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L2 Neuro/Clinical S2 > ADHD 2 > Flashcards

ADHD 2 Flashcards

1
Q

previous theories in ADHD

A
  • although there are abundant ‘theories’ of what underlies ADHD, there is no consensus
  • classical theories:
    1. many psychiatric and neurological disorders are associated with frontal cortex dysfunction (from schizophrenia to Parkinson’s disease)
    2. newer drugs (atomoxetine, guanfacine) affect noradrenaline not dopamine
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2
Q

frontline treatments for ADHD

A
  • DL-amphetamine or methylphenidate
  • both of which are Class B drugs
    –> i.e. .e. they have significant abuse potential
    –> we give these to kids
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3
Q

new approach to ADHD

A
  • 3 presentations:
    1. inattentive
    2. hyperactive/impulsive
    3. combined
  • may not be productive to look for single ‘cause’ or single therapeutically relevant action of drugs
  • ‘distractibility’
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4
Q

distractibility

A
  • since the work of A.A Strauss in the 1940s and 50s, distractibility has been considered a core symptom of ADHD
  • ‘is often easily distracted by extraneous stimuli’ (DSM 5)
  • linked to inattentive side of ADHD
  • useful focus: substrate mediating distractibility is well known
    –> brain area / part of brain is linked to distractibility
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5
Q

superior colliculus and and distractibility

A
  • areas of our brain are known to pull our attention
    –> can be good (i.e. food) or bad (i.e. predators)
  • distractibility intimately linked with the superior colliculus
    –> sits in midbrain (back surface, the dorsal)
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6
Q

general function of the superior colliculus

A
  • most important subcortical part of the visual system
  • lots of visual input goes to the colliculus
  • highly conserved
    –> in humans, one of the main functions is to control eye movements
  • collicular lesions decrease distractibility
    –> in rats, cats and monkey’s
    –> without superior colliculus, animals get less distracted
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7
Q

Goodale and Murison (1975) - superior colliculus

A
  • animals have their superior colliculus removed on both sides or its intact
  • animals trained to run across arena and run through a door
  • door is illuminated
  • if they run through the right door they get rewarded
  • sometimes a noise was present, sometimes a flashing light was present on the side of the arena
    –> act as distractors
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8
Q

predicted results / actual results of Goodale and Murison (1975)

A
  • those with an intact superior colliculus (normal animals) will attend to it
    –> they get distracted
    –> may freeze, or run over to light to investigate
  • those with their superior colliculus removed, do not get distracted
    –> they ignore the lights and sounds
    –> run straight across the arena to the doors
  • important is the rats aren’t blind
    –> they can see light, just aren’t distracted
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9
Q

Gaymard et al. (2003) - lesion in superior colliculus

A
  • lesions to superior colliculus can still be functional in humans
  • 51 yr old woman with a lesion affecting the projection from the cortex to the superior colliculus (prefronto-tectal tract) on the left hand side
  • more distractible on that side of the visual field (right visual field)
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10
Q

retinas, visual fields and superior colliculus

A
  • left hand side of the retina in BOTH eyes goes to left superior colliculus
  • right hand side of the retina in BOTH eyes goes to right superior colliculus
  • left visual field goes to right superior colliculus
  • right visual field goes to left superior colliculus
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11
Q

the anti-saccade paradigm

A
  • investigate distractibility
  • Ps fixate on spot in the middle of the visual field
  • target is presented (left or right)
  • have to move eyes in opposite direction to the prime
  • those with damage to left colliculus, struggled when prime was in RIGHT VISUAL FIELD
    –> got distracted
  • those with damage to left colliculus and prime was in LEFT VISUAL FIELD, did better and wasn’t distracted
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12
Q

ADHD and superior colliculus (the new theory to ADHD)

A
  • distractibility in ADHD can be explained by hyper response in the colliculus
    –> hyper responsive colliculus reflects distractibility in ADHD
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13
Q

evidence needed to support hyper responsiveness of superior colliculus

A
  • at least 4 types of evidence:
    1. Hyper-responsiveness in an animal model?
    2. Is there a ‘hot line’ to the brain’s interrupt system?
    3. Any collicular impairments in ADHD?
    4. Do ADHD treatments affect the colliculus?
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14
Q

how long have vertebrate brains had the superior colliculus?

A

500 million years

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15
Q

hyper-responsiveness in an animal model

A
  • brain cells encode information by ‘firing’
  • allows a message to get sent from one structure and delivered to another
  • cells in sensory structures fire when an appropriate sensory stimulus is encountered
  • fire more when something is seen and attention is being paid to it
  • you can measure action potentials normally in animals
  • then add flashes (stimuli) and see how brain activity changes
  • put this data on a graph
  • animal model of ADHD has greater response to stimuli than control rat
    –> more response in the colliculus
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16
Q

hot line to the brain’s interrupt system

A
  • use tract system
  • anatomical technique to investigate connection and interaction between brain areas
    –> inject chemical into cell body of one cell
    –> this travels around the body and into projectors of other cells
  • acts as a tracker
  • can inject chemical into superior colliculus and see where this tracker goes (where is the label located?)
  • sub-thalamic nucleus is very important in the brain’s interrupt system
17
Q

sub-thalamic nucleus

A
  • involved in stopping what you’re doing now
  • interrupts actions
  • over activity in the STN keeps brain in an ‘off mode’
    –> i.e. those with Parkinson’s fail to move
18
Q

collicular impairments in ADHD

A
  • working on a clinical (children with ADHD) population in the UK is difficult
  • fortunately ADHD is present in adults
  • ADHD is a continuum disorder (ASRS)
    –> adult ADHD rating scale
    –> based entirely on sympto-patterns in the DSM
  • self-report way of reporting ADHD symptoms
  • those with lots of the symptoms can be seen to be ‘highly likely to have ADHD’ but have no diagnosis
  • can have low levels of diagnosis, but high levels of people with those traits
19
Q

multi sensory integration in the colliculus

A
  • Colliculus is involved in multi-sensory integration
    –> visual, auditory and somatosensory inputs converge onto a common pool of neurons
    –> multisensory neurons show enhanced responses to multisensory stimuli, if the stimuli are close together in space and time
20
Q

Panagiotidi et al. (2017)
- Simultaneity Judgement Task

A
  • subjects presented with multisensory stimuli (auditory beep and a visual pattern at a range of stimulus onset asynchronies)
    –> either together
    –> or one before the other
  • subjects asked to determine if auditory and visual stimuli occur at same time or different times
  • main measure = proportion of trials stimuli are reported as simultaneous
  • compared High and Low ADHD (ASRS) groups
21
Q

Panagiotidi et al. (2017) - results

A
  • the bigger the gap between auditory and visual stimuli, the less likely people are to say its simultaneous
  • smaller the gap, more likely to say they were simultaneous
  • lower chances of those with high ADHD saying things were simultaneous if they weren’t
    –> see the world as separate, distinct entities and separate modalities
  • more to process and so could be more distracting
22
Q

ADHD treatments and the colliculus

A
  • light shone in the rat’s eye
    –> measure colliculus response
  • amphetamine given to the rat
    –> very effective treatment in ADHD
  • more amphetamine, less response in the colliculus
  • turns it down
  • less response in colliculus with more amphetamine
23
Q

summary

A
  • superior colliculus is involved in distractibility in animals and humans
  • animal models of ADHD exhibit visual hyper-responsiveness
  • the colliculus has a hot line to the brain’s interrupt system
  • multisensory integration in people with high levels of ADHD-like traits is suggestive of collicular hyper-responsiveness
  • Amphetamine is able to ‘turn off’ or ‘turn down’ the colliculus
    –> would bias system so that distractions only occur to more salient stimuli
24
Q

colliculus and dopamine

A
  • colliculus not only mediates distractibility but it also regulates 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
25
Q

colliculus transmits visual info to dopamine neurons

A
  • colliculus is primary source of visual input to dopamine neurons
    –> dopamine neurons are regulated by sensory neurons
  • single unit recording of dopamine neurons
  • effect on responses of dopamine neurons to visual stimulation
    –> when light is flashed in eyes, what happens?
  • awakened deep layers of the colliculus with bicuculline
    –> wakes up the inhibited colliculus (which occurs due to antiesthetic)
26
Q

visual activation of dopamine neurons

A
  • pre-drug baseline: no light response
  • after bicuculline: colliculus starts to ‘see’ light
  • so do dopamine neurons
    –> excitatory = 17/35
    –> inhibitory = 13/35
27
Q

effect on dopamine release in the forebrain

A
  • visual activation of dopamine neurons via the input from the colliculus leads to dopamine release in the forebrain
  • can measure dopamine release by amperometry
  • no electrochemical response to light without collicular bicuculline
  • bicuculline into colliculus induced light response
  • amplitude and duration of this response increased by nomi-fensine (an SSRI)
28
Q

amperometry

A
  • a constant potential (voltage) is applied to the working electrode
  • will oxidise dopamine at the tip, which then creates a small current that can be measured
29
Q

hotspots for methylphenidate in England

A
  • Northwest
  • Southeast
30
Q

colliculus and frontal cortex dysfunction

A
  • colliculus receives signals from widespread areas of the cortex
    –> many areas
    –> including the frontal cortex
  • retrograde tracing = whereabouts are the cell bodies
    –> travels from back to front (end to start)
  • anterograde tracing = whereabouts are the terminal
    –> tracker travels from front to back (start to end)
31
Q

interaction between cortex, dopamine neurons and colliculus

A
  • cortex transmits sensory information to dopamine neurons via the colliculus
  • effects of local chemical manipulation of colliculus on responses of dopamine neurons to barrel cortex stimulation
  • stimulate cortex
  • record dopamine neurons and see the effects
  • wake up the colliculus, stimulate the cortex (barrel cortex) and see the effects no
  • use light flashes as control (no barrel cortex stimulation)
32
Q

effects of barrel cortex stimulation

A
  • dopamine neurons have no change between barrel cortex stimulation and light flash stimulation
    –> colliculus is inhibited (asleep)
  • when colliculus is awake:
    –> big changes
    –> when barrel cortex is stimulated, dopamine neurons are also activated
  • functional connection between colliculus and cortex
    –> they stimulate the dopamine neurons
33
Q

How does the collicular theory of ADHD sit alongside the classical theories?

A
  1. frontal cortex
    –> the colliculus receives inputs from widespread areas of the cerebral cortex, including the frontal cortex
  2. Dopamine
    —> the colliculus sends projection to the dopamine neurons in the midbrain
    –> colliculus involved in sensory regulation of dopamine neurons
34
Q

implications of the new theories & classical theories of ADHD

A
  • step closer to understanding the underlying neural dysfunction in ADHD
  • can now think of screening non-addictive drugs for their ability to depress collicular function
  • opens up the possibility of drug companies developing new drugs that have a collicular target

L2 Neuro/Clinical S2 (9 decks)

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