PSY2003 S2 W7 ADHD II

Question 1

What are previous theories of ADHD?

Answer 1

‘Classical’ theories:

Many psychiatric and neurological disorders are associated with frontal cortex dysfunction (from schizophrenia to Parkinson’s disease)

Newer drugs (atomoxetine, guanfacine) affect noradrenaline not dopamine

Question 2

What is frontline treatment for previous theories?

Answer 2

Frontline treatments: DL-amphetamine or methylphenidate
Both of which are Class B drugs according to the Misuse of Drugs Act (1971) – i.e. they have significant abuse potential.
And we’re giving them to kids. We need a new approach.

Question 3

What is a novel approach for ADHD?

Answer 3

Several presentations (inattentive, hyperactive/impulsive, combined).

May not be productive to look for single cause’ or single therapeutically relevant action of drugs.

Since 1940s and 50s: distractibility has been considered a core symptom of ADHD.
‘Is often easily distracted by extraneous stimuli’ (DSM 5)

Useful focus: substrate mediating distractibility is well known

Question 4

What part of the brain is linked to destructibility?

Answer 4

Superior Colliculus (SC)
Distractibility intimately linked with the superior colliculus.
Most important subcortical visual system.
Highly conserved [eye movements]
Collicular lesions decrease distractibility [rat, cat, monkey]
Retina projects to the superior colliculus.

Question 5

What did Goodale and Murison 1975 find about destructibility and SC?

Answer 5

1. Rat ran towards door, opened door, got reward.
2. As the animal ran there was a flashing light, which was unexpected.

Take away Superior colliculus aka destructibility = The rat doesn’t even notice the light and runs right through the room. It is not distracted.

Normal Animals = Animal goes towards light in first trial, second trail freezes (fear) for a brief moment and gets rewards. Last trial so scared they don’t even come into the room.

Question 6

What did Gaymard et al. 2003 find?

Answer 6

Still appears to be functional in humans.
51 yr old woman with a lesion affecting the projection from the cortex to the SC (prefronto-tectal tract) on the left-hand side.
Expectation: she would face problems in the right visual field but not her left visual field

Question 7

What paradigm investigated destructibility?

Answer 7

Distractibility was investigated by the anti-saccade paradigm.

Move eye in the opposite direction to the blob.

She could not stop herself from looking at the blob, that stimulus was pulling her attentions, she was distracted by it: right visual field: affected field.

Her performance on the left-visual field is similar to the control.

Question 8

What is new theory for ADHD and what sort of evidence would you need?

Answer 8

Distractibility in ADHD reflects a hyper-responsive colliculus

Distractibility in ADHD reflects a hyper-responsive colliculus? What sort of evidence would you need?

At least 4 types:
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?

Question 9

Hyper-responsiveness in an animal model?

Answer 9

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.
Put a electrodes in the colliculus and observe the firing of the colliculus.

Question 10

Clements et al. 2013

Hyper-responsiveness in an animal model

Answer 10

Firing light in animal eye: shows response in sensory structure. Genetically hypotensive (GH) (ADHD) rat compared to control (right)

Question 11

Is there a ‘hot line’ to the brain’s interrupt system?

Answer 11

Neuronal tracer, chemical is injected locally in the area of cell bodies. Cell bodies take it up, and transport it down the axon to the labelled zone. It shows where the labelled zone is located.

Coizet et al. 2009: STN involved in Parkinson’s.

Question 12

Any collicular impairments in ADHD?

Answer 12

Panzgiotidi et al. (unpublished)
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)
Participants were not required to have a ADHD diagnosis but had to complete ASRS to see where participants sat on the spectrum.

Question 13

What is colliculus involved in what?

Answer 13

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

Question 14

What did Panagiotidi et al. 2017 find?

Answer 14

Simultaneity Judgement Task:

Subjects presented with multisensory stimuli (auditory beep and a visual pattern at a range of stimulus onset asynchronies).

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 Hi and Lo ADHD (ASRS) groups

Results:
High ADHD group less likely to say the two stimuli were combined.
High levels of ADHD trait were perceiving environment as being lots of separate stimuli within the environment.

Question 15

Do ADHD treatments affect the colliculus?

Answer 15

Gowan et al. 2008
Give a dose of amphetamine – gradually higher and higher doses. SC goes from being really big to being nothing at all. Treatment has an useful in treating ADHD effects SC.

Question 16

What is the superior colliculus involved with?

Answer 16

involved in distractibility in animals and humans

Question 17

What do animal models of ADHD exhibit ?

Answer 17

Animal models of ADHD exhibit visual hyper-responsiveness

Question 18

How is multisensory integration link to ADHD?

Answer 18

Multisensory integration in people with high levels of ADHD-like traits is suggestive of collicular hyper-responsiveness

Question 19

What is able to turn off or turn down te colliculus?

Answer 19

Amphetamine is able to ‘turn off’ or ‘turn down’ the colliculus

Question 20

What has a hot line to the brain’s interrupt system?

Answer 20

The colliculus

Question 21

Does colliculus link to dopamine?

Answer 21

Yes. Colliculus not only mediates distractibility but it also regulates dopamine neurons.

Question 22

What is the tectonigral projection?

Answer 22

A direct pathway from the deep layers of the colliculus to the ventral midbrain
Terminates on dopamine and non-dopamine neurons….

Colliculus not only mediates distractibility but it also regulates dopamine neurons (Comoli et al. 2003)

Question 23

What did Dommett et al. 2005 investigate?

Answer 23

Primary source of visual input to dopamine neurons.

Single unit recording of dopamine neurons
Effect on responses of dopamine neurons to visual stimulation.

Awakened deep layers of the colliculus with bicuculline

Flashlight before you put chemical, then continue to flash the light into the animal’s eye.

Only get a response from the flashing light when w/ chemical.

Question 24

What are the Electron microscopy results?

Answer 24

Synapse (arrow) between labelled bouton [b] and TH+ dendrite….
When it is activity, it makes this cell more likely to release an action potential.

Question 25

What is the visual activation of dopamine neurons?

Answer 25

Pre-drug baseline: No light response After bicuculline: colliculus starts to see light So do dopamine neurons (excitatory 17/35) Inhibitory: 13/35 Each dot is a trial, flashing light trail to trail. Putting them all together you get the histogram.

Question 26

What was the effect on dopamine release in the forebrain?

Answer 26

Visual activation of dopamine neurons via the input from the colliculus leads to dopamine release in the forebrain. Can measure dopamine release by amperometry. 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 No electrochemical response to light without collicular bicuculline. Bicuculline into colliculus induced light response Amplitude and duration of this response increased by nomifensine [selective dopamine re-uptake inhibitor] Level of dopamine present in the forebrain when you flash a light in the eye. Green is flash of light, before you get very light, put you get spikes of dopamine release after the release of the colliculus.

Question 27

What is the colliculus involved with?

Answer 27

the colliculus is involved in the regulation of dopamine neurons. May explain the dopamine dysfunction in ADHD. However, ADHD has also been thought to arise from a dysfunction of the cerebral cortex.

Question 28

Where does the colliculus receive from?

Answer 28

from widespread areas of the cortex. Receives a big input from the whole cortex. Tract tracing . Every area of the cortex sends inputs to the colliculus. Leiriche et al. Frontal cortex – lots of cells. Projects heavily into the colliculus. Strong connection between superior colliculus and the cortex.

Question 29

What does the cortex transmit?

Answer 29

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. Light flash used as control. Bertram et al. 2014 Barrel cortex stimulation

Question 30

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

Answer 30

1. Frontal cortex The colliculus receives inputs from widespread areas of the cerebral cortex, including the frontal cortex Primary dysfunction? 2. Dopamine The colliculus sends projection to the dopamine neurons in the midbrain Colliculus involved in sensory regulation of dopamine neurons

Question 31

What are the implication?

Answer 31

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

Question 32

Is the Barrel cortex and dopamine neurons linked?

Answer 32

What is happening in the superior colliclus: light flashing nothing is happening in the deep layers of the colliculus. Superficial layers are active. Barrel cortex stimulation: very little happening. Tiny bit of activation of the superior collicluus when you activate the cortical input of the Barrel cortex. Activating the cortex with the colliclulus asleep doesn't change the activity in the domain system different to when you wake the colliculus up: Massive response in colliclus with light flash and with the stimulation fo the barrel cortex. And now the dopamine neurons are starting to respond to the cotcial stimulation (can be an increase or a decrease in aactivity) Littlel circuit: link the cortex to the dopamine neurons viea the superior colliclus, all involved in ADHD. Superior colliculus adds them.

Question 33

What did Overton & Clements 2009 find? | Reading

Answer 33

We suggest that in ADHD the colliculus may be hyper-responsive to sensory inputs, leading to the core symptom of increased distractibility. Reward processing identified in ADHD could reflect a collicular dysfunction, given the role played by the SC in the regulation of the dopamine systems. ADHD patients have a general problem inhibiting eye movements (saccades), which involve the SC. Saccadic deficits in ADHD include defects in the production of anti-saccades and express saccades, which are associated with the colliculus. Covert shifts in attention, argued to involve the SC, are also impaired in ADHD.