autism

Autism spectrum disorder (ASD)

●      ASD is a neurological + developmental disorder that begins in early childhood + lasts throughout a person's life

●      Called a "spectrum" disorder b/c people with ASD can have a range of symptoms

○      Vary from person to person

○      Symptoms can vary in tensity between individuals

●      ASD affects how a person acts and interacts with others, communicates, and learns

●      People with ASD display a range of strengths and abilities, May excel in math or science and have exceptional ability to problem solve

○      Direction, order, time

The autism spectrum

●      Up until the DSM5, individuals on the extreme end of the autism spectrum were diagnosed with autistic disorder.  Those with higher levels of function were diagnosed with Asperger’s syndrome.

●      In the DSM5, this scheme has changed.  Asperger’s has been folded into Autism Spectrum Disorder, which is now given a numerical grade based on the functional impairment.

○      Grades range from 3 – “Requires very substantial support” to 1 – “Requires support”.

●      Thus high-functioning autism and Asperger’s syndrome are now diagnosed as different levels of Autism Spectrum Disorder.

Clinical description

●      ASD appears in early childhood, often being first recognized during the second year of life.

○      Around the same time social behavior is supposed to begin developing.

●      Parents often report a roughly normal pattern of development up to the 12 month mark, followed by a startling decline in function in following years.

○      This pattern of development has given rise to many superstitious theories of autism, for example the putative link to vaccines (the delivery of which coincides with sudden declines in function).

●      The autism spectrum disorders are characterized by three major areas of difficulty:

1. Impaired communication

2. Impaired social interactions

3. Restricted behavior, interests, and activities

Impaired communication

●      People with autism nearly always have problems or delays in communication.

○      Language skill can vary widely, with some individuals showing extremely high levels of function.

○      On average, about 1/3 of people with autism never acquire speech at all.

●      For those who develop speech, the pattern of communication is often quite unusual.

○      Echolalia – repeating the speech and intonation of others is common.

○      Children may possess an odd combination of verbal abilities, for example knowing the alphabet but not their own name.

○      Individuals who may have an overly literal understanding of language may have difficulties understanding analogies and metaphors.

Impaired social interaction

●      Social Cognition: how you think about yourself and your social world,also the knowledge of the perceptions, ideas, and intentions of others

○      Theory of mind: ability to understand that other people have mental states, such as beliefs, desires, intentions, and feelings

■      Others are separate selves, with own points of view and feelings

○      Low function ASD children never get theory of mind

●      Distinctions between:

○      What is more and less important

■      e.g., first words: “ball, kitty, cookie” vs. “wall”

○      What is social and nonsocial

■      People more important

○      Low functioning kids do not do this

○      High functioning kids are highly social

■      Stymied by give and take

●      Affective social competence: coordination of capacities to experience emotion, send emotional messages to others, and read others' emotional signals

○      Low functioning kids are unable to do this

○      High functioning kids lack actual sense of feeling of emotion

■      Do not talk about emotions, but more robotic

Restricted behavior

●      Individuals with autism often exhibit repetitive, apparently pointless behaviors called stereotypies.

○      Since these behaviors seem to be concerned with sensory self-stimulation, the practice is also called stimming.

○      Example stereotypies include: rocking, hand flapping, yelling etc.,

○      These can often be self-injurious.

●      Autism is associated with an intense preference for the status quo – individuals like things to stay the same.

●      Ritualistic behaviors may also be apparent, for example lining up one’s blocks in order from largest to smallest.

Prevalence of ASD

-        1/66 people

-        1/42 males

-        1/165 females

-        75% diagnosed by age 8

-        Prevalence is not the same world wide 1/597(Iran) and 1/294 (Taiwan)

-        A 4:1 male to female ratio is consistent everywhere

-        Suggests possibility of one of two things:

-        Biology of ASD related to male development

-        ASD manifests itself differently in females

Etiology of ASD: genetics

●      Highly heritable

○      Concordance rate for monozygotic twins is 36-91%; DZ twins 0-5%

○      Enormous genetic complexity of ASD-related conditions makes it a significant challenge to understand the exact genetic inheritance patterns, with a growing number of genes (close to a thousand) involved

■      Genetic predisposition combined with an environmental impact

■      Genes involved in intellectual disability + neuropsychiatric disorder, common pathway genes, ASD-risk genes, multigenic contributions, de novo mutations

●      Vaccines ruled out as causes of autism

Environmental risk factors

●      Maternal diet: deficient in essential nutrients and fatty acids; affects gut microbiome, immune responses

●      Folic acid status

●      Maternal smoking, exposure to alcohol or other drugs during pregnancy

●      Maternal infection during pregnancy (related to immune activation?)

●      Low maternal education level

●      Exposure to air pollutants

●      Poor socioeconomic status

●      Advanced maternal and paternal age

●      No single environmental factor is sufficient to influence the predisposition to ASD; combination of factors

The microbiome

●      Gut microbiota: microorganisms, bacteria, viruses, protozoa and fungi that are present in the gastrointestinal tract

●      Gut-Brain Axis: The gut microbiome can influence brain function, potentially affecting behaviors and symptoms associated with autism

○      Signals to the brain both directly and indirectly (via the immune system)

Autism and medical comorbidities

●      Immune dysregulation and gastrointestinal disturbances are common among individuals with ASD

○      Post-mortem brains of ASD patients show increased microglia activation, elevated proinflammatory cytokines

○      Greater prevalence of gastrointestinal disorders compared to controls, e.g., diarrhea/constipation, abdominal pain, reflex

Emerging links to gut dysbiosis

●      Mouse models of ASD (maternal immune activation) results in impaired social communication and stereotyped behaviours, as well as disturbed GI and immune functions!

●      Microbiota is the intersection between genes and environment à composition depends on genetics, and is shaped by environment

●      Some symptoms of autism are improved with antibiotics (vancomycin) or dietary adjustments (gluten and casein free diets)

Neurobiology of autism

●      ASD no longer viewed as a focal impairment in a specific brain region or circuit

●      Instead, condition resulting from overall brain reorganization, beginning early in development

●      Overall findings:

○      Accelerated brain development early in life (“early brain overgrowth”)

■      results in overall brain under-connectivity (with local over-connectivity in frontal / occipital regions)

○      Morphological abnormalities at the microstructural level

Prenatal testosterone

●      Numerous subtle psychological traits are correlated with prenatal testosterone.

●      Eye contact at 12 months of age is correlated with prenatal testosterone.

○      Males naturally make less eye contact than females, and this is exacerbated by excess prenatal testosterone.  Interestingly, this is also a trait on the autism spectrum.

●      Prenatal testosterone also seems to reduce performance at “mind-reading” tasks.

○      These are experimental tasks where children are asked to look at a picture of a person, and guess what that person’s emotional state may be.

Extreme male brain theory

●      Simon Baron-Cohen

●      Sex-linked dimensions of brain functioning

○      Eg. Logical, systematic thinking in men vs. relational empathy in women

●      Autism is extreme example of "normal" male profile

●      Exposure to testosterone during development?

The mirror neuron system

●      Mirror neurons are neurons that will fire both when an individual performs a certain action and when they observe that action being performed by someone else

○      Mirror neurons can be in a variety of places throughout the cortex, thought they were first discovered in the premotor cortex

●      The mirror neuron system may provide a neurobiological basis for social cognition.

○      Social cognition is the knowledge of the perceptions, ideas, and intentions of others (an ability that is notably absent or deficient in individuals on the autism spectrum).

●      Mirror neurons respond to the understanding of an action, not to some superficial aspect of it.

○      For example: if you had discovered a mirror neuron that responded to picking up a certain object, it would only fire in response to that object.  Moreover, it would fire not only when the action is directly seen, but also when it is implied but hidden (say behind a screen).

●      Mirror neurons have also been found in the cingulate cortex, and the insula.  These neurons may play a role in empathy.

●      It seems that many of the deficits seen in autism are precisely those skills that are controlled by mirror neurons.

●      Example of someone lacking the mirror neuro, is not knowing or not realizing that a conversation has ended

Do people with ASD have a dysfunctional mirror neuron system?

●      fMRI while observed or imitated facial emotional expressions

●      Kids with ASD showed reduced activity in the frontal mirror neuron system (pars opercularis [part of Broca’s area] of inferior frontal gyrus)

●      Correlated with severity of disorder

○      Higher severity – lower activity in MNS

Current therapeutic advances

●      No pharmacotherapy available

●      Behavioural based therapies, are the most common (Applied behaviour analysis)

○      Emphasize play, social interaction, and communication initiation, the "natural consequence" are the reward

○      Controversial