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Archive for May, 2006

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-Thomas

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Gene-hyped as we are here at BrainEthics, I'm mentioning a few articles that are highlighting the relationship between genes, brain and mind. As neuroscience deals with the wet matter of the mind – the fatty, information-processing and massively energy consuming body part we call the brain – we must also realize that the basic building block of the brain is the genome.

This is not as simple as it may sound. Genes simply do not merely encode how a cell is to look like or function. Genes only react to the environment in which they are situated. The development of, say, a hippocampal cell is not encoded in the genome per se; it stems from the influence of the local environment of that part of the brain, and how the brain cell (at the developmental stage actually more like a stem cell) migrates and connects to the network that will develop into the hippocampus. Neuroscience is certainly sorting out the nitty-gritty details on this, with the fantastic work by people such as Pasco Rakic. IMHO, even neuroimaging cannot escape this turn: we must move from the "blobology" of fMRI, PET and all other neuroimaging methods (this even applies to the clever diffusion fMRI, as described recently), and towards a better understanding of what goes on within these blobs. Just as I briefly mentioned in my post about Nikos Logothetis.

So here's a few additions in the story about imaging genetics, the study where neuroimaging is informed by genetic variations:

What is the hidden structure of the genome? The human genome is much more diverse and dynamic than what one could get the impression of through normal genotyping studies. Variations abound, and in a number beyond what we normally think. These are not just curiosities; they play important roles in the way that the body (and brain) develops and functions. In a news article in Nature, Andrew Sharp briefly presents two ways to study the genome, and how the new insight about variability influences current research. From the article: "The genetics community is only just beginning to appreciate the extent of structural variation present in the human genome and its role in human disease. Although we now have a finished human genome sequence in hand, geneticists have begun to appreciate that this is in fact a highly dynamic structure. The realization that the long-awaited reference sequence represents only one version of the human genome, which has significant large-scale variation between any two individuals, means that techniques such as these for investigating genome structure will be in high demand."

What is a gene? In another Nature news article, Helen Pearson discusses how RNA is becoming the new field of studying how genetic information is implemented in the organism. From the article: "In classical genetics, a gene was an abstract concept – a unit of inheritance that ferried a characteristic from parent to child. As biochemistry came into its own, those characteristics were associated with enzymes or proteins, one for each gene. And with the advent of molecular biology, genes became real, physical things – sequences of DNA which when converted into strands of so-called messenger RNA could be used as the basis for building their associated protein piece by piece. The great coiled DNA molecules of the chromosomes were seen as long strings on which gene sequences sat like discrete beads. This picture is still the working model for many scientists. But those at the forefront of genetic research see it as increasingly old-fashioned – a crude approximation that, at best, hides fascinating new complexities and, at worst, blinds its users to useful new paths of enquiry."

How heritable is Alzheimer's Disease? According to a study by Margaret Gatz and colleagues, the influence of genetics is very high, and higher than often thought. For a best-fit model estimation, genes are though to be responsible for 79%. Environmental risk factors do indeed play a role, but not as high as we might think from previous reports.

How to read the genome and its functional implications? Simon Fisher and Clyde Francks have a nice review in Trends in Cognitive Science on the genetic influence of dyslexia. Dyslexia is being used here as a model to explain how to use genotyping in a meaningful way to study the genetic influence on cognitive function and dysfunction.

These are just to mention a few important articles from this burgeoning scientific field. More are bound to follow, and we'll cover them the best we can here at BrainEthics.

(BTW, the image used here is from the Rakic Lab, illustrating the migration of brain cells during development. At the Human Brain Mapping conference in Toronto last year, Rakic held a superb talk showing movies of migrating cells. It was a true eye-opener to those of us who had not realized how much actually goes on during development. I can see that they are setting up a page for a media gallery, hopefully that will cover some of these excellent movies. I'll be watching that page closely.)

-Thomas

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In a thorough and very good review in PLoS Genetics, James Sikela writes about the comparative genetics between the chimp and the human genome. From the article:

It has been pointed out that the primary molecular mechanisms underlying genome evolution are 1) single nucleotide polymorphisms, 2) gene/segmental duplications, and 3) genome rearrangement. In addition, a “less-is-more” hypothesis has been proposed that argues loss of genetic material may also be a source of evolutionary change. Given these factors, what are we learning about their respective roles now that we can compare multiple primate genome sequences?

As we have pointed out repeatedly in this blog, the study of genetic influence on the brain is going to change our understanding of what a human is, how and why our thoughts are formed (and restricted) the way they are. This review surely puts the finger on the pulse and notes:

One of the most important findings to emerge from the latest human and primate genome-wide studies is that a fundamental assumption underlying this model has changed: the interspecies genomic changes are numerous and diverse, and, as a result, there appear to be many additional types of genomic mechanisms and features that could also be important to the evolution of lineage-specific traits. Given this new perspective, we now know that the degree of difference between our genome and that of the chimp depends on where, and how comprehensively, we look. The multitude of genomic differences that we now know exists should provide an abundance of fertile genomic ground from which important lineage-specific phenotypes, such as enhanced cognition, could have emerged. 

Here is the abstract:

The jewels of our genome: the search for the genomic changes underlying the evolutionary unique capacities of the human brain

James M. Sikela

The recent publication of the initial sequence and analysis of the chimp genome allows us, for the first time, to compare our genome with that of our closest living evolutionary relative. With more primate genome sequences being pursued, and with other genome-wide, cross-species comparative techniques emerging, we are entering an era in which we will be able to carry out genomic comparisons of unprecedented scope and detail. These studies should yield a bounty of new insights about the genes and genomic features that are unique to our species as well as those that are unique to other primate lineages, and may begin to causally link some of these to lineage-specific phenotypic characteristics. The most intriguing potential of these new approaches will be in the area of evolutionary neurogenomics and in the possibility that the key human lineage–specific (HLS) genomic changes that underlie the evolution of the human brain will be identified. Such new knowledge should provide fresh insights into neuronal development and higher cognitive function and dysfunction, and may possibly uncover biological mechanisms for information storage, analysis, and retrieval never previously seen.

-Thomas 

______________________________

John Hawks has a very good discussion about this article. 

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_blogmondaymorning.jpgUh, two paper reviews so close? Good thing there's an abundance of interesting stuff out there. Come to think of it, we could actually run paper reviews every day! Though it would take a lot of time gathering all items, it would certainly be possible. This highlights one of the shortcomings of this (or any) kind of communication: we can only tap into a minor part of all of what's going on. Show the tip of the iceberg, so to speak. Oh well, here goes:

The journal Biological Psychology runs a special issue this month on animal vs. human cognition. Articles include comparisons of hippocampal function, fear conditioning, and the influence of maternal programming on gene expression (!).

In Cognitive Neuropsychology Iftah Biran and colleagues propose a model for understanding alien hand syndrome, in which brain-damaged patients experience their limb performing seemingly purposeful acts without their intention. They suggest a three-factor model: 1) a disinhibited and reactive limb; 2) the limb is under less volitional control; and 3) the person has a relatively intact self-monitoring system. I think that one more level should be added, in between 2 and 3; i.e. 2½) the limb performs automatisms and other unconsciously controlled behaviours.

My story about the new way to use diffusion MRI to measure brain activation really spurred some activity web-wise. We got the number of visitors reaching an all-high with this post. Just a few links here, here, here and here just to mention a few. While at it, we should not forget another promising (and well known) fMRI method, perfusion fMRI (good page here). While this method still needs to be improved, e.g. in terms of signal intensity, it has the advantage over other methods such as BOLD, and now diffusion, fMRI in that it suffers from less susceptibility artefacts. This is a real advantage if you're studying areas close to air filled areas such as the nasal cavities. Areas such as the orbitofrontal cortex and medial temporal lobe (e.g. amygdala, hippocampus, perirhinal and entorhinal cortex, anterior fusiform gyrus and parahippocampal gyrus) are suffering from distortions during BOLD fMRI paradigms, and will do so using diffusion fMRI, too.

The obvious next step would be to compare all three methods, BOLD, diffusion and perfusion MRI, to get an estimate of the best sequences for different tasks. In addition, it could shed light on the workings of the brain, running all three paradigms on a specific cognitive task. By comparing to BOLD and perfusion fMRI we could learn more about the mechanisms behind diffusion MRI. Hm, maybe my next project?

 

I thought Martin was going to blog about this story (if he did, sorry for the duplicate): Svante Pääbo from the Max Planck Institute for Evolutionary Anthropology has sequenced the first nuclear DNA from a Neanderthal! A story in Nature covers it nicely. Should this project be successful, we should have plenty of studies comparing human and Neanderthal genes. As such, they are bound to have an impact on the way we understand our own species.

-Thomas 

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Yes, yes, it's all very embarassing, but I never got around to doing my Monday paper Survey. Sorry, folks. I've been busy getting people to commit to a book I'm editing, and I've been preparing a talk for this event. (If it so happens that you will be participating as well, please come by the Friday "aesthetics" session and say hi!) So, there…Luckily, Thomas has been posting some very nice stuff, giving us the greatest ever number of visitors this Thursday. He also wrote about the very intereting Science study indicating that bonobos and orangutangs may be able to think ahead. In the spirit of this post I thought I would do a themed Saturday Paper Survey to make up for my wrongs, focusing on work on mental time travel (MTT) – i.e., the ability to recall past events and plan ahead.

The major discussion point among researchers on MTT has been whether or not other animals than humans posses it. The best entry point to this discussion is Nicola Clayton et al.'s review paper in Nature Reviews Neuroscience that argues that food-caching birds do have some kind of MTT ability [link to paper here], and a paper in Trends in Cognitive Science by Thomas Suddendorf and Janie Busby that dismisses Clayton's arguments [link to paper]. A short debate between Clayton and colleagues and Suddendorf and Busby ensued [Clayton's letter; and Suddendorf and Busby's reply].

So what does the data say? Volume 36, issue 2 of the journal Learning and Memory is a great special issue on "cognitive time travel in people and animals". Clayton and Suddendorf both have contributed illuminating papers. There are a papers on rats, birds, and great apes, as well as some interesting papers on MTT mechanisms in humans. [Link to whole issue.]

Apart form the fascinating discussion of whether or not other animals share a MTT ability with us, much interest is naturally focused on what cognitive mechanisms actually underlie MTT. A recent study by Lesley Fellows and Martha Farah in Neuropsychologia suggests a dissociation of temporal discounting – a hotspot of current neuroeconomics research – and future time perspective. From the abstract: "The present study contrasted the effects of dorsolateral and ventromedial frontal lobe damage on two distinct aspects of future thinking in humans. Temporal discounting, the subjective devaluation of reward as a function of delay, is not affected by frontal lobe injury. In contrast, a normal future time perspective (a measure of the lenght of an individual's self-defined future) depends on the ventromedial, but not dorsolateral, frontal lobes." [Link to paper.]

-Martin

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Lebihan.gif

In a just published paper in PNAS by Le Bihan and colleagues, a technique called diffusion MRI is used to measure the activation of the brain. This is rather unusual. Diffusion MRI is normally used to measure the diffusion, or movement, of water in the brain. Grey matter is relatively disorganized and water is less restricted than in white matter, where myelinated fibres constrain the direction of molecular movements. This is illustrated by a figure that I have made for an upcoming Elsevier textbook (full size image opens in new window).

Using this method it is possible to map out the major fibre tracts in the brain. Even better, it is possible to do tractography: following the white matter fibre bundles from a seed point and calculate the physical connections from this (see figure below)

Le Bihan and colleagues takes diffusion MRI one step further by applying it to study the brain's activation! The background assumption is: as neurons get (relatively more) activated, a lot of physical movement occurs in and around the neurons. The neuron consumes more oxygen and nutrients; internally in the cell, a lot of movement of these substances, and the movement of signal substances occur, inaddition to energy distribution throughout the cell; and the whole cascade of neurotransmitter release and effects is due to movement across the synaptic cleft. So neural firing causes movement both inside and outside the cell.

Now, what did diffusion MRI do again? It measures the movement (!) of water molecules in the brain. As a brain region gets activated, molecules move relatively more than at rest. As a reult, it should be possible to measure brain activity by looking at where in the brain that molecule movement increases. This is exactly what Le Bihan and colleagues have done. And they provide neat results that it actually works! And, as they argue, diffusion fMRI is a more direct measure of neural activation than the more used BOLD fMRI, which is an index of a complex and delayed mechanism of relative blood oxygenation in regions of the brain.

What remains to find out is what the signal really represents. While it is thought that neuroimaning tools such as BOLD fMRI and EEG measures the activation and energy consumption in the dendrites, we know little about the underlying neural mechanism in diffusion fMRI. Could it be mostly due to movement across the synaptic cleft, and hence be a measure of action potentials; could it be due to movement within the cells; or due to transport of molecules (oxygen + nutrients) across the cell membrane; or all at once? Today, this is an open question. But the mere idea of having yet another MRI tool for measuring the brain's activation, and with good spatial resolution plus the promise of better temporal resolution, is really worth noticing.

We'll be tracking the development of this tool closely!

-Thomas

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Several studies today are looking at different changes in the brain structures in healthy vs. non-healthy development, and other brain diseases. In a study just published in the Journal of Neuroscience, David van Essen and colleagues studied the brains of people suffering from Williams syndrome, a rare genetic developmental order that is characterised by "a distinctive, "elfin" facial appearance, an unusually cheerful demeanor, ease with strangers, mental retardation coupled with an unusual facility with language, a love for music, cardiovascular problems such as supravalvular aortic stenosis, and transient hypercalcemia."

In this study, van Essen found that the brains of these people were different in 33 areas, and that there was a surprising bilateral symmetry to the differences from the control group. 16 changes in the left hemisphere was mirrored by 16 changes in the right hemisphere. In addition, hemispheric asymmetry of the temporal lobe was generally smaller in this group compared to controls.

Since Williams syndrome is caused by a deletion of material in region q11.2 of chromosome 7, we can speculate that these functions normally subserve both the development and function of these brain regions, in addition to an effect of strength of hemispheric specialization and lateralization. One interesting point is that the genes affected here produce diverse changes in the brain, not strictly following traditional cognitive-functional borders. Williams syndrome is not a brain-only disease, also affecting other somatic functions such as the cardiac system. One can only speculate at this point how many regions of chromosome 7 affects the brain, how many the cardiac system, and to what extent there is an overlap between gene-brain-body mapping.

Here is the abstract:

Van Essen D, Dierker D, Snyder A, Raichle ME, Reiss A, Korenberg J. Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses. The Journal of Neuroscience, May 17, 2006.

We analyzed folding abnormalities in the cerebral cortex of subjects with Williams syndrome (WS), a genetically based developmental disorder, using surface-based analyses applied to structural magnetic resonance imaging data. Surfaces generated from each individual hemisphere were registered to a common atlas target (the PALS-B12 atlas). Maps of sulcal depth (distance from the cerebral hull) were combined across individuals to generate maps of average sulcal depth for WS and control subjects, along with depth-difference maps and t-statistic maps that accounted for within-group variability. Significant structural abnormalities were identified in 33 locations, arranged as 16 bilaterally symmetric pairs plus a lateral temporal region in the right hemisphere. Discrete WS folding abnormalities extended across a broad swath from dorsoposterior to ventroanterior regions of each hemisphere, in cortical areas associated with multiple sensory modalities as well as regions implicated in cognitive and emotional behavior. Hemispheric asymmetry in the temporal cortex is reduced in WS compared with control subjects. These findings provide insights regarding possible developmental mechanisms that give rise to folding abnormalities and to the spectrum of behavioral characteristics associated with WS.

While discussing Williams syndrome, it is important to mention the work of Andreas Meyer-Lindenberg, who is doing an impressive amount of work on this rare disease, and reporting dazzling findings on the relationship between genes, brain and (social) behaviour.

-Thomas

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