2023 Autism Lectures PDF

Autism (2023) 3 lectures Lecture 1 1. Define pervasive developmental disorders (PDD) and the autistic spectrum disorders (ASD). 2. Discuss the relationship between the signature behaviours that diagnose the condition. 3. Address the concept that autistic spectrum relate to extremes of “normal”(neur...

Autism (2023) 3 lectures Lecture 1 1. Define pervasive developmental disorders (PDD) and the autistic spectrum disorders (ASD). 2. Discuss the relationship between the signature behaviours that diagnose the condition. 3. Address the concept that autistic spectrum relate to extremes of “normal”(neurotypical) human behaviour such that individuals are diagnosed as neuroatypical. Lecture 2 and 3 (distilled to a single lecture). 1. Highlight neurobiological evidence for autism. 2. Genetic architecture of autism to illustrate molecular pathways underlie autism and evidence they point to it being a “synaptopathy” using animal models (neurexin/neuroligin). 3.Use neuroligin as an examples to show how dysfunction can generate the distinct aspects of the triad highlighting experimental approaches. 4. List some strategies used for autistic therapies. References. Neurobiology of mental illness. Chapter 58 Neurobiology of autism. Eds. D.S. Charney, E.J. Nestler and B.J. Bunney. Oxford Press. Good historical coverage of autism and PPD. Happe, F., Ronald, A. and Plomin, R. (2006) Time to give up on a single explanation for Autism. Nat. Neurosci.1218-1220. Good coverage of the difficulty in providing a precise frame work for ASD. Baron-Cohen, S., Knickmeyer, R.C., Belmonte, M.K. (2005) Sex differences in the brain. Implications for explaining autism. Science. 310. 819-823. Touching on differences in females ability to emphasize over males preference for systemizing as potential indicator for the autistic brain. Persico, A.M. and Bourgeron, T. (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. TiNS 29. 349-358. Nice systematic listing of the genes implicated in autism and discussion of how their dysfunction might underlie autism. Saffen,D (2015) The genetic architecture of autism spectrum disorders (ASDs) and the potential importance of common regulatory genetic variants Science China Life Sciences 58. 968–975.  Autism and related disorders 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.” 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”. Autistic triad and a spectrum of disorders. Impaired social interaction Impaired restricted activity Verbal communication or particularly focussed to reduced language skills inanimate objects Asperger’s syndrome Autism (autistic)  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. Cognitive dysfunction can confound diagnosis high level functioning autistics over low level confuse diagnostics. 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. Syndromes like Rett’s and Fragile X where defective gene is identified. Asperger’s Autistic disorder without the Range As for autism but defining genes not dysfunctional verbal communication. 1-60/10 000 clear. Autism Triad of dysfunction in social, 10/10 000 Monozygotic twins and significant communicative repetitive behaviours. sibling indicate genetic component. Clear complex (polygenic) underpinnings. Further environmental interactions. PDD-NOS (not otherwise Low level autistic spectrum, more 1/200 As for autism less studied specified) common but better prognosis. Heller’s Normal development followed by 1/100 000 Unclear but neuropathology Childhood Disintegrative dysfunction in many areas beyond seen Implicated. Disorder in autism. Social skills less disrupted than classic autistic. Severe decline in language skills Fragile X syndrome Mental retardation modest autistic 1/5000 Fragile X gene. RNA binding protein phenotype. male>girls mutated. Rett’s Syndrome Similar early symptoms (pre-school) 1/12 500 MECP nuclear methyl DNA binding progresses to mental retardation. protein.  Emerging depiction of the Autistic phenotype. Breadth of behaviours that can be scored. Diagnostic and statistical manual of mental disorders DSM V. This represents a maturation through DSM I-IV Mature understanding of the spectrum and clean up classification and sub-classification of Pervasive Development Disorders. DSM V- matured DSM-5 refined definition of the triad. 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: 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. B. RESTRICTED, REPETITIVE PATTERNS OF BEHAVIOR, INTERESTS, OR ACTIVITIES AS MANIFESTED >2 OF 4 SYMPTOMS 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). C. SYMPTOMS MUST BE PRESENT IN EARLY CHILDHOOD BUT MAY NOT BECOME FULLY MANIFEST UNTIL SOCIAL DEMANDS EXCEED LIMITED CAPACITIES). The disturbance is not better accounted for by Fragile X and Rett's syndrome or Childhood Disintegrative Disorder 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 recognize empathy and associated social skill in the young. Reality is that most with an ASD diagnosis are not high performing https://www.youtube.com/watch? v=8jrqpn60d4A Summary of DSM-V recognizes the spectrum  When does neurotypical become neuroAtypical. Autism is more prevalent or more often diagnosed in the male population. Good evidence for a general difference at a population level in male and female behaviour (e.g. map reading (male), verbal fluency (female). Human females Empathize: Do well in behavioural scores of ability to predict and respond appropriately to others (normally peoples) mental state. Human Males Systemize well: predict and respond to the behaviour of nonagentive deterministic systems by predicting rules that govern the system. Population plot of E/S distribution Behavioural scoring of individual E/S quotient Extreme male brain in autistics. Increasing tendency to a type E 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.  http://personalitytesting.info/tests/EQSQ.php Empathizing Quotient is 46. Baron-Cohen (2003) suggests "you have an average ability for understanding how other people feel and responding appropriately. You know how to treat people with care and sensitivity". Systemizing Quotient is 18. Baron-Cohen (2003) suggests that this means "you have a lower than average ability for analyzing and exploring a system".  Does the triad represent a unique spectrum or overlap of traits Fractionabl Integral Social Social Verbal Repetitive Verbal Repetitive e Scoring linkage in behaviours in general population argue for fractionated disorder Score play, verbal communication and rigid/repetitive behaviours in general population. Linkage levels Social/verbal>verbal/repetitive>social/repetitive but non showed a significant inkage. 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 test tease out associations. Genetic inheritance of individual traits in the triad (in twin studies) argues for fractionation of traits. Distilling out the distinct behaviours with brain imaging Cortical regions: Dysfunction in Caudate Social Medial frontal cortex, Verbal voice centres Repetitive putamen temporparieatal junction, of the cortex temporal suculus and poles.  Biological basis of the autism. Infer that it is a disorder that is underpinned by changes in brain structure and function. Electroencephalograms in autistics identify unusual patterns of electrical activity Reinforced by the strong association with seizures (about 30%) in autism. Changes in brain size relative to control populations (slow neonatal and rapid post natal growth). Series of imaging and post-mortem studies define abnormal development and connectivity but in a non-obvious way. Cell Number increases Imaging studies Cell Number decreases relatively physiological but post-mortem counts Cell size might change suffer from a life time of experiences (drugs, Cell density increases treatments) and variation of deaths. Connectivity may change  Helping to define/rationalize the PDD nature of Autism. A scheme cartooning important stages in brain development Early Progenitor Neurogenesis (proliferation) Cell death Migration Cell death Neuronal Differentiation Neurite outgrowth Retraction and shrinkage During synapse formation Synapse formation Presynapse After Maturation (pruning synaptic Late sculpturing) Maturation and stabilization Postsynapse  Genetic basis providing insight to a synaptic locus for autism Monozygotic twins have 90% coincidence of autism. Sibling association is indicative of underlying genetic cause. Not simple association but polygenic in nature or complex regulation of de novo mutations. Mutations (M) can be followed by tracking the inheritability of genes. Chromosomal rearrangements (CR) cytoarchitecture identified and mutant associated with re-arrangement. Linkage or association (L/A) using markers (microsatellite or single nucleotide polymorphisms in genome to track regions of the genome associated with trait and infer molecular associated with this. Genome wide association studies (GWAS): using genomic variation to map disease associated alleles (Am J Psychiatry 2009; 166:540–556). Genetic architecture of autism Strong genetic association Genetic Increased risk of variations ASD Low penetrant Rare, variations highly present at a penetrant high frequency variations in ASD Over 1,000 genes have been implicated in ASD so far Diagram modified from Bourgeron, 2015  Many genes but good rationale to describe SYNAPTOPATHY Now >800 genes implicated https://sfari.org/resources/sfari-gene for critique. Support a neurobiological and particularly synaptic basis for pathophysiology. Control transcription and expression of other genes involved in the formation and stabilization of synapses. Regulate the cytoskeleton and form and function of dendrites. Protein organizers of the synapse. Directly control chemical transmission and excitability. Cell signalling thus synapse function. Cell-cell and synaptic contacts. Developmental processes that lead to synapse formation. Mutations make a case for a key role in synapse formation, structure and/or function. Migration of neurons and elaboration or stabilization of synaptic processes (dendrites). Cell number, cell density and connectivity. Impact on synaptic contact and stabilization Impact on the balance of inhibitory and excitatory synapses. Neuroligin deficiency in animal models does not give the expected effect but does have an autistic phenotype. Neuroligin contacts partner neurexin to drive synapse formation and stabilization. (additional) copy. Human males have Y linked NGL gene 4 genes extensively spliced synaptic tags. potentially (1000s of isoforms) likely transcripts) and multiple splice variants 4 genes, alternative promoters (8 major -Mice lacking neuroligins have a brain, have synapses and expected number of synapses (hippocampus/cortex). -Die because brain stem (respiratory neural network) has disrupted neural activity. Functions by a balance of inhibitory and excitatory in neural circuit. -Brain stem has normal numbers of synapses but functionally both the Glutamate (excitatory) and GABA (inhibitory) transmitters are reduced. In normal brainstem inhibitory input dominates. -In neuroligin deficient mouse model the ratio of inhibitory/excitatory transmission is reduced so excitatory transmission dominates. -Synaptic dysfunction without loss of cells or synapses appears real possibility-argues for synaptic maturation playing a role in autistic condition. -potential for relevance of dysfunction in synapse-synapse contact phenomenon driving autistic phenotype by the largest linkage study of autistic pedigrees revealing NEUREXIN AS prime candidate susceptibility gene.  Translating conceptual understanding to molecular mechanism Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T; Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003 May;34(1):27-9. Clarity and complication in human and animal models of autism Likely De novo mutation seen in two brothers: 1. Has severe ASD symptoms including seizure 2. Asperger’s with DSM diagnosis but milder. (points to a more complex genetic interaction). Veracity (face value) of the animal model. Tabuchi et al. (2007) A neuroligin-3 mutation implicated in Autism increases inhibitory synaptic transmission. Science 318 71. “Reports a strong social interaction deficit behaviourally” R451C Chadman et al., Minimal Aberrant Behavioural phenotypes of Neuroligin-3 R451C knock-in mice. “Refutes any effect of social interaction behaviour” How do widely expressed broad synaptic adhesion molecules selectively disrupt sub-behaviours  Neuroligins-mouse models of the human condition? Wild-type Neuroligin-3 (mutated) Neuroligin-3 knocked out Identified in human Identified in humans Presynapse Postsynapse 451 Arg-Cys Retained and degraded but small proportion gets to synapse Neuroligin/Neurexin. Relatively normal synapse number Relatively normal synapse Interaction involved Normal synapse structure Increase metabotropic in synapse maintenance Increased inhibition glutamate receptor. or maturation Impaired social behaviour Disrupted plasticity in Modified (improved) learning cerebellum.  Using animal models of genetic lesion to define key circuits underpinning the “fractionatable” pathophysiology of “autism” circuits. NLG-3 knock out and functional null NLG-3R451C do not directly overlap. Motor learning study indicate shared ability to for hyper-function in motor control. Is this a propensity to repetitive behaviour Key foci of motor learning Shifted balance in the outputs of the appear normal (including Nucleus Accumbens (Ventral Striatum). (full of medium spiny GABA neurons). dorsal striatum). Rothwell et al. (2014) Cell 158,198–212 Neuroligin 3 loss of function (KO and R451C) reduces 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 models autism.  Therapy/treatment in autism. Pervasiveness and the developmental essence of the disorder means there is no cure. Behavioural therapies to induce “behavioural plasticity”. 1. Sensory or play therapies to refine behaviour by bringing individual out oneself. 2. Encourage interaction with environment and others (often involve carer programs). 3. Cognitive therapy: identify deficiencies, instil awareness and teach or school affected individuals to develop strategies to overcome these. Drug therapies based on three areas (treat symptoms not the cause). 1.Target neurochemistry that underpin autistic triad. Serotonergic and dopaminergic drugs can act on social impairments and stereotypic behaviour (e.g. Haloperidol (dopamine receptor antagonist) and Resperidone (dopamine and serotonin antagonist). Several selective serotonin reuptake inhibitors (SSRIs e.g. fluoxetine) been used to target the repetitive behaviours associated with autism. Isolated indications of successful use of lithium, valproate and carbamazepine 2. Transmitter pathways that underlie behavioural disorders associated with autism Sleep disorders and aggressive behaviour are seen with autistic individuals and have been treated with propranolol, or clonidine (adrenergic antagonists). 3. Organic interventions associated with vitamin supplements or diet include Mg2+, vitamin B6 and B12. Issue with all the above is that evidence for efficacy tends to be clinical/anecdotal Few full trials on the efficacy of drug or behavioural treatments.