Semester 1 Flashcards
what does TMS do?
create virtual cortical “lesions” by depolarising neurons in a small, circumscribed area of cortex
what is the TMS “neural noise” approach?
uses single-pulse TMS to disrupt cognitive processing. if this interference has a functional impact this is a powerful demonstration of a certain brain region’s causal involvement in this function and also provides information about the timing of the brains reaction to the electronic current
what is the TMS “virtual lesion” approach?
using repetitive TMS to interrupt or enhance cognitive processing. It is also possible to inhibit cognitive functions for a longer period of time by applying repetitive TMS (rTMS)
It can then be measured whether (and for how long) a specific cognitive task is impaired (usually slowing instead of total loss of function)
what is the TMS “probing excitability” approach?
Instead of aiming at disrupting cognitive functions (and measuring the effect of TMS on performance), the measure of interest is how strongly the motor cortex “reacts” to the pulse itself. The excitability of the primary motor cortex can be measured by recording “motor evoked potentials” (MEPs) using the electromyogram (EMG), which is electrical activity of muscles
what is the TMS “paired pulse” approach?
Uses two pulses, delivered in brief succession – one is usually sub-threshold while the second one is supra-threshold. The question is how strongly the first pulse influences the effect of the second
what are a clinical applications of TMS?
treatment of depression on the basis that it is caused by hemispherical imbalance
what is the alpha level usually set at?
0.05
what is t equal to in a t-test?
t = M(sample mean)-m(pop mean)/standard error of the mean
between groups or independent measures tests are what? pros and cons
two groups, and the values come from different people (i.e. each person is providing one measure in one group only)
- pro: don’t have to worry about learning effects due to repeated exposure
- con: People in the different groups might be quite different in various ways (can be overcome with large groups or counterbalancing)
Repeated-measures tests are what? pros and cons
one group, and the values for both experimental conditions come from the same people (i.e. each person is providing two measures)
pro: we don’t have to think about differences in baseline, personality, IQ, motivation, etc., because this will always affect both conditions equally
con: order effects and effects of learning
single-sample test compare results to what?
the likelihood of chance results using the null hypothesis
standard error of the mean is equal to what?
standard deviation/square root of the sample size
the standard deviation is equal to?
the square root of the variance (sum of squared differences)
df equals?
n-1
When the critical value is the same as the empirical value is it statistically significant or not?
no, not significant
assumptions of a t-test
- The observations must be independent
- The populations from which the samples are drawn must be normal
- If comparing two populations (independent-measures t-test), the samples must have equal variances (if the variances are not homogenous, calculating the pooled variance becomes a problem)
Electroencephalography (EEG)
is a method of detecting neural activity by placing electrodes on the scalp. These electrodes pick up small fluctuations of electrical signals, originating from activity of (mostly cortical) neurons
pros and cons of EEG
pros: temporal resolution is great (timely reflection of brain activity)
cons: spatial resolution is not good (understanding of structures from output)
why is PET no longer used much?
involves large amounts of radiation
MRI studies the structure of what?
the brain
MRI functions based on the fact that 70% of the brain is made of what?
water
The axis along which the magnetization is build up in the scanner is called
the z-axis
MRI measures the what of protons
the relaxation of protons after the emission of a radio frequency
how does MRI image a brain?
The transversal magnetization of the protons decays with different speeds depending on the tissue so structural brain image depends on when signal is recorded during this process
what is the slice selecting axis?
the x-axis
what is the frequency encoding gradient axis?
the y-axis
how does fMRI measure brain activity?
Neural activity is also accompanied by a local oversupply in oxygenated blood and therefore a better Blood Oxygen-Level Dependent (BOLD) signal. These areas of enhanced activity can then be mapped onto a structural image of the brain. Significantly stronger activation in region X for task A compared to task B is interpreted as involvement of the region in task A
BOLD
- Is an indirect measure of brain activity
- Enhanced neural activity impacts on (in a complex way) how much oxygen is in the blood, how fast the blood flow is and how much oxygen can be extracted (i.e. when blood flow is faster, relatively less oxygen is extracted per unit time, but because there is more of it, in total more oxygen is extracted…)
- This means, we have to be careful when interpreting differences in BOLD signal
- There is also a substantial temporal lag between neural activity and the peak of the BOLD response – in the order of 8 seconds!
- The BOLD signal further needs ~16 seconds before reaching baseline again
- It is also not valid to compare signals between different regions of the brain because the signal change is different
- The measured response looks very similar across regions and is described by the Heamodynamic Response Function (HRF)
Limitations of BOLD fMRI:
- fMRI shows regions of activity but cant show the full networks involved in most brain processes - leading to a tip of the iceberg scenario where the functional units that actually matter aren’t mapped
- Poor temporal resolution due to the slow processing of the machine compared to the brain’s speed
- The spatial resolution is better than other methods but still not great (measured in voxels which are 3D units of 3x3x3mm and containing around 100,000 neurons)
- Need for multiple comparisons and use of t-tests that set a p-value less than .01. With 50,000 voxels in the brain, 500 false positives are expected (which a lot!). To overcome this the strictest correction is Bonferroni-correction: divide the significance level (e.g., 0.01) by the number of tests (= voxels), and use this new significance level for each test: 0.01 / 50,000 = p < .0000002 (corresponds to the overall risk of 1% to have one false positive)
- Circularity and double-dipping: use of regions of interest (ROIs) to avoid the multiple-comparison issue leads to measurement of areas twice - first to find the ROIs and then in more depth. This would be fine, but requires independent analyses which can be difficult because of the circular nature of the issue - in order to find ROIs they’re using a flawed test which has false positives so any subsequent results will also be flawed
- Overinterpretation of null results: we should always avoid concluding that brain regions are not involved in cognitive processes even if a null result suggests we fall back on the null hypothesis as we don’t know whether our method might just not be sensitive enough to detect small differences
Sohn et al. study with fMRI found that
Found that an area in the prefrontal cortex and the posterior parietal lobe were activated during task switching. Are these regions controlling the switching? All we have is a correlation not an understanding of the interactions or role
Kanwisheretal et al. study with fMRI found that
attempted to investigate how faces are represented in the brain. They presented their participants with images of faces and contrasted BOLD signals to when participants saw objects. An area in the fusiform gyrus responded more strongly to faces than to objects. To rule out that this result was simply due to using objects, they replicated the study with faces > scrambled faces and than again with houses and again with hands. The result was the same: the region in the fusiform gyrus showed again stronger activation for faces
Gauthier and co study with fMRI found that
the fusiform gyrus may actually just be involved with recognition expertise rather than specifically faces
Malach and co study with fMRI found that
argued that coding is driven by resolution needs – the FFA is good for everything that usually requires “high resolution” - We usually encounter faces in the centre of our vision, and not in the periphery. We usually need a high resolution to recognise faces, simply because we need to really see the details. The “module” for places/houses (the Parahippocampal place area, PPA) is in reality just very suited for processing the periphery, not houses per se – but that’s where places/houses usually are in our visual field
Poldrack and the Reverse Inference Problem:
- If a brain region is activated by many cognitive functions, we learn very little from observing activation in those areas
- We need to know how good th task actually is for understanding cognitive process X. If the tasks measures more than one cognitive function, we also don’t learn much
at rest the neuron has a _ charge
negative
an action potential is triggered when the charge becomes sufficiently _
positive
Ion channels
Ion channels act like a “gate” for ions which opens when a neurotransmitter binds to the receptor. These channels are often selective and only let some ions pass through
G-protein coupled receptors
work through secondary messengers i.e. when the neurotransmitter binds to the receptor it activates a second messenger system that can either open a channel or cause other things to change within the cell (e.g. DNA being transcribed and new proteins being made)
Neurotransmission
A chemical substance released from a neuron at an anatomically specialised junction (synapse), which diffuses across a narrow cleft to affect one or sometimes two postsynaptic neurons, a muscle cell, or another effector cell. Can be either inhibitory or excitatory
Neuromodulation
A chemical substance released from a neuron in the central nervous system, or in the periphery, that affects groups of neurons, or effector cells that have the appropriate receptors. It may not be released at synaptic sites, it often acts through second messengers and can produce long-lasting effects.
- Slower process that alter the subsequence responses of neurons
- Presynaptic: alters neurotransmitter release
- Postsynaptic: alters neurotransmitter action
- May cause changes in neural function or structure
Psychopharmacology
the study of drug induced changes in mood, sensation, thinking and behaviour
Cycle of Neurotransmitters (seven steps)
- Synthesis
- Release from synaptic vesicles
- Binds to receptors
- Positive or negative influence on the post synaptic neuron
- Broken down by enzymes
- Reuptake of transmitted
Formation and storage in synaptic vesicles
Non-Traditional Neurotransmitters include
- Peptides
- Gases
- Lipids
- Nucleosides
drugs can be either
agonists (increasing effects of neurotransmitters) or antagonists (decreasing effects of neurotransmitters)
Cohen’s d and r2 both
quanntify the effect in the experiment, but only d is truly independent of the sample size as it calculated by dividing the mean difference (of the measure of interest) by the standard deviation (of the measure of interest).
maximum spatial resolution of fMRI is approx
1-3mm
the typical temporal resolution of fMRI is approximately
2000ms
Glutamate is the MAIN _ neurotransmitter in the brain (increasing likelihood of the post-synaptic neuron firing)
excitatory - it is released by ALL excitatory neurons
glutmate is synthesised from
glutamine
glutamate receptors include (4 types)
- NMDA receptor (these are also alcohol, ketamine and PCP receptors)
- AMPA receptor
- Kainite receptor
- G-coupled protein receptor
GABA (gamma-amino butyric-acid) is the primary _ neurotransmitter - decreases the likelihood of the post-synaptic neuron firing
inhibitory - without it the result would be seizure
GABA is synthesised from
glutamic acid
GABA receptors (2 types)
- ion channel
- G-coupled receptor
Generalized Seizures
widespread & involve most of the brain
Partial seizures
Definite focus and restricted to small part of the brain (often a scarred region caused by injury or developmental abnormality)
○ Simple: can cause changes in consciousness but not loss of consciousness
○ Complex: leads to loss of consciousness
Epilepsy is believed to be caused by
abnormality of the GABA neurons and/or in the GABA receptors
Dopamine is synthesised from
tyrosine
Dopamine is involved in
rewards and reward prediction error
Reward Prediction Error
- If an unexpected reward occurs DA neurons become more active and release more dopamine
- If reward is given repeatedly after a stimulus, the reward will become expected and DA will not be released at the time of the reward but rather at the time of the stimulus (conditioned)
- If a reward is expected and not provided, the DA neuron will be suppressed - THIS IS WHY GAMBLING IS SO ADDICTIVE
- DA is not just a measure of how much you like something, but rather the difference between expectations and reality (when expectations are low and something unexpectedly good happens, more DA is released)
Rewards can be:
- Real (food or sex)
- Symbolic (money)
- Virtual (points in a game)
Cognitive control and reward
- Our brain calculates what the expected reward is for doing a task and therefore whether it is worthwhile
- We aim to maximise our reward and minimise the cost
- DA’s role in this not to do with the calculation, but rather sustaining belief in the coming reward so that we can maintain our interest
- Opportunity costs = everything else rewarding you could be doing at a particular time
why is a substance like cocaine addictive?
Because it blocks the reuptake of dopamine, meaning neurons are continuously firing and increasing our experience of pleasure. We get addicted to this feeling, rather than the side effects of the drug. Addictive DA drugs are ALWAYS coded by the brain as “better than expected” even when it is expected - this is not normally the case.
Essentially, dopamine is supposed to motivate behaviour, do this or don’t do that in order to get something you desire. This escalates quickly for addictive drugs - people will do anything to get their next hit.
where is noradrenaline synthesised?
in the Locus Ceruleus (LC)
noradrenaline is synthesised from
dopamine (tyrosine) and is only one synthesis step away from becoming adrenaline
noradrenaline has a role in:
- Sympathetic nervous system (flight or fight)
- Arousal/vigilance
- Anxiety
- Exploitation vs Exploration
- Reward/addiction
- Memory consolidation
high NA leads to
a state of hyperarousal adapted for evolutionarily important situations where individual or sexual fitness is involved
High levels of LC/NA activity can lead to the following, depending on the trigger and duration:
- Stress: often experienced when LC/NA Activity is sustained due to environmental Factors (social, emotional, physical etc).
- Anxiety: excessive, uncontrolled and often irrational “worry” (diagnosis requires symptoms for 6 months).
- Panic attacks: brief intense episodes believed to reflect spikes of LC/NA activity triggered by:
○ apparently random events
○ internal thoughts
○ learned associations (PTSD)
role of NA in decision making
- At moderate levels of LC activity, Noradrenaline acts to consolidate decisions.
- Adaptive behaviour represents a trade off between exploiting known sources of reward and exploring the environment for alternative sources of reward (food, water, sex etc).
- When presented with two options, bursts of NA release “tip the balance” in favour of the winner (through increasing the strength of activating and inhibiting signals) followed by an absence of NA preventing changes in attention, or moving back to debating options
- Low levels of LC activity and NA release = tired, vague & poor performance.
- High levels of LC activity and NA release = restless, stressed & poor performance.
- Optimal performance requires moderate activity with large intermittent bursts.
serotonin is linked to such a range of processes including
sleep, temperature, appetite and mood, based on the type of serotonin receptor activated
Brain imaging studies show a _ in some types of serotonin receptors in the brain of un-medicated depressed patients
reduction
A gene involved in the transportation of serotonin is linked to…
to increased risk of developing depression
A proposed model of depression
- There is variation in serotonin function across the population
- Impaired serotonin function may be a “risk factor” leading to people being vulnerable to developing depression
- Depression is 5-6 x more likely after stressful events
- Stress leads to increased release of a range of hormones such as cortisol. Serotonin function is important in managing the feedback control of the brain’s stress response
Serotonin Antidepressants (SSRI’s)
- Slow working (weeks)
- These long effect times can be explained by neurogenesis - which reinforces mood-related circuits in the brain
- Shut off elevated stress responses underlying depressive symptoms and allows for important neural adaptations (neurogenesis)
- SSRIs could promote new brain cell growth and protect against damage associated with depression
- In healthy people SSRIs increase empathy and prosocial behaviour (personality changes)
MOA’s (Monoamine oxidase inhibitors)
- Blocks the breakdown of serotonin
- Powerful antidepressant drug
- Used as a last resort under strict dietary controls
Peptides as neurotransmitters
- Opioids are the best known peptide neurotransmitters
- Involved in pain relief (thus, panadol)
- Include heroin, morphine and opium
- These drugs are not particularly neurotoxic but can cause death through respiratory failure and destroys lives due to addiction
- This fast reaction time associated with heroin is what causes its highly addictive properties
Lipids as neurotransmitters
- Endocannabinoids are the main lipid neurotransmitter
- Act to modulate the modulators
- Effects of cannabis include appetite, time perception, arousal (relaxation/anxiety) and states of apathy
- Therapeutically used to reduce nausea, relieves asthma and decreases pressure in the eyes in glaucoma and more recently has been used to treat children with severe epilepsy but there is limited evidence to suggest this is better than other available treatments
Nucleosides as neurotransmitters
- Subunit of nucleic acids
- Modulate the modulators and often “co-transmitters”
- Adenosine is released from the astrocytes and supports neural function i.e. supplying energy to neurons
○ Is an inhibitory neurotransmitter
○ Forms from breakdown of adenosine triphosphate
○ Builds up over the day and leads to sleepiness - Caffeine is the nucleoside that blocks adenosine receptors (antagonist) thus increasing alertness and preventing the sleepy feeling that naturally occurs
Gases as neurotransmitters
- Nitric oxide is involved in learning and memory through effects on synaptic plasticity and dilates the blood vessels in regions of the brain that become metabolically ative
- As a gas, NO is not synthesised and stored in vesicles but is produced throughout the cell including dendrites and leaves the cell as soon as it is produced
- It is very short lived and is degraded or reacted within a few seconds of being produced
- Acts on the neighbouring cells by diffusing through rather than through a receptor
formula for phenotypic variance
P=G+E+(GxE)+2covGE; the phenotypic variance is equal to the variation in the genes plus the variation in the environment plus the variance from gene-environment interactions plus the covariance from genes and the environment
formula for heritability
h2=G/P; heritability is equal to the genotypic variance over the phenotypic variance
heritability is
the proportion of the phenotypic variance due to genetic causes which depends on the amount of genetic and environmental variation
what is the least heritable trait discussed?
depression
what is the most heritable trait discussed?
autism spectrum disorders
genetic epidemiology
exploit the fact that related individuals all share a predictable amount of genetic material i.e. twin studies
Co-inheritance in pedigrees of a phenotype with directly genotyped genetic markers (with known locations on the genome) suggests
the disease-influencing genetic locus is physically close to the marker
A haplotype is
a specific combination of markers
Fragile X syndrome is a
monogenetic disorder because the trait is present with the presence of a single gene
Fragile X syndrome is categorised by
Repeats in the noncoding region of the FMRI gene that is needed for synaptic plasticity. This expansion of the gene triggers methylation of the DNA, constricting the X chromosome and causing the “fragile” appearance
polygenetic traits are
those for which there is no single gene. this describes most traits, including schizophrenia, depression, autism and anxiety. In these cases, GWAS are used to examine the genetic causes
GWAS stands for
genome-wide association studies
GWAS examine
psychiatric disorders, psychological traits and cognitive traits
Genome-wide association studies examine the _ between a phenotype and many _ throughout the _.
statistical association; SNP markers; genome
In an indirect association in GWAS, the phenotype has a functional association with a
non-genotyped SNP that is in linkage disequilibrium with a genotyped SNP
In a direct association in GWAS, the phenotype has a functional association with a
genotypes (measured) SNP
Allelic dosage models are used for _ traits
quantitative - is there an association between the phenotype and the number of copies of the allele?
Allelic association model are used for _ traits
categorical and binary - is one of the two alleles statistically over-represented in a phenotypic group?
Manhattan plots…
graphically summarises the results of all of the individual tests of association in a GWAS
thresholds for significance are stringent in GWAS because multiple comparisons increase the likelihood of
Type I error - false positive finding through the rejection of the null hypothesis when no appropriate
alpha threshold for a GWAS
5x10^-8 (Bonferroni correction)
imputation predicts
genotypes at non-genotyped SNPs relying on data from a reference panel of individuals genotyped at high density (genomes from the 1000 genomes project)
conservation indicates
the rate at which a sequence is maintained across species - where high conservation suggests an important function across evolution
in a Manhattan plot, “skyscrapers” can be explained by
- multiple SNPs in linkage disequilibrium with a functional SNP
- multiple functional SNPs in the same gene
What genes are associated with bipolar disorder according to GWAS, and what is an effective treatment?
ANK3 and CACANA1C genes which regulate the flow of ions in and out of neurons during an action potential. a current treatment is lithium
larger samples in GWAS provide _ statistical power to detect _ effects
more; smaller
Effects of GWAS (three):
- GWAS can provide new evidence for existing hypotheses (schizophrenia and abnormal dopamine)
- GWAS can raise new possibilities (role of MHC in schizophrenia)
- GWAS can point to environmental risk factors (association between genes for schizophrenia and heavy smoking)
endophenotypes are
a precise and reliable measure of a single qualitative trait with an immediate relationship to biology. they do not however, aid in diagnosis
difference between neuromodulators and neurotransmitters
neuromodulators are transported to neurons far from where they are released and are slower acting for longer periods of time than neurotransmitters
the magnetic field of fMRI is usually
3 Tesla
the magnetic field of MRI is in the range of
1.5-9 Tesla
EEG measures
the small electrical signals created (dipoles) when a neurotransmitter binds to a post-synaptic neuron
