Archive for the ‘Insula’ Category

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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old class photo with grandpa, 1923
Image by freeparking via Flickr

Back in the day, when the fam would get together at my parents’ house, I would enjoy shuffling through their box of old photos.  Looking at childhood pictures of myself and relatives, it was natural to compare our adult selves to the old pictures and look for similarities – emotional expressions, gestures, etc. – that have carried on through the years and are (were) a part of who we are (became) today.  It’s always amazing what you think you can see, and if you’re like me, you may be somewhat amazed by how much of your adult self was already in full swing as a child.  The manner in which the developing brain confers such stability over time and over generations (now I see my own childhood traits in my son – yikes!) is of course a timeworn question among families and scientists alike.

That the genome would contribute to cross generational parent-child similarities in personality and temperament is fairly obvious, but not so apparent is how the genome interacts with the environment to exert an influence on psychological development.  Along this line of inquiry, a research article entitled, “Influence of RGS2 on anxiety-related temperament, personality, and brain function” by Smoller and colleagues [free access] provides an amazing perspective – from a single gene.  RGS2, eponymously named as a regulator of G-protein signaling, was first identified as a factor that regulates emotional behavior in mice [PMID] and subsequently as a risk factor for schizophrenia [PMID] as well as anxiety disorders in humans [PMID].  In the current study, the team examined the temperament of children (119 families), personality of adults (744 undergraduates) and brain activity in adults (55 participants) to ascertain whether the adult risk for anxiety conferred by RGS2 might be related to actions of the gene that occur much earlier in development – such as on the systems that regulate temperament in children.  Specifically, they focused on behavioral inhibition in children (shy, avoidant, restrained in novel situations) and introversion in adults – as these traits have been associated with increased risk for anxiety disorders.

What is so interesting to me is that RGS2 (particularly the G allele of the 3’UTR SNP rs4606) was found to be associated with both childhood temperament and adult personality.  Thus, an introverted adult who looks through an old photo album and sees themselves to have been a shy or inhibited child, may be experiencing – to a small degree – the effects of the RGS2 gene.  The team suggests, via additional brain imaging-genetic studies, that RGS2 is of particular relevance to activity in circuits containing the insular cortex and amygdala – when subjects perform an emotional face matching task.

My own 23andme record does not contain the rs4606 SNP but does contain the data for rs1819741 where a T allele was significantly associated with introversion.  Since I’m a C/T heterozygote, I guess I’ll have to look a bit harder at my old pictures to see signs of behavioral inhibition.

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Angry face
Image via Wikipedia

Indeed, learning how to manage one’s response to the negative emotions of others and stay out of trouble is an important life skill. At some point, most of us learn to just avoid angry, mean or melodramatically negative people and save ourselves the strife. Roy Perlis and colleagues, in their recent paper, “Association of a Polymorphism Near CREB1 With Differential Aversion Processing in the Insula of Healthy Participants“, show how the transcriptional regulator CREB might exert an influence on this learning process. By having subjects view images of various facial expressions, the investigators found that individuals with the TT genotype at rs4675690 (C/T) showed less negative activation in the left insula, a brain region that is known to activate when subjects feel disgust, but not happiness, desire or fear. Subjects with the TT genotype have been shown to require more effort in the management of negative emotions and are at greater risk for suicide when being treated for depression. In the Perlis et al., study, TT subjects showed less of an effort (as measured in key presses) to avoid viewing emotionally distressing pictures. The known role of CREB in neural plasticity suggests that this gene may facilitate neural changes associated with memory. Unfortunately, 23andMe does not cover this SNP, so I’ll just have to hope that (during the upcoming election) my insula keeps me on the path to enlightenment.

Update: Thanks so very much Brian for the info on rs7591784. This explains a lot – I’m a GG here, which means I’m a TT at rs4675690 – and have always had difficulty handling it when folks are rude to me.

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