Posts Tagged ‘Cognition’

If you’re a coffee drinker, you may have noticed the new super-sized portions available at Starbucks.  On this note, it may be worth noting that caffeine is a potent psychoactive substance of which – too much – can turn your buzz into a full-blown panic disorder.  The Diagnostic and Statistical Manual for psychiatry outlines a number of caffeine-related conditions mostly involving anxieties that can arise when the natural alertness-promoting effects are pushed to extremes.  Some researchers have begun to explore the way the genome interacts with caffeine and it is likely that many genetic markers will surface to explain some of the individual differences in caffeine tolerance.

Here’s a great paper, “Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety” [doi: 10.1038/npp.2008.17] wherein polymorphisms in the adenosine A2A receptor (ADORA2A encodes the protein that caffeine binds to and antagonizes) – as well as the dopamine D2 receptor (DRD2 encodes a protein whose downstream signals are normally counteracted by A2A receptors) — show associations with anxiety after the consumption of 150mg of caffeine (about an average cup of coffee – much less than the super-size, super-rich cups that Starbucks sells).  The variants, rs5751876 (T-allele), rs2298383 (T-allele) and rs4822492 (G-allele) from the ADORA2A gene as well as rs1110976 (-/G genotype) from the DRD2 gene showed significant increases in anxiety in a test population of 102 otherwise-healthy light-moderate regular coffee drinkers.

My own 23andMe data only provides a drop of information suggesting I’m protected from the anxiety-promoting effects.  Nevertheless, I’ll avoid the super-sizes.
rs5751876 (T-allele)  C/C – less anxiety
rs2298383 (T-allele) – not covered
rs4822492 (G-allele) – not covered
rs1110976 (-/G genotype) – not covered

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Summer, Brody and Audric Hug
Image by cobalt123 via Flickr

If you have a minute, check out this “Autism Sensory Overload Simulation” video to get a feel for the perceptual difficulties experienced by people with autism spectrum disorders.  A recent article, “Critical Period Plasticity Is Disrupted in the Barrel Cortex of Fmr1 Knockout Mice” [doi: 10.1016/j.neuron.2010.01.024] provides some clues to the cellular mechanisms that are involved in this phenomenon.  The authors examined the developing somatosensory cortex in lab mice who carry a mutation in a gene called FMR1.  The normal function of this gene is to help synapses mature and optimize their strength through a process known as activity-dependent plasticity.  This a kind of “use-it-or-lose-it” neural activity that is important when you are practicing and practicing to learn something new – say, like riding a bike, or learning a new language.  Improvements in performance that come from “using” the circuits in the brain are correlated with optimized synaptic connections – via a complex set of biochemical reactions (eg. AMPA receptor trafficking).

When FMR1 is not functioning, neuronal connections (in this case, synapses that connect the thalamus to the somatosensory cortex) cannot mature and develop properly.  This wreaks havoc in the developing brain where maturation can occur in successive critical periods – where the maturation of one circuit is needed to ensure the subsequent development of another.  Hence, the authors suggest, the type of sensory overload reported in the autism spectrum disorders may be related to a similar type of developmental anomaly in the somatosensory cortex.

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Novelty candles may be used.
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Everyone has a birthday right. Its the day you (your infant self) popped into the world and started breathing, right?  But what about the day “you” were born – that is – “you” in the more philosophical, Jungian, spiritual, social, etc. kind of a way when you became aware of being in some ways apart from others and the world around you.  In her 1997 paper, “The Basal Ganglia and Cognitive Pattern Generators“, Professor Ann Graybiel writes,

The link between intent and action may also have a quite specific function during development. This set of circuits may provide part of the neural mechanism for building up cognitive patterns involving recognition of the self. It is well documented that, as voluntary motor behaviors develop and as feedback about the consequences of these behaviors occurs, the perceptuomotor world of the infant develops (Gibson 1969). These same correlations among intent, action, and consequence also offer a simple way for the young organism to acquire the distinction between actively initiated and passively received events. As a result, the infant can acquire the recognition of self as actor. The iterative nature of many basal ganglia connections and the apparent involvement of the basal ganglia in some forms of learning could provide a mechanism for this development of self-awareness.

As Professor Graybiel relates the “self” to function in the basal-ganglia and the so-called cortico-thalamic basal-ganglia loops – a set of parallel circuits that help to properly filter internal mental activity into specific actions and executable decisions – I got a kick out of a paper that describes how the development of the basal-ganglia can go awry for cells that are born at certain times.

Check out the paper, “Modular patterning of structure and function of the striatum by retinoid receptor signaling” by Liao et al.   It reveals that mice who lack a certain retinoic acid receptor gene (RARbeta) have a type of defective neurogenesis in late-born cells that make up a part of the basal ganglia (striatum) known as a striosome.  Normally, the authors say, retinoic acid helps to expand a population of late-born striosomal cells, but in the RARbeta mutant mice, the rostral striosomes remain under-developed.   When given dopaminergic stimulation, these mutant mice showed slightly less grooming and more sterotypic behaviors.

So when was “my self’s” birthday?  Was it when these late-born striosomal cells were, umm, born?  Who knows, but I’m glad my retinoic acid system was intact.

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Diagram to illustrate Minute Structure of the ...
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For a great many reasons, research on mental illness is focused on the frontal cortex.  Its just a small part of the brain, and certainly, many things can go wrong in other places during brain/cognitive development, but, it remains a robust finding, that when the frontal cortex is not working well, individuals have difficulties in regulating thoughts and emotions.  Life is difficult enough to manage, let alone without a well functioning frontal cortex.  So its no surprise that many laboratories look very closely at how this region develops prenatally and during childhood.

One of the more powerful genetic methods is the analysis of gene expression via microarrays (here is a link to a tutorial on this technology).  When this technology is coupled with extremely careful histological analysis and dissection of cortical circuits in the frontal cortex, it begins to become possible to begin to link changes in gene expression with the physiological properties of specific cells and local circuits in the frontal cortex. The reason this is an exciting pursuit is because the mammalian neocortex is organized in a type of layered fashion wherein 6 major layers have different types of connectivity and functionality.  The developmental origins of this functional specificity are thought to lie in a process known as radial migration (here is a video of a neuron as it migrates radially and finds its place in the cortical hierarchy).  As cells are queued out of the ventricular zone, and begin their migration to the cortical surface, they are exposed to all sorts of growth factors and morphogens that help them differentiate and form the proper connectivities.  Thus, the genes that regulate this process are of keen interest to understanding normal and abnormal cognitive development.

Here’s an amazing example of this – 2 papers entitled, “Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: Signature of altered neural development?” [doi:10.1016/j.nbd.2009.12.013] and “Molecular markers distinguishing supragranular and infragranular layers in the human prefrontal cortex [doi:10.1111/j.1460-9568.2007.05396.x] both by Dominique Arion and colleagues.  In both papers, the authors ask, “what genes are differentially expressed in different layers of the cortex?”.  This is a powerful line of inquiry since the different layers of cortex are functionally different in terms of their connectivity.  For example, layers II-III (the so-called supragranular layers) are known to connect mainly to other cortical neurons – which is different functionally than layers V-VI (the so-called infragranular layers) that connect mainly to the striatum (layer V) and thalamus (layer VI).  Thus, if there are genes whose expression is unique to a layer, then one has a clue as to how that gene might contribute to normal/abnormal information processing.

The authors hail from a laboratory that is well-known for work over many years on fine-scaled histological analysis of the frontal cortex at the University of Pittsburgh and used a method called, laser capture microdissection, where post-mortem sections of human frontal cortex (area 46) were cut to separate the infragraular layer from the supragranular layer.  The mRNA from these tissue sections was then used for DNA microarray hybridization.  Various controls, replicate startegies and in-situ tissue hybridizations were then employed to validate the initial microarray results.

In first paper, the where the authors compare infra vs. supragranular layers, they report that 40 genes were more highly expressed in the supragranular layers (HOP, CUTL2 and MPPE1 were among the most enriched) and 29 genes were highly expressed in the infragranular layers (ZNF312, CHN2, HS3ST2 were among the most enriched).  Other differentially expressed genes included several that have previously been implicated in cortical layer formation such as RLN, TLX-NR2E1, SEMA3E, PCP4, SERPINE2, NR2F2/ARP1, PCDH8, WIF1, JAG1, MBP.  Amazing!! A handful of genes that seem to label subpopulations of projection neurons in the frontal cortex.  Polymorphic markers for these genes would surely be powerful tools for imaging-genetic studies on cognitive development.

In the second paper, the authors compare infra vs. supragranular gene expression in post-mortem brains from patients with schizophrenia and healthy matched controls. Using the same methods, the team reports both supra- and infragranular gene expression changes in schizophrenia (400 & 1200 differences respectively) – more than 70% of the differences appearing to be reductions in gene expression in schizophrenia. Interestingly, the team reports that the genes that were differentially expressed in the infragranular layers provided sufficient information to discriminate between cases and controls, whilst the gene expression differences in the supragranular layers did not.  More to the point, the team finds that 51 genes that were differentially expressed in infra- vs. supragranular expression were also differentially expressed in cases vs. controls  (many of these are also found to be associated in population genetic association studies of schiz vs. control as well!).  Thus, the team has identified layer (function) -specific genes that are associated with schizophrenia.  These genes, the ones enriched in the infragranular layers especially, seem to be at the crux of a poorly functioning frontal cortex.

The authors point to 3 such genes (SEMA3E, SEMA6D, SEMA3C) who happen to members of the same gene family – the semaphorin gene family.  This gene family is very important for the neuronal guidance (during radial migration), morphology, pruning and other processes where cell shape and position are regulated.  The authors propose that the semaphorins might act as “integrators” of various forms of wiring during development and in adulthood.  More broadly, the authors provide a framework to understand how the development of connectivity on the frontal cortex is regulated by genetic factors – indeed, many suspected genetic risk factors play a role in the developmental pathways the authors have focused on.

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In his undergraduate writings while a student at Harvard in the early 1900’s E. E. Cummings quipped that, “Japanese poetry is different from Western poetry in the same way as silence is different from a voice”.  Isabelle Alfandary explores this theme in Cummings’ poetry in her essay, “Voice and Silence in E. E. Cummings’ Poetry“,  giving some context to how the poet explored the meanings and consequences of voice and silence.  Take for example, his poem “silence”




ing;edge, of

(inquiry before snow

e.e. cummings

Lately, it seems that the brain imaging community is similarly beginning to explore the meanings and consequences of the brain when it speaks (activations whilst performing certain tasks) and when it rests quietly.  As Cummings beautifully intuits the profoundness of silence and rest,  I suppose he might have been intrigued by just how very much the human brain is doing when we are not speaking, reading, or engaged in a task. Indeed, a community of brain imagers seem to be finding that the brain at rest has quite a lot to say – moreso in people who carry certain forms of genetic variation (related posts here & here).

A paper by Perrson and colleagues “Altered deactivation in individuals with genetic risk for Alzheimer’s disease” [doi:10.1016/j.neuropsychologia.2008.01.026] asked individuals to do something rather ordinary – to pay attention to words – and later to then respond to the meaning of these words (a semantic categorization task). This simple endeavor, which, in many ways uses the very same thought processes as used when reading poetry, turns out to activate regions of the temporal lobe such as the hippocampus and other connected structures such as the posterior cingulate cortex.  These brain regions are known to lose function over the course of life in some individuals and underlie their age-related difficulties in remembering names and recalling words, etc.  Indeed, some have described Alzheimer’s disease as a tragic descent into a world of silence.

In their recordings of brain activity of subjects (60 healthy participants aged 49-79), the team noticed something extraordinary.  They found that there were differences not in how much the brain activates during the task – but rather in how much the brain de-activates – when participants simply stare into a blank screen at a small point of visual fixation.  The team reports that individuals who carry at least one copy of epsilon-4 alleles of the APOE gene showed less de-activation of their their brain (in at least 6 regions of the so-called default mode network) compared to individuals who do not carry genetic risk for Alzheimer’s disease.  Thus the ability of the brain to rest – or transition in and out of the so-called default mode network – seems impaired in individuals who carry higher genetic risk.

So, I shall embrace the poetic wisdom of E. E. Cummings and focus on the gaps, empty spaces, the vastness around me, the silences, and learn to bring my brain to rest.  And in so doing, perhaps avoid an elderly descent into silence.


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One of the complexities in beginning to understand how genetic variation relates to cognitive function and behavior is that – unfortunately – there is no gene for “personality”, “anxiety”, “memory” or any other type of “this” or “that” trait.  Most genes are expressed rather broadly across the entire brain’s cortical layers and subcortical systems.  So, just as there is no single brain region for “personality”, “anxiety”, “memory” or any other type of “this” or “that” trait, there can be no such gene.  In order for us to begin to understand how to interpret our genetic make-up, we must learn how to interpret genetic variation via its effects on cells and synapses – that go on to function in circuits and networks.  Easier said than done?  Yes, but perhaps not so intractable.

Here’s an example.  One of the most well studied circuits/networks/systems in the field of cognitive science are so-called basal-ganglia-thalamcortical loops.  These loops have been implicated in a great many forms of cognitive function involving the regulation of everything from movement, emotion and memory to reasoning ability.  Not surprisingly, neuroimaging studies on cognitive function almost always find activations in this circuitry.  In many cases, the data from neuroimaging and other methodologies suggests that one portion of this circuitry – the frontal cortex – plays a role in the representation of such aspects as task rules, relationships between task variables and associations between possible choices and outcomes.  This would be sort of like the “thinking” part of our mental life where we ruminate on all the possible choices we have and the ins and outs of what each choice has to offer.  Have you ever gone into a Burger King and – even though you’ve known for 20 years what’s on the menu – you freeze up and become lost in thought just as its your turn to place your order?  Your frontal cortex is at work!

The other aspect of this circuitry is the subcortical basla ganglia, which seems to play the downstream role of processing all that ruminating activity going on in the frontal cortex and filtering it down into a single action.  This is a simple fact of life – that we can be thinking about dozens of things at a time, but we can only DO 1 thing at a time.  Alas, we must choose something at Burger King and place our order.  Indeed, one of the hallmarks of mental illness seems to be that this circuitry functions poorly – which may be why individuals have difficulty in keeping their thoughts and actions straight – the thinking clearly and acting clearly aspect of healthy mental life.  Certainly, in neurological disorders such as Parkinson’s Disease and Huntington’s Disease, where this circuitry is damaged, the ability to think and move one’s body in a coordinated fashion is disrupted.

Thus, there are at least 2 main components to a complex system/circuits/networks that are involved in many aspects of learning and decision making in everyday life.  Therefore, if we wanted to understand how a gene – that is expressed in both portions of this circuitry – inflenced our mental life, we would have to interpret its function in relation to each specific portion of the circuitry.  In otherwords, the gene might effect the prefrontal (thinking) circuitry in one way and the basla-ganglia (action-selection) circuitry in a different way.  Since we’re all familiar with the experience of walking in to a Burger King and seeing folks perplexed and frozen as they stare at the menu, perhaps its not too difficult to imagine that a gene might differentially influence the ruminating process (hmm, what shall I have today?) and the action selection (I’ll take the #3 combo) aspect of this eveyday occurrance (for me, usually 2 times per week).

Nice idea you say, but does the idea flow from solid science?  Well, check out the recent paper from Cindy M. de Frias and colleagues “Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task.” [PMID: 19642882].  In this paper, the authors probed the function of a single genetic variant (rs4680 is the Methionine/Valine variant of the dopamine metabolizing COMT gene) on cognitive functions that preferentially rely on the prefronal cortex as well as mental operations that rely heavily on the basal-ganglia.  As an added bonus, the team also probed the function of the hippocampus – yet a different set of circuits/networks that are important for healthy mental function.  OK, so here is 1 gene who is functioning  within 3 separable (yet connected) neural networks!

The team focused on a well-studied Methionine/Valine variant of the dopamine metabolizing COMT gene which is broadly expessed across the pre-frontal (thinking) part of the circuitry and the basal-ganglia part of the circuitry (action-selection) as well as the hippocampus.  The team performed a neuroimaging study wherein participants (11 Met/Met and 11 Val/Val) subjects had to view a series of words presented one-at-a-time and respond if they recalled that a word was a match to the word presented 2-trials beforehand  (a so-called “n-back task“).  In this task, each of the 3 networks/circuits (frontal cortex, basal-ganglia and hippocampus) are doing somewhat different computations – and have different needs for dopamine (hence COMT may be doing different things in each network).  In the prefrontal cortex, according to a theory proposed by Robert Bilder and colleagues [doi:10.1038/sj.npp.1300542] the need is for long temporal windows of sustained neuronal firing – known as tonic firing (neuronal correlate with trying to “keep in mind” all the different words that you are seeing).  The authors predicted that under conditions of tonic activity in the frontal cortex, dopamine release promotes extended tonic firing and that Met/Met individuals should produce enhanced tonic activity.  Indeed, when the authors looked at their data and asked, “where in the brain do we see COMT gene associations with extended firing? they found such associations in the frontal cortex (frontal gyrus and cingulate cortex)!

Down below, in the subcortical networks, a differerent type of cognitive operation is taking place.  Here the cells/circuits are involved in the action selection (press a button) of whether the word is a match and in the working memory updating of each new word.  Instead of prolonged, sustained “tonic” neuronal firing, the cells rely on fast, transient “phasic” bursts of activity.  Here, the modulatory role of dopamine is expected to be different and the Bilder et al. theory predicts that COMT Val/Val individuals would be more efficient at modulating the fast, transient form of cell firing required here.   Similarly, when the research team explored their genotype and brain activity data and asked, “where in the brain do we see COMT gene associations with transient firing? they found such associations in the right hippocampus.

Thus, what can someone who carries the Met/Met genotype at rs4680 say to their fellow Val/Val lunch-mate next time they visit a Burger King?  “I have the gene for obesity? or impulsivity? or “this” or “that”?  Perhaps not.  The gene influences different parts of each person’s neural networks in different ways.  The Met/Met having the advantage in pondering (perhaps more prone to annoyingly gaze at the menu forever) whist the Val/Val has the advantage in the action selecting (perhaps ordering promptly but not getting the best burger and fries combo).

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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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