Autism and related disorders: from bench to bedside (Part 1)

I just returned from an extended stay in France where I attended an autism conference in La Ciotat. The organizer of the meeting was Yehezkel Ben-Ari, the Founder and Honorary Director of INMED (Institute de Neurobiologie de la Mediterranee). Dr. Ben-Ari proved to be a most gracious host inviting us to his house and later on providing a tour of the city. The meeting itself had a distinguished list of speakers including Nobel Prize winners and members of our National Academy of Science. The conference honored the life and achievements of Paul Patterson, a good friend, who passed away recently (http://bit.ly/1lYS68o). In a striking turn of events the meeting was heavily biased towards molecular biology and genetics both of them fields whose importance, according to Paul, was overstated. Paul actually argued in favor of rebalancing the budget of funding organizations to emphasize studies and interventions that could lead to research of immediate importance to patients.

The meeting opened in the Eden Theater, home of the Luminere brothers credited for being the first filmmakers in history. Soon after the opening speech the lights went off and I could not take notes (I thought it would be rude to use a laptop). In this regard I will summarize the presentation of some of the speakers. This is a biased selection as to those presentations that I found of interest and had some clinical significance. Given the number of presentations I will divide them among two or three blogs.

Christopher Gillberg

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Christopher was probably the most renowned clinician at the meeting. He is a Professor of Child and Adolescent Psychiatry at the University of Gothenburg, Sweden and heads his own Center there (the Gillberg Neuropsychiatry Center). He wrote the famous book “The Autisms” which stands as a reference textbook for anybody interested in autism spectrum disorders (ASD). I could not spend much time with Chris socializing as he had a sciatic pain and was under heavy medication. This made his appearance at the meeting rather sporadic. I wish him a speedy recovery.

Title of Presentation: Autism Plus- Comprehensive Assessment in “Autism”

Abstract of presentation: The reported prevalence of autism is going up. Much of the increase in the rate of ASD is probably driven by “Autism Plus.” Autism Plus refers to autistic features with comorbidities (including intellectual developmental disorder, language disorder, and attention deficit/hyperactivity disorder), and this is what is now increasingly being diagnosed by clinicians as ASD. In clinical practice, a diagnosis of ASD much more often entails that the child will receive support at school and in the community, which is not the case for other diagnoses. In the past the comorbidities were given diagnostic priority and the “autistic features; might, or might not be mentioned as the “plus bit” in the diagnostic summary. It is high time that the comorbidities, sometimes even more important the autism, came back on the diagnostic and assessment agenda. Autism is but one of the Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examination (Essence), not the one and only. Clinical assessment in “autism” needs to be at least as focused on all the “comorbidities” as on the autistic features. The patient, not the disorder, needs to come back into the limelight.

Sometime later, after his presentation, we took a poll among the audience to see who believed that the prevalence of autism was truly increasing or whether it was artifactual (as suggested in Chris presentation). The vote from those participants that actually saw patients was unanimously in agreement that the rise in prevalence was real. Non-clinicians (basic scientists) favored Christopher’s observations. I believe that basic scientist have an abstract and incomplete understanding of autism. This is one of my major peeves as I believe that many of them have been given a position of authority to direct research at a national level without having a complete understanding of autism.

S. Wendy Roberts

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Wendy is a Professor Emerita in Pediatrics (Developmental pediatrics) from the University of Toronto. I first met Wendy a good number of years ago and we have remained friends ever since. I enjoy her company and in different meetings we have opted to sit together allowing us to socialize a little bit. During our meeting in France she spent a good amount of time discussing some patients with Randi Haggerman. It appears that they were following several patients together and they wanted to discuss the best therapeutic options for them. It was impressive to see how much importance they placed on the patients but also on their families which they knew quite well. Note: By any account Wendy Roberts and Randi Haggerman, would be the dream team when considering a group of clinicians for ASD.

Title of Presentation: The earlier, the better: intervention at first signs of an Autism Spectrum Disorder

Abstract: As information regarding the early signs of autism comes from many different studies in different countries, it is possible to identify, with greater precision, those children a thigh risk for developing autism. Most studies to date have followed younger siblings of children with autism from early infancy through at least their third birthday and have shown that children who go on to develop autism, have identifiable high risk markers as early as one year.

The main importance of early recognition of high-risk status is to take advantage of neuronal plasticity by initiating intervention very early in infancy. All children’s development will benefit from the naturalistic, developmentally appropriate intervention that is being studied in a variety of autism research programs. Evidence is emerging around the benefit of parent coaching as well as direct intervention to develop and improve the infant’s social communication and to show changes in brain function as a result. Preliminary data suggests encouraging outcomes in terms of reduction of severity of autism symptomatology in infants receiving treatment starting by 12 to 18 months of age.

Note: As an aside, I have heard many speakers talk about “naturalistic” interventions in ASD. In my mind they do not seem to differ from employing common sense, using tender loving care and spending time with your kids.

John F. Cryan

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John is a Professor and Chair of the Department of Anatomy and Neurosciences at the University of Cork in Ireland. I had never met him before but was highly impressed by his demeanor and presentation. With his booming voice he was the only speaker that did not need a microphone for his presentation. Several times during his presentation and in the discussion session John emphasized the complexity of gut problems in ASD. John believes that special diets, medications and environmental factors (e.g., lack of exercise) could play a role in the gut problems observed in autism. Without having definite information he underlined that we don’t know if gut problems in autism are primary to the core pathology or secondary to the previously mentioned factors.

Title of Presentation: The gut microbiome: a key regulator of neurodevelopment and behavior

Abstract: Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to a variety of diseases. Accumulating data no indicate that the gut microbiota also communicates with the CNS- possibly through neural, endocrine and immune pathways- and thereby influences brain function and behavior. Understanding the mechanisms underlying such effects especially during early life may be crucial for gaining an understanding of neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and stress-related psychiatric disorders including depression and anxiety.

The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the hosts early in life. The infant gut microbiome is dynamic, and radial shifts in composition occur during the first 3 years of life. Disruption of these developmental patterns and the impact of the microbial composition of our gut on brain and behavior, has attracted much recent attention. Early-life perturbations of the developing gut microbiota can impact on the central nervous system and potentially lead to adverse mental health outcomes alter in life.

Strategies John has used to sparse the microbiome-gut brain axis include studying the effects of probiotic bacterial strains, many of which can generate neuroactive metabolites, on behavior and stress response. In parallel, germ-free animals are important tools in investigating the impact of microbiota on brain development and John has taken advantage of this model in the context of behaviors relevant to stress and sociability.

Specific lactobacilli and Bifidobacteria strains have marked defects on anxiety and cognitive behaviors and can attenuate the stress response. These effects were coupled with alterations in GABA receptor levels in many key brain areas. Interestingly, the vagus nerve is needed for these effects to be manifested. Additionally, John has shown that male but not female germ-free animals have a significant elevation in the hippocampal concentration of 5-HT and its main metabolite coupled with a decreased expression of the neurotrophic factor BDNF. Perturbed anxiety responses in the light-dark box were also observed in germ-free animals. In the context of social development, male germ-free mice exhibited robust deficits in social behaviors in a 3-chamberedd sociability test including social avoidance and diminished preference for social novelty relative to conventionally colonized mice. Germ-free mice spent a decreased proportion of time engaged I repetitive self-grooming behavior during social interaction in the social transmission of food preference test. These behaviors which are akin to those observed in autism were normalized following bacterial colonization in adulthood.

Some of the photographs we took while in La Ciotat:

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2 responses to “Autism and related disorders: from bench to bedside (Part 1)

  1. “The vote from those participants that actually saw patients was unanimously in agreement that the rise in prevalence was real.”

    Can confirm real increase in prevalence.
    Source: Have eyeballs and common sense

    The maddening thing about the argument regarding diagnostic shifting as a participant in increase is that it is undoubtedly true to some extent and impossible to disprove for any extent. If autism rates were reported at 1 in 25 tomorrow, the ‘no increase’ argument would remain exactly the same, and would not suffer any loss of credibility when compared to older numbers. [No one seems to notice how *awful* people must have been at detecting autism in the 90s and early 00s. God were those guys awful!] If autism were reported at 1/10 the day after, we could all just say, ‘We sure are getting good at recognizing all this autism that has been here all along!’. It is akin to the ‘god of the gaps’ gambit in evolution ‘debates’; the epidemic of awareness/diagnosis argument can fill in any void necessary without need for messy (and scary) analysis.

    I’ve had some thoughts on ways to look at this problem from a bioinformatic approach. California has been storing blood spots for a long time for a large percentage of their births; if genetic expression, (maternal?) blood antibody presence, or other biomarkers suggestive of risk could be culled from stored blood (a big if!), we could build a timeline of risk in our newborns for the past few decades.

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  2. I know there is a real increase in prevalence in ASD. When I started Neurology several decades ago, textbooks said that you would see at most 2 children in your practice. Now I see them everywhere. The attempt to explain away the rise in prevalence by a diagnostic shift has come and gone. This argument itself has been disproved as incapable of explaining the effect size of the change in prevalence. The argument has therefore ceased to be a rational one.

    I like the idea of the bioinformatics approach. Thanks for the comment.

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