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ref: Israel-2008.01 tags: review DBS caudate putamen STN date: 01-25-2012 00:56 gmt revision:3 [2] [1] [0] [head]

PMID-17949812[0] Pathophysiology of the basal ganglia and movement disorders: From animal models to human clinical applications

  • MPTP monkeys:
    • resting tremor is not easily repeated in MPTP treated macaque monkeys, though it does occur in green (vervet) monkeys.
    • low doses of MPTP seem to first cause mild frontal cognitive deficits in monkeys without motor signs. (strange...); this acute MPTP treatment produced DA depletion that is equal or more severe in the caudate nucleus than in the putamen.
    • in comparison, lower, longer doses of the toxin, which is thought to better emulate the progression of PD, causes a greater decrease in the putamen.
    • frontal eye effects and cognitive deficits are observed before motor signs, which is in line with early cog. deficits found in human MPTP and PD.
    • MPTP treatment results in an increase in the number of neurons that fire in bursts.
    • physiological studies of the pallidum in MPTP-treated monkeys demonstrate that their pair-wise crosscorrelograms become peaked and oscillatory, suggesting that DA depletion induces an abnormal coupling of basal ganglia loops (could test this in my data).
  • tonic firing rate of STN neurons is (they claim) about 20Hz; this increases to about 25Hz after MPTP treatment. The firing rate of neurons in the GPi increase with MPTP, GPE decrease.
  • their description of the ''box and arrow' model of pathophysiology of PD is quite easy to understand, as are their critiques - that it fails to explain the dynamic manifestations of the disease, namely resting tremor and rigidity.
  • there are hyper-direct projections from the motor cortex to the STN
  • the box and arrow model does not accurately predict the result of removal of GPi: according to the direct/indirect pathway model, removal of the GPI should alleviate akinesia, bradykinesia, and rigidity. However, pallidotomy has been shown to be primarily effective in alleviating l-dopa induced dyskinesias (involuntary movements, like tic or chorea) -- exactly the opposite of what the model would predict.
  • a better (or at least more recent) model is that the striatum / pallidus / STN are involved in selection of actions & inhibition of competing actions; this is achieved via focused striatial inhibition.
    • problem: changes in pallidal activity lag behind movement initiation (!)
  • even better hypothesis: that the basal ganglia perform reinforcement driven dimensionality reduction. This has been discussed by Graybeil and others, but it's implication to PD is only lightly touched here (they mention that it is more in accord with neurons in the striatum involved in the same actions to no show an increase in correlation as would be expected from an action-selection hypothesis.
  • remind us that exposed-metal microelectrodes have a tendency to stimulate fibers, not cell bodies.
    • nevertheless, the effect of DBS in PD is remarkably similar to lesion; the exact mechanism is still under intense study. (hypotheses: depolarization block, stimulation of bypassing inhibitory pathways, induction of GABA release from GPe projection neurons. )
    • their hypothesis: DBS enforces a constant spatio-temporal firing pattern of the discharge structures of the basal ganglia. The null output of the globus pallidus is ignored by the rich thalamic & cortical circuits, which can 'take over'.
  • ( in the conclusion: quote: "These findings may call for development of future therapies that will target this abnormal synchronization (Tass, 1999 P.A. Tass, Phase Resetting in Medicine and Biology, Springer, Berlin (1999).Tass, 1999)." exactly!!


[0] Israel Z, Bergman H, Pathophysiology of the basal ganglia and movement disorders: from animal models to human clinical applications.Neurosci Biobehav Rev 32:3, 367-77 (2008)