Download Cortical afferents to the smooth-pursuit region of the macaque

Exp Brain Res (2005) 165: 179–192
DOI 10.1007/s00221-005-2292-z
R ES E AR C H A RT I C L E
Gregory B. Stanton Æ Harriet R. Friedman
Elisa C. Dias Æ Charles J. Bruce
Cortical afferents to the smooth-pursuit region of the macaque monkey’s
frontal eye field
Received: 27 July 2004 / Accepted: 25 January 2005 / Published online: 7 June 2005
Ó Springer-Verlag 2005
Abstract In primates, the frontal eye field (FEF) contains separate representations of saccadic and smoothpursuit eye movements. The smooth-pursuit region
(FEFsem) in macaque monkeys lies principally in the
fundus and deep posterior wall of the arcuate sulcus,
between the FEF saccade region (FEFsac) in the anterior wall and somatomotor areas on the posterior wall
and convexity. In this study, cortical afferents to FEFsem were mapped by injecting retrograde tracers (WGAHRP and fast blue) into electrophysiologically identified
FEFsem sites in two monkeys. In the frontal lobe, labeled neurons were found mostly on the ipsilateral side
in the (1) supplementary eye field region and lateral area
F7; (2) area F2 along the superior limb of the arcuate
sulcus; and (3) in the buried cortex of the arcuate sulcus
extending along the superior and inferior limbs and
including FEFsac and adjacent areas 8, 45, and PMv.
Labeled cells were also found in the caudal periprincipal
cortex (area 46) in one monkey. Labeled cells were found
bilaterally in the frontal lobe in the deep posterior walls
of the arcuate sulcus and postarcuate spurs and in cingulate motor areas 24 and 24c. In postcentral cortical
areas all labeling was ipsilateral and there were two
major foci of labeled cells: (1) the depths of the intraparietal sulcus including areas VIP, LIP, and PEa, and
(2) the anterior wall and fundus of the superior temporal
sulcus including areas PP and MST. Smaller numbers of
G. B. Stanton (&)
Department of Anatomy, Howard University
College of Medicine, 520 W St., N.W.,
Washington, DC 20059, USA
E-mail: [email protected]
Tel.: +1-202-806-5274
Fax: +1-202-265-7055
H. R. Friedman Æ E. C. Dias Æ C. J. Bruce
Department of Neurobiology, Yale University
School of Medicine, New Haven,
CT 06520-8001, USA
E. C. Dias
Nathan Kline Institute, 140 Old Orangeburg Rd,
Orangeburg, NY 10962, USA
labeled cells were found in superior temporal sulcal
areas FST, MT, and STP, posterior cingulate area 23b,
area 3a within the central sulcus, areas SII, RI, Tpt in
the lateral sulcus, and parietal areas 7a, 7b, PEc, MIP,
DP, and V3A. Many of these posterior afferent cortical
areas code visual-motion (MT, MST, and FST) or visual-motion and vestibular (PP, VIP) signals, consistent
with the responses of neurons in FEFsem and with the
overall physiology and anatomy of the smooth-pursuit
eye movement system.
Abbreviations
Cortical areas 3a: Sensorimotor cortex (Krubitzer et al.
2004) Æ 7a: Subdivision of Brodmann’s area 7 (Cavada
and Goldman-Rakic 1989a) Æ 7b: Subdivision of
Brodmann’s area 7 (Cavada and Goldman-Rakic
1989a) Æ 8: Brodmann’s area 8 (Preuss and GoldmanRakic 1991) Æ 23b: Subdivision of Brodmann’s area 23
(Vogt et al. 1987) Æ 24: Brodmann’s area 24 (Vogt et al.
1987) Æ 24c: Subdivision of Brodmann’s area 24 (Vogt
et al. 1987) Æ 45: Brodmann’s area 45 (Preuss and
Goldman-Rakic 1991) Æ 46: Brodmann’s area 46 (Preuss
and Goldman-Rakic 1991) Æ DP: Dorsal prelunate area
(Colby et al. 1988) Æ F2: A dorsal premotor area (Matelli
and Luppino 2001) Æ F7: A dorsal premotor area
(Matelli and Luppino 2001) Æ FEFsac: Saccade part of
the frontal eye field (Bruce et al. 1985) Æ FEFsem:
Smooth-pursuit part of the frontal eye field (MacAvoy
et al. 1991) Æ FST: Fundus of the superior temporal
sulcus area (Boussaoud et al. 1990) Æ LIP: Lateral
intraparietal area (Blatt et al. 1990) Æ M1: Primary
motor cortex (Dum and Strick 1991) Æ MIP: Medial
intraparietal area (Colby et al. 1988) Æ MST: Medial
superior temporal area (Boussaoud et al. 1990) Æ MT:
Middle temporal area (Boussaoud et al. 1990) Æ
PE: Parietal area E (Brodmann’s area 5) (Marconi et al.
2001) Æ PEa: Subdivision of area PE (Marconi et al.
2001) Æ PEc: Subdivision of area PE (Marconi et al.
2001) Æ PMv: Ventral part of the premotor area (Fujii
180
et al. 2000) Æ PP: Posterior parietal area (Colby et al.
1988) Æ RI: Retroinsular area (Grüsser et al.
1990) Æ SEF: Supplementary eye field (Schlag and
Schlag-Rey 1987) Æ SII: Secondary somatosensory area
(Cipolloni and Pandya 1999) Æ STP: Superior temporal
polysensory area (Boussaoud et al. 1990) Æ Tpt:
Temporoparietal (auditory) area (Seltzer and Pandya
1989) Æ V3A: A visuotopic prestriate area (Colby et al.
1988) Æ VIP: Ventral intraparietal area (Bremmer et al.
2002a)
Sulcal abbreviations as: arcuate sulcus Æ cs: central
sulcus Æ ips: intraparietal sulcus Æ las: lateral sulcus Æ lus:
lunate sulcus Æ ots: occipitotemporal sulcus Æ pas:
postarcuate spur Æ ps: principal sulcus Æ sts: superior
temporal sulcus
Introduction
In addition to its saccade-related functions (Bruce et al.
2004), the primate frontal eye field (FEF) also plays a role
in controlling smooth-pursuit eye movements. In macaque monkeys the smooth-pursuit eye movement region of
FEF (FEFsem) is located principally in the fundus and
deep posterior wall of the arcuate sulcus (MacAvoy et al.
1991; Gottlieb et al. 1993), between the saccade region of
FEF (FEFsac) in the anterior wall and posterior somatomotor areas. Microstimulation in FEFsem elicits
continuous, smooth eye movements, clearly distinguishable from elicited saccadic eye movements obtained in
FEFsac and closely resembling natural smooth pursuit
(Gottlieb et al. 1993; Tanaka and Lisberger 2002a).
Neurons in FEFsem discharge before and during smooth
pursuit (Fukushima et al. 2000; Gottlieb et al. 1994; Tanaka and Fukushima 1998; Tanaka and Lisberger 2002b,
c). Reversible inactivation in FEFsem dramatically reduces pursuit gain (Shi et al. 1998), and aspiration lesions
of FEFsem cause permanent pursuit deficits (Keating
1991, 1993; MacAvoy et al. 1991). Humans also have a
smooth-pursuit representation near FEFsac (Berman
et al. 1999; O’Driscoll et al. 2000; Petit et al. 1997; Rosano
et al. 2002) and pursuit deficits often accompany frontal
lobe lesions in man (Morrow and Sharpe 1995). To further understand the role of the FEF in smooth pursuit, we
examined cortical afferents to FEFsem by making injections of retrograde tracers at physiologically identified
smooth-pursuit sites in two rhesus monkeys. Parts of
these data were published earlier in abstract form (Stanton et al. 1993).
Materials and methods
All surgical and behavioral procedures were approved by
the Yale Institutional Animal Care and Use Committee
(animal protocol #7651) and complied with United
States Public Health Service policy on the humane care
and use of laboratory animals. Two adult female rhesus
(Macaca mulatta) monkeys (SYB and SUZ) were prepared for chronic single-neuron recording using aseptic
surgical procedures under pentobarbital anesthesia (see
Gottlieb et al. 1994, for details). During experimental
sessions they sat in a primate chair with their head held
stationary. Eye position was obtained from a search coil
implanted in one eye. To enhance the accuracy and
reproducibility of electrode penetrations and subsequent
injections, a plastic grid with 1-mm spacing between
adjacent holes (Crist Instrument) was secured inside the
recording well. The microelectrodes and injection needles traveled inside 23-gauge guide tubes secured in this
grid and through intact dura into the brain.
We located sites in FEFsem by studying the responses
of isolated neurons during smooth-pursuit eye tracking
and by examining eye movements evoked by electrical
stimulation through the tip of the recording electrodes.
Parameters of microstimulation and methods of testing
pursuit neurons have been described elsewhere (Gottlieb
et al. 1993, 1994; Shi et al. 1998). Sites were found where
pursuit-like eye movements were electrically elicited and/
or where neurons specifically responded during smooth
pursuit and not in conjunction with saccades. When a
suitable site was located the exact electrode depth was
noted and the electrode was removed from the guide
tube and replaced with a 27-gauge beveled needle connected to a 10-lL Hamilton syringe filled with neuroanatomical-tracer solution. The needle was lowered into
the brain through the guide tube to the desired depth
using the top of the guide tube as a reference point. The
volumes injected were 0.1 lL of WGA-HRP (SYB) and
0.4 lL fast blue (SUZ) over periods of 20 min.
After post-injection survival periods of 2 days for
SYB and 7 days for SUZ, the monkeys were given sodium pentobarbital (50 mg kg 1) and were then perfused through the heart with phosphate buffered saline
and buffered fixative solutions (1% paraformaldehyde
and 1.25% glutaraldehyde, SYB; 4% paraformaldehyde,
SUZ). The fixative solutions were followed by buffered
sucrose washes of increasing sucrose concentrations
from 10 to 30%. The brains were exposed, blocked in
the stereotaxic frontal plane, and stored in buffered sucrose/glycol solution at 4°C. Frozen tissue sections were
cut from the brain blocks at 40 lm. In SYB, two series
of sections (section spacing 240 lm) were developed
with TMB histochemistry for detection of WGA-HRP
tracer (Mesulam 1982). One series was counterstained
with neutral red solution, and the other was left unstained to enable optimum detection of labeled neurons.
The sections were mounted on to glass slides and viewed
with brightfield and darkfield microscopy. In SUZ,
mounted Nissl-stained and unstained sections were
viewed using brightfield and fluorescence microscopy.
Plots of tissue section contours and landmark features
and retrogradely labeled cell bodies were made with the
aid of an X–Y plotter driven by potentiometers attached
181
Verification of FEFsem physiology at the injection site
in the right hemisphere of monkey SYB is shown in
Fig. 1. A neuron recorded there responded best during
upward smooth pursuit and had little response in conjunction with saccadic eye movements (Fig. 1A), and
electrical stimulation at this site elicited smooth, continuous eye movements (Fig. 1B) and not saccades. The
single injection of WGA-HRP made at this site spread
throughout the posterior portion of the fundus of the
arcuate sulcus and into the deep, inferior wall of the
postarcuate spur. Some tracer spread superficially along
the needle track onto a small fold of the anterior wall of
the arcuate sulcus (Fig. 2A, f). Only layers I and II of
this fold of cortex were exposed to tracer. The injection
site indicated by necrotic tissue and its relation to two
marker lesions of stimulation sites are shown in Fig. 2A.
In monkey SUZ, two injections of fast blue were
aimed at the center of a 0.5-mm portion of an electrode
track in the right hemisphere where most neurons had
responded tonically during ipsilateral (leftward) smooth
pursuit. As shown in Fig. 2B, tracer from these injections was most concentrated near the fundus of the
arcuate sulcus with more spread of tracer along the
needle track through the anterior wall of the arcuate
sulcus than the amount of tracer spread along the needle
track in SYB.
Overall, the injection site in monkey SUZ was smaller
and more anteriorly located than the injection site in
monkey SYB. The effective location and extent of the
injections can be judged by comparing the pattern of
labeled cells in the contralateral arcuate regions. Basically, the labeled cells in the contralateral arcuate sulcus
of both cases are concentrated at the fundus; however,
most labeled cells in SYB are in the posterior fundus
adjacent to the posterior wall as it extends along the
postarcuate spur (Fig. 3A, f, g) whereas labeled cells in
the contralateral arcuate sulcus of monkey SUZ are
mostly in the anterior portion of the fundus and deeper
Fig. 1 Responses of a smooth-pursuit (SP) neuron recorded near
the HRP injection site in monkey SYB and the smooth eye
movements elicited by microstimulation at the same site. A Raster
of the neuron’s spike responses (top); peristimulus time histogram
summing these data (middle); and sample eye (solid) and target
(dashed) traces (bottom), all during tracking of constant-velocity
motion (18° s 1) in the neuron’s optimum direction (70°, upright). This neuron was one of several in this neighborhood that
discharged strongly for smooth pursuit and much less or not at all
in conjunction with saccades. B Continuous, smooth movements
similar to the neuron’s preferred smooth pursuit were elicited by
electrical stimulation at the site of this neuron (biphasic 0.2-ms
pulses at 300 Hz). The elicited smooth eye movements had a
direction of 100° (up and slightly left), a latency of 50 ms, and
a threshold current of 20 lA. Top B: When stimulation was
applied during steady fixation of a stationary target, gaze moved
smoothly for 100 ms, reaching a velocity of 10° s 1 (dashed
line), and then gradually slowed and stopped moving even though
the stimulation train lasted 500 ms. Bottom B: When stimulation
was applied while the target’s position was temporarily yoked to
the eye’s position (‘‘foveal-afterimage’’ experiment, Gottlieb et al.
1993), the elicited smooth movement reached a velocity of
15° s 1 (dashed line) and continued for the entire 500-ms train
duration
to the microscope stage. Raw plots were digitized,
traced, and labeled using graphics software (Canvas 8).
Cortical areas were identified with reference to previous
studies cited in the ‘‘Abbreviations’’.
Results
Location and physiological verification of injection sites
182
Fig. 2 Drawings from photographs of the right hemispheres from
monkeys SYB (A) and SUZ (B) showing the location of frontal
sections displayed in this and subsequent figures. Drawings of
three frontal sections in each monkey show injected tracers (gray
areas) centered on FEFsem microstimulation sites. The anterior
wall and fundus of the posterior arcuate sulcus between the
superior and inferior limbs of the sulcus is shown in sections e
and f in SYB and e–g in SUZ. The fundus and posterior wall of
the arcuate sulcus at the junction with the postarcuate spur (pas)
are shown in section g of SYB. Approximately 1,100 lm separates
the anterior and posterior sections in each case. Notice that both
injections were made in the depths (fundus) of the posterior
arcuate sulcus. However, effective spread for SYB was largely in
the posterior wall and spur of the arcuate sulcus whereas spread
for SUZ was principally into the anterior wall above the injection.
The area enclosed by the rectangle in section g of SYB was
photographed from an adjacent Nissl-stained section and is
displayed below. Photomicrograph A shows a necrotic area
(asterisk) resulting from injected WGA-HRP. Two microelectrode
marker lesions (arrowheads) identify locations where smoothpursuit eye movements were elicited within FEFsem. Magnification bar, 500 lm. Photomicrograph B shows the depth of the
anterior injection of fast blue (asterisk) in SUZ in relation to
large, layer V pyramidal neurons (arrowheads) in the fundus of
the arcuate sulcus. The area of the photomicrograph is marked by
the rectangle in section e. A dashed line marks the border between
white and gray matter in both photomicrographs. Magnification
bar, 500 lm
half of the anterior wall (Fig. 3B, f, g), with less label in
the depths of the sulcus.
inferior limbs of the sulcus. Label in the deep, posterior
fundus of the arcuate sulcus (Fig. 3A, e–g; 3B, g, h) was
probably within FEFsem whereas label in the anterior
wall at caudal levels was within FEFsac (Fig. 3A, c, d;
3B, d). In monkey SYB, label was found anterior to
FEFsac in the fundus of the inferior limb of the arcuate
sulcus (area PMv; Fig. 3A, c) and in monkey SUZ, label
anterior to FEFsac was found on the anterior wall of the
arcuate sulcus (areas 8 and 45; Fig. 3B, a–c), and in the
caudal periprincipal area 46 (Fig. 3B, a–d).
Frontal lobe afferents
Prearcuate and FEF
Both monkeys had labeled cells in the buried cortex of
the arcuate sulcus that extended along the superior and
183
Dorsomedial cortex
Distinctive patches of label were found in the area of the
supplementary eye field (SEF) in both cases (Fig. 3A, a,
b; 3B, c, d). Other labeled cells were found medial to the
superior limb of the arcuate within the lateral part of
area F7 (Fig. 3A, c; 3B, a–c) and in area F2 (Fig. 3A, d–
f; 3B, i). Small clusters and isolated cells were found in
the dorsomedial convexity near the midline and on the
medial wall and cingulate cortex in both animals
(Fig. 3A, b–d; 3B, b–d).
Posterior arcuate and cingulate areas
Labeled cells were found in the depths of the postarcuate
spurs and on the convexity at their posterior endings
(Fig. 3A, g–i; 3B, i–m). Large patches of labeled cells in
the contralateral spurs were also found (Fig. 3A, f, g;
3B, i–k). Small, distinct, patches of labeled cells were
found in ipsilateral and contralateral cingulate motor
areas 24 and 24c (Fig. 3A, f–i; 3B, i–L). Except for an
isolated patch of cingulate label in monkey SYB
(Fig. 3A, c), patches of labeled cells in cingulate areas
were coextensive with the postarcuate spurs.
Table 1 summarizes the relative concentration of
frontal cortical neurons that project to FEFsem in the
ipsilateral hemisphere in each case. Most afferent neurons are located in the buried cortex of the arcuate
sulcus extending along the superior and inferior limbs,
including FEFsac, and in cortex along the fundus of the
postarcuate spur. Afferent neurons anterior to FEF were
found in the deep, anterior walls (areas 8, 45), and
posterior walls (areas PMv) of the arcuate sulcus, in
posterior periprincipal area 46, and in cortex medial to
the superior limb of the arcuate sulcus (areas F2 and
F7). The numbers of labeled neurons found in SEF and
posterior cingulate motor areas 24 and 24c were small
but densely concentrated into distinct locations. The
different patterns of labeling in the two monkeys probably reflect differences in the injection sites in anterior vs
posterior aspects of FEFsem and also spread of tracer
into adjacent cortical areas. For example, some of the
labeled neurons in rostral area 8 and the periprincipal
cortex in SUZ may have resulted from spread of tracer
into FEFsac (Barbas and Mesulam 1981; Huerta et al.
1987). Likewise, labeled cells in M1 cortex in SYB
(Fig. 4A, j—not included in the table) were attributed to
uptake of tracer at the injection site by cells in area PMv
(Matelli et al. 1986).
Parietal and temporal lobe afferents
In parietal cortical areas, labeled neurons were most
concentrated in the posterior parietal wall of the superior temporal sulcus (Fig. 4A, n–q; 4B, u–x). Some of
the labeling here seems to overlay the dorsal anterior
aspect of area MST, but most labeled cells were more
superficially situated. We have designated this area PP
according to illustrations in Colby et al. (1988), but,
unlike Colby, we have made a distinction between this
area and areas 7a and 7b on the convexity of the inferior
parietal lobule. A second concentration of labeled cells
in these animals was in the fundus and buried walls of
the intraparietal sulcus (area VIP and the deep part of
area LIP) (Fig. 4A, m–r; 4B, s–y) and area PEa
(Fig. 4A, L–q). Small numbers of cells were seen in
cortex at the end of the lateral sulcus and lip of the
superior temporal sulcus (area Tpt) (Fig. 3A, m, n; 3B,
t–v), area 7a (Fig. 4A, n–q; 4B, y) and 7b (Fig. 4A,
L, m), area 3a within the central sulcus (Fig. 4A, j; 4B,
n), cingulate cortical area 23b (Fig. 4A, m; 4B, p), and
posterior parietal areas V3A, MIP (Fig. 4A, r; 4B, x),
and PEc (Fig. 4A, r, s; 4B, x), PE (Fig. 4A, o, p), and
area DP (Fig. 4A, s).
Most labeling in the temporal lobe was found on the
fundus of the superior temporal sulcus, particularly in
area MST but also in rostral area STP, and more lateral
and posterior areas FST and MT (Fig. 4A, L–p; 4B, r–x).
Small clusters of labeled neurons were present in area SII
(Fig. 4A, k; 4B, n–p) and in the retroinsular (RI) area in
monkey SYB (Fig. 4A, L, m). In the monkey with the
more anterior injection (SUZ) isolated labeled cells were
found in visual areas on the inferior wall of the superior
temporal sulcus (Fig. 4B, t–v), V3 near the occipitotemporal sulcus (Fig. 4B, t), and the lunate sulcus (Fig. 4B, x).
Table 2 summarizes the posterior cortical areas with
projections to FEFsem in the ipsilateral hemisphere. The
greatest concentrations of afferent neurons were found
in the depths of the intraparietal sulcus (area VIP and
deep parts of areas LIP and PEa) and in the anterior
wall of the superior temporal sulcus (areas PP and
MST). Small numbers of afferent neurons were also
found in parietal areas 3a, PEc, MIP, and V3A and in
temporal areas MT, FST, STP, and SII. Labeled
neurons found in parietal areas 7a, 7b, PE, DP, area
PEa, cingulate area 23 and retroinsular area RI in
monkey SYB, but not in monkey SUZ, resulted from the
more posterior tracer injection site in SYB. We considered the possibility that some labeling of PEa neurons in
monkey SYB resulted from spread of injected tracer into
postarcuate premotor areas. In other studies, however,
there were few labeled cells in PEa from PMv/F5 postarcuate injections (Tanné-Gariépy et al. 2002) and labeled neurons from superior premotor injection sites
(F2, F7/PMd) (Jones and Stanton 2001; Marconi et al.
2001; Matelli et al. 1998; Tanné-Gariépy et al. 2002),
seemed to be located more superficially in PEa along the
medial wall of the intraparietal sulcus than the cells labeled by the FEFsem injection in monkey SYB. In
contrast, the greater numbers of labeled cells found in
monkey SUZ in superficial area LIP and area MT and
the isolated cells in cortical visual areas along the
superior temporal, occipitotemporal and lunate sulci
(not included in Table 2), probably resulted from spread
of tracer into FEFsac (Huerta et al. 1987; Schall et al.
1995).
184
Discussion
Our results show that the FEFsem in macaque monkeys
receives inputs from a diverse spectrum of neocortical
areas, including multiple vestibular areas, motor and
sensory areas in which neck representation seems likely,
and several visual and visuomotor areas. In this section
we organized these areas into five functional groups: (1)
visual-motion areas; (2) vestibular areas; (3) areas associated with generation of saccades and vergence move-
185
b
Vestibular areas
Fig. 3 Plots of retrogradely labeled, individual neurons (filled
circles) shown in sections through the frontal lobes of monkeys
SYB (A) and SUZ (B) Sections are arranged from anterior, top, to
posterior, bottom. No label was seen on the contralateral side in
SYB sections a, b or in SUZ, a–d. The tracer injections in each case
are shown as gray-shaded areas as in Fig. 2. An area of tissue
damage in the anterior prefrontal cortex in SUZ is marked by
diagonal lines. The core of the injections is indicated by the dense
labeling of commissural neurons in the fundus of the contralateral
arcuate sulcus. Labeled afferent neurons were most concentrated
along the postarcuate spurs, bilaterally, and along the fundus and
deep walls of the arcuate sulcus including the saccade part of the
FEF. Small, discrete patches of labeled cells were seen in the
cingulate motor areas 24/24c on both sides. Smaller numbers of
labeled cells were found in dorsomedial cortical areas SEF, F7 and
F2. Notice that the more posterior injection (case SYB) labeled
cells in PMv and greater numbers of cells in F7 and F2 whereas
labeled cells in areas 46, 45, 8 were found only in the more anterior
injection (monkey SUZ). See ‘‘Abbreviations’’
ments; (4) frontal somatomotor and prefrontal areas; and
(5) spatial orientation areas important for localization of
external stimuli. Each of these afferent groups are discussed separately below. We then compare our results
regarding the cortical afferents of FEFsem in the oldworld macaque monkey with the findings of Tian and
Lynch (1996b) for FEFsem in the new-world cebus
monkey. Finally, we compare and contrast the FEFsem
afferents found here with the connections of FEFsac of
the macaque as reported by Huerta et al. (1987) and
Schall et al. (1995).
Visual-motion areas
Smooth pursuit is principally elicited by visual-motion,
and these results show that FEFsem receives direct inputs from several cortical areas in the superior temporal
sulcus that have been linked to visual-motion processing, including areas MST, FST, MT (Boussaoud et al.
1990; Desimone and Ungerleider 1986), STP (Bruce
et al. 1981; Scalaidhe et al. 1997), VIP (Bremmer et al.
2002a; Colby et al. 1993), and PP (Kawano et al. 1980).
Our results are supported by earlier studies showing
projections to the FEFsem region from MST/FST
(Boussaoud et al. 1990; Maioli et al. 1998) and from a
posterior parietal region that includes area PP (Petrides
and Pandya 1984).
Because 65% of pursuit neurons in FEFsem also respond to a vestibular stimulation in the absence of visual-motion (Fukushima et al. 2000), it is not surprising
that several of the cortical areas with projections to
FEFsem are potential sources of vestibular information.
Area PP, which contains visual-motion neurons that are
also responsive to vestibular stimulation (Kawano et al.
1980), had a high concentration of FEFsem afferent
neurons. Furthermore, cells in the PP region project to
the vestibular nuclei (Akbarian et al. 1994; FaugierGrimaud and Ventre 1989) and receive vestibular-thalamocortical afferents (Faugier-Grimaud and Ventre
1989). Area VIP, another multisensory area with neurons responsive to vestibular stimulation (Bremmer et al.
2002b), also had a strong projection to FEFsem. Lewis
and Van Essen (2000) found abundant projections from
the FEFsem region to VIP and adjoining ventral LIP,
indicating a strong, reciprocal relationship of FEFsem
with VIP and ventral LIP.
Small numbers of afferent neurons to FEFsem were
also found in other vestibulo-cortical areas including
area RI in monkey SYB (Grüsser et al. 1990), 3aV
(Guldin et al. 1992; Ödkvist et al. 1974), and area Tpt
(vestibular area T3 of Akbarian et al. 1994). All of these
areas are known to have efferent connections with the
vestibular nuclei (Akbarian et al. 1994).
FEFsem afferent neurons that we found in the fundus
of the postarcuate spur also seem to be linked to vestibular functions, though only the postarcuate convexity
ventral to the spur was considered as vestibular area 6pa
(Akbarian et al. 1994). However, Ebata et al. (2004)
found strong projections to the vestibular nuclei from
the buried cortex of arcuate sulcus and postarcuate spur;
in the same cortex, field potentials could be evoked after
vestibular nerve stimulation indicating direct vestibulothalamo-cortical input to this area. Earlier, Fukushima
et al. (2000) found single pursuit-related neurons in the
postarcuate spur fundus can respond to vestibular
stimuli and head velocity, and to retinal-image motion
and eye velocity.
We did not find label in vestibular area 2v (Fredrickson and Rubin 1986) at the rostral tip of the intraparietal sulcus, or in the vestibular part of the motor
cingulate cortex (6c–23 cv) near the medial end of the
central sulcus (Akbarian et al. 1994). Perhaps the lack of
Table 1 Relative numbers of labeled neurons in ipsilateral frontal lobe areas after tracer injections in the FEFsem of monkeys SYB and
SUZ
FEFsem
SYB
SUZ
++++
++++
FEFsac
++
++
Rostral
area 8
+++
Periprincipal
area 46
++++
Dorsomedial
premotor
SEF
F7
F2
PMv
+
+
+
+
+++
+
++
+=5–50 cells; ++=50–100 cells: +++=100–150 cells; ++++=>150 cells
Postarcuate
spur
Cingulate
areas 23/23c
++++
++++
+
+
186
Fig. 4 Sections through postcentral cortical areas of monkeys SYB
(A) and SUZ (B) showing plots of retrogradely labeled, individual
neurons (filled circles). The sections are arranged from anterior,
upper right, to posterior, lower left, and their location in each brain
can be seen in Fig. 2. In section j of SYB two lines drawn in the
cortex mark the extent of layer V Betz cells indicating M1 cortex.
The main foci of labeled afferent neurons to FEFsem in both
animals were areas PP, MST, VIP, and ventral LIP cortex and, in
monkey SYB, the buried cortex of area PEa. Small amounts of
label were seen in areas 3a, PEc, PE, MIP, V3A, SII, STP, FST,
Tpt, and MT in both monkeys. The more posterior injection
(monkey SYB) resulted in cell labeling in area PEa, the convexity of
the inferior parietal lobule (areas 7a and 7b), areas DP, 23, and RI
exclusively, and greater numbers of cells in VIP and MST. Greater
numbers of labeled cells were found in posterior area LIP and area
MT in the more anterior injection (monkey SUZ)
input to FEFsem from these areas and the meager inputs
to FEFsem from areas RI, 3a and T3 might be because
these areas function at a simpler level of vestibular
information processing than cortical areas VIP and PP,
both of which projected strongly to FEFsem.
The topography of the connectivity of FEFsem with
vestibular areas may be related to the functional orga-
nization within FEFsem. Gottlieb et al. (1993) found
that in the posterior wall of the arcuate sulcus, pursuit
movements were directed both ipsilaterally and contralaterally and were significantly affected by orbital position of the eye at the time of stimulation. In contrast,
they found pursuit movements elicited in the fundus to
be more exclusively ipsilateral and less effected by
187
Fig. 4 (Contd.)
orbital position. As noted above, the posterior arcuate
wall and fundus of the postarcuate spur also has a higher
concentration of vestibular-evoked responses and cor-
tico-vestibular neurons (Ebata et al. 2004; Fukushima
et al. 2000). All of this suggests that the range of pursuit
direction and sensitivity to orbital position might be
tightly linked to head movements, and that inputs to this
area from somatosensory area PEa (see below) and
Table 2 Relative numbers of labeled neurons in ipsilateral parietal, temporal, and cingulate areas after tracer injections into the FEFsem
of monkeys SYB and SUZ
Parietal
Cingulate area 23 Temporal
Anterior
3a 7b 7a
Posterior
PEa
VIP
Anterior
LIP
PP
PEc PE DP MIP V3A
SYB + + ++ ++++ ++++ ++ ++++ ++ + + +
SUZ +
++
+++ ++++ +
+
+
+
RI SII STP FST Tpt MST
+
+=5–50 cells; ++=50–100 cells; +++=100–150 cells; ++++=>150 cells
+ + +
+ +
+
+
MT
+ +++ +
+ ++ ++
188
vestibular areas help FEFsem coordinate pursuit
movements of the eye and head.
Saccade and vergence areas
Our data show inputs to FEFsem from the three
principal cortical saccadic eye-movement areas: FEFsac, SEF, and LIP. These findings are supported by
anterograde tracing studies of afferents to the FEFsem
region from LIP (Cavada and Goldman-Rakic 1989b;
Schall et al. 1995), SEF (Huerta and Kaas 1990;
Tanné-Gariépy et al. 2002), and FEFsac (Barbas and
Mesulam 1981; Huerta et al. 1987; Stanton et al. 1993;
Tian and Lynch 1996a). The afferents from FEFsac
that we found were mostly from cells near the fundus
of the arcuate sulcus where ‘‘small saccade’’ neurons
are more abundant (Bruce et al. 1985; MacAvoy et al.
1991; Sommer and Wurtz 2000). Imaging studies suggest that secondary sources of saccadic eye movement
input to FEFsem might be cells in cortex at the posterior end of the principal sulcus, containing labeled
cells in monkey SUZ, and cortex along the postarcuate
spur (Koyama et al. 2004; Moschovakis et al. 2004). In
addition to saccadic neurons, the posterior periprincipal cortex is the site of neurons responsive to vergence
stimuli (Gamlin and Yoon 2000). Afferents to FEFsem
from this area are appropriate for depth pursuit
movements that are known to occur in FEFsem
(Fukushima 2003).
Somatomotor and prefrontal areas
Labeled FEFsem afferent neurons in cingulate motor
areas 24/24c and the fundus of the postarcuate spur lie
adjacent to, and partially overlap, corticospinal neurons
that project to C2–C4 cervical levels (Dum and Strick
1991). This pattern of retrograde labeling after our
FEFsem injections was not seen after injections into
premotor areas medial or lateral to the postarcuate spur
on the convexity of the hemisphere (Barbas and Pandya
1987; Ghosh and Gattera 1995; Jones and Stanton 2001;
Kurata 1991; Marconi et al. 2001; Matelli et al. 1986).
Our findings suggest that axon collaterals of cells in
these areas might send neck somatomotor signals to
FEFsem. In contrast, postarcuate and cingulate corticospinal neurons that terminate at levels C4–T1 containing forelimb motoneurons (Dum and Strick 1991) do
not seem to project to FEFsem. Neck movements have
been evoked by microstimulation in the buried cortex of
the postarcuate spur (Mitz and Godschalk 1989) and, as
noted previously, neurons responsive to vestibular
stimuli were also found in this cortex. Therefore, neurons in the cortex of the postarcuate spur and cingulate
gyrus that project to FEFsem may also project to the
vestibular nuclei for the control of head and neck
movements via vestibulocolic reflexes, and/or directly to
spinal cord levels containing neck motoneurons.
The posterior area F2 and lateral parts of area F7 are
two other premotor areas that project to FEFsem. Labeled cells that we found in F2 in monkey SYB seem to
coincide with an oculomotor subregion of a somatomotor area. Low-threshold saccades were elicited at this
site but the properties of these saccades differed from
saccadic properties of FEFsac neurons (Fujii et al.
2000). Other workers found visually responsive neurons
in this area of premotor cortex (Fogassi et al. 1999).
Area F7 afferents might also carry information to
FEFsem for orientation to auditory and/or visual stimuli (Vaadia et al. 1986). Upper body somatomotor
projections to FEFsem may provide one mechanism for
the high degree of coordination existing between ocular
and manual tracking (Engel et al. 2000).
Spatial orientation areas
FEFsem received afferents from several parietal areas
where neural activity is related to spatial orientation.
Optic flow information in areas 7a (Phinney and Siegel
2000) and VIP (Bremmer et al. 2002a) might be conveyed
to FEFsem for generation of smooth-pursuit eye movements during self-motion. Cells in VIP are frequently
multisensory, responding to combinations of visual,
somatosensory, and vestibular stimuli (Bremmer et al.
2002b; Duhamel et al. 1998), and are most responsive to
stimuli in near extrapersonal space (Colby et al. 1993;
Colby and Goldberg 1999). Over half of the neurons
recorded in this area responded to direction of visual
pursuit (Schlack et al. 2003). Other parietal areas sending
afferents to FEFsem are sources of spatial information
with reference frames within arm’s reach (MIP, Colby
and Goldberg 1999; PEc, Battaglia-Mayer et al. 2001).
Areas PEa and 7b are interconnected, predominantly
somatosensory, areas that were labeled in monkey SYB.
Earlier studies also found projections to the FEFsem
region from area PEa (Chavis and Pandya 1976) and 7b
(Cavada and Goldman-Rakic 1989a). Most of the labeled neurons in PEa that we mapped were located
closer to the intraparietal sulcal fundus than cells labeled
by tracer injections into C3–C4 or thoracic spinal levels
(Matelli et al. 1998), which suggests that FEFsem
afferent cells may overlap with neck corticospinal neurons that project to the highest cervical levels. This
pattern of labeling was comparable with the distribution
of labeled FEFsem afferent cells in the postarcuate sulcal
fundus that project to spinal levels C2–C4 rather than
more superficially located corticospinal neurons that
project to levels C4–T1 (Dum and Strick 1991) (see
‘‘Somatomotor and prefrontal areas’’ above). Area PEa
neurons encode movement kinematics (Kalaska et al.
1990) and have bilateral somatosensory receptive fields
primarily sensitive to muscle and joint stimulation of the
shoulders and arms (Taoka et al. 1998). Input from these
areas to FEFsem might mediate cross calibration between the arm and eye during self-tracking pursuit
movements (Scarchilli et al. 1999).
189
Comparisons of FEFsem afferents in the macaque and
cebus
The afferent connections of the FEFsem in the newworld cebus monkey were described by Tian and Lynch
(1996b). The cebus FEFsem is located on the dorsolateral frontal convexity, medial to the end of the superior
limb of the arcuate sulcus (Tian and Lynch 1996a) and
clearly different from the location of FEFsem in the
macaque monkeys. Although there are some similarities
between the cebus and macaque connections, e.g. projections from SEF, there are also substantial differences.
Most notably, the amount and location of label near the
principal sulcus, in the intraparietal sulcus, and on the
posterior medial wall of the hemisphere were markedly
different in the two species. For example, the cebus
FEFsem receives afferents from ‘‘posterior LIP, near the
shoulder of the intraparietal sulcus and extending slightly
on to the ... gyrus’’ and, as they show, near the lunate
sulcus (Tian and Lynch 1996b). These authors also suggest that this labeled area is comparable with areas
containing pursuit-related neurons in macaque monkeys
(Kawano et al. 1984; Sakata et al. 1983). However, the
areas studied by Kawano et al. (1984) and Sakata et al.
(1983) are rostrolateral to the area that Tian and Lynch
described, near the end of the lateral sulcus, and more
like the distribution of labeled neurons that we charted in
our monkeys. Another clear difference is the strong
labeling in area 7m on the posterior, medial wall of the
parietal lobe in the cebus, in contrast to light labeling in
the most comparable area (PEc) in our macaques.
Moreover, we found several sources of cortical input
to FEFsem in the macaque that were not found in the
cebus. These include cingulate motor areas, postarcuate
cortical areas, parietal areas PP, VIP, PEa, 3a, and
temporal areas RI, SII, MT, FST, and STP. The substantial differences between these results and those of
Tian and Lynch (1996b) suggest either that there are
marked species differences between the macaque and
cebus monkeys in the organization of neocortical afferents to FEFsem, or that the smooth eye movement area
identified by Tian and Lynch (1996a) on the dorsomedial surface medial to the superior limb of the arcuate
sulcus of the cebus is simply not the homolog of the
FEFsem buried in the posterior arcuate sulcus of the
macaque. In support of this latter idea is the finding that
a retrograde tracer injection into macaque area F7
(Marconi et al. 2001), which is similar in location to the
cebus FEFsem, results in a similar pattern of labeling in
the posteromedial parietal lobe as that seen following
cebus FEFsem injections.
Comparison of afferents to FEFsem with afferents to
FEFsac
Many of the cortical visual areas labeled by tracer
injections into FEFsem in this report were also labeled
by tracer injections into FEFsac (Huerta et al. 1987;
Schall et al. 1995) but substantial differences were also
found. The similarities are consistent with the strong
visual responses found in both regions of FEF and the
fact that both types of eye movement are principally
triggered by visual stimuli. Conversely, the differences in
the topography of visual afferents are consistent with
known differences in single-neuron responses in these
two regions of FEF, and also seem to reflect differences
in the ways the saccadic and smooth-pursuit systems use
visual and vestibular information. For example, visual
responses of FEFsem neurons are elicited by moving
visual targets almost anywhere in the entire visual field
(Gottlieb et al. 1994; MacAvoy et al. 1991) whereas
FEFsac visual receptive fields are generally circumscribed (Bruce and Goldberg 1985). Thus it makes sense
that the inputs from the superior temporal motion areas
to FEFsem are dominated by the higher order areas
(MST, FST, PP) with relatively large receptive fields and
relatively weak visual topography. These same areas also
project to FEFsac, but mainly to the large saccade region (Schall et al. 1995). In contrast with the robust
projections to FEFsem from areas MST and PP that we
describe, there are fewer afferents to FEFsem from area
MT, a striate recipient area with a well-defined topography and relatively small visual receptive fields (Gattass
and Gross 1981), and virtually none of these FEFsem
afferents originate in the central visual field region of
MT where projection neurons to FEFsac were found
(Schall et al. 1995).
We saw only isolated cells in the ventrolateral temporal cortex in monkey SUZ, an indication of minimal
uptake of tracer by FEFsac neurons, whereas distinct
foci of labeled cells were seen in and near the occipital
temporal sulcus from FEFsac injections (Huerta et al.
1987; Schall et al. 1995) and in the posterior wall of the
superior temporal sulcus and lateral temporal cortex
(Schall et al. 1995). Therefore, FEFsac receives inputs
from some visual areas that do not send projections to
FEFsem, and visual areas that send afferents to FEFsac
are generally lower in the hierarchy of cortical processing (Felleman and Van Essen 1991) than are the visual
areas that project to both FEFsem and FEFsac.
Differences in the locations of afferent cells projecting
to FEFsem and FEFsac from the intraparietal cortex
also seem to be functionally based. Cells with projections to FEFsem were found mainly in areas VIP and
ventral LIP where neural activity related to smoothpursuit movements has been recorded (Bremmer et al.
2002a, b; Schlack et al. 2003), whereas cells with projections to FEFsac tended to locate higher on the posterior wall of the sulcus in area LIP, an area associated
with saccade functions (Andersen et al. 1992).
Finally, we also found that FEFsem receives afferents
that could carry head movement information, both from
somatosensory neurons in PEa and somatomotor and
vestibular neurons in the fundus of the postarcuate spur,
and in areas RI, 3aV, Tpt, VIP, and PP. Most of these
cortical areas, with the notable exception of areas VIP
and PP (Schall et al. 1995), were not found to project to
190
FEFsac in other studies (Huerta et al. 1987; Schall et al.
1995; Tian and Lynch 1996a). As discussed earlier, these
FEFsem inputs are consistent with the finding that
pursuit-related neurons in the postarcuate spur can respond to vestibular stimuli and head velocity, and to
retinal-image motion and eye velocity (Fukushima et al.
2000). This key difference between FEFsac and FEFsem
also seems to reflect the general principle that smoothpursuit has a more intimate relationship with head
movement and the vestibulo-ocular reflex whereas saccades have a simpler additive relationship with the vestibulo-ocular reflex that is largely implemented
downstream of FEFsac (Constantin et al. 2004). The
vestibular and neck inputs may enable FEFsem to participate in the fine coordination of head movements and
eye movements during accurate pursuit of moving visual
targets.
Acknowledgments This work was supported by National Eye
Institute Grant EY-04740 and National Institute of Mental Health
Grant MH-44866. Address reprint requests to Gregory B. Stanton,
Department of Anatomy, Howard University College of Medicine,
Washington DC 06520-8001.
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