Download Vagal Input to Lateral Area 3a in Cat Cortex

J Neurophysiol 90: 143–154, 2003.
First published January 15, 2003; 10.1152/jn.01054.2002.
Vagal Input to Lateral Area 3a in Cat Cortex
Shin-Ichi Ito and A. D. (Bud) Craig
Atkinson Pain Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona 85013
Submitted 22 November 2002; accepted in final form 8 January 2003
Application of noninvasive functional imaging methods to
the human brain have demonstrated the involvement of numerous cortical regions in visceral sensation. Particularly, they
have confirmed Penfield’s sensory homunculus, which included an abdominal representation in its most lateral part
(Penfield and Rasmussen 1950). Functional magnetic resonance imaging (Aziz et al. 2000b; Binkofski et al. 1998),
magnetoencepholography (Furlong et al. 1998; Hecht et al.
1999), and positron emission tomography (Aziz et al. 1997;
Ladabaum et al. 2001) have demonstrated activation in the
corresponding region of the human cerebral cortex in response
to esophageal or stomach stimulation. Thus there seems to be
a region in the neighborhood of the primary somatosensory
cortex (S1) that receives sensory input from abdominal organs
and might be involved in conscious sensations from these
organs. However, this region has not been anatomically or
functionally identified, and the afferent pathway responsible
for this abdominal activation has not been determined. Furthermore, it contrasts with the standard view that visceral sensation
involves primarily the insular cortex (Cechetto and Saper
1990).
Very recently, it was reported that the most lateral part of S1
in rats receives input from vagal afferents (Ito 2002). This
provided the first anatomically identified demonstration of this
putative visceral region in experimental animals. The results
suggested that this region is continuous with the intraoral
trigeminal representation in S1. However, these results did not
provide a direct comparison with human cortex because the
organization of S1 cortex differs substantially between rat and
human. While the sensorimotor cortex in rats seems to be a
combined entity (or a mosaic) with respect to submodalities of
somatic input (Gioanni 1987), the corresponding cortex in
many mammals including humans has distinct cytoarchitectonic areas that receive input from different submodalities. In
particular, area 3b receives cutaneous mechanoreceptive input
and is considered to be S1 proper, and area 3a receives proprioceptive input and is considered an adjunct of motor cortex
(Jones 1985; Kaas 1993; Weisendanger and Miles 1982). To
address the issue of an S1 visceral region across species, it is
crucial to clarify whether the vagal input arrives in area 3a,
area 3b or both. If vagal input is directed to area 3b, or S1, this
would support the implication of Penfield’s homunculus that
S1 is involved in the perception of visceral sensations. On the
other hand, if the vagal input is received by area 3a, a fairly
different scheme of the visceral sensory system would emerge
because area 3a is distinct from area 3b not only in the sensory
submodalities represented but also in the cortical networks
involved. In addition to proprioceptive input, area 3a receives
nociceptive afferent input (Craig 1995; Tommerdahl et al.
1996) that may be important for perception (Perl 1984). Thus
the distinction of the area of sensorimotor cortex that receives
vagal afferent input impacts the possible role of these regions
in motor control and sensation.
With regard to this issue, cats have several advantages; they
have distinctively different cytoarchitectonic areas (Avendano
and Verdu 1992; Ghosh 1997; Hassler and Muhs-Clement
1964; Leclerc et al.1994) with well-documented deep (area 3a)
and cutaneous inputs (area 3b or S1 proper) (Felleman et
al.1983; Jones and Porter 1980). The S1 representation of the
trigeminal intraoral region has been mapped (Iwata et al. 1985;
Taira 1987) and can guide localization of the vagal region (Ito
2002). Finally and most importantly, the vagal-evoked potential in the region of sensorimotor cortex has been repeatedly
Address for reprint requests: A. D. Craig, Atkinson Pain Research Laboratory, Division of Neurosurgery, Barrow Neurological Institute, 350 W.
Thomas Rd., Phoenix AZ 85013 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked ‘‘advertisement’’
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
INTRODUCTION
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Ito, Shin-Ichi and A. D. (Bud) Craig. Vagal input to lateral area 3a
in cat cortex. J Neurophysiol 90: 143–154, 2003. First published
January 15, 2003; 10.1152/jn.01054.2002. Penfield’s sensory homunculus included visceral organs at its lateral extreme, and vagal input
was recently identified lateral to the intraoral representation in primary somatosensory cortex (S1) of rats. We tested whether vagal
input is similarly located in cats where area 3b (equivalent to S1) is
clearly distinguishable from adjacent regions. Field potentials were
recorded from the intact dura over the left hemisphere using electrical
stimulation of the left or right cervical vagus nerve in seven cats. A
surface positive-negative potential was evoked from either side in the
lateral part of the sigmoid gyrus. Finer mapping made at the pial
surface with a microelectrode identified a focal site anteromedial to
the anterior tip of the coronal sulcus. Depth recordings demonstrated
polarity reversals and multi-unit vagal responses, indicating that the
potentials were generated by an afferent activation focus in the middle
layers of the cortex. The S1 mechanoreceptive representation was
localized by mapping multi-unit somatosensory receptive fields in the
middle cortical layers near the coronal sulcus. The vagal-evoked
potential site was distinctly anterior to the intraoral S1 representation
and adjacent to the masseteric-nerve-evoked potential focus. Lesions
made at the focal site revealed that this site is cytoarchitectonically
located in area 3a not area 3b. Thus vagal input to the sensorimotor
cortex in cats resembles deep rather than cutaneous somatic input,
similar to the localization of nociceptive-specific input to area 3a in
monkeys. The possibilities are considered that this vagal input is
involved in motor control and in the sensory experience of visceral
afferent activity.
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S.-I. ITO AND A. D. CRAIG
METHODS
Animal preparation
The experimental protocol was approved by the Institutional Animal Care and Use Committee, and all procedures complied with the
guiding principles for the care and use approved by the American
Physiological Society.
Seven cats of either sex weighing 2.4 – 4.5 kg were used; three were
anesthetized with chloralose and four with alphaxolone/alphadolone
(Saffan, Glaxo). Chloralose anesthesia (60 mg/kg iv) was preceded by
ketamine (50 mg im) and supplemented with intravenous pentobarbital sodium as necessary. Animals that received Saffan anesthesia
(12–18 mg/kg iv) were first tranquilized with acepromazine (0.3
mg/kg im); Saffan was continuously supplemented with infusion
pump (8 –12 mg 䡠 kg⫺1 䡠 h⫺1). In all cats, a bolus injection of
dexamethasone (10 mg iv) was given. The neck, head, and face were
shaved. A rectal thermistor was inserted, and an infrared lamp as well
as a heated water pad was used to maintain core temperature at
37.5°C. Eye salve was applied, 0.5% bupivicaine was injected subcutaneously at incision sites, and a local anesthetic was sprayed in the
ear canals. Blood pressure and heart rate were monitored with the
catheter inserted in the right carotid artery (contralateral to the examined hemisphere). End-tidal CO2 was maintained at 3.5– 4.5%. Depth
of anesthesia was monitored with the width of the pupil and reflexive
change in blood pressure and heart rate and also with reflexes to pinch
and corneal contact before introduction of paralytic agent.
After cannulation of the trachea and the carotid artery, the cervical
vagus nerves were bilaterally isolated. Each nerve was attached with
a cuff electrode consisting of two pairs of platinum wires 30 or 50 mm
apart; one pair was used for stimulation and the other for recording the
compound action potential. The nerves were ligated distally to the
electrode to avoid any vagal efferent-mediated responses confounding
the cortical recording and to exclude possible contamination of sympathetic afferent activity (because the cervical vagus nerve may contain nerve fibers from the superior cervical ganglion).
Each animal’s head was mounted in a stereotaxic frame so that the
head was tilted with the left side up (only the left cerebral hemisphere
was studied). The zygomatic arch, the postorbital processes, and the
upper part of the mandible were removed. The eyeball was pulled
ventral or, in one cat, removed. A craniotomy was made to expose the
anterolateral cerebral cortex. Mineral oil or Tyrode’s solution were
often applied to keep the exposed area from drying out.
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Vagal stimulation/recording
The vagus nerves were electrically stimulated with either a single
rectangular pulse (duration: 0.3 or 2.0 ms) or a train of pulses (3
0.3-ms pulses at 1 kHz). The stimulus strength was initially adjusted
to be supramaximal for A-delta fiber activation in the compound
action potential recorded from the vagus nerve; it produced C-fiber
activation as well (though the cortical response we recorded could not
have resulted from C-fiber afferents based on the latency).
The cortical surface was photographed with a digital camera, and
the recording sites were plotted on the printed photographs. The
vagal-evoked field potential was recorded with both low- and highresolution methods. A low-resolution map was made with a tungsten
or platinum macroelectrode to isolate the focal region and differentiate it from the orbital focus. The dura was left intact. The electrode
was moved in two dimensions on a 1 ⫻ 1-mm grid with a manipulator
which was independent of the stereotaxic frame and aligned nearly
parallel to the cortical surface. For mapping, the intensity of vagal
nerve stimulation was increased so that it was twice that needed to
produce a maximal cortical-evoked potential recorded at an arbitrary
site near the coronal gyrus; it varied from 0.7 to 10.0 mA in the
different cases.
In the four cats anesthetized with Saffan, high-resolution microelectrode recordings were made after the rough mapping described in
the preceding text. The dura over the focal site was cut and reflected.
A platinum-plated tungsten-in-glass microelectrode (tip size: ⬃15
␮m) was used to record the evoked potential from the pial surface.
The cortex was often moving (due to respiration and arterial pulse
pressure), so a slight pressure was usually imposed on the surface by
the microelectrode, which produced a variable degree of dimpling. At
the focal site, the laminar profile of the evoked potential was examined with the same microelectrode by advancing it and penetrating the
cortex with steps of several hundred micrometers. The penetration
angle was oblique to the cortical surface because of the curvature of
the target cortex near the coronal sulcus.
The indifferent electrode was a silver wire wound in a disk shape or
a stainless steel clip attached to nearby muscle. Signals were amplified
with a band-pass of 1 Hz to 1 kHz for the macroelectrode and 10 Hz
to 10 kHz for the microelectrode. Multi-unit spike activity was recorded with a band-pass of 300 Hz to 10 kHz. The signals were stored
in a digital signal-processing system (CED Power 1401 and Spike 2
program). Field potentials were averaged and amplitude and latency
were measured with this system.
Somatosensory mapping
The somatosensory mechanoreceptive representation (S1) was
mapped to determine its positional relationship with the vagal-evoked
potential focus. Because the detailed S1 map of the trigeminal intraoral region has been established (Taira 1987), it was sufficient to
examine the receptive fields of middle layer neurons at several arbitrarily chosen sites to extrapolate the location and extent of S1. After
the surface and depth recordings of the vagal potential were completed, the dura was further opened widely to expose S1 posterior to
the coronal sulcus. The microelectrode was inserted to a depth of ⬃1
mm, and multi-unit responses were recorded from the middle cortical
layers in response to natural tactile stimulation of the head, oral, and
forelimb regions. The stimuli were tapping, brushing, or rubbing the
skin and intraoral structures and moving the jaw, forelimb, and toes to
stimulate all available mechanoreceptors, including in the pharynx
and nares. Receptive fields were recorded on standard drawings.
Histology
During the microelectrode recordings, several penetrations were
marked with lesions made by cathodal current (15–30 ␮A for 30 s). In
the macroelectrode recordings, several recording sites were marked
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examined in the cat. After Siegfried described the region for
the first time (Siegfried 1961), others (Aubert 1970; Aubert and
Legros 1971; Korn and Masson 1963; Massion et al. 1966)
clearly differentiated the evoked potential in the lateral sigmoid
gyrus, at the lateral extent of sensorimotor cortex, from the
evoked potential focus in the orbital gyrus, which corresponds
to the insular visceral region of humans, monkeys and rats.
Unfortunately, these prior authors did not provide a cytoarchitectonic description, although they described the waveform,
amplitude, latency, or laterality in some detail. It was even left
undetermined whether the evoked potential focus was in the
somatosensory or motor portion of sensorimotor cortex.
In the present study, we focused on identifying the cytoarchitectonic location of this vagal-potential region in cats. The
site was localized with microelectrode recordings from the pial
surface and from the cortical depth to demonstrate the generator site. Somatosensory receptive fields were mapped in the
nearby S1 to determine the relationship between the vagal
input focus and S1. Finally, the cytoarchitecture of the site was
determined. It is located in area 3a not 3b. A preliminary report
of this study was made (Ito and Craig 2002).
VAGAL INPUT TO AREA 3A
with dye deposits (Pontamine skyblue, ⬃100 ␮A for ⬃1 min under
microscopic observation) at the termination of the experiment. After
the experiment, the animals were injected with a lethal dose of
barbiturate and the cortex was removed. The tissue block was soaked
in 10% Formalin for 1 wk, then in 30% sucrose in Formalin for 1 wk,
and then cut in serial 60-␮m coronal frozen sections and stained with
thionin. Cytoarchitectonic areas were determined using criteria based
on Avendano and Verdu (1992), Ghosh (1997), Hassler and MuhsClement (1964), and Leclerc et al. (1994). Digital photomicrographs
were taken with a Leaf Microlumina, and the images were processed
with Adobe Photoshop for adjustment of brightness and contrast as
well as insertion of indications and anatomic landmarks.
RESULTS
Macroelectrode surface map
the tip of the coronal sulcus. The gradient of the potential
decay with distance from the focal site was relatively weak,
and the potential field extended widely both medially and
laterally to the sulcus. However, the potential amplitude was
generally greater in the region medial to the sulcus than laterally, and it was clearly focused at a site anteromedial to the tip
of the sulcus. In fact, in every animal (n ⫽ 7) the macroelectrode focal site was just medial to the anterior tip of the coronal
sulcus, and no other potential focus was evident in the region
just lateral to the coronal sulcus.
Histological examination of sites marked with dye after
macroelectrode surface mapping in two cats showed that the
center or the largest response site of the evoked potential
region appeared to be in area 3a (arrowhead, Fig. 1C), characterized both by a well developed granular layer and large
pyramidal cells in the fifth layer. This is consistent with the
general concept in prior histological studies (Avendano and
Verdu 1992; Hassler and Muhs-Clement 1964) that the cortex
adjacent to the anterior tip of the coronal sulcus, including both
medially and laterally adjacent regions, consists of area 3a.
Microelectrode surface map
The vagal-responsive field examined with macroelectrode
recordings from the intact dura was broad and poorly focused.
By contrast, potential mapping from the pial surface with a
microelectrode gave far better localization of the focal area.
Figure 2 shows an example of such mapping. Although the
surveyed area was smaller than that of Fig. 1, Fig. 2 still shows
that negligible responses were obtained in the periphery of a
very clear response focus. The large-amplitude evoked potentials were concentrated in a region just larger than 1 mm2. The
difference in amplitude of the recorded potential between the
response center and periphery was so dramatic that it was easy
to demarcate the focus of the vagal-evoked potential region on
the cortical surface. With microelectrode mapping, it was
clearer that the vagal-responding region was restricted to the
area medial to the coronal sulcus even though it closely adjoined the sulcus.
FIG. 1. Epidural surface map made with a macroelectrode. A: lateral view of the cat left cerebral cortex indicating the location of the coronal sulcus. B: a vagalevoked potential map at points spaced ⬃1 mm along
orthogonal coordinates showing a regional focus anteromedial to the tip of the coronal sulcus. C: a photomicrograph of a coronal section showing a dye mark (double
arrowhead) made at the center of the responsive region.
Open arrows delimit area 3a. Cru, cruciate sulcus; Cor,
coronal sulcus; Pre, presylvian sulcus.
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Vagal stimulation produced a biphasic positive-negative potential over a broad region of the sigmoid, coronal, and orbital
gyri in chloralose-anesthetized animals. The field was quite
broad in chloralose-anesthetized cats but more focused in Saffan-anesthetized cats (see DISCUSSION). Even though the response was diffuse, there were two sites with larger response
amplitude than neighbors: one in the anterior part of the lateral
sigmoid gyrus and another more posterolaterally in the orbital
gyrus. The former region is the subject of the present study,
whereas the latter corresponds to the well-established “insular
visceral sensory cortex” (Clasca et al. 1997). Stimulation of
either right or left vagus nerves elicited the evoked potential in
the sigmoid gyrus. The contralateral (right) nerve or the ipsilateral (left) nerve was primarily used to examine the evoked
potential with macroelectrode recording in three cats or one
cat, respectively, and in the other three cats, the evoked potentials on both sides were examined. No systematic difference
was observed in the focal sites or amplitude related to the
laterality of stimulation (see also Aubert and Legros 1970).
The evoked potential on the sigmoid gyrus was focused near
the anterior (lateral) tip of the coronal sulcus. Figure 1 shows
a surface map of this potential field in a cat anesthetized with
Saffan. The potential distribution was centered just anterior to
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In four cats anesthetized with Saffan, a complete microelectrode map was recorded from the pial surface with contralateral
vagal stimulation. The latency and amplitude of the evoked
potential were both relatively invariable among cats; the average peak amplitude was 685 ␮V (range: 482–780), and the
mean value of the peak latency was 11.0 ms (range: 9.4 –12.1).
Figure 3 illustrates the distribution of vagal potentials relative
to the coronal sulcus in all four animals (Fig. 3, A–D). The
recording sites were spaced ⬃0.5 mm in general and ⬃0.2 mm
at the focal sites. In all four animals, the largest evoked
potentials were obtained from a stripe-like region rather than a
focal concentric region, and they were restricted to a small
region anteromedial to the coronal sulcus. Slight variations in
peak amplitude at adjacent points in the focal site were ascribed to variability in the contact pressure of the microelectrode due to surface movement and dimpling.
Somatosensory mapping
With the vagal-evoked potential focus well localized on the
anteromedial side of the anterior tip of the coronal sulcus, we
investigated its relationship with the physiologically determined S1 somatosensory representation in three cats by making depth recordings with the microelectrode. The region surrounding the anterior part of the coronal sulcus was mainly
examined, in accordance with the maps produced by Felleman
J Neurophysiol • VOL
Depth recording
The same microelectrode used for surface mapping of the
vagal-evoked potential and for mapping of multi-unit mechanoreceptive responses was also inserted into the cortex in the
vagal response region to determine whether the generator site
could be demonstrated by a polarity reversal indicative of the
current sink. Because the vagal region was quite well localized,
only a few penetrations at the focal site were needed for this
purpose. The penetrations were not always perpendicular to the
cortical surface, so that even a penetration at the center of the
focal site did not always record the deep negative potential
with an amplitude comparable to the surface positivity. Nonetheless, in all three animals in which depth recordings were
made, deep negative potentials with comparable latency were
recorded, and reversals were observed in the cortical depth
below the surface focal sites.
Figure 5 shows an example of depth recording at the penetration corresponding to the most posterior and lateral of the
focal recording sites indicated by large dots in Fig. 3A (open
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FIG. 2. Pial surface map made with a microelectrode. A: photograph of the
mapped region at the anterior tip of the coronal sulcus. Dots indicate recording
sites. B: focused map of vagal-evoked potentials obtained at the sites indicated
in A. These data are from a different animal than those in Fig. 1.
et al. (1983) and by Taira (1987). Figure 4 shows two examples. In Fig. 4A, the most anterior mechanoreceptive responses
were obtained with stimulation of the ipsilateral anterior
tongue (site 1). More posteriorly, receptive fields on the contralateral hard palate (site 2), lower teeth (site 3), upper gingiva
(site 4), and lip (site 5) were found in this order. Further
posteriorly, extraoral receptive fields were found, such as the
subnostril regions (sites 6 and 7). In the case illustrated in Fig.
4B, the most anterior responsive site was found with bilateral
glottal stimulation (site 1); more posteriorly, the lip (site 2) and
facial responding sites (sites 3–5) were found. Outside this
oral/facial region, penetrations encountered neurons with receptive fields on the forelimb (sites 6 – 8). All but one (site 7)
of these sites were located lateral to the coronal sulcus. In the
three cats, the most anterior somatosensory representation in
the region of the coronal sulcus was the tongue (Fig. 4A, site
1), glottal region (Fig. 4B, site 1), or front teeth (not shown).
Penetrations were made further anterior to these sites and no
further mechanoreceptive responses were obtained. The most
anterior mechanoreceptive region was separated by ⱖ1 mm
from the vagal response focus.
On the other hand, multi-unit responses to proprioceptors of
the forelimb were found medial to the sulcus (Fig. 4B, sites 6
and 8), at the anteroposterior level of the facial representation.
They responded to claw movement or forepaw tap (cf. Dykes
et al. 1980). The area just lateral to this deep input region and
medial to the vagal site was unresponsive to conventional
stimulation, including press/pinch of the contralateral cheek or
intraoral palpation. In one animal (Fig. 4A), evoked potentials
were obtained in response to stimulation of the ipsilateral
masseteric nerve in this region, just anterior and medial to the
coronal sulcus. Although the focal site was closer to the vagal
site than the forelimb response sites, it was still separate by ⬃1
mm (posterior and medial) from the vagal-evoked potential
focus.
Because the cytoarchitectonic location of S1 is well established, we examined histologically only few of the recording
sites of somatic receptive fields. They were found in either area
3b or 3a according to whether surface or deep receptive fields
were recorded, respectively, as established in the literature.
VAGAL INPUT TO AREA 3A
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arrow). The evoked field potential was recorded at five different depths, and a lesion was made at the deepest point (site 5).
The surface positive potential became larger in the middle of
the track (sites 2 and 3, corresponding to layer III of the
cortex), and it reversed to a negative potential in the depth
(sites 4 and 5, layers IV and V/VI border, respectively). Figure
5C also shows a multi-unit response recorded at site 2; many
spikes responded to the stimulation with latencies between 8
and 22 ms, consistent with the onset and peak latencies of the
field potential recorded at the same site of 5.8 and 10.4 ms,
respectively. Multi-unit responses to vagal stimulation and
polarity reversals of the evoked field potential were obtained in
all three depth recordings (open arrows) located at the anterior,
middle, and posterior parts of the surface vagal focus in this
particular animal. Multi-unit responses in penetrations with
polarity reversals were also obtained in one other cat. These
results definitely demonstrated that there was a cluster of
neurons activated at short latencies by vagal input in the center
of the response focus determined by the surface mapping.
Cytoarchitecture
FIG. 4. Location of vagal-evoked potential foci with respect to primary
somatosensory (S1) cortex, identified by depth recordings of somatosensory
responses. In both examples (A and B), the multi-unit receptive fields at the
numbered symbols along the coronal sulcus (Cor) were found at the sites
indicated by the numbers on the drawings. F, tactile responses; E proprioceptive responses; ‚, strong vagal-evoked potentials. Activation from the forepaw
occurred by mechanoreceptors on the glabrous skin of the digit (7) or movement of the claw (6, 8).
J Neurophysiol • VOL
Figure 5D shows the entire electrode track for the penetration just described, from the entry (arrow) to the lesion (double
arrowhead), in a Nissl-stained section. In this photomicrograph, the area demarcated by the four open arrows is recognizable as area 3a. Area 3a was most clearly distinguished
when situated as the transitional area between areas 4 and 3b at
more posterior levels (cf. Fig. 7). Area 4 was characterized by
both the lack of layer IV and the presence of the dark-stained
giant pyramidal cells in layer V. By contrast, area 3b was
characterized by a thick layer IV and a cell-sparse stripe-like
layer V. Area 3a was distinguishable as an area intercalated
between these two areas with clear but less thick layer IV
overlying giant pyramidal cells in layer V. Area 3a was also
distinguishable from areas 3b and 4 by the sublamination of
layers III and VI in the latter two areas. At more anterior levels,
such as Fig. 5D, area 4 was replaced by area 6, which made the
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FIG. 3. Distribution of vagal-evoked potentials in 4
(A–D) surface microelectrode recording experiments. In each
figurine, the dots indicate the amplitude of the evoked potential at each recording site, plotted relative to the anterior
tip of the coronal sulcus (Cor), according to the sizes in the
legend. The length of directional arrows corresponds to 1
mm. The open arrows in A and C indicate the sites where
depth recordings were made; the recordings at the most
caudal arrow in A and the 2 arrows in C are shown in Figs.
5 and 6, respectively, and the corresponding histological
photomicrographs are shown in Figs. 5 and 7.
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S.-I. ITO AND A. D. CRAIG
medial border of area 3a less clear. However, by tracing
anterior from the more easily distinguished posterior levels, it
was possible to follow and delineate area 3a with its characteristically well-developed granular layer and darkly stained
large pyramidal cells in layer V. The penetration shown in Fig.
5D was entirely within the limits of area 3a. That is, the large
positive potential in the upper layers, the smaller negative
potential in the deeper layers, and the multi-unit responses in
the middle layers were recorded in area 3a. In all four brains in
which microelectrode mapping and depth recordings were
made, large positive supragranular potentials and negative infragranular potentials were recorded within area 3a, as histologically verified.
Figure 6 shows the deep field potential recordings in another
FIG. 6. Microelectrode potentials recorded at different depths in penetrations at the 2 sites indicated in Fig. 3C, showing reversal in the middle layers
900 –1,200 ␮m deep in each penetration.
J Neurophysiol • VOL
case in which penetrations were made at the two sites indicated
by arrows in Fig. 3C. In this cat, the penetrations were nearly
normal to the cortical surface. Figure 7 shows the reconstructed
cytoarchitectonic limits of area 3a surrounding two microelectrode penetrations across a series of consecutive sections
spaced 120 ␮m apart. The lesions marked in Fig. 7 were made
at the approximate depth of the reversal of the field potential in
each penetration. The lesions are evident in the accompanying
photomicrographs of the indicated sections. Both penetrations
were, like that shown in Fig. 5, just medial to the anterior tip
of the coronal sulcus. This part of the cortex was occupied
entirely by area 3a; the lateral border of area 3a with area 3b
was at almost the same location in the sulcus throughout this
level. The medial border of area 3a shifted significantly along
the anteroposterior sequence. Posteriorly, the cortex medial to
the coronal sulcus included, from medial to lateral, areas 4, 3a
and 3b, and area 3a was wide at this coronal plane. On the other
hand, anteriorly, as described earlier, area 4 was replaced by
area 6, which extended ventrally, and area 3a became restricted
to a narrow region just above the coronal sulcus or the dimple
of its anterior tip. Thus the location of the two penetrations
differed with respect to the extent of area 3a, though they were
similar in position relative to the coronal sulcus.
As apparent in Fig. 7 (B and C), both the entry point and the
lesion of both penetrations were within area 3a. Because these
two penetrations were made at the anterior and posterior parts
of the surface potential region, these two sections probably
correspond to the anterior and posterior limits of the vagal
potential generator area in this brain. The anterior section was
at almost the anterior limit of area 3a; in the section only 360
␮m anterior, area 3a was no longer detectable. Thus, comparison with the extent of the vagal focal site in Fig. 3C suggests
that, in this cat, the vagal afferent region occupied almost all of
the most anterior (and lateral) part of area 3a, and it extended
posteriorly in the most lateral (ventral) part of area 3a.
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FIG. 5. Demonstration of microelectrode depth recording at the vagal response focus. This penetration
was made at the surface site marked with the caudal
open arrow in Fig. 3A. A: reconstruction of the electrode track on a line drawing of the cortical section. The
labeles IV and V indicate the 4th and 5th layers, respectively. Open arrows demarcate the cytoarchitectonic borders of area 3a. The numbers along the track
indicate the sites of the recordings shown in B. C:
multi-unit activity recorded at site 2. D: photomicrograph of the corresponding coronal section. Open arrows indicate cytoarchitectonic borders. Filled arrow
indicates the entry point and direction of the penetration, and the double arrowhead indicates the lesion
made at the bottom of the track. Roman numerals
indicate cortical layers.
VAGAL INPUT TO AREA 3A
149
DISCUSSION
Our results indicate that the vagal input to sensorimotor
cortex is located in area 3a. The vagal input in this region thus
resembles deep somatic input and must be considered as part of
a different cortical subsystem than the cutaneous part of sensorimotor cortex, or S1. The classical sensory homunculus,
based on stimulation-evoked sensory paraesthesia (Penfield
and Rasmussen 1950), suggested that visceral organs are represented in the primary somatosensory cortex in the same
manner as the cutaneous body surface. Early findings in cats
(Aubert 1970; Siegfried 1961) and more recent findings in rats
(Ito 2002) seemed to support that scheme, but the present
observations in the more differentiated cortex of cats do not
support that view. Because areas 3a and 3b are distinguished in
the sensorimotor cortex of primates similarly to cats, the same
visceral cortical organization could be present in primates,
including humans.
Technical considerations
We mapped the evoked field potential. A field potential
study is advantageous for mapping a broad region because it
examines mass activity. Possible contamination by far field
potentials (Dong and Chudler 1984) was mitigated by using
subdural recording with a high-impedance electrode. The response field was in each case restricted and focused, with a
steep amplitude gradient around the focal site (Fig. 2) that
J Neurophysiol • VOL
made it relatively easy to demarcate. Although it lay adjacent
to the coronal sulcus, the vagal response focus was not buried
in the sulcus. The depth recordings made at the focal sites
demonstrated phase reversal, a criterion for the presence of a
current sink or generator site within the cortex. Clusters of
neurons that responded at comparable latency indicated that the
potentials represented neuronal activation at the site. Therefore
the focal sites revealed with microelectrode mapping apparently represent dense vagal afferent input at the potential
generating region.
The stimulating electrodes were embedded among neck
musculature so that any stimulus spread would have involved
the neck muscles. The short latency of our vagal potential is
compatible with neck-muscle-evoked potentials. However, the
neck muscles are innervated by cervical spinal nerves and
consequently represented in the posterior sigmoid gyrus (Barbas and Dubrovsky 1980), posteromedial to the vagal focal
region. We did not observe any potential foci in that region
during macroelectrode mapping. Furthermore, we stimulated
the masseteric muscle at the lateral side of the cranium, which
is even more anterior in the body, and its evoked potential site
was distinctly posterior and medial to the vagal-evoked potential site. Thus it is unlikely that the present results included
responses originating from afferents from surrounding muscles.
We used two anesthetics, chloralose and Saffan. We initiated
this study with chloralose because it had been used in previous
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FIG. 7. A summary of the cytoarchitecture of the vagal response region in 1 reconstructed case. Top: a series
of drawings of coronal sections at 120-␮m intervals extending rostral (left) to caudal (right) from the experiment
shown in Fig. 3C. The solid lines indicate the borders of
area 3a, and the dots indicate lesion sites. Bottom: photomicrographs of the indicated sections containing the
lesions (arrowheads); the open arrows indicate the borders of area 3a. Dorsal up, lateral right.
150
S.-I. ITO AND A. D. CRAIG
studies of vagal-evoked potentials (Aubert 1970; Korn and
Massion 1964; Massion et al. 1966). However, under chloralose, the vagal-evoked potential field was large and difficult to
delimit just as somatic-evoked potentials are (Harding et al.
1979). Under Saffan anesthesia, the vagal-evoked potential had
a comparable peak amplitude but a more delimitable focus
(Fig. 1). In addition, Saffan has less suppressive effects on
autonomic function than chloralose (Child et al. 1972; Ness
and Gebhart 1988; Timms 1981), and it does not produce the
variable late-evoked potential components that can confound
studies under chloralose (Boissonade and Matthews 1993).
Thus, in contrast to prior studies of vagal-evoked potentials
under chloralose or pentobarbital, we found consistently short
response latencies under Saffan (see following text).
Composition of the vagus nerve: a mixture of “visceral” and
“somatic” afferents?
J Neurophysiol • VOL
Comparison with prior vagal-evoked potential studies in cats
Our results confirmed and expanded the results of prior
studies regarding the vagal response focus in the sensorimotor
cortex in cats. This site corresponds to Siegfried’s (1961, 1962)
“area A,” in contrast to “area B” in the orbital gyrus (insular
cortex). Subsequent studies (Aubert 1970; Aubert and Legros
1970; Korn and Massion 1964; Massion et al. 1966) generally
located the region as lateral, instead of medial, to the anterior
tip of the coronal sulcus in their summary diagrams, although
they described the area as between the anterior end of the
coronal sulcus and the presylvian sulcus just as Siegfried did
(Sigfried 1961). Our surface mapping always included the area
lateral to the coronal sulcus but never identified a potential
focus there, and the focal site was anteromedial to the coronal
sulcus in all animals. Furthermore, in none of the prior studies
did the actual mapping data show the focus lateral to the
sulcus, and at least one figure (Fig. 6 of Aubert and Legros
1970) clearly illustrated the focal site anteromedial to the tip of
the coronal sulcus; this is consistent with our observations.
Therefore despite the discrepancy with their summary statements, it is apparent that the vagal response focus we identified
is the same as that observed in the prior studies and identified
first as area A by Siegfried (1961).
The prior studies detailed the latencies of early and late
vagal-evoked potentials. The latency of the peak response in
the present study (9.4 –12.1 ms) was comparable to that of the
earliest response in the prior studies (8 –25 ms) (Aubert 1970;
Aubert and Legros 1970; Korn and Massion 1964; Massion et
al. 1966), which is attributable to myelinated vagal afferents.
One study reported that both fast and slowly conducting myelinated fiber groups contribute to the evoked potentials in both
the sensorimotor cortex and the insular cortex (Massion et al.
1966). Potentials at latencies attributable to unmyelinated vagal afferents were not clearly distinguished in the present nor
in the prior studies. Unmyelinated C-fibers may be too variable
(dispersed) in their conduction times to form a coherent, observable evoked waveform (Porter 1963), or they may be more
susceptible to anesthetic than myelinated afferents (cf. Kalliomaki et al. 1993), although vagal C-fiber responses have been
observed in rat insular cortex (Ito 1994).
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While the cardiopulmonary and subdiaphragmatic branches
of the vagus consist entirely of afferents which innervate
visceral organs that contain smooth muscle, the cervical vagus
nerve that we stimulated contains in addition afferents that
innervate oropharyngeal tissues that are characterized by
mixed smooth and striate muscle and so could be regarded as
“somatic.” In particular, it contains afferents from the recurrent
laryngeal nerve that innervate the pharynx, larynx, trachea, and
upper (distal) esophagus. Our vagal stimulation must have
activated these afferents simultaneously, and consequently, the
cortical potential we recorded probably represents activation of
both oropharygeal afferents as well as afferents from cardiopulmonary and subdiaphragmatic visceral tissues. The vagalevoked potential we recorded over the anterior sigmoid gyrus
(sensorimotor cortex) has essentially the same latency and
shape as the potential that can be recorded over the orbital
gyrus (insular cortex; see Aubert 1970; Korn and Massion
1964; Massion et al. 1966), consistent with the view that
similar or identical sets of afferents contribute to both projection sites. A subsequent analysis of the sensorimotor corticalevoked potential from cardiopulmonary and subdiaphragmatic
vagal afferents could directly validate this view; however,
several additional considerations support the inference that the
evoked potential we recorded in the anterior sigmoid gyrus
includes activation by cardiopulmonary and subdiaphragmatic
vagal afferents and can be regarded as a putative visceral
activation site. First, the evoked potential focus we identified
lies in area 3a, not 3b, indicating that it is not part of the
mechanosensory (“somatic”) afferent representation in cortex.
Second, it lies at the lateral part of the sensorimotor cortical
strip; this is consistent with the activation observed in human
cortex by natural stimulation of both the upper esophagus
(which contains both striate and smooth muscle layers) and the
lower (proximal) esophagus (which contains only smooth muscle), as well as by distension of the stomach and the colon
(Aziz et al. 1997, 2000b; Binkofski et al. 1998; Furlong et al.
1998; Hecht et al. 1999; Ladabaum et al. 2001; Lotze et al.
2001). This area appears to be homologous to the site we
identified in cat (see following text). Third, a recent study
suggests that the conscious sensation produced in humans by
distension of the upper esophagus, despite its potential designation as somatic, differs significantly from the sensation produced by stimulation of the overlying chest wall, in that it is
diffuse, poorly localized, and distinctly unpleasant, consistent
with the sensations elicited from other “visceral” organs
(Strigo et al. 2002). Fourth, single-unit recordings in the region
of the vagal-evoked potential site in sensorimotor cortex of the
rat directly indicate activation by afferent input from viscera,
consistent with this inference (Hanamori et al. 1998; Zhang
and Oppenheimer 1997). Finally, the vagal afferents that innervate the upper trachea and esophagus have been regarded by
some as somatic in part because they terminate in the marginal
layer of the trigeminal subnucleus caudalis and the upper
cervical dorsal horn (Contreras et al. 1982; see also Panneton
1991); however, that pattern of termination for visceral afferents is also present in the spinal cord, where afferents that
parallel sympathetic efferent fibers similarly terminate in lamina I of the superficial spinal dorsal horn. Therefore whereas
the following comments refer empirically to the “vagal-evoked
potential site” in sensorimotor cortex, we infer that this represents a putative visceral afferent activation site.
VAGAL INPUT TO AREA 3A
Comparison with prior vagal-evoked potential studies in
other species
Cytoarchitectonic location of the vagal response focus
The present results indicate that the region responsive to
vagal input is entirely outside the S1 representation, including
J Neurophysiol • VOL
the representation of the intraoral structures. The somatosensory map of the cat S1 along the coronal sulcus is well
established (Felleman et al. 1983; Taira 1987). The most anterior and lateral portion represents the ipsilateral and contralateral intraoral mechanoreceptors, and then the lips and
extraoral structures are represented progressively more posteriorly and medially (Taira 1987). Our recordings in S1 reproduced this pattern, and furthermore, we found pharynx- and
glottal-responding neurons anterolateral to the representation
of the tongue (Fig. 4B). Nonetheless, the vagal-responsive
region was distinctly anterior and medial to the S1 representation, and a region with no somatic response was intercalated
between the vagal region and the S1 representation.
The vagal response focus was anterior and medial to the
anterior tip of the coronal sulcus, and cytoarchitectonic studies
and our observations indicate that it lies within area 3a. Indeed,
Hassler and Muhs-Clement (1964) showed the anterior and
lateral border of area 3a crossing the coronal sulcus to include
even the region lateral to the anterior part of the coronal sulcus.
Avendano and Verdu (1992) construed this lateral extension
only at the most anterior tip of the coronal sulcus. Our reading
of the present material was even more conservative, and area
3a appeared to be restricted entirely to the medial bank of the
coronal sulcus and the lateral sigmoid gyrus.
Lesions made at microelectrode penetrations in which field
potential reversals and multi-unit responses were observed
were all histologically identified within area 3a. This indicates
that the current sink producing the surface positive potential is
definitely located in area 3a not in area 3b. Although depth
recordings were made only in the neighborhood of the focal
site, there is no reason to expect additional generator sites that
are not revealed by surface potentials. It is possible that vagal
input may also activate neurons outside the borders of area 3a,
but the main focus is certainly within area 3a. At the anterior
end of area 3a where it is narrow (Figs. 5 and 7B), all of area
3a appears to be occupied by the vagal-responsive region.
More posteriorly, at the level of Fig. 7C, the vagal-responsive
region is restricted to the most lateral part of area 3a. Thus, the
present observations indicate that the vagal response focus
occupies the most anterolateral part of area 3a in the cat.
Input source
Area 3a in cat receives its principal proprioceptive and
vestibular inputs from the thalamic region that lies along the
border between the ventral posterior and the ventrolateral nuclei, that is, between the lemniscal somatosensory relay and the
cerebellar motor relay (Dykes et al. 1986; Jones and Porter
1980; Kaas 1993). Activation of group I inputs, for example,
evokes in area 3a a so-called thalamocortical primary response
with an initially positive surface wave that reverses polarity in
deep layers (Landgren and Silfvenius 1969; Odkvist et al.
1975). Iwata et al. (1985) described a masseteric-nerve-evoked
potential, which reversed to a deep negative component at a
depth of 1.5–2.5 mm, in the rostral part of cat area 3a, consistent with our observations. This depth profile is in good agreement with that of the present vagal potential, consistent with
the hypothesis that the vagal input to area 3a arrives by a direct
thalamocortical projection like the proprioceptive or vestibular
input. The presence of sacral visceral (pelvic nerve) input to
neurons in the ventral periphery of the thalamic ventral poste-
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In addition to cats, a vagal response focus has been observed
in the most lateral portion of sensorimotor cortex in rats, goats,
and monkeys (Ito 2002; O’Brien et al. 1971; Siegfried 1962).
As in Penfield’s homunculus in human cortex, the vagal area
was generally located lateral to the intraoral representation in
each of these species. This correspondence suggests that the
sensorimotor vagal area may be homologous throughout mammals. Few studies have examined cytoarchitecture.
In rats, the vagal area was shown to occupy parietal “granular” cortex, implying that it is within S1 (Ito 2002). However,
the differentiation of sensorimotor cortex in the rat is primordial, and there is overlap between the regions that receive input
from cutaneous and deep receptors (Gioanni 1987). That is,
there is not a clear distinction between areas 3a and 3b in the
rodent. Although it has been suggested that the transitional
dysgranular part of S1 in rats receives deep input like area 3a
of more encephalic animals (Chapin and Lin 1984), this region
was identified only in the spinal representation. Thus the location of the vagal region in the granular cortex lateral to the
trigeminal region in the rat does not necessarily contradict the
localization of the vagal region in area 3a in the more differentiated cortex of other mammals.
In macaque monkeys, the vagal-evoked potential was recorded in the inferior precentral region at the lateral extreme of
sensorimotor cortex (O’Brien et al. 1971). Convergent responses to laryngeal and tongue stimulation were obtained in
the same region, anterior to S1, so the authors viewed this
region as motor cortex (O’Brien et al. 1971). However, others
have regarded the inferior precentral cortex as area 3 extending
anterior and lateral from the tip of the central sulcus and
providing either the sensory representation of the ipsilateral
intraoral region (Manger et al. 1996) or a taste-related region
(Benjamin et al. 1968; Ogawa et al. 1985, 1989; Pritchard et al.
1986). Thus the possibility remains that the vagal potential site
in monkey sensorimotor cortex is also located in area 3a.
In humans, direct electrical stimulation of the lateral S1
region elicited conscious alimentary sensation (Penfield and
Rasmussen 1950). Esophageal (Aziz et al. 1997, 2000b;
Binkofski et al. 1998; Furlong et al. 1998; Hecht et al. 1999),
gastric (Ladabaum et al. 2001) or rectal (Lotze et al. 2001)
distension elicited activation in functional imaging studies in
the same general region around the lateral end of the central
sulcus. The pathway responsible for this cortical activation,
and whether it represents motor or sensory activity, has not
been determined. Although these alimentary structures are
dually innervated by cranial and spinal nerves (Collman et al.
1992), a vagal contribution is strongly suggested by the sequence of cortical topography, consistent with the present
findings.
Thus in all representative mammals that have been investigated, an area at the lateral end of sensorimotor cortex has
consistently been observed that could represent vagal afferent
activity. However, the cytoarchitectonic location of the vagal
response site has not been previously resolved.
151
152
S.-I. ITO AND A. D. CRAIG
On the possible role of area 3a in visceral motor and
sensory functions
Stimulation in the somatic portion of area 3a evokes striate
muscle contractions (Preuss et al. 1996; Widener and Cheney
1997; Wu et al. 2000), and stimulation of this region can also
have autonomic effects. In cats, it can change respiratory
rhythm (Kaada 1951) via the phrenic as well as the recurrent
laryngeal nerves (Bassal and Bianchi 1981, 1982). Thus area
3a appears to participate in visceral motor control via both
sympathetic and parasympathetic pathways as well as in somatic motor control (Jones and Porter 1980; Wiesendanger and
Miles 1982). Stimulation in the lateral precentral region of the
monkey cortex evokes swallowing (Martin et al. 1999) or
changes in heart rate (Hast et al. 1974), although whether that
region is cytoarchitectonically area 3a remains to be resolved.
It has not yet been determined whether area 3a is involved in
the conscious perception of any sensory event. Activity in
muscle afferents is essential for the sense of joint position
(Clark et al. 1985; Gandevia 1985; Goodwin et al. 1972), so
area 3a, as the primary cortical target of deep receptor afferents, may be involved in this sensation (Jones and Porter 1980),
J Neurophysiol • VOL
although it is heavily interconnected with area 2 posterior to S1
(Porter 1991). As part of the same cytoarchitectonic area, the
vagal afferent projection field in the lateral portion of area 3a
could share a role with the insular cortex in sensations such as
“sinking feeling,” “sick feeling,” “choking sensation,” “nausea,” and “shaking in the heart,” descriptors evoked by direct
electrical stimulation of the corresponding human cortex (Penfield and Rasmussen 1950).
Cortical homeostatic afferent network
In addition to the region at the lateral end of sensorimotor
cortex, two other cortical regions are activated by vagal afferent input, namely, the insular and the cingulate cortices, which
also receive vagal input by way of a direct thalamic pathway
(Bachman et al. 1977; Cechetto and Saper 1987; Hallowitz and
MacLean 1977). The insular cortex has direct interconnections
with both area 3a and with the cingulate cortex (cat: Clasca et
al. 2000). These three regions apparently constitute the main
visceral afferent activation sites in the cortex and form together
a visceral afferent cortical network. This interpretation is supported by the consistent activation of all three areas in imaging
studies of visceral stimulation in the human brain (Aziz et al.
2000a). Notably, the same three regions (area 3a, the insular
and cingulate cortices) also constitute the main regions activated in the human cerebral cortex by painful stimulation (see
Craig 2002), and prior evidence in the cat indicates that area 3a
also receives nociceptive thalamocortical input (Craig and
Kniffki 1985). Thus the present findings are consonant with the
fundamental concept that pain and visceral sensation are different aspects of a common homeostatic afferent system that
activates limbic sensory (insular) cortex, limbic motor (cingulate) cortex, and a particular portion of sensorimotor cortex
(area 3a) (Craig 2002). The role of area 3a in this network
remains to be resolved.
We thank M. Castro, who provided excellent technical assistance during
these experiments.
Support for this laboratory was provided by National Institutes of Health
Grant NS-25616 and the Atkinson Pain Research Fund administered by the
Barrow Neurological Foundation. S.-I. Ito was on leave from Kumamoto
University.
Present address of S.-I. Ito, Dept. of Physiology, Shimane Medical University, 89-1 En-ya, Izumo City, Shimane 693-8501, Japan.
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