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Posts Tagged ‘Twin’

Genetics is a lot like politics.  Mainly, a whole lotta fuss about sex & selfishness.  Take it from the Economist:

“Deciding whether or not to be part of a particular group, whom else to admit to your group, how to keep or share resources, and how much sexual freedom to afford oneself, one’s neighbors and one’s children are all, and always have been, lively matters of political debate.  But they are also matters that have an impact on the crucial Darwinian business of getting genes into the next generation.”

thanks Amanda-Edwards for the pic

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If I pay to have my house fire-proofed, it creates a free economic benefit for my next-door neighbors.  If I smoke and barbecue all day long, the smoke creates an economic risk or cost for those same folks.  These are examples of what economists call “externalities … a cost or benefit, not transmitted through prices, incurred by a party who did not agree to the action“.

So, what happens if I publish my genome sequence online … does anyone else get a benefit? or incur a cost?  My children?  My siblings?  What if I were an identical twin?

Do twins favor being more similar? … in which case, maybe, they might see positive externalities?

Are the epigenomes of identical twins similar?

How does your genome influence your economic behavior?

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Television icons
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just a pointer to a great SciVee episodeGenetic Contribution To Variation In Cognitive Function In Twins

Their data suggest that genetic influences on cognitive function act outside of the brain areas most commonly activated during cognitive tasks.  The areas where genes seem to exert influence on brain activity are quite variable from person to person (which is why they don’t show up in group-level analyses).  Thus folks with different genetic variability use slightly different brain areas to accomplish the same cognitive task.

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Twin studies have long suggested that genetic variation is a part of healthy and disordered mental life.  The problem however – some 10 years now since the full genome sequence era began – has been finding the actual genes that account for this heritability.

It sounds simple on paper – just collect lots of folks with disorder X and look at their genomes in reference to a demographically matched healthy control population.  Voila! whatever is different is a candidate for genetic risk.  Apparently, not so.

The missing heritability problem that clouds the birth of the personal genomes era refers to the baffling inability to find enough common genetic variants that can account for the genetic risk of an illness or disorder.

There are any number of reasons for this … (i) even as any given MZ and DZ twin pair shares genetic variants that predispose them toward the similar brains and mental states, it may be the case that different MZ and DZ pairs have different types of rare genetic variation thus diluting out any similar patterns of variation when large pools of cases and controls are compared …  (ii) also, the way that the environment interacts with common risk-promoting genetic variation may be quite different from person to person – making it hard to find variation that is similarly risk-promoting in large pools of cases and controls … and many others I’m sure.

One research group recently asked whether the type of common genetic variation(SNP vs. CNV) might inform the search for the missing heritability.  The authors of the recent paper, “Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls” [doi:10.1038/nature08979] looked at an alternative to the usual SNP markers – so called common copy number variants (CNVs) – and asked if these markers might provide a stronger accounting for genetic risk.  While a number of previous papers in the mental health field have indeed shown associations with CNVs, this massive study (some 3,432 CNV probes in 2000 or so cases and 3000 controls) did not reveal an association with bipolar disorder.  Furthermore, the team reports that common CNV variants are already in fairly strong linkage disequilibrium with common SNPs and so perhaps may not have reached any farther into the abyss of rare genetic variation than previous GWAS studies.

Disappointing perhaps, but a big step forward nonetheless!  What will the personal genomes era look like if we all have different forms of rare genetic variation?

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Church Steeple
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Humans are spiritual creatures – there’s no denyin’.  How & why we got this way is one of THE BIG questions of all time.  Since our genome shapes the development of our brain and its interaction with our culture, its not a surprise to see that, from time to time, folks will look for and find genetic links to various forms of spiritual and religious behavior.  Here’s a recent paper from Kenneth Kendler’s research team at the Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine entitled, “A Developmental Twin Study of Church Attendance and Alcohol and Nicotine Consumption: A Model for Analyzing the Changing Impact of Genes and Environment” [link to abstract].  An analysis of more than 700 pairs of twins found that the correlation between alcohol and nicotine consumption and church attendance (more church predicts less smokin’ and drinkin’) is more than 50% influenced by genetic factors – in adults.  In children and teens, the genetic contribution to the correlation is much less and the strength of the correlation stems more from shared environmental factors (parents, school etc.).  Is there a gene for going to church? Nope.  Are there genes that shape a person’s inclination toward novelty or conscientiousness? More likely so.  Are they distributed across all races and cultures? Yep.  Lots to ponder next Sunday morning.

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Just a pointer to onetime University of Edinburgh Professor C.H. Waddington’s 1972 Gifford Lecture on framing the genes vs. environment debate of human behavior.  Although Waddington is famous for his work on population genetics and evolutionary change over time, several of his concepts are experiencing some resurgence in the neuroimaging and psychological development literatures these days.

One term, CHREOD, combines the Greek word for “determined” or “necessary” and the word for “pathway.” It describes a system that returns to a steady trajectory in contrast to homeostasis which describes a system which returns to a steady state.  Recent reviews on the development of brain structure have suggested that the “trajectory” (the actual term “chreod” hasn’t survived) as opposed to any specific time point is the essential phenotype to use for understanding how genes relate to psychological development.  Another term, CANALIZATION, refers to the ability of a population to produce the same phenotype regardless of variability in its environment or genotype.  A recent neonatal twin study found that the heritability of grey matter in neonatal humans was rather low.  However it seems to then rise until young adulthood – as genetic programs presumably kick-in – and then decline again.  Articles by neurobiologist Jay N. Giedd and colleagues have suggested that this may reflect Waddington’s idea of canalization.  The relative influence of genes vs. environment may change over time in ways that perhaps buffer against mutations and/or environmental insults to ensure the stability and robustness of functions and processes that are both appropriate for survival and necessary for future development.  Another Waddington term, EPIGENETIC LANDSCAPE, refers to the limitations on how much influence genes and environment can have on the development of a given cell or structure.  Certainly the environment can alter the differentiation, migration, connectivity, etc. of neurons by only so much.  Likewise, most genetic mutations have effects that are constrained or compensated for by the larger system as well.

Its amazing to me how well these evolutionary genetic concepts capture the issues at the nexus of of genetics and cognitive development.  From his lecture, it is clear that Waddington was not unaware of this.  Amazing to see a conceptual roadmap laid out so long ago.  Digging the book cover art as well!

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We hope, that you choke, that you choke.
Image by Corrie… via Flickr

Coping with fear and anxiety is difficult.  At times when one’s life, livelihood or loved one’s are threatened, we naturally hightenen our senses and allocate our emotional and physical resources for conflict.  At times, when all is well, and resources, relationships and relaxation time are plentiful, we should unwind and and enjoy the moment.  But most of us don’t.  Our prized cognitive abilities to remember, relive and ruminate on the bad stuff out there are just too well developed – and we suffer – some more than others  (see Robert Saplosky’s book “Why Zebras Don’t Get Ulcers” and related video lecture (hint – they don’t get ulcers because they don’t have the cognitive ability to ruminate on past events).  Such may be the flip side to our (homo sapiens) super-duper cognitive abilities.

Nevertheless, we try to understand our fears and axieties and understand their bio-social-psychological bases. A recent paper entitled, “A Genetically Informed Study of the Association Between Childhood Separation Anxiety, Sensitivity to CO2, Panic Disorder, and the Effect of Childhood Parental Loss” by Battaglia et al. [Arch Gen Psychiatry. 2009;66(1):64-71] brought to mind many of the complexities in beginning to understand the way in which some individuals come to suffer more emotional anguish than others.  The research team addressed a set of emotional difficulties that have been categorized by psychiatrists as “panic disorder” and involving sudden attacks of fear, sweating, racing heart, shortness of breath, etc. which can begin to occur in early adulthood.

Right off the bat, it seems that one of the difficulties in understanding such an emotional state(s) are the conventions (important for $$ billing purposes) used to describe the relationship between “healthy” and “illness” or “disorder”.  I mean, honestly, who hasn’t experienced what could be described as a mild panic disorder once or twice?  I have, but perhaps that doesn’t amount to a disorder.  A good read on the conflation of normal stress responses and disordered mental states is “Transforming Normality into Pathology: The DSM and the Outcomes of Stressful Social Arrangements” by Allan V. Horwitz.

Another difficulty in understanding how and why someone might experience such a condition has to do with the complexities of their childhood experience (not to mention genes). Child development and mental health are inextrictably related, yet, the relationship is hard to understand.  Certainly, the function of the adult brain is the product of countless developmental unfoldings that build upon one another, and certainly there is ample evidence that when healthy development is disrupted in a social or physical way, the consequences can be very unfortunate and long-lasting. Yet, our ability to make sense of how and why an individual is having mental and/or emotional difficulty is limited.  Its a complex, interactive and emergent set of processes.

What I liked about the Battaglia et al., article was the way in which they acknowledged all of these complexities and – using a multivariate twin study design – tried to objectively measure the effects of genes and environment (early and late) as well as candidate biological pathways (sensitivity to carbon dioxide).  The team gathered 346 twin pairs (equal mix of MZ and DZ) and assessed aspects of early and late emotional life as well as the sensitivity to the inhalation of 35% CO2 (kind of feels like suffocating and is known to activate fear circuitry perhaps via the ASC1a gene).   The basic notion was to parcel out the correlations between early emotional distress and adult emotional distress as well as with a very specific physiological response (fear illicited by breathing CO2).  If there were no correlation or covariation between early and late distress (or the physiological response) then perhaps these processes are not underlain by any common mechanism.

However, the team found that there was covariation between early life emotion (criteria for separation anxiety disorder) and adult emotion (panic disorder) as well as the physiological/fear response illicited by CO2.  Indeed there seems to be a common, or continuous, set of processes whose disruption early in development can manifest as emotional difficulty later in development.  Furthermore, the team suggests that the underlying unifying or core process is heavily regulated by a set of additive genetic factors.  Lastly, the team finds that the experience of parental loss in childhood increased (but not via an interaction with genetic variation) the strength of the covariation between early emotion, late emotion and CO2 reactivity.  The authors note several limitations and cautions to over-interpreting these data – which are from the largest such study of its kind to date.

For individuals who are tangled in persistent ruminations and emotional difficulties, I don’t know if these findings help.  They seem to bear out some of the cold, cruel logic of life and evolution – that our fear systems are great at keeping us alive when we’ve had adverse experience in childhood, but not necessarily happy.  On the other hand, the covariation is weak, so there is no such destiny in life, even when dealt unfortunate early experience AND genetic risk.  I hope that learning about the science might help folks cope with such cases of emotional distress.

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Last year I dug a bit into the area of epigenetics (indexed here) and learned that the methylation (CH3) and acetylation (OCCH3) of genomic DNA & histones, respectively, can have dramatic effects on the structure of DNA and its accessibility to transcription factors – and hence – gene expression.  Many of the papers I covered suggested that the environment can influence the degree to which these so-called “epigenetic marks” are covalently bonded onto the genome during early development.  Thus, the thinking goes, the early environment can modulate gene expression in ways that are long-lasting – even transgenerational.  The idea is a powerful one to be sure.  And a scary one as well, as parents who read this literature, may fret that their children (and grandchildren) can be epigenetically scarred by early nutritional, physical and/or psycho-social stress.  I must admit that, as a parent of young children myself, I began to wonder if I might be negatively influencing the epigenome of my children.

I’m wondering how much physical and/or social stress is enough to cause changes in the epigenome?  Does the concern about epigenetics only apply to exposure to severe stress?  or run of the mill forms of stress?  How much do we know about this?

This year, I hope to explore this line of inquiry further.  For starters, I came across a fantastic paper by Fraga et al., entitled, “Epigenetic differences arise during the lifetime of monozygotic twins” [doi:10.1073/pnas.0500398102].   The group carries out a remarkably straightforward and time honored approach – a twin study – to ask how much identical twins differ at the epigenetic level.  Since identical twins have the same genome sequence, any differences in their physiology, behavior etc. are, strictly speaking, due to the way in which the environment (from the uterus to adulthood) shapes their development.  Hence, the team of Fraga et al., can compare the amount and location of methyl (CH3) and acetyl (OCCH3) groups to see whether the environment has differentially shaped the epigenome.

An analysis of some 40 identical twin pairs from ages 3-74 years old showed that – YES – the environment, over time, does seem to shape the epigenome (in this case of lymphocytes).  The most compelling evidence for me was seen in Figure 4 where the team used a method known as Restriction Landmark Genomic Scanning (RLGS) to compare patterns of methylation in a genome-wide manner.  Using this analysis, the team found that older twin pairs had about 2.5 times as many differences as did the epigenomes of the youngest twin pairs.  These methylation differences also correlated with gene expression differences (older pairs also had more gene expression differences) and they found that the individual who showed the lowest levels of methylation also had the highest levels of gene expression.  Furthermore, the team finds that twin pairs who lived apart and had more differences in life history were more likely to have epigenetic differences.  Finally, measures of histone acetylation seemed consistent with the gradient of epigenetic change over time and life-history distance.

Thus it seems that, as everyday life progresses, the epigenome changes too.  So, perhaps, one does not need extreme forms of stress to leave long-lasting epigenetic marks on the genome?  Is this true during early life (where the team did not see many differences between pairs)?  and in the brain (the team focused mainly on lymphocytes)?  Are the differences between twins due to the creation of new environmentally-mediated marks or the faulty passage of existing marks from dividing cell-to-cell over time?  Will be fun to seek out information on this.

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Surgeon holding scalpel.
Image by bethd821 via Flickr

Whether you are a carpenter, plumber, mechanic, electrician, surgeon or chef, your livelihood depends on a set of sturdy, reliable, well-honed, precision tools.  Similarly, neuroscientists depend on their electrodes, brain scanners, microscopes and more recently their genome sequencers.  This is because they are not just trying to dissect the brain – the physical organ – but also the psychological one.  As the billions of neurons connected by trillions of synapses process electrical impulses – a kind of neural information – it is the great endeavor of cognitive-molecular-neuro-psychology (or whatever you wish to call the art) to figure out how all of those neurons and connections come into being and how they process information in ways that lead to your personality, self-image, hopes, dreams, memories and the other wonderful aspects of your mental life.  How and why does information flow through the brain in the way it does? and how and why does it do so in different ways for different people? Some, for instance, have informally related Sigmund Freud‘s models of mental structure to a kind of plumbing wherein psychic energy was routed (or misrouted) through different structural aspects of the mind (pipes as it were).  Perhaps such a model was fitting for the great industrial era in which he lived – but perhaps not in today’s highly information-based, inter-connected and network-oriented era.  If our understanding of mental life is a product of our tools, then perhaps we should be sure that our modern tools are up to the job.

One recent paper reminded me of how important it is to double check the accuracy and precision of one’s tools was the research article, “Quantifying the heritability of task-related brain activation and performance during the N-back working memory task: A twin fMRI study” [doi:10.1016/j.biopsycho.2008.03.006] by Blokland et al..  In this report, the team summarizes the results of measurments of the brain activity – not structure – but rather activity as measured by their chosen tool, the MRI scanner.  This research team, based in UCLA and known as one of the best in the field, asks whether the so-called BOLD response (an indirect measure of neural activity) shows greater concordance in identical (monozygotic) vs. fraternal (dizygotic) twins.  To generate brain activity, the research team asked the subjects to perform a task called an N-back  workng memory task, which entails having to remember something that happend “N” times ago (click here for further explanation of N-back task or play it on your iphone).  If you’ve done this, you’ll know that its hard – maddeningly so – and it requires a lot of concentration, which, the researchers were counting on to generate activity in the prefrontal cortex.

After looking at the brain activity patterns of some 29 MZ pairs and 31 DZ pairs, the team asked if the patterns of brain activity in the lateral frontal cortex were more similar in the MZ pairs vs. the DZ pairs.  If so, then it would suggest that the scanning technology (measurement of the BOLD response) is sufficiently reliable and precise enough to detect the fraction of individual differences in brain activty that arise from additive genetic variation.  If one actually had such super-precise tool, then one could begin to dissect and tease apart aspects of human cognition that are regulated by individual genetic variation – a very super-precise and amazing tool – that might allow us to understand mental life in biologically-based terms (and not Freud’s plumbingesque analogies).  If only such a tool existed! Somewhat amazingly, the scanning tools did seem to be able to detect differences between the BOLD response correlations of MZ pairs vs. DZ pairs.  The BOLD response correlations were greater for MZ vs. DZ in the middle frontal gyrus, angular gyrus, supramarginal gyrus when activity for the 2-back task was compared to the 0-back task.  The team were cautious to extend these findings too far, since the standard deviations are large and the estimates of heritability for the BOLD response are rather low (11-36%), but, overall, the team suggests that the ability to use the fMRI methods in conjunction with genetic markers shows future promise.

Meanwhile, the literature of so-called “imaging-genetic” findings begins to grow in the literature.  I hope the tools are reliable and trustworthy enough to justify conclusions and lessons about human genetic variation and its role in mental life.  Will certainly keep this cautionary report in mind as I report on the cognitive genetics literature in the future.

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morph_slicer_demoThe brain is a wonderfully weird and strange organ to behold.  Its twists and folds, magnificent, in and of themselves, are even moreso when we contemplate that the very emotional experience of such beauty is carried out within the very folds.  Now consider the possibility of integrating these beauteous structure/function relationships with human history – via the human genome – and ask yourself if this seems like fun.  If so, check out the recent paper, “Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study” [doi:10.1016/j.neuroimage.2009.09.043].

Here the research team – members of the Biomedical Informatics research Network – have carried out the largest and most comprehensive known twin study of brain structure.  By performing structural brain imaging on 404 male twin pairs (important to note here that the field still awaits a comparable female study), the team examined the differences in identical (MZ) vs. fraternal (DZ) pair correlations of the structure of some 96 different brain regions.  The authors now provide an updated structural brain map showing what structures are more or less influenced by genes vs. environment. Some of the highlights from the paper are that genes accounted for about 70% of overall brain volume, while in the cortex, genes accounted for only about 45% of cortical thickness.  Much of the environmental effects were found to be non-shared, suggesting, as expected, that individual experience can have strong effects on brain structure.  The left and right putamen showed the highest additive genetic influence, while the cingulate and temporal cortices showed rather low additive genetic influences (below 50%).

If you would like to play around with a free brain structure visualization tool, check out Slicer 3D, which can be obtained from the BIRN homepage or directly here.  I had fun this morning digitally slicing and dicing grey matter from ventricles and blood vessels.

slicer

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Human Genome
Image by Dollar Bin via Flickr

pointer to: download Power Point presentation hosted on the HUGO website entitled, “From the human genome to human behaviour: how far have we travelled?” (both English and Russian text) – by Ian Craig and Nick Yankovsky, Education Council Human Genome Organisation.

Covers recent findings on MAOA and 5HTT several and others also covered here.

Congrats to Hsien on the new position!

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Genetic Data
Image by giumaiolini via Flickr

As the personal genomics era dawns, it becomes clear that the new genetic information will lead to more new questions than answers.  Consider a well-intentioned parent who finds any number of suspicious risk factors in the genome of their child.  Perhaps a genetic risk variant for mental illness – an anxiety disorder perhaps?  What can be done?  What, if anything, should be done?

Of course there is no simple answer to this question.  Nevertheless, the technology itself may create strong demand for answers in the near future.  If it were me, I certainly would want to know – something, anything – to help.  Furthermore, there are already examples of willful misinformation in the consumer genetic marketplace that seem to prey on anxieties of parents, and which could ultimately heighten the need for reliable, evidence-based guidance.

To this end, the recent research article entitled, “A Genetically Informed Study of the Association Between Childhood Separation Anxiety, Sensitivity to CO2, Panic Disorder, and the Effect of Childhood Parental Loss“[Arch Gen Psychiatry. 2009;66(1):64-71], caught my attention. In this article, the authors consider Panic Disorder, a condition which can lead to the disruption of a healthy personal and professional life.  Genetic studies have shown that specific genes can contribute to the risk of the disorder, but also that these genes interact with early life and adult life experience.  What might these genes be doing in early life – and if we knew – then might we intervene early on to prevent the onset of the disorder later in life?

Again, there are more questions than answers here, but the research team of Battaglia et al., show – using 712 young adult twins – that a common genetic factor underlies childhood separation anxiety and the adult onset of panic disorder.  Thus, it may be the case that the sames genes that contribute to the risk of panic disorder, also may contribute to a form of childhood anxiety.  Having found evidence for a particular form of developmental continuity, the research team is one step closer to learning how a genomically-guided child-based early intervention might be structured.

Because there are many pathways that can lead to mental illness and many ways in which the genome interacts with the environment – it will be complex, if not impossible, to design early interventions that prevent the onset of mental illness.  In most cases, it is rather likely that most children who carry risk for mental illness, will – due to the probablistic nature of gene-gene and gene-environment interactions – just develop typically and not develop mental illness.  Neverthess, some will and its worth learning more.

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Binocular Smile
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Is the human brain a blank slate? or a pre-programmed machine that is ready to take the S.A.T.s right out of the box? Obviously neither, or both as it were. Some have gingerly waded into the nature vs. nuture debate and suggested that the human brain comes pre-wired to receive certain experiences – experience expectant – and thus acknowledge the importance of natural selection in shaping an organism via heritable factors but also the need to be able to use the brain to learn from experience and adapt on the fly.

In their paper entitled, “Nature versus Nurture in Ventral Visual Cortex: A Functional Magnetic Resonance Imaging Study of Twins [DOI:10.1523/JNEUROSCI.4001-07.2007] Thad Polk and colleagues provide a wonderful example of this.  The team suggested that the brain (visual system) should be somewhat innately (genomically if you will) prepared to process visual stimuli such as faces and objects, but not so for stimuli such as pseudo words.  They proposed to test the role of the genome by comparing patterns of brain activity in identical vs. fraternal twins.  If the brain activity patterns were very similar for identical twins, and less so for fraternal twins, then it is likely that the genome plays some role in the generation of brain (at least with respect to blood flow) responses to such stimuli. The team used fMRI to assess 13 pairs of identical twins and 11 pairs of fraternal twins for their brain responses to pictures of faces, houses, chairs and non-word strings on letters as well as control “scrambled” images that were comparable in visuo-spatial frequency.

Interestingly, the team found that for faces and houses, there were significant identical vs. fraternal differences in the “activation maps” of the twins but no such differences for chairs and pseudowords.  Thus it seems that the genome plays a role in the way the brain processes faces and houses (or perhaps faces and places in general), but not so much for items that are not found (or weren’t found by our evolutionary ancestors) in a natural setting.

I’m surprised by the chair result … although perhaps being a couch potato is something evolution does not select for.

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facial expressions
Image by ibiscus27 via Flickr

One of the difficulties in understanding mental illness is that so many aspects of mental life can go awry – and its a challenge to understand what abnormalities are directly linked to causes and what abnormalities might be consequences or later ripples in a chain reaction of neural breakdown.  Ideally, one would prefer to treat the fundamental cause, rather than only offer palliative measures for symptoms that arise from tertiary neural inefficiencies. In their research article entitled, “Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk“, [doi: 10.1176/appi.ajp.2008.08020261] (audio link) Rasetti and colleagues explore this issue.

Specifically, they focus on the function of the amygdala and its role in responding to, and processing, social and emotional information.  In schizophrenia, it has been found that this brain region can be somewhat unresponsive when viewing faces displaying fearful expressions – and so, the authors ask whether the response of the amygdala to fearful faces is, itself, an aspect of the disorder that can be linked to underlying genetic risk (a type of core, fundamental cause).

To do this, the research team assembled 3 groups of participants: 34 patients, 29 of their unaffected siblings and 20 demographically and ethnically matched control subjects.  The rationale was that if a trait – such as amygdala response – was similar for the patient/sibling comparison and dissimilar for the patient/control comparison, then one can conclude that the similarity is underlain by the similarity or shared genetic background of the patients and their siblings.  When the research team colected brain activity data in response to a facial expression matching task performed in an MRI scanner, they found that the patient/sibling comparison was not-similar, but rather the siblings were more similar to healthy controls instead of their siblings.  This suggests that the trait (amygdala response) is not likely to be directly related to core genetic risk factor(s) of schizophrenia, but rather related to apsects of the disorder that are consequences, or the state, of having the disorder.

A follow-up study using a different trait (prefrontal cortex activity during a working memory task) showed that this trait was similar for the patient/sibling contrast, but dissimilar for the patient/control contrast – suggesting that prefrontal cortex function IS somewhat linked to core genetic risk.  Congratulations to the authors on this very informative study!

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English: Visualization of a DTI measurement of...
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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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PhotoImage via Wikipedia Like most parents, I enjoy watching my children develop and marvel at the many similarities they bear to myself and my wife. The reshuffling of physical and behavioral features is always a topic of discussion and is the definitive icebreaker during uncomfortable silences with the inlaws. In some cases, the children are blessed with the better traits, but in other cases, there’s no option but to cringe when, “Look – wow, he really has your nose – hmmm”, is muttered. Most interesting, is the unfolding of patterns of behavior that unfold slowly with age. Differences in temperament and personality can instill great pride in parents but also can be a grating source of friction. One of my F1’s has recently taken to sessions of shrill, spine rattling, screaming which I hope will pass soon.

Why ? Many parents ask. “Have WE been raising him/her to do this ? – surely that’s what the neighbors must think”. “Is it something in the family ? I heard Aunt Marie was a bit of a screamer as a child – hmmm.”

In one of several of their landmark studies on the genetic regulation of pediatric brain development, Jay Giedd and colleagues, now provide in their recent paper, “Variance Decomposition of MRI-Based Covariance Maps Using Genetically-Informative Samples and Structural Equation Modeling”, a core framework on the relative contribution of genes vs. environment for the developing cortex. The paper is part of an ongoing longitudinal study of pediatric brain development at the Child Psychiatry branch at NIMH. Some 600 children participated – including identical twins, fraternal twins, siblings and singleton children.

The team used an analytical approach known as MACAAC (Mapping Anatomical Correlations Across the Cerebral Cortex) to ask how much does the variation in a single part of the brain co-vary with other parts ? Then the team used structural equation modeling to explore how much this co-variation might differ across identical twins vs. fraternal vs. siblings vs. age-matched singleton children. In locations where there is an high genetic contribution to co-variation in cortical thickness, identical twins should co-vary more tightly than fraternal twins or siblings etc. In this way, the team were able to parse out the relative influence of genes vs. environment to the developing brain.

In general terms, the team reports that a single genetic factor accounts for the majority of variation in cortical thickness, which they note may be consistent with a major mechanism of development of cortical layers involving the migration of neurons along radial glia. Genetic co-variances across separate locations in the brain were highest in the frontal cortex, middle temporal gyrus and left supramarginal gyrus. Interestingly, when environmental covariations were observed, they were usually restricted to just one hemisphere, while genetic covariations were often observed bilaterally.

Figure 5 of this paper is really incredible, it shows which areas of the cortex are more influenced by genes vs. environment. If I can just find the areas involved in screaming, the next time one of my neighbors looks askance at my F1, I’ll be able to explain.

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Example of a subject in a Ganzfeld experiment.Image via Wikipedia Mind reading, telepathy, clairvoyance, precognition ? Not possible you say ? Or perhaps misunderstood ? You may once have had a premonition or a feeling and later been surprised to find that it coincided with an actual event. Once, for example, when I was 15, my pal and I absconded with his mother’s car for a late night joyride – mortifyingly resulting in a dented front fender and busted radiator. Upon return, we were greeted in the driveway by his disconcerted mom who had apparently woken from a nightmare involving her son in a car crash. Boy, did HE ever get it !! and by ‘it’, I don’t mean a lecture on parapsychology. While many scientists may dismiss parapsychology research as quackery akin to Bill Murray in Ghost Busters, Samuel T. Moulton and Stephen M. Kosslyn of Harvard University provide an interesting update on current research in this field (you can get a copy of the paper by email) entitled, “Using Neuroimaging to Resolve the Psi Debate” (Journal of Cognitive Neuroscience (2008) 20:182-192). Because accounts of paranormal events often involve closely related or emotionally close individuals, Moulton and Kosslyn invited identical twins and family members to participate. So-called ‘senders’ were instructed to ‘transmit’ information regarding a specific visual stimulus while ‘receivers’ were instructed to chose between a matching and non-matiching stimulus while laying in an MRI scanner. Not surprisingly, receivers were no more accurate than if they were choosing at random (out of 3,687 responses, the correct matching response was chosen 1842 times (49.99% accuracy) and no significant differences were observed in brain activation in receivers when senders were sending matching visual images. Professor Kosslyn is highly regarded as an expert in visual imagery and so this particular team is well suited to interpret the findings. As the paper inevitably shows however, no evidence of brain activity was found to support telepathy, clairvoyance or precognition. My own extra sensory perception tells me that this is not likely to be the last word in this area of research.

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Comparison of zygote development in monozygoti...Image via Wikipedia Twin studies are oft used to gauge the role of the genome in behavioral science. A recent report, “Nature versus Nurture in Ventral Visual Cortex: A Functional Magnetic Resonance Imaging Study of Twins” by Polk et al., (DOI) shows that brain activity during early stages of visual processing is more similar in twins vs. unrelated subjects across several object categories such as faces, houses, pseudowords and a control category consisting of -ok- chairs? When the brain activity of identical vs. fraternal twins was examined, the activity associated with faces showed the greatest difference in similarity of activity compared to other categories. Its always fun to speculate about why the genome might weigh-in more heavily when it comes to face processing – certainly an important skill for our primate order.

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Brad carves the turkey
Image by Salim Virji via Flickr

It has long been known that complex neuropsychiatric and neurodevelopmental illnesses have familial patterns of inheritance and that concordance in identical twins is greater than in fraternal twins. The genetic influences of mental illness – whilst apparent – do not, however, provide clues about which genes, of the 20,000 or so to choose from, confer risk. Hallucinations, mania, mood-swings, paranoia, disorganized thinking – to describe some of the difficulties that patients experience – do not immediately suggest specific candidate molecules. In an effort then, to pinpoint the specific neural processes that go awry in one particular complex mental illness, the The Consortium on the Genetics of Schizophrenia has published a landmark analysis of 183 nuclear families consisting of affected and unaffected siblings to address this problem. In their paper, “Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia” (Arch Gen Psychiatry. 2007;64(11):1242-1250) the team examine so-called endophenotypes, often consisting of cognitive assessments designed to engage discrete, anatomically characterized neural networks in order to zero-in on where in the brain the genetic risk exerts an effect. The critical point the authors make is that these endophenotypes must be shown to be reliable, stable, and, most importantly, heritable. In other words, while many neural proceeses may go awry in schizophrenia, not all of these processes will have been influenced by genetic factors. Hence the analogy to carving up the complex system (turkey) along the proper genetic lines (joints). Their analysis showed that a great many of their candidate endophenotypes are indeed heritable, such as pre-pulse inhibition of the startle response, the antisaccade task for eye movements, Continuous Performance Test, California Verbal Learning Test, Letter-Number Sequencing test, Abstraction and Mental Flexibility, Face Memory, Spatial Memory, Spatial Processing, Sensorimotor Dexterity, and Emotion Recognition. Other processes such as suppression of the P50 ERP was not found to be heritable, and thus may not be a process that is affected by genetic risk. Interestingly, as reported by the authors, “The genetic correlations observed between the CVLT and LNS, between Abstraction and Mental Flexibility and Spatial Memory, and between Spatial Processing and the antisaccade task, CPT, LNS, and Abstraction and Mental Flexibility were significant at the P .001 level and remained significant after correction for multiple testing. These results suggest that overlapping genetic architecture (pleiotropy) underlies some of these endophenotypes”. Further dissection of these validated endophenotypes may therefore yield more specific neural processes, and perhaps specific synaptic connections, that would more readily provide clues to the molecular players in these complex developmental disabilities.

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