here exemplified with the three primary nodes. The genotype dimension is a categorical variable that divides subjects into two or three classes, while the age dimension is continuous (inset, top left).

-Thomas

Neuroaesthetics the other way

I don’t know about you, but I often get fascinated by the mere visualization of brain imaging data. Aside with the neuroimaging blobologies, but looking at more detailed visualizations of brain parts and processes strike me as merely beautiful and fascinating. And, as the fascination of looking at a star may be deepened by knowing more about that exact star (e.g., it’s the leftovers from a supernova), knowing what you see in the image of the brain may provide more understanding of what we see, and why it looks just that way.

Just as with this cover image from a recent issue of Cerebral Cortex, in which the caption says:

Photomontage showing two consecutive coronal sections of an E12 mouse embryo after 24 hours of being in toto culture. After a CFDA injection into the rostro-medial telencephalic wall, labeled cells (green) migrate tangentially by the ventral telencephalon and reach the olfactory cortex, which is immunohistochemically stained against calretinin (red) and calbindin (pseudocolor orange). The blue color shows the DAPI unspecific staining of nuclei. Superimposed, the black and white figure shows an embryo head injected with the fluorescent tracer DiI (red).

Or, put more simple, it’s an image showing how cells migrate during embryonic development. The article can be found here.

-Thomas

Serotonin and value-based decision making

Can antidepressive medicine alter your decision behaviour? A recent paper in Science now demonstrates that alterations in subjects’ serotonin levels leads to significant changes in their decision making behaviour. In the study, subjects were set to play the Ultimatum Game repeatedly. Subjects had to do the task two times at two different days, and at one of the days they were administered an acute tryptophan depletion (ATD), i.e., their serotonin levels would drop for a period of time. The design was double-blind and placebo controlled.

The Ultimatum Game is an experimental economics game in which two players interact to decide how to divide a sum of money that is given to them. The first player proposes how to divide the sum between themselves, and the second player can either accept or reject this proposal. If the second player rejects, neither player receives anything. If the second player accepts, the money is split according to the proposal. The game is played only once, and anonymously, so that reciprocation is not an issue.

What the researchers found was that the ATD led subjects to reject more offers, but only unfair offers. That is, ATD did not interact with offer size per se, and there was no change in mood, fairness judgement, basic reward processing or response inhibition. So serotonin seemed to affect aversive reactions to unfair offers.

The study is a nice illustration of how we now are learning to induce alterations in preferences and decision making. Along with other studies using, e.g., oxytocin to increase trust in economic games (see also my previous post about this experiment), one may expect that increasing the serotonin level may actually make subjects less responsive to unfair offers.

This knowledge is also important to learn more about, as it poses a wide range of ethical problems. If our preferences and decisions are really influenced by these stimuli, can this be abused? It should be mentioned that many of these substances are not necessarily detected (oxytocin is odourless), so we may be influenced without our consent or knowledge. The wide applicances could include casinos, stores (e.g. for expensive cars), dating agencies and so on. If we did not accept subliminal messages in ads, how can we accept this?

-Thomas

Brain plasticity and sexual aberrations

I’m having the pleasure of reading The brain that changes itself by Norman Doidge, as a reviewer for a potential translation here in Denmark. Brain plasticity, or neuroplasticity, has always been a hot topic, from it’s (re)birth in modern neuroscience, and all the way up until today, where researchers are still fiercely debating how plastic the brain is and how functions relate to brain structures - aka the debate of modularism. In its early days, the neuroscientific community strongly believed that the modularity of the brain was established during childhood, and that little, if any, change could occur later on. Researchers suggesting otherwise were eschewed, heavily criticized on the ground that their data/ideas did not fit into the existing model. The land did not fit onto the map, so to say. This book is dedicated to the idea of neuroplasticity.

The book introduces brain plasticity in a very vivid and close-up manner, as Doidge tells the story from the inside, through some of the biggest names in this research, including the late Paul Bach-y-Rita, Michael Merzenich, and Gerald Edelman. Not only is the book very interesting to read as a historical background, but it also takes a look behind the scenes in two ways. Doidge has talked the researchers himself, and bring their experience of how plasticity came to go from a ignored (and carreer risky business) field, to a scientifically acceptable and highly influential topic. Even today, one may claim that we do not fully comprehend or apply the insights from this research.

Doidge also does a great job in describing patient cases of brain plasticity, including:

(…) a woman born with half a brain that rewired itself to work as a whole, a woman labeled retarded who cured her deficits with brain exercises and now cures those of others, blind people learning to see, learning disorders cured, IQs raised, aging brains rejuvenated, painful phantom limbs erased, stroke patients recovering their faculties, children with cerebral palsy learning to move more gracefully, entrenched depression and anxiety disappearing, and lifelong character traits altered.

(from the book cover)

The stories from both researchers and patients are written in a most vivid and entertaining way, and the first 100 pages alone makes the book a page-turner. The book as a whole is filled with these fantastic descriptions and stories that equal great writers such as Oliver Sacks.

So how about the sex part? Yes, this is where I got a little puzzled, too. Going from the insights of neuroplasticity, Doidge turns his attention to sexual disorders and abberations. This is, of course, both a very interesting, challenging and risky choice, but it is also a topic that Doidge is intimately close to through his clinical work. In much the same manner as the description of neuroplasticity cases, we are presented to patients of Doidge (or his peers) that suffer from psychological illnesses, in particular sex related problems. Interestingly, it seems that the insights from plasticity can be applied to these disorders and problems, and Doidge does a great job in presenting and discussing these issues.

My quarrel, however, is with Doidge’s theoretical position — psychoanalysis. Is it not itself strange to combine the insights from the edgy yet stringent scientific approaches of neuroplasticity with the unscientific theoretical (armchair) century old approach? Doidge does use the suggestions from Freud to interpret the psychological cases he presents. This includes the interpretation of dreams, a business receiving a lot of criticism, too. At best, I think this part of the book becomes an anachronism. The problem lies in why, at all, Doidge needs to invoke a theoretical position like psychoanalysis at all in order to understand what is going on. This is where science becomes fiction, and where the book breaks down. But not totally. If one is aware of the problems associated with psychoanalysis and science, the book is still a wonderful read.

-Thomas

Big fMRI error in Science!!!

This really gets me freaked out! Martin says I’m just a grumpy old (?) man. So let me lie along the Neurocritic approach just for a minute, and just air my frustration:

HOW CAN YOU GET A SCIENCE PUBLICATION WITH A HUMONGOUS ERROR?

Take a look at this image. It’s from a 2007 article in Science by Depue et al.

It’s supposed to show activation in the hippocampus and amygdala. Looks innocent, right? Let’s take a closer look.

Slice number 3 really provides the best errors:

I spent quite a while figuring the figues out. Did the yellow names indicate the blobs or where the structures actually are? For one thing, the blue blobs don’t fit into amygdala or hippocampus, but rather the entorhinal cortex. But let me comment on two big errors related to this slice.

First, the hippocampus is not present on this slice, so why put the name there? And why put it that lateral? This is really bothering. Do the researchers (and reviewers) really think that the hippocampus has anything to do here?

Second, the rightmost activation blob is centered in white matter. Hmm.. would that not give you the opportunity to speculate whether your coregistration was correct? I would. Related to this, let me just comment briefly on the two leftmost slices:

If you look at the blob, it really looks as if it fits better into the hippocampus. The entorhinal cortex is a thin slice with a whole different orientation. My guess: the hippocampus.

Next slide:

As before, I’m really curisous whether this is only a sign of poorly coregistered (and checked) fMRI images to the structural template brain. Or can it be just another example of why standard spatial normalization in this region is too problematic.

Guys, let’s face it: this is probably one of the bigger, non-spotted errors one can find in visualization of fMRI data. Does it help validate fMRI as a method? NO. How can this error be allowed? I have no idea. But would I trust ANY of the other spatial localizations in this article? NO WAY!

Get a grip, guys! Check your images, and get your medial temporal lobe your anatomy right!

-Thomas

HBM presentations available as podcasts

If you didn’t go the HBM meeting this year you might be interested in hearing that the organizing committee now has put up most of the keynote presentations - for some reason, the talk by Michael Gazzaniga is missing - as well as all the talks from this year’s educational courses as podcasts. You can find them here.

The keynotes include talks by Mel Goodale, Mark D’Esposito (on the top-down modulation of FFA and PPA activation in visula perception), David van Essen (brain maps!, brain maps!), and Aina Puce (on social neuroscience). The educational workshops include talks on “Advanced fMRI”, “Basic fMRI/EEG”, “Diffusion Imaging and Tractography”, and “From Dynamic Modeling to Cognitive Neuroscience”. So, if you want to brush up your knowledge about neuroimaging methodology these podcasts offer a good opportunity.

By the way, I still plan to write a couple of posts about my impressions of the meeting. Stay tuned for that!

-Martin

Sedbergh Festival of Ideas

Here is a heads up for the upcoming Sedbergh Festival of Ideas. Martin is going over to bring our view on the neuroethics of consciousness science research. Unfortunately, I’m unable to attend, but Martin will cover our ideas very nicely.

The event Martin is talking at is “Event 4 — Varieties of consciousness“, together wih no other than Geraint Rees, Ilona Roth and Max Velmans. If you are in the vicinity, why not attend? I hope Martin is going to blog about this meeting, just as he will with his recent trip to the HBM conference.

UPDATE: Here is the program (I just received from Andi Chapple):

Session 1 - Science and Consciousness
10am - 1.30pm, Saturday 19 July
People’s Hall, Howgill Lane, Sedbergh, Cumbria LA10 5DE, England
£15 (£6 concessions) for the whole session, £6 (£2.50 concessions) for the discussion (introduced and moderated by Prof. Velmans) from 11.45am to 1.30pm.

Professor Geraint Rees, Institute of Cognitive Neuroscience, UCL, London
Dr. Ilona Roth, Psychology in Science Group, Open University
Martin Skov, Danish Research Centre for Magnetic Resonance, Copenhagen
Professor Max Velmans, Goldsmiths College, London

Professor Tom Ormerod, University of Lancaster introduces the speakers.

Session 2 - Varieties of Consciousness
10am - 1.30pm, Sunday 20 July
People’s Hall, Howgill Lane, Sedbergh, Cumbria LA10 5DE, England
£12 (£5 concessions)

Speakers will lead short hands-on sessions so the audience can get personal experience of what they are talking about, then present their area of interest, and then there will be a general discussion.

Dr. Michael Daniels, Liverpool John Moores University (transpersonal
psychology and parapsychology)

Dr. David Scott (Zen and ‘Big Mind’ techniques)
Ian McPherson (t’ai chi and qi gong)

-Thomas