The Neurobiology of Autism. Brain Pathology,

Autism Spectrum Disorder

Dr. Katie Dabrowski, PT, DPT

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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

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

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

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

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

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

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

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

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

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).

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