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Caudal Zona Incerta for the Treatment of Tremor with Deep Brain Stimulation
responsive STN will be transmitted divergently to the globus pallidus Figure 4: Pathogenesis of Parkinson’s Disease Tremor
externa (GPe), GPi and the substantia nigra reticulata (SNr), further
~10 and 20Hz ~10 and 20Hz
promoting abnormally synchronised oscillations in the basal
ganglia–thalamocortical pathways that will also be transmitted back to ~5Hz
the cZI. Tremor oscillations will be generated in the VL thalamocortical
neurons when they receive these potent GABAergic and frequency
synchronised oscillations from their cZI afferents that will cause them
~10 and 20Hz
to become progressively hyperpolarised and then rebound burst fire at
4–6Hz. During peripheral limb movements, discrete patterns of high Basal
frequency (~60–80Hz), oscillations will disrupt the synchronised low-
ganglia ~10 and 20Hz
frequency oscillations and tremor will be suppressed (see Figure 4).
Support for the New Model
In support of this hypothesis, Jellinger et al.,
in an autopsy study,
~10 and 20Hz bursts ~10 and 20Hz
have demonstrated that in tremor-predominant disease, there is loss
of dopamine to the subthalamic region (including STN and ZI), in
contrast to akinetic, non-tremulous PD where dopamine loss
predominantly affects the striatum. This association is also supported
in 1-methyl-4-phenyl–1,2,3,6–tetrahydro-pyridine (MPTP)-lesioned The γ-aminobutyric acid (GABA)ergic output with its synchronising function is shown as black
primate models of PD where the sensitivity of the midbrain
ZI = zona incerta; STN = subthalamic nucleus; VA = ventral anterior nucleus of the thalamus;
dopaminergic nuclei to the toxin varies between species. In the rhesus VL = ventrolateral nucleus of the thalamus; RRA = retrorubral area; mSNc = medial part of
monkey, MPTP causes destruction of the substantia nigra compacta
substantia nigra compacta.
(SNc), the median raphe nuclei and the locus coeruleus,
resulting that PD tremor is generated in VL thalamocortical neurons by
in parkinsonism but no resting tremor. Resting tremor is only converting 12–15Hz GPi GABAergic afferents from the basal ganglia to
expressed in the MPTP-lesioned vervet monkey where, in addition to a lower 3–6Hz frequency by step-down hyperpolarisation and rebound
the above neuronal loss, there is loss of retrorubral area (RRA) burst firing of the thalamocortical neurons. While frequency step-down
dopamine neurons, which contributes to the subthalamic dopamine transformation has been demonstrated in thalamocortical neurons
This projection arises from the medial part of the SNc, the both
in vitro and in vivo,
the major shortcoming of Pare’s
RRA and the ventral tegmental area (VTA)
and synapses pre- and hypothesis is that the VL nucleus does not receive basal ganglia
post-synaptically on glutamatergic afferents from the motor cortex to afferents.
It is therefore most likely that the afferents carrying
both the STN
and the ZI,
thereby modulating glutamate release abnormally synchronised GABAergic α and β oscillations to VL are
and effect. Loss of this dopaminergic projection causes the STN from the cZI.
These are known to synapse at the necks of the VL
to become increasingly responsive to its glutamatergic afferents and neuron dendrites and will thus have a potent effect on their activity.
become hyperactive, adopting a burst-like firing pattern.
The same Pyramidal neurons in the primary motor cortex upon receiving ~5Hz
pattern of burst firing is seen in the ZI
and probably involves a synchronised burst firing oscillations from VL will be driven to oscillate
similar mechanism. Although there is a strong association between at the same frequency and manifest as PD tremor. These oscillations
loss of subthalamic dopamine and the presence of tremor, an isolated along with ~20Hz and ~10Hz synchronised oscillations will also be
surgical lesion of the SNc or the midbrain dopaminergic area (RRA, transmitted back to the basal ganglia
and have been
VTA) does not induce a resting tremor,
but the subsequent systemic recorded in both locations.
administration of p-chlorophenylanine (serotonin synthesis inhibitor),
which suppresses release of serotonin from the median raphe nuclei, Further Support for the New Model
A surgical lesion in the ventromedial tegmentum involving the To further substantiate the role of cZI in the proposed model, we
RRA and VTA dopaminergic areas and the serotoninergic raphe nuclei recently conducted an experiment in which α- and β-frequency
induces a resting tremor,
and this can be abolished by the oscillations were imposed on the cZI using DBS leads in previously
administration of L-dopa or systemic 5-hydroxytryptophan (a serotonin non-tremulous patients whose PD has been treated at this target. The
Other evidence in support of the role of serotonin in generation of tremor and its frequency were quantified using
tremor generation comes from positron emission tomography (PET) accelerometry during stimulation of the cZI at 5, 10, 20, 40 and 80Hz, and
imaging studies where loss of putamenal dopamine does not correlate the effects were compared with a control group of patients with akinetic
with PD tremor
but the loss of midbrain serotonin does.
parkinsonism who had DBS electrodes implanted in other subcortical
Additionally, selective serotonin uptake inhibitors taken for depression targets within or associated with the known tremor circuits. These
in PD can cause a worsening of tremor in the initial months of included the VL thalamic nucleus, the GPi and the STN, which are
as they result in decreased serotonin release from the established targets for tremor control, and in addition we evaluated
terminals during the first weeks of treatment.
Serotonin acts as a stimulation of the centromedian parafascicular nuclei (CM/Pf) and the
neuromodulator to improve the signal-to-noise ratio of neural pedunculopontine nucleus (PPN).
We observed, with maximal
transmission by hyperpolarising the post-synaptic neuron (via action tolerated stimulation of the cZI, the STN and the VL nucleus within the
on KAHP channels), thus acting as a noise filter.
If the ZI and STN are frequency range of 5–40Hz, that a 4–6Hz resting hand tremor was
deprived of their serotonin afferents by degeneration of the median induced in non-tremulous, akinetic parkinsonian patients. However, the
raphºe nuclei, they will become increasingly responsive to their motor STN group required high stimulation voltages compared with the cZI and
cortical drivers and this will augment their burst-like firing pattern the VL nucleus groups and did not manifest tremor with <5 volts
resulting from dopamine depletion. In 1990, Paré et al.
hypothesised stimulation. Tremor could not be induced with maximal stimulation of
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