Your basal ganglia looks out of date sir!

I know some of you are going to scroll down and think I’m not reading all that! For those of you, I have a small summary paragraph at the end. If you’re more a “bring it on kinda person”, then read the whole thing. I realise the basal ganglia can be a confusing topic, hence this post, if you come across terms your not familiar with, you can look them up in my neuroanatomy primer post. The plan for this post will be as follows, the first part will focus on describing the basal ganglia and its relationship to other important adjacent structures, the second part will briefly look at the function of the basal ganglia. The third part will be looking at the circuitry, the direct and indirect pathways, these pathways provide a good model for understanding how the basal ganglia work and also helps explain many of the features of conditions such as Parkinson’s and Huntington’s chorea.

What are the basal ganglia (nuclei)?

Now the title may seem a bit pointless, but it is actually important to define what the basal ganglia are from an anatomical perspective. The basal ganglia are a paired (left and right) group of nuclei sitting under (sub-cortical) the left and right cerebral cortices. What do we mean by nuclei (sing. nucleus)? Nuclei are a type of grey matter consisting of a collection of neuronal cell bodies (having a similar function). A nucleus is, therefore, a region of grey matter which is surrounded by white matter in the CNS. The other type of grey matter is cortex, which is found on the edges of the CNS (outer grey edges of the cerebrum and cerebellum). Now ganglia are a collection of cell bodies in the peripheral nervous system, not the CNS. Therefore calling this group of nuclei, the basal ganglia is a historical misnomer, the correct term is basal nuclei.

The constituent parts of the basal nuclei have changed as our understanding has improved. Historically the basal nuclei consisted of the following nuclei: corpus striatum (caudate, putamen and globus pallidus), claustrum and the amygdala. However, we now understand functionally the basal nuclei consist of:

  1. striatum:
    • caudate
    • putamen
  2. globus pallidus:
    • globus pallidus external
    • globus pallidus internal
  3. subthalamic nuclei
  4. substantia nigra
    • substantia nigra pars compacta
    • substantia nigra pars reticulata

Figure 1 Constituent nuclei of the basal nuclei, adapted from Gray’s Anatomy

The caudate and putamen together are considered as one functional unit called the striatum; it is the main input for the basal nuclei. You may come across an old term, the lentiform nucleus (lens-like appearance), this is rarely used now and refers to the putamen and globus pallidus as one morphological unit. The substantia nigra (black substance) can be subdivided into two parts, the pars reticularis and pars compacta. The pars reticularis shares functional similarities to the globus pallidus internal. Thus both are considered the functional output of the basal nuclei. The pars compacta projects (nigrostriatal pathway) to the striatum and its neurones release dopamine, which is essential for efficient movement. The subthalamic nucleus is a key part of the indirect pathway and receives projections from the globus pallidus external, the subthalamic nucleus itself projects to the globus pallidus internal.

Where are the basal nuclei?

It is a good idea to understand the relationship of the basal nuclei to adjacent structures, understanding the neuroanatomy will help you to identify structures on CT and MRI imaging. Regarding general location, the striatum is in the telencephalon (see neuroanatomy primer post if you’re lost), the subthalamic nucleus is located in the diencephalon, and the substantia nigra is in the upper part of the brainstem, known as the midbrain or mesencephalon.

In terms of adjacent structures to the basal nuclei, look at Figure 2, in the coronal section: the midline structure is the third ventricle, on either side of the third ventricle are the thalami, lateral to each thalamus is an important strip of white matter known as the internal capsule (ascending and descending axons), lateral to this is the globus pallidus and putamen. Going further laterally is another strip of white matter called the external capsule, then a thin strip of grey matter called the claustrum, lateral to this is another band of white matter known as the extreme capsule and finally there is a strip of cortex (grey matter on the edge of the CNS) called the insula.

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Figure 2 Coronal section showing the basal nuclei and adjacent structures, Adapted From Gray’s Anatomy, The Anatomical Basis Of Clinical Practice

Looking at an axial section (Figure 3) the internal capsule appears like a V-shaped structure, with the apex pointing medial. You may have noticed that I’ve not mentioned the caudate nucleus, on the coronal section image, the caudate appears superior to the internal capsule and lateral to the ventricles. The caudate nuclei (one on each side), when looked at from the side (laterally – sagittal image) are C shaped, with a head, body and tail, the body arches over the thalamus and the tail curves under, see Figure 4. You should be able to identify these structures now on coronal and axial sections of the brain.

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Figure 3 Axial view showing the basal nuclei, Adapted From Gray’s Anatomy, The Anatomical Basis Of Clinical Practice

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Figure 4 Lateral view showing the basal nuclei, Adapted From Gray’s Anatomy, The Anatomical Basis Of Clinical Practice

What do the basal nuclei do?

Figure 5 Flow of information through the basal nuclei

First things first, the basal nuclei is not only associated with motor activity, but it also is thought to influence our emotional response and behaviour. Research is investigating the role of the basal nuclei in conditions such as Schizophrenia and Tourettes’ syndrome.

In relation to motor activity, it’s a common misconception that moving necessitates only the motor cortex, corticospinal/nuclear tract, LMN and then the appropriate muscles; however remember the motor cortex executes movements but does not plan or initiate movements. In actual fact when initiating a movement, the intention regarding this originates in the prefrontal cortex, perhaps your wanting a sip of your coffee from the mug on the table. The prefrontal cortex communicates with the motor cortex (where countless motor plans are stored), all relevant motor plans are relayed via corticostriate fibres to the basal nuclei, the basal nuclei processes these motor programs from the motor cortex; the basal nuclei ensures the correct programs are selected, while inhibiting inappropriate competing programs, this information is then relayed through the thalamus and finally on to the primary motor cortex. The primary motor cortex then executes this plan through the appropriate tracts (corticospinal/nuclear).

The basal nuclei maintain a balance between motor programs that facilitate and inhibit competing movements. By regulating this balance between opposing movements, this permits fluid motion. Hence in diseases where the basal nuclei are functioning abnormally, this can cause either poverty of movement (Parkinson’s disease) or excessive movements (Huntington chorea), depending on which particular circuits are being affected.

Basal nuclei circuitry

Signals come into the basal nuclei and signals leave the basal nuclei, the striatum is the part of the basal nuclei which has incoming signals from the entire cortex (motor, sensory, visual etc.); the output pathway consists of globus pallidus internal (GPi) and the substantia nigra pars reticularis (SNr). These input and output components are common to both direct and indirect pathways. When a decision is taken to perform an action, multiple competing motor programs are sent to the striatum. The basal nuclei ensure the correct program is selected using the direct and indirect pathways. Thus initiation of movement begins in the cortex, but the selection of the appropriate pathway occurs in the basal nuclei.

When trying to remember which neurotransmitters are involved, a basic fact to remember is that axons from the cortex, thalamus and subthalamic nucleus are glutamatergic (neurotransmitter: glutamate), glutamatergic axons are excitatory when they synapse. Axons travelling from the striatum to the globus pallidus and all axons from the globus pallidus are GABAergic axons (neurotransmitter: GABA), which are inhibitory when they synapse. At the end of each pathway section, I have summarised the effect of each pathway mathematically, using the number 1 to represent the positive effect of glutamate and the number -1 to represent the effect of GABA.

Direct and Indirect PathwaysFigure 6 Direct and Indirect pathways

Direct Pathway

See Figure 6. Glutamatergic axons from the cortex synapse on medium spiny neurones in the striatum (caudate and putamen), these cortical axons are part of the corticostriate tract and have an excitatory effect on spiny neurones in the striatum causing them to fire more, these neurons are GABAergic, and they synapse on neurones in the globus pallidus internal (GPi) and substantia nigra pars reticularis (SNr). The increased inhibition of these GPi and SNr neurones, means they fire less. The GPi and SNr neurones are also GABAergic and their axons synapse on neurones in the various nuclei within the thalamus. Therefore the net effect is that the inhibitory effect of the GPi and SNr on the thalamus is reduced, so that glutamatergic neurones in the thalamus increase firing, they have an excitatory effect on the motor cortex, promoting movement. So to summarise, the direct pathway promotes movement and is an example of a positive feedback loop.

Glutamate (1) x GABA (-1) x GABA (-1) x Glutamate (1) = 1 (excitatory effect overall)

Indirect pathway

See Figure 6. Think of this literally as an indirect version of the direct pathway, the beginning and end destinations are the same, but a detour is involved (hence indirect) and the consequence of the detour is that instead of promoting movement (like the direct pathway), it inhibits movement. So once again we start off in the cortex, corticostriate axons synapse on neurones in the striatum, from here the striatal neurone axons travel towards the globus pallidus external (GPe), not the internal as in the direct pathway. If you recall, the cortex has an excitatory effect, causing the striatal neurone to increase firing, the striatal neurone itself is GABAergic. Therefore its effect is to increase inhibition on the neurone in the GPe. Therefore the GPe neurone, which is also a GABAergic neurone fires less now, thereby reducing its inhibition on the neurone it synapses within the subthalamic nucleus. The subthalamic neurone is a glutamatergic neurone, it is now less inhibited by the neurone in the GPe, therefore increases firing. This subthalamic neurone’s axon synapses with a neurone in the GPi, causing it to fire more. This GPi neurone increase firing, and is a GABAergic neurone and increases the level of inhibition on the neurones it synapses within the thalamic nuclei. The end results are decreased firing of the glutamatergic neurones in the thalamic nuclei and therefore reduced stimulation of the motor cortex. Hence the indirect pathway reduces movement (the opposite of the direct pathway) and is an example of a negative feedback loop.

Glutamate (1) x GABA (-1) x GABA (-1) x Glutamate (1) x GABA (-1) x Glutamate (1) = -1 (inhibitory effect overall)

Dopamine and acetylcholine circuits

You may have come across the neurotransmitter dopamine in popular literature, it is often mentioned in articles talking about habits which are difficult to break. Dopamine is recognised as an important neurotransmitter involved in rewarding and reinforcing actions. In the case of movement, dopamine from the substantia nigra pars compacta (SNc) acts on the striatal neurones (this is known as the nigrostriatal pathway) to further boost the effects of the direct pathway and inhibit the indirect pathway. How does it both excite and inhibit the direct and indirect pathways respectively? Striatal neurones involved in the direct pathway have D1 receptors and striatal neurones in the indirect pathway have D2 receptions. When dopamine binds to D1, this causes depolarization and has an excitatory effect. When it binds to D2, this causes hyperpolarization and has an inhibitory effect, see Figure 6. Dopamine thus reinforces the direct pathway.

Finally, we have a small number of cholinergic neurones in the striatum, they do not leave the striatum, but rather projects to other neurones inside the striatum and hence are interneurones. Some of these cholinergic neurones synapse with striatal neurones of the direct pathway and are inhibitory. The other cholinergic neurones synapse with striatal neurones of the indirect pathway and are excitatory. Thus acetylcholine turns down motor activity by inhibiting striatal cells in the direct loop and exciting striatal cells in the indirect loop.

Clinical correlation

In Parkinson’s disease, there is degeneration of the substantia nigra pars compacta, leading to depletion of dopamine. Hence the direct pathway loses its reinforcement and the balance shifts towards the indirect pathway, favouring the cholinergic interneurones which promote the indirect pathway. The overall effect is to excessively inhibit the thalamus and thus motor programs, reducing movement. The treatment involves exogenous dopamine in the form of levodopa and also using anticholinergic drugs to dampen the cholinergic circuits discussed above. An electrode can also be placed in the subthalamic nucleus, when stimulated this prevents subthalamic neurones firing, thus decreasing excitation of GPi neurones and therefore decreasing the inhibition on the thalamus.

In Huntington’s chorea, the opposite effect is essentially happening, there is an imbalance between the direct and indirect pathways in favour of the direct pathway. This is due to an inherited autosomal dominant gene defect, resulting in damage to the striatal neurones of the indirect pathway. The inhibition on the thalamus is markedly reduced, causing excessive increase stimulation of the motor cortex and movements known as chorea. Tetrabenazine can be used to attempt to suppress the chorea, by preventing the uptake of dopamine into presynaptic vesicles, thus when vesicles fuse with the presynaptic membrane no dopamine is released.

Summary

So to summarise, the direct pathway promotes movement and the indirect pathway inhibits movement. Dopamine promotes the direct pathway and inhibits the indirect pathway, acetylcholine does the exact opposite. Parkinson’s disease is due to a loss of dopaminergic transmission resulting in the balance shifting in favour of the indirect pathway and thus a decrease in movement. Huntington’s chorea is an autosomal dominant gene defect, resulting in the destruction of striatal cells of the indirect pathway, thus the balance shifts in favour of the direct pathway resulting in reduced inhibition of the thalamus and motor cortex, causing excessive movements.

References:

  • Clinical Neuroanatomy, Richard Snell
  • Gray’s Anatomy: The Anatomical Basis of Clinical Practice,  Susan Standring

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