The Centre Surround model and Disorders of the Basal Ganglia

Hello! after a break that was far too long I'm back to the blogging (those first two posts obviously took it out of me!). Hopefully I can pick up a bit of momentum this time round and manage a few more in quick succession. For this post I want to follow on from the first I did about the Basal Ganglia, in particular let's talk about how the centre surround model I introduced in the first post has helped clinical scientists in understanding what causes lie behind symptoms they observe in patients with a range of high profile disorders of the Basal Ganglia. I'll be taking my first post as a start point and building on that because I want to avoid any returning readers (wishful thinking?) from having to read the same things twice (plus I'm lazy and don't want to type the same thing multiple times) so now would be a good time to go back now and have a look here.



Once you've had a read of the first post continue on with this one (or carry on regardless, I can't really stop you!).

The Center Surround model predicts the main motor symptoms of Parkinson's and Huntington's disease and Hemiballismus

The centre surround model is built upon the decades of research into the anatomy of the Basal Ganglia and its connections. Researchers took this anatomical knowledge and combined it with theoretical accounts of potential ways the brain could select actions to create a model of Basal Ganglia function in action selection (Redgrave et al, 1999 and Mink, 1996). But how does this model tally with how the Basal Ganglia functions in "real life", well we saw in the earlier post that recordings of electrical activity recorded through the Basal Ganglia fit with the models prediction that their are different excitatory and inhibitory pathways of different speeds through the Basal Ganglia. But another line of evidence comes from the world of clinical neuroscience and the observations of patients with disorders that effect the Basal Ganglia such as Parkinson's and Huntington's disease and hemiballismus. Patients suffering from these disorders often display motor symptoms that tally with what would be predicted if the Basal Ganglia functions in the way suggested by the centre surround model. You can split these disorders in to two subtypes: hypokinetic disorders and hyperkinetic.

Hypokinetic Disorders and Hyperkinetic Disorders

Hypokinetic disorders are characterised by a reduction in motor output and hyperkinetic disorders by an increase in motor output, in particular an increase in involuntary movements i.e. we aren't talking about disorders or illnesses that increase anxiety or restlessness leading people to move around more because they're fidgety.

Now I'm really going to start relying on the previous blog so if you don't want to get lost go back and read it NOW!!

When we're talking about disorders caused by Basal Ganglia dysfunction hypokinetic symptoms are believed to arise from an excess of Basal Ganglia output - remember that the output of the Basal ganglia motor circuits is inhibitory on regions of the brain that control the initiation of movements. The overactivity of these circuits acts an over zealous brake on movement initiation so that as well as functioning normally to block the initiation of innapropriate movements the Basal Ganglia output also ends up blocking the initiation of some or all appropriate movements and hence the patients shows an overall reduction in movement.

Hyperkinetic symptoms on the other hand are thought to arise from a reduction in Basal Ganglia output meaning that there is a weakening or complete loss of the inhibition of unwanted and inappropriate movements by the Basal Ganglia, so as well as "chosen" movements being initiated other innapropriate movements can end up involuntarily leaking through.

Parkinson's disease

Parkinson's is a hypokinetic disorder where patients display an inability to initiate (referred to as akinesia) and coordinate and complete movement. This includes a general slowing and reduction in the amplitude of their movements (called bradykinesia). At the anatomical level this hypokinetic state is thought to be caused by a degeneration of dopamine containing cells in the Substantia nigra pars compacta (SNc) (not to be confused with the substantia nigra pars reticulata which I talked about in the previous post). 

Dopamine containing cells in the SNc project to the striatum and early on in PD progression patients show a significant reduction in the levels of dopamine in the striatum, especially the putamen which is the part of the striatum most important for movement control. But why would loss of dopamine input to the striatum cause this hypokinetic state?

The medium spiny neurons of the striatum (the inhibitory neurons that project to either the GPi/ SNr in the direct pathway or GPe in the indirect pathway) usually express only one of two dopamine receptor types: D1 and D2. The MSNs that project to the GPi/ SNr and make up the direct pathway express D1 receptors. When these D1 receptors are activated by dopamine they cause an excitation of the cells that express them. So when the SNc neurons release dopamine in to the striatum the activity of the direct pathway MSNs increases which in turn decreases GPi/SNr activity and so you get less inhibition of the motor regions- in other words dopamine signalling to the striatum facilitates movement initiation.

Back to Parkinson's then... when you get a degeneration of dopamine input to the striatum this leads to a reduction in the striatums inhibtion of the GPi/ SNr and the inhibitory signals from these output nuclei barrage the motor initiation regions unchecked leaving patients often unable to initiate movements and causing poor coordination and decreased velocity of movements they do manage to initiate. This account is supported by studies of primates (non-human ones!) where a loss in dopaminergic neurons is accompanied by an increase in the measured electrical activity in the GPi/ SNr and Parkinson's like movement dysfunctions.

So if a decrease in activiation of the direct pathway leads to a decrease in movement what do we see in disorders where activation in the indirect or hyperdirect pathways is disrupted.

Huntington's disease

Whilst Huntington's disease is a neurodegenrative disease that effects Basal Ganglia functioning like Parkinson's, unlike Parkinson's it's a hyperkinetic disorder. Huntington's is a form of chorea, a chorea being a movement disorder where patients exhibit random and jerky involuntary movements. Unlike Parkinson's where multiple risk factors have been identified the sole causal factor of Huntington's is known to be a mutation in a single gene Huntingtin. This mutation causes a faulty version of the corresponding protein to be expressed in the patients cells and this faulty version of the protein in turn damages nerve cells leading to their degeneration. The whole brain is vunerable to this neurodegeneration but the striatum is particularly vulnerable early on, specifically the MSNs which project to the GPe and constitute the indirect pathway are particularly vulnerable to degeneration.

When the GPe loses its inhibitory input from the striatum its activity goes up, ramping up the inhibition it sends to the STN. Bearing in mind that the STN sends excitatory signals to the GPi/ SNr this ramping up of GPe inhibition culminates in a marked reduction in GPi/ SNr output to motor regions. Without this inhibition mediating the activity of their target motor regions innapropriate signals have a bigger influence over motor region activity and leads to involuntary movements to be initiated more often.

Hemiballismus

Another, some what similar basal ganglia disorder is called hemiballismus. Unlike Huntington's which is characterised by jerky, whole body writhing movements sufferers of hemiballismus mostly show involuntary flinging movements of the limbs. In the scientific study of movement ballistic refer to short-lived but high velocity movements, hence Hemiballismus from the aggressive flinging movements.

Hemiballismus can be caused by damage centered in many different areas of the brain, however the most severe forms are seen in patients with lessions focused on the STN, or its input or output pathways. Although the mechanism is different to Huntington's the outcome is similar- the decrease in or complete loss of STN activity driving the GPi/ SNr leads to a reduction of Basal Ganglia output and hence an increased probability that inappropriate movements will be initiated involuntarily.

Summary 

So as I said at the top of this post, a lot of the motor symptoms seen in PD, Huntington's and Hemiballismus can be understood if the Basal Ganglia operates in the way proposed by the center surround model. This understanding give us huge potential is directing us toward avenues for treatment in some of these disorders or at the very least methods for ameliorating some of the more debilitating symptoms of these disorders. Bearing this in mind I'm going to commit now to writing the next blog post within the next two weeks not the next two months! Hopefully I should be able to keep to this deadline because my next planned blog is yet another follow on linked to this post. My next post will be about electrical stimulation of the brain and in particular the use of implanted stimulators as treatment for some brain dysfunctions in humans. The link comes from the the fact that one of the biggest success stories in the therapeutic use of "deep brain stimulation" is in the treatment of Parkinson's.

Anyway thats me for now, I hope you enjoyed this post and if you did make sure to check back every once in a while over the next week or two to read my next post!

Further reading:

Basal Ganglia disease Wikipedia entry

References, if your feeling adventurous and want to have a read some more advance accounts:

Crossman, A. R. (2000). Functional anatomy of movement disorders. Journal of Anatomy, 196(Pt 4), 519-525.

Mink, J. A. (1996). The Basal Ganglia: Focused Selection and Inhibition of Competing Motor Programs. Progress in Neurobiology, 50(4), 381-425.

Redgrave, P., Prescott, T., & Gurney, K. N. (1999). The basal ganglia: A vertebrate solution to the selection problem? Neuroscience, 89, 1009-1023.