Tremor amplitude and tremor frequency variability in Parkinson’s disease is dependent on activity and synchronisation of central oscillators in basal ganglia
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Abstract
Rest tremor is one of the four main clinical features of Parkinson's disease (PD),
besides rigidity, bradykinesia and postural instability. While rigidity, bradykinesia
and postural instability can be explained with changes in neurotransmitter concentrations
and neuronal activity in basal ganglia, the pathogenesis of parkinsonian tremor is
not fully understood. According to the leading hypothesis tremor is generated by neurons
or groups of neurons in the basal ganglia which act as central oscillators and generate
repetitive impulses to the muscles of the body parts involved. The exact morphological
substrate for central oscillators and the mechanisms leading to their activation are
still an object of debate. Peripheral neural structures exert modulatory influence
on tremor amplitude, but not on tremor frequency. We hypothesise that rest tremor
in PD is the result of two mechanisms: increased activity and increased synchronisation
of central oscillators. We tested our hypothesis by demonstrating that the reduction
in rest tremor amplitude is accompanied by increased variability of tremor frequency.
The reduction of tremor amplitude is attributed to decreased activity and poor synchronisation
of central oscillators in basal ganglia; the increased variability of tremor frequency
is attributed to poor synchronisation of the central oscillators. In addition, we
demonstrated that the recurrence of clinically visible rest tremor is accompanied
by a reduction in tremor frequency variability. This reduction is attributed to increased
synchronisation of central oscillators in basal ganglia. We argue that both mechanisms,
increased activity of central oscillators and increased synchronisation of central
oscillators, are equally important and we predict that tremor becomes clinically evident
only when both mechanisms are active at the same time. In circumstances when one of
the mechanisms is suppressed tremor amplitude becomes markedly reduced. On the one
hand, if the number of active central oscillators is very low, the muscle-stimulating
impulses are too weak to cause clinically evident tremor. On the other hand, if central
oscillator synchronisation is poor, the impulses originating from different central
oscillators are not in phase and thus cancel out, again leading to reduced stimulation
of muscles and reduced tremor amplitude. Our hypothesis is supported by our measurements
on patients with PD and by experimental data cited in the literature. The proposed
two mechanisms could have clinical implications. New medical treatments, which would
specifically target only one of the proposed mechanisms (oscillator activity or synchronisation),
could be effective in reducing tremor amplitude and thus supplement established antiparkinsonian
treatments.