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Archive for the ‘COMT’ Category

Cheap? Yes. Fake? Not at all.  It’s another genetic study on the placebo effect and it highlights the fact that our brains are not static input-out machines that were built from scratch using a genetic blueprint.  Rather, what we expect and believe matters … a lot.

How does it work?  Nobody knows for sure, but dopamine has been implicated in synaptic mechanisms that are used to register the fulfillment or violation of expectations.  For example, if you believe that a certain something will happen … and something better happens, your brain produces a burst of dopamine.  If something worse happens, then you get a drop in dopamine.  Your expectations and beliefs influence your dopamine levels.

Apparently, some of us metabolize dopamine faster vs. slower which may be related to a weaker vs. stronger placebo response.  For example, my rs4680 GG fast dopamine metabolizing genotype says, the “medicine in my mind” is not very strong.  But, on the other hand, I do watch A LOT of Grey’s Anatomy.

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Perhaps someday, but it’s complicated. This is because the brain is not a simple input-output device.  If we step on a thumbtack, it hurts … but can hurt more if you are feeling sad and lonely and much less if you are in love and just won the lottery.  Expectations and memories matter, and so – our genotype – is something that reflects the development brain systems used for processing emotions, memories and expectations (like, um, the whole brain does this).

This paper explored this question using a shoulder exercise soreness assay and the COMT genotype and found that:

Participants that endorsed cognitions consistent with pain catastrophizing and had a genetic predisposition to low COMT enzyme activity had significantly higher pain intensity and pressure pain ratings when compared with groups with 1 or no risk factors.

Pain catastrophizing” is a measure of how much a person ruminates (unable to suppress or divert attention away from pain-related thoughts) and/or focuses on and exaggerates the threat value of a painful stimuli and/or feels helpless and unable to cope with the adversity of painful stimuli.  It may be the most important aspect of coping with pain … an understanding that your perspective modulates your pain.

This may be worth noting given the  “dramatic increase in accidental deaths associated with the use of prescription opioids and also an increasing average daily morphine equivalent dose” despite the finding that “there is no clear evidence that long-term opiate therapy for chronic back pain is efficacious”.


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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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MFrankIf you’re interested in the neurobiology of learning and decision making, then you might be interested in this brief interview with Professor Michael Frank who runs the Laboratory of Neural Computation and Cognition at Brown University.

From his lab’s website: “Our research combines computational modeling and experimental work to understand the neural mechanisms underlying reinforcement learning, decision making and working memory. We develop biologically-based neural models that simulate systems-level interactions between multiple brain areas (primarily basal ganglia and frontal cortex and their modulation by dopamine). We test theoretical predictions of the models using various neuropsychological, pharmacological, genetic, and neuroimaging techniques.”

In this interview, Dr. Frank provides some overviews on how genetics fits into this research program and the genetic results in his recent research article “Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation”. Lastly, some lighthearted, informal thoughts on the wider implications and future uses of genetic information in decision making.

To my mind, there is no one else in the literature who so seamlessly and elegantly interrelates genetics with the modern tools of cognitive science and computational neurobiology.  His work really allows one to cast genetic variation in terms of its influence on neural computation – which is the ultimate way of understanding how the brain works.  It was a treat to host this interview!

Click here for the podcast and here, here, here for previous blog posts on Dr. Frank’s work.

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A column of the cortex
Image by Ethan Hein via Flickr

Here’s a new addition to a rapidly growing list of findings for the valine-to-methionine substitution in the COMT gene (rs4680).  The paper, “Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents” by Shaw and colleagues at the NIMH [doi:10.1038/mp.2008.121] finds that when genotype was used as a regressor for cortical thickness measures in children (8-14 years of age) significant associations were found in the right inferior frontal gyrus and the right superior/middle temporal gyrus (in both areas, the met/met group had thicker cortex).  The team notes that the findings in the frontal cortex were expected – as many others have found associations of COMT with this brain area using other imaging modalities.  However, the temporal lobe finds are something new.  No speculations on the mechanisms/implications are provided by the researchers on this new finding, but known interconnectivities of these two brain regions exist – perhaps supporting aspects of language, memory and/or other cognitive processes?

Perhaps the findings provide a clue to an important role that genes may play in the development of cognitive function.

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vix

In 1802, in a letter to then Secretary of the Treasury, Albert Gallatin, Thomas Jefferson warned that, “If the American people ever allow private banks to control the issue of their money, first by inflation and then by deflation, the banks and corporations that will grow up around them (around the banks), will deprive the people of their property until their children will wake up homeless on the continent their fathers conquered.” (source)  Although the US now does have a central government bank, Jefferson’s warning still chillingly echoes through our current crisis as we teeter on this very brink.

The reasons why the US financial system lies stricken now (not to mention many times before) are complex for sure, but for a neuroscience & genetics buff like myself, its fun to consider the underlying mechanisms of human biology and behavior within a macroeconomic framework.  What role for the brain and human nature? How does our understanding of human social and emotional behavior reconcile with the premise of so-called “rational” behavior of investors and consumers in a marketplace? Can we regulate and design a debacle-proof economic system that accounts for human social and emotional influences on otherwise rational behavior? Luckily, if you are interested in these questions, you need only to pick up a copy of “Animal Spirits: How Human Psychology Drives the Economy, and Why It Matters for Global Capitalism” by George Akerlof and Robert Shiller, who cover this very topic in great detail and provide a broad framework for neuropsychological research to inform macroeconomic policy.  A lofty and distant goal indeed, but perhaps the only way forward from such spectacular wreckage of the current system.

One such aspect of so-called “animal  spirits” could be, for example – fear – which has been blamed many times for financial panics and is covered in great measure by Akerlof and Shiller.  During the depths of the great depression, FDR famously tried to shake people loose from their animal spirits by suggesting “Only Thing We Have to Fear Is Fear Itself” (listen to the audio).   As another example, consider the chart at the top of the post – a 5yr trace of the VIX an index of volatility in the price of stock options over time.  In a bull or a bear market, when there are clear economic signals that stock prices should rise or fall, the VIX is rather low – since people feel relatively certain about the overall direction of the market.  Note however, what happened in the fall of 2008, when the heady days of the housing boom ended and our current crisis began – the VIX rockets toward 100% volatility – indicating rather dramatic swings in future earnings estimates and hence, tremendous uncertainty about the future direction of the market.  Indeed, for high flying investors (who may reside in tall buildings with windows that open) the VIX is sometimes referred to as the fear index.

What – in terms of brain mechanisms – might underlie such fear – which seems to stem from the uncertainty of whether things will get better or worse?  What do we know about how humans react to uncertainty and how humans process uncertainty?  What brain systems and mechanisms are at play here? One recent report that uses genetic variation as a tool to peer into such brain mechanisms suggests that dopamine signaling modulates different brain areas and our propensity to respond in conditions of low and high uncertainty.

In their article, “Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation“, [doi:10.1038/nn.2342] Michael Frank and colleagues examine individual differences in a so-called exploration/exploitation dilemma.  In their ‘‘temporal utility integration task’’, individuals could maximize their rewards by pressing “stop” on a rotating dial which can offer greater rewards when individuals press faster, or when individuals learn to withold and wait longer, and, in a third condition when rewards are uncertain.  The authors liken the paradigm to a common life dilemma when there are clear rewards to exploiting something you know well (like the restaurant around the corner), but, however, there may be more rewards obtained by exploring the unknown (restaurants on the other side of town).  In the case of the VIX and its massive rise on the eve of our nations financial calamity, investors were forced to switch from an exploitation strategy (buy housing-related securities!!!) to an exploration strategy (oh shit, what to do?!!).

The neurobiological model hypothesized by Frank and colleagues predicts that the striatum will be important for exploitation strategies and find supporting data in gene associations with the striatally-enriched DARPP-32 gene (a marker for dopamine D1-dependent signalling) and DRD2 for the propensity to respond faster and slower, respectively, in the exploitative conditions (rs907094 & rs1800496).  For the exploratory conditions, the team found an association with the COMT gene which is well-known to modulate neural function in the prefrontal cortex (rs4680). Thus, in my (admittedly loose) analogy, I can imagine investors relying on their striata during the housing boom years and then having to rely more on their prefrontal cortices suddenly in the fall of 2008 when it was no longer clear how to maximize investment rewards.  Egregious bailouts were not yet an option!

Click here and here to read more breakthrough neuroeconomics & genetic research from Michael Frank and colleagues.  Here and here for more on Shiller and Keynes.

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U.S. Treasury Secre...

Image by Getty Images via Daylife

Amidst the current economic panic, I’m feeling more shocked than usual when listening to the flip-flopping, falsehoods, fabrications, backstepping, about-facing and unabashed spin-doctoring spewing forth from the news media. If watched long enough, one may even develop empathy for Henry Paulson who carries the weight of the global economy on his shoulders. Nevertheless, what do we know about making mistakes ? Not necessarily global financial catastrophies, but little everyday mistakes. Why do some of us learn from our mistakes ? What’s going on in the brain ? Enter Michael Frank, Christopher D’Lauro and Tim Curran, in their paper entitled, “Cross-task individual differences in error processing: Neural, electrophysiological and genetic components” [Cognitive, Affective, & Behavioral Neuroscience (2007), 7 (4), 297-308]. Their paper provides some amazing insight into the workings of human error-processing.

It has been known for some time that when you make a mistakke – oops! – mistake, that there are various types of electrical current that emanate from the frontal midline (cingulate cortex) of your brain.  The so-called error related negativity (ERN) occurs more strongly when you are more focused on being correct and also seems to be more strong in people with certain personality traits (apparently not news commentators or politicians) while the error positivity (Pe) occurs more strongly when you become consciously aware that you made an error (perhaps not functioning in news commentators or politicians). Perhaps the ERN and Pe are basic neural mechanisms that facilitate an organisms adaptive ability to stop and say, “hey, wait a minute, maybe I should try something new.” The Frank et al., paper describes a relation between learning and dopamine levels, and suggests that when dopamine levels dip – as happens when our expectations are violated (“oh shit!, I bought stock in Lehman Brothers) – that this may facilitate the type of neural activity that causes us to stop and rethink things. To test whether dopamine might play a role in error processing, the team examined a common variant (rs4680) in the catechol-o-methyl transferase gene, a gene where A-carriers make a COMT enzyme that is slower to breakdown dopamine (a bulky methionine residue near the active site) than G-allele-carriers. Subjects performed a learning task where correct responses could be learned by either favoring positive feedback or avoiding negative feedback as compared to neutral stimuli. The team suspected that regardless of COMT genotype, however, there would be no COMT association with learning strategy, since COMT influences dopaminergic activity in the frontal cortex, and not in the striatum, which is the region that such reinforcement learning seems to be stored.

Interestingly, the team found that the error positivity (Pe) was higher in participants who were of the A/A genotype, but no difference in genetic groups for the error related negativity (ERN). This suggests that A/A subjects deploy more attentional focus when they realize they have made an error. Lucky folks ! My 23andMe profile shows a GG at this site, so it seems that when I make errors, I may have a normal ERN, but the subcortical dopamine that dips as a result does not (on average) result in much greater attentional focus. Oh well, I guess its the newsmedia pool for me.

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