A window into the biology of autism
Dr Florina Uzefovsky
Update of research
for the British Friends of Haifa University
supporting a postdoctoral fellowship at the Autism Research Centre,
Department of Psychiatry, Cambridge University, UK
Background
Autism is a neurodevelopmental condition characterized by deficits in social
interaction and in verbal and nonverbal communication, alongside unusually
repetitive behavior and extremely narrow interests. Autism shows heterogeneity,
varying in clinical presentation across a spectrum of behavior. Here we use the term
‘autism’ as shorthand for Autism Spectrum Disorders (ASD). The prevalence of
autism is high, with up to 1% of children affected (Baird et al., 2006), and males are
affected more often than females, in a 4:1 ratio (Kogan et al., 2009). The worldwide
prevalence of autism has increased substantially in recent decades (Baio, 2012); this,
combined with very high costs of treatment – two-to-three fold higher than other
neurodevelopmental conditions (Flanders, Engelhart, Pandina, & McCracken, 2007) –
makes research into the origins and the nature of autism extremely important.
The biology of autism
Autism is highly heritable, with genetic factors explaining 50-80% of the
diagnosis (Hallmayer, Cleveland, Torres, & et al., 2011). Much research has been
dedicated to investigating the genetic basis of autism employing the candidate gene
approach. Over 700 genes have been implicated in autism (SFARI database), but the
ones relevant to social development include the Oxytocin Receptor (OXTR) and the
Vasopressin 1a Receptor (AVPR1a) genes (Lerer et al., 2008; Yirmiya et al., 2006).
The contribution of each gene to autism is very small (~1%) and this is not surprising,
as the path from genes to behavior is not direct; genes do not affect behavior directly
but through the influence they exert on brain structure and activity directly and
through their influence on the chemical environment in the brain, and mediated by
learning and experience. Much research has also been dedicated to describing the
differences in structure and activity of the brain in typical populations versus children
and adults with autism. Findings point to differences in both brain structure and
activity. For example, the amygdala, a brain area considered to be part of the ‘social
brain’ and which expresses oxytocin receptors, is under-active in people with autism
(Baron-Cohen et al., 2000). These findings are extremely important in advancing our
understanding of the neurobiological basis of autism. In order to understand the
biological basis of autism several research projects have been undertaken by Dr
Florina Uzefovsky as a collaboration between the University of Cambridge and the
University of Haifa.
Imaging genetics
This method integrates genetic with neurobiological methods. This technique
allows us to examine how variations in genes are associated with brain function, i.e.
how an individual’s genotype affects brain activity, and how the combined effect of
genes and brain function are associated with autism. This enables us to overcome
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some of the inherent problems of each method and increase our ability to understand
autism. In particular, we aim to investigate how individual variation in genes involved
in social cognition such as the aforementioned OXTR and AVPR1a, are associated
with activation of social brain regions such as the amygdala, and how both are
associated with diagnosis and severity of autism. Florina has analyzed the imaging
data and is expecting to begin analyzing the genetic data in August 2015. In the
meantime, she is using data collected as part of the National Database for Autism
Research (NDAR) and is available for researchers from around the world, to analyze
similar questions regarding the role of the OXTR and AVPR1a genes in the brain
structure of autism and controls.
Baseline vasopressin levels
Saliva and blood contain traces of the different hormones and other chemicals
that are circulating through our bodies. Although these may be different to the levels
of the same substances in the brain (which cannot be measured unobtrusively),
baseline levels of relevant hormones could act as markers of autism. In this study we
are using available saliva and blood samples from 246 individuals with autism, their
parents as well as controls and their parents to investigate the role of vasopressin in
autism, as well as related traits such as empathy. Saliva samples are being analyzed
for vasopressin levels and blood samples are planned to be analyzed in August 2015.
We hope to analyze the same samples for oxytocin levels in the fall of 2015.
Genetics of empathy in a large sample
The Cambridge BioResource (CBR) is a dedicated resource for researchers in
the University of Cambridge that partially funds and helps with recruitment of
participants for research. The CBR has recruited more than 1,700 participants who
will be genotyped for polymorphisms in the OXTR. This unique large-scale data set
allows to investigate the role of OXTR in empathy across the typical range to better
understand how it may be associated with social cognition. An understanding of the
role of OXTR in the typical range complements our efforts to understand how it may
also be involved in manifestations of difficulties with empathy at the atypical range in
the spectrum. More than 1,700 participants have been recruited for the purposes of
this study and have filled out the Empathy Quotient (EQ) and the Reading of the
Mind in the Eyes Test; both measures to assess different aspects of empathy and
mental state understanding. Genotyping is planned for the winter of 2015-2016.
The role of oxytocin in promoting synchrony and empathy in autism
Synchrony is defined as behavior matching in time (Hove & Risen, 2009), and
is thought to promote empathy by allowing us to feel the physical state of another
person with our own body. Two studies of the effect of intranasal administration of
oxytocin on synchrony were conducted in Prof. Simone Shamay-Tsoory’s lab at the
University of Haifa. The first showed that motor coordination, as assessed by a
computerized drawing task, increased after intranasal administration of oxytocin
(Arueti et al., 2013). The second showed that oxytocin increased synchrony in dance.
The purpose of the proposed study is to assess the relationship between endogenous,
baseline levels of oxytocin and synchrony. Basal levels of oxytocin reflect the
baseline of the oxytocin system and may be indicative of biologically based trait
levels of empathy. In the proposed study we seek to answer the following questions:
First, can baseline oxytocin levels predict levels of synchrony? Second, do levels of
oxytocin increase following a synchronous experience? Finally, are oxytocin levels
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different in autism vs. controls, and if so how does this relate to their levels of
synchronization? To answer these questions we aim to recruit 120 participants (split
into 30 dyads of participants with autism and 30 dyads of typical controls) and ask
them to participate in a social interaction together. Using dedicated statistical methods
we will analyze the levels of synchrony exhibited within the dyad and the relationship
between synchrony and levels of oxytocin. Oxytocin saliva samples will be collected
three times (before, during and after the social interaction). This experiment will be
conducted at the University of Haifa under the direction of Prof. Shamay-Tsoory, and
the collected oxytocin samples will be analyzed at the University of Cambridge. Data
analysis and publication will be conducted in full collaboration between Prof.
Shamay-Tsoory’s lab and Dr. Florina Uzefovsky and Prof. Simon Baron-Cohen. The
proposed study will shed light on the importance of nonverbal cues related to
empathy, in both the typical population and in autism. Better understanding of the
neurobiology of human social cognition has important implications for the
development of novel clinical approaches for autism. We aim to begin recruitment for
the study in the winter of 2015-2016.
References
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