Autism Flashcards
LO
- Define pervasive developmental disorders (PDD) and the autistic spectrum disorders (ASD).
- Discuss the relationship between the signature behaviours that diagnose the condition.
- Address the concept that autistic spectrum relates to extremes of “normal” (neurotypical) human
- behaviour such that individuals are diagnosed as neuroatypical.
- Lecture 2 and 3.
- Highlight neurobiological evidence for autism.
- Genetic architecture of autism to illustrate molecular pathways underlie autism and evidence they
- point to it being a “synaptopathy” using animal models (neurexin/neuroligin and mGluR).
- Use neuroligin, glutamate receptor and oxytocin signalling as examples to show how dysfunction
- can generate the distinct aspects of the triad highlighting experimental approaches.
- List some strategies used for autistic therapies.
In 1943, what did Leo Kanner describe?
1943 Leo Kanner described cohort children that could not relate (social dysfunction), poor or stunted language skills (communication), prone to repetitive behaviours (restricted behaviour). These grow out of otherwise prior normal development coined term “autism.”
In 1944, what did Leo Asperger describe?
1944 Leo Asperger described cohort of children lacking social skills and obvious difficulty with non-verbal communication, clumsiness and focussed special interests. unaware of Kanner but termed the “autistic psychopathy”.
What is the Autistic triad and spectrum of disorders,
What is included in Aspergers and Autism
When does neuroatypical behaviour appear?
How does this change as one ages?
The neuroatypical behaviour appears in development and is sustained.
Autism is a pervasive developmental disorder
Developmental can mature over time.
Initial diagnosis as autistic that better defined by other syndromes.
What can cognitive dysfunction confound?
Can confound diagnosis in high level functioning autistics over low level confuse diagnostics
What type of behaviours does major cognitive syndrome present?
With behaviours that appear autistic but major or defining dysfunction is mental retardation Rett’s and Fragile X are not autism
What is identified in syndromes like Rett’s and Fragile X?
A defective gene is identified
What are some different social disorders?
Asperger’s
Autism
PDD-NOS (not otherwise specified)
Heller’s childhood disintegrative disorder
Fragile X syndrome
Rett’s syndrome
Tell me about asperger’s syndrome
Tell me about Autism
Tell me about PDD-NOS (not otherwise specified)
Tell me about Heller’s childhoos disintegrative disorder
Tell me about fragile X syndrome
Tell me about rett’s syndrome
The emerging depiction of the autistic phenotype. Breadth of behaviours that can be score, how can they be scored?
Diagnostic and statistical manual of mental disorders DSM V. This represents a maturation through DSM I-IV
What depictions refined the definition of the triad?
DSM V- matured DSM-5 refined definition of the triad.
What are the three main things that are scored in the DSM V?
A. Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays, and manifest by 3 of the 3 symptoms
B. Restricte, repetitive patterns of behaviour, interests or activites as manifested >2 of 4 symptoms
C. Symptoms must be present in early childhood but may not become fully manifest until social
For
A. PERSISTENT DEFICITS IN SOCIAL COMMUNICATION AND SOCIAL INTERACTION ACROSS CONTEXTS,
NOT ACCOUNTED FOR BY GENERAL DEVELOPMENTAL DELAYS, AND MANIFEST BY 3 OF 3 SYMPTOMS:
What are the three main symptoms and explain a bit about each one
A1. Deficits in social‐emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth conversation through reduced sharing of interests, emotions, and affect and response to total lack of initiation of social interaction.
A2. Deficits in nonverbal communicative behaviours used for social interaction; ranging from poorly integrated‐ verbal and nonverbal communication, through abnormalities in eye contact and body‐language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures.
A3. Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers); ranging from difficulties adjusting behaviour to suit different social contexts through difficulties in sharing imaginative play and in making friends to an apparent absence of interest in people.
For
RESTRICTED, REPETITIVE PATTERNS OF BEHAVIOR, INTERESTS, OR ACTIVITIES AS MANIFESTED >2 OF 4 SYMPTOMS
What are the 4 main symptoms and explain abit about each one
B1. Stereotyped or repetitive speech, motor movements, or use of objects; (such as simple motor stereotypies, echolalia, repetitive use of objects, or idiosyncratic phrases).
B2. Excessive adherence to routines, ritualized patterns of verbal or nonverbal behaviour, or excessive resistance to change; (such as motoric rituals, insistence on same route or food, repetitive questioning, or extreme distress at small changes).
B3. Highly restricted, fixated interests that are abnormal in intensity or focus; (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).
B4. Hyper‐or hypo‐reactivity to sensory input or unusual interest in sensory aspects of environment; (such as apparent indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects).
For the scoring system of DMV, what are the 3 disturbances not better accounted for by?
Fragile X and Rett’s syndrome or childhood disintegrative disorder
What is the Ute Firth: Sally Anne test and the theory of mind
Professor Frith: In the 1960s, when I started out as a PhD student, autism was hardly known, and cognitive neuroscience did not exist. I had now idea that my career would take me deep into these mysterious directions. I suppose it was the very mysteriousness of autistic children, which attracted me to study them.
A test to recognise empathy associated social skills in the young
In this test there are two people with baskets. ‘sally’ would put a jewel in her basket and then would leave the room. During that time ‘anne’ has taken the jewel and put it in her own basket. When sally renters the room, the child is asked where ‘sally’ thinks the jewel is. A non-autistic child would say ‘sally’ whereas an autistic child would say ‘anne’ as not thinking about how sally has been out of the room and wouldn’t be aware of it moving
Reality is that most with an ASD diagnosis are not high performing
Reality is that most with an ASD diagnosis are not high performing
https://www.youtube.com/watch?v=8jrqpn60d4A
video of a 20-year-old with autism and how withdrawn he is from the outside world
What are the different security levels of ASD?
Level 3: Requiring very substantial support
Level 2: Requiring substantial support
Level 1: Requiring support
Tell me about the social communications for each of the security levels for ASD
Tell me about the restricted interests and repetitive behaviours for each of the different security levels for ASD
Is autism more prevalent or more often diagnosed in the male or female population?
The male population
What evidence is there for the general difference in a population in male and female behaviour
Whats the main difference in the characteristic traits between males and females?
Human females empathise do well in behaviour scores of abilities to predict and response appropriately to others (normally peoples) mental state
Human males systemise well: predict and response to the behaviour of nonagentive deterministic systems by predicting rules that govern the system
Correlates/postulates- Male have increased white matter subserving local neuronal connections that underpin systemizing the increased proportion of local circuits promote focussed behaviour. In an extreme male brain (Autistic) may underpin focussed and act against empathizing nerve activity.
Argues for a role in prenatal androgens exposure in mechanisms that give rise to the autistic phenotype. Androgen production does impact on early brain development.
Personally testing
Does the triad represent a unique spectrum or overlap of traits/
What do scoring linkage in behaviours in the general population argue for?
Fractionated disorder
When calculating the scoring linkage in behaviours in the general population, what sort of things are scored and what are the linkage levels?
Score play, verbal communication, and rigid/repetitive behaviours in general population.
Linkage levels Social/verbal>verbal/repetitive>social/repetitive but non showed a significant linkage.
What the difference between what typical and atypical individuals show with the scoring triad?
Normal Individuals show dysfunction (difficulty) in one aspect of triad.
Poor expression of the individual traits of the triad in autism (e.g., Dysfunction or repetitive behaviour appears after verbal/social). Not complete fractionation as some socially biased tests teases out associations.
Genetic inheritance of individual traits in the triad (in twin studies) argues for fractionation of traits
What areas of the brain are involved in each aspect of the triad?
Social
Verbal
Repetitive
What does the biological basis of autism infer about the disorder?
That it is underpinned by changes in brain structure and function
What do EEGs of individuals with autism identify?
Unusual patterns of electrical activity
What is the biological basis of autism reinforced by?
The strong association with seizures (about 30%) in autism
What does the biological basis of autism show in regards to changes in brain size?
Changes in brain size are relactive to control populations (slow neonatal and rapid post-natal growth)
What are the different brain regions that are affected in autistic patients
- Cerebral cortex
- Cerebellar cortex
- Deep cerebellar nuclei
- Inferior olivary nucleus
- Entorhinal cortex
- Facial nucleus
- Hippocampus
- Amygdala
How is the cerebral cortex altered in autistic individuals
- Increased cell density
- small cortical minicolumns
- Ectopic neurons
- Neuronal disorganisation
- Areas of increased cortical thickness
- Poor lamination in the anterior cingulata cortex
How is the cereballar cortex altered in autistic individuals
- decreased purkinje cells number
- modest decrease in granule cell counts
How is the deep cerebellar nuclei altered in autistic individuals
- increased cell size before age 12 and decreased cell counts after age 22
- dysplasia in the dentate nucleus
- Subcortical ectopic grey matter
How is the inferior olivary nucleus altered in autistic individuals
- increased cell size before age 12 and decreased cell size after age 22
- Olivary dysplasia
What are the major stages which help to define/ rationalise the PDD nature of autism.
Tell me what the genome wide association studies using genomic variation to map disease associated alleles has shown and what cohorts are used
What does the genetic architecture of autism show?
- strong genetic association
- Is a spectrum disorder due to the variety of different genes which can be implicated
What are some more targeted approaches about autism focused on?
Exon sequencing
and
methods of copy number often provide rarer but stronger effects which are good for understanding the mechanism
What are two genetic mechanisms to be aware of with autism that could be contributers to the disorder?
- Rare de novo (these could be nonsense, missense or deletion mutations)
- Rare transmitted (heterozygous –> homozygous transmittance of traits, also one could be silent in the mother but then is expressed when inherited by offspring)
There are many genes but good rationale is used to describe synaptopathy
Tell me about this
- Now >800 genes implicated https://sfari.org/resources/sfari-gene for critique.
- Support a neurobiological and particularly synaptic bases of pathophysiology
- Genetically controlled programmes that contribute to synapse formation and function
Mutations make a case for a key role in synapse formation, structure and/or function, explain the types of effects that mutations can have
- Migration of neurons and elaboration or stabilisation of synaptic processes (dendrites)
- Cell number, cell density and connectivity
- Impact on synaptic contact and stabilisation
- Impact on the balance of inhibitory and excitatory synapses
Tell me about the selective use of molecules and how they can define synapses, explain with examples
- Selective use of molecules can define synapse (e.g., neuroligin 1 excitatory: neuroligin 2
- Inhibitory 3 and 4 more mixed).
- Make multiplex protein complex that are adhesive and bring about signalling.
- Neurexin is a pre-synaptic compound that makes links with neuroligin
- Glutamate receptors are post-synaptically important
- Cell adhesion contacts which help mature synapse (e.g., neurexin and neuroligin)
- Neuroligin 2 is important for the maturation and stabilisation of GABA synapse
- Neuroligin 1, 3 and 4 is important for the excitatory glutamate synapse
Neuroligin deficiency in animal models does not give the expected effect but does have an autistic phenotype
What are the fractionable triads and integral aspects of autism?
Explain the neuroligins-mouse models of the human condition under the following situations;
- Wild-type
- Neuroligin-3 (mutated) identified in humans
- Neuroligin-3 Knocked out identified in humans
How do they effect the synapse?
Selectivity and complexity of autism related gene mutations
(didn’t cover in lectures but be aware)
Neuroligin-3 mutants (KO and R451C) have shared deficiency in endocannabinoid signalling that underpins the common increase in GABA release
(didn’t cover in lectures but be aware)
- All synapses are not equally dependent of nlg-3
- mGluR receptor activation leads to production lipid mediator (2-AG)
- This acts on the cannabinoid receptors (CB1R) that reduce transmitter release.
- In the KO and R451C there is a shared disruption of CB1R signalling.
- If you lose inhibition, you increase transmitter release
Tell me about the experiments done on mice models of genetic lesions to define the key circuits underpinning the ‘fractionatable’ pathophysiology of ‘autism’ circuits
Specifically NLG-3 KO mice
- R451C mutation is a null mutation and is the same as a KO mice
- Mice can learn and approve; they do this over time and is seen in both the Wt and KO mice (top image)
- Wanted to make the task more demanding by increasing the rod speed. When this additional strain is added the Wt don’t learn the task, but the KO and mutant do (deficit in motor learning is that they learn better)
Was the following structures of the brain effected in NLG-3 KO mice;
- dorsal striatum, cerebellum, striatum and motor cortex
- Substantia nigra, dorsal striatum, ventral striatum, VTA
Explain the differences and similarities between Normal NL3 and NL3 loss of-function synapses for D1 and D2
How does it effect the following;
- cell type specific synaptic disinhibition
- Imbalances nucleus accumbens output
- repetitive motor routine
Neuroligin 3 loss of function (KO and R451C) reduced inhibitory signals from GABA releasing onto D1 but not D2 neurons without affecting excitation
- Distinct synapses are not equally dependent on NLG-3.
- This case has a consequence in behavioural trait that model’s autism.
- One type expresses D1 receptors and the other expresses D2 receptors (anatomically and functionally distinct)
- D2 acts against and inhibits the D1 pathway when activated
- 4 different synapses; 2 glutamatergic and 2 GABA (excitatory and inhibitory)
- Neuroligin-3 is expressed in all the synapses
- In Neuroligin null mutant with respect to 4 synapses; the effect is not equivalent, no effect on excitation on D1, no effect on excitation on D2, no effect on GABA D2 but is effect on selective function and loss in the GABA D1 neuron
- If you inhibit an inhibitory neuron, you have disinhibition and there is a shift in excitation
- Output is improved learning (increasing the repeat behavioural sequence which is why as explained above the rat mutants can learn the rod experiment quicker)
Hypothesising about the value of behavioural therapy as treatment of dysfunction
Sensory pathways a way into the dysfunctional brain and training could modify it
MGluR5 receptor and Fragile X and Autism
Fragile X mice are deficient in senosry dependent exploration, give examples for this
Open field (measure of how and methods used to explore area of space).
Novel object recognition (measure how animals interact with novel objects).
