Download Direct and Indirect Activation of Cortical Neurons by Electrical

J Neurophysiol 96: 512–521, 2006;
doi:10.1152/jn.00126.2006.
Invited Review
Direct and Indirect Activation of Cortical Neurons by Electrical Microstimulation
E. J. Tehovnik,1 A. S. Tolias,2 F. Sultan,3 W. M. Slocum,1 and N. K. Logothetis2
1
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts; 2Max Planck Institute
for Biological Cybernetics, Tuebingen; and 3Department of Cognitive Neurology, Hertie-Institute for Clinical Brain Research, University
of Tuebingen, Tuebingen, Germany
Submitted 5 February 2006; accepted in final form 30 April 2006
INTRODUCTION
Electrical stimulation of neural tissue has been in use for
over 100 yr (at least since 1870, Fritch and Hitzig) and,
although some have argued it is an imprecise technique for
understanding the detailed mechanisms underlying different
neural computations, microstimulation has actually contributed
to important successes both in clinical applications and in
uncovering the secrets of how the brain mediates various
psychological processes. For example, electrical stimulation
has made it possible to restore hearing to deaf patients by
delivering microampere pulses by implanted electrodes to
different regions of the cochlea (Bierer and Middlebrooks
2002, 2004; Fu 2005; Middlebrooks and Bierer 2002; Snyder
et al. 2004). Stimulation of the basal ganglia has been remarkably effective in restoring motor function to Parkinsonian
patients (Dostrovsky and Lozano 2002; Dostrovsky et al. 2000;
Limousin et al. 1995; MacKinnon et al. 2005). In the same
vein, microstimulation of the visual pathway is currently regarded as a very promising method for making the blind see
again (Bartlett et al. 2005; Bradley et al. 2005; DeYoe et al.
2005; Merabet et al. 2005; Pezaris and Reid 2004; Schmidt et
al. 1996; Tehovnik et al. 2005a; Zrenner 2002).
Address for reprint requests and other correspondence: E. J. Tehovnik,
Massachusetts Institute of Techology, Bldg. 46-6041, Cambridge, MA 02139
(E-mail: [email protected]).
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Equally important is the contribution of microstimulation in
suggesting causal links between brain structures and behavior.
Stimulation has been used to study pathways in the brain that
subserve reward (Gallistel et al. 1981), as well as pathways
involved in locomotion and startle responses (Yeomans and
Frankland 1996; Yeomans and Tehovnik 1988). Its use has
disclosed topographic maps in primary visual cortex (area V1),
the supplementary eye fields, frontal eye fields, and the superior colliculus for the generation of ocular responses (Robinson
1972; Robinson and Fuchs 1969; Schäfer 1988; Tehovnik and
Lee 1993). Additionally it has led to the elucidation of topographic maps in the motor and supplementary motor areas for
the execution of skeletomotor responses (Fritch and Hitzig
1870; Graziano et al. 2002; Penfield and Boldrey 1937; Strick
and Preston 1978; Woolsey et al. 1952, 1979). Finally, electrical stimulation has been used to study cortical function as it
pertains to the sense of vision, hearing, and touch (Britten and
van Wezel 1998; DeAngelis et al. 1998; Penfield and Boldrey
1937; Penfield and Perot 1963; Romo et al. 1998; Salzman et
al. 1990).
Many investigators are currently using electrical microstimulation routinely in behaving monkeys to make inferences
on how neocortex mediates a range of behaviors, from target
selection to avoidance responses (e.g., Cooke et al. 2003;
Cutrell and Marrocco 2002; Moore and Armstrong 2003;
Moore and Fallah 2001; Opris et al. 2005; Schiller and
Tehovnik 2001; Tehovnik et al. 2005a). In all such studies it is
important to characterize the neural circuits that are activated
during microstimulation both locally about the electrode tip
and in projection sites. In this regard, two issues are of
paramount importance: the need of accurate estimates of
effective current spread and its effects on the excitable
elements of the tissue. Our review therefore discusses both
issues based on single-cell recording, behavioral methods, and
neuroimaging.
EFFECTIVE CURRENT SPREAD USING DIRECT
ACTIVATION OF CORTICAL NEURONS
Spread and excitability properties
It is commonly accepted that the sites of direct activation of
a neuron with electrical microstimulation are at the initial
segment and nodes of Ranvier (Gustaffson and Jankowska
1976; Nowak and Bullier 1998a,b; Porter 1963; Rattay 1999;
Swadlow 1992). These zones contain the highest concentrations of sodium channels, thereby making them the most
excitable segments of a neuron (Catterall 1981; Nowak and
Bullier 1998a,b; Waxman and Quick 1978). The amount of
0022-3077/06 $8.00 Copyright © 2006 The American Physiological Society
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Tehovnik, E. J., A. S. Tolias, F. Sultan, W. M. Slocum, and N. K.
Logothetis. Direct and indirect activation of cortical neurons by
electrical microstimulation. J Neurophysiol 96: 512–521, 2006;
doi:10.1152/jn.00126.2006. Electrical microstimulation has been used
to elucidate cortical function. This review discusses neuronal excitability and effective current spread estimated by using three different
methods: 1) single-cell recording, 2) behavioral methods, and 3)
functional magnetic resonance imaging (fMRI). The excitability properties of the stimulated elements in neocortex obtained using these
methods were found to be comparable. These properties suggested
that microstimulation activates the most excitable elements in cortex,
that is, by and large the fibers of the pyramidal cells. Effective current
spread within neocortex was found to be greater when measured
with fMRI compared with measures based on single-cell recording
or behavioral methods. The spread of activity based on behavioral
methods is in close agreement with the spread based on the direct
activation of neurons (as opposed to those activated synaptically).
We argue that the greater activation with imaging is attributed to
transynaptic spread, which includes subthreshold activation of
sites connected to the site of stimulation. The definition of effective current spread therefore depends on the neural event being
measured.
Invited Review
ACTIVATION BY ELECTRICAL MICROSTIMULATION
trode was advanced toward and beyond the element being
stimulated.
The effective current spread from an electrode tip can be
expressed as the square root of the current divided by the
square root of the excitability constant, i.e., (I/K)1/2. This
relationship is illustrated in Fig. 1A for a group of pyramidal
tract neurons that were identified antidromically by pontine
stimulation in cats (Stoney et al. 1968). To activate a neuron
from the cortex, a 0.2-ms cathodal pulse was delivered through
a microelectrode (Fig. 1, methods). The amount of current
required for the evocation of an action potential 50% of the
time defined the current threshold. As the electrode was
advanced toward and past the neuron, the current threshold
dropped and then increased accordingly (Fig. 1, methods,
electrode S: a– c). The rate of change of the current threshold
with electrode displacement was used to deduce the excitability
constant. For the group of pyramidal tract neurons, the average
excitability constant was 1,292 ␮A/mm2. This constant reflects
FIG. 1. Current-spread and excitability properties of pyramidal tract neurons determined using single-cell recordings within motor cortex of the cat. A: radial
distance (in millimeters) of direct activation of pyramidal tract neurons using the equation radial distance ⫽ (K/I)1/2, where K is the current– distance constant
and I is the current used. Curve represents the amount of current required for the antidromic elicitation of an action potential 50% of the time using a single
cathodal pulse of 0.2-ms duration. For the 12 cells studied the average K value was 1,292 ␮A/mm2. Shaded gray area about the curve represents 1 SE, with K
values ranging from 1,037 to 1,547 ␮A/mm2. Data derived from Stoney et al. (1968). B: current threshold normalized to the rheobase current (IRo) is plotted
as a function of pulse duration for the direct activation of 6 pyramidal tract neurons. Rheobase current is the current used at the longest pulse duration of 1.0
ms. Each curve represents data from a single neuron. A curve represents the amount of current at a given pulse duration required for the antidromic elicitation
of an action potential 50% of the time using a single cathodal pulse. Shaded area represents the range of chronaxies for the neurons stimulated. A chronaxie is
the pulse duration at a current level of twice the rheobase current. Data from Asanuma et al. (1976) and Stoney et al. (1968). Method used by Asanuma et al.
(1976) and Stoney et al. (1968) to derive the data in A and B is illustrated on the right. Recording electrode (R) and stimulating electrode (S), both situated next
to the pyramidal tract cell, are depicted to scale. Exposed microelectrode tips, shown as a black triangle, were constructed to have a diameter of 10 ␮m and a
length of 15 ␮m. Each dotted circle represents the field of effective stimulation produced by one cathodal pulse that activates the neuron’s initial segment (IS),
which is the lowest current threshold site at the cell body before the start of the axon (Gustaffson and Jankowska 1976). Each field of effective stimulation is
centered on a different electrode tip (a– c), indicating the path of the stimulating electrode. Electrode tip b is located at the lowest-threshold locus for current as
indicated by the smallest field of stimulation. A scale bar is shown.
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current injected through a microelectrode to directly activate a
neuron (i.e., cell body or axon) is proportional to the square of
the distance between the neuron and the electrode tip. This is
expressed as I ⫽ Kr2, where I is the current level (in microamperes [␮A]), r is distance (in millimeters [mm]), and K is the
excitability constant (in ␮A/mm2). This relationship is derived
from studies of cortical and corticospinal neurons of rats, cats,
and primates (Asanuma et al. 1976; Marcus et al. 1979; Nowak
and Bullier 1996; Shinoda et al. 1976, 1979; Stoney et al.
1968); dopaminergic fibers of the medial forebrain bundle in
rats (Yeomans et al. 1988); cerebellar and reticulospinal fibers
of rats, rabbits, and cats (Akaike et al. 1973; Armstrong et al.
1973b; Hentall et al. 1984a; Jankowska and Roberts 1972;
Roberts and Smith 1973); cell bodies of cat spinal motor
neurons (Gustaffson and Jankoska 1976); and axons of spinal
interneurons of cats (Jankowska and Roberts 1972). In these
studies, a single cathodal pulse was used to evoke an antidromic extracellular action potential as the stimulating elec-
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TEHOVNIK ET AL.
Strength– duration functions and estimates of excitability
To deduce the excitability of stimulated neurons, current can
be traded off against pulse duration to elicit some response
(Armstrong et al. 1973a; Asanuma et al. 1976; Bartlett et al.
2005; BeMent and Ranck 1969; Brindley and Lewin 1968;
Dobelle and Mladejovsky 1974; Farber et al. 1997; Grumet et
al. 2000; Hentall et al. 1984b; Jankowska and Roberts 1972; Li
and Bak 1976; Matthews 1977; Nowak and Bullier 1998a;
Ronner and Lee 1983; Rushton and Brindley 1978; Sekirnjak
et al. 2006; Shizgal et al. 1991; Stoney et al. 1968; Swadlow
1992; Tehovnik and Lee 1993; Tehovnik and Sommer 1997;
Tehovnik et al. 2003; Tolias et al. 2005; West and Wolstencroft
1983; Yeomans et al. 1988). This procedure is used to generate
a strength– duration function. Normalized strength– duration
functions for pyramidal tract neurons are illustrated [Fig. 1B,
derived from Asanuma et al. (1976) and Stoney et al. (1968)].
As the pulse duration is increased, the amount of current
needed to evoke an action potential 50% of the time diminishes
to some asymptotic level; this level is called the rheobase
current. The excitability or chronaxie of a stimulated element
is expressed as the pulse duration at twice the rheobase current.
The range of chronaxies for pyramidal tract neurons is illustrated in Fig. 1B in gray. These neurons exhibit chronaxies
ranging between 0.1 and 0.4 ms.
The shorter the chronaxie the more excitable a directly
stimulated neural element. Axons have shorter chronaxies than
those of cell bodies (axons: 0.03–7 ms; cell bodies: 7–31 ms;
Nowak and Bullier 1998a; Ranck 1975), and large, myelinated
axons have shorter chronaxies than those of small, nonmyelinated axons (large: 0.03– 0.7 ms; small: ⬎1.0 ms; Li and Bak
1976; Ranck 1975; West and Wolstencroft 1983). A chronaxie
is negatively correlated with the conduction velocity of axons
(Nowak and Bullier 1998a; Swadlow 1992; West and Wolstencroft 1983) and positively correlated with their refractory
period (Shizgal et al. 1991). The chronaxie is related to the
time constant of the directly stimulated membrane of a neuron
(Ranck 1975), which depends on a membrane’s resistance and
capacitance (Bostock 1983; Bostock et al. 1983).
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EFFECTIVE CURRENT SPREAD USING
BEHAVIORAL METHODS
Spread properties
Several investigators have used behavioral methods to
estimate how far current activates neural tissue mediating
behaviors such as eating (Olds 1958), self-stimulation (Fouriezos and Wise 1984; Milner and Lafarriere 1986; Wise
1972), and lateral head and body movements (Yeomans et
al. 1986). These estimates are based on the activation of
subcortical fibers. Two groups have studied the currentspread properties of electrical stimulation within neocortex
using behavioral methods. Murasugi et al. (1993) studied
such properties in extrastriate area MT (middle temporal
cortex) and Tehovnik et al. (2004, 2005b) conducted current-spread studies in striate area V1.
Murasugi et al. (1993) stimulated area MT of monkeys with
1-s trains composed of 0.2-ms pulses delivered at 200 Hz to
bias a monkey’s discrimination of the direction of dot motion.
The motion stimuli were presented in the receptive field of the
stimulated neurons, which were tuned to a particular direction
of motion. Murasugi et al. found that for the range of currents
tested (i.e., 10 to 80 ␮A), currents ⬎20 ␮A biased a monkey’s
discrimination abilities less well and began to obscure performance. Thus it can be presumed that ⱕ20 ␮A activates neural
tissue confined to roughly one “directional” column in MT.
The approximate width of such a column is about 0.2 mm
(Albright et al. 1984). The average excitability constant of the
activated elements in MT is therefore estimated to be 2,000
␮A/mm2 [K ⫽ 20 ␮A/(0.1 mm)2]. Finally, for pulse frequencies as high as 500 Hz (using 10-␮A current pulses), a
monkey’s performance on the discrimination task was never
obscured; this suggests that such high frequencies delivered in
1-s trains exhibit effects confined to 0.2 mm of cortical tissue.
Tehovnik et al. (2004) found that microstimulation of V1
(with 100-ms trains using 0.2-ms pulses delivered at 200 Hz)
systematically delayed the execution of visually guided saccades as long as the stimulation was delivered immediately
before a monkey generates the saccade (i.e., at the end of the
fixation period before the onset of the visual target) and as long
as the visual target was punctate (⬍0.4° of visual angle) and
located within the center of the receptive field of the stimulated
neurons. No delay effect occurred to targets located outside of
the receptive field of the stimulated neurons. It was later found
that the size of the visual field affected by the stimulation,
called a delay field, varied as a function of the site of stimulation within the operculum of V1 and it also varied as a
function of current (Tehovnik et al. 2005b). A summary of the
data from this study is illustrated in Fig. 2, A and B. As the
stimulating electrode was situated further from the foveal
representation of V1 the size of the delay field increased. For
stimulations of cells having receptive field centers at 2, 3, and
4° from the fovea, the size of the delay field was 0.14, 0.24, and
0.35° of visual angle when using 100 ␮A and 0.09, 0.19, and
0.29° of visual angle when using 50 ␮A, respectively. The size
of the visual field affected by stimulation can yield an estimate
of how far the current spreads in V1 by using the visual
magnification factor for V1 to convert size of visual field to
area of tissue responsive to that field (see caption of Fig. 2C for
detailed calculation). The amount of V1 tissue activated with
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the excitability of a neural element 1 mm away from the
electrode tip such that an element having a constant of 1,292
␮A/mm2 would require a 1,292-␮A current to be activated 1
mm away 50% of the time.
Increases in the excitability constant have been associated
with decreases in the conduction velocity of an axonal element
(Hentall et al. 1984a; Jankowska and Roberts 1972; Nowak
and Bullier 1996; Roberts and Smith 1973). The conduction
velocities of myelinated pyramidal tract neurons range from 3
to 80 m/s with the largest of these neurons exhibiting the
highest velocities (Calvin and Sypert 1976; Deschenes et al.
1979; Finlay et al. 1976; Macpherson et al. 1982; Phillips
1956; Takahashi 1965); the conduction velocities of small
unmyelinated cortical fibers are ⬍1 m/s (Nowak and Bullier
1996; Swadlow 1985). The excitability constant derived with a
0.2-ms pulse can be as low as 300 ␮A/mm2 for the largest
myelinated cortical neurons and as high to 27,000 ␮A/mm2 for
the smallest unmyelinated cortical neurons (Nowak and Bullier
1996; Stoney et al. 1968). In other words, this constant is
inversely related to the size of a neuron’s axon and to whether
it is myelinated.
Invited Review
ACTIVATION BY ELECTRICAL MICROSTIMULATION
50- and 100-␮A current was estimated to be 0.572 and 0.736
mm, respectively, yielding a spread of 0.286 and 0.368 mm
from the electrode tip. The average excitability constant of the
directly activated elements in V1 is therefore estimated to be
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675 ␮A/mm2 [K ⫽ {50 ␮A/(0.286 mm)2 ⫹ 100 ␮A/(0.368
mm)2}/2]. Using this value, the distance of the effective spread
of stimulation in V1 is plotted as a function of current ranging
from 10 to 1,000 ␮A (Fig. 2C).
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FIG. 2. Using the stimulation-evoked delay of visually guided saccades in monkeys to make inferences about current spread and neuronal excitability in the
primary visual cortex (area V1). A: latency difference between stimulation and nonstimulation trials for the generation of visually guided saccades to the target
is plotted as a function of target eccentricity with respect to the receptive-field (RF) location of the stimulated neurons for 100 ␮A. A zero eccentricity along
the x-axis indicates that the target and the RF center of the stimulated neurons were in register (see icon at the bottom right of the figures). Negative values along
the x-axis indicate target positions situated between the fixation position and RF center of the stimulated neurons. Positive values indicate target positions
eccentric to the RF center of the stimulated neurons. Noting the eccentricity value at 50% of the maximal delay for both negative and positive eccentricity values
and computing an average, which was 0.49° of visual angle in this case, determined the size of a delay field. Parameters of stimulation were as follows: anode-first
biphasic pulses were used and current, train duration, pulse duration, and frequency were fixed at 100 ␮A, 100 ms, 0.2 ms, and 200 Hz, respectively. These
parameters (including the use of anodal pulses over cathodal pulses) were selected to optimize the delay effect (see Tehovnik et al. 2004). Anodal pulses are
most effective at activating cell bodies and terminals, whereas cathodal pulses are most effective at activating axons even though in both cases it is the outward
current at the initial segment or nodes of Ranvier that excite a neuron (Armstrong et al. 1973b; McIntyre and Grill 2000; Porter 1963; Ranck 1975; Rattay 1999).
RF center of the stimulated units was at 4.3° from the fovea. Target used was brighter than background at 33% contrast (using the Michaelson contrast equation)
and was 0.2° in diameter. Data from Tehovnik et al. (2005b). B: size of a delay field is plotted as a function of the eccentricity of the RF center of the V1 cells
stimulated for 2 levels of current: 50 and 100 ␮A. Delay-field data points were fitted to linear functions. Stimulation sites were located from 0.9 to 2 mm below
the cortical surface. Parameters of stimulation are indicated in A. Data from Tehovnik et al. (2005b). C: distance of effective current spread is plotted as a function
of current. Function is derived from the data in B as follows: amount of visual field affected by 50 and 100 ␮A was used to infer the amount of tissue activated
at V1 sites coding for 2, 3, and 4° of visual field eccentricity. Based on this, the amount of tissue activated in V1 was determined by noting the magnification
factor for V1 sites coding for 2, 3, and 4° of visual field eccentricity. Amount of tissue activated per current level was then used to estimate the average K (i.e.,
675 ␮A/mm2) using the current– distance equation, K ⫽ I/(R)2 (see Fig. 1A). Following is a detailed calculation for the derivation of a single K value from the
data in B: at an eccentricity of 3°, the size of the delay field was 0.24° using 100 ␮A. Magnification factor at this eccentricity is 0.32°/mm, on average (Dow
et al. 1981; Hubel and Wiesel 1974; Tootell et al. 1988). Therefore the estimated current spread at this V1 site is 0.375 mm [(0.24°/0.32°/mm) ⫻ 1/2].
Current– distance equation yields a K value of 711 ␮A/mm2 [100 ␮A/(0.375 mm)2]. D: current threshold normalized to the rheobase current (IRo) is plotted as
a function of pulse duration. Rheobase current is defined here operationally as the current used at the longest pulse duration (i.e., 0.7 ms). Each of 10 curves
represents the current threshold for inducing a 20-ms increase in latency for saccades generated to a target located at the RF location of the stimulated neurons.
Latency difference of 20 ms is ⬎3 SDs of the mean difference observed when comparing nonstimulation and dummy stimulation trials (SD ⫽ 4.3, n ⫽ 35;
Tehovnik et al. 2004). Each curve shows data from a single stimulation site. Sites were located from 0.5 to 1.5 mm below the cortical surface. See A for details
about the electrical stimulation and visual target parameters. Pulse duration at which a curve intersects 2 units of threshold (designated by the dotted horizontal
line) indicates the chronaxie of the stimulated elements at a site of study. Shaded region indicates the range of chronaxies of the stimulated elements. Data from
Tehovnik et al. (2004). Methods (left): for all trials, a monkey was required to fixate (fix) a fixation spot for 600 ms. At the termination of the fixation spot, a
visual target appeared (targ) and the monkey was required to generate a saccadic eye movement (sacc) to the target to obtain a juice reward (juice). On 50%
of trials electrical stimulation (stim) was delivered at the end of the fixation period to determine whether the stimulation delayed the visually guided saccade.
Methods (right): visual target was presented at various locations with respect to the fixation spot (fix) and RF center of the stimulated neurons.
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Excitability properties
EFFECTIVE CURRENT SPREAD USING fMRI
Spread properties
Recently, Tolias et al. (2005) used fMRI (functional magnetic resonance imaging) that relies on the BOLD (blood
oxygen level– dependent) signal to study to the spread properties of electrical microstimulation delivered to V1 cortex in the
anesthetized monkey. An anesthetized preparation was used to
avoid motion artifact, which would have greatly compromised
the accuracy of the current-spread estimates. All stimulations
of V1 were conducted through microelectrodes positioned
within the gray matter of V1; electrode-tip positions were
validated using anatomical MRI. The electrically evoked
BOLD response was measured using a 4.7-Tesla scanner. To
evoke a BOLD response, a 4-s train of stimulation composed
of 0.2-ms pulses delivered at 100 Hz was used. The train
duration of 4 s concurs with the duration of visual stimulation
used to evoke a fMRI response from V1 (Logothetis et al.
1999, 2001). Figure 3A shows that for current levels of 159 to
1,651 ␮A some 2 to 4.5 mm of cortical tissue was activated
from the electrode tip. For currents ⬎458 ␮A the spread began
to saturate between 3 and 5 mm. The extensive spread of
current as measured with fMRI is consistent with the spread
observed using optical imaging of neocortex where lower
currents were used (Seidemann et al. 2002; Slovin et al. 2003).
Excitability properties
Tolias et al. (2005) determined strength– duration functions
for the activation of 40% of the maximal volume of gray matter
within the operculum using fMRI in anesthetized macaque
monkeys. Some five sites were studied using five monkeys.
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DISCUSSION
This review describes the excitability of neurons and effective spread of electrical microstimulation in neocortex using
three different methods: 1) single-cell recordings of antidromically identified cortical neurons that were activated directly by
the stimulation; 2) behavioral methods used to infer the cortical
spread of the current required to evoke a behavioral response
such as biasing a monkey’s visual behavior by MT stimulation
or delaying a monkey’s visually guided saccades by V1 stimulation; and 3) imaging methods that measured the extent of
neural activation about a stimulating electrode positioned in
cortical area V1. The three methods produced very similar
strength– duration functions yielding chronaxie values that
overlapped and fell between 0.1 and 0.4 ms (cf. Figs. 1B, 2D,
and 3B). In other words, behavioral and imaging methods
corroborate the electrophysiological evidence that electrical
microstimulation activates the most excitable elements in neocortex, that is, primarily the pyramidal fibers (Asanuma et al.
1976; Stoney et al. 1968). The three methods, however, produced different current-spread estimates for cortical stimulation. Single-cell recording and behavioral methods yielded
estimates that were comparable (Fig. 3A, cf. T, S, M). fMRI, on
the other hand, yielded estimates roughly fourfold greater than
those observed using the other methods (Fig. 3A, compare
fMRI “histogram” with functions T, S, and M).
An obvious reason that could account for the observed
difference between the fMRI data and the other measures of
effective current spread is the appreciably larger currents and
longer train durations used in the fMRI study (Tolias et al.
2005). In the unit recording and behavioral experiments the
current was ⬍150 ␮A and the train duration was ⱕ1 s, whereas
in the fMRI experiments the current was greater, typically
falling between 150 and 2,000 ␮A with train durations ⱕ4 s.
To compare the two data sets, the current-spread data of the
unit recording and behavioral experiments had to be extrapolated into the milliampere range using the current– distance
equation, I ⫽ Kr2 (Fig. 3A). It is possible that the greater
functional spread of activation with fMRI does not hold at low
currents and short train durations. However, Seidemann,
Slovin, and colleagues delivered low currents (⬍100 ␮A) and
short train durations (⬍250 ms) to neocortex and found activation far beyond the field of direct stimulation when measured
with optical imaging (Seidemann et al. 2002; Slovin et al.
2003). Moreover, Slovin et al. (2003) reported that a single
pulse of 15 ␮A can activate cortical tissue between 1.5 and 3
mm from the electrode tip. Therefore the greater spread of
activation obtained with fMRI might instead be related to
transynaptic activation.
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The excitability properties of stimulated neurons mediating
a variety of behaviors including self-stimulation (Matthews
1977), conditioning (Bartlett et al. 2005), ocular responses
(Tehovnik and Lee 1993; Tehovnik and Sommer 1997;
Tehovnik et al. 2003, 2004), and phosphene induction (Brindley and Lewin 1968; Dobelle and Mladejovsky 1974; Rushton
and Brindley 1978) were determined by generating strength–
duration functions. As discussed, strength– duration functions
yield the chronaxies of the activated neurons eliciting the
stimulation-evoked response. It is commonly assumed that
chronaxies derived using behavioral measures reflect the current
integration characteristics of the directly stimulated elements and
not those of the follower cells or innervated muscles (for a review
of arguments see Gallistal et al. 1981; also see Tehovnik 1987).
Chronaxies have been deduced for V1 elements inducing the
delay of visually guided saccades (Tehovnik et al. 2004).
Recall that Tehovnik et al. (2005b) used this behavioral response to determine the current-spread properties of stimulation delivered to V1 cortex. The chronaxies of the elements
mediating the delay of saccades ranged between 0.1 and 0.3 ms
(Fig. 2D), which overlaps with the chronaxies described for
pyramidal tract fibers (Fig. 1B). Therefore the stimulated neurons that mediate the delay effect are probably composed of the
largest and most excitable fibers that reside in V1. This is
consistent with the relatively low excitability constant found
for the V1 elements mediating this effect (K ⫽ 675 ␮A/mm2).
Currents from 200 to 1,600 ␮A and pulse durations from 0.05
to 0.6 ms were tested. The chronaxies of the stimulated
elements yielding the stimulation-elicited fMRI response averaged 0.18 ms (Fig. 3B). This value suggests that the evoked
fMRI response does not arise from the activation of relatively
unexcitable tissues such as smooth muscle, which exhibit
chronaxies between 6 and 13 ms (Sibley 1984). The value
coincides with the chronaxies reported for pyramidal fibers
(see Fig. 1B). Therefore the fMRI response generated by
activation of macaque V1 is likely explained by the excitation
of the most excitable cortical neurons.
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Two observations support this notion. First, V1 is composed
of columns that are interconnected by horizontal projections
(Gilbert and Wiesel 1989). In monkeys, these projections
extend laterally by 1 to 4 mm (Blasdel et al. 1985; Fisken et al.
1973; Fitzpatrick et al. 1985; McGuire et al. 1991). This
distance concurs with the lateral spread of the fMRI response,
which is 1.5 to 3.5 mm beyond the fringe of direct stimulation
(Fig. 3A, compare fMRI “histogram” with function S). This
maximal extent corresponds to the maximal extent of the
horizontal projections in V1 and suggests that horizontal projections within cortex might put an upper limit on how much
tissue is activated by focal electrical stimulation when using
fMRI.
Second, stimulation of V1 is found to activate regions of
extrastriate cortex that are connected monosynaptically with
V1 as measured with fMRI. Such stimulation elicits the fMRI
response in V2, V3, V3A, V4, and MT with noticeable gaps in
activity between the site of stimulation in V1 and its extrastriate targets (Tolias et al. 2005). These findings agree with the
known anatomical connections between V1 and the extrastriate
cortex (Lund et al. 1975; Maunsell and van Essen 1983; Perkel
J Neurophysiol • VOL
et al. 1986; Rockland and Pandya 1979, 1981; Sincich and
Horton 2003; van Essen et al. 1986; Yukie and Iwai 1985; Zeki
1978). This transynaptic activation may be dominated by
subthreshold responses over neuronal spiking (Akgören 1996;
Logothetis et al. 2001; Mathiesen et al. 1998).
The larger than expected spread as measured with fMRI
might also indicate the presence of spiking activity beyond the
site of direct stimulation, however. It is well established that
even a single electrical pulse delivered to neural tissue activates fibers transynaptically within a cortical structure
(Asanuma and Rosén 1973; Asanuma et al. 1976; Butovas and
Schwarz 2003; Jankowska et al. 1975; McIlwain 1982; Stoney
et al. 1968). A 4-␮A (at 0.2-ms pulse duration) current pulse
delivered to motor cortex can activate neurons laterally and
transynaptically out to 1.5 mm from the electrode tip
(Asanuma and Rosén 1973). Delivering a train of four 30-␮A
pulses (at 400 Hz) to the superior colliculus can activate tissue
ⱕ2 or 3 mm laterally and transynaptically from the electrode
tip (McIlwain 1982).
One way of testing whether the lateral connections from the
site of stimulation are activated directly is to measure the
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FIG. 3. Using functional magnetic resonance imaging (fMRI) of V1 of anesthetized monkeys to study current spread and the excitability of neurons activated
by microstimulation. A: distance of activation from the electrode tip (shown by the histograms) is plotted as a function of current ranging from 159 to 1,651 ␮A.
SE values are shown. Four-second trains of stimulation were delivered to the gray matter within the operculum of V1 while the elicited blood oxygen
level– dependent (BOLD) response was measured. All data from Tolias et al. (2005). Black curve (S) (with SE values) represents current-spread estimates from
the pyramidal tract data of Stoney et al. (1968) as illustrated in Fig. 1A. Dashed curve (T) represents current-spread estimates based on the V1 data of Tehovnik
et al. (2005b) as illustrated in Fig. 2, B and C. Dotted curve (M) depicts current-spread estimates derived from the MT data of Murasugi et al. (1993). B: current
threshold to activate 40% of the maximal volume of gray matter within the operculum about the electrode tip (as measured using BOLD) is plotted as a function
of pulse duration. Maximal volume activated was defined as the maximum number of statistically activated voxels in gray matter of area V1 for a particular
strength (number of activated voxels) duration curve. Curve represents data from 5 experiments. Average chronaxie was determined using the method of Weiss
(1901). This method is required when a limited range of pulse durations is tested such that the rheobase current must be estimated. See Tolias et al. (2005) for
complete details. Methods (top): an iridium electrode (e) was inserted into the operculum of V1. Methods (middle): 4-s trains of stimulation were delivered to
V1. Each train was followed by a 12-s rest period. Methods (bottom): trains composed of cathode-first biphasic pulses delivered at 100 Hz. Pulse duration was
fixed at 0.2 ms unless otherwise indicated.
Invited Review
518
TEHOVNIK ET AL.
J Neurophysiol • VOL
whereas laterally connected fibers exhibit postsynaptic potentials without spiking (Bringueir et al. 1999).
A third and related possibility of why microstimulation of
neocortex evokes precise responses is that the neurons activated directly make a more significant contribution to the
evoked response because they are more synchronously activated compared with the neurons further away from the electrode tip activated transynaptically in cortex (Tolias et al.
2005).
In conclusion, the established observation that electrical
microstimulation of cortical tissue activates the most excitable
cortical neurons receives support from studies using different
methodologies, including neuroimaging. The greater lateral
spread of the hemodynamic, fMRI signal, in the worst case,
could denote the extent of subthreshold activation of nearby
neurons, although spiking cannot be ruled out. At present one
can only note that the definition of effective current spread
necessarily depends on the measured quantity. We suggest that
field potentials and neuroimaging are likely to give larger
current-spread estimates because they reflect both dendritic
spikes and perisynaptic events, such as population excitatory
and inhibitory postsynaptic potentials, as well as afterpotentials. For the behaviors described in this review, it seems that
the directly activated elements contribute disproportionately to
the evoked behavioral response given the likeness of the
effective current-spread estimates for the electrophysiological
and behavioral experiments. We are hopeful that this review
compels investigators to do more excitability and currentspread studies using a variety of techniques—i.e., fMRI, optical and two-photon imaging, multiple unit recording with
arrays, and so on—to examine various behavioral systems so
that we can make direct links between behavior and the
biophysics of the brain.
ACKNOWLEDGMENTS
We thank S. Smirnakis for helpful comments on the manuscript.
GRANTS
This work was supported by the Max Planck Society, by a National
Research Service Award from the National Eye Institute (NEI) to A. S. Tolias,
by Deutsche Forschungsgemeinschaft Grant SFB550-A9 to F. Sultan and N. K.
Logothetis, and by NEI Grant EY-08502 to P. H. Schiller to support E. J.
Tehovnik and W. M. Slocum.
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