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The Journal of Neuroscience, May 1, 2000, 20(9):3263-3281
Laminar Distribution of Neurons in Extrastriate Areas Projecting
to Visual Areas V1 and V4 Correlates with the Hierarchical Rank
and Indicates the Operation of a Distance Rule
Pascal
Barone,
Alexandre
Batardiere,
Kenneth
Knoblauch, and
Henry
Kennedy
Cerveau et Vision, Institut National de la Santé, et de la
Recherche Médicale U371, 69675 Bron Cedex, France
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ABSTRACT |
The directionality of corticocortical projections is classified as
feedforward (going from a lower to higher hierarchical levels),
feedback (interconnecting descending levels), and lateral (interconnecting equivalent levels). Directionality is determined by the combined criteria of the laminar patterns of the axon terminals as well as the cells of origins and has been used to construct models
of the visual system, which reveals a strict hierarchical organization
(Felleman and Van Essen, 1991
; Hilgetag et al., 1996a). However,
these models are indeterminate partly because we have no indication of
the distance separating adjacent levels. Here we have attempted to
determine a graded parameter describing the anatomical relationship of
interconnected areas. We have investigated whether the precise
percentage of labeled supragranular layer neurons (SLN%) in each
afferent area after injection in either visual areas V1 or V4
determines its hierarchical position in the Felleman and Van Essen
(1991) model. This shows that pathway directionality in the Felleman
and Van Essen model is characterized by a range of SLN% values. The
one exception is the projection of the frontal eye field to area V4,
which resembles a feedforward projection. Individual areal differences
in SLN% values are highly significant, and the number of hierarchical
steps separating a target area from a source area is found to be
tightly correlated to SLN%. The present results show that the
hierarchical rank of each afferent area is reliably indicated by SLN%,
and therefore this constitutes a graded parameter that is related to
hierarchical distance.
Key words:
primate; monkey; extrastriate cortex; visual processing; hierarchical models; feedback
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INTRODUCTION |
Rostral directed projections allow
outflow of activity away from striate cortex [visual area V1] and are
thought of as feedforward (FF) pathways. These projections originate
largely from supragranular layers, target layer 4, and contrast
with the reciprocal projections that originate in infragranular layers,
terminate outside of layer 4, and are thought of as feedback (FB)
pathways (Kuypers et al., 1965; Cragg, 1969; Spatz et al., 1970; Tigges
et al., 1973, 1981; Lund et al., 1975; Kaas and Lin, 1977; Spatz, 1977;
Wong-Riley, 1978; Van Essen and Zeki, 1978; Rockland and Pandya, 1979;
Wall et al., 1982; Maunsell and Van Essen, 1983; Weller et al., 1984; Kennedy and Bullier, 1985; Weller and Kaas, 1985; Barbas, 1986, 1995;
Andersen et al., 1990; Boussaoud et al., 1990; Morel and Bullier, 1990;
Baizer et al., 1991; Colby and Duhamel, 1991; Webster et al., 1991,
1994; Sousa et al., 1991; Distler et al., 1993; Nakamura et al., 1993;
Barone et al., 1995; Barbas and Rempel-Clower, 1997; Felleman et al.,
1997; Gattass et al., 1997).
The laminar patterns of corticocortical connections have been used to
propose a hierarchical ranking of primate cortical areas in different
sensory systems (Fitzpatrick and Imig, 1980; Friedman, 1983; Maunsell
and Van Essen, 1983; Barbas, 1986; Pons and Kaas, 1986; Ungerleider and
Desimone, 1986; Colby et al., 1988; Boussaoud et al., 1990; Van Essen
et al., 1990; Felleman and Van Essen, 1991; Webster et al., 1991;
Young, 1992; Distler et al., 1993; Webster et al., 1994; Hilgetag et
al., 1996a; Barbas and Rempel-Clower, 1997; Felleman et
al., 1997b; Kaas et al., 1999).
These models are constructed by categorizing connections between
huge numbers of pairs of areas and ascribing each area to a
hierarchical level in an optimal configuration. However, the number of
possible configurations is enormous because of lack of criteria
defining the distance separating levels (Hilgetag et al., 1996a,b).
Here we have sought to overcome this problem by defining a single
quantitative parameter of connectivity that will allocate areas to
graded levels. Such a parameter could be provided by the proportion of
supragranular layer neurons (SLN%) participating in FF and FB pathways
(Kennedy and Bullier, 1985; Barbas, 1986; Barone et al., 1995;
Rockland, 1997; Batardière et al., 1998a).
Quantitative techniques were used to investigate SLN% in individual
areas projecting to visual areas V1 and V4 in macaque. Area V1, the
primary visual area, is interconnected to areas in both the ventral and
dorsal stream. Area V4 is a higher order visual area in the ventral
stream and receives FF, lateral, and FB projections from higher order
areas in the dorsal stream and ventral stream.
The SLN% alone successfully ranks cortical areas and is tightly
correlated to the number of steps separating areas. The present findings, showing a graded parameter tightly correlated to hierarchical rank, indicate the existence of a hierarchical distance rule (Kennedy and Bullier, 1985; Rockland, 1997), which will allow an improved exploration of the organizational constraints of the interareal relationships in the visual system.
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MATERIALS AND METHODS |
Twenty-two retrograde tracer experiments were performed on 12 cynomolgus monkeys (Macaca fascicularis; Table
1).
Anesthesia and surgery. After premedication with
atropine (1.25 mg, i.m.) and dexamethasone (4 mg, i.m.), monkeys were
prepared for surgery under ketamine hydrochloride (20 mg/kg, i.m.) and chlorpromazine (2 mg/kg, i.m.). After intubation, anesthesia was continued with halothane in a
N2O/O2 (70:30) mixture.
Heart rate was monitored, and artificial respiration was adjusted to
maintain the end-tidal CO2 at 4.5-6%. The
rectal temperature was maintained at 37°C. All the procedures used
follow the National and European regulations concerning animal
experiments and have been approved by the authorized national and
veterinary agencies.
Injection of retrograde tracers. Single injections of
retrograde fluorescent tracers [fast blue (FsB) and diamidino
yellow (DY), 3% in H2O] were made by
means of Hamilton syringes. In three cases [M56 right hemisphere (RH)
FsB, M56 RHDY, M73 left hemisphere (LH)] multiple injections
were made in area V1 (Table 1). In the remaining 19 cases, injections
of tracers spanned 1-5 mm and were made in a stereotypical manner.
Injections were made in area V4 according to the definition of Desimone
and Ungerleider (1986). They were centered on the prelunate gyrus
between the lunate sulcus, the infero-occipital sulcus, and the
superior temporal sulcus in area V4 containing the representation of
the central visual field (Maguire and Baizer, 1984; Gattass et al.,
1988). Injections aimed at area V1 were made on the operculum in area
V1 containing the representation of the central visual field (Hubel and
Wiesel 1974; Van Essen et al., 1984). When an FsB and a DY injection were made side-by-side, they were separated by ~3 mm. Elsewhere we
have characterized the uptake zone of FsB and DY tracers (Bullier et
al., 1984; Kennedy and Bullier, 1985). Examination of sections at
regular intervals throughout the injection site makes it possible to
determine those restricted to gray matter. All the injections but one
was restricted to the cortical gray matter. The one injection that
involved the white matter (BB135) returned similar values to the other
injections, which confirms previous results (Barone et al., 1995;
Batardière et al., 1998a). After injections, bone flaps were
closed, and the scalp was stitched back into position.
Histological processing. After a survival period of 10-13
d, animals were deeply anesthetized before being perfused
transcardially with 200 ml of 2.7% saline, 1-3 l of 8%
paraformaldehyde/0.5% glutaraldehyde mixture in phosphate buffer (0.1 M, pH 7.4), 0.5 l of 10% sucrose, 0.5 l of 20%
sucrose, and 1 l of 30% sucrose in phosphate buffer (0.1 M, pH 7.4). Brains were immediately removed, blocked, and
horizontal or parasagittal sections (Table 1) were cut on a freezing
microtome (section thickness, 40 µm). One section in three was
mounted in saline onto gelatinized slides. Sections at regular
intervals were reacted for cytochrome oxidase (Silverman and Tootell,
1987) and acetylcholinesterase activity (Hardy et al., 1976; Mesulam
and Geula, 1994).
Examination of material. Sections were observed in UV light
with oil-immersion objectives using a Leitz fluorescent microscope equipped with a D-filter set (355-425 nm). The properties and description of neurons labeled with FsB and DY are described by Keizer
et al. (1983). Neurons labeled by DY exhibit a yellow nucleus, whereas
neurons labeled by FsB exhibit a blue coloration in their cytoplasm.
Labeled cells are observed in both infragranular and supragranular
layers. An x-y plotter electronically coupled to the
microscope stage was used to trace out sections and to record the
position of labeled neurons. After observation, sections were counterstained with cresyl violet and projected onto charts of labeled
neurons to relate the position of labeled neurons to histological borders.
Areal and laminar distribution of labeled neurons. The areal
extent of a population of retrogradely labeled neurons in a cortical area after injection in the target area is referred to as a projection zone (Fig. 1A-C). The
proportion of supragranular layer neurons falls off from a peak in the
center of the projection zone to minimal values in the periphery (Fig.
1D) (Meissirel et al., 1991; Barone et al., 1995;
Batardière et al., 1998a). This, coupled with the curvature of
the cortex, necessitates estimating the relative proportions of large
numbers of labeled neurons in supragranular and infragranular layers by
counting neurons at regular intervals throughout each projection zone
in each of the visual areas studied (Barone et al., 1995;
Batardière et al., 1998a). The laminar distribution for each
projection zone is expressed as the SLN% with respect to the overall
population of infragranular and supragranular labeled neurons.
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Figure 1.
A-C, Analysis of a projection zone
in area V2 after injection in area V1. A,
Two-dimensional reconstruction of the projection zone. Area V1-V2
border is to the left (arrow), and fundus of the lunate
sulcus is to the right. B, Density
profile in the dorsoventral direction, showing the number of neurons
counted at regular intervals on parasagittal sections. Counts are
aligned on the V1-V2 border indicated by an arrow
(0 on the x-axis, 12 is
toward the fundus of the LS). C, Density profile in the
lateromedial direction showing numbers of labeled neurons per section.
0 is an arbitrary start point that corresponds to
absence of labeling. D, E, Projecting
zone in area MT after an injection in area V4. D,
Density profile of the labeled neurons in supragranular and
infragranular layers. The SLN% values are indicated and show that on
individual sections SLN% values can range in the center of the
projection zone from 16-36%. E shows the effects of 10 and 20% of maximum neuron thresholds on the dimensions of the
projection zone (PZ). When these thresholds are applied,
the size of the projections zone is reduced by 22 and 39%,
respectively, whereas the SLN values change for <0.3%.
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Criteria for the location of cortical areas. Injections of
tracers in areas V1 and V4 leads to dense labeling of an extensive region of extrastriate cortex in the parietal and temporal regions (Zeki, 1978; Maunsell and Van Essen, 1983; Kennedy and Bullier, 1985;
Yukie and Iwai, 1985; Perkel et al., 1986; Tanaka et al., 1990;
Felleman and Van Essen, 1991; Baizer et al., 1991; Krubitzer and Kaas,
1993; Shipp and Zeki, 1995). Label in extrastriate cortex was observed
in different known visual areas: V1, V2, V3, V3A, V4, middle temporal
area (MT), fundus superior temporal area (FST), temporal occipital area
(TEO), temporal area (TE), lateral intraparietal area (LIP), and
TH-TF, as well as frontal eye field (FEF) (Fig. 2). Multiple criteria were used to
allocate labeled neurons to one of these 12 areas. It was important to
optimize the criteria used to distinguish different cortical areas to
be able to count neurons throughout a maximum extent of the projection
zones in individual areas. Some architectonic limits were obtained
using Nissl staining, cytochrome oxidase, or acetylcholinesterase
histochemistry, but a major criteria is the pattern of labeling itself.
Because the injection sites involved cortex containing the
representation of the central visual field, cortical areas that share
borders where the far periphery of the visual field is represented show a discontinuous pattern of labeling. This gap in the labeling provides
an important indication of the limits of the cortical area (Fig.
3).
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Figure 2.
Horizontal sections showing the location of
labeling in the extrastriate and frontal areas examined in this study.
All cortical areas but one (V3A) that project to area V4 also project
to area V1. MT, Middle temporal area;
TEO, temporal occipital area; TE,
temporal area; FST, fundus superior temporal area;
LIP, lateral intraparietal area; FEF,
frontal eye field; LS, lunate sulcus;
POS, posterior occipital sulcus; STS,
superior temporal sulcus; IOS, inferior occipital
sulcus; AS, arcuate sulcus; LatS, lateral
sulcus; CeS, central sulcus; PS,
principal sulcus; IPS, intraparietal sulcus;
CaS, calcarine sulcus.
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Figure 3.
Laminar pattern of retrogradely labeled cells in
adjacent cortical areas projecting to V4. A, The
labeling in area V3A in the anterior bank of the LS can be
distinguished from the labeling in V2 in the posterior bank of the LS
by an increase of density in infragranular layers. Labeling in V3A is
separate from the labeling in V2 because V3 shows weak or no projection
to area V4. Labeling is isolated from the intrinsic labeling in V4
(indicated in gray) surrounding the injection sites
(shown in black). Very few labeled cells are observed in
area V1. B, Despite the fact that V4t and V5 share a
border with a central field representation, labeling in these two areas
was largely discontinuous as shown in this example (see Results).
C, Discontinuity of labeling between the areas TE and
TH-TF. Individual values of SLN% calculated in regions delimited by
arrows are indicated. Scale bars, 1 mm.
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Area V1 is located in the posterior part of the brain, and the limits
with area V2 are easily identified using cresyl violet staining. The
location of extrastriate areas is shown in Figure 2. Area V2 is located
in the posterior bank of the lunate sulcus (Van Essen and Zeki, 1978;
Gattass et al., 1981) where it can be identified with cytochrome
oxidase and acetylcholinesterase histochemistry (Tootell et al., 1983;
Livingstone and Hubel, 1984; Barone et al., 1994).
Area V3 is located laterally in the fundus of the lunate sulcus and
more medially in the posterior part of the anectant gyrus, whereas area
V3A is located anterior to V3 in the anterior bank of the lunate sulcus
(LS) (Zeki, 1971, 1978; Van Essen et al., 1986; Gattass et al., 1988;
Felleman et al., 1997b). Mediodorsal injections in the perifoveal
representation of area V1 led to restricted labeling in the anectant
gyrus corresponding to area V3, as defined by Felleman et al. (1997b).
This region corresponds to a subregion of the dorsomedial visual area
(DM) following the definition of Beck and Kaas (1999).
Labeling in area V3 is separated from labeling in area V2, which is
located more medially. After injection in area V1 no labeled cells are
found in area V3A in the anterior bank of the LS in agreement with
previous observations (Van Essen et al., 1986; Felleman et al., 1997b).
After injections in area V4, labeling was restricted to area V3A. In
most cases there is a gap between the labeling in area V2 and V3A, and
going from area V2 to V3A, there is a distinct increase in the density of labeling in the infragranular layers of area V3A (Fig.
3A).
Area MT is located in the posterior bank of the superior temporal
sulcus (STS) and stretches from the fundus to approximately halfway up
the sulcus (Zeki, 1974; Desimone and Gross, 1979; Van Essen et al.,
1981; Maunsell and Van Essen, 1983; Ungerleider and Desimone, 1986).
After V1 injection, the labeling in the dorsal part of the STS is well
isolated from the labeling in the prelunate gyrus. This gap is more or
less pronounced in cases of V4 injections, which induce a strong
labeling in the adjacent area V4t (Fig. 3) (Desimone and Ungerleider,
1986; Gattass et al., 1988; Felleman and Van Essen, 1991).
After V1 and V4 injections, labeling is found in the visual motion area
FST in the floor of the STS, which is anterior and ventral to area MT
(Seltzer and Pandya, 1978; Desimone and Ungerleider, 1986; Ungerleider
and Desimone, 1986; Boussaoud et al., 1990).
Labeling in the posterior and lateral bank of the intraparietal cortex
is isolated from labeling in other areas and corresponds to the LIP
(Andersen et al., 1990; Blatt et al., 1990; Boussaoud et al., 1990;
Baizer et al., 1991; Colby and Duhamel, 1991; Shipp and Zeki, 1995;
Colby et al., 1996).
The major input to area V4 from higher order areas is from the visual
areas in the temporal lobe. Only scattered labeled cells were observed
in the temporal lobe after injection in V1. Area TEO is located on the
temporal lobe between the inferior occipital sulcus and the superior
temporal sulcus (Iwai and Mishkin, 1969; Baizer et al., 1991; Boussaoud
et al., 1991; Distler et al., 1993). Labeling is discontinuous between
V4 and TEO. Anterior and ventral to TEO in the inferior temporal cortex
is the temporal area TE (see also Van Essen et al., 1990; Webster et
al., 1991, 1994).
In the ventral region of the temporal lobe in the parahippocampal
cortex is the lateral cortical area TF and the medial area TH. These
cortical areas are located medial to the rhinal fissure and posterior
to the perirhinal cortex (Amaral et al., 1987; Suzuki and Amaral,
1994a,b; Suzuki, 1996). Anteriorly and medially, labeling in TF/TH
shows a gap with labeling in the ventral part of areas TE at the level
of the rhinal fissure (Fig. 3C).
In the frontal cortex, labeled neurons are found systematically in the
anterior bank of the arcuate sulcus, which is known to house the FEF
(area 8) (Bruce and Goldberg, 1985; Huerta et al., 1987; Stanton et
al., 1989).
Statistical tests. A multinomial ANOVA (Woodward et
al., 1990) was used to test the hypothesis that the SLN% is equal
across visual areas. Infragranular and supragranular layers were
treated as within-subject factors in the analysis. By testing
proportions, the problem of the variation in total number of cells is
removed. The analysis does, however, incorporate the total numbers of
labeled cells in the estimates of variance for each proportion, so that proportions based on small total numbers have less precision than those
based on larger numbers. When a significant difference between areas
was observed, the multinomial ANOVA allows us to do planned comparisons
to identify the areas that violate the null hypothesis. To test the
relationship between SLN% and the number of levels that separate two
interconnected areas, we used the nonparametric Spearman rank
correlation test.
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RESULTS |
Injections of areas V1 and V4 were performed in a stereotypical
manner, they were large and spanned 1-5 mm, a method that reduces the
possibility that patchiness of the target area (DeYoe et al., 1994)
will influence the SLN values obtained (Scannell et al., 2000).
Injections in areas V1 and V4 led to dense retrograde labeling
throughout a large extent of extrastriate cortex. The criteria used to
allocate neurons to individual areas is given in Materials and Methods.
Retrogradely labeled neurons in the thalamus after injections in
areas V1 and V4 are confined to the relevant thalamic nuclei, in the
lateral geniculate nucleus and the lateral pulvinar (Kennedy and
Bullier 1985; Tanaka et al., 1990; Baleydier and Morel, 1992; Shipp and
Zeki, 1995).
Laminar distributions: fluctuation within the projection zone
For each cortical area and in each animal, numbers of neurons in
each laminar compartment were computed for one in every three or four
sections (see Materials and Methods). The regional extent of the area
that contains the labeled neurons is referred as the projection zone. A
representative two-dimensional reconstruction of a projection zone is
shown in Figure 1A, which illustrates the spatial
distribution of labeling in area V2 after injection in area V1. At the
periphery of the projecting zone, the number of labeled neurons is low
and increases to reach a maximum at the center. Density profiles (Fig.
1B,C) provide a one-dimensional reconstruction of the
projection zone and constitute a graphic representation of labeling,
which make it possible to ensure that the appropriate sampling
frequency and choice of sections have been used for each projection
zone in each area. Density profiles for all projection zones were
prepared that show numbers of neurons per slide going through the
projection zone where the x-axis is distance in
millimeters. Here and elsewhere (Barone et al., 1995; Batardière et al., 1998a) SLN% is found to vary throughout the projection zone, including the core regions (Fig.
1D). A major factor that contributes to this
phenomena is the curvature of the cortex with respect to the plane of
section, which results in single sections providing an uneven sampling
of individual layers. Calculating SLN% at regular intervals across the
projection serves to overcome this problem of cortical curvature. A
representative density profile for each cortical area is shown in the
right-hand side of Figures
4-9.
Examination of the density profiles show that peak percentages are
located toward the centers of projection zones and fall off to zero in
the periphery (Figs. 4-8). The density profiles illustrate the
problems associated with estimating the laminar distribution. For
example, because of cortical curvature and changing plane of section,
peak levels of supragranular and infragranular layers frequently do not
coincide (e.g., Fig. 4, top left-hand density curve; Fig. 6, three of
the four density curves for MT and for LIP).
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Figure 4.
Distribution of retrogradely labeled neurons in
extrastriate areas V2, V3, and V3A. Left-hand column,
Plots of retrogradely labeled neurons taken from the center of the
projection zone as determined from density profiles.
Middle and right-hand columns, Neuron
density profiles. Plots and neuron density profiles have been chosen
from different animals. Scale bars, 1 mm.
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Figure 5.
Distribution of retrogradely labeled neurons in
ventral stream areas (TEO, TE, and TH-TF). Conventions as in Figure
4.
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Figure 6.
Distribution of retrogradely labeled neurons in
dorsal stream areas (MT, FST, and LIP). Conventions as in Figure
4.
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Figure 8.
Distribution of retrogradely labeled neurons
in areas V4 and V1. The V1-V2 border is indicated by an
arrowhead. Conventions as in Figure 4.
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Figure 9.
Distribution of retrogradely labeled intrinsic
neurons. Scale bar, 0.5 mm. Conventions as in Figure 4.
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Changes of plane of section of the cortical compartments also
contribute to the variability of the number of neurons in each compartment even on neighboring sections (Batardière et al., 1998a). For example, in area V2 after injection in area V1 in the case
of M71 LH FsB (Fig. 4, top) individual sections in the central region show a SLN% range of 12-67%. When the SLN% is
calculated throughout the projection zone, this injection returns a
value of 50%. Similar results are obtained after the V4 injections
(Fig. 1D). For example, in BB119 the DY injection in
area V4 (Fig. 4, bottom) leads to SLN% in the central
region of the projection zone of area V3A ranging between 34 and 64%,
whereas global values are 47%. These observations again demonstrate
the necessity to calculate global values of SLN% throughout the
projection zone to characterize the laminar distribution for a single
injection (Kennedy et al., 1989; Meissirel et al., 1991; Barone et al., 1995; Batardière et al., 1998a).
Variation of the SLN% across the projection zones could also mean that
individual projection zones are hybrid for FF, FB, and lateral
connections, as suggested elsewhere (Ungerleider and Desimone, 1986;
Andersen et al., 1990). The possibility that projection zones
are hybrid reinforces the need to calculate the laminar distribution of
connectivity after large injections and computing SLN% throughout the
whole of the projection zone, thereby obtaining a global value for the
connection being studied.
Analysis of the effect of threshold values shows that projection zone
structures are reasonably robust. Figure 1E shows the effect of taking a 10 or 20% threshold of the maximum labeling on an
individual projection zone in area MT after injection in area V4.
Collectively, a 10% cutoff for all projection zones pooled leads to a
3% drop in the numbers of neurons counted and 0.4% change in SLN% value.
Examination of the density profiles for projections zones in individual
cortical areas makes it possible to select representative charts of
labeled neurons from the center of the projection zones (Figs. 4-8,
left-hand side).
Reliability of allocation of labeled neurons to individual
cortical areas
In the present study we have used the pattern of labeling as a
major criteria for the allocation of neurons to individual areas. Here
we shall examine the reliability of this method. Injections of areas V1
and V4 were performed in a stereotypical fashion and concerned the
representation of the central visual field. This means that one can
expect a gap of labeling between adjacent areas when they share a
border representing the peripheral visual field. In the present
study, injection of area V1 led to weak or no label in area V3A, and
injection of area V4 gave weak label in area V3, confirming previous
findings (Van Essen et al., 1986; Felleman et al., 1997b). This means
that injections in area V1 led to extrinsic label in areas V2, V3, V4,
MT, FST, LIP, TE, TEO, TH-TF, and FEF. Injections in area V4 led to
labeling in areas V2, V3A, V4t, MT, FST, LIP, TE, TEO, TH-TF, and FEF.
Areas that share a border that represents the central visual field and
where labeling can be continuous are V4t-V5 and V3A-V4 (Van Essen and
Zeki 1978; Gattass et al., 1988; Boussaoud et al., 1991). In the
present study, we do not attempt to distinguish label in V4 and V4t.
This leaves the possibility of imperfect separation of labeling between
V3A-V4 and V4t-MT. This does not influence our main conclusions in
the present study for the following reasons. First, because labeling was continuous in V4t-MT after one of seven injections, we can therefore discount an effect of continuous labeling on estimates of
SLN% in area MT. Second, although labeling in V3A-V4 was continuous, this concerned a minority (three of seven) of injections. Quantitative analysis of the V3A projection zones, as illustrated in Figure 1, shows
that a 20% cutoff for this area leads to a 2% change in SLN%
accompanied by a 1.6 mm shift of the V3A border. This would put the
areal border well outside of the region that is commonly thought to be
V4. In other words, if we were to repeat the analysis using a highly
conservative location of V3A that would exclude V4t neurons, we would
obtain very similar SLN% values for V3A to those obtained using the
full projection zone as in the present study.
Distributions in areas sharing FB and FF projections to both
target areas
After injections in areas V1 and V4 labeled neurons are found in
similar densities in supragranular layers of area V2. This contrasts
with the densities in infragranular layers, which are relatively high
after injections in area V1 and virtually absent after injection in
area V4 (Figs. 3A, 4).
Quantitative results for different injections are reported in Table 1.
Altogether labeling was successfully analyzed in area V2 for 11 injections in area V1 and returned a mean value of 48% SLN (range,
35-55%). Seven projection zones were analyzed in area V2 resulting
from injection in area V4 and gave a mean SLN value of 93% (range,
89-99%).
In area V3, injections in area V1 led to peak densities in
infragranular layers, and four injections gave a mean SLN value of 9%.
Injections in V4 led to peak densities in area V3A in supragranular layers (Fig. 4), and the seven injections gave a mean SLN value of 60%
(Table 1).
Figure 4 shows that those cortical areas (i.e., areas V2 and V3/V3A)
that have FB projections to area V1 and FF projections to area V4 show
complementary patterns of labeled neurons so that FF projections are
characterized by high SLN% and FB by low SLN%.
Distributions in ventral stream areas
Areas in the temporal lobe are known to possess FB projections to
both areas V1 and V4 (Morel and Bullier 1990; Distler et al., 1993;
DeYoe et al., 1994; Felleman et al., 1997a), and the present results
show that the density of these projections is considerably higher to
area V4 than to area V1 (Fig. 5). Whereas the FB projections to area V1
from both TEO and TE are exclusively from infragranular layers, the FB
projections to area V4 show large SLN% values. In TEO and TE, four
projection zones from V1 injections were analyzed and returned a mean
SLN% inferior to 0.5%, whereas the seven projection zones after
V4 injections returned a mean SLN% of 40% in TEO and 26% in TE
(Table 1).
Labeled neurons are present in the parahippocampal areas after
injections in areas V1, confirming results of others (Rockland and Van
Hoesen, 1994). However, these neurons were extremely sparse and
exclusively located in infragranular layers (Table 1). Labeling in
TH-TF was reasonably strong after injection in area V4, and labeled
neurons were almost exclusively located in the infragranular layers
(Fig. 5, bottom).
Distributions in FB and lateral projections from dorsal
stream areas
Areas MT and FST both belong to the dorsal stream and are known to
project to areas V1 and V4 (Maunsell and Van Essen, 1983; Kennedy and
Bullier, 1985; Perkel et al., 1986; Ungerleider and Desimone, 1986;
Tanaka et al., 1990; DeYoe et al., 1994; Rockland and Van Hoesen, 1994;
Hof et al., 1996). MT is thought to have a FB projection to area V1 and
a lateral projection (i.e., connecting areas on equivalent hierarchical
levels) to area V4 (Maunsell and Van Essen 1983; Ungerleider and
Desimone, 1986). The density and laminar distribution of the labeled
neurons in MT are seen to differ to a large extent according to their
target (Fig. 6, top). The FB projection from MT to area V1
showed low densities with the majority of labeled neurons principally
in the infragranular layers, whereas the densities of labeled neurons
projecting to area V4 were considerably higher and equally distributed
in supragranular and infragranular layers. In MT, nine projection zones
from V1 injections were analyzed and returned a mean SLN% value of
5%, whereas the seven projection zones after V4 injections returned a
mean SLN% value of 47% (Table 1).
Area FST possesses FB projections to both areas V1 and V4 (Boussaoud et
al., 1990; Tanaka et al., 1990; Felleman et al., 1997a). The density of
the FB projection to area V4 was higher than that for the projection to
V1, and whereas all the neurons projecting to area V1 were located in
infragranular layers, some labeled neurons were located in
supragranular layers after injection in area V4 (Fig. 6,
middle). In FST, the seven projection zones after V4
injections returned a mean SLN of 14% (Table 1).
LIP possesses FB projections to V4 (Cavada and Goldman-Rakic, 1989;
Andersen et al., 1990; Blatt et al., 1990; Tanaka et al., 1990; Shipp
and Zeki, 1995). The present results show that there is a hitherto
undescribed projection to area V1 that is however extremely sparse and
originated almost exclusively from the infragranular layers (Table 1).
The projection from LIP to area V4 was considerably stronger than the
V1 projection, and a non-negligible proportion of neurons was found in
the supragranular layers (Fig. 6, bottom). In LIP the seven
projection zones after V4 injections returned a mean SLN% value of
27% (Table 1).
Distributions in the FEF
Several authors have described projections from the FEF to area V4
(Huerta et al., 1987; Schall et al., 1995; Shipp and Zeki, 1995;
Stanton et al., 1995; Bullier et al., 1996). In the present study, one
of the three cases in which multiple injections were made in area V1
was examined for labeled neurons in FEF and showed a very sparse
projection (six labeled neurons) entirely originating from the
infragranular layers (Table 1). This result, along with the finding in
LIP (see above), confirms that anterior cortical areas that project to
area V4 also project to area V1. For the projection of FEF to area V4,
the present results show that although it is a weak projection, it is
at least as strong as the projection from FST to V4. Surprisingly,
after all seven injections in area V4, the projection to area V4 from
FEF largely arises from the supragranular layers (mean SLN% value,
73%; Fig. 7).
Reciprocal projections between areas V1 and V4
It has been suggested that reciprocity is a universal feature of
corticocortical pathways (Rockland and Pandya, 1979), but in the visual
system ~20% of the connections are unidirectional (Felleman and Van
Essen, 1991; Salin and Bullier, 1995). We have been able to examine
this issue directly for connections linking areas V1 and V4. The top
part of Figure 8 shows typical labeling in area V4 after
injection in area V1. This gives a range of numbers of neurons per
section in the order of 10-60 (Table 1). This contrasts with the
results in area V1 after injection in area V4. Of the seven projection
zones analyzed in area V1, that illustrated by the density profile in
Figure 8 has the highest number of neurons, the average being less than
nine neurons per projection zone, which is <0.1% of the intensity of
the V4 to V1 projection (Table 1).
Distribution of intrinsic labeled neurons
Labeled neurons within the area injected showed very high
densities and typically extended further in area V4 than in area V1
(Fig. 9), confirming the results of others (Yoshioka et al., 1992). The
four projection zones analyzed returned a mean SLN of 61% in area V1
and in 64% in area V4 (Table 1). It could be that part of the labeled
neurons located close to the injection sites are interneurons. Because
extrinsic connections are uniquely from pyramidal neurons, we wanted to
restrict our measurement to the pyramidal population of
intrinsic neurons. By deleting from the counts the labeled cells at a
distance of <250 µm from the pick-up zone, we excluded a large
proportion of the inhibitory intrinsic neurons (Tanigawa et al., 1998).
Counts of the total population of labeled cells were reduced by 6% (in
area V1) and 12% (in area V4), but the laminar distribution remained
stable (paired t test; p > 0.05) in both
areas (V1, SLN%: 63 vs 61%; V4, SLN%: 65 vs 64%).
SLN% characterizes individual projections
The SLN% values in the projections to areas V1 and V4 for
individual injections are shown in Table 1, and a summary of the means
are provided in Figure 10. Statistical
analysis (Table 2) reveals that SLN%
values vary across areas for V1 (multinomial ANOVA, p < 0.001) and V4 afferents (p < 0.001). In all
animals in which a double injection was performed, the analysis did not reveal statistical variability because of the type of dye used (FB vs
DY; all cases p > 0.05). Furthermore, in cases of V4
injections in which complete data from all the projecting areas were
obtained, the multinomial ANOVA did not show statistical variations
across subjects (
2 = 4.75;
p = 0.09). Comparisons of the SLN% values for adjacent hierarchical levels (as determined by the scheme of Felleman and Van
Essen, 1991) showed that of the total 46 comparisons, 41 were statistically significant (Table 2). This analysis shows that each
projection is characterized by a specific SLN% value.
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Figure 10.
Histograms of the mean SLN% values in individual
cortical areas that project to areas V1 (A) and
V4 (B). In each case, FB (gray
bars), FF (white bars), and intrinsic
projections (black bars) are distinguished.
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Hence, injections in area V1 showed a significant stepwise decrease in
SLN% in the sequence V2-V3. Beyond V4 there was a significant stepwise decrease in percentages in the dorsal stream going from MT to
FST and in the ventral stream in the sequence V4-TEO-TE
TH-TF. However, our results did not show a significant decrease in SLN% going
from V3 to V4 despite the fact that it has been reported that V3 has a
FF type projection to area V4 (Felleman et al., 1997a).
Injection in area V4 showed a significant stepwise decrease in SLN%
values in the ascending pathway in the sequence V1-V2-V3A. In the
feedback pathways, there was a significant stepwise decrease in the
percentages in the dorsal pathways in the sequence MT-LIP-FST and in
the ventral pathway in the sequence TEO-TE-TH-TF.
These results suggest that in the case of FB connections the greater
the projection distance, the more it involves cells located in the
infragranular layers. For FF projections the converse is true so that
there is a proportional increase in SLN% with increasing distance.
SLN% and hierarchical organization of the visual system
We have used the Felleman and Van Essen (1991) hierarchical model
of the visual system shown in Figure
11A and related it to the SLN% of V1 and V4 afferents. For each connection we have
calculated the number of hierarchical steps separating the
interconnected areas (Fig. 11B). For example, areas
V1, V2, and V4 are on hierarchical levels 1, 2, and 5, respectively. In
the case of the FB projection from V2 to V1, the projection crosses one
level in a positive direction (difference of levels: 2 
1 = +1). The FF projection from V2 to V4 crosses three levels, but the
difference is negative (difference level: 2 5 = 3). In
this way numbers of hierarchical steps ranges from 4 (FF pathway
going from V1 to V4) to +9 (FB pathway going from TH-TF to V1).
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Figure 11.
A, Felleman and Van Essen (1991)
hierarchical model of the visual system. B, Table
indicating the number of levels separating individual areas from areas
V1 and V4. C, Correlation of SLN% with the numbers of
hierarchical levels calculated from the model of Felleman and Van Essen
(1991). Crosses correspond to intrinsic values.
Arrowhead points toward the SLN% value observed for the
FEF to V4 projection.
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The relationship between the SLN% values and number of hierarchical
steps is highly consistent across the 20 corticocortical pathways
projecting to areas V1 and V4 (Fig. 11C). The correlation factor for the pooled SLN% values is high
(r2 = 0.77) and statistically
significant (Spearman; Rho = 0.89; p = 0.0001).
The correlation is not generated by one of the two sets of afferents
because the same analysis for V1 and V4 independently generates only a
slightly lower correlation factor (V1,
r2 = 0.69; V4,
r2 = 0.70), which remains
highly significant (Spearman; V1: Rho = 0.87; p = 0.004; V4, Rho = 0.73; p = 0.02).
Figure 11C shows that the pooled values of SLN% for
individual projections correlate remarkably well with numbers of
hierarchical steps. Figure
12A shows the
correlation of SLN% values with hierarchy for individual V4
injections. For individual cases, variations are small both for the
slopes (Fig. 12B; mean, 9.41 ± 0.36) and the
correlation factors (Fig. 12C; mean, 0.66 ± 0.03), and
are statistically significant in all cases (Spearman; all cases
p < 0.05). For individual injections in both areas V1
and V4 we found that pairwise comparison of hierarchical relationship
shows a 77% (range, 71-90%) fit with the Felleman and Van Essen
(1991) model. This fit increases to 82% (range, 78-90%) if FEF is
not included. These results are highly significant because they show that hierarchical relations can be inferred from the results of a
single injection, provided the SLN% values are accurately determined for all areas projecting to the target area.
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Figure 12.
A, Correlation for single
injections in area V4 of SLN% with the number of hierarchical levels
that separate individual afferent areas. Slopes
(B) and r2
(C) calculated from the individual correlograms
shown in A.
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Malcolm Young's group has claimed that the precise ordering of the
monkey visual areas cannot be specified exactly, mostly because of
incertitude about the hierarchical levels of areas located at higher
stages (Hilgetag et al., 1996a). However they have proposed an optimal
peak hierarchy (Hilgetag et al., 1996b) that overlaps with a large
number of solutions. Using this model we found that the laminar pattern
of projections to V1 and V4 is highly correlated to the hierarchical
organization of the visual system
(r2 = 0.61; Spearman, Rho = 0.83; p = 0.0001).
Hierarchy suggested by areal differences of SLN%
We have used the SLN% values to modify the Felleman and Van Essen
(1991) model. Statistical tests (see Materials and Methods; Table 2)
differentiated areas according to their SLN% after V1 or V4 injections
and consequently placed them on distinct hierarchical levels (Fig.
13). Injections in area V4 values place
areas V1 and V2 on successive levels. Area V3A (60%) is on a level
immediately below area V4. Injections in V1 place V1, V2, and V3 on
successive levels but fail to separate areas V3 and V4. This would
suggest that the hierarchical distance separating area V3 and V4 is
small, and we therefore placed V3 on a level just below V4. Injections in V1 show that the SLN% in MT is lower than in V4, suggesting that MT
is on a higher level than V4. V4 injections suggest that MT and TEO are
on the same level. V4 injections place LIP below FST on the same level
as TE. TH-TF have minimum SLN% values and are placed at the highest
level. We left one empty level below areas TH-TF to eventually
accommodate areas (such as area 7a and the polysensory areas of the
superior temporal sulcus) that are not interconnected with areas V1 and
V4 but project to the parahippocampal cortex and are thought to occupy
a higher rank than FST (Felleman and Van Essen, 1991).
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Figure 13.
Hierarchical model obtained after paired
comparison (Table 2) of the proportion of supragranular projecting
cells in V1 and V4 afferents. Conventions as in Figure 11.
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The model that we have derived from the SLN% does not make pairwise
comparisons of connections between areas, which is the basis of the
Felleman and Van Essen (1991) model. Instead rank is directly derived
from SLN%, so that the injections in V1 show that MT is further than
V3, which is further than V2. In one sense our handmade approach is a
hybrid of the Felleman and Van Essen (1991) model because we have
retained discrete levels. It is expected that a mathematical approach
will generate a graded distance values between areas and consequently
provide a better determinacy of the hierarchical status of the visual
areas. The correlation for the Felleman and Van Essen model (1991)
(r2 = 0.77) is lower than that
proposed above (r2 = 0.87;
Spearman, Rho = 0.91; p = 0.0001), indicating
that we have successfully optimized hierarchical levels with SLN% values.
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DISCUSSION |
We shall first review in detail how areal relationships suggested
by SLN% values compare to the hierarchical relationships reported in
the literature. We shall briefly discuss the relevance of hierarchical
schemes for understanding visual processing before concluding on the
potential of SLN% to constrain models of visual cortex.
Ascending pathways
The projections from areas V1, V2, and V3A to area V4 have been
shown to confirm to a FF sequence (DeYoe and Van Essen, 1985; Livingstone and Hubel, 1987; Tanaka et al., 1990; Nakamura et al., 1993; DeYoe et al., 1994; Barone et al., 1995; Felleman et al.,
1997b). After injections in area V4, maximum SLN% values are located
in areas V1 (100%) and V2 (93%) and significantly less in area V3A
(60%). Similarly, V2 and V3 send FB projections to area V1, and again
the SLN% in V2 is higher compared to V3 (47 vs 9%). These results
place areas V3 and V3A on a higher level than area V2 in agreement with
other reports (Felleman and Van Essen, 1991; Felleman et al., 1997b;
Gattass et al., 1997).
Area V3 is reported to have FF projections to area V4 (Felleman et al.,
1997b). We find that V1 injections return similar SLN% values
in V3 and V4 and we have shifted area V3 to a level immediately below
V4 and on the same level as V3A. Although it has been questioned
whether V3 and V3A are distinct areas (Krubitzer and Kaas, 1993), it is
claimed, on the basis of qualitative data that V3A and V3 exchange FF
and FB projections (Felleman et al., 1997b). Our data suggests only a
very small separation of these two areas so we place them on the same level.
Lateral connections
MT is reported to have a lateral projection to V4 (Maunsell and
Van Essen, 1983; Ungerleider and Desimone, 1986). Although after V4
injection, area MT has SLN% values midway between FF and FB, we have
placed this area one level above V4 because (1) V4 and MT have
significantly different SLN% values after injection in V1 and (2) MT
SLN% are significantly different from those of areas V3A and LIP
(Table 2), which are reportedly on the hierarchical level below and
above MT.
The descending pathways
The Felleman and Van Essen (1991) model places TH-TF, TE, and TEO
on levels 10, 9, and 7. Recent studies support this sequence (Webster
et al., 1991; Distler et al., 1993). Our SLN% values (1, 26, and 40%)
suggest that these areas should be on levels 10, 7, and 6 (Fig. 13).
These ventral areas send a sparse but consistent FB projection to area
V1 (this study; Rockland and Van Hoesen, 1994). Area TEO has
significantly higher SLN% values compared to areas TE and THTF,
which is compatible with the levels we have allocated to these areas.
Injections of tracers in FST led to labeled cells in LIP in both
supragranular and infragranular layers, whereas the terminals are
located in all layers (Boussaoud et al., 1990). This has led Felleman
and Van Essen (1991) to classify FST and LIP as sharing lateral
connections and to place these two areas on the seventh level. FST is
reported to exchange FF and FB projections with V4 and MT (Boussaoud et
al., 1990). Together these results therefore support the suggestion of
Felleman and Van Essen (1991) that areas FST and LIP reside on a level
above areas V4 and MT. However, our results return SLN of 27% for LIP
and 14% for FST, suggesting that these two areas might be on different levels.
To conclude, the Felleman and Van Essen (1991) model contradicts six of
the relations suggested by the SLN%, which are V3 = V3A; V4 < MT; MT = TEO; LIP < FST; TEO < FST; LIP = TE
(FF is >, FB is <, and lateral is =). Three of the relations
suggested by the SLN% are compatible with the optimal hierarchy
proposed by Hilgetag et al. (1996b). There are three categories of
disagreements between the two models. First, in the Felleman and Van
Essen (1991) model two of these relations were lateral (MT = V4
and LIP = FST) (Maunsell and Van Essen, 1983; Ungerleider and
Desimone, 1986; Boussaoud et al., 1990). Although we have placed these
areas on separate levels based on statistical differences of SLN%, the distance suggested is small and therefore could be smaller than the
nonparametric value of a level in the Felleman and Van Essen (1991)
model. Second, some of the differences of the two models concern
connections that have been reported as weak and/or inconsistent (MT-TEO; TEO-FST) (Morel and Bullier, 1990; Distler et al., 1993). Third, our suggestion that LIP = TE is in agreement with Webster et al. (1994). Finally, in our model V3 = V3A, where as in the Felleman and Van Essen (1991) model V3 < V3A. Once again this could be attributable to the SLN% model detecting small differences that are not easily detected by the laminar analysis used in the Felleman and Van Essen (1991) model, which relies largely on
qualitative data.
Relationship of visual areas with FEF
It is known that area V4 projects to FEF in an FF manner (Barbas
and Mesulam, 1981). However, little is known about the reciprocal projection. Despite the absence of any quantitative data, Felleman and
Van Essen (1991) have allocated FEF to the eighth level, and accordingly it should possess a strong FB connection to area V4. However, our results do not show projections from FEF to area V4 to be
FB projections, because they show a SLN% of 72% indicative of FF.
Alternatively we cannot exclude the possibility that anatomical characterization of FF and FB connections do not extend to the frontal
cortex (Webster et al., 1994).
A number of other anatomical studies question putting FEF at the top of
the hierarchical series. In the ventral stream, injections of
retrograde and anterograde tracers in TEO revealed lateral connections
with FEF (Distler et al., 1993; Webster et al., 1994; Schall et al.,
1995). Likewise, injections of anterograde tracers in TE suggested that
this structure exhibits FB projections to FEF, whereas retrograde
tracers injected in TE suggest a lateral connectivity with FEF (Webster
et al., 1994). Anterograde and retrograde tracer investigations of the
relationship of FEF with the dorsal stream failed to give conclusive
results with respect to FF and FB classification schemes (Boussaoud et
al., 1990; Schall et al., 1995).
There is physiological evidence in favor of FEF not having a purely FB
relationship with extrastriate visual areas. Many neurons in FEF
respond to visual stimulation with shorter latencies than a large
proportion of neurons in more caudal extrastriate visual areas (Bullier
and Nowak, 1995; Thompson et al., 1996; Nowak and Bullier, 1997;
Schmolesky et al., 1998). One possible cortical route for such early
visual responses in FEF is via V1 projections to MT (Maunsell and Van
Essen, 1983; Ungerleider and Desimone, 1986).
Physiological significance of hierarchical organizations
Our results suggest that the relative proportion of supragranular
and infragranular layer neurons is a general defining feature, at least
in the visual system, of FB and FF pathways. Differences in the SLN%
in different pathways could be of functional significance, given the
experimental evidence suggesting that pyramidal neurons in upper and
lower layers have different physiological properties (Lagae et al.,
1989; Douglas and Martin, 1991; Nowak et al., 1995; Raiguel et al.,
1995; Ahmed et al., 1998), histochemical features (Hof et al., 1996,
1997), and topographical relationships (Barbas, 1995; Barone et al.,
1995). These different properties could contribute to shaping the
function of FF in the construction of receptive fields (Zeki 1993;
Bullier et al., 1994; Hubel 1995; Vanduffel et al., 1997) and FB
pathways in visual imagery (Ishai and Sagi, 1995; Miyashita 1995) and
figure ground discriminations (Zipser et al., 1996; Hupé et al.,
1998; Lamme et al., 1998).
Hierarchical distance and the organization of visual areas
The analysis of topology and patterns of laminar connectivity
converge to indicate a hierarchical organization of the cortical visual
system (Felleman and Van Essen, 1991; Young, 1992). Hierarchy in the
Felleman and Van Essen (1991) model is derived from the pairwise
analysis of the laminar patters of interareal connectivity in which
each connection is defined as an FF, FB, and lateral connection largely
on the basis of nonquantitative data. Mathematical modeling of the same
database confirms the hierarchical nature of the organization but
importantly indicates that there are huge number of possible solutions
(Hilgetag et al., 1996a). This indeterminate nature of the proposed
organization in part stems from the absence of an indication of the
distance separating levels in the hierarchical scheme. The present
study shows that the SLN% for a set of areas leads to an interareal
ranking, which largely fits with the Felleman and Van Essen (1991)
model. This suggests that SLN% reflects an underlying functional
principle and further provides an indication of the relative
hierarchical distance separating areas. A distance rule of hierarchical
relationships derived from SLN% values might be a universal feature of
the organization of the cortex, as revealed by the laminar organization
of afferents to the frontal lobe (Barbas, 1986) and to the
somatosensory system in the monkey (Batardière et al., 1998b).
Future modeling of an extended quantitative database of this type holds
the promise of providing a determinate model of the organization of
visual cortex. The present database based on laminar location of parent
cell bodies does not exclude the possibility that quantitative analysis
of the laminar location of axon terminals (Barbas and Rempel-Clower,
1997) might be equally important and possibly complementary.
Our analysis of the hierarchical relationships of the visual areas is
based on the nomenclature provided in the review paper of Felleman and
Van Essen (1991). However, the definition and the integrity of some of
these visual areas is still under debate (Kaas, 1996) and will have to
be taken into account in future models of the visual cortex.
Furthermore, heterogeneity of individual areas, such as a differential
representation of the central and peripheral fields, might be
accompanied by changes in connectivity with eccentricity (Perkel et
al., 1986; Baizer et al., 1991; Stepniewska and Kaas, 1996; Gattass et
al., 1997), which in turn could lead to differences in the hierarchical
relationships of cortex subserving the central and peripheral visual
fields (Falchier et al., 2000).
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FOOTNOTES |
Received Nov. 15, 1999; revised Feb. 4, 2000; accepted Feb. 7, 2000.
This work was supported by the
TOP
ABSTRACT
INTRODUCTION
