What is the insula?

If you decided to write a term paper on the insula 20 years ago, it probably would have been a bad idea. First off, your teacher might have thought you were just trying to impress her by choosing an obscure area of the brain that even she knew nothing about. Second, you would have had a hard time even finding enough sources to write the paper with. Since the mid-1990s, however, this deeply-buried region of the brain has begun to garner much more attention.

The insula is tucked away inside a prominent fissure of the brain called the lateral sulcus. Its concealment is one reason why it went mostly unnoticed for such a long time. But neuroimaging, along with studies involving patients with damage to the region, have helped us to recognize the insula as an area of the brain that seems to play a role in a number of everyday activities. However, the imprecision of neuroimaging and clinical studies have also led to vagueness about what exactly that role is.

Indeed, the insula appears to be activated during a wide array of events. Depending on whom you ask, the insula is involved in pain, love, emotion, craving, addiction, the enjoyment of music, or even the tasting of wine. So, what is really going on here?

The answer may be that the insula is at least partly responsible all of these seemingly disparate things because it facilitates our concept of self-awareness. This would include the awareness of our bodies and emotions, and how they interact to create our perception of the present moment. This sounds very metaphysical, and is only a hypothesis, but it would help to explain why the insula seems to be involved in such a diversity of thoughts and behaviors.

The idea that the insula is involved in the formation of our present-moment awareness can be traced back to what is known as the somatic marker hypothesis. Put forth by Antonio Damasio in the 1990s, the somatic marker hypothesis suggests that people use bodily signals to help them make decisions (e.g. a queasiness in your stomach about walking down a dark side street at night might cause you to stick to the well-lit main street). Damasio suggested that the insula plays an important role in the processing of these bodily sensations so they may be used to influence decision making.

The role of the insula in the somatic marker hypothesis was expanded upon by A.D. Craig, who has developed a hypothesis that the insula is the cornerstone of our overall awareness. Craig suggests that the insula constantly receives a heaping of information about the location and condition of our bodies, our subjective emotions, and the key features of our environment. It then incorporates the salient, or important, information into what Craig calls a “global emotional moment.” A global emotional moment is an image of ourselves at one point in time that includes all of the information that is important to us (e.g. I am happy, stimulated, yet hungry). It is the stringing together of these global emotional moments, according to Craig, that allows us to be subjectively aware of the present moment, and it all happens in the insula.

Of course, one should take caution when attributing such a grand function like the generation of awareness to any one brain region. For now, the insula’s true role remains something of a mystery. It is activated by a wide variety of stimuli, but exactly why is unclear. It may be the cornerstone of our conscious awareness, or its function may be much more mundane. It has become a prominent part of neuroscience, however, which is quite an accomplishment for a brain region that was essentially unheard of a few decades ago.

Craig AD (2009). How do you feel--now? The anterior insula and human awareness. Nature reviews. Neuroscience, 10 (1), 59-70 PMID: 19096369

Existential crisis? Try taking a Tylenol

Whether it’s for a stress headache, sore muscles, or recovery from a night out on the town, most of us will occasionally open the medicine cabinet to find some over-the-counter pain relief. However, you’ve probably never thought to reach for something like acetaminophen when going through the pain of a breakup. And the chances are astronomically slim that you've ever thought to take Tylenol because you were feeling anxious about your eventual demise. Recent research published in Psychological Science, however, suggests this may not be as ludicrous as it sounds.

Although we tend to think of physical and mental or emotional pain as very distinct things, there is some evidence the neurobiological mechanisms that process them overlap. For example, variations in the genes that code for opioid receptors (receptors whose activation mitigates the pain response) are associated with sensitivity to social rejection. Perhaps this makes sense, as for the evolutionary ancestors whose genetic lineage we have inherited, social rejection could have meant the difference between life and death. This would have been (and still is) especially true for children, who need social relationships to have someone to defend and provide for them. Thus, being rejected socially would warrant a strong biological impact to make us aware of its seriousness; having pain associated with it provides such an impact.

A study published in Psychological Science in 2010 investigated the potential of acetaminophen to mitigate emotional pain. They had participants take acetaminophen on a daily basis and assess feelings of social pain each evening using a questionnaire. The group taking acetaminophen showed a steady decline in daily social pain compared to the group receiving a placebo. In another experiment, participants took acetaminophen every day for 3 weeks, then engaged in a virtual game while in an fMRI scanner. During the game, they were excluded by the game’s two other participants who—sorry if this brings back any painful playground memories—simply stopped throwing the ball to them. Those who had been taking acetaminophen displayed less activity in the dorsal anterior cingulate cortex (dACC) and anterior insula. When patients experience damage to these areas of the brain they report that they can feel sensations of pain, yet they aren’t bothered by those sensations. Thus, the dACC and anterior insula are potential candidate regions where the neurobiological representation of physical and emotional pain might overlap.

Another group of researchers investigated a similar, although seemingly more tangential, phenomenon recently when they looked at the effects of acetaminophen in easing anxiety related to thinking about one’s death. After writing two paragraphs about what would happen to their body after death, participants were asked to assign a punishment for a theoretical criminal violation. Studies in the past have found that subjects who experience a threat will tend to compensate by being more punitive. Those who received a placebo acted as if they had experienced a threat by increasing the punishments they levied for someone convicted of prostitution. Participants who were administered acetaminophen before the writing exercise, however, were not more punitive, indicating that perhaps acetaminophen mitigated the unease associated with contemplating mortality.

While the research into this area is preliminary, it represents an interesting line of investigation. For, if we can come to understand the overlap between physical and emotional pain, it may create a new way of treating acute emotional distress. With the current problems surrounding the over-prescribing of antidepressants, this could be an important discovery.  

Randles, D., Heine, S., & Santos, N. (2013). The Common Pain of Surrealism and Death: Acetaminophen Reduces Compensatory Affirmation Following Meaning Threats Psychological Science DOI: 10.1177/0956797612464786

Neuroligin and Autism

The rapid increase in autism spectrum disorder (ASD) diagnoses over the last 15 years is alarming. A number of reasons for the rise have been suggested, some of which have sparked debate that occasionally becomes laden with vitriol. Many people, surprised and frightened by what they see as the unprecedented appearance of a novel disorder, are looking for answers and pointing fingers at parties they feel may be culpable. The etiology of ASD is unknown, and perhaps we will find that some of the impassioned claims made by groups like Generation Rescue are valid. But the idea that the emergence of such a disorder occurred overnight is not completely accurate.

Perhaps the earliest documented case of autism was that of Hugh Blair in 1747 (he was 39 at the time). Over the years other cases were identified, while many were misdiagnosed (frequently as infantile schizophrenia). In the 1940s, Leo Kanner and Hans Asperger developed the foundation for the modern diagnosis of autism by laying out a clearer description of the disorder. Interestingly, Kanner was disturbed by how quickly the rate of diagnosis of new cases of autism rose after his paper was published. This was in the 1950s. Since then, of course, the diagnosis has been refined and subsequently broadened, resulting in the class of ASDs we are familiar with today. In many ways, the history of autism up to this point is not so different from the history of other debilitating disorders like schizophrenia in that it consists of slow acknowledgement of a unique set of symptoms, followed by attempts at classification and an increase in the number of diagnoses due to clearer diagnostic criteria.

How the story of autism plays out is yet to be seen. But as the debate over vaccines and other potential causes continues to smolder, science is plodding along attempting to develop animal models for the study of the disorder. Several genetic mutations have been associated with ASDs. Mutations in genes that encode for proteins involved in the healthy functioning of synapses, called neuroligins and neurexins, have been directly linked to ASD. The result has been that many now classify the disorder as a synaptopathy, or a disease that is primarily caused by synaptic dysfunction. This has also led to the development of neuroligin-3 knockout (KO) mice as a rodent model for ASD.

A study in this month’s issue of The Journal of Biological Chemistry goes a step further in determining exactly how mutations in neuroligin can result in synaptopathies. The group coerced cultured neurons to express neuroligin mutations, which caused the protein to be folded improperly after it was manufactured. Furthermore, the misfolded proteins were not sent from the cell body out to the limits of the neuron. Thus the dendrites had a dearth of the protein, a factor that could be at least partly responsible for the unhealthy synaptic function that occurs when the neuroligin gene is mutated.

Protein misfolding is a culprit in Alzheimer's and Parkinson's disease as well, among others. While this study is an important step toward understanding autism, there are many more questions to be answered about how dependent the disorder may be upon protein misfolding and what other factors may be contributing to its variety of symptoms. And unfortunately attempts at developing treatments for protein misfolding diseases have not yet met with much success. Regardless, this is a positive development in understanding ASDs, a task that remains important not just for their treatment but for quelling the anxiety of a public struggling to understand the troubling incidence of the disorder.

De Jaco, A., Lin, M., Dubi, N., Comoletti, D., Miller, M., Camp, S., Ellisman, M., Butko, M., Tsien, R., & Taylor, P. (2010). Neuroligin Trafficking Deficiencies Arising from Mutations in the / -Hydrolase Fold Protein Family Journal of Biological Chemistry, 285 (37), 28674-28682 DOI: 10.1074/jbc.M110.139519

The Many Sides of GABA

If you have a superficial level of knowledge about neuroscience, you probably won’t associate psychostimulants with gamma-aminobutyric acid (more commonly known as GABA). Just as you learn in early biology that a mitochondrion is the “powerhouse of the cell”, you learn in early neuroscience that GABA is the “primary inhibitory neurotransmitter of the brain”. And while this is often true (exceptions are being found on a regular basis), it perhaps doesn’t do justice to the diversity of roles that GABA can play.

There are, for example, many instances of GABA having an inhibitory effect on another inhibitory neuron. This can in effect stop the inhibition, potentially allowing for excitation by another neurotransmitter. Exactly this happens every time you make a voluntary movement. Neurons in the striatum release GABA that inhibits the action of neurons in the globus pallidus. These neurons normally inhibit areas of the thalamus that are necessary for movement but when they are inhibited the thalamus is essentially freed up, allowing us to move.

So, GABA-ergic actions don't necessarily mean inhibition as an end result. This is also true when it comes to the addictive properties of drugs. Dopamine (DA) neurons in the nucleus accumbens (NAc) directly modulate GABAergic connections to the ventral pallidum (VP), which itself sends GABAergic projections back to the NAc. Thus, it is easy to imagine that influencing DA transmission in the NAc, an inevitable outcome of drug use, also has an effect on GABAergic activity throughout the reward system.

Because of this, researchers like Claire Dixon and colleagues have been interested in how GABAa receptors are affected by the administration of drugs like cocaine. In a study published earlier this year in PNAS, Dixon et al. used knockout (KO) mice that had the gene for the alpha2 subunit of the GABAa receptor deleted. GABAa receptors containing these subunits are highly expressed in the NAc.

While these KO mice still demonstrated a stimulant response to cocaine (based on locomotor assays), they failed to show sensitization to the drug, i.e. their activity remained the same on repeated administrations while the wild-type (WT) mice's activity progressively increased. Additionally, cocaine's ability to facilitate conditioned reinforcement (lever pressing) was vastly reduced in the KO mice.

This indicates that GABA may have a role in mediating an addictive response to drugs. The authors hypothesize that the ability of cocaine to increase behaviors associated with environmental cues connected to the drug (lever pressing), and with conditioned activity (sensitization), may depend upon GABAa receptors. Alpha-2 subunits may allow cocaine to strengthen the association between cues and a drug, an association that underlies some of the most compulsive aspects of addiction. Thus, perhaps GABA receptors represent a potential, if not unlikely, target for treating addiction.

Dixon et al. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAa receptors. PNAS, 107, 2289-2294.

Encephalon Celebrates its Emerald Anniversary

Welcome to a landmark edition of Encephalon, the cream of the crop of brain science blog carnivals. This is the 55th edition of Encephalon, an anniversary achieved by less than 5% of married couples. Thus, this edition is a testament to the dedication of neuroscience bloggers: they don’t even take vows, yet they still stay committed to providing their readers with scintillating perspectives on developments in brain science. While more than 95% of married couples give up before their emerald anniversary, brain bloggers keep typing away, upholding their pledge to inform. (We will conveniently disregard the fact that Encephalon occurs biweekly, not annually, which, if considered, would make the analogy to marriage somewhat ridiculous.) Anyway, on to a selection of the best and brightest neuroscience blogs from the last couple of weeks.

Jeremy, a contributor to SharpBrains, provides a superbly written piece about assessing the affects of video games on adolescents. The rational perspective is greatly appreciated.

Greg from Neuroanthropology discusses neuroplasticity, and why the process has been oversimplified, the term overused, and the hype a little unjustified (hmmmm...this reminds me of mirror neurons).

The Neurocritic applies his caustic wit to the sensationalism that surrounds studies of the underlying personality traits of liberals and conservatives.

Cognitive Daily looks at a study of teenagers' sexual behavior. Listen up, abstinence-only advocates...

Dr. Shock MD reviews targets in the brain for deep brain stimulation, an intriguing treatment for highly resistant depression.

Mo at Neurophilosophy has an excellent and thorough discussion of a fascinating disorder: developmental topographagnosia.

Brain Blogger contributes its usual group of insightful posts. One discusses the potential antipsychotics may have in reducing the risk of suicide in depressed patients, something that current antidepressants fail at doing (they sometimes actually increase it). Another examines a little-known treatment for diabetes: the ketogenic diet.

Neuronism continues to impress with well-written contributions to Encephalon. This one is an overview of computational neuroscience, a little-understood but increasingly important field.

Dan at Sports are 80 Percent Mental is exceptional at getting us to consider the neuroscience of sports. This time he describes the success of different cognitive strategies in golf.

The Mouse Trap has two interesting postings about 8 common adaptive problems that drive evolution across species, they are here and here. Another post discusses a suggested expansion of the big five personality traits.

That's it for the emerald edition of Encephalon. Thanks for all your submissions! The next edition will be hosted by Combining Cognits on October 13th. Send your submissions to encephalon {dot} host {at} gmail {dot} com.