L23 - The Basal Ganglia (Movement)

Question 1

What are the different parts of the basal ganglia and where are they in the brain?

Answer 1

• Caudate - known as tail
• Globus pallidus is hidden behind putamen and caudate nucleus

Question 2

How has our understanding of the role of the basal ganglia in movement come about?

Answer 2

• Early understanding of BG based on 2 “extrapyramidal” diseases
  
  • Huntington’s disease
  • Parkinson’s disease
• Post-mortem examinations found that it was the basal ganglia that was mostly damaged
  
  • Huntington’s - Putamen + Caudate nucleus = Striatum was the damaged area
• Both disease characterised by motor dysfunction and BG degeneration
• Suggested that BG involved in execution of movement

Question 3

What do the Basal Ganglia do?

Answer 3

• Anatomically, BG have NO direct projections to motor output structures.
  
  • How do they control movement?
    
    • Hints from electrophysiology:
      
      • Neurons in BG very active just before and during movement, but always after cortex becomes active;
      • Neural activity in basal ganglia does not code for particular movements - wouldn’t be able to know what movement is being formed by looking at basal ganglia alone

Question 4

How can we understand how the Basal Ganglia is involved in movement through connectivity?

Answer 4

BG form closed feedback loops with the cortex and thalamus

• No boundary between caudate and putamen
• Striatum and globus pallidus are connected
• The striatum projects to the globus pallidus & recieves a lot of input from the cortex
• GP projects to thalamus and thalamus projects to cortex
• 3 feedback loops - all anatomically distinct
  
  1. Direct Path” via globus pallidus pars interna (GPi)
  2. “Indirect Path” via GP pars externa (GPe)
  3. “Indirect Path” via subthalamic nucleus (STN)

Question 5

What is the direct path feedback loop?

Answer 5

• Lots of projection from the cortex into the striatum
  
  • Excitatory glumtamateric projections - Glutamate exciting neurons in the striatum
• Striatum projects to the internal part of the globus pallidus (GABA projections) so they inhibit CPi
• GPi is inhibitory towards the thalamus (the neurons the project back to the cortex - the neurons that started to loop)
• ****GPi is normally inhibitory to the thalamus so when GPi is actually inhibited in the direct path, the thalamus is no longer inhibited (it is disinhibited) so leads to excitatory feedback****
• Consequence of direct path
  
  • Excitatory feedback to the cortex

Question 6

What is the first indirect loop?

Answer 6

• Have opposite effect to direct path - shutting down excitatory feedback
• Different population of striatal neurons (compared to direct path) project to the external globus pallidus (also GABAergic) - inhibits GPe which actually means GPi is not excitatory as normally the GPe is inhibitory towards GPi
• Now GPi inhibits the thalamus so shuts down the excitatory feedback to the cortex from the thalamus

Question 7

What is the second indirect loop?

Answer 7

• Additional step but same effect of shutting down excitatory feedback to cortex
• GPe normally inhibits Sub-thalamic nucleus (STN) so it is no longer inhibited so excites GPi
• GPi is now more effectively inhibiting the thalamus and therefore feedback to the cortex
• Occurs simultaneously with other indirect loops

Question 8

How do these pathways relate to movement and the models of basal ganglia function?

Answer 8

• Feedback loops is a way of the basal ganglia to control the amount of activity in the motor cortex
  
  • Different neural networks that code for different movements - we need to boost activity in the specific neural network to get a specific type of movement
  • So we modulate motor programmes originating in cortex through “scaling” of movement
    
    • Positive feedback via direct loop helps to initiate movement
    • Negative feedback via indirect loop helps to stop movement
      
      • E.g. stop signal task - whenever you see a certain symbol you have to press button but symbol changes that indicates you shouldn’t push the button while you’re mid movement - we can cancel our movement - requires basal ganglia
• Focusing/filtering of movement
  
  • Positive feedback through direct loop boosts appropriate motor programmes (from central pattern generators)
  • Negative feedback through indirect loops filters out inappropriate motor programmes (competing central pattern generators).
    
    • i.e, like stereo amplifier, enhancing signal-to-noise ratio
    • So improving signal to noise ratio of motor activity
    • Permissing one movement while cancelling out others
  • 10% of striatal neurons respond to signals for reward and synapse on other striatal neurons (ie, do not project outside striatum)
    
    • motivational control over response selection?
• Error connection
  
  • The BG loops provide central (internal) feedback to cortical response systems:
    
    • Provide “predictive” feedback, allowing faster correction than permitted by slow peripheral feedback. (… like climate modeling)
    • If we didn’t have internal feedback and just went on what we see it would be a long pathway - need this internal shortcut/model
    • Can make smaller corrections so movement becomes more stable

Question 9

What are multiple parallel loops?

Answer 9

• Not all the pathways go through all of the same neurons
• We actually have multiple neurons running in parallel
• Multiple loops originating from different cortical regions remain segregated through BG, returning to their cortical areas of origin
• Diversity of function in what the basal ganglia is contributing to
  
  • E.g. involved in disorders such as OCD
• Funneling or conveging of inputs projecting to striatum
  
  • Concentrates into stronger inputs
• Divergence from striatum to GP
• This amplifies the signal back to the cortex

Question 10

How is the substantia nigra involved in the feedback loop?

Answer 10

• Two different types of dopamine receptors in the striatum (D1 and D2)
• Located on the direct pathway (D1) and indirect pathway (D2)
• Simultaneously amplifying direct pathway and shutting down whatever is in the indirect pathway
• Dopamine release in substantia nigra is essentially increasing the positive feedback to the cortex

Question 11

What is Huntington’s disease?

Answer 11

• Carry gene for disease but don’t develop disorder until mid-life
• Genetic disease causing progressive loss of GABA neurons in striatum (especially caudate nucleus).
• Symptoms
  
  • Twitches in face and hands, progress to tremors through body.
    
    • Tremors can resemble voluntary movements
• ## Movement disorder accompanied by dementia as basal ganglia is involved in cognition

Question 12

How do we explain Huntington’s disease?

Answer 12

• Loss of GABA neurons in striatum leads to decreased output from GPi to thalamus
  
  • Inappropriate motor programmes are not filtered out and so intrude into behaviour
  • • Not inhibiting the Part externa so it can inhibit the GPi and STN so not excitatory input to GPi so cannot inhibit the thalamus so stimulus the cortex in an indiscriminate way creating unwanted movement
• Expressing the noise that basal ganglia normally supresses - losing the filtering process

Question 13

What is Parkinson’s disease and how is the basal ganglia involved?

Answer 13

• Afflicts people over 60, incidence climbs with age.
• Major symptom: great difficulty moving, particularly initiating actions (“sticking”), abnormal gait (shuffling) and don’t swing arms. Also resting tremor - not the same as a tremor that occurs when you’re trying to do something
• Degeneration of DA-containing neurons in substantia nigra (blacker areas) that project to caudate & putamen (nigro-striatal pathway).
  
  • Normally substantia nigra is increasing activity in the direct pathway and decreasing activity in the indirect pathway
  • In Parkinsons we lose the input from the substantia nigra
• Loss of dopamine input causes filter to close, blocking all motor signals (appropriate and inappropriate) from cortex
• Initiation of any movement becomes extremely difficult
• Less inhibition in D2 - so increased activity in indirect pathway but weaker from the direct pathway
• GPi is very active - so inhibiting thalamus more so filtering out BOTH signal and noise - not motor movements signals are boosted - hard to initiate movements

Question 14

How can we possibly treat Parkinson’s disease?

Answer 14

1. Dopamine agonist drugs (eg L-dopa).
   
   1. Effect is limited - only works when you have dominergic neurons working
2. Cell transplant techniques are being developed:
   
   1. Healthy dopamine cells (either from foetal tissue or grown in vitro in tissue cultures) are put into brain;
   2. Poor results in Parkinson’s patients, but experiments in Sweden produced excellent results with young (and otherwise healthy) patients poisoned by MPTP.
3. Brain lesions to GPi or STN.

• Damage it to ensure that inhibitory signal are no longer sending

4. Deep brain stimulation in STN

• You would think it increases GPi activity but it actually stops the STN from working so less excitation of the GPi