Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons) based on: "Crystal structure of the neurophysin-oxytocin complex" Rose, J.P., Wu, C.K., Hsiao, C.D., Breslow, E., Wang, B.C. (1996) Nat.Struct.Biol. 3: 163-169

I recently enjoyed a truly mind-blowing talk at the New York Academy of Sciences. The Neuroeconomist (yes, he studied Economy and is founding director of Claremont´s Center for Neuroeceonomic Studies) Paul J. Zak spoke about his research on the brain chemical oxytocin (OXT) – the so-called “love hormone” – and how he showed that OXT is the source of love and prosperity, triggering a wide variety of physical and psychological effects in both women and men. In his experiments he measures OXT levels found in the blood stream of thousands of people in a variety of settings: attending a wedding, playing football, on Facebook, or play economic games in a lab. By comparing OXT levels before and after those emotionally-charged activities, he found that the level always spiked up during the activity. And interestingly, this is followed by more relaxed, trusting and caring social behavior. Oxytocin seems to be a hidden master controller of human behavior.

The hormone’s influence on our behavior and physiology originates in the brain, where it’s produced by a structure called the hypothalamus, then transferred to the pituitary gland, which releases it into the bloodstream. Like antennas picking up a signal, OXT receptors are found on the outside of cells throughout a body. As Dr. Zak showed, OXT levels tend to be higher during both stressful and socially-bonding experiences (see references for details). So how did it evolve?

Oxytocin is a peptide hormone found in almost all mammals. The present day OXT molecule evolved from a fish “fight-or-flight” molecule called vasotocin. By a random mutation, vasotocin changed one day into a two-amino acid shortened version, called isotocin. Isotocin reduced anxiety in the fish so it relaxed, which facilitated mating instead of a fight-or flight stress response. A variant of isotocin then finally became oxytocin. Similarly, vasopressin evolved into the variant arginine-vasopressin which still works in modern humans as a molecular guide towards reproductive and moral behavior. Oxytocin and vasopressin are the only hormones released by the posterior pituitary gland that can affect cells in distant parts of the body.

For a long time OXT was best known for its role in sexual reproduction, in particular during and after childbirth. But recent studies show that OXT also plays a role in ‘tribal’ behavior and trustworthiness.

Oxytocin helps our brains break down the barrier between self and others, allowing us all to practice empathy and feeling towards others.  And so our brains respond to observed pain or pleasure in the same way as the pain would be happening if we were actually experiencing it; we literally experience the other person’s pain or pleasure as if it were our own.

The higher our OXT level, the closer we appear to act on the Golden Rule: You be nice to me and I´ll be nice to you. On a cellular level we need OXT-producing neurons and functioning OXT receptors in the brain. Oxytocin also directly influences the release of the two feel-good neurochemicals: dopamine and serotonin. However stress, trauma, testosterone, mental conditioning and genetic anomalies can inhibit this effect and with dropping OXT levels our moral behavior strays from the Golden Rule (though, depending on the circumstances this could be a good thing, too!).

People with chronic OXT deficiency do have altered social behavior, depending on the degree of OXT impairment. This can range from high-functioning and brilliant autism to psychopaths. Furthermore, genetic differences in the OXT receptor gene (OXTR) have been associated with maladaptive social traits, such as aggressive behavior.

The good news is that we can consciously use the “moral molecule” to make our own lives better. Oxytocin can be easily transiently boosted by a loving relationship, meditation, dance, connecting via social media and even a simple hug. Dr. Zak – who refers to himself as “Dr. Love” – told the audience I was part of to “share the love” and give a minimum of eight hugs a day! He promises that if you give eight hugs a day you´ll be happier, and the world will be a better place because you will be actively causing other people’s brains to release OXT.

Let´s hope that they are susceptible to the moral molecule and in turn will treat others more generously, causing them to release more OXT….you got the idea! The Beatles already sung it: “Love is all you need….”

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Further reading:

Zak, Paul J. (2012), The Moral Molecule: the source of love and prosperity. Dutton, Penguin Publishing group.

www.moralmolecule.com

Zak PJ, Stanton AA, Ahmadi S (2007). Brosnan, Sarah. ed. “Oxytocin Increases Generosity in Humans”. PLoS ONE 2 (11): e1128. doi:10.1371/journal.pone.0001128. PMC 2040517. PMID 17987115.

Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005). “Oxytocin increases trust in humans”. Nature 435 (7042): 673–6. doi:10.1038/nature03701. PMID 15931222.

Kirsch P, Esslinger C, Chen Q et al. (2005). “Oxytocin modulates neural circuitry for social cognition and fear in humans”. The Journal of Neuroscience 25 (49): 11489–93. doi:10.1523/JNEUROSCI.3984-05.2005. PMID 16339042.

Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y (2009). “Intranasal administration of oxytocin increases envy and schadenfreude (gloating)”. Biological Psychiatry 66 (9): 864–70. doi:10.1016/j.biopsych.2009.06.009. PMID 19640508.

What is clear from this recent paper (Neal et.al. Patterns and rates of exonic de novo mutations in autism spectrum disorders, Nature, advance online publication, http://dx.doi.org/10.1038/nature11011) is that ASD is highly polygenic in origin, i.e. hundreds of genes influence autism risk. Getting to this answer, including two genes in particular that were determined to be very strongly linked with autism (CHD8 and KATNAL2), was a real technical achievement in that in involved analyzing the genomes of 175 trios (mother, father, autistic child). Sequencing 525 human genomes is something that would have been unimaginable just a few years ago. While it is clear that we still have much to understand about this complicated disease, the technological limitations that previously limited progress are beginning to fall away. Hopefully many more important clues are just around the corner.

So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

The neurons fire pulses with periods of rest in between. This is commonly seen in sleeping adults. These pulses were seen between neurons located in the cerebral cortex. The cerebral cortex is involved in sensory information, thinking, emotion and consciousness. Even when they are not receiving input, the neurons will continue the pattern of firing and resting. When we sleep, our neurons will fire and rest as a way of reminding the rest of the brain that even though those cells are no longer working, they’re still alive! It’s as if the neurons are reminding the rest of the brain that they’re still there. Because this is seen in adults and in fetuses, this suggests that this alternative firing and resting activity is a very basic feature of the brain that starts occurring in very early developmental stages.

But now why are they firing so early in life? A mouse’s neurons will fire in synchronized waves. This plays a role in wiring the nervous system during development in order to link the neurons to corresponding body parts. Could this be the same for the human brain? Researchers are unsure if the developing neurons in lab dishes are in synch. If they are, the firing could be part of a mapping process during development.

Using this research, researchers might be able to soon look into what the result is when these neurons don’t form in the right places. The wrong positions might result in numerous disorders. Autism Spectrum disorders may also be related to improper firing.

E. coli gets a bad reputation and I understand that. My students immediately cringe and I know what goes through their minds. They think of the E. coli outbreaks we’ve had in our foods as of late such as the ones that are leading to cases of severe food poisoning and death. I can quickly reassure them that this bacteria does not have this capability. In fact, many are surprised to learn that not all bacteria can cause harm.  With the bad also comes the good and there are good bacteria as well.

Bacteria have taken up residence everywhere on and in you. Hundreds of species of bacteria live on your skin, live in your mouth, and in your intestines. Everyone is born sterile (completely clear of bacteria), but soon after birth bacteria moves in and multiplies enough to include more bacteria cells than human cells in your body.

Don’t get too grossed out! These bacteria strains are important. For example, Biologist Jeffrey Gordon of Washington University has a group of mice that are completely gut bacteria free. These mice are very different from their non-sterile cousins in the way that they are extremely skinny. Food passes right through their intestines, mainly undigested. Thus it is shown that the gut bacteria are more efficient at digesting our food than we are alone.

Today, the bacteria in our guts seem to do more things than originally thought. They are currently under investigation in studies of Autism. There is a hypothesis that these gut bacteria might be releasing chemicals that are contributing to the onset of Autism. Autism has already been linked to gastrointestinal problems. These gastrointestinal problems also seem to appear around the same time as behavior symptoms, so perhaps these gastrointestinal microbes have something to do with it.

Researchers in the UK are studying chemicals in the urine of people with Autism compared to those without the condition to detect any chemical differences. These metabolic changes might be detected in the urine. Using nuclear magnetic resonance (NMR) spectroscopy, the urine was analyzed. The results showed a clear difference between the two groups.

There is a theory that these gut bacteria are producing a toxin that might interact and disrupt brain development. One compound that was identified using the NMR spectroscopy was N-methyl-nicotinamide (NMND) which has already been linked to Parkinson’s disease.

At the University of Western Ontario in Canada, Derrick MacFabe and his colleagues have discovered that clostridium bacteria produce a short-chain fatty acid that many cause autism-like behavioral and biochemical changes in rats that can be reversed.

With this possible link, there might be a simple urine test for Autism. This test, done early enough, might then lead to earlier therapy and treatment options.

So that finally puts the autism-vaccination link to bed, right? Wrong. To read some responses in the blogosphere, one could assume that The Lancet had declared war on all humanity. In Natural News, Mike Adams writes that “The Lancet is doing exactly what George Orwell described in 1984 — rewriting history by obliterating scientific truth and removing it from their archives.” In the Age of Autism, Mark Blaxill refers to the General Medical Council’s judgment that precipitated the retraction as “deep and profound censorship”. Now, I have no intention of picking a fight with these people, but what we have here is a failure of logic and some profound cherry-picking of scientific literature. Thus:

1) In 1998, The Lancet publishes a paper suggesting a link between vaccines and autism. The Lancet is right.
2) In 2010, The Lancet retracts the paper. The Lancet is not only be wrong, but corrupt as well.

I want to ask Mr. Adams and Mr. Blaxhill just one question. At what point in the 12 years between publishing an article that confirms your beliefs and the subsequent retraction was The Lancet usurped by Orwellian propagandists?

I suspect the issue here (and I am sure even Mr. Adams and Mr. Blaxhill will agree) is a failure to trust. Some of us choose to trust the medical/pharmaceutical establishments, some don’t. If you don’t have confidence in these institutions, no amount of pronouncements will change your mind. For many, the primary reason to mistrust Big Pharma is that it is profit-motivated. But so are farmers (yes, even organic ones), private hospitals, and the people that make your seat belts. Occasionally they make mistakes and do stupid things but this is not evidence of conspiracy.

If this retraction is a sign of anything, it is of a healthy peer-review process. The Lancet made a judgment, reviewed it, and found it to be in error. It would be great if we were all capable of such logic.

It is important to remember that savantism is not autism, although it very often occurs with severe forms of autism, what really is key to the condition is memory. Mr. Peek could read a book in a fraction of the time it would take a normal person. He would read the left page with his left eye and the right page with his right eye; and whatever he read, he remembered. Some savants can memorize digits to thousands, or tens-of-thousands of decimal places, play complex music after one hearing, or recreate images or scenery of vast complexity from a glimpse. What underlies all of these abilities is a fantastic memory. Will we ever understand, how Kim Peek, the most brilliant memory documented by science worked? Many are trying to figure out this neurological puzzle.

One of the clues to Mr. Peek’s inner workings might lie not in the gain of some abilities, but instead in the loss of ability. According to the Wisconsin Medical Society, “He had an enlarged head, with an encephalocele, according to his doctors. An MRI shows, again according to his doctors, an absent corpus callosum — the connecting tissue between the left and right hemispheres; no anterior commissure and damage to the cerebellum.” Some neuroscientists have argued that these missing structures allowed his brain to work in its own unique way, and that what really was different about Mr. Peek was not that he could remember, but that he could recall, and in fact not forget what he had learned.

What would it be like to have at least some of these abilities? What I think all savants show us is that there is some untapped potential within all of us, a potential that we somehow are unable to access. We also see that these abilities seem to come at a high price of diminished social or physical functioning. Will there be a time when we can access these abilities, when we understand more about the brain? Would these abilities be as valuable as they appear to be? I guess we will have to answer that question if any when we get there.

Great info and Videos on Kim Peek:

http://www.wisconsinmedicalsociety.org/savant_syndrome/savant_profiles/kim_peek

At the time of writing this, the GMA website, which usually posts follow-ups, has nothing on their site, which I found a little strange. The mother also appeared not with another member of her family, but a lawyer, who was also a family friend. I wondered how these unusual, but small anomalies reflected on modern society’s schizoid views on drugs. I certainly do not approve of “drugs”, the term which brings to mind things like cocaine, methamphetamine, or marijuana. It should also however bring to mind things like coffee, chocolate, and aspirin. Marijuana is a Schedule I drug in the U.S., which, according to definition, means it has no medical use. This is interesting since there has recently been quite an effort to promote so-called medical marijuana. So really our question should be what is a medicine?

In theory a reasonable definition might have medicine as being some sort of foreign substance that effects treatment of disease. Autism is certainly a disease, but is there any evidence that marijuana can “cure” autism? Without doing any research, we should already be skeptical that the answer could possibly be yes.

For one thing, autism is really a spectrum disorder. That means that there may be many causes, both genetic and environmental that produce the constellation of symptoms we call autism. If a doctor were treating you for cancer, he would first have to know whether it was brain cancer or skin cancer to choose a proper treatment. There are certainly anecdotal sources like this GMA news story, but also other places on the Internet that will tell you that someone has cured their child with marijuana brownies, but do you really know that that child was diagnosed with autism? How can a parent know if the supposedly cured child has the same etiology (same cause of the disease) as their own child? Marijuana, or at least its active component, THC, certainly has a psychotropic affect, as it interacts with cannabinoid receptors in the brain. Can this mean that somewhere somehow marijuana can have some unrecognized benefits for autistic individuals? At this time, there simply is insufficient information to come to a conclusion.

You can certainly understand the desperation of any parent who wanted to get the best treatment possible for their child. While the American Pediatric Society continues to oppose medical marijuana, they are in favor of at further investigation into its applications as a drug. Until then, even so-called medical marijuana is still illegal under federal and most state laws. Hopefully however, if a clinical application for autism is found, stigmas about the idea of marijuana as a “drug,” will not hinder scientific debate and progress.

In a recent review of autism research, Brent Bill and Daniel Geschwind (Current Opinion in Genetics & Development Volume 19, Issue 3, June 2009, Pages 271-278) survey the latest advances in tackling autism spectrum disorders. As is explained in the review, pinning down traits and genes is extremely difficult for mental illnesses which involve aspects of cognition that are still only just beginning to be understood.

When it comes to eye color, even a 5 year old can tell you that someone has green, blue, or brown eyes. If we wanted to be a bit fancier, we could imagine that with a chart and camera, we could put eye colors into dozens of systematic categories. But measuring and evaluating the cognitive defects that characterize autism (impaired social behavior, language deficits, repetitive behavior, ect.) is far more challenging.

That is not to say that defining where along the autistic spectrum an individual is an impossible task, but that it is as yet still somewhat imprecise. After all, can you imagine characterizing other complex cognitive traits, humor for example? How funny is a particular comedian? Maybe there is funny or unfunny, but what is the difference between Jerry Sienfeld funny and Victor Borge funny?

Difficulty in characterizing the traits of autism also hampers the high throughput techniques that have made finding genes for other simpler illnesses much more effective. As mentioned in the paper, increases in orders of magnitudes of subjects in some studies have not yielded the desired results, and further increases in subjects will be needed. This is not to mention the further confounding fact that traits which appear similar on the surface may have vastly different genetic causes. After all, if you were looking at humor, and only counted something as funny based upon someone laughing, would that really tell you a lot the difference between Three Stooges funny and Woody Allen funny?

Despite these challenges, there has been progress in identifying some areas of the genome that may have a significant role in autism

What are CNVs?

Copy number variations are spontaneous mutations in the genome that result in duplications or deletions of the genomic sequence. Duplications can produce extra copies of a gene, deletions can remove it altogether. CNVs are an interesting biological phenomenon because they are not inherited from ones parents. Rather, they are acquired de novo when certain sequences of genetic code fail to copy properly. Acquisition of CNVs is unpredicted, random, and spontaneous. Smaller variants are probably very common—each one of us may have one or two.

A raft of studies over the last five-years has propelled CNVs to the forefront of mental health research. CNVs have been linked with a number of disorders including Alzheimer’s (e.g. Rovelet-Lecrux, 2006), autism (e.g. Sebat et al. 2007), bipolar disorder (e.g. Lachman, 2007), and schizophrenia (e.g. Walsh, 2008). The broad theme of these association studies is that individuals with these disorders have more CNVs than the general population. As such, CNVs may be a major causal factor in cognitive (and other) illness.

What is the evidence?

Currently, there is not a great deal of evidence to support Crespi’s hypothesis. A 2008 Nature review paper by Cook & Schere, highlights two genomic loci particularly associated with both: 15q11 – 15q13 and 22q11. However, these are also associated with other disorders including mental retardation. Similarly, there are many loci associated with schizophrenia and not autism and vice-versa. These findings are not a fatal blow to Crespi’s hypothesis, but do recommend a certain level of skepticism.

Crespi also invokes behavioral (phenotypic) evidence, noting that these disorders have similar symptoms, which manifest in opposite directions. Language, social skills, etc., the hypothesis states, are underdeveloped in autistic-spectrum conditions and overdeveloped on the psychotic spectrum. Again, I am not convinced that there is sufficient evidence to substantiate these claims. Crespi points out that glutamate, the brain’s main neurotransmitter, is deficient in schizophrenia and overactive in autism. However, glutamate is associated with a myriad of disorders. Conversely, many biochemicals are associated with schizophrenia and autism.

Professor Jeffrey Lieberman discusses the glutamate hypothesis of schizophrenia.

To Conclude..

Crespi’s hypothesis is interesting and certainly worthy of further comment. Right now, the evidence is not there to substantiate the hypothesis, but that is not to write it off entirely. As genomic technology becomes more powerful, it is increasingly likely that it will be used to inform how we think about diagnosis and psychiatric disorders. Psychologists are compelled to take note of developments in molecular biology, and the two communities are beginning to merge in places. I suspect we will be seeing many papers of this kind in the next few years.

Read more…

G2C Online, schizophrenia resources:

• http://www.g2conline.org/#Schizophrenia

G2C Online, autism resources:

• http://www.g2conline.org/#Autism

CSHL Harbor Transcript article on CNVs (written by me!):

• http://www.cshl.edu/public/HT/pdfs/07_summer_autism.pdf

A review from Science magazine:

• http://www.sciencemag.org/cgi/content/full/324/5924/162b?rss=1