Wednesday, March 10, 2010

Oxytocin and the autism anti-treatment movement

Unless you were not paying attention last month (or possibly in a comma), you were sure to notice the new study involving oxytocin and autism. In this small study, researchers demonstrated that an inhaled form of oxytocin could improve social behaviors in adults with high functioning autism. The result is very tentative but, assuming that the results can be replicated in future studies, oxytocin has the potential to be a powerful treatment for people with autism.

This is not the first study to show a link between autism in oxytocin. Prior research has shown oxytocin also can help improve other aspects of social behavior, such as emotion recognition, in young adults with autism. People with autism are known to have genetic defects on genes associated with oxytocin while others have epigentic disregulation of said genes. It has also been shown that children and adults with autism have lower levels of oxytocin in their blood.

Or in simpler terms, we have a known genetic and environmental issue, a method of detecting the problem, and a potential way to address it. And, if the current study is any indication, addressing the deficiency has the potential to improve functioning in one of the core deficits of autism, at least in some people with autism.

If you remember what I wrote a few weeks back, there is some evidence that the first deficits of autism to emerge in infants are social ones and that some of delay in acquiring other skills, such as speech, might be due to problems with social learning. What would happen if we were able to detect these problems in very young children when they are first developing and correct them? I am thinking that it would be possible to prevent other problems from developing and help the infant progress at a normal pace.

The above is complete speculation on my part and a substantial amount of work still needs to be done before any treatments involving oxytocin are even possible. But the potential is there for this to become of the first treatments to target the core problems with autism.

Who could possibly be against that?

Well, Michelle Dawson for one. As I have written about before, Ms Dawson is one of the people who feel that it is somehow unethical to try to treat autism. Try as I might, I simply cannot understand why she opposes helping children or adults with autism. But I can easily point out the absurdity of her arguments against the current study.

As I said above, the current study demonstrated that oxytocin can improve social functioning and it is the way that it demonstrated this improvement that is the core of what Ms Dawson is objecting to.

This study was not an extended study of the effectiveness of oxytocin but rather a relatively simple test of whether there was any significant effect. The researchers were giving a nasal form of oxytocin and the effects of the dose were very short lived. As a result, the test used had to be a simple yet an effective measure of social functioning.

The researchers chose a simulated ball game that was played on a computer with three other players - A, B, and C. The study participants were under the impression that the other players were real people but, in reality, they were simulated by a computer program. The way the game was played was that once a player received the ball, they had to chose another player to pass it to. That player would then in turn pick one of the other players and pass the ball to them. And so on and so forth. Each game lasted a good number of rounds (passes).

The games always started off "fairly" and the three computer players (A, B, and C) would pick another participant at random to pass the ball to. But after a few rounds, the three computer players changed how they decided who to pass the ball to.

Player A (the "good" player) would choose to pass the ball more often to the study participant while Player C (the "bad" player) would choose not to pass the ball to the study participant very often. Player B would remain neutral.

To further stack the deck, the researchers told the participants that each time a player received the ball, they would earn 2 euro. So when the participant received the ball and earned money, they then had the option of returning the favor to person who passed them the ball or of passing the ball to another player. Thus, the game was a really a test of reciprocity. As most knowledgeable people would tell you, reciprocity is one of those social skills that can be disrupted in people with autism.

The study participants were divided into three groups - a "normal" group, a treatment group, and a placebo group. The treatment group and placebo groups both contained people with autism but the treatment group received a dose of oxytocin while the placebo group received a placebo.

As would be expected, once the bias of the other players became clear, the "normal" participants strongly favored passing the ball to player A (the "good" player), presumably because A was much more likely to pass it back to them, and much less likely to pass the ball to player C (the "bad" player), presumably because C was not as likely to return the favor.

The participants in the placebo group, unlike the "normal" participants, did not show a preference for passing the ball to any other player but seemed to pass it to the other players almost equally.

However, the participants in the oxytocin group more closely resembled the "normal" group and showed a preference for passing the ball to player A (the "good" player) while excluding player C (the "bad" player).

To confirm these findings, the researchers staged a second trial with a modified game using another group of adults with autism. The participants were once again divided into placebo and treatment groups but the game was modified to remove all mention of monetary rewards. The results were again the same, with the placebo group not showing any preference while the treatment group showed a preference for player A while excluding player C.

Based mostly on this finding (and several other secondary findings), the researchers concluded that oxytocin might help restore "normal" social functioning in people with autism.

To perfectly honest, this test is somewhat simplistic and not very indicative of what oxytocin would do for social skills in general. Based on the results of this one study, we cannot generalize the finding and say that oxytocin would be a good treatment for autism.  But for what it is, this study was well done and the results are pretty solid.

Now that I have explained the game, lets return to Michelle Dawson and her opinions of the study. Ms Dawson apparently feels that the reason the placebo group passed the ball randomly in the face of biased behavior is that -
The autistic [placebo group] in contrast displayed no such selfish and discriminatory behaviour. They continued to throw the ball to the other players in equal proportion, ignoring their self-interest in favour of keeping all players equally included.
Further, subjective ratings of the other players revealed that the autistic [placebo group] did not have the kinds of biases that are routinely called hypocrisy. They did not judge C, who shared the most with B, as worse or less trustworthy than A, who shared the most with themselves.
According to Andari et al. (in press), autistics "cannot understand or engage in social situations," as evidenced by autistics' outstandingly altruistic performance in this game. It is this profound social deficit, this altruistic autistic behaviour, that was targeted for treatment.
Basically, Ms Dawson feels that the placebo group was able to understand the social situation and made a conscious choice not to "judge" or engage in "hypocrisy". These "austicis" took the feelings of the other players into account and decided to act in an altruistic manner so that no other player felt left out. Taking this argument to the logic conclusion, the treatment group had to have lost the ability to act in an altruistic manner and decided to be hypocritical and purposely exclude the other players from the game.

Since these statements are contrary to everything that we know about autism as well as the very definition of what the medical condition of autism is, I would respectfully suggest a simpler explanation to fit the facts. The reason that the placebo group acted the way they did because was because they simply failed to react to the social situation.

If you look at the results of the game in the initial rounds before the other players started showing their biases, the "normal" group was sending the ball to the other players equally. It is only once the bias become obvious that the "normal" and treatment groups started changing their actions. This is a typical - and desirable - social trait. We are more likely to respond favorably to people who respond favorably to us and less likely to act favorably to those who discriminate against us.

But Ms. Dawson would have you believe that people with autism someone have a superior grasp of social situations and consciously chose to be altruistic.

Which of these sounds like autism to you?


References

Wermter AK, Kamp-Becker I, Hesse P, Schulte-Körne G, Strauch K, Remschmidt H. Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):629-39. PubMed PMID: 19777562.

Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4389-94. Epub 2010 Feb 16. PubMed PMID: 20160081.

Liu X, Kawamura Y, Shimada T, Otowa T, Koishi S, Sugiyama T, Nishida H, Hashimoto O, Nakagami R, Tochigi M, Umekage T, Kano Y, Miyagawa T, Kato N, Tokunaga K, Sasaki T. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J Hum Genet. 2010 Jan 22. [Epub ahead of print] PubMed PMID: 20094064.

Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, Hickie IB. Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders. Biol Psychiatry. 2009 Nov 6. [Epub ahead of print] PubMed PMID: 19897177.

Gurrieri F, Neri G. Defective oxytocin function: a clue to understanding the cause of autism? BMC Med. 2009 Oct 22;7:63. PubMed PMID: 19845973; PubMed Central PMCID: PMC2770459.

Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, Langford CF, Worley G, Delong GR, Murphy SK, Cuccaro ML, Persico A, Pericak-Vance MA. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009 Oct 22;7:62. PubMed PMID: 19845972; PubMed Central PMCID: PMC2774338.

Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C, Levin H. Plasma oxytocin levels in autistic children. Biol Psychiatry. 1998 Feb 15;43(4):270-7. PubMed PMID: 9513736.

3 comments:

  1. I did not see this in your list
    Nature. 2010 Feb 24.

    An intrinsic vasopressin system in the olfactory bulb is involved in social recognition.
    Tobin VA, Hashimoto H, Wacker DW, Takayanagi Y, Langnaese K, Caquineau C, Noack J, Landgraf R, Onaka T, Leng G, Meddle SL, Engelmann M, Ludwig M.

    [1] Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK [2] These authors contributed equally to this work.

    Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders and obsessive-compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

    I wonder about how the olfactory system , affected in autism in the context of sensorial disorder at an individual level , is not also involved.

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  2. and
    J Neuroendocrinol. 2010 Feb 20. [Epub ahead of print]

    Performance, properties, and plasticity of identified oxytocin and vasopressin neurones in vitro.
    Armstrong WE, Wang L, Li C, Teruyama R.

    Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

    Abstract The neurohypophysial hormones oxytocin (OT) and vasopressin (VP) originate from hypothalamic neurosecretory cells in the paraventricular and supraoptic (SON) nuclei. The firing rate and pattern of action potentials arising from these neurones determine the timing and quantity of peripheral hormone release. We have used immunochemical identification of biocytin-filled SON neurones in hypothalamic slices in vitro to uncover differences between OT and VP neurones in membrane and synaptic properties, firing patterns, and plasticity during pregnancy and lactation. In this review we summarise some recent findings from this approach: 1) VP neuronal excitability is influenced by slow (sDAP) and fast (fDAP) depolarising afterpotentials that underlie phasic bursting activity. The fDAP may relate to a transient receptor potential (TRP) channel, type melastatin (TRPM4 and/or TRPM5), both of which are immunochemically localised more to VP neurones, and especially, to their dendrites. Both TRPM4 and TRPM5 mRNAs are found in the SON, but single cell RT-PCR suggestsTRPM4 might be the more prominent channel. Phasic bursting in VP neurones is little influenced by spontaneous synaptic activity in slices, being shaped largely by intrinsic currents. 2) The firing pattern of OT neurones ranges from irregular to continuous, with the coefficient of variation determined by randomly distributed, spontaneous GABAergic, inhibitory synaptic currents (sIPSCs). These sIPSCs are 4-5 fold more frequent in OT vs. VP neurones, and much more frequent than spontaneous excitatory synaptic currents. 3) Both cell types express Ca(++)-dependent afterhyperpolarisations (AHPs), including an apamin-sensitive, medium duration AHP and a slower, apamin-insensitive AHP (sAHP). In OT neurones, both AHPs are enhanced during pregnancy and lactation. During pregnancy, the plasticity of the sAHP is blocked by antagonism of central OT receptors. AHP enhancement is mimicked by exposing slices from Day 19 pregnant rats to OT and oestradiol, suggesting central OT and sex steroids program this plasticity during pregnancy by direct hypothalamic actions. In conclusion, the differences in VP and OT neuronal function are underlain by differences in both membrane and synaptic properties, and differentially modulated by reproductive state.

    Please look at this
    The firing pattern of OT neurones ranges from irregular to continuous, with the coefficient of variation determined by randomly distributed, spontaneous GABAergic, inhibitory synaptic currents (sIPSCs).

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  3. Hi Maria,

    I did miss those two, thanks for the pointers. I will have to take a look at them. Thanks.

    ReplyDelete