Neurological Diseases Flashcards
Describe the cellular organisation of the human neocortex and hippocampus:
- Even within the neocortex, different parts e.g. visual cortex, motor cortex, have different cortical layering patterns
e. g. visual cortex has 6 layers - Cellular layering is very important in the hippocampus
What are the cellular and molecular processes of neural development?
- Proliferation:
- cell division to form billion of neurons, microglial cells and astrocytes - Migration:
- Movement of neurons from site of birth to final destination in brain (neurons are born in the subventricular zone, and must migrate out to their respective cortical layers) - Aggregation:
- Adhesion of similar cells into specific brain structures - Differentiation:
- Commitment to become a particular type of cell e.g. dopaminergic neurons will secrete dopamine - Circuit formation:
- Growth of axons and dendrites followed by synapse formation - Pruning and programmed cell death:
- Loss of extra neurons (many) and synapses
- Deficits in this pruning stage can lead to autism
Describe the 2 different forms of neuronal migration in the cerebral neocortex:
- Radial migration:
- Occurs in excitatory neurons
- Use scaffold provided by radial gilal cells to move up to the dorsal surface of the brain
- Inside-out organisation - Tangential migration:
- Occurs in inhibitory neurons (interneurons)
- These neurons originate from the ganglion eminence- ventral surface of vesicles
- They migrate tangentially and synapse of excitatory neurons that have previously migrated to regulate their activity
Describe prenatal neural development:
- Embryonic:
- First 8 weeks of pregnancy
- Primordium of the CNS arises
- Development of neural tube and 3 ventricles
- Vast majority of congenital abnormalities occur during this period - Fetal:
- Characterised by significant growth (40x increase in brain weight)
- Appearance of sulci and gyri on brain surface
Describe postnatal brain development:
- Birth:
- Gross anatomy of CNS resembles adult
- Repertoire of neurons of neocortex largely established - Infancy:
- Massive outgrowth of dendrites and axons
- Synaptogenesis, gliogenesis and myelination
- Neurogenesis in cerebellum is still occurring
Describe the changes that take place in the adolescent brain:
Structural:
- Reduction in grey matter in neocortex (due to pruning)
- Increase in white matter (due to increased connectivity and myelination)
- Axonal sprouting and growth in circuits in the amygdala and cortex (due to development of emotions and intelligence
- In animal studies: overexpression in dopamine, 5-HT, adrenaline, GABA etc.
Social changes:
- Increased social behaviour
- Novelty and sensation seeking
- Emotional instability
- Impulsivity
What is a critical period in neural development?
- A critical period in brain development is when neural circuits responsible for a particular process can be sculpted or radically changes by the environment of experiences
- A period of time when the brain is most plastic
e. g. Critical period for processing sensory information:
- Infancy
e. g. Critical period for language:
- Between infancy and childhood
e. g. Critical period for higher cognition:
- Occurs during childhood
What is a neurodevelopmental disorder?
- NDDs are a group of psychiatric illnesses that are the result of abnormal brain development
e. g. deficit in neurogenesis, progenitor cell proliferation, migration, synapse formation and myelination - Symptoms include disabilities in cognitive, social, motor and effective function
- Most common NDD is autism spectrum disorder
- The impairment is generally detected at birth, during infancy e.g. ASD and sometimes adolescence e.g. schizophrenia usually manifests in adolescence
- Have both a genetic and environmental component
- Most NDDs are highly heritable (generally polygenic)
- Examples of monogenic NDDs are Angelman’s and Fragile X syndrome
How are neurodevelopmental disorders treated?
Pharmacotherapy:
- Anti-psychotics to treat psychosis or ADHD by stimulating certain pathways
- Stimulants to treat ADHD
- Adjunct therapy to treat other co-morbidity such as OCD, depression, seizures
What is the excitatory/inhibitory imbalance theory for ASD and schizophrenia?
- Behaviour symptoms of NDD are very similar: social interaction and cognitive deficits, emotion processing problems, executive dysfunction
- Imbalances in excitatory and inhibitory neurons may manifest themselves in behavioural symptoms
What properties should a good animal model of NDD possess?
- Construct validity:
- confirming to the underlying rationale of the disease e.g. for an animal to model ASD, they need to have an imbalance in excitatory and inhibitory neurons - Face validity:
- Mimicking some characteristics of the disease e.g. for an model to mimic ASD, there should be social interaction deficits - Predictive validity:
- Allow the prediction of novel disease symptoms e.g. for an animal to model ASD, there should be some hyperexcitability
How is Autism diagnosed?
- DSM:
- Persistent deficits in social communication/interaction
- Restricted, repetitive behaviours, interests and activities - WHO ICD:
- Abnormal development of receptive/expressive language
- Impaired development of selective social attachments/reciprocal social interaction
- Markedly restricted repertoire of activity and interests
Other symptoms of ASD:
- Social anxiety
- OCD
- GI dysfunction
- Sleep disturbances
- Motor problems: lack refined coordination
What is the prevalence of ASD?
- Estimated to affect 1 in 100 people worldwide
- More prevalent in boys
- Difficult to ascertain exact prevalence as it is a spectrum disorder with a broad range of phenotypes
What are the core, other behavioural and functional symptoms of ASD?
- Core symptoms generally detectable in children before age of 3
Core symptoms:
- Persistent deficits in social communications and interactions
Other behavioural symptoms:
- Anxiety
- Hyperactivity
- Agitation
- Impulsivity
- Aggressive behaviour
Functional symptoms:
- Sensory hypersensitivity
- Seizures
- GI disorders
What are the phenotypes of ASD?
- Intellectual disability (5%)
- Language disorders (50%)
- Epilepsy (5-15%)
- ADHD
- Anxiety disorders (up to 85%)
- OCD (50%)
- Motor disorders (95% of ASD patients with no intellectual disability)
What are the biomarkers for ASD?
Neuroimaging:
- Young children with ASD have an enlarged and thickened cortical volume
- Connectivity: young children have hypersensitivity to certain sensory stimuli as they have connections that have not been pruned
- Functional: certain patterns in fMRI
Plasma:
- Potential abnromal levels in BDNF (brain derived neurotrophic factor)
- Serotonin consistently higher in 30% of ASD patients
- Decreased nighttime production of melatonin
- May not be correlated with changes to the brain
What is the neuropathology observed in ASD?
- Early brain enlargement between years 1 and 2:
- Increased cortical thickness and folding in parietal love
- Decreased pruning
- Decerased GABA (inhibitory) expression in superior frontal lobe and parietal cortices
- Abnormal columnar structure in neocortex
- Hypometabolism in front regions - Increased brain volume dissapears around ages 6-8
- Due to abnormal slowness in brain growth - Abnormaliites in limbic structures in older individuals:
- Reduction in volume (smaller more tightly packed neurons)
- In hippocampus, amygdala and cingulate cortex - Cellular abnormalities:
- Decreased volume, size and number of Purkinje cells (major cell type in cerebellum) - Morphological/organisatioon deficits in cortex:
- 5 year old autistic child has many more cells in the cortex, more defined smaller columns, more neural connection, more smaller cells
- Leads to inflammatory response against structural abnormalities
- Displacement of interneurons (disruption of excitatory/inhibitory ratio)
What are the genetic factors involved with ASD?
- ASDs are highly heritable (approx 90%)
- No identifiable chromosomal regions found
- Large number of ASD susceptibility genes including:
1. scaffold proteins (SHANK 2 and 3)
2. Adhesion molecules (cadherins)
3. GABA receptor subunits
4. Voltage gates calcium subunits
5. Regulators of chromatin remodelling
6. Proteins involves in synapse formation - Many single nucleotide variants have been found- but each only has low risk
- De novo copy mutations are also seen
- It is hypothesised that many variants of genes contribute to tipping an individual into ASD diagnosis
What are the theories of ASD?
- Impeded plasticity:
- Abnormal regulation of cell division and apoptosis
- Hyper- followed by hypo- connectivity
- Used to be very popular, less so now - Excitation and inhibition dysregulation:
- Imbalance of glutaminergic and GAGAergic synapses
- Can explain epilepsy
- Most favoured theory - Theory of mind:
- Impaired theory of mind leads to deficit in social behaviour and communications - Mirror neurons:
- Dysfunction in mirror neuron system is thought to generate social and cognitive impairments
What are the risk factors for ASD?
- Infection/Immune dysfunction:
- CSF of ASD children contains atypical levels of autoantibodies against neural antigens
- Maternal infection could play a role - Endocrine factors:
- Maternal stress: intrauterine expsosure to cortisol and thyroxine - Obstetric factors:
- Low birth weight, preterm/c-section delivery
- Uterine bleeds - Environmental factors:
- Maternal exposure to prescription medications, illicit drugs, heavy metals (mercury), environmental toxins and cigarette smoke
How is oxytocin related to ASD?
- At birth oxytocin mediates a sudden reduction in intracellular Cl- which dacilitates the shift which protects GABAergic neurons from anoxic episodes
- The hormone plays an important role in social behaviour
- ASD children have lower baseline levels of oxytocin
- Intranasal administeration of oxytocin is being trialled as a therapy for the core symptoms of ASD
How is ASD treated behaviourally?
Intervention models:
- Discrete trial training (early intensive behavioural training)
- Naturalistic training (embedding teaching with play)
- Learning experiences an alternative program: promote social interaction in curriculum of children with ASD
- Early Start Denver Model: individualised interventions in consultation
Skill based models:
- Functional communication training, positive behaviour support, self-management, speech generation
How is ASD treated phamacologically?
- Medications such as anti-psychotics and stimulants to treat symptoms (do not treat cause)
- Intra-nasal oxytocin being trialed
How is ASD modelled in animals?
- There are currently no ideal animal models (all models have major limitations)
- Neonatal lesions:
- In amygdala, cerebellum and medial prefrontal cortex - Maternal intervention:
- Prenatal valpronic acid exposure: affects the epigenome at critical developmental stages
- Prenatal expoure to infection - Genetic models:
- BDNF overexpression: high seizure susceptability, depression and anxiety behaviour, but no change in social behaviour
- Fragile X mental retardation
- GAGARB3 subunit KO: seizure susceptability, hyperactivity, stereotyped behaviour, learning and memory defects, impaired social interaction