ADHD 2 Flashcards
flaw with classical theories of ADHD - frontal cortex and dopamine
frontal cortex:
many psychiatric and neurological disorders are associated with frontal cortex dysfunction (from schizophrenia to Parkinson’s disease) - not just ADHD
dopamine:
new drugs (atomoxetine, guanfacine) affect noradrenaline NOT dopamine
ADHD drugs - act on noradrenaline
atomoxetine
guanfacine
2 classical theories of ADHD and 1 novel theory
classical:
- frontal cortex dysfunction
- dopamine
novel:
- collicular (sensory) hyper-responsiveness
frontline drug treatments of ADHD
DL-amphetamine and methylphenidate
these are both class B drugs (Misuse of Drugs Act, 1971) –> therefore have significant abuse potential
therefore an issue that we give these to kids!
novel approach to ADHD treatment
several presentations - inattentive, hyperactive/impulsive, combined
may not be productive to look for a single cause or single therapeutic drug action
instead look at specific symptoms not the overall disorder
novel approach to ADHD - symptom of distractability
Strauss (1940s/50s) - distractibility as a core symptom of ADHD
DSM-V = “is often easily distracted by extraneous stimuli”
useful focus = neural substrate mediating distractibility is well known (not just in extremes of ADHD, just a general system)
distractibility neural substrates
intimately linked with superior colliculus
primitive system - animal response to things around them, both good and bad - pull attention away to other things
can be distracted to important or unnecessary things
superior colliculus = subcortical, dorsal (top/back part) of the brain stem (images on ppt if you want)
idea that SC still appears to be functional in humans as a distractibility circuit
superior colliculus and distractibility circuits
SC is part of the visual system
important subcortical visual system
retina projects to the SC
in rats, SC is the biggest area of visual input (not in primates as much)
highly conserved - across many species
humans = SC controls eye movements - idea that the eyes can be moved to new info and pull attention away to it
superior colliculus - collicular lesion and distractibility in rats
collicular lesions in rats decrease distractibility
Goodale and Murison (1975)
- lesion SC in rats
- rats are trained to run to a set of doors in an arena - one is illuminated - to get a reward (brightness discrimination task)
- after training, a distraction is added (flashing light or noise)
- normal SC = attend to distraction, pause, attend to it, or freeze and don’t cross arena (fear)
- with a SC lesion = don’t respond to it at all
– go straight across to get their reward
Gaymard et al (2003) - case study lesion to SC
lesion in a 51 year old woman which affects the projection from the cortex to the SC (prefronto-tectal tract) on the left hand side
at the inferior colliculus - lost her inhibitory control
SC is often controlled by higher centres - but this lesion interrupts these pathways
she became more distractable on the right visual field (not right eye, right side of both eyes) –> as issue was on the left of the brain
–> left visual field inputs to the right SC
–> right visual field inputs to the left SC
used an anti-saccade paradigm to test:
- patient fixates on a spot in the middle of a visual field
- then a target appears - don’t look at it and instead need to look the opposite direction to the target (anti-saccade)
- target either in left or right visual field
results:
- measured % errors (error = look at target)
- target in right visual field = lots of errors
- target in left visual field = patient did very similar to control
conclusion:
- cannot resist looking at presented target on the right –> left lesion = distractable (hyperresponsive to target)
- taking away inhibitory input of colliculus = more responsive = increased distractibility ( look at target not away from it)
- seemed almost unable to not look at it when presented on the right
- presented left = able to move eyes and look to the right –> able to not attend to it
distractibility in ADHD and a hyper-responsive colliculus
idea that distractibility circuits in the brain are through the SC
increased activity = increased distractibility (less inhibitory control)
how long have vertibrate brains had a SC
500 million years
4 types of evidence needed for hyper-responsive colliculus in ADHD
hyper-responsiveness in an animal model
is there a “hot line” to the brains interrupt system:
- need to stop the one activity to be distracted by another
- continual interruption of what you’re doing to do something else
any collicular impairments in ADHD
do ADHD treatments effect the colliculus
hyper-responsiveness of SC in rats - light flash study
study of action potentials in SC in rats when lights of different brightness is flashed
brighter light = more action potentials fired
genetically hypotensive rat = used as an animal model of ADHD
- shows higher responsiveness to all levels of light brightness than a control rat
peak amplitude = higher at all light levels in GH rats than control
study of the link between distractibility and interrupt systems
use tract tracing:
- anatomical method to look for connections in rat brains
- anterograde tracing from SC cell body down axons using chemical labelling
- leave a few weeks and study post mortem - where the label ends up
results = found in STN (subthalamic nucleus)
STN = part of the interrupt system - stops you doing what you are currently doing
STN
subthalamic nucleus
interrupt system - stops you doing what you’re doing right now
e.g. Parkinsons = high activity in STN which “jams” brain in an “off” position so they find it hard to move
ADHD as a continuum disorder - study in adults
difficult to work with kids (ethics) but adults can have ADHD too
ADHD is a continuum disorder (ASRS - adult ADHD rating scale - based on DSM) - find the results in a population fall on a bell curve (normal distribution)
ASRS is not a diagnostic tool - idea that lots of people have high traits of ADHD but no diagnosis
continuum disorder = symptoms grade into normal population (everyone is distractible, some more tho) –> therefore not categorical - where is the line to distinguish between people
can study a subclinical population - high traits but no ADHD diagnosis
colliculus function - layers, responses
SC is a visual area
BUT also is involved in multisensory integration
SC has 7 layers
shallower layers are purely visual
deeper layers are multisensory - visual, auditory, and somatosensory converge onto a common pool of neurons here
supra-additive response (mixed modalities gives bigger response than just adding individual responses together) - enhanced response to multisensory if they are close together in space and time
studying collicular impairments in ADHD - simultaneous judgement
Panagiotidi et al (2017)
simultaneity judgement task:
- participants given multisensory stimuli (auditory beep and visual pattern)
- at a range of stimulus onset asynchronies (SOAs)
- determine if auditory or visual were at same or different times
measure = proportion of trials that are reported as simultaneous
compared high and low ADHD (ASRS) groups
results:
- bell curve shape - both ends are less likely to be thought to have been presented together as the SOA is larger
- 0s is the middle of the curve (simultaneous presentation)
- in high ADHD group, always perceive as ore distinct stimuli - less viewed as simultaneous –> could this be the cause of distraction
- low ADHD - perceive much more as simultaneous stimuli
- low ADHD curve appears to be ontop of high ADHD curve
view as more separate = could be more distracting –> less cohesive
effect of amphetamines on colliculus
amphetamine used on rats
reduces superior colliculus’ response to visual stimuli with higher doses
anatomical link between colliculus and and dopamine
pathway and how it has been seen
colliculus mediates distractibility and dopamine neurons
The tectonigral projection:
- a direct pathway from the deep layers of the colliculus to the ventral midbrain
- terminates on dopamine and non-dopamine neurons
electron microscopy has shown this - terminal of axon from colliculus with dopamine neuron
bouton and dendrite together
link between colliculus and dopamine - light flash study methods
dopamine and reward - this is really linked to sensory system
colliculus is a primary source of visual input to dopamine neurons
study:
- anaesthetise a rat
- flash a light in its eye - with colliculus asleep or when it is awake
- single unit recording of dopamine neurons
- look at effect on responses of dopamine neurons to visual stimulation
awakened deep layers of the colliculus with bicuculline (GABA antagonist - prevents neurotransmitter from getting access to receptor)
light flash study results - visual activation of dopamine neurons
record cells in colliculus (multi-unit) and dopamine cell (single cell)
flash a light and measure response:
pre-drug baseline = no light response in deep layers (superficial layers of colliculus always respond - visual only)
after bicuculline = colliculus (deep layers) starts to “see” light - responds to light stimuli
dopamine neurons also respond to the light
how to measure dopamine levels in very specific brain areas
can use electrodes (amperometry) in the forebrain to measure dopamine levels in a very small area
by establishing a small voltage which changes chemical composition of dopamine through oxidation
results in dopamine releasing electrons which is measured by electrode
visual activation of dopamine neurons via the input from the colliculus leads to dopamine release in the forebrain
light flash study - effect of dopamine release in the forebrain
no electrochemical response to light without collicular bicuculline - wake up colliculus
nomifensine:
- selective DA re-uptake inhibitor
- increases amplitude and duration of light response
what this shows:
- colliculus can change level of activity in dopamine system
- connectivity chain is very important into the forebrain
- indication that dopamine theory and colliculus hyper-responsiveness MAY be related
where are hotspots for prescribing methylphenidate in england
northwest and southeast
retrograde vs anterograde tracing
anterograde tracing = cell body to terminal - direction of action potential
retrograde tracing = to find cells of origin = opposite to action potential
cerebral cortex dysfunction and ADHD - how they find the link to colliculus
use retrograde tracing - inject into SC to find cells of origin which project into deeper layers of SC (link to dopamine)
want to find origins from cortex - cortical projections
found they come from almost all areas of cortex - including frontal
all areas of frontal cortex in rats project into SC
can the cortex cause change in DA neurons via superior colliculus
barrel cortex study in rats - method
would show a chain of command through these ( cortex changes DA via SC)
effects of local chemical manipulation of colliculus (to “wake it up” on responses of dopamine neurons to barrel cortex stimulation
method:
- anesthetise a rat
- stimulate the sonatosensory cortex and see if the DA neurons change activity
- then wake the SC and see if that changes the effect of cortical stimulation on DA
- light flash used as control (seen in previous studies)
results:
when SC is asleep:
- SC = no reaction to light flash and very small reaction to barrel cortex stimulation
- DA neuron = no reaction to flash or stimulation
when SC is awake:
- SC = large increase in activity from light flash and barrel cortex stimulation
- DA neuron = massive increase in DA from light flash, barrel cortex stimulation also increases DA
conclusions:
- functional from cortex to DA via colliculus
- the same can happen in reverse e.g. stimulation leads to decrease in DA
