Bio psych Flashcards
What is Transcranial Magnetic Stimulation (TMS)
“Non-invasive” technique to create virtual cortical “lesions”
How is TMS applied?
externally - coil placed on scalp producing rapidly changing magnetic field inducing electrical currents in brain
What does TMS do?
○ Depolarises neurons in small circumscribed area of cortex
○ TMS-induced current causes neurons to fire randomly - acting as neural noise - masking neurons that are firing correctly
○ Creates so much noise that nothing gets through anymore
What is required for TMS
100-200mews and short discharge durations
Different approaches to TMS
- Injection of neural noise
- Virtual lesion approach
- Probing excitability approach
- Probing information transfer approach
What is the neural noise approach to TMS?
- single-pulse TMS to disrupt cognitive processing
- If a single TMS pulse to a specific region of the cortex disrupts cognitive function - powerful demonstration of its causal involvement in process
- to infer causality: interfere with process of interest at exactly time window during which region is required eg delay movements or disrupt visual processing
- Regions do not stop working
What is the alphabetical neural noise study?
- Researchers used 3 alphabetical letters as stimuli presented under difficult viewing conditions using illuminated frames/backgrounds
- Three letters next to each other
- Stimulated 2cm above inion over visual cortex
- Critical period - 40-120ms stimulation affected detection performance - how long it takes visual cortex to process information and when is it over
- When moving TMS stimulation from top to bottom at midline and letters were displayed verticallly, stimulation about reference line supressed letters at the bottom of the display
- Stimulating below centre was not possible (inion bone in the way)
What is the visual mask neural noise study?
- Investigated whether ‘visual mask’ can itself be masked using single-pulse stimulation - unmasking the stimulus
- Without TMS: 100ms between unmasked letters and masked letters - detection rate was 37%
- TMS following the mask detection rate increased to 90%
- Unmasking was found between 60 and 140 ms stimulation after the mask
What is the virtual lesion approach?
- using repetitive TMS to interrupt or enhance cognitive processing
- Possible to inhibit cognitive functions for a long period of time using rTMS
- Can then be measured whether (and for how long) a specific cognitive task is impaired (usually slowing function instead of total loss of function)
- Used so that you don’t miss the critical window which can happen with TMS
- Need to be safety restrictions (can stimulate epilepsy in epileptic people
What is the ‘probing excitability’ approach?
- single-pulse TMS
-For motor system - does not disrupt cognitive functions - makes neurons fire more strongly
- measured by recording motor evoked potentials (MEPs)
using electromyogram (EMG) (electrical activity of muscles) - Stimulating left side of motor cortex can make muscles twitch on right side
- cannot measure causality
What is the mental rotation study?
- ‘probing excitability’ of TMS approach
- found that there was a good chance you need primary motor cortex when mentally rotating
- does not depend on strategy
What is the ‘probing information transfer’ approach to TMS?
- uses paired-pulse TMS
- Using two pulses delivered in brief succession: one usually sub-threshold while the other is supra-threshold
- Give sub-threshold TMS pulse to one brain region, then give stronger one (supra-threshold) to another brain region you think would communicate with the other one
- Pulse should trigger communication with first region - should send signals which would be already met by excitable cortex
- If there is an effect (ie if it there is a higher response, then you know that there is communication)
- Tests how brain regions talk to each other
What is the schizophrenia ‘probing information transfer’ study?
- it is suggested that there are abnormalities in motor cortex inhibition in schizophrenics (Cortical silence period (CSP) (period of suppression of tonic motor activity follows descending excitatory activity) is reduced)
- Researchers produced excitatory activity by first TMS stimulus to left motor cortex and measured excitability by assessing effect of second pulse
Results showed with and without medication showed stronger response to second pulse - Schizophrenics have stronger excitability of motor cortex - takes them longer to get rid of extra activity
What are the clinical applications of TMS?
- can be used for depression
What are the experimental t-test designs?
- one sample design
- between groups/independent measures design
- within-groups/repeated measures design
What is a one sample experimental design?
○ One group with values coming from different people -
compared to a single values
○ Advantages:
- Can be used to compare group data to
known values
○ Disadvantages
- May not always know population values
- May want to compare two groups, or
investigate change of behaviour over time
What is an independent measures experimental design?
○ Two groups and values come from different people
○ Results of the two groups are compared to each other
○ Advantages:
- Independent measurements
- Don’t have to worry about learning effects due to repeated exposure
○ Disadvantages
- People in the different groups might vary in
various ways - need large sample sizes to
average out these effects/need to
counterbalance all factors that we know
might have an influence on the results
- Cannot study behaviour over time
What is a repeated measures experimental design?
○ Single group provides data for both conditions at different time points
○ Advantages:
- Don’t have to think about differences
across groups
- Can study changes in behaviour over time
- Can usually test less people
○ Disadvantages
- Measurements are not independent - need
to calculate variance (t-test) differently
- People know the treatment after first
condition - can’t be naïve in second round
- Need to counterbalance conditions to
avoid unwanted order effects
What are the t-test assumptions?
- Observations must be independent (people must not influence other people’s values; no systematic biases when assigning people to groups)
- Populations from which samples are drawn must be normal
- If comparing two populations, sample must have equal variances
What is an EEG?
• Electroencphalography - method of directing neural activity by placing electrodes on scalp
• Electrodes pick up small fluctuations of electrical signals originating from activity of (mostly cortical) neurons
○ Reason we get this is because neurons communicate using electrical pulses when they generate actual potentials
○ Essentially listening to brain while it is thinking
• While raw signal recorded are noisy - systematically related to cognitive processes
• Can use these signals to learn something about cognition when people perform tasks
• Non-invasive
• Also possible to record intra-cranial EEG by measuring activity directly at exposed cortex - would only do for people who have skull already open and exposed like surgery patients
• Cheap and relatively easy to conduct
• Put a sensor on back of ear because there is a big bone there so you won’t receive neural signals, therefore can use it as a baseline to compare other results to
What is an advantage of EEG?
Temporal resolution is great
What is a disadvantage of EEG?
Spatial resolution is not so good
What is used to record an EEG?
- Electrode cap
- Amplifier
- Experimental stimulation
- EEG recording
What is the neurophysiology of an EEG?
• EEG activity does not reflect action potentials but originates mostly from post-synaptic potentials - voltages that arise when neurotransmitters bind to receptors on membrane of post-synaptic cell
○ Where axon of one neuron meets another
neuron (at the dendrites), they release
neurotransmitters
○ If neuron membrane is depolarised, new
action potential is created which travels
down the axon to continue passing on the
message
○ EEG does not reflect immediately when a
neuron fires, but it actually reflects the negative
potentials adding up at the dendrites, which are
the potentials that arise when neurotransmitters
bind to receptors because they have incoming
information for that neuron
○ Negative pole at dendrites and positive at cell
body
○ Causes ion channels to open or close leading
to graded changes in potential across the
membrane
○ This is understood as a small ‘dipole’
• Signals from single cells not strong enough to be recorded outside of the head, but if many neurons spatially align, their summed potentials add up and create signals we can record
• This pooled activity from groups of similarly oriented neurons mostly comes from large cortical pyramid cells
• Orientation of neurons determines sign of the recorded potentials (+ or -)
• Some orientations lead to signals which cannot be recorded
○ Eg if positive is facing sideways and negative is sideways, so no sign is pointing toward skull you get no signal recorded, or if they are facing against each other so the signs cancel each other out/if one layer is below another
• EEG signals do not reflect all activity in brain
What is the functional unit for an EEG?
• Functional unit is >10 000 simultaneously activated neurons
○ Meaning if you get more than 10 000 neurons in one place with the same orientation, then you can pick up signal with EEG
What are limitations of EEG
○ EEG is biased to signals generated in superficial layers of cerebral cortex on the gyri (ridges/peaks in brain formation) directly bordering skull
○ Signals from sulci (dips in brain formation) are harder to detect than from gyri and may additionally be masked by signals from the gyri
○ Meninges, cerebrospinal fluid (CSF) and skull smear EEG signal making it difficult to localise source
- Known as the inverse problem
□ If sources are known, resulting scalp reconfiguration of signals can be reconstructed, but reverse is not true - one scalp configuration of signals can have multiple dipole solutions
How are EEG signals measured?
-From scalp in relation to reference electrode
- To do this, can take average of all electrodes as
reference
□ However because brain has many dips and isn’t perfectly round, so bit noisy to use average of everything
○ Reference should be a neutral point (eg tip of nose/behind ear) but some people reference to the average of all scalp electrodes
What is the typical amplitude of an EEG signal?
10-100 microvolts
- Tiny signals so need to be amplified typically by a
factor of 1 000 to 100 000
- Signal then digitalised (sample frequency is typically
256-1024 Hz but can be >4000Hz)
How is EEG signal filtered?
○ Signal is band-pass filtered to remove the low (<0.5-1Hz) and high (>35-70 Hz) because cannot reflect brain activity
○ Signal is notch-filtered (at 50-60Hz) to remove line noise which is also not brain activity
- Attempting to remove those signals that are not from the brain
What are artefacts?
- Signals that are not brain signals
○ Eye blinks and movements have a strong impact on EEG signal because eye can be regarded as a dipole itself
○ Signals originating from the eye will contaminate the signal of interest - will be much larger
○ These signals can be recorded by placing electrodes next to and under the eye to capture vertical and horizontal eye movements
○ Eye-related signals can then be removed by excluding contaminated trials, or mathematical algorithms, such as independent component analysis (ICA)
What are the limitations of single-trial EEGs?
-Not likely to be very good and are very noisy - not very useful when you need to find brain activity that is reliably related to cognitive processes of interest
○ Need to collect a large number of trials (eg 20)
and average all of them to get a clearer pattern
• There Is a lot of variance between sessions from same participants and between participants - even with averaging
How to you obtain the Event Related Potential (ERP)?
• Average across all like events in the trials (eg in this example there were expected events and unexpected events - so need to average cognitive brain activity across all expected events and then separately average the activity in the unexpected events – now you can compare the two)
○ Isolate where modulation of your brain activity occurs when comparing expected vs unexpected events
How do you measure ERPs?
There are different aspects of the ERP component of interest that can be analysed
- Peak amplitude (used in 70% of studies)
- Area under the curve (because sometimes it is of
interest that although a peak may be higher, it is also
much narrower) (used in 20%)
□ Narrow peak could represent that cognitive
process finishes very fast, and wider
represents a more ongoing process
- Peak-to-peak (distance between negative and
positive peaks) (used in 10%)
□ The significance is in the rise of the peak, not
the highest height
○ No clear rule - results may differ between measures
○ Another option is to determine the onset of a component
- Looking at when a component starts to rise
-Difficult to determine exactly when it is rising
and when it is fluctuating
Why use ERPs?
○ One reason is that many components are very well studied
- Finding that a specific component is modulated by
the experimental task might shed light on what
cognitive process is involved
What did Woodman and Luck’s study on attention show/do?
- Used N2pc component - known to index attention: strongest over the posterior cortex contralateral (opposite side) to where observer is attending (shifting attention without moving eyes)
- Found that if you are attending to the left hemisphere/field, there will be a stronger (more negative) N2pc component in right hemisphere
- Interested in difference between N2pc for right and left
- Experiment:
□ Asked participants to search for a target (coloured
square open to the left)
□ Need to ignore all distractors
□ Can you do this by taking in an entire scene at once
and finding it (parallel search - don’t have to shift
attention around) or do you need to shift attention
around (serial search)
□ Theory using N2pc - attention should only shift if
need to serial search
- If search is parallel nothing should change
□ To get people to attend to one hemifield first -
manipulated probability that a specific colour was
the target
- One had 75% one had 25%
□ Prompted participants to quickly attend to the most
likely colour first and researchers could monitor
attention while participants were scanning field
□ Tested what happened on trials where there was no
target
□ Found:
- When no targets: found that when the two
colours where in different hemifields of the
screen, N2pc shifted - attention shifted to
field with more likely colour then to less
likely colour
◊ Serial search
- Not much shift was shown when there were
no targets and stimuli in same hemifield
- When more likely stimulus was target and
in different hemifield as other stimulus - no
attention shift
- When less likely stimulus was target and
stimuli in different hemifields - attention
shift
□ Therefore attention only shifts when serial searching is used
What did Gehring et al’s study on error-related negativity show/do?
□ Asked whether there is a cognitive mechanism for detection of and compensation for errors
□ Asked participants to emphasise either accuracy or speed in a Flanker-task
□ Incongruent displays should lead to more errors and error detection should only matter in accuracy condition
□ Found:
- ERN was strongest when emphasising accuracy,
weakest for speed
□ Is ERN indicative for compensating for errors?
- It it did we would expect that ERN should also reflect
attempt to break the error
- Greater ERN lower response force (force at which
they press button) - trying to correct error
- Greater ERN, higher probability to get it right on next
trial
◊ Successful learning from errors
- Greater ERN, slower response on next trial
What is fMRI?
- Functional Magnetic Resonance Imaging
- Creates an image - EEG and TMS don’t
- Good spatial resolution
- Measure signal - BOLD signal
- Use reverse inference to draw conclusions about cognitive processes from the presence of activation
- We usually want to know something about cognitve processes
- Know cognition happens in the brain
- How much can we really learn about it?
- Temporal resolution of fMRI is poor - takes a long time to record whole brain
why use MRI?
• One method used to scan the brain was Positron Emission Tomography (PET) - involves administering a radioactive isotope to the patient
○ Exposes patient to significant amount of
ionising radiation
• fMRI - do not work with radioactive substances - super harmless
How does MRI work (practically)?
• Creates a magnetic field
○ 1.5-9 Tesla (usually 3T for most functional imaging)
○ Earth magnetic field is 65microT - fMRI is a very
strong magnetic field
○ Cannot feel magnetic field - harmless
• Patient placed on the bed and moved to centre of magnetic field
• Head coil - like a helmet
• Experiments can be controlled from outside scanner room - tests can be given to patients while in the fMRI machine
• Can really investigate cognitive processes as you would in a lab
• Cannot have any metal in the lab
• Patient has a maximum of 1 mm movement - cannot move
• Participants can see a projection (usually computer-controlled experiment) via mirrors mounted on the head coil
• Responses can be given via scanner-compatible keys, joysticks, or a touchpad
• Head position is fixed to avoid any movement
Why does MRI work (in terms of physics)?
○ Human brain is 70% water
○ Hydrogen atoms can be thought of as small bar magnets “processing” (rotating) like a spinning top about an axis
○ Random spin directions of protons can be aligned parallel or anti-parallel to an externally applied very strong magnetic field in the MRI scanner - because they are a little bit like magnets
○ Align with the magnetic fields of the MRI but still processing about an axis - instead of doing it in random direction, now do it in systematic direction
○ Not perfectly aligned - also not static - keep processing in a random fashion
○ Some align with the field and some against, but most of them align with the field
○ Precession frequency of protons depends on strength of magnetic field
○ Axis along which the magnetisation is built up in the scanner = z-axis
Magnetisation along z-axis cannot be measured
A radiation frequency pulse (RF) is applied perpendicular to the magnetic field (delivered through head coil)
Also harmless
Frequency of the RF matches the precession frequency (frequency at which the protons ‘process’ about their axis)
○ Matching the frequency will cause the protons to absorb energy - has two additional effects
- It tilts the magnetisation vector into the
traversal plane (x-y plane)
- Aligns precession of the spins - protons’
rotations are in phase
○ The transversely rotating magnetisation vector can then be recorded as a signal
- The head coil is used to send the RF pulses
but it is also the receiver
○ Trick is to now switch off the RF pulse
- After switching it off, transversal magnetisation
decays - protons emit excess energy
- Lose phase coherence - every proton does
their own thing - still aligned with magnetic
field by processing at different stages
- Magnetisation along z-axis returns and
transversal magnetisation disappears -
processes are called relaxation - signal goes
away
- Independent
○ We are interested in how fast the signal goes away during relaxation
- Summed effect of many protons undergoing
relaxation is measured
○ Transversal magnetisation decays at different rates depending on the brain tissue (ie where in the brain)
- One reason is because of proton density - lose
coherence because they will be influenced by
other protons in their environment
- Different tissues have different number of
protons
○ The signals from different protons will get out of phase with each other and begin cancelling each other out
- Structural brain image depends on when signal is recorded during this process
How do you reconstruct brain images?
• First step: divide brain into slices
○ Can now vary the gradient field along the z-axis and know that the different slices were exposed to different field strengths
○ Slice-selecting gradient
○ Thus if different protons are in different magnetic
fields, precession frequencies will be different
○ Only one slice of the brain will be excited at a
time using specific RF pulse because the
precession frequency will not be matched for
the others
○ By exciting one slice at a time we get the z-
coordinate of all resulting signals
• Now can use second gradient to change magnetic field within this slice - vary along the y-axis
○ Protons in each slice also have different precession
frequencies
○ Gradient is called frequency encoding
gradient
○ Gives us the x-coordinate of the measured
signal
• Finally, very briefly using a gradient along the y-axis causes protons to speed up their precession according to the strength of the magnetic field for a short time
○ When switching off this gradient, all protons are
back to the same precessing frequency but are out
of phase with each other
○ Phase encoding gradient
• Allows you to specify the exact place within the brain after all three gradients because there is only one spatial position that could have a particular position/frequency
• Now we know precisely what we have done to the protons at each location in space - can use technique called Fourier transformation to reconstruct entire space
• Can measure slices in ascending, descending, or interleaved order to get 3D image of brain
What is a disadvantage of fMRI/why does it have poor temporal resolution?
- This whole process takes a lot of time to measure the brain just once
• Usually measuring one full 3D image takes 1-3 seconds (1.5-2s is standard)
What is difference between fMRI and MRI?
fMRI goes beyond MRI - measures brain activity
Images of the functioning brain
how does fMRI work?
• Oxygenated blood, oxyhaemoglobin, is diamagnetic, enhancing the signal (signal gets better)
• Deoxygenated blood, deoxyhaemoglobin, is paramagnetic - introduces field distortions (susceptibility artefacts) decreasing signal
• Neural activity is accompanied by a local increase in blood oxygenation - brlood is pumped to that region
○ Oxygenated blood is needed for glucose
metabolism
• Neural activity is also accompanied by local oversupply in oxygenated blood and therefore gives a better Blood Oxygen-Level Dependent (BOLD) signal
- large blood vessels cause ‘brighter areas’ (better signals) in the scans
• This technique makes use of the fact that all neurons need oxygen supplied from the blood
Means we can see local activity directly in the scans because the signal is slightly better
• In a typical fMRI experiment, BOLD signal within a region is measured while participants engage in a cognitive task
• Need to compare the activity against a control
• Differences in BOLD signals tell us about whether a brain region is involved in a task
Does fMRI measure brain activity?
No:
measures BOLD signals - an indirect consequence of neural activity
What is Statistical Parametric Mapping?
The analysis of fMRI results:
• Areas of enhanced activity can be mapped onto structural image of the brain
○ For the analysis, a General Linear Model is usually fitted to brain activity at each measurement point (voxel): significantly stronger activation in region X for task A compared to task B is interpreted as involvement of the region in task A
Why is repeated measurement of the brain needed for an fMRI?
• Repeated measurement of brain activity is required for the whole brain while performing experimental tasks because signal is very noisy
○ Like EEG - need to average the activity after
all the trials to get an accurate view of what
brain regions are active
What are the limitations of the BOLD signal due to biological foundations?
○ we have to be careful when interpreting differences in BOLD signal
- If all these complex processes are driving the
signal, it’s not a one-to-one mapping onto neural
activity
○ There is a substantial temporal lag between neural activity and the peak of the BOLD response - in the order of 8 seconds (signal reaches peak about 8 seconds after neural activity)
○ BOLD signal further needs up to 16 seconds before returning to baseline again
• Not valid to compare signals between different regions of the brain because the signal change is different
○ Can only compare the BOLD signal in one
region and then the BOLD signal in the same
region for a different tasks
What is the Haemodynamic Response Function (HRF)?
HRF is the measured response of different regions during fMRI (which look very similar in terms of shape)
What are the neural processes driving the BOLD signal?
• BOLD signal does not represent ‘neurons firing’
• Logothetis describes local cortical excitation-inhibition networks (EIN), small and highly interconnected functional microunits, which show massive recurrent feedback
○ Like when you and your group of friends are talking about going to the movie - lots of excitement with some very keen to, others not so keen to - doesn’t matter if you reach consensus so long as there was excitement in your group
○ Not neurons firing or causing anything to happen, you can only see the interactions/excitement in the brain
• Feedback processing within EINs (which determine what the output of the microunit will be) might account for most activity measured by the BOLD fMRI
What are the limitations of the fMRI?
• Problem 1:
○ Because we see blobs in the brain, the organisation of the brain’s architecture must be ‘modular’ (brain has one functional unit in charge of each activity)?
- This is not true - often we do not see the
full networks involved
- fMRI only shows ‘tip of the iceberg’
- Can never conclude that nothing else is
going on than shown by BOLD signals
- fMRI might not always map the functional
units that matter
- Just because it’s what we see in our scans
does not mean it is exclusively what is
happening
• Problem 2:
○ fMRI has poor temporal resolution (takes time)
- Given that HRF is slow, very fast processes are
very difficult to image
- Because it takes about 2 seconds to measure
the brain at once this does not allow exploring
any processes that take place within these 2
seconds
- We need to use some tricks in our
experimental designs to separate events of
interest if we don’t wait for HRF to reach
baseline every time
• Problem 3:
○ Spatial resolution for fMRI is good but
- It’s also not great - smallest measurement
unit is a voxel - a 3D pixel
- Standard voxel size is 3x3x3 mm and we do
not learn anything that happens within a voxel
- But one voxel still contains >100 000 neurons
• Problem 4:
○ Multiple comparisons problem
- For such a complicated method only run a t-
test for every voxel in the brain for comparison
of condition A vs B
□ Two values per voxel
- However we have more than 50 000 voxels in the brain and we somehow need to correct for false positive findings (if it was caused by chance even if there is only 5% that it was) which are very likely to occur with so many tests
□ 5% risk of making a false judgement
with every voxel - this really sums up
if we do it 50 000 times
- Would expect 5000 false
positives
- Strictest correction of this is Bonferroni-correction - divide significance level by number of tests (eg voxels) and use this new significance level for each test - therefore overall risk of false positive will be 5 (or whatever the normal value is for p)
what did Kanwischer’s fMRI study of the brain’s recognition of faces show?
○ Presented participants with images of faces and contrasted BOLD signals to when participants saw objects (some faces some not faces)
○ Why is the brain so good at processing faces?
○ Found that a region located in the fusiform gyrus (in temporal lobe) responds more strongly to faces than to objects
○ They could show this result reliably in most of their participants, and could replicate it with different participants
○ Does that mean this area is specialised in the processing of faces?
○ To rule out this result being imply due to using objects as a control category, they replicated the study with a different control category: faces vs scrambled faces
- Taking elements from the face and rearranging
them so they no longer look like a face
○ The same brain area was strongly activated for faces but not for scrambled faces
○ Maybe it’s the same for other body parts, not just faces
- Contrasted faces with hands
- Same brain region was activated with faces rather
than hands
○ Led researchers to name the region ‘fusiform face area (FFA)’ - so sure this is the brain’s module for face processing
What are other brain ‘modules’ in the visual brain?
○ Fusiform Face Area (FFA)
○ Parahippocampal Place Area (PPA) - houses and places
○ Extrastriate Body Part Area (EBPA)
What are some criticisms of FFA and its implications of brain modularity?
○ 1: If our brain has one are specifically designated just to faces or places, what does that mean about other millions of objects we recognise? Not enough brain space
- Could it be that it only looks like this region is
specialised in faces
- Gauthier et al. Greeble study:
□ Asked participants to distinguish
between different ‘Greebles’ - made
up faceless figures which no
participant had ever seen before
□ During the experiment, participants
learned the family structures and
became experts for Greebles
□ First, when they did not know much
about Greebles, FFA responded
strongly to faces, but not to Greebles
as predicted
□ However, after learning to
distinguish really well between
individual Greeble families, the FFA
also responded for Greebles
□ Therefore FFA is not a face area, it is
an expertise area
○ 2: visual system might not be organised by specific object categories, but by where in our visual field objects are usually encountered
- Organisation in ventral visual cortex might follow
cortical topography (eccentricity mapping) - where
do you usually encounter things
- Coding is driven my resolution needs - FFA is good
for everything that usually requires ‘high’ resolution,
faces just happen to be centre of our vision
- Face area corresponds to brain regions that would
also activate when you focus on a very specific
point
- We encounter faces in the centre of our vision not
the periphery
- We usually need a high resolution to recognise
faces, simply because we need to see the details
- Might not be a matter of what it is but where it is
- The module for places/houses is in reality better suited for processing the periphery - that’s where house are usually encountered
What does the evidence of the FFA and its criticisms suggest?
• Researchers have found evidence for all three theories - suggested all might be true to some extent
• The fMRI signal might therefore reflect a mixture of all three coding schemes
○ Can’t tell from the BOLD signal that it’s all true
§ Might be overlooking evidence that is equally likely to produce the results - ‘tip of the iceberg’ - does not represent the only thing that is going on
What was Haxby’s argument against brain modularity?
○ Argued that in order to represent all possible objects we know, objects must be represented in a distributed fashion - meaning all objects are represented in the entire ‘object region’ in the brain
○ In their study, they showed participants many exemplars for different objects - including objects - while fMRI was recorded
- Ran correlations between distributed activation
patterns for exemplars within object categories and
between object categories
- If the entire pattern codes for an object, then there
should be high correlations for objects within
categories as opposed with between categories
- Found that correlations were higher within
categories than between categories
- This was still true when most responsive voxels for
each category were excluded - eg FFA for faces
(so basically when you don’t consider the FFA, the
correlations were still stronger when comparing
face-face response as opposed to face-object
response and the same for all of the objects)
- Therefore throw away the brain area for faces and
the brain still recognises faces
- The distributed patterns of large and small
responses, not just modules, were associated with
the object categories
What is the Problem of Reverse Inference with regards to fMRI?
○ Usually apply following logic:
- In this study, when task A is done, then region Z is
active
- In other studies, when cognitive process X
happens, then brain region Z is active
- Therefore, in this study, activity in Z –>
engagement of cognitive process X
○ One problem is that the second point is not exclusive - brain region Z could be active for many tasks
- Brain regions are very flexible
○ Problem is if we find activation in a region which is part of this multiple-demand network we still don’t really know what the region is doing
○ If a brain region is activated by many cognitive functions, we learn very little from observing activation in those areas
○ How good is task A at manipulating the cognitive process X?
- If the task measures more than one cognitive
function, we also don’t learn much
○ The probability of that we really learn from fMRI results that cognitive process X is involved depends on:
- The quality of the task to measure the cognitive process
- The specificity of region for this cognitive process
How does the difficulty to understand the prefrontal cortex show an example of a region being active for multiple tasks?
- Some researchers have concluded from looking at results from many studies that many anterior regions (towards front of brain) represent more abstract information, and more posterior regions represent more specific information
- Others concluded that most regions in the frontal cortex can actually be found to be activated in many different tasks
- Duncan argued that the frontal cortex shows relative, but not absolute specialisation
□ Means prefrontal regions might just be recruited ‘more strongly’ if the task at hand becomes more difficult
□ True for other regions too
Explain the other issue with fMRI (being the overinterpretation of null results)?
○ What does it mean if you find that no region was significantly stronger activated for task A vs task B?
- We don’t really know
○ Our statistical tests are designed to make it difficult for the H1, not the H0, meaning we can’t really interpret null results
○ Also don’t know whether method might just not be sensitive enough to detect small differences (if just some neurons within each voxel might show differences, but not many, or there are neurons coding for both/many conditions within a voxel)
- Should always avoid concluding that brain
regions are not involved in a cognitive process
What are nucleotides?
The building blocks of the genetic code
What are the four different bases in DNA?
§ Adenine (A)
§ Cytosine ( c)
§ Guanine (G)
§ Thymine (T)
What are amino acids?
the building blocks of proteins
- A specific sequence of three bases constitutes
genetic code for a particular amino acid
How many bases are in the human genome?
○ 3 billion bases in the whole human genome
○ 20-25 thousand genes that code for proteins
What is the structure of DNA?
○ DNA helix is double stranded
- Two strands carry redundant information
- Each base pair has a partner on the other side
□ C-G
□ A-T
- So if you know the base on one side you
automatically know the base on the other
○ DNA bundled in chromosomes
- Human karyotype comprises 46 chromosomes
□ 22 pairs of autosomal chromosomes
(1-22)
□ Two sex chromosomes (XX/XY)
What is a codon?
Sequence of 3 bases representing an amino acid
How do genetic variants occur?
○ Function of a protein is determined by its structure
○ Structure of a protein is determined by its sequence of amino acids
○ A change to a single base can change the amino acid (not always)
- Changing the amino acid can change the
structure and function of the protein
○ A single-nucleotide polymorphism (SNP) is a position on the genome at which the base (nucleotide) differs between individuals
- EG some may have a G where others have a T
- The two alleles of a SNP are the alternative
bases
□ In this example, T is the major (most
common) allele, and G is the minor
- An individuals genotype at a SNP is
determined by the two alleles on the copies of
the chromosome
- An individuals phenotype is the presence,
absence or value of a trait of interest
□ Psychological diagnosis (binary
phenotype)
□ Parenting style (categorical
phenotype)
□ IQ (quantitative phenotype)
What are possible genetic variants?
○ Insertion-deletion variant
- Bases added or missing (where one might have
GCG, that is not in the other one)
○ Block-substitution variant
- Multiple bases substituted
○ Inversion variant
- Bases are replaced with reverse sequence of the
other strand (so if the sequence on one is AATCG,
the other one would have the backwards-version
of the base pair: CGATT)
○ Copy-number variant
- Sequence of bases repeated multiple times
Is a mutation rare or common?
§ Rare: <1% of alleles in population
Is a polymorphism rare or common?
Common: greater than or equal to 1% of alleles in population
How is an excess dosage of the X chromosome proteins in females avoided?
one copy of the X chromosome in each cell is silenced or inactivated
- This process is random in each cell
○ When there are two X chromosomes in one cell
- XIST gene produces an RNA transcript (an
intermediate step in the process of converting a
gene encoded in DNA to a protein) that coats one
chromosome, which is inactivated as a Barr body
- TSIX gene on the other chromosome produces an
RNA transcript that suppresses transcription of
XIST
- TSIX is antisense partner of XIST
□ Both are encoded by the same stretch of DNA but are transcribed in opposite directions
What is heritability?
○ Phenotypic variance (P) = variance from genes (G) + variance from environment (E) + variance from gene-environment interactions (GxE) + covariance between genes and environment (2covGE)
○ Heritability (h) is proportion of phenotypic variance due to genetic causes
§ H2=G/P
§ Local measurement: specific to a given population at a particular time
§ Varies with amount of variation there is in a population in genes and environment
How do we measure heritability?
§ Before advent of molecular genetics, used genetic epidemiology
§ Study designs in genetic epidemiology exploit the fact that related individuals share a predictable amount of genetic material
§ Eg twin studies: look at concordance in twins (if one twin has a trait or disorder does the other have it too?)
□ Monozygotic (MZ) twins share 100% genetic material, dizygotic (DZ) twins share 50% genetic material
□ Higher concordance in MZ pair than DZ pairs suggests genetic component
® Assumes they are equally similar environmentally
What are the two modes of inheritance?
§ Dominant vs recessive:
□ Dominant traits require mutation on one copy of the chromosome for expression of the phenotype
□ Recessive traits require mutation on both copies (or only copy) of the chromosome
§ Autosomal vs x-linked
□ Autosomal traits are carried on one of the first 22 chromosomes
□ X-linked traits are carried on the x chromosome
What are the rules for dominant traits?
- Dominant traits can’t skip generations
- Two unaffected parents of a dominant trait cannot have affected offspring
What are the rules for recessive traits?
Two affected parents cannot have unaffected offspring
What are the rules for autosomal traits?
Equally common in both sexes
What are the rules for x-linked traits?
- Cannot transfer father to son
-If dominant: daughter of affected father must be affected - If recessive: Father of affected daughter must be affected
◊ More common in males
What is fragile X-syndrome?
- Fragile X syndrome is monogenic disorder because we can tract its origins to a single gene
-Can cause sever mental retardation - average IQ
of 40
- Results from a copy-number variant of CGG
sequence in the 5’-untranslated region (UTR -
contains the promotor region where chemicals
bind to start the process of transcribing a gene
into a protein) of the gene FMR1 (fragile-X mental
retardation protein)
-FMR1 - critical to synaptic plasticity
-Synapses to strengthen or weaken
over time in response to
increases/decreases in their activity
- forms neural basis of learning
- Expansion of the repeated CGG sequence of
bases triggers methylation process (many
repeated CGG sequences triggers methylation
whereby chemical compound call methalyn binds
to DNA)
- Constricts the X chromosome and results
in ‘fragile’ appearance
○ Methylated promotor region prevents
transcription of the gene - promotor region
also becomes bound by methalyn meaning
it isn’t there when it’s required to allow
synaptic plasticity
What are the two types of disorders?
• Monogenic disorders
○ Can trace the origins to a single gene
§ Huntington’s disease (HTT)
§ Fragile X syndrome (FMR1)
• Polygenic disorder
○ Monogenic disorders are the exception to the rule in behavioural and psychiatric genetics
§ No single gene for schizophrenia, autism, bipolar disorder, depression or anxiety
What is the purpose of Genome-wide association studies (GWAS)?
• Examine the statistical association between a phenotype and many SNP markers throughout the genome
○ Typically 500 000 - 2 000 000 markers
Why do you not need huge samples in a GWAS?
• Can sample common variation sparsely (about 1 in every 1500-6000 bases is genotyped on average - median size of a human gene is 25000 bases) because linkage disequilibrium (LD) allows us to observe indirect observations
○ Chromosomes are mosaics and many variants are correlated
• In a direct association the phenotype has a functional association association with a genotype (measured) SNP
• In an indirect association, the phenotype has a functional association with a non-genotyped SNP that is in LD with a genotyped SNP
Essentially:
• We don’t have to take huge samples, because even if the sample you take does not contain the SNP you are looking for, the linkage disequilibrium (LD) means the desired SNP can have indirect effects on the SNPs near it
What is the allelic dosage model?
-Used for quantitative traits
○ Categorise everyone according to whether they are a major homozygote, heterozygus, or minor homozygote
- Plot phenotype score according to genotype
- Is there a statistical association between the phenotypic measurement and the number of copies of the minor allele?
- Could be used to determine frequency of alcohol use and IQ - (quantitative traits)
What is the allelic association model?
- used for categorical and binary (yes/no) traits
-compare the case group with the control group
○ Is one of the two alternative alleles statistically overrepresented in a phenotypic group?
○ Could be used for diagnosing bipolar disorder (because it is a binary trait - you either have it or you don’t)
What is the Manhattan plot
- Graphically summarises reuslts of all individual tests of association
- Each point represents outcome of a test for one SNP
- Physical location of the genome and within a chromosome is on horizontal axis
- Transformed p value is on vertical axis
- Lower p values are higher on the axis - indicating strongest associations
- Threshold for significance are stringent because multiple comparisons increase the likelihood of type 1 error
- threshold is p=0.00000005
- Corresponds to Bonferroni correction for approx. 1 million independent uncorrelated tests
What are imputations of Manhattan plot?
○ Predict genotypes at non-genotyped SNPs
- Relies on data from a reference panel of
individuals genotyped at high density
§ Applies patterns of LD discovered in the reference
panel - use those to predict genotypes in non-
genotyped SNPs independent of phenotype
§ Run those tests of statistical association as though
though impudent SNPS were really genotyped
What does the genetic distance and recombination rate reflect?
the frequency with which two markers are inherited together
○ Helps define the region likely to contain the functional variant
What does conservation indicate?
the extent to which a sequence is maintained across species
High conservation suggests an important function preserved during evolution
How could ‘Skyscrapers’ observed in Manhattan plots could be explained
○ Multiple SNP LD with a functional SNP
○ Or multiple functional SNPs in the same gene
What are the molecular genetics of bipolar disorder?
○ Meta-analysis of bipolar disorder GWAS found association with the ANK3 and CACNA1C genes
§ Proteins transcribed from both of these genes regulate the flow of ions in and out of neurons during an action potential
§ Both genes are down-regulated (much less of the protein is transcribed) by lithium
§ Lithium is an effective treatment for bipolar
How can GWAS provide new evidence for existing hypotheses?
○ Schizophrenia has previously been linked to abnormal dopamine signalling
○ Antipsychotic drugs block dopamine receptors - has been primary evidence in favour of the dopamine hypothesis
○ Find now from GWAS that DRD2 (a dopamine receptor gene) is associated with schizophrenia
How can GWAS raise new possibilities
○ In this case of schizophrenia, most significant association is the major histocompatibility complex (MHC)
- MHC genes code for cell-surface proteins that
allow the immune system to recognise foreign
substances
- Does acquired immunity play a role in the aetiology of schizophrenia?
How can GWAS point to environmental risk factors?
○ Variants in the CHRNA5-A3-B4 gene cluster are known to be very strongly associated with heavy smoking
§ Encode subunits of nicotinic acetylcholine receptor, chlolinergic receptors that also respond to nicotine
○ Smoking has more than 80% prevalence in people with schizophrenia
○ Association of schizophrenia with CHRNA5-A3-B4 variants suggests heavy smoking may contribute to schizophrenia risk
What are some issues with the diagnosis of psychological disorders?
○ Can result from complex interaction of genes and environment
○ Diagnostic categories
§ Individuals with similar symptomotologies may be given different diagnoses and individuals with the same diagnoses may share no symptoms
○ Interference of multiple deficits
§ Measuring any individual symptom is problematic when multiple deficits are present
What do endophenotypes do as an alternative to diagnosing psychological disorders?
- measure association between genotypes and quantitative endophenotypes (functional abnormalities associated with psychiatric disorder)
○ More immediate relationships with underlying genetic mechanism
○ Single quantitative traits
§ Relatively easy to measure reliably
○ Can use psychologically normal participants
What are some endophenotypes proposed for psychiatric disorders?
○ Cognitive measures
§ Wisconsin card sorting test
□ Given a set of cards with different coloured numbers of shapes on them, and need to sort the cards according to a number rule, a colour rule, a shape rule
□ Then rule changes
□ Interested to see how long it takes for participant to adapt to rule change
○ Neurophysiological measures
§ Pre-pulse inhibition of startle response
○ Psychomotor measures
§ Antisaccade oculomotor task
□ Get participants to stare at a dot. The dot moves - but the task is to not follow the dot but move your eyes the same distance in the opposite direction
□ Measurement of how well you can inhibit these very automatic movements
○ Anomalies of basic visual perception
§ Neural mechanisms particularly well characterised
How can Endophenotypes of psychological disorders yield larger genetic effects than diagnoses?
○ Avoids difficulties assigning diagnostic categories
○ Allows testing of psychologically normal participants
○ Underlying biological mechanisms are likely to be simpler than for psychological disorders
How are distrubances of visual sensitivity associated with schizophrenia and autism according to GWAS?
• In a GWAS of visual sensitivity in a psychologically healthy population, the strongest association signal was at a marker on chromosome 1q21.1
○ Known risk region for both schizophrenia and autism
• The marker is situated in the 5’-untranslated region of the gene PDZK1
○ If functional SNP is situation in the 5’-untranslated region, it likely effects protein trnascribtion rather than structure
• PDZ proteins hold other proteins in appropriate configuration for localisation on the surface of cells
○ PDZK1 interacts with NMDA receptors
§ NMDA receptors play critical role in contrast gain control in the retina
§ Perceptual abnormalities in schizophrenia have been suggested to arise from NDMA receptor dysfunction
○ PDZK1 interacts with DLG4
§ Disruption of DLG4 in mouse produces an ASD-related phenotype
• Therefore, perceptual abnormalities observed in two different disorders may be linked by common genetic elements that affect synaptic function
What are forward genetics?
○ Phenotype effect on genotype/mutation
○ Neural complexity and length of lifecycle are positively correlated
○ Techniques that rely on breeding multiple generations simply aren’t feasible in more complex species
How do forward genetics work?
- Mutagenesis - introduces random mutations into genome of model organism
- Mutagenised animal is then crosses (process of ‘crossing’) with a strand without mutations (wild-type strain) across several generations
- Get offspring - look for the phenotype of interest
- Take the offspring that exhibit the phenotype of interest and genotype them
- So forward genetic is going from the phenotype and genotyping them to determine how they are genetically different from those not displaying the phenotype of interest
○ Advantages of using model organism:
- Might have phenotypes available to use that aren’t
available in humans
□ Eg anatomical phenotypes
□ Learning phenotypes
- Social behaviour
What are reverse genetics?
○ Targeted mutations are introduced and the effect of the phenotype is measured
- Going from genotype to phenotype
○ CRISPR-Cas9 system is a natural part of a bacterium’s defence against invading viruses
- Can be used to create targeted genetic mutations
in model organisms
- Cas9 is a nuclease protein (a nuclease is an
enzyme that can cut chains of nucleotides)
- Guide RNA directs Cas9 protein to the desired
DNA sequence, where the Cas9 cuts the DNA
- The random repair process can disable the gene, or targeted sequences can be introduced to be inserted during repair
What are optogenetics?
○ Not necessarily interested in determining the genetic causes of the behaviour, rather manipulating things at a genetic level so that we can better understand the links between brain and behaviour
How do Optogenetics work?
○ Several types of microbial opsins that have been identified as suitable for optogenetic control - each type responds differently to light stimulation of particular wavelengths
- ChR2 (channelrhodopsin-2 pump)
□ After it’s illuminated by blue light, lets positive
ions (mostly sodium) into the cell
□ Rapidly depolarises the cell and leads to
excitation
□ More likely to fire with blue light
- NpHR (halorhodopsin) pump
□ Activated by yellow light
□ Lets negative chloride ions into the cell
□ Leads to hyperpolarisation and neuronal
inhibition
□ Cell become less likely to fire with yellow light
- They can be introduced into neural tissue by a viral
vector
□ Adeno-associated virus (AAV) is commonly
used to introduce the required genetic
material
□ Using a virus to deliver material into cells to
introduce new genetic material into cells by
including the genetic code for the opsin
genes with the virus
□ By fusing these genes with the promotor
sequences, get restricted opsin expression
to particular cell types
- Physically introduce the light into the brain to
activate the rhodopsin pumps
□ Delivered through implanted optic fibre
□ When the pumps are activated, brings cells
closer to action potentials - more likely to fire
□ What behaviours are evoked or suppressed when particular cells are excited or inhibited?
How can optogenetics and reverse genetics work alongside each other?
• Combination of optogenetic system and CRISPR-Cas9 allows:
○ Light-controlled protein transcription
- Can switch on or off activity of certain
activities of certain cells using lights
○ Light-controlled genome editing
- In animals DNA can be altered in cells using
this combo
How/why are animal models used?
• Animal models
○ Genetic associations with ehaviour can only hint at
the biological pathways involved
○ Using bioinformatics, can translate a human
genetic mutation to target a homologous gene in a
model organism
○ Model organisms allow more direct measurement
at multiple levels
- Structure
- Function
- Behaviour
What is epilepsy?
○ Epileptic seizures arise from sudden excitation in groups of neurons with a loss of inhibitory potential
- Reduction in amount of inhibition that is coming in
to a particular neuron, which means that there is no
limit to the excitatory input for the neuron, meaning
the cell becomes overly excited - seizure ensues
○ Every neuron receives excitatory input and inhibitory input from other neurons
- Information is added together and determines how
excited a neuron is
- In most normally functioning neurons there is a
balance
- With excitatory synapses, the most common
excitatory neurotransmitter is glutamate - expelled
from one neuron, crosses synaptic gap, and excites
another neuron
□ Role is to increase the spread of excitation
with network of neurons
- Most common inhibitory neuron = GABA
□ Purpose is to increase nervous stability -
reduces/impairs excitatory processes
- With seizures - lack of normal balance between
glutamate and GABA
□ Insufficient GABA causes heightened
excitability - seizures
What is temporal lobe epilepsy (TLE)
○ Informed us more than any other condition about memory function
○ Definition
- Recurrent, unprovoked seizures originating from
medial or lateral temporal lobe
○ Simple partial seizures (without loss of awareness, originates in one part of brain) and complex partial seizures (with loss of awareness)
What are simple partial seizures?
- Originate in one part of the brain, not the whole brain
- Not associated with loss of awareness
What are complex partial seizures?
Associated with loss of awareness
What is the psychopathology of temporal lobe epilepsy (TLE)?
○ Most common is hippocampal sclerosis (HS)
- Neuronal loss and increase in gliosis (excess
growth of glial cells (support cells that support
surrounding neurons), after neuronal cell loss
occurs in a region - take up space created by the
death of neurons) - results in scar tissue (sclerosis)
in hippocampus
- Often occurs early in life
- Other aetiologies include past infections, tumours,
and vascular malformations (abnormally formed
blood vessels in brain)
- Form many people, medication is not enough for
people to continue functioning in every day life
- Surgical removal of the lesioned (damaged) hippocampus can cure or reduce the number of seizure
Describe the case of HM
-HM was 27 and had severe temporal lobe epilepsy
○ Underwent bilateral resection (tissue was taken out of both sides of brain) of extensive amount of mesial temporal tissue
- Included amygdala, most of hippocampi, part of
parahippocampal gyrus
○ Memory post-op
- Seizures were reduced
- Tested before and after surgery
- Normal attention span, preserved intelligence
- Retrograde memory was largely recovered over
time - only couldn’t remember 6 months before
operation
- Severe anterograde amnesia
□ Declarative memory impaired
- Had to be moved to a highly supported
residential house
- Even after 10 months of moving in,
couldn’t find new home - got lost
- Unable to recall names and faces of new
people (even when he saw them every
day)
- Language largely frozen in 1955 - didn’t
pick up modern words or concepts (eg
computers)
◊ Some exceptions (remembered rock
and roll and Ayotollah - 20 years after
surgery)
- Remembered that his mother died (which
happened after surgery)
□ Procedural memory was normal
- Could learn new skills even when he
didn’t remember learning them
- Star-mirror task
What is retrograde amnesia?
Impairment of memories prior to injury
What is anterograde amnesia?
Impairment of memories after injury
Impairment in learning new information
What is declarative memory?
Conscious access to previously-learned information
What is procedural memory?
Remembering how to do something
What does HM tell us about memory?
○ Mesial temporal lobe structures are essential for memory function
- This surgery is no longer offered - only one side is
removed now (and a smaller part)
○ Mesial temporal lobe structures more essential for anterograde memory
○ Distinction between Declarative and Procedural memoryWhat have we learned since HM?
○ Intact memory function does not solely rely on temporal lobes it relies on a neuroanatomical network involving many brain regions
○ Temporal Lobes are engine of memory
- They are the primary key structures without which
memory will not happen
○ Functional asymmetry
- Left and right temporal lobes do somewhat
different things
Describe memory function in TLE patients
○ Patients have ‘material-specific’ memory deficits related to involved mesial temporal lobe (MTL)
○ Left MTL lesion results in verbal memory impairment
○ Right MTL results in non-verbal/visual memory impairment
Where is the hippocampus?
- Located in mesial temporal lobe bilaterally
* Region of the brain first identified to support memory
What is the role of the hippocampal formation?
○ Hippocampal formation and surrounding structures are essential for learning and consolidating novel information
○ Consolidation Theory:
- After a period of consolidation, information can
be retrieved independently of hippocampal
formation involvement
○ Multiple Trace Theory (MTT):
- Retrieval of autobiographical/episodic
experiences always involves hippocampal
formation
○ Particularly necessary for relational memory tasks
○ Paired associate Learning tasks
- Required to remember an association between arbitrary (unrelated) pieces of information eg word and object
How does information pass through the hippocampal formation for learning to occur?
○ Information is integrated in sensory systems, sent to hippocampal formation for long-term storage
○ Memories can then be accessed by reciprocal connections between hippocampal formation and temporal neocortex
What are the three regions of the extra-temporal brain are particularly involved in memory?
○ Papez’s circuit
○ Frontal lobes (FL)
Diencephalon
What brain region did James Papez propose was devoted to emotional experience and expression?
Papez circuit + Amygdala = Limbic system
What does the Papez circuit comprise of?
Mammilliary bodies, fornix, anterior thalamic neuclei (ATN) (at the front end of thalamus), cingulate gyrus, and hippocampus
What does damage to the Papez circuit cause?
□ Lesions to components of the Papez circuit results in declarative memory impairment (poor relational memory/encoding)
□ Declarative memory impairment more reliable when hippocampus or ATN are lesioned - it is fundamentally essential for memory function
□ Difficult to be certain the extent to which reduced function to that particular area of the brain results in memory problems as opposed to the fact that making that area damaged also damages the connections that region has with other areas of the brain
□ All parts of Papez’s circuit are not equal - you are most reliably going to get damage to memory systems if one of two areas are damaged: hippocampus or ATN
What are the frontal lobes responsible for?
- Motor programming
□ Motor and premotor cortices (posterior FL) - Cognitive control processes eg problem solving, planning, reasoning, self-correction, and monitoring
□ Prefrontal cortex (anterior FL)
How are frontal lobes involved in memory?
□ Involved in developing and implementing strategies for appropriate memory encoding and retrieval
□ In charge of the organisation of memory
□ Impairment in remembering contextual details eg source of information, chronological order of memories (dosral lateral prefrontal cortex - DLPFC)
□ Damage to orbito frontal prefrontal cortex (OFPFC), or ventromedial prefrontal cortex (VMPFC), results in confabulation - production of statements involving bizarre distortions of memory
- May tell strangely bizarre stories that they tell as
though it is a memory - they have no way of
recognising what is a memory and what is not - the
verification and filtering process is damaged
What is the Diencephalon?
- ‘interbrain’
- At the back part of the forebrain
- Made up of two structures
- Thalamus
- Hypothalamus
What is the thalamus?
- Carefully structured so that different parts of thalamus connects with different parts of brain
- Richly connected with all parts of the brain’s cortex
- Although thalamus is in the centre of the brain, it has strong connections with the outside cortical regions of the brain
- Trying to understand its role in memory function is difficult - very few cases that have very discrete, specific, clean lesions to a very small focal area in 1 nucleus of the thalamus that does not affect surrounding nuclei
- Anterior and medial lesions are likely to cause memory deficits than posterior or lateral lesions
- Dense amnesic syndrome is associated with damage to the mammillo-thalamic tract (MMT connects anterior thalamus and hippocampus)
- Cases with Dorsal Medial Nucleus, Midline and/or Internal Medullary Lamina damage but spared MMT show specific retrieval difficulties - similar to memory impairment after frontal damage
- Damage to thalamic neuclei
◊ Dorsal medial nucleus: deficits in selecting the
appropriate information to be retrieved
◊ Intralaminar/midline nuclei: deficits seen in memory
retrieval and semantic memory
What is the amygdala’s role in memory?
○ Plays key role in supporting memory for emotionally arousing/laden experiences
- Classical fear conditioning
- Facilitates rich representations of emotional
experiences
- Causes stress hormones (adrenaline and
glucocorticoids) to be secreted from adrenal glands
- cascading series of chemical changes occur -
means that the amygdala uses these hormones to
enhance the consolidation and storage of memory
occurring in Mesial temporal lobes
□ Increases ability to remember and learn in
situations where there is a high degree of
emotional richness in experience
○ Lesions result in
- Loss of conditioned fear and impairment of new fear learning
- Reduced memory for emotionally laden events
What is an action potential?
○ Electrical pulse sent down through a cell body’s axon to the axon terminals
○ Allows communication with the cells it has synapses with
○ Action potential is generated in the Axon hillock (when the cursor is)
- Propagates its way down the axon to the terminal
projections by a series of jumps from node of
Ranvier to Node of Ranvier
- Each time it regenerates - it reaches the end of the
axon with little loss of signal
How do action potentials occur?
- Nerve cells have resting electrical potential - they have the capacity to change their electrical voltage and at rest they have a particular potential
- Resting membrane potential = -70mV
- If the cell receieves excitatory input from other cells, then the electrical charge will go up (depolarising)
- If it receives lots of inhibitory input it will hypopolarise - go down to less membrane potential than at rest
- A cell always recieves both inputs
□ It is added together and if excitatory input is
greater than inhibitory input, and crosses over
threshold of -55 mV, it sparks an action potential
□ You don’t need to have increasing excitatory input,
you only need enough to push it over the threshol - The cell will fully depolarise - increase of voltage, it peaks and then drops away (and so too does the electrical potential - it will overshoot - be less than a rest, and then return to the resting potential)
- The increase in excitation of the cell = excitatory post-synaptic potential (EPSP)
- The result of the inhibitory input = inhibitory post-synaptic potential (IPSP)
How does a neurotransmitter exchange occur?
- Inside each of the axon terminals are vesicles
- When the electrical impulse arrives at axon terminals, it causes little gateways in the skin of the neuron to open
□ Axon terminals are voltage gated - when they
receive a certain amount of voltage, they will open
and expel the vesicles into synaptic cleft (the gap
between the axons and the dendrites
□ The vesicles contain neurotransmitter, which
crosses the synaptic cleft and bind with the
receptors on the dendrites of the other cell
□ The combining with the receptors results in EPSP
or IPSP in the other cell
What does learning involve?
○ Learning involves synaptic plasticity (potential for synapse to change)
- The biochemistry of synapses change to alter the
effect on the post-synaptic neuron
What is long-term potentiation (LTP)?
- A long-term increase in the excitability of a neuron to a particular synaptic input caused by repeated high frequency activity of that input
□ If cell A fires repeatedly and at very high
frequency, the biochemistry of the connection with
cell B will change - Seeing LTP:
□ Measure baseline EPSP for a single electrical
stimulus
□ Then undertake process required for LTP - 100
electrical stimuli delivered rapidly
□ The increased EPSP for subsequent single
electrical stimulus - LTP
What is Hebb’s rule?
- LTP occurs when an axon of cell A excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency in firing cell B is increased
How does Long-term Potentiation cause synaptic changes?
- Glutamate - excitatory neurotransmitter
- Glutamate receptors are inserted in the post-synaptic membrane if LTP occurs - results in synaptic changes
□ More glutamate receptors, so when glutamate is
released across synaptic cleft, there are more
receptors to receive it and add to EPSP - LTP causes a number of changes at the synapse that allows LTP to continue beyond a few hours, up to months
□ Increased sensitivity of receptors to glutamate
□ Increased amount of glutamate released by the
pre-synaptic terminal button
□ Protein synthesis in post-synaptic dendrites
Where does Long-term potentiation occur?
- Occurs in hippocampus (particularly CA1 and dentate gyrus), also in entorhinal cortex
□ Not just perforant pathway - Prefrontal cortex, thalamus, motor cortex, amygdala, visual cortex
What are other mechanisms of synaptic plasticity
- Long-term depression - opposite effect
□ Low frequency stimulation at synapse can decrease synaptic strength - Habituation
□ Repeated stimulation reduces the strength of synaptic response (reduced neurotransmitter released) - Sensitisation
□ Single noxious stimulus causes a very exaggerated response in cell A in response to repeated presentation of noxious stimulus
□ Results in exaggerated response to future presentations of noxious stimulus
What is memory?
○ Maintaining information over time
○ The mental processes of acquiring and retaining information for later retrieval
○ Timed component - can keep information and access it at a later time
What is the difference between implicit/explicit and procedural/declarative memory?
○ Implicit/explicit memory
- Nature of memory tasks define these terms
□ Knowledge about the test which determines
whether you are talking about someone’s
implicit or explicit memory
- Do not measure cognitive theory or map onto
neuroanatomy
□ When you have damage on neuroanatomical
structures, it doesn’t discriminate clearly
between implicit and explicit memory tasks
○ Procedural/declarative memory
- Derived from dissociable cognitive theories
□ We develop tests to test those theories
- Measurement tools developed to test these
theories
- Map onto neuroanatomical systems
○ In studies of amnesia procedural/declarative distinction is more meaningful - because we are more interested in neuroanatomical structures and what damage to them means
What is procedural memory?
○ Our ability to remember/store/learn skills and procedures
○ Important for motor performance
○ Supported by memory systems that are independent of hippocampal formation
○ Involves areas of brain like:
- Cerebellum
- Basal Ganglia
-Does not involve medial temporal lobe, basal forebrain, or diencephalon
What is declarative memory?
○ Accumulation of facts/data derived from learning experiences
○ Memory is outcome of processing by various higher-order systems, which feed into the hippocampal formation
○ Activation of declarative memory causes activation of related memories
- Because of relational nature of hippocampal
formation is so fundamental to declarative memory
system, declarative memory is also in nature
relational
○ Memory activation can be independent of environment
- When you remember a particular experience, you have representational flexibility - can remember experience irrespective of whether you are in the same environment of when it happened the first time
What are the two types of memory model?
○ Serial models - information is being process consecutively
- Atkinson-Shiffrin model
- Levels of Processing model
- Tulving’s model
○ Parallel model - memory processing is all happening at the same time in parallel with one another
- Parallel Distributed Processing Model
What is the Attkinson-Shiffin model?
○ Information fades very quickly
○ If it isn’t tended to it is lost, if it is attended to it will move into working memory
○ Sensory memory: Iconic (visual) and Echoic (auditory)
○ Working memory is a capacity-limited system - Miller’s
notion that we have 7+/2 items of information that can
be processed at any given moment
○ Sensory memory and working memory represent short-
term memory
○ Long-term memory is much more stable
- Where information from WM is encoded into long-
term memory store
- Doesn’t create absolute truths of an event
- Memories are based on your own personal
perceptions and interpretations of what’s
happening - not objective replay of what happened
- Tend to encode this info based on schemata -
notions of what you expect to be happening and
why things are happening
- When info is rehearsed, information will be added
and that will affect memories being stored in long-
term memory
- Info is stored in long-term memory in a semantically
meaningful way (in a way that makes sense to you)
What is the Levels of Processing model?
○ Craik and Lockhart, 1972
- More interested in long-term memory
- How likely was it that someone will remember
something
○ Information retained according to level of processing it has undergone
- Shallow-deep continuum
□ Shallow memories are more fragile, can be
more conceptualised like short-term memory
(though not entirely)
□ Deep memories are more durable memory
traces
□ Depends on how much processing that has
occurred to that memory as to how
durable/fragile it is
- Maintenance vs elaborative rehearsal
□ Maintenance rehearsal:
- Repeating information to yourself in the
same way it was presented
- Results in shallower memory - less
durable, more easily forgotten
□ Elaborative rehearsal
- Process information and try to integrate it
with prior images and experiences, to
understand the meaning/interpretation
and incorporate it into existing semantic
network
- Deeper levels of processing
- Analysing info based on meaning - will
end up with more durable memory traces
What is Tulving’s model of memory?
○ Came out of lesion studies - not based on normally functioning people as the previous studies were ○ STM - LTM (like Atkinson-Shifrin model) ○ LTM - Procedural □ Remember how to do something - Episodic □ Remember events - Semantic □ Knowledge of facts
What is the parallel Distributed Processing model?
○ Information is not sequentially processed
○ There is a distributed network of connections and
activations happening simultaneously in parallel
○ A given memory is just the activation of the connection
in different areas
○ A different pattern of activation with different strengths
of some connections and less in others is what
distinguishes one memory from another
○ Come out of computer modelling literature
- Places emphasis on linkages and connections
rather than the elements/nodes themselves
○ The pattern of activation that you see at a given time that results in that experience of memory or knowledge
○ Learning occurs by changing that pattern of activation
- Strength of connections is changed between
relevant sites
Compare the models of memory
○ None of the models fully account for all the research data in isolation
○ All the models are true in different ways
○ Serial models are most useful for studying amnesia
- Tulving’s model is most useful because it has been
most useful in understanding what is going on for
individuals who have damage to memory systems
What is William James’ conceptualisation of memory?
○ The knowledge of an event or fact, of which meantime we have not been thinking, with additional consciousness that we have thought of or experienced it before
- Describes episodic memory - refers to ability to
remember events as opposed to facts
What is episodic memory?
○ A memory system that makes possible ‘mental time travel’ through subjective time, from the present to the past and the future, a feat that other memory systems cannot do
○ According to Tulving it works by
- Allowing individuals to re-experience, through
autonoetic awareness, previous experiences and to
project similar experiences into the future
□ Autonoetic awareness - highly personalised
feeling of reexperiencing oneself in the
autobiographical past or present
□ Sense that this is your personal
experience/memory that you are retrieving
from memory banks
- Allows people to have a conscious recollection of
their own personal past
○ Episodic has developed more recently in terms of evolution
○ Develops late in childhood
○ Dependent on semantic and other forms of memory
○ Shares neural mechanisms and cognitive processes with other systems
○ Is additionally subserved by specific mechanisms and process that are not components of any other systems
What is semantic memory?
○ Knowledge memory
○ Memory system that allows us to acquire and retain factual information
○ Not purely concerned with language or verbal information
○ No autonoetic awareness of personal past
Why do Squire and Zola view semantic and episodic memory as entirely parallel and independent systems within declarative memory?
- Declarative memory is reliant on the hippocampal network
- Damage results in equal impairment to the episodic and semantic memory systems
- They operate in parallel - neither is reliant on the other system, but they both depend on the hippocampal system
- Amnesic patients have equal difficulties with event and fact memory
Explain Tulving’s view that episodic and semantic memory share many features and are not entirely parallel independent systems
- Serial Parallel Independent hypothesis (SPI)
□ Encoding is serial, retrieval is parallel
□ Encoding into semantic memory depends on
semantic system
□ Encoding into episodic memory depends on
semantic system
□ Episodic memory is a unique extension of semantic
memory
□ Retrieval is independent, and can be supported by
either system independently of the other
□ PRS = perceptual Representation System -
perceptual memory system
□ Allows for some predictions for how some people
will behave with different types of measures
depending on what is damaged in the brain - allows
us to predict and test whether model is accurate or
not
- By determining whether there are
dissociations between different aspects of this
model
- You can have no dissociation, single
dissociation or double dissociation
- Can use this to determine what role a part of
the brain is having in different
processes/cognitive functions
□ Encoding has a single dissociation, retireval has
double dissociation
What are the types of dissociation and what do they mean?
• You have system with X and Y parts - do they work in parallel to produce A and B outcomes, or can they dissociate (is there some degree of independence?
○ No dissociation: damage to X results in damage to
A and B equally, and the same for damage to Y
○ Single dissociation: You damage X and it only
affects A and not B, but damage to Y damages A
and B equally
○ Double dissociation: You damage X and it only
affects A, you damage Y and it only affects B
What is an example of single dissociation?
○ Television with X and Y components
- Are both colour (A) and picture (B) equally
dependent on X and Y components?
□ If you lose X you can lose colour (A), but still
have picture (B)
□ If you lose Y you can lose colour (A) and
picture (B)
- Single dissociation - both A and B rely on Y, but A
also relies on X
What is an example of double dissociation?
○ Television with transmission Y and Z componenets: are picture (B) and sound ( C) equally dependent on Y and Z?
○ You damage Y and lose picture (B), and still have sound (C )
○ You can damage Z and losesound (C ), but keep picture (B)
○ Double dissociation - B independently relies on Y and C independently relies on Z
describe Vargha-Khadem’s study on bilateral medial temporal lobe injury
• Investigated 3 patients who suffered very early bilateral medial temporal lobe injury
○ Beth
- 14 y.o. at assessment
- Had heart attack at birth (heart stopped 7-8
minutes)
- 2 hours after resuscitation had generalised
seizures
- Good recovery after 2 weeks
- Memory difficulties noted when she was 5 and
started school
○ Jon
- 19 at assessment
- Premature baby (26 weeks)
- On incubator for 2 motnhs (tube fed and
ventilated)
- Afterwards developed normally
- Age 4 - had 2 protracted, afebrile convulsions
(2 long seizures without fever - 1.5-2 hours
each)
- About 1.5 years after that, parents noticed
severe memory impairments (entering
schooling)
○ Kate
- 22 at assessment
- Up until 9 she was an avergare student
- At 9, she took a toxic dose of asthma
medication
- Number of seizures, was unconscious, and
had respiratory arrest (stopped breathing)
- Left her profoundly amnesic
- Age 17 developed temporal lobe epilepsy, well
controlled with medication
• Neuropathology
○ They were assessed with MRI and spectroscopy
○ All have abnormally small bilateral hippocampi
○ All have intact extra-hippocampal temporal lobes
• All 3 cases had very significant impaired memory capacity relative to intellectual capacity
○ Memory capacity is proportional to intellectual
capacity
• Memory assessed with standard clinical measures of memory (tests of episodic memory)
• Memory was so impaired they could not function independently
○ Every day memory deficits include
- Spatial memory
□ Couldn’t find their way around
- Temporal memory
□ Couldn’t remember day/time - didn’t
know what class to go to
- Episodic memory
□ Didn’t remember what they’d done during
the day
• Educational achievement
○ All faired relatively well in mainstream education
○ Educational achievement is consistent with IQ
- Important because educational achievement
essentially relies on factual knowledge -
semantic memory system
○ All had factualy knowledge within the normal
range
• Conclusions
○ Intact semantic memory, impaired episodic
memory
- These systems must be functionally
dissociable (single dissociation)
○ Episodic memory relies on hippocampal memory
circuit
Combine Tulving and V.K. study
• V-K study findings fit with Tulving’s SPI model
○ Episodic memory function relies on semantic
memory
○ Semantic function does not rely on intact episodic
memory
• However, people with semantic dementia have impaired semantic memory but intact episodic memory
○ Means double dissociation is possible
• It is meaningful to consider episodic and semantic functions as separate from each other, but need to use this as a heuristic guide rather than an absolute truth to understand patient populations who differ in semantic and episodic memory ability
○ Interaction between systems occurs, but it is not
yet fully understood
What is Alzheimer’s disease?
○ Commonest primary dementing illness (where disease process itself operates directly on neuronal tissues)
- Autopsy studies report approx 50% of all dimensias
are AD
○ Very affected by age
- Prevalence: approx 2% in age bracket of 65-70
□ 20% of people over the age of 80 have AD
- Problem of ageing population
□ Largest group of people is baby boomers
□ Eventually become dependent and enter
supported accomodation
□ Will be very costly to look after them all
Why is Alzheimer’s disease difficult to diagnose?
Diagnosing
- Diagnosis can only be made through pathology
□ Definitive diagnosis: if we have a bit of brain
under microscope and find very specific
features in brain tissue
□ That happens through two mechanisms:
- Biopsy living person’s brain
- Look at brain in autopsy after death
□ What actually happens is we can only
diagnose dimentia of the Alzheimer’s type
(DAT)
- Syndrome that occurs in those people
who are shown to have AD at death
- Compilation of symptoms that people
who are later found to have AD
demonstrated
What is the cause of late onset Alzheimer’s disease?
- Majority do not have family history - occurs sporadically: especially with late onset (AD after 60-65)
□ Only genetic relationship that has been found is
on
the ApoE gene (epsilon 4 allele of apoliprotein E
gene)
- Shown to elevate risk of developing AD
- Only gene that has been shown to have any
relationship with late onset AD
what is the cause of early onset Alzheimer’s disease?
- Rare, early onset AD (before 60-65) - autosomal dominant cases
□ Where lots of people in the family across
generations have early onset AD
□ Mutations in 3 genes:
- Amyloid precursor protein (APP)
◊ Important in development in amyloid ß
peptide
- Presenilin 1 (PSEN1)
- Presenilin 2 (PRSEN2)
◊ Both PRSEN proteins are involved in
converting APP into Aß peptide
□ All alter production of amyloid ß (Aß) peptide -
principle component of senile plaques
What is the relationship between Alzheimer’s disease and Down syndrome?
- Individuals with Down Syndrome
□ Unusually prone to developing AD
□ Develops very early - approx 40
Are there any precipitating factors known for Alzheimer’s disease?
□ No one particular thing that trigger onset of AD
□ Some suggestion that head injury results in increased risk, but issue is that the science isn’t great quality
- Only for moderate to severe head injury in males
What does sudden decompensation refer to with regards to Alzheimer’s disease?
□ Many people who have a stroke, or brain infection, radio therapy in cancer treatment who seem to develop AD shortly after
□ However, we know that with these people they already have subclinical disease going on
- Not severe enough to bring it to medical attention
- Have this experience of stroke (for eg), results in decompensation (brain doesn’t recover as well as expected), and reveals subclinical AD that is going on in the background
- Doesn’t mean the stroke caused it, it just revealed the symptoms that have slowly been developing
What are the clinical features of Disease of the Alzheimer’s type?
○ Onset: insidious
- Do not wake up suddenly with symptoms, they
develop slowly in an increasing way over a number
of years
- Usually 1-2 years prior to diagnosis
○ Course: slow deterioration in function
- Over a number of years
- Occasionally see plateaus in deterioration
□ Doesn’t tend to lengthen period of disease
process, just slows it down for a period of
time before it speeds up again
- Death: mean is 8.5 years after onset (range is 2-20)
What is the first phase of Alzheimer’s disease process?
- Phase 1:lasts 2-3 years
□ Failing memory (amnestic presentation)
□ Muddled inefficiency in Activities of Daily Living
(ADL)
□ Spatial disorientation
- Particularly at night
□ Mood disturbance can occur (agitated or
apathetic)
What is the second phase of Alzheimer’s disease?
- Phase 2: more rapid progress of deterioration
□ Intellect and personality deterioration
□ Focal symptoms appear
- Dysphasia
◊ Anomia: word-finding difficulties
- Dyspraxia
◊ Can do motor movements required for an
activity, but have trouble sequencing their
motor movements
- Visual Agnosia
◊ Despite eyes functioning normally, unable
to recognise what visual objects are
- Acalculia
◊ Complete loss of function
◊ Cannot calculate because no longer
understand arithmentic function in the
same way - understand that 10 apples is
more than 3 oranges, but do not know
how to multiply, divide and then add and
subtract - loss of arithmetic function)
□ Disturbance of posture and gait - increased muscle
tone
- Look stiff when they move
□ Delusions/hallucinations can occur
What is phase 3 of Alzheimer’s disease?
- Phase 3: terminal stage
□ Profound apathy - become bed ridden
□ Eventually lose neurological function
□ Bodily wasting occurs
- Because not eating
□ Usually people will die from pneumonia because
they’re no doing anything or eating much
What is McKhann’s criteria for identifying Alzheimer’s disease?
- Probable AD
□ Deficits in 2 or more areas of cognition
- Amnestic presentation: most common
- Nonamnestic presentations: language,
visuospatial, executive dysfunction
□ Progressive worsening of memory and/or other
cognitive functions - deteriorating process
□ No disturbance of consciousness
□ Onset between 40 and 90
□ No other reasons for deterioration
□ Biomarkers are not required
- Biological markers that are typically seen in
blood, and it says in probably AD - if you have
presence of certain biomarkers, it increases
likelihood that you have probable AD, but not
having them doesn’t mean you don’t have
probable AD - Possible AD
□ Made on the basis of dimentia syndrome if there
are variations in the onset, presentation, or course
- Like Probable AD but less certain - slight
variations
□ Can be made in presence of other disorder, which
is not considered to be the cause of dimentia - Definite AD
□ Need histopathological evidence of AD obtained
from biopsy or autopsy
- Need evidence of specific abnormality at level
of the cell
What is the pathology of Alzheimer’s disease?
○ Grossly atrophied brain (shrunken look because of death of neurons)
- Affects frontal and temporal lobes, and less
obvious is parieto-occipital regions
○ Extensive degeneration of neurons
- Loss of cholinergic neurons, which introduce
acetylcholine (neurotransmitter) into synapse)
○ Accompanying glial proliferation
○ Extensive amounts of senile plaques (contain Aß peptide)
- Senile plaques - histological structure that contains
Aß peptide, particularly present in hippocampi and
amygdaloid nuclei
○ Extensive amounts of neurofibrillary tangles (NFT) - abnormal form of tau protein
- NFT occur diffusely through grey matter particulalry
in hippocampi
- As a major component they have tau protein
○ Intensity of neuropathological features (esp tau protein) correlates closely with severity of dimentia
What is the course of neuropathological changes in amnestic version of DAT?
- Presence of senile plaques and NFTs commence in
hippocampal formation and mesial temporal lobes
- Particularly NFT - have predominance in this
region
Pathology spreads posteriorly towards parietal cortex
Then spreads ultimately forwards to involve frontal cortex
Spread of disease is different to the atrophy
Also spreads to lateral and posterior temporal lobes
Eventually the whole neocortex is affected
Onset of neuropathological changes commence many years before symptoms are experienced (Preclinical stage)
Tau pathology is most related to symptom expression of cognitive difficulties and dementia stage
What is the clinical pattern of cognitive impairment in DAT (amnesic presentation)?
○ Initially see MTL (mesial temporal lobe) memory impairment due to early predominance of hippocampal/MTL involvement (Tau pathology) - episodic memory impairment
- Anterograde memory:
□ Impaired new learning
□ Impaired delayed recall
□ Poor recognition memory (prompts do not
assist recall)
- Retrograde memory
□ Intact for remote memories
□ Reduced for recent retrograde memories
- As memories get closer to where they
currently are, they have more difficulty -
temporal gradient
- Develops as disease develops
○ Wernicke-type aphasia
- Word-finding difficulties
- Fluent (grammatically correct speech)
○ Visuospatial deficits and topographical disorientation due to spread into parietal lobes
- Dyspraxia
- Visual agnosia
- Acalculia
○ See behaviour change due to spread of disease into frontal lobes
- Apathy
- Agitation
○ Eventually disease affects all of neocortex, see generalised impairments in all domains
○ Must see functional impacts for a diagnosis of dementia
What is the treatment and prevention of DAT?
○ Some pharmacological treatment has been developed
- Work by trying to rebalance the action of
acetylcholine
- Prevent the reuptake of acetylcholine from the
synapse through deactivating the molecules that
encourage the reuptake of it back into the cell
○ They are not particularly effective - work for a couple of
years, and maintain the current quality of life for longer
so they don’t get worse, but they ultimately stop
working and then the person’s disease process speed
up to where it otherwise would have been - life
expectancy doesn’t change
○ Considerable research is being done in this area
○ No clear evidence that anything we have or can do
prevents AD
- Diet and physical, social, and cognitive activity can
help in reducing the risk of cognitive decline in AD
What is the difference between AD and normal ageing?`
○ Changes that occur in AD also occur in normally ageing individuals
- Pathological changes are much more severe in AD
○ Cognitive deterioration evident in normal ageing, but in DAT cognitive function is significantly impaired relative to same aged peers
How many synapses are in the cortex?
0.15 quadrillion
What are receptors?
○ Located on the outside of the cell membrane allow the
released neurotransmitters to influence post-synaptic
neurons
○ Each receptor can only be activated by one
neurotransmitter (or a drug that is designed to mimic
that neurotransmitter)
○ Have very specific function/action
- When neurotransmitter binds to the receptor it will
trigger the same event every time (either opening a
channel or triggering a second messenger event)
- Not simple ‘open/shut’ gates - have complex
structures and it is often a small change in their
shape that will ‘open’ their channel
What are the two types of receptors?
- Ion channels
- G-protein coupled
What are ion channel receptors?
□ Act like gates for ions
□ When a neurotransmitter binds onto the ion channel, it
will cause a change in receptor shape and will allow
ions to flow through
□ Normally selective and only allow one of a few types of
ions to pass through when they are open (eg calcium
channel)
What are G-protein coupled receptors?
□ Work through second messengers
□ When neurotransmitter binds to receptor, it activates a
second messenger system that can either open a
channel or cause other things to change within the cell
(eg DNA being transcribed and new proteins being
made)
□ Effectively gives energy to a second messenger system
- allows attached enzyme to do its thing
What is neurotransmission?
○ Chemical substance released from 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
- Very direct communication between one neuron to
the next
- Directly impacts activity or subsequent cell
○ Either excitatory or inhibitory
○ Serves rapid (millisecond), precise, point to point
communication
What is neuromodulation?
○ A chemical substance is released from the neuron in
the central nervous system, or in the periphery, that
affects groups of neurons, or effector cells with
appropriate receptors
- Doesn’t have to be released at synaptic sites
- Often acts through second messengers
- Can produce long lasting effects
- Doesn’t have single impact on subsequent
neurons - it’s about modulation of neural activity
○ Slow (milliseconds to seconds) processes that alter the subsequent responsiveness of neurons
• Presynaptic
○ Alters neurotransmitter release
• Post synaptic
○ Alters neurotransmitter action (eg alters
excitability/firing pattern)
• Neuromodulation may cause changes in neural function or structure (ie sustained neuromodulator activity can drive changes in the brain related to synaptic plasticity
Are neurotransmitters slow or fast?
- Synthesis and transport to the synapse is relatively slow
* But the neurotransmitter action is extremely fast because it sits ready for release
How do drugs act at the receptor?
○ Act by mimicking neurotransmitter/modulator
○ Can act as agonists
- Activating the receptor like the natural compound
○ Or an antagonist
- Blocks receptor and prevents natural compound
from activating it
What is the cycle of neurotransmitters?
○ 1: Synthesis ○ 2: Relase from synaptic vesicles ○ 3: Bind to receptors ○ 4: +/- influence on post synaptic neuron ○ 5: broken down by enzymes ○ 6: Re-uptake of transmitter ○ 7: Formation and storage in synaptic vesicles ○ *Drugs can affect all stages*
How can the synthesis during neurotransmission be interrupted?
○ Neurotransmitter can be altered by increasing or decreasing synthesis of the neurotransmitter
How are hormones different to neurotransmissions?
- Signalling molecules produced by glands and transported through bloodto regulate physiology and behaviour
- While they are chemical messengers, they are produced in glands rather than neurons, and circulated by the blood
What defines non-classical neurotransmitters?
• Do not satisfy all criteria for a neurotransmitter, which are:
○ Present in synaptic terminals
○ Released from presynaptic terminals after neuron
fired
○ Existence of receptors on postsynaptic neurons
What are the types of non-classical neurotransmitters?
Peptides
Nucleosides
Lipids
Gases
Describe peptides
- Compounds that consist of 2 or more amino acids
- Not synthesised from smaller compounds, but are a product of larger protein molecules (poly-peptides) being broken down into peptides within the neuron before release at the terminal button
- Most peptides serve as modulators, however many peptides known to be hormones also act as neurotransmitters and are often co-released with other neurotransmitters
- Same compound having different roles and functions in different contexts in brain regions
- Best known family of peptides are endogenous opiods
□ Highest density of opiate receptors are in areas
involved in pain - Examples
□ Heroin
□ Morphine
□ Opium
What are does heroin do and how do you treat dependence or overdose?
- Not neurotoxic - doesn’t damage brain cells
- Can cause death by respiratory failure
- Destroys person’s life, not brain - so addictive
- Full agonist at opioid receptors
- Pleasant effect - causes people to want it again
- Types of treatment to heroin dependence or overdose
◊ Buprenorphine
- Partial agonist
- Treats dependency
- Activates receptor to smaller degree - don’t
get same high
- Still addicted but to buprenorphine not heroin
◊ Naloxone
- Full antagonist
- Works quickly
- Can block effects of heroine
- Used for overdose
- Stops effects like a plug
- Rapid withdrawal
◊ Methadone
- Agonist
- Used in treatment of dependency
- Much slower time course than heroin
- If someone had both heroin and methadone, it
blocks heroin’s ability to activate the receptors
- Need to take it for years - allows them to live
their lives
What are nucleosides?
- Subunit of necleic acids
□ Hereditary-controlling components of all living cells
such as DNA and RNA - Usually obtained by chemical/enzymatic breakdown of
nucleic acids - Often co-transmitters hat serve to modulate the release
of other transmitters - modulating the modulators - Adenosine
□ Forms from breakdown of adenosine triphosphate
(ATP)
- Primary energy source in cells for transport
systems and many enzymes
□ When you are awake levels gradually rise - part of
energy biproduct
- Body uses that biproduct of energy
consumption to trigger sleep and suppress
arousal
- The more excersise and energy you burn
triggers a sleep-promoting response
□ At synapses where adenosine is the primary
neurotransmitter, a high post-synaptic firing rate
leads to sleepiness
- Increased firing = reduction in arousal - Caffeine
□ For plants, it acts as a pesticide that paralyses and
kills insects that attempt to feed the plants
□ Acts as adenosine receptor antagonist
- Blocks natural action of adenosine
□ Because adonsine increasing firing rate increases
sleepiness, caffeine increases alertness by
reducing the firing/activation of these neurons
□ Different to other stimulant drugs - doesn’t act as a
stimulant, but blocks sedation effects
What are lipids?
- Naturally occurring molecules that include fats, waxes
and many others - Hydrophobic - repel water
- Main biological function is energy storage, signalling, and
provide the structural components of the cell membrane - Synthesis pathways remain unclear for many lipids that
serve as neurotransmitters/modulators - Endocannabinoids
□ Internal cannabis-like substances
□ 2 known cannabinoid receptors:
□ CB1
- Found in the brain
- Responsible for the main psychological effects
- Receptor activation: shortens the duration of
action potentials in presynaptic neuron -
decreases amount of neurotransmitter released
□ CB2
- Found in peripheral tissue
□ By regulating the activity of those neurons and
release of neuromodulators, these receptors act to
modulate the modulators - Cannabis
□ Active component is tetrahydrocannabinol
□ Dried and consumed by inhalation
□ Effects range from change in appetite, time
perception, arousal (relaxation/anxiety), and have
been linked to states of apathy and
underachievement
□ Used to reduce nausea, relieves asthma attacks,
decreases pressure within the eyes in glaucoma
□ Multiple epilepsy trials are underway
What are gases?
- Air-like fluid substance which expands freely to fill any
space available - Soluble gasses - dissolve in fluid (dependent on
pressure and temperature) - Neurons use two gasses as neurotransmitters
□ Nitric oxide
- Produced from amino acid Arginine in
subpopulation of 1-2% of neurons in cortex
- Exact function and role in the brain is unclear
◊ Involved in learning and memory through
effects on synaptic plasticity
◊ Dilates blood vessels in regions of the
brain that become metabolically active
- Very different to traditional neurotransmitters
◊ Not synthesised or stored in vesicles
◊ Produced throughout the cell including
dendrites and defuses out of cell as soon
as it is produced
◊ Does not activate receptors, simply enters
neighbouring cell
◊ Very short lived and is degraded or
reacted within a few seconds of being
produced
◊ Can act on several nearby neurons
◊ Short half-life - doesn’t flow around brain
with huge effects
□ Carbon monoxide
What is the role of Glutamate?
○ Main excitatory neurotransmitter in brain
- When glutamate is released - increases chance of
post-synaptic neuron firing
○ Released by all excitatory neurons
○ Estimated that over half of brain synapses release glutamate
○ Glutamic acid (one of the amino acids)
○ Synthesis:
- Amino acid that acts as a neurotransmitter in its
original form, but this amino acid does not pass
through blood-brain barrier, so it still needs to be
synthesised in the brain
- Is synthesised from glutamine which is released by
cells neighbouring the neurons
What are the receptors for glutamate?
- 4 major types
□ 3 of which are ion channels
- NMDA receptor (only need to worry about this
one)
- AMPA receptor
- Kainate receptor
□ 1 is G-protein-coupled (metabotropic)
- The metabotropic glutamate receptor
◊ Allows changes using secondary
messengersDescribe excitatory neurotransmitters
- Found in most long projection neurons throughout the cortex
- Excitatory connections are ‘point-to-point’
- Many region-specific functions
- Information flows through visual hierarchy
What conditions must be satisfied for the NMDA receptor to open its ion channels?
○ There is also a glycine molecule (another type of amino acid)
○ If magnesium ion is not bound to the inside
Why is the NMDA receptor so complex?
-NMDA is particularly complex
-6 different binding sites so has lots of complex functions
• Other binding sites modulate receptor function
• NMDA receptor is critical for learning, memory, perception, and synaptic plasticity in general
• Large genetic studies identify NMDA receptor as relevant for schizophrenia, but also to general function and IQ
○ Hard to tease things apart - can’t block all NMDA receptor to see - end up comatosed
Describe the effects of alcohol on the NMDA receptor
○ NMDA antagonist
- Blocks NMDA receptor
○ Reduction in glutamate is believed to contribute both to the general sedative and memory effects of alcohol
- Information is not coded as well as it could be
○ Also GABA agonist which further leads to brain inhibition
- GABA is an inhibitory neurotransmitter
○ Drug is both blocking ‘activation’ neurons, and activating inhibition neurons
Describe the effects of ketamine and PCP on the NMDA receptor
○ PCP - Phencyclidine ‘angel dust’
○ Ketamine - ‘special K’, horse tranquilizer
○ Both are NMDA antagonist
○ Both cause dissociative hallucinations (people feel disconnected rather than perceiving visions)
○ Risk of suicidal behaviour
○ ketamine itself is remarkably safe on body
- Often give ketamine to different sized animals,
kids, or in war time (so can’t always measure
appropriate dosages according to body types)
because it is very unlikely to experience overdose
in terms of heart or breathing failure - can use it on
different body sizes
- Also anaesthetizes person/animal with eyes open -
good for animal studies because you can check
pupils etc
- Not used heavily in usually hospital environments
because causes unpleasant experiences -
dissociations and risk of suicidal behaviour
What is psychosis?
- Psychosis - symptom cluster, not a diagnosis
- Schizophrenia - ~1% population
- Psychotic symptoms may effect 3% of population at some time in their life
- Prominent feature of schizophrenia, but exists in other conditions
- Can have drug-induced psychosis
What are the symptoms of psychosis?
○ Delusions ○ Hallucinations ○ Depression ○ Anxiety ○ Suicidal thoughts or actions ○ Difficulty functioning ○ Disorganised speech - switching topics erratically
What is the relationship between Glutamate and psychosis?
- Suggested link between Glutamate and psychosis, but it is contraversial and is likely to involve other neurotransmitters such as dopamine
- Regardless of exact neurotransmitter involvement, the symptoms suggest widespread disruption and lack of coherent integration of sensory information
- Genetic studies point to a large number of genes rhat all may contribute to a small amount of risk for psychosis
- Very unclear, and may just reflect altered synaptic activity (communication between neurons) in psychosis
What are the effects of psychosis on the brain?
• No major structural differences in psychosis
○ Illustrates the importance of chemical balance in healthy perception and cognition
What was the unusual case of acute psychosis in an adolescent?
○ Previously healthy female was hospitalised with acute psychosis
○ Treated her wth medication but found her state deteriorated
○ Scan of brain and spine showed no problems
○ Did have an autoimmune response to NMDA receptor
- Body was fight NMDA receptors
- Caused complete dysfunction of NMDA receptors
- Ended up comatosed
○ About 75% of people in these cases (NMDA receptor encephalitis) recover completely
- Rceovery occurs in step-like manner in reverse
order
□ In some cases experience intermediate bouts of psychosis as they improve until final recovery
What is GABA?
• Gamma-amino butyric-acid
• Primary inhibitory neurotransmitter
○ Decreases likelihood of post-synaptic neuron firing
• Without inhibitory synapses, brain would cascade into endless firing
○ Uncontrollable state
○ This is what happens in seizures
• Most short local neurons are inhibitory, so they form a dense web around and between excitatory neurons
• In healthy brain, GABA helps delicate coordination of neurons to signal very specific information
• Neurons are selective but not perfect
○ Inhibitory networks reduce likelihood that neurons
will fire for their non-preferred stimulus
• Doesn’t determine what information is being passed on, but increases selectivity of glutamate signal being passed around brain
• Produced from glutamic acid
○ Same amino acid as Glutamate
• Glutamate is converted into GABA and GABA can be converted back into glutamate
What are the two types fo GABA receptors?
○ GABAA receptors - ion channels
○ GABAB receptors - G-protein-coupled
How common are seizure disorders?
- Relatively common - 400 000 in AUS
* Seizure - sudden excessive activity in neurons (can cause muscle convulsions but not always)
What is the relationship between epilepsy and GABA?
• Epilepsy is a neurological disorder characterised by seizures
○ Believed to be caused by abnormality of GABA neurons and/or in GABA receptors
What are the types of seizures?
○ Generalised seizure
- Widespread and 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 - common after brain
trauma
- Simple
□ Can cause changes in consciousness (altered
sensory, autonomic responses etc) but not
loss of consciousness
- Complex
□ Lead to loss of consciousness
Describe Febrile seizures in kids
○ 3% of children under 5 have seizures associated with high fevers
- Most don’t go on to have epilepsy
○ Genes have been linked to epilepsy
- Those with the gene generally have first spileptic
fit at ~2-3 years old when they get a fever
- Majority of genes identified so far control ion
channels (which control positive and negative
charge of the neuron driving the action potential)
- But most seizures are not genetic, and instead are
due to abnormal brain tissue and require surgical
treatments
○ Vaccination might trigger fever and seizure, but without vaccinations seizures arrive within months anyway
What are the dopamine pathways?
• All of dopamine synthesised in the brain originates either in
○ Substantial Nigra (SN)
- In charge of motor control
○ Ventral Tegmental Area (VTA)
- Motivation and emotion response
- Reward, desire, goal-directed behaviour
Describe Dopamine synthesis
• Starts from basic building block - Tyrosine (amino acid found in food)
• Tyrosine is converted to DOPA
• Dopa is translated into Dopamine
• From there, this compound is broken down from dopamine and turned into noradrenaline
• Possible to boost the synthesis and generation of Dopamine with drug L-DOPA (increase levels of Dopamine in brain)
○ Artificial synthetic version of DOPA
○ Treated exactly the same way by naturally
occurring enzymes
○ Gets converted into Dopamine that is completely
indistinguishable from the naturally occurring
Dopamine
What is Parkinson’s disease and how is it related to Dopamine?
○ Caused by death and break down of dopamine cells in Substantia Nigra
○ Disease initially characterised by motor tremor,
○ Later sympoms include cognitive impairments and dementia
○ Sympoms often include reduced executive function
○ No cure but symptoms can be reduced through drugs and deep brain stimulation
○ Sometimes treatment of the disease can cause impulsivity, hypersexuality, gambling, addictive behaviours
Describe the Reward Prediction Error
• If an unexpected reward occurs DA (dopamine) neurons become more active and release a burst of DA
• Receiving money is a positive experience (and losing it is negative), but it is jus paper
○ We like money because we associate it with items
of activity or value
○ If the gain or loss is unexpected, the feelings
associated with that are more intense
What was the study with monkeys regarding the Reward Prediction Error?
○ Monkeys would be given some juice as a ‘reward’
○ When that happened - at that time there was a large spike in DA
○ Started to give a beep and then the juice reward
○ Found that after many trials (so that the animal was expecting the reward after the beep), the dopamine burst happened straight after beep, not when reward came
○ The dopamine release does not represent the actual signal (being presented with juice), but represents how good something is relative to what was expected
- DA only peaks at the beep, when the actual reward
comes the dopamine levels are no higher than
usual - no addition dopamine released for the
actual reward
○ If the beep is given with no reward
- DA burst at the beep, and a few milliseconds later,
when reward was expected to come, there is a
suppression of neuron activity
□ Reflects that outcome is worse than expected
What are the three types of rewards?
○ Real (eg food and sex)
○ Symbolic (eg money)
○ Virtual (eg points in a game)
• DA is involved in all cases
How does reward help with cognitive effort?
• It is currently unclear why attention and cognitive tasks are ‘effortful’ and why task engagement is aversive (our brains are also very active when we relax or watch TV)
• The feeling of cognitive effort seems particularly linked to working memory and cognitive control
• It is proposed that DA codes both goal reward and effort costs and that the aversive feeling of cognitive effort reflects ‘opportunity cost’
○ If you’re doing one thing, it is at the expense of
doing something else
• Task persistence is justifiable only while progress outpaces accruing costs
• For an animal/human to be successful in life, they need to have balance of task persistence being maintained only while progress towards a positive outcome is being made
• Dopamine is released as you make progress
○ The cost of engaging in a particular thing becomes
greater the more time you spend on that thing
- The longer you stay engaged in a particular
task, the more opportunity lost doing other
things
○ Make sure you have incentives along the way -
increase dopamine, and reduce the likelihood of
disengaging
○ As long as there is a signal of progress/incentive, It
makes sense to keep going
What is the relationship between Gambling and Dopamine?
○ Unpredictability adds to the boost of DA (reward prediction error)
○ If you predictably lose 70% of your money every bet, it would not be addictive
○ If you have unexpected large wins (but still losing an average of 70%), the wins are coded as extremely positive
- Disproportionately good compared to boring losses
Define drug addiction
○ A chronic relapsing disorder which consists of a compulsive pattern f drug seeking and drug taking behaviour
○ Not about the volume of the drug being taken, but the extent to which the behaviour takes place at the expense of other activities and the behaviour persists despite the adverse consequences
What are drugs involving dopamine?
§ Cocaine
§ Amphetamine
§ Methylphenidate (Ritalin)
How is Dopamine involved in cocaine?
□ Blocks reuptake of DA into presynaptic neuron
- When normal DA is released, and you’re taking
cocaine, there’s much more dopamine available in
the synapse - whatever the downstream messages
are that code for positive outcomes, that signal is
much stronger - positivity is much higher
How is dopamine involved in Amphetamines?
□ Ice (pure) and speed (less pure)
□ Reverses uptake transporter actively expelling DA and NA (noradrenaline) out of the neuron
- Prevents reuptake
- Also adds additional dopamine into synapse
- Boosts dopamine signal for postsynaptic neuron
How is dopamine involved in Methylphenidate/ritalin?
□ Dopamine and noradrenaline reuptake inhibitory
□ Treatment for ADHD
□ Has much slower time course than amphetamines
□ Pairing of tablet with change in brain-state don’t get associated with one another - not addictive
How do addictive DA drugs hijack the reward response?
□ Normal response
- When reward is expected no additional dopamine
is released (ie only when the beep occurs, not
when the actual reward comes)
□ Addictive drug response
- Addictive DA drugs are always coded by the brain
as better than expected
◊ DA reward response always follows the cue
◊ DA is released at the cue AND at the actual
reward
Describe animal modes of addiction
○ In animals, if they push on a lever and it releases heroin/opioids, the animal will push the lever until it dies
- Will consistently choose lever over food until it
starves to death
○ If animals press a button and their dopaminergic reward system is electrically stimulated, they will self-administer this electric shock until they die
What is the relationship between addictive drugs and dopamine?
• While there is a strong link to DA function and addiction, some drugs cause addiction with relatively less involvement of DA
○ Possibly depending on opioid system
• DA might be more important in the behaviour/habit and cognitive control aspects than the pleasant feeling
What are problems with addiction and free-will?
• 1st problem
○ Drugs initiate a ‘wanting’ in addicted people
- Leads to drug urges or cravings
• 2nd problem
○ Cognitive (top-down) control is reduced by
impaired function of the prefrontal cortex (PFC)
caused by excessive dopamine
- Failure of top-down control and rational part of
the brain - not failure of thought porcesses,
but failure of logical brain having control over
behaviours
- Imagining studies show PFC abnormalities
• Final result -addictive behaviour
○ Failures of top-down control would contribute to
loss of control over the urge to take drugs
Describe addiction beyond drugs
- Cases of addiction exist for most things that are rewarding (symbolic, real, and virtual)
- More individual differences in susceptibility compared to drug addiction
