Archive for the ‘Cingulate cortex’ Category


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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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.


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William Faulkner
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What hurts more – a broken toe or a broken heart?  Ask a parent and their forlorn 15 year-old who was not invited to the party that everyone is going to, and you might get different answers.  In some cases, the internal anguish of social exclusion or estrangement, may even – paradoxically – be relieved by self-infliction of physical pain, which is construed by some neuro-psychiatrists as a coping mechanism, wherein endogenous opioids are released by the physical injury (cutting, for instance) and may then soothe the internal feeling of anguish.

While there are many social, and psychological factors pertaining to the way in which people cope with internal and external pain, a recent research article from Dr. Naomi Eisenberger’s lab sheds light on a very basic aspect of this complex process – that is – the similarities and differences of neural mechanisms underlying social and physical pain.  In their recent paper, “Variation in the μ-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection” [doi:10.1073/pnas.0812612106] the authors asked healthy participants to lay in an MRI scanner and play a video game of catch / toss the ball with other “real people” by way of a computer interface.  During the game, the participant was rudely socially excluded by the other two players in order to induce the feelings of social rejection.  Participants also completed an instrument known as the “Mehrabian Sensitivity to Rejection Scale” and were genotyped for an A-to-G SNP (rs1799971) located in the opioid receptor (OPRM1) gene.  Previous research as found that the G-allele of OPRM1 is less expressed and that individuals who carry the GG form tend to need higher doses of opioids to feel relief from physical pain, and GG rhesus monkeys (interestingly, we share the same ancient A-to-G polymorphism with our primate ancestors) demonstrate more distress when separated from their mothers.

The results of the study show that the participants who carry the AA genotype are somewhat less sensitive to social rejection and also show less brain activity in the anterior cingulate cortex (an area whose activity has long been associated with responses to physical pain) as well as the anterior insula (an area often times associated with unpleasant gut feelings) when excluded during the ball-toss game.  Further statistical analyses showed that the activity in the cingulate cortex was a mediator of the genetic association with rejection sensitivity – suggesting that the genetic difference exerts its effect by way of its role in the anterior cingulate cortex.   Hence, they have localized where in the brain, this particular genetic variant exerts its effect.  Very cool indeed!!

Stepping back, I can’t help but think of the difficulties people have in coping with internal anguish, which – if not understood by their peers – can, mercilessly, lead to further exclusion, estrangement and stigmatization.  Studies like this one reveal – from behavior, to brain, to genome – the basic biology of this important aspect of our social lives, and can help to reverse the marginalization of people coping with internal anguish.


The picture is of William Faulkner who is quoted, “Given the choice between the experience of pain and nothing, I would choose pain.”  I wonder if he was an AA or a G-carrier?  I feel rather lucky to find that my 23andMe profile shows an AA at this site.

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

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

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OK, there’s not really a “coolest” part of the brain, but, some areas are pretty darn weird & wild.  Consider the cingulate cortex (shown here).  Electrical stimulation of the pACC region in humans can produce overwhelming fear – even a feeling that death is imminent – while stimulation of white matter tracts adjacent to area 25 can relieve treatment resistent depression. Activity in the MCC region is often associated – not with emotion – but with motor planning and selection of actions.  Stimulation of this area evoked the feeling of “I felt something, as though I was going to leave.” Interestingly, this region also contains a unique type of large neuron known as a von Economo cell,  found in humans and Bonobo chimpanzees, but not other primate species – leading some to speculate that this area must contribute to something that makes us uniquely human.  The PCC and RSC regions seem to be involved in how your brain computes where you are in 3-dimensional space, since activity in the PCC rises when participants mentally navigate pathways and routes of travel or assess the “self-relevance” of sensory stimuli, while lesions in RSC lead to topographic disorientation.  Whew, that’s a lot of functionality !  Indeed, with so many functions, its not surprising that this region is often linked to mental illness of all sorts.  In schizophrenia, for example, patients have difficulty controlling their actions (MCC regions have been implicated) as well as their emotions (ACC regions have been implicated) and maintaining a coherent sense of “self” (PCC & RSC regions have also been implicated).

Since we know that this brain region is implicated in mental illness and we know that mental illness arises – in part – due to genetic risk, it is of interest to begin to understand how genetic factors might relate to the development of structure, connectivity and function of the 4 sub-regions of the cingulate cortex.  With this in mind, it was great to see a recent paper from Brent Vogt and colleagues at the Cingulum Neurosciences Institute [doi: 10.1002/hbm.20667] which has begun to examine differential gene expression in these 4 subregions !  They examined the expression of an array of neurotransmitter receptors (at the protein level actually) and asked whether the expression of the receptors was able to differentiate (as lesions, activity and architectonics do) the 4 subregions.  In a word – yes – with the ACC region showing highest AMPA receptor expression and lowest GABA-A receptor expression.  This was very different from the MCC region which had the lowest AMPA receptor expression while PCC had the highest cholinergic M1 receptor expression.

This seems a great foundation for future studies that will continue to dissect the many interconnected – yet separable – functions of the cingulate cortex.  The “holy grail” of which might be to understand the evolutionary origins of the von Economo cells which are unique to our human lineage.  The genome encodes the story – we just need to learn to read it aloud.

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One of the weird things about chronic pain is that it can sometimes be more “in your brain” than, say “in your back” or “in your elbow“.  Take for example, a phenomenon known as phantom limb pain – where individuals who lose a limb, can still complain of feeling pain in that very missing limb.  As described here, it is possible to “unlearn” this pain – which is a learning process involving changes in synaptic connectivity in the brain.

Where then, and how, might pain and learning related to chronic pain be happening “in your brain” rather than in your back or elbow. Well, a recent paper from Min Zhuo’s lab at the University of Toronto have reported some new insights into synaptic mechanisms of pain.  In their recent paper [doi:10.1186/1744-8069-4-40], “Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex” they evaluate the role of presynaptic glutamamte release in a brain region known as the anterior cingulate cortex – a region whose activity is well-known to correlate with reports of pain.

One of the cool tricks they used to evaluate the role of pre- vs. post-synaptic actions of glutamate was to use mice that carry a G-protein coupled receptor from the sea slug (Aplysia) which can respond to octopamine (a chemical not normally found in mouse brains) to activate glutamate release pre-synaptically.  When mice were administered octopamine in the cingulate cortex, became more sensitive to chronic pain.  This identifies a very specific biochemical pathways and brain area for which pharmacologic and behavioral therapeutics might be designed for the treatment of chronic pain.

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