Abstract
Measurements
of the chronaxie time with extracellular stimuli have been used to conclude
that large diameter axons are responsible for the effects of deep brain
stimulation. We hypothesized that, because action potentials initiation occurs
in the axons of CNS neurons, extracellular chronaxie times would be similar for
cells and axons. Computer simulation was used to determine the sensitivity of extracellular
chronaxie times to the neural element stimulated. The results demonstrate that chronaxie times were dependent on the polarity of the
extracellular stimulus and the electrode-to-neuron distance, but in general chronaxie
times were not sensitive to the neuronal element being stimulated.
1. Introduction
Deep brain stimulation (DBS) is used to treat
a number of movement disorders, including essential tremor, multiple sclerosis,
and Parkinson’s disease. However, the mechanisms by which high-frequency
extracellular stimulation has its effects are unclear, and knowledge of the
interactions between the applied currents and the neurons of the central
nervous system (CNS) is lacking. This
lack of knowledge prevents full understanding of the mechanisms of action of
DBS and will hamper full development of this treatment.
A number of plausible hypotheses have been
proposed for the mechanism of DBS [2]. However, these hypotheses are difficult
to support or refute because it is not known what neural elements are affected
by stimulation. Local cells and axons respond at similar stimulation
thresholds, and this lack of selectivity complicates our understanding of the
mechanisms of DBS. The temporal excitation properties of the effects of DBS may
provide a means to determine the neuronal elements that are affected by DBS.
Measurements of the chronaxie times of
effects or responses produced by DBS have been used to infer the neuronal
elements responsible for the observed effect [1, 3]. These measurements were premised on differences in the chronaxie
times between axons and cells [7], and the conclusion from these studies was
that the short chronaxie times indicated that the neuronal element responsible
for the observed effects were large diameter axons. However, during extracellular stimulation in the CNS, action
potential initiation in local neurons occurs in the axon rather than in the
cell body [4]. Therefore, we
hypothesized that extracellular chronaxie times would be similar for
extracellular stimulation of axons and local cells, thereby complicating
interpretations of the neuronal elements responsible for a particular
effect. The purpose of this study was
to determine the sensitivity of extracellularly measured chronaxie times to the
neuronal element activated.
Figure 1: Computer simulation was used to determine the
strength-duration properties of extracellularly activated axons of passage and
local cells.
2. Methods
We used computer-based models of CNS neurons [5] to
determine the sensitivity of chronaxie time to the neuronal element being
stimulated (local cell vs. passing axon) for a range of positions of an
extracellular point source electrode. Chronaxie times were determined for
single neurons with electrodes positioned over a node of Ranvier of the axon,
over an internode of the axon, over the initial segment, over the cell body,
and over the dendrites at six electrode to neuron distances: 0.1, 0.2, 0.5, 1,
2, and 5 mm (fig. 1). Thresholds to
generate propagating action potentials were determined using monophasic
rectangular cathodic or anodic pulses with durations of 0.02 – 2 ms. Thresholds to activate 20%, 50%, and 80% of populations
of one hundred identical, non-communicating local cells or axons randomly
distributed in a 3 mm radius sphere with a stimulating electrode at the center were
also determined using the same stimuli.
Strength-duration data were fit by the log of strength-duration equation using least squares regression: log[Ith(PW)] = log[Irh(1+Tch/PW)], where Ith is the threshold current, Irh is the rheobase current, Tch is the chronaxie time, and PW is the pulsewidth.
Figure 2: Using cathodic monophasic stimuli, chronaxie times were dependent on the position of the
electrode and the electrode to neuron distance.
3. Results
The chronaxie
times were dependent on the polarity of the extracellular stimulus and the
electrode-to-neuron distance. Using monophasic anodic stimuli, chronaxie times were
similar for all neural elements. Using monphasic cathodic stimuli, chronaxie
times were longer for electrodes positioned over the soma or dendrites (1.3-2.6
ms) and to a lesser degree for electrodes positioned over the initial segment
(0.36-0.42 ms) than for other neural elements (0.07-0.13 ms), but only when the
electrode was ≤ 0.2 mm from the neuron (fig. 2). For larger electrode-to-neuron
distances, chronaxie times were comparable for all neural elements (0.13-0.22
ms).
Figure 3: The chronaxie times for
extracellular activation of populations of local cells or axons were dependent
on the polarity of the stimulus and the % of the population that was activated.
Chronaxie
times to activate populations of local cells or axons were dependent on the
polarity of the stimulus and the percent of the population that was stimulated
(fig. 3). With anodic stimuli chronaxie
times for axons and local cells within the population were very similar
(0.09-0.12 ms) for all degrees of activation of the population. With cathodic
stimuli chronaxie times for activation of local cells were similar to those for
local axons when smaller parts of the population were activated (20-50%
activation), but when 80% of the population was activated the chronaxie time
for activation of cells was approximately five times longer than that for
activation of axons.
3. Summary and
Conclusions
During extracellular stimulation of neurons,
action potential initiation occurs in the axon, even for electrode positioned
over the cell body or dendrites [4]. This
led to the hypothesis that the chronaxie times for extracellular activation of
cells and axons would be similar. In the present study computer simulation was
used to determine the sensitivity of extracellularly measured chronaxie times
to the neuronal element stimulated (axon vs. local cell).
The chronaxie
times were dependent on the polarity of the extracellular stimulus and the
electrode-to-neuron distance. With monophasic anodic stimuli the chronaxie
times with electrodes positioned over the dendrites, cell body, or initial
segment were similar to chronaxie times with electrodes positioned over the
axon for all conditions examined. Using monophasic cathodic stimuli, the chronaxie times were longer for
electrodes positioned over the soma or dendrites than for electrodes positioned
over the axon, but only when the electrode to neuron distance was ≤ 0.2 mm. For larger electrode-to-neuron distances the
chronaxie times were comparable for all electrode positions.
For activation of populations of neurons
with anodic stimuli, chronaxie times for the cells and axons were
indistinguishable. With cathodic stimuli, chronaxie times for activation of
local cells were comparable to chronaxie times for activation for axons, except
when a large percentage of the population was activated.
Results from vitro experiments in a
cortical slice preparation [6] corroborate the finding that there is little
difference between the chronaxie times of axons and cells activated by
extracellular stimuli. While the mean chronaxie time for intracellular stimulation of cells (15 ms) was substantially longer
than chronaxie times for extracellular
stimulation of axons (0.27 ms), the mean chronaxie time for extracellular stimulation of cells (0.38
ms) was comparable to that for extracellular stimulation of axons.
In general, there are not significant
differences between the chronaxie times of cells and axons measured with
extracellular stimulation. This lack of sensitivity of the chronaxie time to the
neuronal element stimulated arises because action potential initiation occurs
in the axon, even with the electrode positioned over the cell [4]. This finding points out the difficulty in
drawing conclusions regarding which neuronal elements are activated based on measurements
of chronaxie times, and thus the conclusion of [1] and [3] that large diameter
axons are responsible for the effects of DBS may need to be reconsidered.
Acknowledgment
This work was
supported by NIH Grant RO1 NS-40894.
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