L7 - Dopamine and Deep Brain Stimulation

Question 1

Where is dopamine found?

Answer 1

• brain
• PNS
• kidneys
• pancreas
• digestive system

Question 2

What is dopamine?

Answer 2

A neurotransmitter which plays a key role in movement, cognition, pleasure and motivation.

Question 3

Stimulation of the reward system at the same time as a behaviour does what?

Answer 3

Reinforces the behaviour - i.e. drives addiction to abusive drugs, or chocolate, etc.

Question 4

Describe the pattern of dopamine in PD.

Answer 4

Full level of dopamine at the pre-manifest stage, lower level during the prodromal stage and extremely low during the fully symptomatic, manifest stage.

Question 5

What does the nigrostriatal pathway connect?

Answer 5

Connects the substantia nigra pars compacta (SNpc) to the dorsal striatum (caudate nucleus and putamen)

Question 6

What is the nigrostriatal pathway associated with?

Answer 6

Motor control

Question 7

Why are dopaminergic neurons in the substantia nigra named ‘black body’?

Answer 7

The neurons there are darkly pigmented with melanin.

Question 8

What does PD result from?

Answer 8

The selective loss of striatal neurons in the direct pathway. The balance between the pathways therefore becomes tipped in favour of the indirect pathway.

Results in loss of movement.

Question 9

What does HD result from?

Answer 9

Selective loss of striatal neurons in the indirect pathway. The balance between the pathways therefore becomes tipped in favour of the direct pathway.

Results in excessive movement.

Question 10

What does hemiballismus result from?

Answer 10

Lesions of the subthalamic nucleus itself, usually resulting from strokes.

Excessive movement.

Question 11

What are the two cardinal symptoms of PD present in every observed patient? What is the 3rd cardinal symptom, where occasionally it is not present?

Answer 11

Bradykinesia and rigidity

Often resting tremor (4-6Hz), but some patients do not have a tremor at all.

Question 12

What are some of the supportive prospective criteria for the definite diagnosis of PD?

Answer 12

3 or more of:

• unilateral onset
• rest tremor present
• progressive
• excellent response (70-100%) to levodopa
• severe levodopa-induced chorea
• clinical course of 10 years or more

Question 13

What does GPi stand for?

Answer 13

Globus palliadus internal

Question 14

What does SNr stand for?

Answer 14

Substantia nigra

Question 15

What does GPe stand for?

Answer 15

Globus pallidus external

Question 16

What does STN stand for?

Answer 16

Subthalamic nucleus

Question 17

Describe basal ganglia motor circuits in normal states. Compare the difference in PD states

Answer 17

Direct pathway:

• motor cortex excites putamen.
• putamen has greater inhibitory effect on GPi/SNr
• GPi/SNr exerts less inhibitory effect (so has an overall excitatory effect) on thalamus
• Increased excitation of the motor cortex by the thalamus (more movement)

Indirect:

• motor cortex excites putamen
• putamen has greater inhibitory effect on GPe
• GPe has less inhibitory effect on the STN
• STN has greater excitatory effect on GPi/SNr
• GPi/SNr has greater inhibitory effect on the thalamus
• less excitation of the motor cortex by the thalamus (less movement)

In PD, there is less excitement of the putamen by the motor cortex, leading to a more overactive GPi and therefore less excitation of the motor cortex by the thalamus.

Question 18

What would occur in a pallidotomy, and what would this help?

Answer 18

Neurosurgical procedure where the GPi is burned/lesioned.

GPi is an output structure of the indirect pathway which, in PD, has an excessively inhibitory effect on the thalamus. Therefore the thalamus increases in it’s excitation of the motor cortex, hypothetically improving symptoms.

Question 19

What are the side effects of pallidotomies?

Answer 19

• Bilateral pallidotomies cause speech deficits, and even used to cause mutism.
• Unilateral can be effective at reducing PD, but can impair language learning if performed on the dominant hemisphere, or visuospatial processing if performed on the non-dominant hemisphere (primarily due to the wrong location being lesioned).

Question 20

Why can’t dopamine be consumed in diet?

Answer 20

It cannot pass the blood-brain barrier

Question 21

Which foods can increase the level of dopamine made?

Answer 21

Foods and fruits high in amino acid
Foods high in folic acid
Apples (high in antioxidants)
Watermelon

Question 22

What is the supposed cause of dyskinesia’s seen after long periods of L-Dopa medication?

Answer 22

Receptors for dopamine in the striatum become more and more sensitive. Any dopamine flips it into excessive movement.

Question 23

What is the alternative function of dopamine that differentiates slightly depending on whether patients are on or off medication?

Answer 23

Patients are better at learning negative outcomes than they are at learning from positive outcomes, off medication.

When on medication, patients are better at learning following reward compared to punishment.

Clear that L-dopa treatment modulates some form of efficiency of the direct and indirect pathways, which are differentially influenced by reward and punishment.

Question 24

What does increased and decreased activity in basal ganglia circuit loops lead to?

Answer 24

Increased leads to reward

Decreased leads to aversion (negative approach behaviour)

Question 25

Why does apathy often co-exist with PD?

Answer 25

The dysfunctional BG/dopamine pathways associated with movement and motor control overlap with pathways associated with reward based learning and motivation.

Question 26

What does LFP stand for and what is it?

Answer 26

Local field potentials

Activity that you record from a population of neurons around an electrode in the brain.

Question 27

What is the difference in activity picked up by LFP between patients on and off levodopa treatment? What does this mean?

Answer 27

Off medication, LFPs are dominated by beta oscillations (20Hz).

On medication, beta activity is suppressed, and oscillations are more predominantly in the gamma band (75Hz max).

Therefore, it may be the pattern of activity, as well as the amount, that defines or is part of the pathophysiology of Parkinson’s.

Question 28

What does DBS stand for and what is it?

Answer 28

Deep brain stimulation

Surgical procedure used to treat a variety of disabling neurological symptoms - most commonly the symptoms of PD such as tremor, rigidity, stiffness, slowed movement and walking problems.

It works by blocking electrical signals from targeted areas in the brain.

Question 29

At present, who is DBS used for?

Answer 29

Only for patients whose symptoms cannot be adequately controlled with medications.

Question 30

How does DBS work practically?

Answer 30

A lead/electrode is inserted through a small opening in the skull and implanted in the brain. The tip is positioned within the target brain area.

The neurostimulator/battery pack is typically implanted under the skin near the collarbone/chest to enable user control.

Question 31

How are skull openings made for a DBS procedure?

Answer 31

1. Stereotactic frame (keeps head in place) attached to head.
2. Surgeon uses MRI/CT scans to plan trajectory of electrode
3. Two burr holes (hole in the skull) are made through the skull while the patient is under local anesthetic (to check for unpleasant side effects before electrode is in place)
4. recording electrode is inserted to a target & test recordings are made
5. recording electrode is replaced with the permanent electrode
6. PD is progressive and symptoms worsen, so patients return to neurologist to adjust stimulation settings when required.

Question 32

What was the early hypothesis for why DBS worked?

Answer 32

High frequency stimulation lead to a reversible lesion as the neurons couldn’t sustain the high activity and so stopped responding, reducing the output of that area.

Question 33

What is the later hypothesis for how DBS works?

Answer 33

DBS entrains neuronal firing in complex patterns and reduces the time spent in burst firing immediately after the end of stimulation.

Question 34

What are bad oscillations in PD?

Answer 34

Recordings in humans show a tendency for basal ganglia neurons to synchronise their oscillatory activity. Most important of which is activity in the beta band (13-30Hz), in which excessive synchronisation is thought to block motor processing, contributing to akinesia’s in PD.

Question 35

What is the idea of coherence in PD?

Answer 35

Dopamine depletion increases the coherence of beta oscillations in the cerebral cortex and STN.

When patients are not on DBS, there is high coherence between motor cortex and muscles.

When DBS is switched on, the coherence drops, meaning you get independence of the muscles from the motor cortex, uncoupling the link between them.

Suggests that coupling between the two areas leads to muscles copying/displaying the malfunctioning signals from the BG.

Question 36

What does PPM stand for and what is it important for?

Answer 36

Pedunculopontine nucleus, very important for walking and gait.