MOTOR SYSTEMS NEUROREPORT

Deep brain stimulation creates an informational

lesion of the stimulated nucleus
Warren M. Grill,CA Andrea N. Snyder and Svjetlana Miocinovic

Department of Biomedical Engineering, Case Western Reserve University, Wickenden Bldg., Rm.114, Cleveland, OH 44106 - 4912, USA
CA
Corresponding Author: wmg@po.cwru.edu

Received 2 February 2004; accepted 2 March 2004

DOI: 10.1097/01.wnr.0000125783.35268.9f

Deep brain stimulation (DBS) is an e¡ective treatment for move-
ment disorders, but the mechanisms are unclear. DBS generates
inhibition of neurons surrounding the electrode while simulta-
neously activating the output axons of local neurons. This dual ef-
fect does not explain two hallmarks of DBS e¡ectiveness:
symptom relief is dependent on using a su⁄ciently high-stimulation
frequency, and clinical e¡ects are analogous to those produced by
lesion. The e¡ect of DBS at di¡erent frequencies on the output of
intrinsically active neurons was studied using computational mod-
els. DBS produced frequency-dependent modulation of the varia-
bility of neuronal output, and above a critical frequency
stimulation resulted in regular output with zero variance. The
resulting loss of information o¡ers an explanation for the two
hallmarks of DBS e¡ectiveness. NeuroReport 15:1137^1140
c 2004
Lippincott Williams & Wilkins.

Key words: Computational neuroscience; Electric stimulation; Movement disorders; Neural model; Tremor

INTRODUCTION
Application of high-frequency (B120–180 Hz) extracellular
stimulation (deep brain stimulation, DBS) in several brain
targets is an effective treatment for movement disorders
including essential tremor, Parkinson’s disease, and dysto-
nia [1]. However, the mechanisms of action of DBS are
poorly understood and this lack of understanding limits the
full development and application of this promising therapy
[2,3].
Any mechanism(s) proposed to explain DBS must be
consistent with two hallmarks of DBS effectiveness. First,
the overt clinical effects of DBS in different brain nuclei are
similar to effects produced by destructive lesions in the
same nuclei, including the ventralis intermedius nucleus of
the thalamus, the internal segment of the globus pallidus,
and the subthalamic nucleus [1,4,5]. Second, the relief of
symptoms by DBS is strongly dependent on stimulation
frequency, with low-frequency stimulation often exacerbat-
ing symptoms and only high-frequency (4100 Hz) stimula-
tion providing symptom relief [6–8]. The similarity in
outcomes between DBS and lesion led to the proposition
that DBS inactivates or inhibits the structures being
stimulated. Recordings made in the stimulated nucleus
show inhibition and/or decreased activity during and after
the stimulus train [9–11]. However, recordings made from
efferent nuclei downstream from the stimulated nucleus
indicate that DBS increases the output of the stimulated
nucleus [12–14]. These results appear to be contradictory,
with the former indicating that DBS inhibits the stimulated
nucleus and the latter indicating that DBS excites the
nucleus. We previously used quantitative models to reveal
that DBS inhibits the cell bodies of neurons surrounding the
electrode, by activation of presynaptic terminals, while
simultaneously stimulating the output of local neurons, by
initiation of action potentials in the axon remote from the
soma [2,15]. This dual effect of DBS resolves an apparent
paradox in the experimental literature, but does not explain
two of the hallmarks of the effectiveness of DBS. Here we
investigate a novel mechanism: activity-dependent changes
in the information content of the output of the stimulated
nucleus. The results demonstrate that frequency-dependent
interactions between intrinsic neuronal activity and extrinsic
stimulation (DBS) account for the frequency dependence of
DBS effectiveness, and that the similarity to lesion arises
from the lack of information content (informational lesion)
present in the output firing of the nucleus during activation
by high-frequency DBS.
MATERIALS AND METHODS
The effect of extracellular stimulation at different frequen-
cies (fext) on the output of an intrinsically active neuron (fint)
was studied using two neuronal models. A simple integrate-
and-fire neuron was used first, and results were subse-
quently confirmed in a three-dimensional cable model of a
thalamocortical relay cell with a full complement of non-
linear membrane conductances [15].
The membrane potential, Vm, in the integrate-and-fire
neuron was given by dVdtm ¼ Rin IðtÞV
m
m
, where Rin is the input
resistance of the cell (15 M O), I(t) is the injected current, and
tm is the membrane time constant (0.01 s). If Vm(t) exceeded
a threshold voltage, T(t), then the cell fired a spike and

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 NEUROREPORT
Vm was reset to zero. T(t) was infinite during the absolute
refractory period (tref ¼ 0.001 s), and thereafter was a time-
variant function given by TðtÞ ¼ ttlast1ref þ Tð0Þ where
t1¼2  105 Vs and T(0)¼0.02 V are constants, and tlast is
the time an action potential was last fired [16]. The integrate-
and-fire neuron exhibited a sigmoidal relationship between
firing rate (0–1000 Hz) and current amplitude over a range
of injected currents (1–1000 nA).
The cable model of a thalamocortical (TC) relay neuron
[15] included explicit representations of the branching
dendritic tree, soma, and axon with geometry obtained
from a three-dimensional reconstruction of a filled TC cell.
The membrane properties were based on previous modeling
and experimental studies, and the model replicated the
electrophysiological properties of thalamic neurons mea-
sured in vitro, including membrane-potential-dependent
responses to depolarizing current steps, steady-state firing
rate as a function of injected current amplitude, and
rebound bursting following release from hyperpolarization.
In both models intrinsic activity was generated using
intracellular current injection where the magnitude and
pattern of the injected current were adjusted to produce
regular spiking, random spiking, or burst firing. Extrinsic
(DBS) stimulation was suprathreshold and generated a
spike in the axon that propagated antidromically back to the
cell body as well as orthodromically to the terminal end. In
the integrate-and-fire neuron, the propagation time from the
axon to the soma was 0.00167 s to model a 0.01 m
propagation distance at 6 m/s. The output of the neuron,
defined by the action potential train in the terminal axon,
was recorded for different patterns of intrinsic activity and
different frequencies of extrinsic stimulation. Output was
quantified by determining the mean and standard devia-
tions of the interspike interval over periods of Z 1 s (Z 2 s
for bursting TC model), and the coefficient of variation,
defined as the standard deviation divided by the mean, was
used as a measure of variability and information content of
the output train [17].
RESULTS
The effect of extrinsic stimulation (fext) on the output of
intrinsically active neurons (fint) was similar for both the
integrate-and-fire model neuron and the thalamocortical
relay cell model. The interaction between the intrinsic
activity and extrinsic stimulation was strongly dependent
on the values of fint and fext. Low-frequency stimulation
evoked activity that approximately superposed with the
intrinsic activity of the neuron (Fig. 1b). The superposition
of intrinsic and stimulation-evoked activity at low fext
increased the coefficient of variation of the output train
(Fig. 1d). As the stimulation frequency was increased above
fint it began to mask the intrinsic activity of the cell and
stimulation decreased the coefficient of variation of the
output train. Above a critical frequency, where fext was
sufficiently greater than fint, the intrinsic activity of the cell
was completely masked by the stimulus train, and the
output of the cell followed one to one with the stimulus
train (Fig. 1c). The suppression of intrinsic activity by
external stimulation resulted in a coefficient of variation of
the output that was equal to zero (Fig. 1d). The critical fext
above which the output firing of the neuron was equal to the
stimulation rate was larger for higher intrinsic firing rates of
the neuron (Fig. 1d).
113 8 Vol 15 No 7 19 May 2004
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W. M.GRILL, A. N. SNYDER AND S. MIOCINOVIC
(a)
(b)
(c)
0 0.2 0.4 0.6 0.8 1
Time (s)
(d)
3 1
Intrinsic firing rate
2.5
0.8
Coefficient of variation
20 ± 5 Hz
Coefficient of variation
2 100 ± 10 Hz
30 Hz 0.6
1.5 90 Hz
0.4
1
0.5 0.2
0
0 50 100 150 200
Stimulation frequency (Hz)
Fig. 1. Interactions between extracellular stimulation and intrinsically
active model neurons. (a^c) rasters of the pattern of output of the inte-
grate-and-¢re neuron model ¢ring at an intrinsic rate of 20 7 5 Hz with
no stimulation (a), 20 Hz extracellular stimulation (b) and100 Hz extracel-
lular stimulation (c). (d) Coe⁄cient of variation of the output ¢ring rate in
the integrate-and-¢re neuron model (¢lled symbols, left axis) and the tha-
lamocortical relay cell model (open symbol, right axis) for di¡erent rates
of intrinsic activity and extrinsic stimulation.
The masking of intrinsic activity by the activity generated
by extrinsic stimulation occurred in two ways. First,
antidromic action potentials generated in the axon by
extrinsic stimulation collided with and abolished intrinsic
orthodromic activity originating in the soma or initial
segment. Second, antidromic activity invaded the soma,
generating an action potential and rendering the cell
refractory to subsequent intrinsic activation.
In model neurons that were bursting (30 ms bursts
appearing at 4 Hz with a 210 Hz intraburst frequency) with
a pattern of activity analogous to that recorded in human
thalamic neurons (Fig. 2a) [18], similar stimulation-
frequency-dependent interactions occurred between the
extrinisic stimulus and the intrinsic activity of the cell.
Low-frequency stimuli superposed with the intrinsic burst
activity (Fig. 2b,c), resulting in an increased variance in the
output (Fig. 2d). High-frequency stimuli masked the
intrinsic burst activity (Fig. 2b,c), and above a critical
frequency reduced the variance in the output to zero
(Fig. 2d). The resulting pattern of coefficient of variation of
the output as a function of fext was similar across the two
 DBS CREATES AN INFORMATIONAL LESION
(a) (d)
1.2
Coefficient of variation
1 IF
TCR
0.8
(b)
0.6
0.4
0.2
0 resulting in increases in transmitter release [14] and
0 50 100 150 200
Stimulation frequency (Hz)
(c) (e)
2 efferent targets of thalamic output in the primary and
Log (tremor)
1 increase the degree of synaptic transmission of information
0
−1
0 5 0 100 150 200
Stimulation frequency (Hz)
Fig. 2. Interactions between extracellular stimulation and intrinsically
bursting neurons. (a) Extracellular recording of a bursting cell in human
thalamus (from [18]). (b) Activity in the integrate-and-¢re model neuron,
made to burst with intracellular current injection, with no extracellular
stimulation (top) and with 20 Hz extracellular stimulation (bottom). (c)
Activity in the thalamocortical relay model neuron, made to burst with
intracellular current injection, with no extracellular stimulation (top),
with 20 Hz extracellular stimulation (middle), and with 100 Hz extracellu-
lar stimulation (bottom). Bar is 0.5 s for a,b and c. (d) Coe⁄cient of
variation of the output ¢ring of bursting integrate-and-¢re (IF) and thala-
mocortical relay (TCR) model neurons as a function of the frequency of
extracellular stimulation. (e) Tremor amplitude as a function of stimula-
tion frequency through a DBS electrode implanted in the ventral inter-
mediate nucleus of the thalamus of a person with essential tremor [8].
models. Further, the shape of this curve, especially from the
TCR model, matched remarkably well the shape of the
trends in tremor amplitude as a function of DBS frequency
measured in a person with essential tremor [8].
DISCUSSION
The present study of the interaction between extracellular
extrinsic stimuli and intrinsic neuronal activity reveals that
deep brain stimulation (DBS) produces frequency-depen-
dent modulation of the variability (and thus information
content) of neuronal output. As stimulation frequency was
increased, the model predicted a decrease in the coefficient
of variation of firing frequency of the stimulated neuron
(which relates to the information content of the firing
pattern). This appears to match with the experimental data
that show that as stimulation frequency increases, tremor
decreases and offers an explanation for the two hallmarks of
the effectiveness of DBS. However, it should be noted that
while DBS may override pathological activity patterns, the
resulting pattern of constant frequency firing is not normal.
Bursting of cells within the basal ganglia appears to be a
common feature of movement disorders, and tremor
appears to result from low-frequency rhythmic oscillation
within the basal ganglia and thalamus [19]. Further, bursting
cells possess and transmit a large amount of information
content [20], and it appears that transmission of this
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
NEUROREPORT
pathological information within thalamus–basal-ganglia–
cortical circuits contributes to symptoms of movement
disorders [21,22]. The present results indicate that DBS
masks this intrinsic activity and the resulting informational
lesion prevents the pathological activity from being trans-
mitted within the basal ganglia.
This finding that DBS activates the output of the
stimulated nucleus is consistent with the findings that
DBS increases the output of the stimulated nucleus,
sustained activation of postsynaptic neurons [12,13] in
efferent nuclei. PET studies suggest that thalamic DBS
increases activity of neurons in the thalamus as well as in
supplementary motor cortex [23]. While bursts appear to
[20], continuous high-frequency activation may lead to
synaptic depression or depletion and neurons activated by
the stimulus train may be unable to sustain signaling [24].
However, the latter possibility was not reflected in record-
ings from post-synaptic efferent nuclei, which revealed
persistent effects over minutes [12,13].
The similarity of findings in the simple integrate-and-fire
model and the complex thalamocortical relay cell model
implies that the specific membrane properties of the neuron
did not play a strong role in the interactions between
intrinsic neuronal activity and extrinsic stimulation. This is
not surprising, given previous results indicating that,
during extracellular stimulation, action potential initiation
occurs in the axon [15,25], and thus its properties dominate.
Therefore, although these simulations were focused on
thalamic neurons, it is likely that the results are representa-
tive of what will occur in other brain regions. Similarly, the
presence of a complement of inhibitory and excitatory
synaptic inputs to the thalamocortical relay cell, activated
with each extracellular stimulus pulse [15], did not modify
in a substantial way the coefficient of variation of the output
of the thalamocortical relay neuron in response to DBS-like
extracellular stimulation (data not shown). This is again
consistent with the finding that, during extracellular
stimulation, action potential initiation occurs in the axon
[25], and is thus minimally impacted by synaptic inputs to
the soma [15].
CONCLUSION
The effect of DBS at different frequencies on the output of
intrinsically active neurons was studied using computa-
tional models. DBS produced frequency-dependent mod-
ulation of the variability of neuronal output, and above a
critical frequency extrinsic stimulation masked all intrinsic
activity. The lack of information content in the resulting
regularly firing output with zero variance offers an
explanation for the two hallmarks of DBS effectiveness:
symptom relief is dependent on using a sufficiently high-
stimulation frequency, and clinical effects are analogous to
those produced by lesion. These results suggest that DBS
has its effects by masking the transmission of pathological
activity within thalamus–basal-ganglia–cortical networks.
REFERENCES
1. Gross RE and Lozano AM. Advances in neurostimulation for movement
disorders. Neurol Res 2000; 22:247–258.
Vol 15 No 7 19 May 2004 113 9
 NEUROREPORT
2. Grill WM and McIntyre CC. Extracellular excitation of central neurons:
implications for the mechanisms of deep brain stimulation. Thalamus Rel
Syst 2001; 1:269–277.
3. Dostrovsky JO and Lozano AM. Mechanisms of deep brain stimulation.
Mov Disord 2002; 17(Suppl. 3):63–68.
4. Obeso JA, Olanow CW, Rodriguez-Oroz MC, Krack P, Kumar R and Lang
AE. Deep-brain stimulation of the subthalamic nucleus or the pars
interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001;
345:956–963.
5. Schurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie
RM et al. A comparison of continuous thalamic stimulation and
thalamotomy for suppression of severe tremor. N Engl J Med 2000;
342:461–468.
6. Benabid AL, Pollak, P, Gervason C, Hoffman D, Gao D, Hommel M et al.
Long-term suppression of tremor by chronic stimulation of the
ventral intermediate nucleus thalamic nucleus. Lancet 1991; 337:
403–406.
7. Limousin P, Pollack P and Bena ouz A. Effect on Parkinsonian signs and
symptoms of bilateral stimulation. Lancet 1995; 345:91–95.
8. Kuncel AM, Cooper SE, Montgomery EB and Grill WM. Effect of
stimulus parameters on tremor suppression and paresthesias evoked by
thalamic deep brain stimulation. Soc Neurosci Abstr 2003; 29.
9. Benazzouz A, Gao DM, Ni ZG, Piallat B, Bouali-Benazzouz R and
Benabid AL. Effect of high-frequency stimulation of the subthalamic
nucleus on the neuronal activities of the substantia nigra pars reticulata
and ventrolateral nucleus of the thalamus in the rat. Neuroscience 2000;
99:289–295.
10. Boraud T, Bezard E, Bioulac B and Gross C. High frequency
stimulation of the internal globus pallidus (GPi) simultaneously
improves parkinsonian symptoms and reduces the firing frequency
of GPi neurons in the MPTP-treated monkey. Neurosci Lett 1996; 215:
17–20.
11. Dostrovsky JO, Levy R, Wu JP, Hutchison WD, Tasker RR and Lozano
AM. Microstimulation-induced inhibition of neuronal firing in human
globus pallidus. J Neurophysiol 2000; 84:570–574.
12. Anderson ME, Postupna N and Ruffo M. Effects of high-frequency
stimulation in the internal globus pallidus on the activity of
thalamic neurons in the awake monkey. J Neurophysiol 2003; 89:
1150–1160.
Acknowledgements: This work is supported by the National Institutes of Health DBS Consortium through NIH R01NS40894.
114 0 Vol 15 No 7 19 May 2004
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
W. M.GRILL, A. N. SNYDER AND S. MIOCINOVIC
13. Hashimoto T, Elder CM, Okun MS, Patrick SK and Vitek JL. Stimulation
of the subthalamic nucleus changes the firing pattern of pallidal neurons.
J Neurosci 2003; 23:1916–1923.
14. Windels F, Bruet N, Poupard A, Feuerstein C, Bertrand A and Savasta M.
Influence of the frequency parameter on extracellular glutamate and
gamma-aminobutyric acid in substantia nigra and globus pallidus during
electrical stimulation of subthalamic nucleus in rats. J Neurosci Res 2003;
72:259–267.
15. McIntyre CC, Grill WM, Sherman DL and Thakor NV. Cellular effects
of deep brain stimulation: model-based analysis of activation and
inhibition. J Neurophysiol 2004; 91:1457–1469.
16. Rappel W-J, Karma A. Noise-induced coherence in neural networks. Phys
Rev Lett 1996; 77:3256–3259.
17. Dayan P, Abbott LF. Information Theory in Theoretical Neuroscience.
Cambridge, MA: MIT Press; 2001, pp. 123–149.
18. Magnin M, Morel A and Jeanmonod D. Single-unit analysis of the
pallidum, thalamus and subthalamic nucleus in parkinsonian patients.
Neuroscience 2000; 96:549–564.
19. Deuschl G, Raethjen J, Lindemann M and Krack P. The pathophysiology
of tremor. Muscle Nerve 2001; 24:716–735.
20. Izhikevich EM, Deai NS, Walcott EC and Hoppensteadt FC. Bursts as a
unit of neural information: selective communication via resonance. Trends
Neurosci 2003; 26:161–167.
21. Llinas RR, Ribary U, Jeanmonod D, Kronberg E and Mitra PP.
Thalamocortical dysrhythmia: a neurological and neuropsychiatric
syndrome characterized by magnetoencephalography. Proc Natl Acad
Sci USA 1999; 96:15222–15227.
22. Timmermann L, Gross J, Dirks M, Volkmann J, Freund H-J and Schnitzler
A. The cerebral oscillatory network of parkinsonian resting tremor. Brain
2003; 126:199–212.
23. Perlmutter JS, Mink JW, Bastian AJ, Zackowski K, Hershey T, Miyawaki E
et al. Blood flow responses to deep brain stimulation of thalamus.
Neurology 2002; 58:1388–1394.
24. Urbano FJ, Leznik E and Llinas RR. Cortical activation patterns
evoked by afferent axons stimuli at different frequencies: an in vitro
voltage-sensitive dye imaging study. Thalamus Rel Syst 2002; 1:371–378.
25. Nowak LG and Bullier J. Axons, but not cell bodies, are activated by
electrical stimulation in cortical gray matter. I. Evidence from chronaxie
measurements. Exp Brain Res 1998; 118:477–488.