Introduction
Electrical
stimulation of deep brain structures has been performed since neurosurgeons
began doing stereotactic surgery aimed at the thalamus and basal ganglia. Acute
electrical stimulation was used to arrest tremor during brain mapping before
burning a thalamotomy lesion. More recently this lead to the use of chronic
electrodes (deep brain stimulation, DBS) to treat movement disorders such as
Parkinson’s disease, essential tremor and dystonia. It is known that high
frequencies (>100 Hz) are required to obtain beneficial effects on motor
function [Benabid et al. 1996]. Anecodotal
reports and one publication from 1960 [Hassler et al.]
suggest that low frequency (5 Hz) electrical stimulation of thalamus can
exacerbate tremor and more recently applied in the subthalamic nucleus can
worsen akinesia [Moro et al. 2002]. The
neural mechanism of this frequency-dependent phenomenon is unknown. The first aim of this study was to determine
whether low-frequency electrical stimulation could worsen tremor amplitude in
patients with thalamic DBS. The second aim was to explore the underlying neural
mechanism through computer modelling.
Methods
Five
patients with essential tremor, who had successful tremor suppression with
thalamic DBS, underwent a frequency protocol while monitoring tremor with a
triaxial accelerometer (EGAS-FS-25, Entran Devices Inc, NJ) on the
contralateral hand, and surface EMG on forearm flexors and extensors
(Bagnoli-8, Delsys, Boston). The frequency of stimulation applied was altered
from 0-185 Hz and the stimulation intensity raised at each frequency to just
sub-threshold for adverse effects, such as paraesthesia (numbness and
tingling), speech disturbance, or muscle contraction. Tremor was monitored for
30-60 s while the limb was placed in an optimal position for eliciting tremor,
most often holding a glass of water. Data was recorded on videotape after
digitization using an 8 channel A-D converter (at 4.5 kHz /channel, VR-100B,
Instrutech, NY).
Off-line,
the data collected was replayed and digitized (CED 1401, Cambridge, UK). The
20-30 s of tremor data was divided into 5 s intervals and tremor amplitude for
each time epoch determined using the root mean square (RMS) function (Spike 2,
Cambridge, UK). For each patient, the RMS tremor amplitude was standardized by
comparison to the tremor RMS amplitude at 0 Hz and reported as the percentage
of tremor amplitude at 0 Hz. Also the power spectrum of tremor at each
frequency of DBS applied was graphed. A fast fourier transform (FFT: 128 bins)
was examined between 1-15 Hz to determine the dominant frequencies of the
resulting tremor. Statistical analyses included non-parametric ANOVA (Friedman
repeated measures) to compare the RMS amplitudes of tremor elicited at each DBS
frequency applied (SigmaStat 2.03). All pairwise multiple comparisons were
carried out using the Tukey method.
Computer
modelling was performed using a three-layer neural network (Nodus). The middle
layer of the network consisted of a pool of thalamocortical neurons, all of
which exhibited rhythmic synaptic potentials mimicking tremor activity. A
proportion of these cells were left subthreshold, while the rest were firing
rhythmic action potentials. The convergent output of this thalamic activity was
then relayed to motor cortex neurons via glutamatergic synapses with mixed AMPA
and NMDA postsynaptic receptors. Based on our previous study in rat thalamic
slices [Kiss et al. 2002], we mimicked the
effects of DBS by introducing a sustained membrane depolarization to all the
thalamic cells. The amplitude of this depolarization, as shown experimentally,
is proportional to the frequency of DBS applied. The frequency and amplitude of
the cortical response was then plotted against different frequencies of
thalamic stimulation, assuming the cortical output reflects end-organ tremor
activity.
Results
Root mean
square tremor amplitude at each frequency of DBS applied is shown in Table 1.
Tremor amplitudes were greater than baseline (0 Hz) at frequencies of 2 - 40 Hz
and amplitudes were reduced at $75 Hz (ANOVA, p<0.001). The most
marked exacerbation was seen at an applied DBS frequency of 20 Hz (ANOVA,
p<0.001), resulting in a complete disruption of motor control of the arm in
4 patients. Even eliminating the outlier (patient 4) from statistical analysis,
a significant increase in RMS amplitude at 20 Hz was identified. Whereas there
was no significant difference in the peak frequency of tremor, at 10-40 Hz DBS
there was a widening and increase in the power spectrum of the tremor recorded.
Table 1RMS
tremor amplitude shown as a % of tremor amplitude at 0 Hz (DBS off)
|
Patient |
2 Hz |
5 Hz |
10
Hz |
20
Hz |
40
Hz |
75
Hz |
100
Hz |
130
Hz |
185
Hz |
|
1 |
112% |
94% |
92% |
225% |
144% |
53% |
40% |
38% |
43% |
|
2 |
39% |
28% |
29% |
44% |
67% |
54% |
43% |
20% |
23% |
|
3 |
187% |
261% |
243% |
275% |
219% |
4% |
4% |
4% |
3% |
|
4 |
183% |
183% |
149% |
659% |
36% |
22% |
20% |
20% |
21% |
|
5 |
109% |
217% |
274% |
324% |
206% |
87% |
130% |
95% |
53% |
|
mean |
128% |
156% |
161% |
309% |
129% |
48% |
52% |
34% |
29% |
To
explore the underlying mechanism, we examined the possibility that the graded
membrane depolarization we have demonstrated in thalamic tremor cells in the
rat simulated DBS slice model [Kiss et al. 2002]
can cause this phenomenon. In our neural network, we found that low frequency
DBS and small membrane depolarizations (~5 mV) invariably enhanced the
amplitude of rhythmic cortical output. Higher frequency DBS and larger membrane
depolarizations started to evoke spontaneous thalamocortical firing unrelated to rhythmic synaptic input. Under this
condition, the cortical output exhibited a DC shift; its output became smaller
and less rhythmic. Further membrane depolarization from this level caused
action potential inactivation (depolarization blockade) in thalamic cells,
leading to an abolishment of rhythmic activities in both thalamus and cortex.
Discussion
Tremor
can be worsened with low frequency thalamic DBS if the intensity of stimulation
is increased above that chronically used to suppress tremor. Around 20 Hz DBS,
in addition to a marked increase in amplitude of tremor, there was a widening
in the tremor frequency spectrum.
Whereas
neurosurgeons have anecdotally reported that low frequency stimulation can
acutely exacerbate tremor [Hassler et al. 1960],
this is the first report to quantify the changes in tremor resulting from
different frequencies of electrical stimulation. Our previous attempts at
worsening tremor with low frequency stimulation were unsuccessful because the
intensity of stimulation was not increased above that required to suppress
tremor chronically. One proposal to explain the tremor exacerbation is that the
current applied spread further and affected more thalamocortical neurons.
However, one would then expect a direct relationship between current applied
and increase in tremor. This was not the case and the highest DBS current
intensity applied occurred with the lowest frequencies (2, 5 Hz) and not with
the 20 Hz DBS. The widening of the tremor power spectrum has been reported with
high frequency stimulation although no mechanism has been proposed [Beuter et al. 2001].
These phenomena can be partially explained using a 3 layer network consisting of afferent inputs, thalamocortical and cortical output neurons. Small membrane depolarizations induced by DBS, enabled more thalamic neurons to fire action potentials at tremor frequency thereby recruiting more cortical motor neurons into the rhythmic firing pattern. Otherwise thalamic neurons had only subthreshold rhythmic synaptic potentials. An increase in the pool of motor neurons firing rhythmically would increase the amplitude of the motor output or movement. The increase in the complexity of the tremor may result from recruitment of more thalamocortical neurons firing at slightly different frequencies. DBS applied at high frequency range can abolish tremor through both its de-rhythmic effect and/or depolarization blockade in thalamic neurons. Finally, this study concerns mainly the short-term effects of DBS, on the scale of seconds to minutes. Long-lasting DBS in human thalamus may involve additional neural mechanisms that still require characterization.
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