Module 17 - Lecture 13 - Basal Ganglia

Question 1

What does the Basal Ganglia (BG) exert control over in the motor hierarchy?

Answer 1

• It ultimately can exert control or modify the UMN such as the primary motor cortex.
• IMPORTANT = The BG itself has no direct input on the local circuits or the LMN, it can only exert its control over the motor system by directing the excitation or inhibition of the UMN itself.

Question 2

What are the “major inputs” to the BG?

Answer 2

• Major inputs come from the cerebral cortex , and more specifically
  
  • Frontal association area
  • Parietal association area
  • Secondary motor cortex

***Important to note that these are not the exclusive areas that the BG receives its input, all other cortical sources will follow these cortical striatal pathways to the striatum.
***The only EXCEPTION of our cerebral cortex areas that do not → are the primary visual and auditory cortex. But their secondary areas can synapse on the BG.
***Important to note that nearly all of our inputs to our BG actually synapse on the striatum, either the caudate if we are dealing with eye, head and neck motion; or the putamen if we are dealing with any other type of motion.

Question 3

Are the major inputs to the BG excitatory or inhibitory?

Answer 3

The inputs are mainly excitatory. We know that in the central nervous system that glutamate is the main excitatory neurotransmitter.

Question 4

What are the modifying inputs to the BG? Where do they come from? What neurotransmitters do they use?

Answer 4

• The substantia Nigra (pars compacta) is the modifying input.
• This structure will essentially release dopamine to the striatum where it can either be inhibitory or excitatory → it is the receptor that ultimately changes if it is excitatory or inhibitory.

Question 5

What are the 2 BG nuclei receiving the inputs and what is their common “collective name”?

Answer 5

Almost all inputs synapse the striatum (composed of the caudate and putamen = 2 BG nuclei)

Question 6

What are the 2 output nuclei of the BG? Are the outputs excitatory or inhibitory? What are the targets of the outputs?

Answer 6

• The major 2 outputs of the BG:
  
  • Globus pallidus (internal)
  • Substantia Nigra (pars reticulata)
• These depend on the type of movement, therefore the Substantia Nigra (pars reticulata) will be the eye, the head and the neck; and Globus pallidus (internal) is dealing with everything else
• The axons of these nuclei that synapse on other structures are inhibitory. They use GABA, the primary inhibitory neurotransmitter used by the central nervous system.
• The main targets of the outputs:
  
  • THALAMUS → the gatekeeper for the cerebral cortex
    
    • Ventral anterior nuclei → which is mainly going to go back to our frontal cortex = secondary motor cortex area
    • Ventral lateral nuclei → which will mainly go back to the primary motor cortex area
    • Reticular formation (midbrain) -
    • Superior colliculus (primarily for eye motion)

Question 7

Explain the connectivity of the “direct pathway” and which neurons are involved for limb motion.

Answer 7

If the movement sequence is any other muscle in the body other than the head, neck and eyes this is the following pathway that they will take: premotor or secondary cortex will connect as excitatory to the → Striatum to either → Caudate or Putamen → then if the striatum reaches threshold → exert an inhibitory influence on the Globus Pallidus (internal) → The Globus Pallidus (internal) is then inhibitory to the Thalamus → if the thalamus is excited it could be excitatory to the UMN.

If the movement sequence from the the head, neck and eyes this is the following pathway that they will take: premotor or secondary cortex will connect as excitatory to the → Striatum to → CAUDATE→ then if the striatum reaches threshold → exert an inhibitory influence on the Substantia Niagra Pars Reticulata → then inhibitory to the Thalamus → if the thalamus is excited it could be excitatory to the UMN.

***NOTICE THE DIFFERENT PATHWAY BETWEEN BOTH INSTANCES***

Question 8

Explain the direct pathway at rest, and when activated. What is the net output on the UMN targets in each state?

Answer 8

At a resting state, there are no planning areas that are trying to excite the Striatum, therefore the striatum is inactive and not producing AP because it is not achieving threshold.

Therefore, the striatum at rest has no relative influence on the Globus pallidus (internal).

The Globus pallidus (internal) is a tonic neuron, and these neurons are going to be propagating AP tonetically, they propagate AP all the time and they naturally produce AP but how frequently these are being sent or if they are sent at all can be modified if we were to have excitatory or inhibitory postsynaptic potential causing further or less depolarization.

Big picture, is at rest the Striatum is not achieving threshold and the Globus pallidus internal is tonically active, which is a inhibitory neuron and using GABA as their neurotransmitter. For that reason, it is inhibiting the ventral anterior or ventral lateral nucleus of the Thalamus, which will then synapse on the primary motor cortex. Because Globus pallidus internal is a inhibitory neuron to the thalamus, therefore the ventral anterior or ventral lateral nucleus is less likely to achieve threshold from other excitatory input that would desire to excite the primary motor cortex.

ACTIVATED

Striatum is now activated and reaching threshold which will produce an AP which will release glutamate. The glutamate will end up inhibiting the Globus pallidus internal. Therefore, the globus pallidus internal that would tonically want to be sending AP, it is inhibited and it may not be sending its AP. This will then cause for the ventral anterior and ventral lateral of the thalamus will not be receiving those inhibitory signals.
The thalamus can now receive other inputs from other excitatory inputs from UMN structures.

Question 9

What is disinhibition?

Answer 9

There is inhibition of inhibition which is what we call disinhibition (-1 x -1 = + 1)→ therefore VA/VL is easier to reach threshold from other EPSP sources.

Question 10

For most limb motions the above pathway, when activated, includes _____ the striatum (putamen), leading to _____ of the GPi. What are the analog structures of each for eye and head motion?

Answer 10

• For most limb motions the above pathway, when activated, includes _excitation _to the striatum (putamen), leading to inhibition of the GPi.
• Analogue structure for the striatum (putamen) = Striatum (caudate)
• Analogue structure for the globus pallidus internal = Substantia Niagra Pars Reticulata

Question 11

Explain the nuclei involved in the indirect pathway. (Which are transient and which are tonic?)

AT REST

Answer 11

• The indirect pathway is used for the inhibition of competing movements → indirect pathway through BG
• The pathway that start off as excitatory once it gets to the Striatum it will act as an inhibitory to the Globus pallidus external branch which then could go to our subthalamic nuclei, which ends up going back to the Globus pallidus internal (still the same as previous which is inhibitory to the thalamus) to take its journey back to the thalamus.
• AT REST:
  
  • The cortical input to the striatum = no AP, thus the striatum is not actively inhibiting the Globus pallidus external. This Globus pallidus external is a tonic neuron, therefore it will be continually sending its AP. The Globus pallidus external they are GABA = inhibitory neurons, which will inhibit the subthalamic nuclei. If the subthalamic nuclei was not actively inhibited by the Globus pallidus external, it too would want to be tonically firing their AP. Then, the subthalamic nuclei will synapse on the globus pallidus internal and those synapses would be excitatory.

TRANSIENT = Striatum 
TONIC = Globus pallidus external, subthalamic nuclei, subthalamic nuclei

Question 12

Explain the nuclei involved in the indirect pathway. (Which are transient and which are tonic?)

WHEN STIMULATED

Answer 12

STIMULATED:
There are these excitatory post-synaptic potential that reach the striatum and they could reach threshold which would fire an AP, thus the striatum actively inhibiting the Globus pallidus external by sending GABA neurotransmitters. This Globus pallidus external is a tonic neuron, therefore it will stop sending its AP. The Globus pallidus external they are GABA = inhibitory neurons, which will inhibit the subthalamic nuclei. If the subthalamic nuclei was not actively inhibited by the Globus pallidus external, it too would want to be tonically firing their AP. Then, the subthalamic nuclei will synapse on the globus pallidus internal and those synapses would be excitatory.

• When the STN tonically excites GPi, the EPSP provides extra inhibition aka faster AP frequency which is extra IPSP of the thalamus !!! Therefore, even less likely to excite the UMN that this pathway is taking.

Question 13

Compare and contrast the nuclei from the indirect and of the direct pathway.

Answer 13

In the indirect pathway, the common input is still the striatum and the common output is still the globus pallidus internal which can exert its control on the thalamus or potentially some other UMN structure.

Question 14

What is the net effect of the indirect pathway when it is at rest and when it is activated? No need to know the whole pathway

Answer 14

• The net effect of the indirect pathway when it is at rest = At rest the BG is inhibitory to the thalamic nuclei, so when we don’t want to move, we don’t move
• The net effect of the indirect pathway when it is activated = When stimulated and when we want to initiate a motor program, our direct pathway is leading to excitation of UMN, where our indirect pathway is leading to extra inhibition of other UMN pathways

Question 15

What is the idea of the direct and indirect pathways for “center and surround”?

Answer 15

• Because neurons are these giant networks where we can have areas that converge into smaller neuron clusters.
• The direct pathway will receive a lot of convergence on a very small popular of the pathway to ultimately excite this very very small lesion of the UMN.
• The conductivity of the indirect pathway is going to be more diffuse, so it includes the area that is ultimately trying to be excited through the direct pathway. It has a wide sweeping larger effect, weaker effect on a larger population of neurons → you will get this larger surround of UMN that are very close to the UMN that we want to activate somatotopically
• THE CENTER = THE ACTUAL UMN POPULATION THAT WE NEED TO GET THE MOTION THAT WE WANT.
• THE SURROUND = UMN THAT SURROUND THE CENTER THAT ARE PRODUCING VERY SIMILAR MOVEMENTS AND WE NEED THESE REGIONS TO BE INHIBITED! IF THEY WERE EXCITED, THE MOVEMENTS THAT ARE COMPETING WITH THE CENTER WOULD ALSO BE RELEASED, THEN THAT MOTOR PROGRAM THAT IS PRODUCED WILL NOT BE AS SOPHISTICATED.
  
  • ULTIMATELY IS NOT ONLY INHIBITING THE SURROUND BUT ALSO THE DIRECT PATHWAY, AND BECAUSE THE INDIRECT PATHWAY IS WEAKER + THE IDEA OF SUMMATION = THE DIRECT PATHWAY HAS A EXCITATORY INPUT OVER POWER THE INHIBITORY INDIRECT PATHWAY.

Question 16

Which pathway is likely “strong, focused and more convergent”?

Answer 16

• Direct pathway when there is excitation from the cortex, there is excitation of thalamus…
  
  • Movement will be facilitated
  • Focused movement (convergence) small portion of GPi at threshold

Question 17

Which pathway is likely “weaker, diffuse and less convergent”?

Answer 17

• Indirect pathway when there is excitation from the cortex, there is inhibition of thalamus…
  
  • Movement will be inhibited
  • Broader movement (center/the focus + curround) large region of the GPe at threshold.

Question 18

What type of dopamine receptors are on the striatum of the “direct” and “indirect” pathways respectively?

Answer 18

• The dopamine that is coming from our substantia nigra pars compacta, it goes to our secondary cortex and depending on whether this is synapsing on a striatum that will project its axons on the direct pathway or the indirect pathway –> it will either be excitatory or inhibitory respectively.
  
  • Dopamine receptors on the striatum of the direct pathway = D1 receptor
  • Dopamine receptors on the striatum of the indirect pathway = D2 receptor

Question 19

Which dopamine receptor is excitatory and which is inhibitory to glutamate/ AMPA receptors?

Answer 19

The D1 receptor are excitatory to glutamate/AMPA receptors
The D2 receptor are inhibitory to glutamate/AMPA receptors

Question 20

What is the net effect of dopamine on the direct pathway? What about the indirect pathway?

Answer 20

• The net effect of dopamine on the direct pathway = If D1 = activated the g-protein and excite to cyclic AMP to enhance excitatory input from cortex
  
  • MAKE THE DIRECT PATHWAY MORE ACTIVE = LESS INHIBITION TO THE THALAMUS
  • INCREASE ABILITY TO GENERATE VOLITIONAL MOVEMENT
• The net effect of dopamine on the indirect pathway = If D2 = activated the g-protein and inhibited cyclic AMP to negate input from cortex.
  
  • MAKE THE INDIRECT PATHWAY LESS ACTIVE = LESS INHIBITION TO THE THALAMUS
  • INCREASE ABILITY TO GENERATE ASSOCIATED MOVEMENTS
• THE NET EFFECT OF DOPAMINE ON BOTH PATHWAYS = EXCITATORY TO THE THALAMUS WHICH CREATES MORE CORTICAL OUTPUT.
• OTHER WAY OF EXPRESSING THIS = THE NET EFFECT OF DOPAMINE IS DECREASED TONIC INHIBITION OF THE THALAMUS AND THUS INCREASED EXCITATION OF THE CORTEX.

THESE EFFECTS ARE TRANSIENT, MEANING THE INCREASED EXCITATION TO THE CORTEX IN THE DIRECT AND INDIRECT PATHWAY OCCURS IN CONCERT WITH SELECTION OF A MOVEMENT.

Question 21

What is the general definition of a hyper and hypokinetic disorder?

Answer 21

• Hyperkinetic disorder
  
  • Filter too lose
  • Too easy to excite UMNs
  • Examples: Huntington’s disease and Hemiballismus
• Hypokinetic disorder
  
  • Filter too tight
  • Difficulty exciting UMN (thalamus, MLR, Sup collicus)
  • Example: Parkinson’s disease

Question 22

What structure is degenerated first with Huntington’s disease? What are the observed symptoms?

Answer 22

• The Striatum neurons that are connected to the indirect pathway is degenerated first with this disease.
  
  • Genetic disorder that leads to this mutation in the gene for protein called Huntingtin
  • Autosomal dominant - 50% chance of inheriting disease
  • Abnormal # of CAG repeats (cytosine-adenine-guasin = glutamine); normal is 15-34 repeats, in Huntington’s usually 42 to > 66
• Symptoms:
  
  • Involuntary “dance like” movements (chorea)
  • Dementia (cortical cells degenerate later)
• ***These symptoms are present when we have a less effective indirect pathway.
• ***There is less inhibition of our globus pallidus external → which leads to less tonic inhibition allowing for the release of UMN that we really didn’t want to participate in the movement.

Question 23

What is the damaged structure for hemiballismus? What are the observed symptoms?

Answer 23

• Lesion (for example a stroke) affecting the subthalamic nucleus
• Symptoms:
  
  • Involuntary ballistic flinging of arm or leg
  • Always contralateral to the damage
• ***Because the subthalamic has been diminished –> can now excite less the globus pallidus internal, therefore you have less inhibition of the thalamus, making it easier to sometimes spontaneously release these undesired motions.

Question 24

What is the degenerating structure in Parkinson’s disease (PD).

Symptoms?

Answer 24

• Progressive degeneration of dopaminergic neurons in substantia nigra pars compacta.
  
  • ***the substantia nigra pars compacta.
• Symptoms:
  
  • Tremor (resting 3-6 Hz)
  • Rigidity (lead pipe)
  • Akinesia/Bradykinesia (dyskinesias) = less motion
  • Because UMN are not excited at the same AP frequency
  • Postural instability
  • Because we have fewer anticipatory postural adjustments – lack of inhibition in the indirect pathway
  • Freezing mid movement
  • Decrease “automatic and spontaneous movements
  • Decrease initiation and cessation of movements
  • Rapid alternating movements

Question 25

Explain why it is harder to initiate/ change/ and terminate motion with Parksion’s disease?

Answer 25

• Direct pathway = less D1 facilitation = increase inhibitory output to the thalamus and decreases the movement = harder to initiate/change/and terminate motion with Parkinson’s disease.
  
  • Too much inhibition for this pathway !!!
• Indirect pathway = less D2 facilitation = increase inhibitory output to CPe = decrease inhibitory output to Gpi and subthalamus = more inhibitory output to thalamus (decrease associated movements)
  
  • Not enough inhibition of this pathway
• The net effect of dopamine loss = inhibition to the thalamus (decrease cortical output)
  
  • Direct pathway = increase ability to generate volitional movement
  • Indirect pathway = decrease ability to generate associated movement

Question 26

What is the mechanism to supplement dopamine for PD? Can dopamine alone be used?

Answer 26

The mechanism to supplement dopamine for Parkinson’s disease: An oral administration of L-Dopa (levodopa) which is the dopamine precursor can cross the blood brain barrier and conversion to dopamine occurs in dopaminergic neurons.

Can dopamine alone be used? The precursor and not dopamine itself is used since dopamine cannot cross the blood-brain barrier. Normal dopamine precursor, tyrosine, crosses the BBB via an amino acid transporter. This transporter also carries L-DOPA but DOES NOT carry dopamine.

Question 27

What can interfere with L-DOPA (think food)? Why is Carbidopa used (no need to know biochemical cascade or enzyme)?
***think of dopamine Supplementation for PD.

Answer 27

What can interfere with L-DOPA (think food)? L-DOPA needs to compete with other amino acids. Eating a high protein meal along with L-DOPA = there is less availability for the L-DOPA to actually cross the BBB to be used as a precursor for dopamine.

Why is Carbidopa used? DOPA decarboxylase is also present in endothelial cells of blood vessels & gut. 99% of orally administered L-DOPA converted to dopamine before reaching the brain (<1% L-DOPA crosses the BBB) Therefore the use of Carbidopa is to block DOPA decarboxylase. Carbidopa cannot cross BBB and it only works in peripheral circulation. As a result more L-DOPA crosses BBB (into the brain) before it is broken down.
Therefore Carbidopa allos for synthesis of dopamine from L-DOPA in the brain.

Question 28

What is on-off fluctuations?

Answer 28

When you give an individual with PD doses of L-DOPA, the concentration seems to change over time and its efficacy in the CNS. These individuals will experience these on-off fluctuations, during the on period they essentially have too much dopamine → therefore they will experience dyskinesia (not enough movement); while during the off period they essentially do not have enough dopamine → therefore they are more immobile.

• You want to be able to stabilize the patient and have a good balance.

Question 29

What is a Deep brain stimulator ?

Answer 29

Neuroprosthesis = Deep brain stimulator

Question 30

What are the target nuclei of deep-brain stimulation?

Answer 30

Globus pallidus (internal) to excite/inhibit the direct pathway 
Subthalamic nuclei to excite/inhibit the indirect pathway

Question 31

What does deep-brain stimulation do?

Answer 31

The electrode is thin insulated wire inserted into the brain and that insulated wire goes from electrode to IPG. The IPG is an impulse generator (battery pack) typically implanted under the skin by the collarbone. These electrodes that are inserted are then able to deliver electrical stimuli to modulate/disrupt atypical patterns of neural activity in the brain.

Question 32

Does L-Dopa still need to be provided when using a deep brain stimulator?

Answer 32

• YES! Since the on off fluctuations are still present but the DBS will improve its general excitability from the BG to keep the patient in a more mobile state.
• Most patients continue to take medication with overall goals of:
  
  • Reducing duration/severity of “off time”
  • More consistent and longer “on time”
  • Improve dyskinesia