The developing brain lecture module 1 autism - . about smiling, making stereotyped movements with - Studeersnel (2025)

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The developing brain lecture module 1 autismAutism historyCoined the word “autismus” derived from the word autós (“self” in Greek)when defining symptoms of schizophreniaIn 1943 paper on autistic disturbance of affective cintact in 8 boys and 3girls  About Donald (5 years old):“happiest when left alone, almost never cried to go with his mother, did not seem to notice his father’s home-comings, and was indifferent to visiting relatives.. about smiling, making stereotyped movements with his fingers... spun with great pleasure anything he could seize upon to spin... to him had a specifically literal, inflexible meaning... taken into a room, he completely disregarded the people and instantly went for objects”.In 1944 article on autistic psychopathy in choldhoof in 4 boys (Aspergersyndrome)  About Fritz (6 years old): “learnt to talk very early... quickly learnt to express himself in sentences and soon talked ‘like an adult’.. able to become integrated into a group of playing children.. not know the meaning of respect and was utterly indifferent to the authority of adults.. distance and talked without shyness even to strangers.. was impossible to teach him the polite form of address... strange phenomenon.. the occurrence of certain stereotypic movements and habitsGrunya Sukhareva was first - Described autistic symtoms in 1936, calling it schizoid psychopathy in children - Described 6 boys and 5 girls with autism in subsequent papers in 1926 - Not clear why kanner and asperger didn’t cite her, but sukhareva was from jewish heritage and asperger affiliated with the Nazi partyAutism spectrum disorder definition - DSM- - Widely used in North America and Europe to diagnose mental health conditions - Role DSM-5 in diagnostics of Neural Developmental Disorders is more and more debated. Is it useful to try to diagnose patients with ASD if the underlying neurobiological mechanisms are different? - All disorders now grouped together as ‘autistic spectrum disorders’

A. It’s a persistent deficits in social communication and social interactionA. Social communication and interaction 1. Deficits in social-emotional reciprocity: 1. abnormal social approach; 2. failure of normal back-and-forth conversation; 3. reduced sharing of interests, emotions, or affect; 4. failure to initiate or respond to social interactions2. Deficits in nonverbal communicative behaviours used for social interaction: 1. poorly verbal and nonverbal communication; 2. abnormalities in eye contact and body language; 3. deficits in understanding and use of gestures; 4. total lack of facial expressions3. Deficits in developing, maintaining, and understanding relationships: 1. difficulties adjusting behavior to suit various social contexts; 2. difficulties in sharing imaginative play or in making friends; 3. absence of interest in peers.B. Restricted, repetitive patterns of behavior, interests or activities 1. Stereotyped or repetitive motor movements, use of objects, or speech: 1. e. simple motor stereotypies; 2. lining up toys or flipping objects; 3. idiosyncratic phrases 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior: 1. e. extreme distress at small changes; 2. difficulties with transitions; 3. rigid thinking patterns; 4. greeting rituals; 5. need to take same route or eat food every day

Fierce debat In the autism community about medicalization of ASD: twocamps or two groups Profound Autism: Severely affected children, non-verbal, inflicting self-harm, need round-the-clock care. Neurodiversity: high-functioning people with autism that don’t need medical attentionIs ASD medical condition or just a differenceCasues of autism spectrum disorders

• For most cases of diagnosed autism, theunderlying cause is unknown
• Current evidence proposes either geneticand/or environmental factors play key roles

Causes of autism – myths and

controversies

The refrigerator mother: A cold, distant, and career-oriented mother asthe prevailing explanation as to why some children develop severeemotional and behavioral problems. - First explanation of autism offered in the 1950s by Leo Kanner and Bruno Bettelheim, both psychoanalytically oriented academic physicians. - Prevailing hypothesis until the 1970s and 1980s, despite lack of epidemiological evidence, biological plausibility, the advent of the feminist movement, and its ridiculous and offensive nature.Vaccines (mumps, measles, and rubella (MMR)): The MMR vaccine isadministered to 12- to 18-month-old children. At this age also the firstsigns of autism become noticeable. - In the late 1990s, the physician Andrew Wakefield published an article in The Lancet, claiming that the measles vaccine triggered inflammation of the colon (dikke darm) which would cause autism. - Since the Wakefield report, any direct connection between autism and the MMR vaccine has been discredited by dozens of studies investigating the epidemiology of autism and the biological effects of MMR and the mumps virus - In 2005, an investigative reporter alerted The Lancet's editors that Wakefield's study had been flawed by severe research misconduct, conflict of interests, and probably falsehood. After investigating the matter, The Lancet retracted the article, and the

British Medical Association took disciplinary actions againstWakefield. It is clearly shown that older theories such as the measles, mumps and rubella MMR vaccines and lack of parental warmth (refrigator mothers) have no statistically significant link to an increases risk of developing an autistic spectrum disorder Environmental risks: use of valproic acid duringpregnancy

• Anti-Epileptic, Mood-Stabilising Drug
• Proposed action via GABAergic modulation (Note: E/I Balance!!See 3rd part of the lecture)
• Chronic treatment with VPA produces ASD symptoms in rodents(Used as animal model for ASD, see 3rd part of the lecture)
• 3-fold increase in risk of autism in children exposed to VPA
• These findings must be balanced against the treatment benefits forwomen who require valproate for epilepsy control.
• Of note: folic acid supplements before conception and during earlypregnancy seem to be protectiveEnvironmental risks: cerebellar injury at birth
• Largest environmental risk factor is cerebellar injury at birth: 36xincreased risk
• Cerebellum and forebrain are bidirectionally linked in an orderlymapping
• Cerebellum may guide thematuration of remote non-motor neural circuitry andinfluence cognitivedevelopment (might beinvolved in establishing long-range connections)Genetic risks
• Largest increase in risk for ASD comes fromgenetic factors

Association of synaptic genes with autism - GWAS show that synaptic genes are overrepresented in the genes associated with ASD - Autism risk genes are associated with specific processes in the synapseSynaptic pathways involved in ASD3 interconnectedpathways 1. Synaptic function: controls synaptic strength and synaptic plasticity 2. WNT signaling: controls key transcriptional programmes that affect neuronal maturation and circuit formation and depends on synaptic activity 3. Translation: localized translation at the synapse underlies synaptic plasticity and cognition and synaptic translation is stimulated by synaptic activityNeurobiological underpinnings of ASD - Currently not a consistent general neurobiological explanation for all forms of ASD - Most common models: A. Morphological and connectivity differences B. Disturbance of excitation/inhibition balance

Morhphological and connectivity differences

Layered and columnar organization of the cortex - Neuronal and synaptic density increases in the cortex during early postnatal development.

• In sensory cortex, neurons are arranged in columns, with a layered structure
• These columns are 500um wide and can also be divided into microcolumns around 50um wide
• Layered and columnar organization is important for information processingIncreased neuronal desnity in ASD
• Studies in postmortem cortical brain samples of ASD andneurotypical controls show increased density of neuronsin cortical layers
• These data suggest that the cortical microcolumn issmaller in ASD.
• The functional consequences of this anatomical change isunknown: it could suggest greater connectivity betweenneurons locally.Decreased long-range connectivity in ASD
• High-functioning ASD subjects and age-matchedcontrols were scanned using fMRI during rest andspecific tasks.
• Researchers calculated connectivity scores foractivation between different brain regions,including many frontal cortical areas.
• ASD subjects had lower connectivity scoresbetween regions than controls, suggestingdecreased long-range activity between theseregions.Opposed changes in long and short range connectivity inASDConnectivity model:
• ASD brains have decreased long-rangeconnectivity (hypoconnectivity).
• ASD brains have increased short-range local connectivity(hyperconnectivity).
• Could be in line with poor or weak “central coherence” in ASD.Many people with ASD are believed to perceive details better thanpeople without ASD, but have difficulty in seeing the largercontext (“cannot see the wood for the trees ...”).

Disturbance of excitation/inhibition balance

Excitation/inhibition (E/I) balance

Delayed maturation of GABAergic synapses in animal models for ASD - GABA has excitatory effect in immature neurons but inhibitory effect in mature neurons - Delayed GABAergic maturation in Fragile X (FRX) and Valproic Acid (VPA) treated rodent models for ASD - Bumetanide restores E/I balance in ASD animal models by rescuing the inhibitory function of GABAergic synapses - Bumetanide clinical trials are underway in children with autism - Bumetanide decreases intracellular chloride concentrations in the cell - Licensed to treat hypertension

Synaptic transmission is affected in patients with mutations insynaptotagmin- - Desynchronisation of neurotransmission in a patient with autistic symptoms and neurodevelopmental delayOutlook: studying neurobiology of ASD in humans - Assessment of sensory sensitivity - Clinical response to E/I targeting drugs - Measuring cellular E/I parameters in iPSC derived neurons - interdisciplinary effort to understand sensory hypersensitivity and E/I balance in ASDMicro-networks of human neurons in a dishN=You Neurodevelopment precision center:Integrating patient assessment, cellular assays and genetics forpersonalised medicineEach case is unique, so you need personalized medicineTesting the “delayed GABA shift” hypothesis for ASD in humans - Measuring GABAergic maturation and the response to bumetanide in IPSC derived neurons of children with ASDUse of human IPSC derived neurons in autism - Increased number of GAGaeric neurons in organoids of idiotypic cases of ASD - Depends on FOXG1 expression - Both duplication and deletion in the 16p11 associated with ASD and Schizophrenia - Clinical characteristics include macrocephaly in deletion carriers and microcephaly in duplication carriers - Altered morphology and physiology