By Leanne Chukoskie, Autism Speaks
In 2008, Autism Speaks kick-started research in the area of non-verbal autism through its High-Risk High-Impact initiative. This year at IMFAR, Autism Speaks-funded research was featured in the Invited Educational Symposium titled Characterizing Cognition in Non-verbal Individuals with Autism: Innovation, Assessment and Treatment.
Geraldine Dawson, Ph.D., Autism Speaks’ Chief Science Officer, chaired the session and set the stage for the audience to appreciate the importance of this particular topic. An estimated 30% of individuals living with autism are functionally non-verbal, yet very little research effort was directed toward helping this group communicate their wants and needs. The inability to communicate leads caregivers and clinicians to the presumption that the cognitive skills in these individuals were low because the tests typically used to assess cognitive skill require verbal or behavioral responses that this group of individuals does not readily produce.
The first speaker was April Benasich, Ph.D. of Rutgers University, who received an Autism Speaks grant for her research. Dr. Benasich presented data on innovative new studies on 3-7 year old non-verbal children with autism. Using tasks that were designed to assess children’s capacity to identify mismatches between sights and sounds. For example, a picture of a frog might be presented with the spoken word “frog” or “cow.” The latter, obviously incorrect, pairing generates a spark of electrical activity in the brain called a mismatch negativity about 400 ms after the stimulus was presented. This sort of task can also be used to probe contextual understanding in non-verbal children by pairing, for example, the frog with “green” or “pink.” Even greater complexity can be tested by presenting sentences with errors in syntax. When heard by children who understand language, these syntax errors generate the same kind of brain potential.
Dr. Benasich and her colleagues developed a training protocol to get the children comfortable with the application and wearing of the EEG net as well as exposing them to all of the concepts presented in the experiment. The results revealed some similarities and some differences in the processing of sensory stimuli in the non-verbal children and this is not unexpected as they continue analyzing these data and also new data on older non-verbal children.
However the real power of using EEG techniques for assessing cognitive capacity is that it can tell us for an individual what we cannot get from standardized cognitive tests. Dr. Benasich presented results from individuals, some of whom were picking up the mismatches in the pictures and sounds, or sentence errors and some of whom did not.
This was the launching point for the next presentation from John Connolly, Ph.D., of Mc Master University. Dr. Connolly typically studies individuals who suffered traumatic brain injury and must be assessed to appropriately design rehabilitative therapy. He and his colleagues adapted a standard test for word comprehension called the Peabody Picture Vocabulary test (PPVT) into a tool that can be used by measuring brainwaves – no oral or manual response required. A grant from Autism Speaks allowed him to adapt his methods to work with non-verbal individuals with autism. By learning exactly what these non-responsive adolescents can and cannot understand, one can more appropriately design therapies to help them move to the next stage of learning.
Nicole Gage, Ph.D. of UC Irvine relayed her studies of both speech and sound processing in minimally-verbal children with autism using a different brain measurement tool called magnetoencephalography or MEG. One advantage of MEG for children is that nothing actually touches the child during the measurement. Although they must lie very still, there is no noise and the device resembles a fancy salon hair dryer. Using this technology, Dr. Gage and her colleagues are finding differences in very early in brain processing responses to tones and mature early in human development. These responses occur at the level of the auditory brainstem and may be at least partially responsible for the atypically responses measured to both tone and speech sounds observed by both Dr. Gage and other researchers at the later stages of brain processing in auditory cortex.
Lastly, but perhaps most importantly, Connie Kasari, Ph.D., of UCLA and the organizer of this special session presented her Autism Speaks-funded treatment research specially tailored for non-verbal children between the ages of 5 and 10 years old. Dr. Kasari uses structured play-based methods to build a scaffold and provide context for encouraging communication in these children. Her randomized controlled trial design encompasses treatment sites at UCLA, Vanderbilt, and Kennedy Krieger and involves the play based therapy especially designed for these children and also a treatment arm that includes an alternative and augmentative communication device. Dr. Kasari showed data from the group thus far – after three months of the six-month treatment trial. Not only are some individual children making incredible strides toward initiating functional communication, but overall 75% of the children in the study are responding to the therapy. Interestingly, looking back at the detailed assessments taken on the participating children upon their entry into the study no particular features distinguished the responders from the non-responders thus far.
These studies break new ground in reaching those with autism who cannot speak. However, the next steps will almost certainly be the most exciting. As more researchers and clinicians learn about these studies and are able to take advantage of the results presented, we will be better able to understand and assist individuals who are now non-verbal. These sentiments were perhaps captured best in the enthusiastic response the speakers received from the loved ones of those affected.
I’ve just come from a morning at the Parents/Families/Community conference that’s associated with the big IMFAR autism science meeting. The conference moves around every year (some of the scientists have a reputation for getting wild) and this year we’re in San Diego. I flew in late last night just in time to sleep three hours and get up bright and early for the cab ride to the University of California at San Diego.
As long as I remain functional, I will be reporting on events here and at the main conference for the next three days. In addition, I hope to visit the San Diego container terminal and perhaps capture novel and exciting images of shipping and transportation.
As much I love ships and trains, I recognized my commitment to autism science and dutifully appeared where I was supposed to be, before I was supposed to be there. I was just in time for the keynote sessions, which I found totally fascinating.
The first talk I’d like to share with you concerned a program called PEERS, which was developed by Liz Laugeson, Psy.D. and Fred Frankel, Ph.D. of UCLA, and presented by Liz at this morning’s session.
PEERS is a science-based program that helps kids make friends. I say its science based because she actually tested and proved out the various concepts in PEERS through trials. By doing that, she was able to quantify what worked and what didn’t.
And that, folks, is a really important thing in the world of therapy.
Most therapists who work with folks on the spectrum do not have autism themselves. Therefore, things that may seem obvious to them may be totally obscure to the folks they are trying to help. Consider the example of a teen who has trouble getting into conversations with strangers.
A person who does not have autism instinctively reads the non verbal signals from people around him. He knows when to speak up and when to be quiet, and he knows how to join a conversation smoothly. At least, that’s the idea. A therapist who grew up with those skills naturally assumes everyone else is similar. That being the case, conversational skill is simply a matter of polishing one’s skill.
Unfortunately, for most autistic people, “polishing” does not work. We lack the ability to read other people, so “watching and slipping in smoothly” is not something we can do at all, without special training and a lot of practice. Yet that deficiency may not be at all apparent to a nypical therapist, even after he’s studied autism. Therefore, the advice that worked for him may totally fail for us, and he may not have any idea why, except to say “we just can’t get it.”
That’s where science and evidence-based therapy development come in. Researchers can try different ways of helping people solve problems, and then measure how well that training works in real life. By testing different strategies, it becomes possible to separate what works from what doesn’t, and to refine what works well into what works better. That is what Drs. Laugeson and Frankel have done with PEERS.
I could cite example after example from the book, but frankly, if you have a personal stake in helping people make friends, I urge you to buy the workbook. It’s written to do group therapy for high school students but it’s immediately obvious to me that the concepts can be used for self-study and even for Asperger adults. I mentioned that to Dr. Laugeson and she agreed but was quick to point out that the work had not been validated yet in adults.
So if you’re an adult Aspergian, or you know one… you can be among the first to try these ideas out. Let me know what you think.
The PEERS workbook is in many ways a clinical version of my “Be Different” book. In that book, I talk about the strategies I’ve used to find success, and how I made the most of my autistic gifts while minimizing my disability. What PEERS does is take those ideas to the next level.
I wrote about making friends from the perspective of my own success as a person with Asperger’s. PEERS approaches the same problem but from the perspective of many young people with autism, not just me.
PEERS was developed with funding from the National Institutes of Health. To me, it’s a great example of the kind of research we should encourage in the autism community. This is work that will be of tremendous benefit to many people growing up with autism now.
Over the next few days, I’ll be looking at all sorts of research. I’ll see work from biologists, geneticists, psychologists, neurologists, and psychiatrists. I’ll even be looking at studies from public health people and statisticians. Stay tuned as I report on highlights to come… after I walk over the check out the container terminal
You can find the book on amazon “Social Skills for Teenagers with Developmental and Autism Spectrum Disorders: The Peers Treatment Manual”
Many journeys to the same location – methods that 21st century scientists are using to identify genes that cause autism
We have asked several scientists who gave presentations at the April 10-11 DAN! conference in Baltimore to share their research and perspectives from the meeting with you here on the blog. The following piece is from Dr. Simon G. Gregory, Ph.D. Dr. Gregory is an Associate Professor in the Center for Human Genetics, Duke University Medical Center His primary area of research involves identifying the complex genetic factors that give rise to cardiovascular disease and multiple sclerosis, Dr. Gregory’s group is also applying high-resolution genomic arrays to the discovery of chromosomal abnormalities and identification of epigenetic factors associated with autism.
For decades scientists have relied on traditional genetic approaches to identify genes that contribute to the development of autism. These approaches have included collecting extended, multi-generation families that contain one or more individuals with autism. Once a sufficient number of these families have been collected, hundreds of DNA markers that can highlight differences between us all at a genetic level (a bit similar to DNA fingerprinting used in CSI) are used to identify a region of the genome is linked with the disorder in the families. More recently, higher resolution technologies that benefitted from the completion of the human genome project have been developed to allow us to look at hundreds of thousands of markers simultaneously. This approach differs from the family-based approach in that it uses thousands of unrelated cases and age/sex/ethnicity matched controls. Together, both approaches have been successful in identifying genes, or at least regions of our chromosomes, that play a role in the development of autism. However, we know that many more genes will likely contribute to autism spectrum disorders (ASDs) and that not all mechanisms that disrupt the normal function of a gene will be based on a single DNA mutation or a variant present in the general population.
My group at the Duke Center for Human Genetics recently embarked on a journey to identify autism genes using an approach that looks at chromosome content, and yet we reached an interesting finding using another technique that doesn’t rely on the sequence of our DNA. For many years it has been known that ASDs can be caused by loss (deletion) or gain (duplication) of chromosomes. These genomic rearrangements can be large or small and some have been shown to cluster in particular regions of the genome, for example on the long arm of chromosome 15 (15q11-13). Our journey began by assessing the genomic content of 119 unrelated autistic children from families that we had collected over a number of years. We used genomic microarrays (microscope slides with printed content spanning our genome) to identify novel or common regions of deletion or duplication within one autistic child from each family. Although we identified a handful of novel regions and confirmed dozens of rearrangements that have increasingly been shown to exist within the ‘normal’ population, we decided to focus on a single deletion in one individual. The deletion, which contained five genes, sparked our interest because one of the genes, the oxytocin receptor (OXTR), had been previously implicated in autism. Previous studies using the traditional genetic approaches (mentioned above) had shown that OXTR was genetically associated with autism, other studies had shown that levels of oxytocin (a neurotransmitter that the receptor binds to OXTR) is important for pro-social behavior and that a knock-out of the receptor in mice can affect this behavior, and very recent studies have tested the supplementation of oxytocin in adults with autism.
After identifying the deletion in the one affected child we screened his family to see if it was novel and causative of his autism, or if he inherited the deletion from his parents. Somewhat disappointingly, his mother also had the deletion, but interestingly she had self reported obsessive compulsive disorder (OCD) for which OXTR has also been implicated. Although we could have stopped the journey at this point, we decided try a different approach. Previous studies have shown that OXTR is controlled in the liver by a chemical group (methyl –CH3) that sits on top of the DNA but which doesn’t change its sequence (click here for more information on epigenetic changes as they relate to autism). The phenomena of DNA methylation is a normal mechanism by which our cells silence parts of the genome that they don’t want to be active (mainly repeat and retro-viral sequences) but they also use it as a switch to turn on or turn off genes for protein production. Significant in our journey was that the child with autism who had the OXTR deletion also had an affected brother. This is significant because when we assessed the methylation status of the whole family we noticed that the affected brother has very high levels of methylation in five different CG bases (among the A’s C’s G’s and T’s of our genome where the methyl group resides) in a 1,600 base pair window that had previously been identified as being methylated in the liver OXTR.
Differential methylation isn’t a novel finding as a possible cause of autism. Previous studies in Rett syndrome, which has ASD like symptoms, have shown that mutations in the methyl CpG binding protein 2 (MECP2) gene not only contributes to the development of Rett syndrome but that these mutations affect the normal functioning of the gene which regulates the expression of other genes by altering their DNA methylation state. Additionally, imprinting (the silencing of a maternal or paternal copy of a chromosome by DNA methylation) has also been established as the basis for the development of Angelman and Prader-Willi syndromes that, again, have ASD like symptoms. Our next step was to validate the observation that increased methylation of OXTR in the affected brother may be a causal mechanism of autism. We expanded our analysis to include evaluation of the methylation status of OXTR in the peripheral blood of 20 controls and 20 individuals with autism, and in a second dataset of the post-mortem samples of temporal cortex tissue (a center for language and learning) in eight controls and eight children with autism. In both datasets we were pleased to see that the individuals with autism had higher levels of methylation than the controls. We next measured the level of gene expression of OXTR because we would expect that increased DNA methylation would result in decreased gene expression – which it did in a very small number of samples that we could test.
So you’re asking yourself, how, if all these other studies had pointed to OXTR being implicated in autism, is this discovery significant? Well, we hope that we have found a unique autism-associated DNA methylation signature in a receptor for a neurotransmitter that is important in social cognition in autism. The next more exciting journey will be to substantiate what we have found in a larger number of samples and to establish if oxytocin treatment can help