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Archive for the ‘White matter’ Category

An historic find has occurred in the quest (gold-rush, if you will) to link genome variation with brain structure-function variation.  This is the publication of the very first genome-wide (GWAS) analysis of individual voxels (voxels are akin to pixels in a photograph, but are rather 3D cubes of brain-image-space about 1mm on each side) of brain structure – Voxelwise genome-wide association study (vGWAS) [doi: 10.1016/j.neuroimage.2010.02.032] by Jason Stein and colleagues under the leadership of Paul M. Thompson, a  leader in the area of neuroimaging and genetics – well-known for his work on brain structure in twin and psychiatric patient populations.

In an effort to discover genes that contribute to individual differences in brain structure, the authors took on the task of statistically analyzing the some 31,622 voxels (per brain) obtained from high-resolution structural brain scans; with 448,293 Illumina SNP genotypes (per person) with minor allele frequencies greater than 0.1 (common variants); in 740 unrelated healthy caucasian adults.  When performed on a voxel-by-voxel basis, this amounts to some 14 billion statistical tests.

Yikes!  A statistical nightmare with plenty of room for false positive results, not to mention the recent disillusionment with the common-variant GWAS approach?  Certainly.  The authors describe these pitfalls and other scenarios wherein false data is likely to arise and most of the paper addresses the pros and cons of different statistical analysis strategies – some which are prohibitive in their computational demands.  Undaunted, the authors describe several approaches for establishing appropriate thresholds and then utilize a ‘winner take all’ analysis strategy wherein a single ‘most-associated winning snp’ is identified for each voxel, which when clustered together in hot spots (at P = 2 x 10e-10), can point to specific brain areas of interest.

Using this analytical approach, the authors report that 8,212 snps were identified as ‘winning, most-associated’ snps across the 31,622 voxels.  They note that there was not as much symmetry with respect to winning snps in the left hemispere and corresponding areas in the right hemisphere, as one might have expected.  The 2 most significant snps across the entire brain and genome were rs2132683 and rs713155 which were associated with white matter near the left posterior lateral ventricle.  Other notable findings were rs2429582 in the synaptic (and possible autism risk factor) CADPS2 gene which was associated with temporal lobe structure and rs9990343 which sits in an intergenic region but is associated with frontal lobe structure.  These and several other notable snps are reported and brain maps are provided that show where in the brain each snp is associated.

As in most genome-wide studies, one can imagine that the authors were initially bewildered by their unexpected findings.  None of the ‘usual suspects’ such as neurotransmitter receptors, transcription factors, etc. etc. that dominate the psychiatric genetics literature.  Bewildered, perhaps, but maybe thats part of the fun and excitement of discovery!  Very exciting stuff to come I’ll bet as this new era unfolds!

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The A-to-T SNP rs7794745 in the CNTNAP2 gene was found to be associated with increased risk of autism (see Arking et al., 2008).  Specifically, the TT genotype, found in about 15% of individuals, increases these folks’ risk by about 1.2-1.7-fold.  Sure enough, when I checked my 23andMe profile, I found that I’m one of these TT risk-bearing individuals.  Interesting, although not alarming since me and my kids are beyond the age where one typically worries about autism.  Still, one can wonder if such a risk factor might have exerted some influence on the development of my brain?

The recent paper by Tan et al., “Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2” [doi:10.1016/j.neuroimage.2010.02.018 ] suggests there may be subtle, but still profound influences of the TT genotype on brain development in healthy individuals.  According to the authors, “homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation.”

The FA (fractional anisotropy – a measurement of white-matter or myelination) results are consistent with a role of CNTNAP2 in the establishment of synaptic contacts and other cell-cell contacts especially at Nodes of Ranvier – which are critical for proper function of white-matter tracts that support rapid, long-range neural transmission.  Indeed, more severe mutations in CNTNAP2  have been associated with cortical dysplasia and focal epilepsy (Strauss et al., 2006).

Subtle changes perhaps influencing long-range information flow in my brain – wow!

More on CNTNAP2 … its evolutionary history and role in language development.

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arinlloydCelebrities and politicians are known for their love of the spotlight.  “Me, me, me!”  are the words to get ahead by in our modern media circus.   As well, it can even be – in the unglamorous world of science – where, in characteristically geeky form, the conventional wisdom is to shout, “my hypothesis, my hypothesis, my hypothesis!”.  Once, for example, I had a grad school professor say she was not allowed by her department to teach about glial cells in her brain development class.  Another distinguished professor once told me, “don’t even bother sending a grant in,  if it is focused on white matter“.   No sir, it appears that modern neuroscience shall only focus on one main hypothesis – the neuron doctrine and not on the lowly support cells (astrocytes, oligodendrocytes & microglia) that, actually, make up more than 90% of the human brain.  Hmmm, who would have thought to find such a cult of neuronal celebrity in the halls of academia?

With this in mind, I really enjoyed the recent paper “Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions” [doi:10.1523/jneurosci.0324-09.2009] by Maezawa and colleagues.  The authors point out several critical gaps in the literature – namely that the expression of MeCP2 (the gene that, when mutated, gives rise to Rett syndrome) in neurons does NOT account for all of the many facets of the syndrome.  For example, when MeCP2 is deleted only in neurons (in a mouse model), it results in a milder form of abnormal neural development than when deleted in all CNS cell types ( the full mouse syndrome: stereotypic forelimb motions, tremor, motor and social behavioral abnormalities, seizures, hypoactivity, anxiety-like behavior and learning/memory deficits).  Also, it is not possible to reverse or rescue these deficits when a functional version of MeCP2 is expressed under a neuron-specific promoter.  However, when re-expressed under its endogenous promoter – it is possible to rescue the syndrome (free access article).

The authors thus looked much more closely at the expression of MeCP2 and found that they could indeed visualize the expression of the MeCP2 protein in cultured ASTROCYTES – who are a very, very important type of support cell (just think of the personal secretary Lloyd to Ari Gold on the TV show “Entourage”).  The team then examined how astrocytes that lack 80% of the expression of MeCP2 might interact with neurons – the very cells they normally support with secretions of growth factors and cytokines.   It turns out that both normal and MeCP2-deficient neurons do not thrive when co-cultured with astrocytes that have weak MeCP2 expression.   The team reports that dendritic length is reduced after a day and also a fews days of co-culture,  suggesting that the MeCP2-deficient astrocytes are failing to provide the proper trophic support for their neuronal celebrity counterparts.  Short dendrites are generally considered a bad-thing since this would predict poorer connectivity, and poorer cognition across the brain.

Hence, it seems that the lowly astrocyte is far more important in understanding what goes wrong in Rett syndrome.  Ironically, in this case however, the celebrity status of the neuron remains untarnished as astrocytes can now be blamed for the consequences of MeCP2 mutations.  The authors suggest that treatment of Rett syndrome via astrocytes is a worthwhile avenue of investigation.  This new direction in the search for a cure will be an exciting story to follow!

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One of the most well-studied genetic polymorphisms in the behavioral- psychiatric- cognitive-genetics area is the 5HTT-LPR, a short repeating sequence that mediates the transcriptional efficiency of the serotonin transporter.  Given the wide-ranging effects of 5HTT on the developing and mature nervous system, it is perhaps not surprising that variation in 5HTT levels can have wide-ranging effects on brain structure, function and behavior (see here and here for 2 of my own posts on this).  One of the latest findings has to do with the issue of  “functional connectivity” or the degree to which 2 separate brain regions co-activate and interact with each other – this type of functional interaction and integration of brain systems being a good thing.

Earlier studies have shown that individuals who carry the “short” allele at the 5HTT-LPR show less coupling of their frontal cortex (perigenual anterior cingulate cortex) with their amygdala – which perhaps indicates that their frontal cortex has a harder time regulating the amygdala.  This may be a mechanistic explanation for why such people have been found to be more prone to anxiety.  A new study by Pachecco et al., seems to support this mechanistic account –  however, they confirm the coupling model using a different neuroimaging modality – which makes the paper especially interesting.  In their article, “Frontal-Limbic White Matter Pathway Associations with the Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism” [doi: 10.1523/JNEUROSCI.0896-09.2009] use a method known as diffusion tensor imaging, a modality that is particularly sensitive to white matter tracts that are known to function as high-speed interlinks between disparate areas of the brain.  They find that a particular tract – the left frontal uncinate fasciculus – is differentially formed, and is less so, in carriers of the short allele.  The authors suggest that the association of the 5HTT-LPR with functional connectivity may be somewhat due to the white matter tracts that connect separate brain regions.  Interestingly, the finding was not seen in other white matter tracts (fasciculi) – which suggests that the genetic polymorphism is interacting with other – yet to be identified – factors (environment perhaps?) that lead to such a specific difference.

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Have you ever had your butt kicked by a 12-year old girl?  OK, maybe when you were an 8-year old boy perhaps – but I mean as a grown up.  Its a humbling experience.  I know.  For once back in college, I sat for a math contest and was amazed by a young girl who was able to answer each question more quickly and accurately than anyone else (other college students) in the room.

How did she do it?  What was different about her brain than mine (illicit substances aside)?  Now, as a parent of children who will, themselves, soon start sitting for exams and contests – wouldn’t I like to know.  Might I perchance endow my children with brain power?  Not likely I imagine, but what is brain power anyway? and what is it about the brain that makes some people perform better in general intelligence assessments?  In their new research article, Genetics of Brain Fiber Architecture and Intellectual Performance [doi: 10.1523/jneurosci.4184-08.2009], Paul Thompson’s team of neurobiologists explore this longstanding question.

In this article, the team asks whether the white matter of the brain (the glial cells that ensheath neuronal axons) might be both heritable and correlated with measures of intelligence.  To measure white matter integrity, the team uses an imaging method known as diffusion tensor imaging (DTI).  It has been shown previously that measures of intelligence are correlated with white matter integrity – presumably because white matter serves as a kind of insulation that speeds up the transmission of action potentials  and thus facilitates interhemispheric communication and other long-range forms of neural network processing.  The team found that white matter integrity was correlated with performance on intelligence assessments in brain regions such as the cingulum, callosal isthmus, corona radiata, internal capsule and other regions.  By imaging 23 pairs of identical and 23 pairs of fraternal twins, the team also found many regions in the brain where white matter integrity was under more than 50% genetic control – particularly in the parietal lobe.  Lastly, the team found that in many of these regions, the correlation between white matter integrity and intelligence could be explained by the same genes.

Amazing research findings indeed, that points to where in the brain and what type of physiological processes are related to efficient brain function.

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An image illustrating the density of astrocyte...Image via Wikipedia James Schummers, Hongbo Yu and Mriganka Sur present their measurements of Ca++ dynamics in response to visual stimuli in the awake ferret and reveal highly refined patterns of astrocyte activity in their paper, “Tuned Responses of Astrocytes and Their Influence on Hemodynamic Signals in the Visual Cortex” (DOI: 10.1126/science.1156120). The genetic regulation of neurovascular coupling is key to understanding the way in which genetic variation may regulate brain function (or at least function as measured by the BOLD response). A closer look at BOLD response and genetic pathways that mediate astrocyte function would be music to my ears – or at least my auditory cortex astocytes.Related articles by Zemanta

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Red = oxygenated  Blue = d...Image via Wikipedia Brain images with red and yellow splotches of activity are now ubiquitous in the psychology literature and well on their way, via neuromarketing, to bamboozling consumers everywhere (eg. this splotch shows that 2/3 people really do prefer Pepsi !). When inappropriately used, fMRI methods can devolve quickly into a high-tech form of phrenology with concomitant hucksters (not unlike recent reports of consumer fraud in genetic testing) and, despite its ubiquity and potentcy as a research tool, the molecular basis for the fMRI signal has remained somewhat mysterious. Generally, when neurons fire, local blood-flow increases and the paramagnetic form of deoxyhemoglobin can be distinguished from the nonmagnetic oxygenated form using the electromagnetic scannner. Hence, splotches that indicate more blood flow (or Brain Oxygen Level Dependent – BOLD reponse) can be a proxy for neural activity. The connection between neuronal firing and blood flow, however, is not necessarily simple nor easily ignored. Amazingly, a recent report from Takano and colleagues, “Astrocyte-mediated control of cerebral blood flow(DOI) shows that a single master regulatory gene, cyclooxygenase-1 (COX-1) is sufficient to regulate blood flow in response to neural activity. Takano and a team led by Maiken Nedergaard show that astrocytes have their hands wrapped around neural synsapses and their feet wrapped around capillaries. When the astrocytes sense synaptic firing (glutamate spillover) they signal to the capillaries and contractile pericyte cells to relax and vasodilate. Using a series of pharmacologic blockers, the team tested a number of candidate regulatory pathways and found that only COX-1 blockade affected vasodilation in response to neural activity. The work of this research team greatly improves the understanding of the fMRI method and provides a well constrained framework through which to understand fMRI data and, moreover, the interplay between brain imaging and genetic data. Hopefully the basic research will stay one step ahead of the hucksters.

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