Exam 2 Flashcards
What were three early indications of neuroanatomical involvement in Autism?
- Abnormal EEG’s
- Increased prevalence of seizures
- large head size
“Modular” approach - define it
particular functions are linked to specific neuroanatomical regions
-“islands”
“Integrative” approach - define it
Neuroanatomical regions are thought about in terms of networks of structures and regions subserving a particular type of behavior
What can neuroimaging be used to do?
assess structural and functional differences across groups of individuals
Structural imaging - what does it examine?
examines the underlying anatomy of the brain
Functional imaging - what does it examine?
examines changes in the activity of the brain while performing tasks
What happens in an sMRI?
Magnetic fields are applied in particular arrangements. These fields affect the behavior of atoms within the brain such that they will align themselves with the fields in the presence of the fields. When the fields are turned off, the atoms return to their normal position/behavior, and in doing so, they emit energy. This energy is transmitted to a computer that uses a bunch of mathematical algorithms to convert this signal to an image
What does DTI look at?
integrative networks by quantifying the structural connectivity between different brain structures
What does DTI measure? What is the most common reported value?
have measures that correspond to the connectivity between areas
-FA
What is the value FA?
estimation of the number of axons and how densely packed they are
-microstructure
What is the value RD?
myelination
Functional Imaging - what does it test for
Relation between structure/regions and function is established through correlations
Name 3 different methods that have been used to compare patient populations to normal controls
-what are the main differences btw these techniques?
- EEG/ERP
- PET
- fMRI
- –each technique assesses “activity” differently and each technique has it’s advantages and disadvantafes
EEG - what does it look for? what are the methods?
Looks at the principle waves
-Places electrodes on the scalp with a conductive gel to pick up population neuronal activity
ERP in EEG studies
different behaviors result in different waveforms
EEG/ERP in Autism and social factors
Individuals with autism or at risk for autism exhibit abnormal ERP responses in face processing
Advantages of MRI
- non-invasive
- good spatial resolution
Disadvantages of MRI
- Susceptible to movement
- Expensive
Advantages of EEG/ERP?
- Great temporal resolution
- Low-cost
Disadvantages of EEG/ERP?
- Poor spatial resolution
- Only assesses surface activity
- Limited task flexibility
PET imaging - what is it? what does it do?
Another way to assess the function of a region
-detects radioactivity
How does the PET scanner work?
Subjects are injected with a radioactively labeled form of glucose and asked to perform a particular task. After completing the task, the subject is then scanned, if a region was activated during the task, it would have taken in the radioactive glucose, which is detected in the PET scanner, transmitted to a computer for mathematical computations that produce an image
PET: Autism and cognitive factors
-what were the results?
When engaged in standard verbal learning test, ASD show lower glucose metabolism indicating a dysfunction of these areas associated with verbal learning
Advantages to PET?
- good spatial resolution
- task is performed outside of scanner
Disadvantages to PET?
- poor temporal resolution
- radioactive material injected into subject
- Subject must remain still during scan
Functional MRI - what does it entail?
-usually involves a task, comparing BOLD changes to a control task
What were the results from the fear-scramble fMRI testing with Autism and social factors?
emotional face processing recruits amygdala, pulivinar, FFA more in ASD than TD
Advantages of fMRI?
- no radioactive ligand
- good temporal resolution
- good spatial resolution
Disadvantages of fMRI?
- mechanisms and implications of patterns of activation not fully understood
- subject must remain motionless
- task must be performed in the scanner
What is required in order to carry out an fMRI test?
Implementation of appropriate control task/condition
What are the core structures of the “social brain”?
- FFA
- EBA
- STS
- AMY
What are the structures within the extended circuit of the “social brain”?
- OFC
- VLPFC
- IPL
- MPFC
- TPJ
What has the orbitofrontal cortex been implicated in?
reward and social reinforcement
What is the medial prefrontal cortex?
reasoning about others’ beliefs, self-reflection, and autobiographical memory
Temporoparietal juction - what is it?
attributing beliefs to others and reasoning about those beliefs
Amygdala - what has it been implicated in?
Recognition of the emotional states of others through analysis of facial expressions
Posterior STS in the right hemisphere - what does it do?
analyzes biological motion cues to interpret and predict the actions and social intentions of others
Extrastriate body area - what happens here?
Visual perception of human bodies
Fusiform face area -what has it been implicated in?
face perception and recognition
What is emotion?
- The affective aspect of consciousness
- The visceral aspects of a physiological response
What are the adaptive benefits of emotion?
- Physiological fight or flight response.
- More efficient decision-making
- Better social interaction
- Stronger memory
What does high arousal mean?
Excited
What does low arousal mean?
Calm
What does positive valence mean?
Approach
What does negative valence mean?
Aversion
Why is the amygdala important?
highly conserved across species
How does info come in to the amygdala?
via the Lateral nucleus and Basal nucleus
After the info gets routed into the amygdala, where does it go? What are the functions?
to the central nucleus, then to the hypothalamus and brainstem
-Flee, Freeze, Autonomic, Hormonal, Responses
The emotional valence attached to the inputs coming from the hypothalamus and brainstem go where? What does it do while there?
routed out from the accessory basal nucleus to the striatum
-Facial expressions, Body postures
Where do the inputs coming from the basal nucleus and accessory basal nucleus go? Why is this important?
routed back to the hippocampus
-hippocampus is important for memory and the amygdala helps to attach emotional meaning to those memories
How does info flow into and out of the amygdala?
The amygdala is made of unique subdivisions (nuclei), and these take incoming information in, emotionally process it, and send it out in a variety of structures so that the body can act on it.
What are the 5 general functions of the amygdala?
- fear processing
- emotional recognition
- emotional modulation of memory
- face processing
- reward learning
What are the 6 symptoms of Kluver-Bucy syndrome?
- Visual agnosia
- hyperorality
- hypermetamorphosis
- hypoemotionality
- dietary changes
- excessive or aberrant sexuality
- changes in social interactions
Hypoemotionality - define it
no longer fearful
hypermetamorphosis - define it
i.e. they took anything that came close to them non-stop
hyperorality - why did this symptom present itself? define it
because of the visual agnosia, they investigated the objects by mouth
visual agnosia - define it
also known as psychic blindness
-they could not recognize objects by sight
Fear processing: Animal literature: what were the takeaways?
- Rodent literature
- Monkey literature
- Rodent literature: rats with amygdala damage are unable to associate neutral cues with an aversive outcome
- Monkey literature: monkeys with amygdala damage also show deficits in fear learning
What is the human case study in fear processing? Who was the subject?
Patient SM
-a rare disease resulted in the calcification of both amygdalae
What is the fear circuitry? I.e. see a snake in the woods
First, extremely rapidly, the visual information of the snake coming from the eyes relays into:
visual thalamus (imprecise)->amygdala->striatum and brainstem
—heart beat and breathing increases
occipital cortex (precise)->amygdala->hippocampus->prefrontal cortex
—fight or flight then decided on
How did researchers test for emotion recognition?
set of pictures of people depicting different facial expressions
-faces presented one at a time and subject is asked to label the emotions
What is greater amygdala activation correlated with?
Better memory
Face processing - what does the amygdala help you do?
Look at the person in the eyes
What does fear learning help us do?
Helps us avoid dangerous situations
What impact does selective damage to the amygdala have?
very subtle effects on learning that involves rewards
-mainly changes our internal drives
Why is the amygdala important for reward learning?
guides our behavior based on our internal emotions
What is the evidence of morphological changes
in the amygdala in ASD?
- Enlarged Amygdalae
- Increased cell densities
- Abnormalities in neuronal firing
Frontal lobe - why is it important? What cortex makes it up?
- recently evolved
- integrates info from many different regions
- mediates goal-directed actions and controls decision making
- implicated in emotional valence and reward association
- —Neocortex -> 6 layers
Who is Phineas Gage?
- Railroad worker
- survived, but sustained frontal damage due to steel tamping rod
Why was Phineas Gage important?
He experienced severe behavioral changes after the frontal damage
- Before: well-loved, respected
- After: irreverent, profane, obstinent
Medial OFC - what is it known for?
identification of items, creating new stimulus associations, story comprehension, sentence completion, risk
Lateral OFC - what is it known for?
Inhibitions, hypothesis testing, face perception, non match to sample (choosing the new), working memory, stimulus association
What is the striatum known for?
Habit learning
What is the hypothalamus known for?
Autonomic functions and arousal
What is the cingulate known for?
involved in detecting errors btw action/outcome
What is the temporal lobe known for?
vision
What is the insula known for?
taste
What does the OFC receive inputs from?
- The olfactory, taste, and somatosensory cortices
- temporal lobe visual area around the temporal sulcus (specifically tuned for face processing)
- cingulate cortex, the striatum, and the hypothalamus
What is the job of the OFC?
not only involved in pairing the “what” aspects of sensory signals with reward expectations, but is also involved in coding for pleasantness of such stimuli
What is an example of something that is coded for in the OFC?
Facial identity and facial emotions are coded for in the OFC, as well as the relationship between facial expression and expected reward outcome
What does the OFC share bidirectional connectivity with?
The amygdala
What are the basic functions of the OFC? Describe them.
Reward -anticipation of reward -evaluation of reward qualities Flexibility -updating contingencies Social Function -appropriate emotional response
Wernicke’s area - what is it important for?
speech production
What is the primary motor cortex involved in?
Actually moving your muscles
Everything before the central sulcus is involved in what?
acting upon the info
-organized from very basic (near central sulcus) to very complex (very front of the brain)
Everything happening after the central sulcus is doing what?
Is taking in info
-the parietal lobe is taking in info about your body and the occipital lobe is taking in visual info
Why was the cerebellum one of the most controversial sites of brain abnormality in ASD? What changed
-Recent evidence show that the cerebellum is also involved in cognitive functions, along with motor and equilibrium
What is the trend regarding the cerebellum across species?
It is highly conserved
What are the three main lobes of the cerebellum?
- anterior
- posterior
- flocculonodular
What is the name of the most medial region of the cerebellum?
Vermis
What are the names of the lateral regions of the cerebellum?
the two lateral regions are the hemispheres
What is the cerebellum involved in?
- voluntary movements
- balance and equilibrium
- muscle tone
What type of function is the cerebellum involved in?
Higher cognitive functions
What is the main function of the frontal lobe?
Conscious motor actions just in front of the central sulcus) and executive functions (more anterior regions)
What is the main function of the parietal lobe?
Somatosensory perception (just posterior to the central sulcus) and visual spatial organization (more posterior regions)
What is the main function of the occipital lobe?
vision
What is the main function of the temporal lobe?
- vision
- memory
- audition (in the lateral fissure)
Where does the cerebellum receive inputs from?
not only the motor areas, but also the prefrontal, parietal, and temporal cortex
What is increased activity in the cerebellum associated with?
performance on tasks measuring executive functions, spatiotemporal skills, and language
What is the main function of the vermis?
Regulation of affect and emotions
What is the main function of the hemispheres of the cerebellum?
regulation of cognitive functions
What is the main function of the anterior lobe?
- Regulation of muscle tone
- coordination of skilled voluntary movements
What is the main function of the posterior lobe?
- planning
- monitory of voluntary activity
What is the main function of the floculonodular lobe?
- balance
- control of eye movements
Be able to locate (cerebellum):
- the primary fissure, - the posterior (or posterolateral) fissure, - the anterior lobe, - the posterior lobe - the flocculonodular lobe - the vermis - the cerebellar hemispheres
look up photo
Where does all info that comes out of the cerebellum come from?
cerebellar nuclei
-no other cells in the cerebellum send their axons outside the cerebellum
What is the outermost layer of the cortex called? What does it contain?
Molecular layer, and it is occupied mostly by axons and dendrites
What layer is directly below the molecular layer? What does it contain?
The Purkinje layer
-Purkinje cells
What layer is directly below the Purkinje layer? What does it contain?
Granular layer
-dense layer of tiny neurons called granule and golgi cells
What is in the center of each folium?
White matter
What do the axons of the Purkinje cells do?
They synapse onto the deep nuclei and will not project outside the cerebellum
Are Purkinje cells inhibitory or excitatory?
Inhibitory
What is responsible for sending excitatory output?
The three deep nuclei
info coming from the brain and the body enters the cerebellum by what two systems of fibers? Are they inhibitory or excitatory?
Mossy fibers and climbing fibers
-Excitatory
Cerebellar injury will result in:
- slow and uncoordinated movements
- difficulty in judging distance and when to stop
- staggering when walking, tendency to fall
- abnormal eye-movements
What is the main function of the premotor cortex?
Planning
What is the main function of the motor cortex?
Execution
What does the primary fissure of the cerebellum do?
divides the bulk of the cerebellum into anterior and posterior lobes
What does the posterior fissure of the cerebellum do?
It separates the posterior lobe from the flocculonodular lobe
What does the horizontal fissure of the cerebellum do?
It divides the posterior lobe into two regions (anterior and posterior)
What are the characteristics of the cerebral cortex?
- Unique to the mammalian brain
- Highly convoluted with gyri and sulci
- 2-4 mm thick
- organized into 5 major lobes and 1 additional region
- organized into layers
What two domains can the cerebral cortex be divided into?
- Functional domain
- Anatomical domain
What is layer 1 of the neocortex? what is it made up of?
Molecular layer
-occupied by dendrites
What is layer 2 of the neocortex? what is it made up of?
External granule cell layer
-granule cells
What is layer 3 of the neocortex? what is it made up of?
External pyramidal cell layer
-variety of cell types , largely pyramidal cells
What is layer 4 of the neocortex? what is it made up of?
Internal granule cell layer
-granule cells
What is layer 5 of the neocortex? what is it made up of?
Internal pyramidal cell layer
-large pyramidal cells
What is layer 6 of the neocortex? what is it made up of?
Polymorphic or multiform layer
-heterogeneous layer of cells that blends into white matter
What are the two main cell types in the cortex?
Pyramidal cells (mostly excitatory) and small granular cells (mostly inhibitory)
Paleocortex - define it
structures that comprise btw 4-5 layers
Archicortex - define it
structures that comprises only 3 layers
What does the layering of neurons in the neocortex provide?
an efficient means of organizing the input-output relationships of neocortical neurons
Uncinate fasiculus - what is it
part of inferior occipitofrontal
-interconnects orbital frontal and anterior temporal
Superior longitudinal fasciculus- what is it
Interconnects Broca’s and Wernicke’s areas
What are the connections within the neocortical layer 4
Layer 4 is mostly stellate cells – where axons from thalamus come in and make synapses
What are the connections within the neocortical layer 2/3?
send axons out to other cortical areas
What are the connections within the neocortical layer 5/6?
send axons down to subcortical structures, and some to other cortical areas
What is the minicolumn?
A vertical assembly of pyramidal neurons, their interconnections, and learning with the cortical column
What is the function of the minicolumn?
To provide fine tuning of info processing and learning within the cortical column
Cortical development can be broadly divided into what two phases:
- genetically determined events occurring in utero
- cell death, connectivity, and pruning occurring both before and after birth
What happens during postnatal development of the cerebral cortex?
Neuronal proliferation and migration continue after birth
Disturbed neuronal migration could account for observations such as:
-Any significance in those with Autism?
- thickened cortex
- high neuronal density
- minicolumnar alterations
- neurons in molecular layer
- irregular laminar patterns
- poor gray-white matter boundaries
- ectopic gray matter
—Most of these have been found in patients with ASD
Microabnormalities of Cerebral Cortex in ASD:
- alterations in cortical columns spacing and number
- Polymicrogyria (too many gyri)
- Macrogyri (large gyri)
- Schizencephaly (abnormal slits or clefts in cerebral cortex)
- Cortical thickening
- Layering changes
Microcephalia vera - define it
characterized by reduced brain size with normal gyral patterns
Lissencephaly - define it. What is it composed of?
characterized by a brain with poor or no sulci
-cortex is composed of 4 layers
Polymicrogyria - define it
characterized by too many abnormally small convolutions
Heterotopias - define it
Gray matter heterotopias are collections of normal neurons in abnormal locations secondary to an arrest of radial migration of neurons
Connectional specificity - define
Cytoplasm of one neuron is separate from the cytoplasm of another neuron
Dynamic polarization - define
Some parts of neurons are specialized for taking info IN, whereas other parts send info OUT
What are the two main classes of brain cells?
- Neurons
- Glial cells
Neurochemicals in the brain -
- Highly variable in size
- Display specific pattern of localization in the CNS
- Mediates fast synaptic transmission and slow modulation of neuronal activity
Agonist - define it
a molecule that binds to a receptor and activates it
—all neurotransmitters are agonists at their receptors
Antagonist - define it
A molecule that binds to a receptor but does not activate the receptor
—prevents agonist binding
Modulator - define it
A molecule that binds to a receptor at a site distinct from where agonists bind
—modulates receptor function
If a person cannot grow new neurons, how does the brain change in order to accommodate new learning?
One mechanism by which the brain adapts to help you learn new information involves the structure on the next slide: the dendrites.
How do brain tumors (cancer) occur?
Unlike neurons, glial cells can divide and grow new cells throughout one’s lifetime. Most brain tumors are limited to glial cells, not neurons.
Soma (cell body)
- contains the cell’s nucleus
- contains DNA
- controls protein manufacturing
- directs metabolism
Dendrites - what are they?
(usually) larger and tree-like. This area receives inputs from other neurons at locations called synapses. The dendrites are “post-synaptic” (with respect to information flow)
Neuronal membrane - what is it?
composed of a lipid bilayer, contains the intracellular fluid. We will see more about the specific properties of this membrane in a minute
Axon - what is it?
Represents the “output”. Electrical signals flow down towards the axon terminals where the synapses are located. This axon is “presynaptic” with respect to this synapse.
What is an interneuron?
Anything that is not sensory or motor
Glutamate - what is it known for?
Fast excitatory synaptic transmission
GABA - what is it known for?
Fast inhibitory synaptic transmission
What do GABA and Glutamate systems in ASD research show?
- decreased brain levels of GAD (important to synthesize GABA)
- Lower levels of Glutamate in cerebral cortex and cerebellum
- Increased expression of glutamate transporter genes
The neurotransmitter remains in the synapse until:
- enzyme breakdown
- presynaptic cell reuptake
- glial uptake
What impact can the different types of receptors have on NTs?
The have different functions that can increase or decrease the efficacy of NTs
How can drugs alter the transmission speed of NTs?
Drugs may block reuptake or reabsorption, leaving the NT in the synapse for longer (more available) or speed up NT removal (making less available)
What are the three main types of biogenic amines?
- Norepinephrine
- Dopamine
- Serotonin
What are the two main types of neuropeptides?
Oxytocin and vasopressin
What are the two different types of other neurotransmitters? What is different about one of them?
- Biogenic amines
- Neuropeptides (not a “true” neurotransmitter)
Norepinephrine - what is it implicated in?
attention, memory, and physiological arousal
Where is Norepinephrine produced? What is the precursor in the diet?
Produced in the locus coeruleus
-phenylalanine
Norepinephrine - significance? ASD ties?
- dysfunctional in depression and anxiety disorders
- not clearly associated with ASD
Dopamine - what is it implicated in?
mood regulation, cognition, movement, and motivation
Where is Dopamine produced?
- Substantia nigra
- ventral tegmental area
Dopamine - significance?
Is disrupted in disorders such as parkinson’s disease, depression, and addictive behaviors such as drug abuse and gambling
Why can too much dopamine be bad?
It can lead to impulsivity and a lack of focus
Dopamine in ASD
Increased DA metabolites in ASD
-Haloperidol (a DA receptor antagonist) has been used to treat some symptoms of ASD
Serotonin - what is it implicated in?
Arousal, mood, sleep, and cognition
-decreases appetite
LIKING, CONSUMMATORY BEHAVIOR
Serotonin - where is it produced?
Raphe Nucleus
Serotonin - significance?
- Variability in serotonin receptors may be related to increased anxiety behaviors
- implicated in depression, anxiety, and OCD
- –One of the most effective anti-depressant classes functions to increase extracellular serotonin
Serotonin and ASD
-In children SER is naturally higher than adult levels early in development. In typical kids, this drops off in mid-childhood, but stays elevated in children with ASD
Name an example of an SSRI
Prozac
Serotonin - treatment
treatment with selective serotonin reuptake inhibitors (ie SSRIs) reduces hyperactivity, increases social competency in ASD
Neuropeptides - what are they used for and how do they work?
- Are used by cells for communication
- Peptides are released by neurons, are not recycled back into the cell, secretion is modulated by external peptidases
Oxytocin and Vassopressin - where are they released? What are they associated with?
They are released from the posterior pituitary
-associated with social behavior
What is Vasopressin specifically associated with?
Paternal behavior and territoriality
What is Oxytocin specifically associated with?
Maternal behavior and bonding
- “love drug”
- released during birth, breastfeeding, sexual intercourse, etc. to promote bonding
Oxytocin and ASD
- OT receptor density is decreased in ASD
- Children with ASD have lower levels of circulating OT than typical children
- OT may be a potential treatment avenue for social dysfunction in ASD
Environment - define it and give some examples
all non-genetic factors
-ie virus/bacteria, medications, chemicals, diet, etc
Epidemiology - define it
the study and analysis of the patterns, causes, and effects of health and disease conditions in a defined population
What are some commonly studied environmental risk factors?
- childhood vaccines
- nutrition and diet
- meds taken during pregnancy
- chemicals in the environment
- infections that cause inflammatory responses
- sociodemographic factors
What type of disorder is ASD?
Multi-factor with multiple etiologies
What are the 5 types of study designs when looking at environmental risk factors?
- Case series
- Ecologic
- Cross-sectional
- Cohort
- Randomized Clinical Trial
Case series - define. Strength of evidence?
Studies on a group of patients with a similar disease and epidemiology and describes their characteristics
-very weak
Case series - pros and cons?
Pros: -easy to carry out (can use patients from a clinic) Cons: -no control group -often retrospective analyses
Ecologic studies - define. Strength of evidence?
Divide population into group (often by geography or time range) and compare rates of exposure with rates of disease and look for correlations
-weak
Ecologic studies - pros and cons
Pros: can use pre-existing data from many sources (e.g. census records, health data)
Cons: no individual data, does not control for confounds at the ecological level (i.e. SES), assumes factors not examined remain constant
Cross-sectional studies - define. Strength of evidence?
Select the study population irrespective of exposure or disease. Calculate prevalence of exposure and disease. Compare disease rate among exposed and non-exposed, and/or by level of exposure
-moderate
Cross-sectional studies - pros and cons
Pros: collect data from participants in one visit, individual data collected on health outcomes and confounding variables.
Cons: cannot determine temporal (causal) relationship between exposure and outcome.
Cohort studies - define. Strength of evidence?
Study population is free of the disease at the start of the study. Rates of disease incidence are monitored over time and compared for those with and without exposure
-strong
Cohort studies - pros and cons
Pros: information about exposure is collected prior to occurrence of disease outcome (permitting causal inferences), exposure data is collected without influence of knowledge of the disease status of the individual, able to collect information on confounds.
Cons: depending on the length and number of follow-ups, subject retention can be difficult
Randomized clinical trial - define. Strength of evidence?
Participants are randomly assigned into exposure groups or placebo. Experimenter and participant are blind to which condition they are in. Compare health outcomes in exposed vs placebo groups
-very strong, especially w/large sample size
Randomized clinical trial - pros and cons
Pros: provides basis for causal inference, if sample size is large enough then random assignment protects against confounds.
Cons: not ethical to study an exposure with significant harm, some participants will refuse to be in a study if they can’t choose a treatment or know what group they are assigned to.
Sociodemographic factors - what are the 3 main ones?
- Level of parental education
- Race/ethnicity
- Parental age
Sociodemographic factor: Level of parental education
-describe it in terms of ASD
- Widely reported positive correlation between education level of parents and incidence of ASD diagnosis
- –diagnosis x2 with postgrad education
- Possible confounds: underassessment in families with less parental education, and differences in access to healthcare.
- –In countries with universal healthcare (e.g. Denmark) these correlations are NOT found.
Sociodemographic factor: Race/ethnicity
-describe it in terms of ASD
No consistent reports of differences in ASD prevalence by race or ethnicity
Sociodemographic factor: Parental Age
-describe it in terms of ASD
- Older parental age (either parent) has been consistently linked to increased risk of ASD via cross-sectional studies
- Cannot determine causality, but it can be interpreted that age is a biomarker of processes yet to be determined
Infections that cause inflammation: list one that was once believed to be related to ASD
-why?
Rubella
-Given the heterogeneity of the kinds of viruses associated with neurodevelopmental illness, current thought is that the specific microorganism is less important than the inflammatory/immune response it provokes
Infections that cause inflammation: Mechanism of Action
-what is it? what happens?
- Neuroinflammation modulates brain function through the activation of microglia and astrocytes
- when activated, these glia secrete cytokines
During development, when and what does glia secrete within infections that cause inflammation?
When activated, these glia secrete cytokines
What happens with excess or chronic activation of cytokines?
With excess or chronic activation, the same cytokines become desstructive
Air pollution - how does it relate to ASD?
Most studies have reported a modest increases in risk for ASD in individuals with higher estimated exposure to air pollution
Air pollution: What are some challenges when looking at this factor?
- Air pollution is a highly complex and variable mixture of compounds that are highly correlated, so it is difficult to determine the impact of specific chemicals.
- It is still difficult to accurately measure/quantify exposure to air pollution over time.
- Difficult to account for confounds (e.g. noise pollution from traffic could cause sleep disturbances)
Air pollution - what is the mechanism of action?
When does oxidative stress occur?
Oxidative stress occurs when excess oxygen radicals are produced in cells, which could overwhelm the normal antioxidant capacity
What can oxidative stress result in?
- The presence of xenobiotics
- The activation of the immune system in response to invading microorganisms (inflammation)
- Radiation, which makes oxidative stress a common denominator of toxicity or stress.
Mercury - how does it relate to ASD?
Few studies to date have found robust differences in Hg levels among ASD individuals and appropriately matched controls (particularly on geographic and dietary variables)
Mercury: describe this environmental factor
-where does it come from? how is it measured?
- Mercury exposure comes from several sources: industrial emissions in air and water, dental amalgams, in fish/seafood, and as a preservative in certain vaccines
- Hair absorbs Hg, and measurements of Hg concentrations in hair are primarily used as a way to estimate exposure
Mercury - what is the mechanism of action?
When Hg enters a neuron, it:
- interferes with ion currents involved in the action potential
- damages the Blood Brain Barrier by altering the cell membranes of astrocytes
- damages tubulin, a protein important for the integrity of microtubules
How do some believe that Mercury impacts ASD?
Some hypothesize that ASD involves alterations in the body’s ability to detoxify, and thus accumulation of toxins, like Hg, are likely to follow
Medications taken during pregnancy
-list two that have been believed to be related to ASD
- Thalidomide
- Valproic acid
Valpoic acid - what is it? what does it do?
Medication used to treat seizures and migraines
-causes birth defects
Thalidomide - what is it? what does it do?
Originally prescribed as a sedative, but then used as an anti-nausea med for morning sickness
Mechanism of action of thalidomide on the fetus? what is sig about it? Relation to ASD?
- MoA is very specific: specific physical changes correspond directly to when the med was taken during gestation
- ASD characteristics were present only in cased with the Opthalmological changes (20-24 post conception)
- —provides evidence for a very specific critical period
Nutrition/diet - a factor for ASD?
GI symptoms and food allergies are common among individuals with ASD, and so dietary factors are also worth considering
Nutrition/diet - Mechanism of Action?
Allergies = immune activation
-“Leaky Gut” hypothesis
What is the “Leaky Gut” hypothesis?
- Intestinal lining is damaged (or maldeveloped), leading to increases in GI permeability
- Increased GI permeability allows toxic proteins to enter the bloodstream and subsequently accumulate in the CNS
Maternal nutrition - describe this factor. Why is it important?
Proper nutrition during pregnancy is essential for fetal brain development, and maternal nutrient deprivation is associated with increased risk for neural tube defects, schizophrenia, and other adverse neurological outcomes
-Folic acid!!! (protects unborn babies against serious birth defects)
Maternal nutrition - how does it relate to ASD?
-study found a trend of decreasing risk for ASD as daily folic acid intake increased
Maternal Nutrition - Mechanism of Action?
- During early stages of gestation, mammalian embryos undergo extensive DNA demethylation, followed by a re-establishment of new methylation patterns
- Folate provides a major source of methyl (carbon) groups, and so low levels could impact mechanisms involving methylation and hence expression or activity of genes, proteins, and neurotransmitters
