required video.
Autism Spectrum Disorder
Dr. Katie Dabrowski, PT, DPT
Overview
• ASD is a developmental disorder that affects communication and behavior
• Symptoms generally appear in the first 2 years of life
• According to DSM-5, people with ASD have:
• Difficulty with communication and interaction with other people
• Restricted interests and repetitive behaviors
• Symptoms that hurt the person’s ability to function properly in school, work, and
other areas of life
• Autism is a “spectrum” disorder because there is great variation in type and
severity of symptoms
NIMH
Signs and Symptoms
• Social communication/interaction behaviors:
• Making little or inconsistent eye contact
• Tending not to look at or listen to people
• Rarely sharing enjoyment of objects or activities by pointing or showing things to others
• Failing to, or being slow to, respond to someone calling their name or to other verbal attempts
to gain attention
• Having difficulties with the back and forth of conversation
• Often talking at length about a favorite subject without noticing that others are not interested
or without giving others a chance to respond
• Having facial expressions, movements, and gestures that do not match what is being said
• Having an unusual tone of voice that may sound sing-song or flat and robot-like
• Having trouble understanding another person’s point of view or being unable to predict or
understand other people’s actions
NIMH
Signs and Symptoms
• Restrictive/repetitive behaviors
• Repeating certain behaviors or having unusual behaviors. For
example, repeating words or phrases, a behavior called echolalia
• Having a lasting intense interest in certain topics, such as numbers,
details, or facts
• Having overly focused interests, such as with moving objects or
parts of objects
• Getting upset by slight changes in a routine
• Being more or less sensitive than other people to sensory input,
such as light, noise, clothing, or temperature
NIMH
Signs and Symptoms
• But there are strengths, too!
• Being able to learn things in detail and remember information for
long periods of time
• Being strong visual and auditory learners
• Excelling in math, science, music, or art
NIMH
Neuroanatomical and
Neurodevelopmental Basis of ASD
Altered brain growth
• One consistent finding in ASD is altered brain growth
• The clinical onset of autism appears to occur after two phases of brain growth abnormalities:
1. Reduced head size at birth
2. Then a sudden and excessive increase between 1-2 months and 6-14 months of age
• In addition to these initial two phases, it is also shown that an abnormal pattern of brain
growth also occurs in areas of the frontal lobe, cerebellum, and limbic structures between 2-4
years of age
• An abnormal slowness in brain growth then follows this initial growth
• We know that these regions are intimately involved with developing social, communication, and motor
abilities that are impaired in ASD
• Head circumference >75th percentile is linked with more impaired adaptive behaviors
• Studies show increased brain volume but decreased inter-regional brain connectivity in ASD
patients, which could result in poor integration of brain areas, resulting in neurobehavioral
developmental issues
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Disconnection between brain regions
• Studies of individuals born without a corpus callosum show similar
language and behavioral deficits as individuals with autism
• Cross-sectional imaging studies show reduced size of corpus callosum
in autism
• The corpus callosum serves to connect the two hemispheres of the
brain, ensuring for information to pass between the two sides
• Symptoms of agenesis or reduced size of the corpus callosum = vision
impairments, low tone, difficulty feeding, hearing impairments,
problems reading facial expressions/vice tone, difficulty with problem
solving, difficulty understanding emotions, delays in developmental
milestones…sounds a lot like autism, doesn’t it?
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Fusiform Face Area
• fMRI studies show hypoactivation of the
fusiform face area (FFA) in individuals
with autism
• Individuals with ASD have difficulties
with face perception
• In normal subjects, tasks that require
the participant to individuate specific
faces show significantly more FFA
activation when compared to
individuals with autism
• Figure 1. Shows hypoactivation of the
FFA
DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager,
S. R., Schmitz, C., Schultz, R. T., Crawley, J., & Young, L. J. (2006). The
developmental neurobiology of autism spectrum disorder. The Journal
of neuroscience : the official journal of the Society for
Neuroscience, 26(26), 6897–6906.
https://doi.org/10.1523/JNEUROSCI.1712-06.2006
Neurotrophins
• Neurotrophins (like BDNF) play a fundamental role in guiding CNS
development and cortical organization (things like cell proliferation,
migration, and survival; axon and dendrite outgrowth; synapse
formation; neuroplasticity)
• Neurotrophins and their receptors are expressed in the cortex and
hippocampus, and patterns of their expression are regulated by
activity, sensory inputs, and stimulation
• They have abnormal expression patterns in ASD
• Elevated levels of BDNF in ASD could be a pathogenic mechanism or perhaps a
secondary reaction to cortical abnormalities in ASD
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Neurotransmitters
• Many studies show abnormalities in serotonin, GABA, and
glutamate pathways in ASD
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Neurotransmitters: Serotonin
• Young children with autism lack the ‘normal’ developmental peak in
brain synthesis of serotonin
• Also possible abnormalities in serotonin-related genes in ASD
• Pharmacological research also suggests a possible link between
serotonin and ASD:
• Drugs acting on serotonin (5-HT2, specifically) receptors cause behavioral
improvements in autistic patients
• Fluoextine (an SSRI – selective serotonin reuptake inhibitor) causes
improvements in social behavior and decreases aggressive behaviors in ASD
children
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Synaptic and dendritic changes
• Experience-dependent synaptic plasticity is disrupted in
ASD
• Dendritic branching is shown to be decreased in
hippocampus of ASD individuals
• Several synaptic changes identified in ASD
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Mirror Neurons
Mirror Neurons
• Check out this quick video on mirror neurons (seriously, it’s
like 2 minutes) first.
Mirror neurons
• We know that imitation plays an important role in human
development and how we learn motor, communication, and
social skills
• di Pellegrino’s 1992 study of macaque monkeys reported,
for the first time, that the premotor cortex has neurons that
fire both when the monkey performs an action, and when it
simply observes an individual performing that same action
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
Mirror neurons
• Pretty cool, right?
• So Iacoboni et al (1999) wanted to study this in humans
• They discovered brain regions (left inferior frontal cortex
and right superior parietal lobule) that became active when
the participant moved his/her finger…and the activation
increased when the participant viewed somebody else
performing the same exact movement
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
Mirror neurons
• Rizzolatti et al (2014), in more recent work, discussed the role the cortical
motor system plays in imitating the behaviors of others
• They propose a mechanism: the mirror neuron mechanism (MNM)
“These new findings have radically changed the traditional view of the motor
system as an executive system that merely follows instructions elaborated
somewhere else. Motor system now stands as a system that allows
understanding the behavior of others, and even as a probe that explores the
external world for interacting with other people and gathering new
knowledge.” – Jeannerod of Oxford Psychology Series.
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
Mirror neurons
• There are many implications of the ability to understand and control motor
actions in individuals with ASD
• The ability to mimic body language of others can influence social
interactions and personal relationships
• We know that individuals with ASD have deficits in imitating the actions of
others and in learning motor actions (simple body movements)
• Learning motor actions has been associated with mimicking the actions of
others, and understanding the purpose of this action – like when and where
to perform a certain social action, like a wave or a handshake (both of which
are impaired abilities in ASD)
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
Mirror neurons
• Take grasping a cup as an example:
• When we see an individual grasping a cup, we see two bits of
information:
• The goal = grasping
• The intention underlying it = grasping for purposes of drinking
• Children with ASD have difficulty in understanding the intention
underlying a motor action
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
The Mirror Mechanism
• Studies show that mirror neurons not only respond to
others’ actions, but also others’ gestures and emotional
responses
• The ‘mirror mechanism’ enables the experience of others’
actions, emotions, and sensations using the same systems
through which we experience these actions, emotions and
sensations ourselves
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
The Mirror Mechanism
• Provides a foundation for the idea that knowledge of others’
behaviors is essentially grounded in our own self-
experiences (and vice-versa) – rather than solely being
based on explicit, language-mediated reasoning
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
The Mirror Mechanism and ASD
• It is suggested that this mirror mechanism is disrupted in ASD
• Individuals with ASD don’t have this automatic flow of shared felt
experiences and self and others to shape their social understanding and
learning
• Instead, these individuals to have to rely on explicit, language-mediated
reasoning as the primary foundation for social understanding and
learning
• Studies show atypical/reduced activation of the sensorimotor
system in response to observing another person’s motor
behavior in ASD
Radwa Khalil, Richard Tindle, Thomas Boraud, Ahmed A. Moustafa, Ahmed A. Karim
CNS Neurosci Ther. 2018 Aug; 24(8): 669–676. Published online 2018 Jul 2. doi: 10.1111/cns.13001
Neuroimmunity, environment, and non-genetic
factors
Neuroglia and neuroimmunity
• Microglia and astrocytes play important roles in neuronal
function and homeostasis – things like cortical organization,
neuroaxonal guidance, synaptic plasticity, and the immune
response of the CNS
• They detoxify excess amino acids, maintain the blood-brain
barrier, and modulate inflammatory responses
• Changes in these cells and produce marked neuronal
dysfunction
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Neuroglia and neuroimmunity
• The role of immunity and immunological dysfunction in the pathogenesis of
ASD is of growing interest
• Several reports link immunological dysfunction with ADS
• Several studies suggest up to 60% of patients with ASD have various types of
systemic immune dysfunction
• Studies show lymphocyte infiltration and increases in pro-inflammatory
cytokines in autistic subjects
• Post-mortem brain studies show active and ongoing neuroinflammatory
processes in the cortex and white matter (characterized by astroglial and
neuroglial activation) in ASD patients
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Oxidative stress
• Oxidative stress occurs when levels of reactive oxygen species
exceed the antioxidant capacities of a cell – leading to cell death
• The brain is vulnerable to oxidative stress, given its very high
oxygen demands and its limited antioxidant capacity
• Studies show decreased levels of antioxidants in blood or serum
of patients with ASD
• Studies show elevations in biomarkers indicating increased
oxidative stress (increased lipid peroxidation) in ASD
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
Maternal factors
• 46% of ASD patient families have two or more members of
their family with autoimmune disorders
• As the number of family members with autoimmune
disorders increases from 1 to 3, the risk of autism was
greater (1.9 to 5.5 odds ratio, respectively).
• Most common autoimmune disorders in these studies: Type
I diabetes, adult rheumatoid arthritis, hypothyroidism, lupus)
Pardo, C.A. and Eberhart, C.G. (2007), The Neurobiology of Autism. Brain Pathology, 17: 434-447. https://doi.org/10.1111/j.1750-3639.2007.00102.x
https://doi.org/10.1111/j.1750-3639.2007.00102.x
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