Stanford/Packard autism researchers seek twins for brain-imaging study

2 Feb

The subject of twins and autism concordance comes up on LeftBrainRightBrain periodically. I find the questions raised to be very interesting and I’ve said a number of times I hope people take a closer look at twins.

Enter Dr. Antonio Hardan of the Lucile Packard Children’s Hospital (LPCH) at Stanford University in California. Dr. Hardan is a Child Psychiatrist with much experience in exploring brain structure in autistics. Yesterday there was a press release (which I can’t find now) calling for subjects for a twin study. The announcement is on the LPCH website.

Stanford/Packard autism researchers seek twins for brain-imaging study

Autism researchers at the Stanford University School of Medicine are recruiting twins for an investigation of the role of genetics in shaping the autistic brain.

“We’re doing a twin study to try to sort the impact of genetics on brain abnormalities in autism from the impact of the environment,” said lead scientist Antonio Hardan, MD, who is a child psychiatrist at Lucile Packard Children’s Hospital and associate professor of psychiatry and behavioral sciences at Stanford. Hardan’s team will use magnetic resonance imaging to scan the brains of 120 pairs of twins, some with autism and some without, to look for gene-brain associations.

Previous research has indicated about 75 to 80 percent of autism is explained by genetics, Hardan said. This means that if one member of a pair of identical twins has autism, the other will usually be affected. Having a fraternal (non-identical) twin or other sibling with autism raises a child’s likelihood of an autism diagnosis, but not as much.

Still, no one knows the degree to which genetic factors explain distinct structural and chemical characteristics in the brains of autistic individuals, which may include differences in total brain size and in the corpus callosum and amygdala.

Hardan’s research team will compare the level of similarity in brain structures of identical twins, who share all their genes, with the brain similarities of fraternal twins, who share half of their genes. They will also compare pairs of twins with autism with typically developing (non-autistic) twins to gain insight into which developmental patterns are distinct to autism. They then hope to figure out whether and to what degree there is a correlation between genetic profiles and the brain metabolites and structures of people with autism.

The team is seeking same-sex twin pairs aged 3 to 14. Study subjects can be identical or non-identical twins. The scientists plan to scan 80 pairs in which one or both twins have autism, and 40 typically developing pairs in which neither twin has autism. The scanning method, MRI, is non-invasive and does not involve any radiation exposure. All subjects will also receive standard cognitive and IQ assessments, as well as a battery of diagnostic tests for autism.

Testing will take four to five hours over two consecutive days, and each twin who completes the testing will be compensated $100. Subjects will receive summaries of their cognitive testing results, and confirmation of whether they are identical or fraternal twins. The twins’ families will also be compensated for travel expenses to and from Stanford.

“The scientific value of the study is a major one,” Hardan concluded. “We don’t know how much is inherited in terms of specific brain abnormalities in autism, and we also need to learn more about how environmental factors play into the development of the autistic brain. This study will help us gain that understanding.”

Hardan’s collaborators on the study include Joachim Hallmayer, MD, associate professor of psychiatry and behavioral sciences, and Allan Reiss, MD, professor of psychiatry and behavioral sciences and of radiology. Reiss also directs the Center for Interdisciplinary Brain Sciences Research at Stanford and practices as a child psychiatrist at Packard Children’s.

To obtain more information or volunteer for the trial, contact the study coordinator, Sue Cleveland, at (650) 723-7809 or cleve@stanford.edu.

There is some interesting research already on twins. One study (I only have the abstract so far) just came out last year: Gyrification patterns in monozygotic twin pairs varying in discordance for autism.

Kates WR, Ikuta I, Burnette CP.

Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, New York 13210, USA. katesw@upstate.edu

In order to disentangle genetic and environmental contributions to cortical anomalies in children with autism, we investigated cortical folding patterns in a cohort of 14 monozygotic (MZ) twin pairs who displayed a range of phenotypic discordance for autism, and 14 typically developing community controls. Cortical folding was assessed with the gyrification index, which was calculated on high resolution anatomic MR images. We found that the cortical folding patterns across most lobar regions of the cerebral cortex was highly discordant within MZ twin pairs. In addition, children with autism and their co-twins exhibited increased cortical folding in the right parietal lobe, relative to age- and gender-matched typical developing children. Increased folding in the right parietal lobe was associated with more symptoms of autism for co-twins. Finally, the robust association between cortical folding and IQ observed in typical children was not observed in either children with autism or their co-twins. These findings, which contribute to our understanding of the limits of genetic liability in autism, suggest that anomalies in the structural integrity of the cortex in this PDD may disrupt the association between cortical folding and intelligence that has been reported in typical individuals, and may account, in part, for the deficits in visual spatial attention and in social cognition that have been reported in children with autism.

I find this to be rather interesting. “We found that the cortical folding patterns across most lobar regions of the cerebral cortex was highly discordant within MZ twin pairs.” In other words, the physical brain structure is different within “identical” twin pairs. Recall the twin pairs in this study “displayed a range of phenotypic discordance for autism”. It is hard for me to simplify that without oversimplification, but the twins do not have the same autistic traits, and perhaps differing ASD diagnoses.

There is also an earlier study by Dr. Hardan and colleagues that seems relevant, even though it is not a twin study: Increased frontal cortical folding in autism: a preliminary MRI study.

Hardan AY, Jou RJ, Keshavan MS, Varma R, Minshew NJ.

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. hardanay@upmc.edu

The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder.

Below is an image from the Hardan study. The “gyrification ratio” is a measure of the inner contour to the outer contour.

Diagram showing manual traces of cortical contours

Manually traced inner and outer cortical contours used for measuring the gyrification index.

The results of the Hardan study were “preliminary”, and there was a statistically significant difference observed in those measurements. What was observed was “Interestingly, there was a significant decrease in the frontal gyrification patterns with age in the autistic group (right side: r=?0.44, P=0.012; left side: r=?0.48, P=0.006), which was not seen in controls (right side: r=?0.12, P=0.51; left side: r=?0.065, P=0.72). ”

I find this interesting–the GI (consider it the “folding” in the brain) differs by age for the autistics but not for the controls.

Again, I find the proposed twin study to be interesting and potentially very valuable. I hope Dr. Hardan can find enough study subjects to complete the study. There probably are not a lot of parents of autistic twins who live near Stanford reading this blog, but who knows?

13 Responses to “Stanford/Packard autism researchers seek twins for brain-imaging study”

  1. passionlessDrone February 2, 2010 at 22:25 #

    Hi Sullivan –

    I find this interesting—the GI (consider it the “folding” in the brain) differs by age for the autistics but not for the controls.

    I would have thought that this wouldn’t really be a time mutable property; i.e., your cortical folds were largely set in utereo. Of course, I may be wrong here. (?) But given that reasonable sounding assumption, I guess my from the hip idea would be that it is possible we are observing similar behavioral manifestations of autism driven by different forces.

    My highest praise for posting something not Wakefield related! And what’s more, this is pretty interesting stuff!

    – pD

    • Sullivan February 2, 2010 at 23:19 #

      Thanks pD.

      I’m sort of tired of the Wakefield saga myself. Unfortunately the straw men arguments have moved to HuffPo, and they are pulling their old War Horse, David Kirby, out of the stables…so I will have to do at least one more Wakefield Post.

      That said, the change in folding struck me as odd at first too. I look forward to Dr. Hardan’s study.

  2. Clay February 2, 2010 at 23:33 #

    I imagine we’ll dust off the Wakefield story again in April, when he loses his license, maybe gets arrested.

  3. Laurentius Rex February 2, 2010 at 23:50 #

    I shall cry ethics again.

    This might not involve radiation, it might not involve invasive procedures a la Wakefield but anyone who has ever had an MRI will know it is not a particularly pleasant procedure if you are highly sensitive to noise or at all claustrophobic.

    But leaving that aside, the niceties and subtleties of experimental procedure are never properly considered becuase I guess the researchers lack the thery of mind to put themselves in a subjects place.

    But leaving that aside, The last bit is interesting, it is coming together isn’t it. Essentially what determines autism or that which we currently call autism is governed by the trajectory of a folding brain, that folding being of course a mathematically described process contingent upon the variety of factors that give rise to the formula that governs it, so that it simply must proceed that way because the process allows no choice. A manifest destiny in the topology of the brain. I am sure Roger Penrose is loving it.

  4. Dawn February 3, 2010 at 15:08 #

    @ Laurentius Rex: I agree that an MRI is not pleasant, even if you are NT. The noise can be awful, even with earplugs. The place I had my MRI done does offer earphones with music, if you prefer. I don’t know if that helps one cope or not. I think the investigators are trying to work ethically, but you are right, there may be issues they have not considered. Do you have any suggestions? As an autistic person, you may be able to give them ideas for helping the tested children cope…unless you feel the testing itself is unethical.

    • Sullivan February 3, 2010 at 16:02 #

      Dawn,

      I can’t and won’t try to speak for Laurentius Rex, but here is my view–

      MRI deservedly won the Nobel prize in medicine. It is very much “science fiction” in the real world–being able to see 3-D images of soft tissue from a non-invasive technique.

      They are noisy. Fist there is the noise of the helium compressors (that rhythmic sound you hear all the time–even when the MRI isn’t operating). During the measurement, the gradient magnets move, and that causes noise. Add to this the claustrophobic feeling many get in the tube. They tried an “open” MRI design, but it didn’t work out.

      Some people need to be sedated for MRI. Consider someone with limited receptive language and a need to stim. I would add the stress of being in a clinical environment–consider the person who has been basically traumatized by numerous tests from early on in life. Going to a clinic, the wait, the doctors in their lab coats. It is a big stressor.

      The question is whether the information gained is worth the price paid by the study subjects. If I had twins and were close to Stanford, I would likely join this study.

      One of the crimes in the Wakefield research is that by screwing up his studies so badly, he disrespected the contributions of his subjects.

  5. Laurentius Rex February 3, 2010 at 16:11 #

    I think there is a big difference between volunteering oneself for an uncomfortable and unpleasant procedure and volunteering ones children.

    I have had four MRI’s to date, all of them clinically necessary, even so they are on the edge of what is tolerable to me, and on the first occasion I pressed the panic button before the procedure had even started.

    I don’t see how I would have been able to accept the procedure as a child, who had to be brought kicking and screaming to the dentist.

    Sedation is really the only option, but the problem is that sedation is not an entirely safe procedure, to be undertaken for the purpose of an experiment, rather than clinical necessity.

    When I have had MRI’s there is a box to tick, if you consent to medical students having access to your scan for teaching purposes, I have ticked yes in all instances.

    It is a serious ethical question, hinging on notions of informed consent and what to do when informed consent is not possible.

    • Sullivan February 3, 2010 at 16:44 #

      Laurentius Rex,

      no one is denying that there is a big difference between volunteering one’s self or one’s child.

      Also, not everyone is like you. As a child I quite enjoyed closed spaces. MRI’s do not bother me at all. I know one person who fell asleep in an MRI. They are not distressful for everyone.

      The parents, the doctors and the institution’s ethics board all have input as to whether the cost expended by the children is warranted by the potential knowledge gained. All three have the ability to veto.

  6. Laurentius Rex February 3, 2010 at 17:38 #

    A plague on all your houses, this is what gets me about so many hubsters, not substantially different from the mercurians at all when it comes down to it.

    If it backs what you say then it is never wrong, there is never any harm in it.

    If it does not back what you say it is the work of the very devil himself.

    I have had enough of double standards. Something is very rotten in the fabric of the ethical review boards.

    Yes I suppose if it hadn’t been Waker’s study at the royal Free, what jolly good fun some children enjoy having there bowells scraped.

    • Sullivan February 4, 2010 at 02:54 #

      Laurentius Rex,

      I am not sure why your response was so harsh. I am merely explaining my position. Perhaps if I made myself more clear.

      You are correct, and I take it as a given that there are informed consent issues involved in medical research involving children. Serious issues. In this research project I mentioned the fact that depending on the disability of the child, he/she might need to be sedated for an MRI. That is a very serious statement, but I can see where it doesn’t come across as such. If a child is actually anesthetized (as opposed to, say, giving some benedryl in hopes the child will sleep), that is very serious. It is one of the problems with Dr. Wakefield’s research that is not mentioned often–children should not be anesthetized without reason. I place it close to as serious as performing colonoscopies without reason.

      I assume this is one reason why Dr. Hardon’s previous study was only on “high functioning” autistics. That would (a) allow the children to have input into whether they would participate and (b) remove the need for sedation.

      MRI’s can be a source of much discomfort for many people. However, not all people feel this way. As I noted, I know of someone who fell asleep in an MRI. I now someone else who nearly panicked. Now, let’s say a child, a study subject, is not discomforted by an MRI (or not overly discomforted). Further, let’s say that this child is capable of and does agree to undergo the procedure.

      Is there a problem with that scenario?

      Now consider the fact that we all benefit from the sacrifices others have made in undergoing clinical trials. That is where the real question comes into play. Believe me, I take the question–both of protecting my kid and responsibility to help others–very seriously.

  7. Lori February 3, 2010 at 20:27 #

    As I join this discussion I glad that so that safety of the children are a priority. MRIs can be scary to some people, but it is a non-invasive procedure (except for needing sedation) I personally am not a fan of enclosed surroundings, however I think that this study could be a starting point to see if there is a genetic component that is being triggered in some children and not others. This is not the first study that twins were being used to study genetic correlations linked to a disease or disorder. I hope this leads us to answer the big question everyone on this blog wants to know. What makes one person autistic and not another?

  8. Laurentius Rex February 4, 2010 at 12:21 #

    My apologies Sullivan, but as you may have percieved I feel very passionatly about the ethics of Autism Research and the misuse of vulnerable children as rungs in an academic ladder.

    On a positive note, I have just recieved word from SBC that I am allowed to submit a non empirical abstract for a poster on ethics at the forthcoming Cambridge Jamboree.

    Doesn’t guarantee acceptance but I hope it will be, as I think it is about time that ethics were on the agenda at these conferences. If it were I would never need to be a heckler on the sidelines as I was at the last IMFAR meet in the UK.

    • Sullivan February 4, 2010 at 19:35 #

      Laurentius Rex,

      no apologies needed. I’m sorry I am not always good at making my points clear and this sometimes leads to tense discussions here and elsewhere.

      I appreciate your passion–I need more people who feel passionately about the welfare of others, especially the disabled.

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