NIH CLINICAL CENTER GRAND ROUNDS
Episode 2010-06
Time: 1:05:37
Recorded February 17, 2010

A Clinical Update on Autism and the Autism Spectrum Disorders
Susan E. Swedo, MD,
Chief, Pediatrics and Developmental Neuroscience Branch, NIMH

Cognition and Brain Functional Connectivity in Autism
Alex Martin, PhD,
Chief, Section on Cognitive Neuropsychology,
Laboratory of Brain and Cognition, NIMH

ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.

(Music establishes, goes under VO)

ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded February 3, 2010. Today, we have a special "Ethics Grand Rounds" presentation on the topic, "Navigating Mismatches in Patient Preference and Staff Expertise." Our speaker is Dr. John Lantos, Director of the Children's Mercy Bioethics Center at Children's Mercy Hospital in Kansas City. We take you now to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland, where Dr. David Wendler, head of the Unit on Vulnerable Populations at the NIH Clinical Center Department of Bioethics is introducing today's speaker.

SWEDO: Hello. I do want to share with you that I have no conflicts of interest and that today we're going to try and cover a lot of material very quickly. So some of it's going to be quite superficial and I apologize for that as well. I did want to just touch on some of the things that you've probably seen in the headlines and the hype around autism, and we continue to be amazed at how much it has really reached into the mainstream media as well as into everybody's life. And one of the reasons is just the reported increased prevalence rates. We'll be talk a bit about that as well as some of the work we're doing here in the intramural program. I hope to set up things for Dr. Martin so when he presents his elegant findings from his research you have a context in which to place those findings.

So autism, it's incredibly important to remember that it's a developmental disorder. This is not something that should be diagnosed in the 14 year old socially awkward boy who has obsessive compulsive disorder but has previous had fairly normal interaction, normal communication patterns, and no presence of other disqualities. The onset has to be before age three years. Now the new criteria may well say it might not be manifested that early because the social demands of the young child may not allow the symptoms to be apparent.

Autism is only one of several pervasive developmental disorders. Many of you in the room probably didn't even know that the general category is pervasive developmental disorder rather than autism spectrum disorder because ASD has really replaced PDD in our medical literature. But pervasive developmental disorder was never really a very good name for this category of symptoms because it is characterized by very specific deficits. Deficits in social interactions, specifically the inability for the person to develop peer relationships, to express themselves verbally and non-verbally. But you can have fairly normal speech as you see in the Asperger group. In the young child, it's the failure to have joint attention. When I look at the screen, you all also look at the screen, or if i call your attention to me, you direct yourself. That doesn't happen in autism, and we'll see an example of that in a moment.

Communication deficits. I once was trying to understand autism a little better and stated "I'm teaching everything I know, and still vying for the things I still don't know." I said to my colleague "it's like me going to France and not speaking the language," and she said "no, it's you going to France with your eyes partially masked and your hands tied behind your back." That is a very good analogy for what it must be like for the individual with autism, as they try to navigate the world without the ability to read others facial expressions and to communicate their own emotional and other needs, non-verbally.

The third criterion is equally important, and in fact some recent data show that the presence of repetitive behaviors in aided interest is probably the most defining symptom of autism spectrum disorders; that repetitive behaviors really does separate the individuals who are not in this group from others. And they're quite specific, so that repetitive behaviors is playing with the wheels on a toy rather than playing with the toy itself.

Unusual attention to details. Certainly missing the forest for the individual tree or preoccupation with one or more restricted interests.

When you talk with the families about what it's like to get their children up out of bed in the morning and dressed and out the door, you're exhausted by the time you have the ritual done. The ritual has to be followed, because one time it was done that way and that became fixated in stone.

And then finally, stereotyped and repetitive motor mannerisms. The families call them stims. Very frequently you'll see flapping and other stimulatary behaviors. When you talk to the adults who are able to speak about these behaviors, they talk about how they actually have some self-soothing role in their life, but also other times it's just clearly the person unaware that it's happening.

This is to show you the failure of joint attention. You can read Stacey's lips and see her say "look at that," and the young girl Rosy will not do it. You can see she's trying to make eye gaze and she won't make eye gaze. Can you play it one more time? She won't make eye gaze here. When Stacey tries to direct her attention over to the corner, actually towards her mother, she doesn't look there either. Thank you very much.

So the core symptom remains again, social impairment, speech communication deficits, repetitive behaviors, and fixated interests.

In the group with autism, they need to have all three symptoms, for Asperger's they only need to have two out of three. Asperger's is one of the most quickly growing diagnoses because of the inability to determine how early the symptoms started and be sure they started before age three. If we did a circle for PDD-NOS it might be that small, or this large, because of the fact that there was major change that apparently happened somewhat by accident, requiring only one of those two associated symptoms (either communication deficits or the repetitive behaviors and fixated interests). So many children have been given the diagnosis of PDD, where a more appropriate diagnosis might be attention deficit hyper activity disorder.

Probably the most frequent headline, at least from my count, was that autism has reached epidemic proportions, and when the word autism is used by the mainstream media it always mean autism spectrum disorders, which include all of those children with pervasive developmental disorders not otherwise specified, as opposed to the 1980 definition of autism which was the three cardinal symptoms required.

The change actually began in the 90's but the first studies were record in the 2000's and the rate has gone very quickly to an almost unbelievable rate, reported to pediatrics in October of 2009, of one in 50 boys and one in 91 children overall.

The CDC also had a press release on Christmas eve reporting similar rates, and those are the ones that are quoted most frequently now, with one in 90 children overall meeting their criteria for autism in some of their vanguard centers.

So you can imagine the autism epidemic has raised a lot of questions and interest and really for me raises the primary question "why are autism rates rising so dramatically?"

I think we have to first correct that question to "why are reported autism rates rising so dramatically?" Look at some of the reasons that that might be. It's absolutely possible there are more cases, and that this is a true epidemic. And in that case, there should be identifiable triggers for that change in prevalence rate. However, we've been limited by the fact we don't have incident studies, we don't have even appropriate prevalent studies prior to some of the definitional changes that make it really, really hard to make those comparisons. The definition changed in going from DSM-3R to DSM-4 which is in 1992, I think. About that same time the department of education also allowed specific services with autism spectrum disorders that were not previously granted.

There has been some discussion about whether this is all diagnostic substitution. Have we substituted autism spectrum disorder from mental retardation? There was one study suggesting that wasn't true. Subsequent studies have suggested that perhaps it is, making sure that children would have been given the true pervasive developmental disorder ie: mental retardation, rather than the more specific and targeted autism spectrum.

There's a very early active awareness campaign with pediatricians, I would say not mandated, but certainly strongly encouraged, to have assessments at 12 months, 18 months and 24 months of age. And we know the autism diagnosis increases, as services provided by school systems increase. That's one of the reasons that school system diagnosis appear to be so high, they have some of the best rates possible. Many of the people counted in a survey demonstrating autism diagnosis were actually immigrants to the county, specifically for the school services.

Another more interesting and curious finding is that the number of advocacy groups in a specific region will also increase with the rates of autism. And that can be by four to eight fold for each advocacy group.

And finally, probably the most appropriated fact, that different methodology and analytic techniques are used. Well the change in definition I told you about, a broader phenotype, is now standard. PDD used to be a very rarely used part of this category, but it now accounts for over 50% of the studies and foundations, where 12 different sites are cumulative individuals with autism for genetic studies. The rates of Asperger's and PDD-NOS tend to be directly proportional. CDC is quite limited by the fact that they use the school records. And the school records they were able to access were for those for special services.

Anybody who has a teacher in their family, such as my mom who is a retired special ed teacher, knows that those IEP's contain exactly the words that are need to give the child the help they need, and to counted (as a means of counting cases) may or may not be appropriate. It would certainly be helpful if that case has been followed up with some kind of in-person evaluation of whether or not the child met the full true diagnostic criteria. But that has not happened. CDC feels there's some evidence that some locales are under-diagnosed, such as West Virginia. It's interesting that the under-diagnosed areas are the only one that haven't had an four to eight fold increase in the last eight years.

In terms of pediatric studies, the one reported in the media as having "shocking and staggering rates" revealed one in 58 boys and one in ninety one children having an ASD diagnosis. The study was done by a telephone survey. It was found that 40% of the children who had ever had a diagnosis of PDD-NOS or autism spectrum disorder, therefore counted in the case, no longer had their symptoms. For a neurodevelopmental disorder that didn't remit, I didn't think this would be possible. The question that was actually asked to ascertain PDD and autism was so long that as a parent trying to listen to it, I think I would have focused in on the developmental disorders that came towards the end rather than all of the things that preceded it. And interestingly, those who had reported that their child had previously had a diagnosis of PDD or autism spectrum disorder and now did not, all maintain learning disabilities or intellectual disabilities.

There's a couple of studies, one study in particular that didn't make the headlines and it's equally curious why that didn't happen. You would think people would be interested in hearing the changes in adults. That would be equally concerning in terms of providing services. A study in England that's now been repeated here in the United States shows that if you apply the criteria used in the CDC study to adults living in households throughout England, that the rate is one percent of the adult population. So not only have we had an epidemic in our eight year old boys counted by the CDC, but also amongst adults, and it clearly has to be a change in criteria. It may be that we've lost Garrison Keillor's Norwegian bachelors; amongst those that may very well meet the criteria if we don't consider this disability, and we need to. So from now on, when I speak about autism, that's what I will be talking about.

The causes of autism are known for very few individuals, and I think that's one of the problems that makes this frightening and frustrating for parents and physicians alike, the fact that about 10 to 11% of children can we assign a genetic or other cause. The vast majority of cases are idiopathic. It's presumed it's a combination of environmental and genetic factors, just as it is for other genetic disorders and diseases. The question is when in development did that occur? Was it in the second trimester, as early technology studies would suggest? Is it the 18 month check up when the child gets their shots, which is something that the parents have concluded? What, when did the damage happen? What will the consequences be?

For genetics, there are two main theories of how genetics contributes to autism. One is you have a rare variance that occurs in an individual case. A small, chromosomal region or single gene disorder may be causally related. The problem is for those who have the genetic defects identified, to date, very, very few of them are specific to autism. They tend to be more broadly associated with mental retardation in general. There are a few that are very exciting. And there are also common variants; just a little dose from a lot of different places can end up giving you the deficits associated with autism.

Environment has gotten a lot of attention. Again, they would claim environment more from the mainstream than from science. One of the reasons is that it's really very difficult to track down an environmental trigger to a neurodevelopmental disorder. We think about Agent Orange, we think about the story where it's something that has happened to the parent 10, 20, 30 years before. Not 30 but 10 or 20 years before the pregnancy occurred that actually had led to the problem. And you can see how difficult it is in autism. Many, many different things have been suggested. Some have actually been proven, such as thalidomide during that epidemic. More recently, things like technological advances, other technical interventions. There's a suggestion that the number of ultrasounds may be correlated with the increased risk of autism and there's scientific work suggesting that maybe actually, ultrasounds may have an effect on the developing brain. Certainly makes that of interest, if not concern.

One of the main questions that have been debated over and over again is does mercury cause autism? This became newsworthy in the 90's and has continued to be maintained, despite the fact that more studies have been done showing that there is no relationship between mercury and autism, than any other environmental consequence and in fact any other factor alone. But advocates Remained convinced there's a real question why that has occurred. Dr. Wakefield has kindly retracted his paper, which fueled this controversy, if not only initiative, it but led to a loss of immunity in the united kingdom following his report that the individuals with autism had enterocolitis in which live measles vaccines were associated. If you want to read the whole story, dr. <…> does a beautiful job of laying it out. I found this book to be one of the most fascinating I read recently.

As scientists and as physicians, we never say never and we almost never say always. Where advocates always do. So you're arguing 100% certainty versus the 99% certainty factor. And even our former director, Dr. Bernadine Healy, got caught up in this by saying we can't be certain that autism couldn't be caused by mercury in a rare individual. We did the calculations. It would be one in five million children. So for that one in five million, it's probably not worth spending the amount of money.

There's certainly conspiracy theory. The CDC is thought to have a conflicting role because of the necessity of their role of vaccinating children. That comes from the fact that other problems, such as the rotavirus vaccine which the doctor has a role, were quickly found. And possibly a role for pending litigation. If it's not mercury, then there has to be something else in the vaccine because my child was fine until he got his shots when he was 18 months old and then he became autistic. Did it occur overnight? No. But that doesn't make the headlines. And it is a very compelling case to say no we're not anti-vaccine, we're just anti-poisoning our children. And I don't know if you can read this, but the vaccine ingredients, the one that has created the greatest difficulty, is this aborted human fetus cells. So there was actually a warning that went out in some of the catholic circulars telling parents that if their children were vaccinated for h1n1, that it was not moral because these vaccines included these aborted human fetus cells. This kind of rumor is really hard to attack as facts so you end up moving forward and trying to find the real cause and the real solution in order to come back. But that question of the child who was normal until they got their 18 month vaccine and then developed autism is really an intriguing one. And we hear it all of the time. So one of the questions becomes is it just truly unrelated, where the child got their vaccines in 18 months because they were healthy, and they got autism at 18 months because that's when it was going to happen? Or is this a causally related fact? Trying to tease that out and separate that out is very, very difficult.

In our intramural program, our boss challenged our group to try and do that. We thought one of the simplest ways might be to look at individuals who had a history of clearly normal development prior to the onset of autism symptoms and compare those against children who had an earlier onset of autism, what we call regression versus non-regression studies. So what we found very quickly is there's no such thing as a dichotomy between autism or excuse me, regression and non-regression, it actually occurs in the continuum. I'll show you one of our best examples of aggressive autism. Remember Rosy who we saw who could not be brought to attention. This is her at six months. Her dad just called her name. She just brightens up and just blossoms. Here she is at her first birthday party. Her dad calls her name just as she turned the pencil over. Probably the most striking one, I apologize for the lack of sound. "Rosy, Rosy." she is clearly looking for something else to attend to and her father's calling her name loudly and with a great deal of love and affection and she doesn't acknowledge his existence. So regression versus non-regression. In fact it's actually continuum in which the largest portion of the children actually follow that middle ground between some abnormalities in early development and also some language that developed and then was lost or some social skills that were developed and lost. Part of that is automatic versus the procedural in social interactions.

Let's just quickly, very quickly move to the question of why would we want to study autistic children and look at the difference between regression and non-regression. We hope to identify abnormalities that would identify the child with vulnerability or susceptibility to environmental triggers in that regressive group, that we didn't find in the others.

The 50/50/50/studies. 50 with autism, 50 with regressive autism and 50 with typically developing controls. Then we had 25 in the contrast group. Some of the early findings are findings that show EEG's were abnormal in approximately 60% of the children in an overnight study, with the presence of frequent epileptic discharges. We did not organize them to a seizure, did not have the format that did interfere with conducting some recent studies. We hope we will provide a new target and have a new direction by initiating a placebo-controlled trial for the discharges in children who do not have seizures doing a six month study to see if that has any effects on both the EEG pattern and the behavior. We hope to enroll 30 children in the placebo group and 30 children in the active treatment, active drug group and compare and contrast the results.

Another problem in autism is comorbid sleep difficulties. They have trouble falling asleep, staying asleep, and parents describe them as very short sleepers. The parents are exhausted because the children don't sleep. In our study, we didn't have many parents with complaints of sleeping with their children because in the regressing study the children were quite young. Some at four years of age. What we found in modified poly sonography, is they had a decrease in sleep efficiency, trouble falling asleep, staying asleep. The most striking fact was they had a decrease total time spent in REM with about a quarter of the children having zero REM sleep throughout the night. With the role of REM in memory, learning consolidation and other cognitive tasks, it isn't difficult to speculate that that might also play a role in the children's problem. Here's the comparison, this is the children with non-regressive autism, children with regressive autism. Here's our group of developmentally delayed children and here's our group of typical. You can see it's just a very striking difference in the mean percentage time in the time the child spends in REM.

Dr. Buckley, one of our fellows, designed a possible treatment for the decrease REM sleep or the final stages of determining the appropriate dose for a larger placebo control trial and has been able to demonstrate relatively small dose Donezpezil, 1.25 to 2.25 milligrams, brings these childrens REM sleep up to the normal range.

Other PDD, we spoke about the larger subtyping study. We talked about these studies and that's drawing to a close, but we're looking to other developmental disorders. We're doing a study of individuals which remitted autism. These are older children and adolescents in which the parents report they had full blown symptoms of autism early in childhood and either treatments with biomedical interventions, behavioral interventions, or spontaneously that the child no longer meets criteria for autism. Again comparing those who remitted with a similarly severely affected group of individuals in whom symptoms did not remit, we hope will provide a secret.

This one, this study is modeled on leukemia studies in which everybody contributed just one or two percent to changing childhood acute lymphoblastic leukemia from a nearly fatal diagnosis to universally treatable. And it was the fact that it was comparison of those who did well versus those who didn't.

Riluzole is a glutamate agent. Dr. <…> is leading a study on OCD, and Carlos <…> is leading a study on adult OCD using Riluzezoilfe for adult symptoms.

We have a couple of hypotheses testing experiments, and our most recent one is being done in connection with doctors from the child health institute which will be doing skin biopsies. For them to look in a lab.

We're looking at studies of Oxytocin versus placebo on specific social tasks as well as Paul Grant is following up with the Riluzole to see if MRS can detect changes in the glutimate glycine ratios.

I want to thank our many collaborators.

I don't want to go to the list but I'll leave the focus instead on the staff who have been heroic in their efforts to tackle this very challenging disorder.

Thank you.

[APPLAUSE]

I left absolutely no time for questions. In fact I stole some of Alex's time so I'll have him come in.

MARTIN: hopefully I can do this quickly enough so we can allow questions for both myself and Sue. So first, with regards to financial disclosure, financial relationships, I got nothing.

[LAUGHTER]

So look. Here's the thing about that. Nobody ever taught you what you would pick up that would make that an ironic statement within the context of the NIH or a younger statement. Right. We all just do this spontaneously and automatically. What you can do and what you just did automatically and spontaneously is exactly what the patients I'm going to be describing to you cannot do

So as Sue just described to you, we consider the entire autism spectrum. It's characterized by a diverse set of symptoms, both socially based and non-social. And these are being constantly modified by developmental forces. So from the standpoint of cognition in the brain, there's a lot about our current knowledge of autism that feels like this kind of story I'm sure you all know, the blind man and the elephant. Everybody's got their particular piece, everybody's got their, you know, particular theory about what's going on and it's very difficult to get a picture of what this whole beast looks like.

Now there's an alternative idea which is expressed here, and that is that there simply is no single entity that needs to be described. And this was described as a tremendous tenatity attributed with this disorder. There's unlikely to be a cognitive formulation or a genetic cause that's going to cause for all the different symptoms associated with autism. I want you all to keep heterogeneity in mind, and I think hopefully you all agree that these kinds of issues are not going to be settled. That is whether there's one or many disorders here until we develop biomarkers. So keep that in mind and the heterogeneity.

I'm going to be focusing on one group of patients that is turning out to be surprisingly homogenous with regards to their symptomatology and this is in the high end of the functioning spectrum. So the plan, and you can use these as the objectives. First, I'm going to quickly describe for you the social processing deficits that are associated with this disorder and these high functioning individuals. Then I'm going to turn to the imaging studies on the integrity of what's been called the social grain. And then the bottom line here is going to be from these first two parts is that these individuals as I just described to you seem to be suffering from the disruption in the circuitry that allows us to spontaneous and automatically generate inferences about our social world. At the end I'm going to turn to this issue of biomarkers and the analysis of task free or resting state MRI data might in fact allow us to map out and to be a potential bio marker for the disorder. I hope that will become clear as we go on.

So the social symptomatology. Faces are in fact a quintessential social object. We use them to infer what other people are thinking and what they're feeling. These studies have kind of documented these individuals have this impaired orienting as sue was showing in very young kids and you can see it in older ones as well. And a good marker for this impaired orienting is abnormal eye gaze that contain people as denied in these studies.

In our lab, we've been looking at this issue specifically with regard to the notion of domain specificity. That is whether these eye movement abnormalities really are central to processing social stimuli or is it a more general problem. This study is being led by Joe Snow in the lab. These are in slab race with the children's medical center. They do all the diagnostics to make sure that the patients that we're seeing do in fact fit into standard diagnostic criteria for high functioning autism. About half of them would be considered Asperger's, the other high functioning. They are mostly teenagers, average age around 17 and they have normal IQ's so that you can see the range is fairly large. So the idea is that we can present these faces within the context of a memory study. One at a time. And the subjects were simply told to try to remember these stimuli and we're going to compare their performance to these non-face objects and this is where the domain specificity argument comes in. In this case, a single basic level object, a fan that certainly shares some general features with faces. And in our high functioning individuals, we do indeed find this kind of data, support this social orienting deficit. And the slides are going to be shown to you are typically developing. That's the TD's. Controls will always be in blue. The patients are shown here in red. Here's an example of their eye movements. Here's the actual data and then what we find is that while they're studying stimuli, they in fact make fewer fixations. They seem to get stuck or fixated as sue mentioned on various parts of the face, for example. And therefore make fewer fixations overall during the study. Whereas to these other stimuli that show no difference to the controls at all. That kind of oriented deficit can have much more severe problems for more higher order kinds of processes so here you can see also this domain specific impairment in their memory. Their recognition memory for the faces versus these fans. Both of these are highly significant interactions. This kind of orienting deficit also seems to carry over to one of the cardinal features of this in high functioning autism and actually throughout the spectrum. That's the inability to properly read the emotional expression from the face.

This is a study led by Greg Wallace, whereas in this example, faces are marked from this neutral example here, the zero percent and 5% increments all the way up to a particular expression, in this example a sad face. Here on the y axis is the percent of subjects who were correctly categorizing these as sad faces as you go along the north dimension. The ad is in red and the PD is in blue. As you can see every one of our subjects, again these are high functioning but all of the ASD individuals, know a hundred % more that this, is of course indeed a sad face. The problem comes in with a more subtle degradations and emotions. For example you can see the 70% morph, whereas 90% of the developing controls will correctly label that as somebody showing sadness. Only about a third of the normal intelligent high functioning subjects do, suggesting in fact that they have this more subtle difficulty inferring emotions from these kinds of queues. So one way to understand this, and this is what I was suggesting at the very beginning, is what we're seeing here is a deficit in this kind of automatic spontaneous behavior that allows us to orient and allow social stimulus and it's only within that realm. This has been suggested by a number of investigators.

There's a really beautiful demonstration/administration of this that was published this past summer in science by the Fritz group showing the same kind of difficulty. Participants retaining explicit knowledge of lots of things said, and they had normal intelligence. But there seems to be these deficits at the more automatic spontaneous level of processing. And that seems potentially to be one of the core central difficulties underlying these most general social difficulties.

This kind of interested something that clinicians have known for a long time and as a result, have developed remediation techniques where they attempt to explicitly teach what we had never really had to learn. So for example, to explicitly teach individuals, what kind of subtle changes in faces would in fact indicate things like being surprised, being upset and so on. These are just various examples called from the literature of the kinds of interventions that clinicians have developed to try to get around this deficit and what looks like an automatic and spontaneous social processing.

So now let me turn to what we've been learning. What clinicians and others have learned about what's going on in the brains of these individuals. And to do that, I'm going to first have to introduce this term of what's been known as and what's been called the social brain. During the past 20 years, studies with both monkeys in humans have kind of identified a relatively well defined circuit or network and well defined both with regards to the location in the brain and the circuitries and their functions and properties. The lateral parts is within the most posterior part of the temporal lobe. Here is a cut showing the basic location of this area which is tied to representing the form of animate things, people, faces and so on. On the lateral surface posterior lobe, posterior sulcus which is involved in representing a perceiving biological motion. The imigula involved in orienting and processing. And within the medial surface, the court sees posterior singular and also in the lateral surface there's more anterior part of the temporal lobe that seemed to be involved in more higher order kind of social issues distinguishing cells from others and so on. The other important thing to know with this circuitry, although there's something about the different functions of each one of these areas I've just described, the whole circuit seems to be utilized with regards to a broad range of tasks and social context ranging from simply perceiving faces to our ability to interpret more abstract representations of social interactions and biological motion all the way up to thinking about ourself and others. And the final point is that this entire network is often shown to be engaged again in the normal brain automatically and spontaneously, for example, when just perceiving a face.

Let me try to quickly summarize a number of studies again from both our lab and others.

The major findings have shown high functioning individuals presented with these concrete stimuli faces, representations of whole bodies, either static or in motion. The entire network gets activated. Normally. So I just showed you a cartoon version of this network.

This is actually data from our ASD subjects and normal controls showing all the areas I just described for you coming on-line when people were doing a simple perceptual task with photographs of faces versus photographs of man-made objects, tools. The whole thing is activated and indiscernible from normal controls. The problem comes in with these more abstract representations of social interactions or of animate beings which I'll demonstrate for you in a moment. So again, the underlying idea here is that what we're seeing, we think, is this function within circuitry, when the information, social information needs to be inferred because it's not directly represented in the stimulus.

So for example, there's no form represented in that stimulus but we can quickly and hopefully, and you all saw that as a jumping jack, infer what the form looks like. So let me describe just very briefly what our other stimuli look like so you can get a sense of a better sense of what's being inferred here. It's been known for well over 65 years now if you show individuals simple geometric forms in motion, you can automatically and spontaneously elicit a higher order number of concepts like adamant see and intention ability. We about 10 years ago developed our own set of stimuli to use in the magnet to probe the social brain. So the idea is just to look at this display and hopefully this is seen as some kind of animated situation. Hopefully baseball, all the kids get that. Relative to a situation here and the main point is that symbol, this object is exactly the same one you just saw here when it ran around the bases and hopefully it's now seen as a non-animate concept as a mechanical situation. Most of us, if you're old enough we call that pinball, our kids called that a video game, but they certainly get a distinction. In fact, let me point out to you in terms of understanding, in terms of looking at descriptions of what's being shown here, we don't see any differences between our high functioning individuals and their match controls. That is they have the explicit knowledge and they know exactly what they're looking at.

What's going in the brain, however, seems to be different. Let me describe with a you're looking at this. It is the fusiform face area. Eventually cut in the coronal. By the way this is the temporal sulcus. This is the actual level of activation in these areas showing the ASD and td the expected category differences. There's no group difference here and there's no interactions anywhere on the network. In contrast when confronted with these more abstract representations, there's quite a marked difference.

Let me just give you something else to look at.

The point is the moral controls that show the category differences for the social and mechanical, that is they reach back in the top down fashion presumably right to the area that we use for representing faces and then you're understanding this as an adamant kind of thing. The network is activated whereas for the ASD, although they're activated, they're not showing the category distinction. The important point here between this comparison is that this is unlikely to be a local problem within this particular area. Because it's activated properly when the right information is directly presented. Rather, it seems to be a problem of inference suggesting the possibility this is really a problem within the circuitry, the way these areas are communicated.

So here is very quickly another example showing the same phenomena using in this case these displays. Same thing. The ASD is activated but not showing the categorical distinction. Any literature is really filled with lots of studies looking at these areas, the sulcus and cortex and so on, depending on the task different types of abnormalities throughout the entire circuitry.

I think what these kinds of studies tell us is that it helps us to define what the social system looks like in the brain, help us to define what the locus of impairment might be. That is a problem with the circuitry.

But in terms of our understanding of ASD, there's a number of problems. And one is the circularity involved in picking out individuals with social deficits and showing they have problems in the social network. And the other is that we're directly limited to testing testable subjects. That is people who can perform.

And this gets us to this last issue which I'm going to have to do very quickly, about the need for biomarkers. So as many of you know this disorder is characterized and soon to be a disorder of connectivity. And it's become clear over the last couple years that one can measure and gauge connections within a circuit by analysis of spontaneous fluctuations recorded at rest. These are very slow fluctuations of the bow signal at around .1 hertz.

Let me give you a demonstration of how these can be across anterior and posterior cortices. One would look for a place for the seed for connectivity. We're working with a view of the connectivity in the brains of these individuals, and the central idea is within each vessel to store it and every other vessel in the brain. These pictures contain between 50,000 or a hundred thousand vessels. This is being done simultaneously. Here's a picture with the lighter areas showing stronger correlations. It's about eight minutes of data. We could then do this with all of our subjects and average them 30 controls, 30 ASD's and then do the statistics in an unbiased way. When we do that for these individuals, that falls out of the analysis and are just the areas I've been talking about. Prefrontal cortices. This is directly engaged with the -- the temple lobe and the -- bilaterally. We can use these, look at connectivity patterns. Look at each individual and see for example here there is in fact less connectivity between the ventral medial prefrontal cortex and the anterior parts of the temporal lobes and look at each one of these individuals and ask questions about this variance.

And here we can address, I think the central question that I want to get to, and that is, is this variability related at all to the functioning of these individuals? It's looking like it is.

So it just gives you one quick example. Here's our 30 subjects. Here's their rating of connectivity in these two areas. And on the x axis is the scores from what's called the social responsiveness scale. These are ratings from the parents of how impaired or how autistic their child is. So the higher the number the more autistic symptoms the parents are rating and as you can see, a fairly good correlation between the measures of connectivity and social processing. This doesn't seem to be driven or at least modified by medication, for example. This individual here has high, good connectivity in response to the stimulus, and very poor social processing. So I'm just going to summarize for you.

What I tried to show you is that these individuals have what we call domain specific cognitive deficits. This can be seen in the brain in terms of both task-based analyses and the functional connectivity. And I want to stress that this whole business about the connectivity is really a proof of concept. I'm not suggesting that autism is limited to involvement of just the social network or prefrontal cortex, for example. Rather what I'm suggesting is one could pick up in an unbiased way that this system that is impaired based on their behavior and task based analysis. So on that sense, it's suggested a resting state, unbiased resting state analyses may in fact be helpful in defining subgroups of patients, setting endpoints for clinical trials and aiding in early diagnosis. And especially this can be accomplished regardless of age or ability. You might get a better idea of what this whole beast actually looks like.

So let me just show you all the people that are involved in these projects. There's children national medical center. Here's our group <…>.

Sorry for going over but thanks for listening.

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Sue and I are willing to take any questions if there are any.

QUESTION: Can I ask one? So Alex, the resting state, does it matter what they are thinking about? While they're lying on scanner. How at rest do they need to be? How slow are these fluctuations? Have you been able to look at whether that differs if they're doing it half the time?

MARTIN: So there's still a lot of outstanding questions about these rest state analyses. There are some animal evidence that they're impervious -- impervious to these devastations. This kind of social system, how it's modified by different states of consciousness, we clearly do not know. What I can tell you is that again we weren't looking for this particular analysis, this particular circuit. It falls out and other circuits why their behavior is good seem to be intact and they're no different. But there are lots of questions about how in fact these circuits are modified and modulated. At least in the short term, there's certainly good evidence that they can be modified by learning and so on.

QUESTION: Hi. Very interesting. This question goes to Susan Swedo although anybody is more than welcome to respond to it. There was a recent article, I don't know if you caught it, Susan, it was about Oxytocin for normal and controlled children and seeing improvements, statistical, statistically significant improvements, although not very large in social behavior. In light of the work of Sue Carter Porges and others, what's your feeling about this? Is this going to be a new step in autism treatment or what?

SWEDO: That's a great question. So there are a lot of additional papers we're following and one of the reasons that Dr. Gozi is taking our comparison of Oxytocin is because of the reports not only the recent paper, but other places suggesting that Oxytocin had a beneficial role with autism. Couple problems, one there's currently not a long acting form of Oxytocin form available. So at this point it's difficult. It is intriguing. There's some questions whether the Oxytocin is even crossing the blood brain barrier but it does in some reports. So that question needs to be answered before we move forward. Probably the one that's peaked my interest the most is a recent paper saying Oxytocin not only increased positive emotional responses but negative as well. So if you're a little bit angry when you came in, you became more so if you were aggravated and frustrated, Oxytocin increased all of those. I'm hoping by Dr. Gozi's study looking at the similarities and difference, we'll have a better answer. Certainly with Dr. Martin's elegant results we'll have a better idea where the brain will want to be paying attention.

Thank you. Go and be well.

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ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds recorded February 17, 2010. Today, we heard two speakers from the National Institute of Mental Health. Dr. Susan Swedo, chief of the Pediatrics and Developmental Neuroscience Branch at the NIMH spoke on the topic, "A Clinical Update on Autism and the Autism Spectrum Disorders." Then, Dr. Alex Martin, chief of the Section on Cognitive Neuropsychology in the Laboratory of Brain and Cognition at the NIMH spoke on the subject, "Cognition and Brain Functional Connectivity in Autism". You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.