reaching beyond the classical receptive field of v1 neurons: horizontal or feedback axons?

Journal of Physiology - Paris 97 (2003) 141–154

www.elsevier.com/locate/jphysparis

Reaching beyond the classical receptive fieldof V1 neurons: horizontal or feedback axons?

Alessandra Angelucci a,*, Jean Bullier b

a Department of Ophthalmology, Moran Eye Center, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USAb Centre de Recherche Cerveau et Cognition, CNRS/Universit�e Paul Sabatier, 133 route de Narbonne 31062 Toulouse Cedex 4, France

Abstract

It is commonly assumed that the orientation-selective surround field of neurons in primary visual cortex (V1) is due to inter-

actions provided solely by intrinsic long-range horizontal connections. We review evidence for and against this proposition and

conclude that horizontal connections are too slow and cover too little visual field to subserve all the functions of suppressive

surrounds of V1 neurons in the macaque monkey. We show that the extent of visual space covered by horizontal connections

corresponds to the region of low contrast summation of the receptive field center mechanism. This region encompasses the classically

defined receptive field center and the proximal surround. Beyond this region, feedback connections are the most likely substrate for

surround suppression. We present evidence that inactivation of higher order areas leads to a major decrease in the strength of the

suppressive surround of neurons in lower order areas, supporting the hypothesis that feedback connections play a major role in

center–surround interactions.

� 2003 Elsevier Ltd. All rights reserved.

Keywords: Corticocortical connections; Primary visual cortex; Extrastriate cortex; Surround modulation; Feedback

1. Introduction

The traditional, feedforward, model of the visual

system invokes a cascade of processing stages, beginning

with relay of retinal input to the neurons of area V1, viathe lateral geniculate nucleus (LGN), and subsequent

processing through a hierarchy of cortical areas [102].

According to this model, cells at each successive stage

process inputs from increasingly larger regions of space,

and code for increasingly more complex aspects of visual

stimuli, a complex abstraction of the visual world

achieved by cells at the highest visual centers. The se-

lectivity of a neuron to a given parameter 1 is supposedto result from the ordered convergence of afferents from

the lower stages. One example is the emergence of ori-

entation selectivity in area V1 neurons. Following the

initial model of Hubel and Wiesel [39], several authors

have claimed that orientation selectivity can be entirely

generated by the ordered arrangement of afferents from

*Corresponding author. Tel.: +1-801-5857489; fax: +1-801-

5851295.

E-mail address: [email protected] (A. Angelucci).1 Orientation, color, direction of movement.

0928-4257/$ - see front matter � 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jphysparis.2003.09.001

the LGN. This view has been subject to debate for

several decades (for reviews see [26,94]). In particular,

there is evidence that local intracortical excitatory and

inhibitory mechanisms play a role in amplifying and

sharpening the orientation tuning of V1 neurons.Although feedforward models can perform a sur-

prising number of object recognition tasks in a simple

environment [98], they fail to identify an object in a

cluttered environment, where the object can be partially

masked or occluded by other objects. Proper interpre-

tation of partially occluded figures requires global in-

formation about the 3D interpretation of the scene to

guide the alignment of edges. The computations relatedto such global-to-local interactions should be flexible,

i.e. different sets of global cues should lead to different

types of local processing of edges. Furthermore, to

mediate perceptual completion across several degrees

of visual angle, these computations should involve

exchange of information across distant regions of the

visual field (often >10�). Finally, to allow for interpre-

tation of an image within the timeframe of inter-sacc-adic times (200 ms), they should be fast.

There is compounding evidence that flexible and

rapid long-distance computations do occur in the visual

mail to: [email protected]

142 A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154

system, even at the lower levels of cortical processing.Thus, for example V2 and V1 cells respond to illusory

contours 2 [34,87,103], and to occluded contours defined

by contextual depth cues [7,96]. More generally, the

response of cells in V1 (and extrastriate cortex) can be

modified by contextual stimuli lying far outside the

neurons’ receptive field [1,10,30,60,67]. What are the

neural circuits underlying these fast, long-distance,

global-to-local interactions? In this chapter we present aset of anatomical and physiological data exploring this

issue.

2. Spatial properties of center–surround interactions in

V1: where is the center, where is the surround?

The typical neural signature of long-range spatialcomputations at the single cell level is represented by

center–surround interactions. These have been described

for the first time in the retina 50 years ago [52], and are

thought to endow retinal ganglion cells with the ability

of signaling relative contrast rather than local lumi-

nance. Center–surround interactions are also observed

in the responses of cortical cells, for which it is possible

to define a discharge center or receptive field, and asurround that is usually silent, 3 but can suppress or

facilitate the center response when both center and

surround regions are simultaneously stimulated.

There are different ways to measure the size of a

cortical neuron’s receptive field (RF) center (Fig. 1a).

One method consists in measuring the visual field region

that elicits an excitatory response (i.e. an increase in

firing rate) when stimulated by a small high contraststimulus, such as a light or dark bar flashed or swept

across the RF. The resultant region is called the mini-

mum response field (mRF) or classical receptive field

[8,35]. More recently, reverse correlation methods have

been developed [21], that consist in briefly presenting at

random positions in the visual field a small high contrast

light or dark bar stimulus, and reconstructing the posi-

tion of the bar at a given time before the emission of aspike. By averaging the positions of the dark and light

bars for a given time delay and for many spikes, it is

possible to build a response map similar to the mRF.

This method has the advantage of providing informa-

tion about the location of ON 4 and OFF 5 regions, and

about the dynamical aspects of the center response, and

it is more quantitative than the classical method of es-

timating mRF size. A third method used to measure the

2 Perceived edges spanning regions with no corresponding lumi-

nance change.3 Activation of this visual field region alone by a small stimulus does

not elicit a response from the neuron.4 Responding to the bright bar.5 Responding to the dark bar.

size of the RF center is to stimulate the cell with amoving high contrast sinewave grating of optimal ori-

entation, spatial and temporal frequencies for the cell,

and to increase its size until the response of the neuron

ceases to increase [20,54,84]. The high contrast sum-

mation RF (hsRF) corresponds to the region of visual

field over which the cell summates stimuli. This method

provides estimates of RF center size larger than the

mRF or the RF center sizes obtained using automaticplotting by reverse correlation (Fig. 1a left and middle).

A distinctive property of the interaction between the

RF center (mRF or hsRF) and the surrounding region

of cortical cells is its orientation specificity: the extent of

facilitation or suppression of the center response pro-

duced by simultaneous stimulation of the surround de-

pends upon the relative orientation and direction of

motion of stimuli in these two regions. Using expandingdrifting gratings as the stimulus, and defining the size of

the RF center as the neuron’s hsRF, center–surround

interactions are usually reported to be suppressive for

center and surround stimuli of similar orientation and

direction, whereas they are less suppressive and can even

be facilitatory for center and surround stimuli of or-

thogonal orientations and opposite directions of motion

[20,50,54,56,88,92]. The orientation selectivity of center–surround interactions in cortical cells, in contrast to non

orientation-selective center–surround interactions in

retinal or LGN neurons [23,24], strongly suggests that

intracortical processing plays a major role in the gen-

eration of cortical modulatory surrounds.

Relating the organization of the responsive and

modulatory regions of cortical neurons to a simple

model with a center and a surround is not as easy as it isfor retinal ganglion cells. A complicating factor is that

the RF center varies in size depending on stimulus

contrast. At low contrast, the summation RF is on ave-

rage twice as large as when it is measured at high con-

trast (Fig. 1a right) [84]. As a consequence, regions

flanking the mRF along the line of optimal orientation

(collinear stimuli) can facilitate the center (mRF) res-

ponse at low contrast, but suppress it at high contrast[45,66,73]. Thus, it is possible to identify three overlap-

ping regions in the RF center of a cortical neuron (Fig.

1a): the mRF, the hsRF and the summation RF at low

contrast (lsRF). Center–surround interactions in ma-

caque V1 neurons have been modeled as a center ex-

citatory gaussian overlapping a surround inhibitory

gaussian, with the center gaussian corresponding to the

lsRF, e.g. [84]. On the other hand, regions beyond theRF center (mRF or hsRF) that suppress the response of

the center to high contrast stimuli have traditionally

been included in the surround. As a consequence, the

regions between the hsRF and the lsRF, that can be

suppressive at high contrast, would belong to the sur-

round. For convenience, we will refer to this region as

the ‘‘proximal surround’’. This extends on average twice

Fig. 1. Extent of the receptive field (RF) and surround field in macaque V1. (a) Different methods of measuring the size of a V1 neuron’s RF center.

Cartoons at the top represent the stimuli used to plot the RF of a given cortical neuron; dashed squares at the bottom are the RF center sizes (number

below square: diameter of the square in degrees of visual angle) obtained for the same cell using the corresponding stimulus and mapping method at

the top. Left column: minimum response field (mRF), mapped using moving small high contrast bar. Middle and right columns: summation RF

(sRF), mapped using expanding gratings. The sRF size is the stimulus diameter at peak response (arrow in inset). The sRF measured at low contrast

(lsRF, right) is about twice the diameter of the sRF measured at high contrast (hsRF, middle). (b) Distribution of surround field diameters for a

population of V1 neurons (n ¼ 59 cells between 2� and 8� eccentricity in the lower visual field), mapped using high contrast expanding gratings

(cartoon), and taking as surround size the stimulus diameter at asymptotic response (arrow in inset). Arrowhead: mean (5.1�±0.6). Mean hsRF size

for the same neuronal population was 1.0�±0.1 (not shown). Modified from [4]. (c) Types of stimuli used in different studies on the contrast de-

pendence of center–surround interactions. Left: using spatially discrete pattern stimuli (iso-oriented and collinear Gabor patches inside and just

outside the mRF) facilitation of the mRF response is most often observed when the center Gabor stimulus is of lower contrast than the flanks.

Suppression is instead seen most often for high contrast center Gabor stimuli. Note that the center and flanking stimuli occupy a region of space

roughly equivalent to the diameter of the summation RF shown on the right. Right: using concentric gratings, the center one matched to the size of

the neuron hsRF, suppression of the center response is most often observed for iso-oriented center and surround stimuli, even for lower contrast

center gratings.

6 This may not be the case in monkey V1 [55,85].

A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154 143

the diameter of V1 neurons’ hsRF [84]. Beyond the lsRF

(or proximal surround) lies the remaining portion of the

surround that we will refer to as the ‘‘distal surround’’.

Using high contrast optimal grating stimuli expanding

over the neuron’s RF center, and taking as surround size

the stimulus diameter at which the cell’s response

asymptotes (i.e. ceases to decrease; see Fig. 1b), surround

sizes in macaque V1 have been found to be on averageabout five times larger than V1 cells’ hsRF [4,55]. Most

neurons have surround sizes extending beyond the

proximal surround, well into the distal surround. The

latter can extend beyond 13� of visual angle (see also

[85]), i.e. over 13 times the size of V1 neurons’ mean

hsRF.

An additional complicating factor is that the modu-

latory surround region is not always organized in aconcentric and symmetric fashion, as is usually the case

for retinal ganglion cells. It has been shown that in cat

area V1, the surround often consists of a single, asym-

metric suppressive or facilitatory zone, 6 and that the

strength of the surround is highest in the region abutting

the RF center [104]. Furthermore, the interaction be-

tween the responses obtained by stimulating the mRF

and the active surrounding regions are often highly non-

linear, at least in terms of number of spikes in the res-

ponse. For example, stimulation of regions just outside

the mRF usually does not produce spikes, but adding astimulus to these regions can increase by a factor of 3 or

4 the response to stimulation of the mRF alone (see for

example [19]). Finally, the relative contrast of stimuli in

the center and surround also determines whether the

observed center–surround interactions are facilitatory or

suppressive [54,66,73], although the exact nature of the

interaction for a given center contrast may additionally

depend on stimulus configuration. Thus for example,


studies using contrast reversal of small iso-oriented andco-axially aligned Gabor patches in the mRF and its

surround (Fig. 1c left) have reported predominantly

facilitatory interactions for low center stimulus contrast,

and suppressive interactions for high contrast central

stimuli [66,73]. However, using the same stimulus con-

figuration, a variety of other kinds of interactions,

facilitatory or suppressive, although less frequently ob-

served, have also been reported [16]. On the other hand,studies using concentric drifting gratings of similar ori-

entation (Fig. 1c right) have more frequently observed

suppressive interactions, even for low contrast center

stimuli [54]. These two different stimulus configurations

have been shown to also have opposite effects psycho-

physically [15,71], consistent with the physiological data.

Despite these differences, both sets of physiological

studies indicate that there are no static facilitatory orsuppressive regions in the surround, as suppression can

turn into facilitation depending on contrast.

The question we address in this paper concerns the

structural basis of center–surround interactions in area

V1 neurons. Two major sets of connections can account

for the presence of an orientation-selective modulatory

surround beyond the RF center of cortical neurons. One

is the set of horizontal or lateral connections within areaV1. We will show below that these connections are un-

likely to underlie all center–surround interactions. The

other set of connections is the feedback connections

from extrastriate cortex to area V1. We present below

arguments in support of a role for these connections in

center–surround interactions. Our conclusion is that

flexible and rapid global-to-local interactions are likely

to be under the main control of feedback connections.

3. Are center–surround interactions mediated by horizon-

tal connections?

3.1. Spatial properties of V1 horizontal connections

V1 horizontal connections are long-range, reciprocal,intra-laminar projections prominent in the upper layers

of V1 [28,75] (but also present in layers 4B/upper 4Ca of

primates and 5 and 6 of primates and carnivores). These

connections arise from excitatory neurons, show a pe-

riodic, patchy pattern of termination, and contact pre-

dominantly (about 80%) excitatory neurons but also

(about 20%) inhibitory neurons [48,62,64]. Horizontal

axons have been found to link preferentially corticalpoints of similar functional properties, such as orienta-

tion preference [29,49,61], direction preference [78],

ocular dominance and cytochrome oxidase (CO) com-

partment [106]. In contrast to thalamic (feedforward)

axons and local (recurrent) intracortical connections,

horizontal axons do not drive their target neurons but

only elicit subthreshold responses [38,105], thus exerting

a modulatory effect on their target cells. Because of theseproperties, most current models of center–surround in-

teractions in V1 have used intrinsic horizontal connec-

tions as their underlying anatomical substrate (e.g.

[27,31,93]).

A recent study has, however, demonstrated that

horizontal connections are not sufficiently extensive to

account for the spatial scale of all center–surround in-

teractions [4]. Injections (0.5–1.0 mm in diameter) ofsensitive bidirectional tracers (cholera toxin B, CTB, or

biotinylated dextran amine, BDA) in macaque area V1

at 2–8� eccentricity label horizontal connections in lay-

ers 2/3 extending on average 6± 0.7 mm (3 mm on each

side of the tracer injection; [4]), ranging up to 9 mm.

Note that this is the largest extent ever reported in the

literature for horizontal connections in macaque V1,

demonstrating the higher sensitivity of the tracers wehave used (especially CTB), relative to previously used

tracers (e.g. biocytin) and even to a recently introduced

tracing method (i.e. an adenovirus bearing the gene for

enhanced green fluorescent protein––EGFP [95]. In the

cat these connections are slightly more extensive, being

on average 6–8 mm long [28,49,62]. Using combined

anatomical tracing with CTB or BDA and electrophys-

iological mapping of RF size and eccentricity in ma-caque V1, Angelucci et al. [4] have shown that the

largest visuotopic extent of monosynaptic V1 horizontal

connections is commensurate with the aggregate lsRF

size of the connections’ cells of origin (Fig. 2). Thus,

these connections play a more important role than

previously appreciated in integrating signals within the

summation RF of V1 neurons, and we hypothesize that

they may shape V1 neurons’ spatial summation prop-erties at low stimulus contrast. These conclusions are

also supported by a recent study in tree shrew [17]. We

have seen in Section 2 that most cells in macaque V1

have surround sizes extending well beyond the size of

their lsRF, i.e. beyond the monosynaptic range of hor-

izontal connections. Although polysynaptic circuits of

horizontal connections could in principle underlie long

distance surround effects, the strong and predominantlysuppressive nature of center–surround interactions, to-

gether with the slow conduction velocity of horizontal

axons (see Section 3.2), would seem to preclude propa-

gation of signals through a cascade of horizontal con-

nections. Thus, V1 horizontal connections are unlikely

to account for the scale of the distal surround region.

However, surround modulation of RF center (mRF

or hsRF) responses can occur within the proximal sur-round region, i.e. within the spatial range of horizontal

connections. One example of proximal center–surround

interactions is collinear facilitation (see Section 2), i.e.

enhancement of the mRF center response to an opti-

mally oriented low contrast stimulus by flanking co-

oriented and co-axially aligned high contrast stimuli

(Fig. 1c left) [45,66,73]. The psychophysical counterpart

Fig. 2. Extent of V1 horizontal connections in visual field coordinates.

Left: Visual field map of a CTB injection site and resulting labeled

horizontal connections in layers 2/3 of macaque V1. The injection site

was in the lower visual field representation of V1 at 6.5� eccentricity, 4�from the vertical meridian (VM). HM: horizontal meridian. The vi-

suotopic extent of the neurons at the injection site (black circles) is

shown for three different methods of measuring RF size (mRF, hsRF

and lsRF, respectively). Dashed gray circle: visuotopic extent of hori-

zontal connections. Note good match in size of the largest black oval

and dashed gray oval. Right: Population means (n ¼ 21) of the relative

visuotopic extent (dashed gray circle diameter/black circle diameter) of

labeled V1 horizontal connections, shown for each of the three dif-

ferent methods of measuring RF size. Error bars are s.e.m. Dashed

horizontal line marks a ratio of 1. Modified from [4].


of this physiological response is an enhancement of the

detection of a target oriented stimulus by flanking co-

oriented and collinearly aligned stimuli [45,71]. These

phenomena are thought to underlie perceptual grouping

of contour elements, i.e. extraction of collinear borders

in a complex and noisy environment [37]. As mentioned

in Section 2, one interpretation of collinear facilitation isthat it simply reflects placement of flank stimuli within

the cells’ lsRF, and can thus be explained by the same

mechanism underlying the expansion of the sRF at low

contrast [46,84]. This interpretation is also supported by

psychophysical and neurophysiological studies demon-

strating that the strength of the facilitation is maximal

for short target-flanker distances [45,71,72], consistent

with both sets of stimuli falling within V1 neurons’lsRF. Intracellular studies in cat [11] have demonstrated

a visually evoked subthreshold depolarizing field ex-

tending well beyond the spiking region (mRF), and

matching in extent the horizontal connections. This

larger subthreshold region is incapable of driving the

cells when stimulated in isolation by a small stimulus,

but can increase the cell’s response when stimulated in

conjunction with its mRF, and can be revealed extra-cellularly in areal summation experiments using ex-

panding gratings. Based on the results of Angelucci et al.

[4], and under the assumption that cats and primates are

similar, this subthreshold depolarizing field matches the

lsRF of V1 neurons, and it is likely to also underlie

facilitatory or summation effects beyond the mRF,

including collinear facilitation. However, not all short-range surround modulation effects are consistent with

this hypothesis, as a variety of other types of interac-

tions, facilitatory or suppressive, have been reported for

different center stimulus contrasts and similar stimulus

configurations ([16]; C. Gray, personal communication).

Furthermore, recent evidence in the cat, that collinear

facilitation can occur for target-flanker distances of up

to 12� [66], indicates that at least these longer-rangefacilitatory interactions cannot be explained by sum-

mation within the neuron’s lsRF, and that collinear

facilitation and RF expansion at low contrast might

instead represent different phenomena. More recently,

Crook et al. [19] have provided evidence supporting a

role for horizontal connections in mediating collinear

facilitation. Using microiontophoresis of GABA to in-

activate V1 neuronal populations located 1–2 mm awayfrom the recorded neuron, and having mRFs co-ori-

ented and co-aligned with that of the center recorded

neuron, they could substantially decrease collinear fa-

cilitation.

Surround suppression of center responses to high

contrast stimuli can also be observed within the spatial

range of the proximal surround [16,54,66,85]. It is not

clear to what extent proximal surround suppression and‘‘shrinkage’’ of the sRF at high contrast are accounted

for by a similar inhibitory mechanism. The observation

that the latter phenomenon can be seen in neurons with

no surround suppression [84] would seem to suggest that

these two phenomena are independent and require dif-

ferent mechanisms.

To conclude, the spatial properties of horizontal

connections are consistent with a possible role for thisconnectional system in mediating the expansion of the

summation RF at low contrast, as well as some short-

range facilitatory and suppressive center–surround in-

teractions, namely those occurring within the spatial

extent of the proximal surround. However, these con-

nections cannot account for distal center–surround in-

teractions.

3.2. Temporal properties of V1 horizontal connections

Experimental evidence indicates that interactions

between distant regions of the RF of V1 neurons tend to

be slow. Visual stimulation of the distal surround alone

can evoke long-latency weak responses, whose onset is

delayed by 50 ms or more compared to the onset of

the response to stimulation of the RF center [41,50,57,58,79]. Using optical imaging in monkey V1, similar

temporal delays have been found for the propagation

of the wave of activation generated by a restricted

visual stimulus [33]. By dividing the cortical extent of

the activated V1 region by the temporal delay of

the signal propagation, Grinvald and his collabora-

tors concluded that these signals travel at a speed of

7 mm of cortex representing 1� of visual space.


0.1–0.2 m/s [33]. These values are remarkably similar tothose reported by Bringuier et al. [11] for the speed of

depolarizing potentials travelling across the RF of

neurons recorded intracellularly in cat area V1. The

conduction velocity of monkey V1 horizontal axons

(median 0.3 m/s), measured directly by electrical stimu-

lation, also confirms the slow nature of these connec-

tions [32]. Together these results suggest that the slow

depolarization wave across the RF center and proximalsurround of V1 neurons can be mediated by horizontal

connections.

Several groups have measured the timing of sup-

pressive effects of surround stimulation on the center

response. For neurons showing general surround sup-

pression (i.e. independent of the orientation or pattern

of the surround stimuli), the onset of suppression is not

delayed with respect to onset of the center response[41,50,68]. This lack of delay is usually interpreted as

resulting from a peripheral suppression mechanism

taking place in the retina or the thalamus. In contrast,

orientation- or pattern-specific surround suppression

has been reported to be delayed relative to the center

response. Thus, Knierim and Van Essen [50] found that

the onset of orientation-selective surround suppression

is delayed by 15–20 ms on average compared to theonset of the center response. This result was confirmed

by Li et al. [57] in the awake animal, and Nothdurft

et al. [68] in the anesthetized monkey. The value of 15–

20 ms reported by these groups was calculated after

averaging all the responses of neurons with inhibitory

surround, irrespective of the latencies of their visual

responses. By aligning the center responses at the same

latency before averaging, Hup�e and his collaboratorsfound that the average delay for orientation-selective

surround suppression is in fact larger, close to 40 ms

[41]. A shorter delay (20 ms) was observed for sup-

pression induced by iso-oriented flanking stimuli located

on either side of the mRF along a line perpendicular to

the optimal orientation [41].

Thus, the delays of the suppressive orientation-

selective effects of surround stimulation are similar tothose reported for the propagation of excitatory acti-

vation interpreted as being mediated by horizontal

connections (see above). It is therefore likely that at least

some of the center–surround interactions in V1 neurons

are mediated by horizontal connections. This may be the

case in particular for the interactions between the center

and the proximal surround. However, for longer dis-

tances in the visual field, it is unlikely that horizontalconnections could be used efficiently due to their slow

nature. As mentioned in Section 2, orientation-specific

surround suppression of parafoveal V1 neurons can be

evoked by surround stimuli located over 13� away from

the recorded neuron [4,55,66]. This corresponds to a

distance on the cortical surface of V1 > 1 cm. At 0.1 m/s,

the transfer of information can therefore take more than

100 ms. Because most of the information is transmittedin the first 100 ms of the response [100], a delay of 100

ms with respect to the onset of the response is detri-

mental to a proper processing of information by the

cortical network. It is clear, therefore, that for long

distances across the visual field, horizontal connections

are simply too slow to underlie center–surround inter-

actions.

4. Are center–surround interactions mediated by feedback

connections?

4.1. Spatial properties of feedback connections to V1

On the basis of laminar origin and termination,

connections between visual cortical areas have beenclassified as feedforward or feedback, and a hierarchical

organization of cortical areas has been proposed

[22,25,76]. Area V1, at the bottom of the hierarchy,

receives its main feedforward inputs from the thalamus,

and sends feedforward projections to several extrastri-

ate cortical areas which, in turn, send projections back

to V1. In both cat and monkey, feedback connections

to V1 arise from supragranular and infragranular layersof extrastriate cortex [14,47,97] and terminate in the

same supra- and infragranular layers of V1 from which

they receive feedforward projections [5]. Feedback

axons from different layers of extrastriate cortex ter-

minate at different depths in V1: supragranular neurons

project to the supragranular layers of V1, infragranular

neurons to both supra- and infragranular V1 layers

[4,18,36]. The laminar location of the cells of origin offeedback connections is also related to the physical (or

hierarchical) distance from V1, especially in the ma-

caque, where the proportion of neurons arising from

the upper layers decreases progressively as one moves

away from V1 [9]. In the macaque, the fields of somata

retrogradely labeled in extrastriate cortex by CTB in-

jections in V1 are more extensive in the lower than in

the upper layers; those in the lower layers increasein extent with cortical distance from V1, whereas the

upper layer fields decrease in extent [4]. The major axis

of the CTB labeled fields in the lower layers of V2, V3

and MT measures on average 6.4 ± 1.2, 7.9 ± 1.2 and

8.9 ± 2 mm, respectively [4]. Thus, feedback connections

to a V1 column arise from larger cortical regions than

horizontal connections to the same column. Since

magnification factor 7 decreases and receptive field sizeincreases with cortical distance from V1, feedback

connections from extrastriate cortex convey informa-

tion to a V1 column from much larger regions of visual

field than the V1 column can access via horizontal

Fig. 3. Extent of feedback (FB) connections to V1 in visual field co-

ordinates. (a) Visual field map of a CTB injection site in V1 (black

circle, aggregate hsRF of neurons at the injection site; same injection

case as in Fig. 2a) and resulting labeled fields of cells of origin of FB

connections in the lower layers of extrastriate cortical areas V2, V3 and

MT (gray circles, aggregate hsRF of neurons in the labeled connec-

tional field). The visuotopic extent of V1 horizontal connections

(dashed gray circle, aggregate hsRF) arising from the same V1 injection

is also shown for comparison. Scale bar: 2.5�. Modified from [4]. (b)

Population means of the relative visuotopic extent (gray circle diam-

eter/black circle diameter) of FB connections (open bars) in the lower

layers of areas V2 (n ¼ 6), V3 (n ¼ 5) or MT (n ¼ 2), and of V1 hor-

izontal connections (filled bar; n ¼ 21). Note cut on the Y axis’ scale.

Horizontal lines are population means of the relative visuotopic ex-

tents of V1 neurons’ lsRF (dashed line: lsRF diameter/hsRF diame-

ter¼ 2.3) and surround field (solid line: surround diameter/hsRF

diameter¼ 4.6).


connections [4]. Furthermore, the size of the visual field

region conveyed to the V1 column gets progressively

larger for feedback connections arising from extrastri-

ate areas further and further away from V1 (Fig. 3a).

Similar visuotopic rules govern the organization offeedback connections to V1 in the cat [80,81].

By making injections of CTB or BDA in electro-

physiologically characterized V1 loci, and estimating the

extent in visual field of the resulting retrogradely labeled

feedback fields in areas V2, V3 and MT, 8 it has recently

been demonstrated that the visuotopic extent of feed-

back connections to V1 is commensurate with the full

spatial range of V1 cells’ center and surround sizes (Fig.3b) [4]. The mean surround size in V1 (�5 ·hsRF, see

Section 2) is significantly more extensive than the

mean visuotopic extent of horizontal connections

(�2 ·hsRF), but is commensurate with the mean vi-

suotopic extent of the feedback fields from V2 to V1

(�5 ·hsRF; Fig. 3b). Because surround sizes can extend

>13 times the size of V1 neurons’ hsRF (see Section 2),

then the larger feedback fields from V3 (�10 · hsRF)

8 Using published values of magnification factor and our own

measurements of receptive field size.

and MT (�27 ·hsRF) can account for these longerdistance center–surround interactions (Fig. 3b). Thus, in

contrast to horizontal connections, feedback connec-

tions can provide a substrate for all center–surround

interactions, including those originating from the distal

surround.

Previous studies, using injections of tritiated amino

acids [63,101], or of WGA-HRP [51,89,90], in extras-

triate areas of various primates species and cat, reportedthat feedback connections are more diffuse and unspe-

cific than feedforward connections. Our recent studies,

using a newer generation of anatomical tracers, includ-

ing BDA or CTB, have instead demonstrated that, ex-

cept for feedback terminations in V1 layer 1 which are

diffuse, terminals of feedback projections from areas V2

and V3 are parcellated into discrete patches in layers 2/3,

4B and 6 of V1. These terminal patches overlap withpatches of V1 feedforward projecting neurons [4]. This

precise alignment of feedback terminal clusters with

clusters of feedforward efferent cells in V1 (also observed

in cats [82] and rats [44]) is well suited to fast transfer of

specific information to and from V1. More recently we

have demonstrated that feedback connections termi-

nating outside layer 1 of V1 are organized in a func-

tionally specific manner, as their terminal patches in V1are specific with respect to CO compartments [3,4,43].

Furthermore, by combining tracer injections in V2 with

optical imaging of areas V1 and V2 in new world pri-

mates, we [6] and others [91] have recently demonstrated

that, similar to patchy horizontal connections within V1,

patchy feedback connections to V1 layers 2/3 link cor-

tical columns of similar orientation preference. This

property is consistent with feedback connections medi-ating orientation-specific center–surround interactions.

In contrast, Stettler et al. [95], using an adenovirus

bearing the EGFP gene (reported to be transported only

anterogradely), claimed that feedback projections from

V2 terminate in V1 layers 2/3 in a diffuse manner, and

are not specific with respect to the CO or orientation

maps in V1. The discrepancy between these studies is

likely residing in the different methods used for axonallabeling. One possible criticism to our [3,4,6] and Shm-

uel et al.’s [91] studies is that the bidirectional tracers we

have used could produce retrograde labeling of local

axon collaterals, thus the apparent patterning of feed-

back terminals may indeed reflect the patterning of the

reciprocal feedforward pathway. However, while this is

possible for BDA labeling, we have previously demon-

strated that CTB labels retrogradely cell bodies, but notthe axon fibers arising from them [2]. This is demon-

strated in Fig. 4a,c which shows retrograde labeling of

cell bodies without any fiber labeling in layer 6 of V2,

following a CTB injection involving V1 layers 1-4C.

Conversely, CTB injections in the deep layers of V2

(Fig. 4b left) result in patchy feedback terminal label

in V1 layer 6 (Fig. 4b right and 4d), and virtually no

Fig. 4. Cholera toxin B (CTB) in the primate labels retrogradely so-

mata but not axons. (a) Terminal CTB label in V2 layers 3/4 (terminals

of feedforward axons from V1), and cell body label in V2 layers 2/3A

and 5/6 (cells of origin of feedback axons to V1), arising from an in-

jection in macaque V1. Cortical layers are indicated to the left. Label in

the dashed white box is shown at higher power in (c); note absence of

retrogradely labeled fibers arising from the labeled somata (a few

proximal dendrites are labeled). (b) CTB injection (dashed white ring)

in the deep layers of marmoset monkey area V2, and resulting ante-

rogradely and retrogradely labeled V2 horizontal connections (left of

V1/V2 border, indicated by black dashed line); to the right of the

border are resulting anterogradely labeled terminals of feedback axons

in V1 layer 6, with only occasional retrogradely labeled cell bodies

(arrowheads). Label in dashed white box is shown at higher power in

(d); note patchy anterograde labeling of axons in the absence of ret-

rograde label (arrowheads point at the only two labeled somata). Scale

bars: 100 lm (a,c,d) and 1 mm (b).


retrograde cell label (Fig. 4d), as this feedback pathway

is not significantly reciprocated by a feedforward path-way from V1 layer 6. Thus, we are confident that CTB-

labeled fibers reflect exclusively anterograde labeling of

axons and terminals. In contrast, the viral method used

by Stettler et al. [95] has not yet been properly validated

as an axonal tracer, and we believe more studies are

needed to demonstrate its suitability to trace long dis-

tance axonal pathways.

4.2. Inactivation experiments: the role of feedback con-

nections on center and surround mechanisms

The role of feedback connections in mediating cen-

ter–surround interactions has been tested in the anes-

thetized macaque, by inactivating high-order areas and

recording neuronal responses in lower-order areas re-

ceiving feedback connections from the inactivated area[13]. These experiments have been performed for two

sets of feedback connections: from V2 to V1, and from

MT to areas V1, V2 and V3. In the first set of experi-

ments, neurons in V2 were inactivated by pressure

ejection of the inhibitory neurotransmitter GABA

through several micropipettes; recordings in V1 were

made from neurons with receptive fields overlapping

those of neurons at the inactivated V2 region. The visualstimulus used resembled that of Knierim and Van Essen

[50] and Nothdurft et al. [68], and consisted of a high

contrast bar of optimal orientation flashed in the re-

ceptive field center and a set of bars of varying orien-

tations in the surround. One effect of inactivating area

V2 was a decrease in the V1 neurons’ responses to the

central bar, suggesting that feedback connections from

area V2 normally act to enhance the response of V1neurons [41]. These results confirmed previous obser-

vations [65,83]. However, when the interaction between

center and surround was tested by comparing responses

to the center stimulus and to the stimuli involving center

and surround, no effect was observed [41]. In other

words, at least this kind of center–surround interactions

in V1 neurons do not depend mainly on the feedback

connections from V2, as it had previously suggested[50,74]. Whether feedback connections from other areas

or horizontal connections play the major role remains to

be determined.

The effect of feedback connections from MT on

center–surround interactions in areas V1, V2 and V3 has

also been tested. The entire extent of MT (and sur-

rounding areas) was inactivated by a cooling probe

positioned in the superior temporal sulcus at the level ofMT. When MT was inactivated by cooling, a clear de-

crease of the response to a moving bar stimulating the

center was observed for approximately 40% of the

neurons [40], thus confirming the conclusion drawn

from the V2 experiments on the facilitatory effect of

feedback connections onto the center mechanism.

In the same experiments, center–surround interac-

tions were studied by comparing the responses to themoving bar in the center, with responses to the same bar

moving together with a background stimulus consisting

of a checkerboard of low contrast light and dark grey

bars of similar length and width as the center stimulus

(Fig. 5). Since the background stimulus did not generate

any response when moved alone across the RF but

strongly suppressed the response to the center bar when

it moved together with it, it can be assumed that it ac-tivated mostly the surround mechanism. By comparing

the responses in these two stimulus conditions, it is

possible to estimate the strength of the inhibitory effect

of the surround upon the center mechanism. This effect

was measured as the percentage decrease of the response

to the center stimulus when the background stimulus

was added. Fig. 5 presents a scattergram of the values of

background suppression for the control condition, andfor the MT inactivation condition. It is clear that in

most cases background suppression was diminished

by MT inactivation and sometimes suppression was

changed into facilitation. This suggests that feedback

connections from MT exert a potent effect on the cen-

ter–surround suppression of neurons in lower order

areas. One important parameter in the effect of MT

Fig. 5. Changes in strength of inhibitory surround of neurons in areas

V1, V2 and V3 when the feedback connections from area MT are in-

activated. The stimuli are shown below the scattergram. The strength

of inhibitory surround (bsup) is measured by the percent decrease of

the response to the central bar when the background is moving. The

salience of the central stimulus was varied by manipulating the ratio of

the contrasts of the central bar and the background. When the ratio is

close to 1, the bar is only visible when it moves across the static

background (low salience). When the ratio is high (up to 20), the

central bar is clearly visible against the background even when both

stimuli are static. Thus, at low salience it is the movement of the bar

that enables its segmentation from the background. The scattergram

presents the strength of the inhibitory surround when area MT is in-

activated by cooling (bsup Cooling) and before the inactivation (bsup

Control). No bsup change corresponds to the diagonal. Negative

values of bsup correspond to suppression, positive values to potenti-

ation of the center response by the surround mechanism. It is clear that

the vast majority of neurons show a decrease in bsup and that this

effect is particularly strong for low salience stimuli (crosses). In a few

cases a suppressive surround is changed into an activating surround by

inactivation of feedback connections (modified from [13]). Thus feed-

back connections potentiate the inhibitory strength of suppressive

surround, particularly for low salience stimuli.


inactivation is the salience of the center stimulus. This

was measured as the ratio of the contrasts of the centerand surround stimuli [40]. When the salience was high,

the center bar was clearly visible above the background;

when it was low, the center stimulus was only visible

when moving against the stationary background. Note

in Fig. 5 that the strongest effect of inactivating area MT

occurred for low salience stimuli, and that only mild

effects were observed for high salience stimuli. The rea-

sons for these differences, and the lack of effect of V2inactivation on center–surround interaction at high sa-

lience in V1 are discussed in Section 5.

Thus, feedback connections enhance the center res-

ponse and, at least for the connections from MT, in-

crease the suppressive effects of moving surround stimuliin V1, V2 and V3 neurons. Anatomically, feedback

projections are organized in a highly convergent and

divergent manner, so that visual activity in a given V1

column is fed forward to large regions of higher cortical

areas which, in turn, feed back signals to the originally

activated V1 column as well as to surrounding V1 col-

umns. Thus feedback connections are always active,

whatever the stimulus diameter. In the concluding par-agraph (see Section 5) we discuss possible mechanisms

by which feedback connections can simultaneously en-

hance activity in the center neurons while mediating

surround suppression of center responses.

4.3. Temporal properties of feedback connections to V1

It is usually assumed that feedforward connectionsare fast whereas feedback connections are slow. This is

in keeping with the idea that feedback connections me-

diate the late modulation of V1 neuron responses for

stimuli consisting of a figure against a background [41]

(but see [107]), and the general assumption that higher

order areas have delayed responses in comparison with

lower order areas. However, a literature survey reveals

that neuronal responses in higher order areas of themacaque visual system are delayed by only a few milli-

seconds relative to the responses of neurons in areas V1

and V2 [12,69]. Therefore, for the feedback effects to be

delayed, these connections would have to be made of

slowly conducting axons. Instead, direct measurements

of conduction velocities of feedforward and feedback

connections show this not to be the case [32,70]. Fig. 6

shows the conduction velocities of feedforward andfeedback axons between macaque areas V1 and V2, as

deduced from the orthodromic latencies (antidromic

latencies gave similar values [32]). Both types of con-

nections are made of fast-conducting axons, usually

between 2 and 6 m/s. In contrast, horizontal connections

have very slow conduction velocities, most of them

being between 0.1 and 0.4 m/s, i.e. about 10 times slower

than the feedforward and feedback connections (Fig. 6).The rapid conduction velocities of feedback action is

consistent with the lack of delay observed in the effect of

inactivating area MT on the responses of neurons in

areas V1, V2 and V3, or of inactivating area V2 on the

responses of V1 neurons [41,42]. If the effects of feed-

back connections were delayed, as suggested by the re-

sults of Lamme et al. [53], one would expect to observe

the effects of inactivation of a higher order area in thelate part of the response. The latency of the effect of

feedback connections onto the center responses was di-

rectly examined for both systems of feedback connec-

tions; in both cases, these effects were found not to be

delayed by more than 10 ms [41,42]. A similar obser-

vation was made for the timing of center surround in-

teractions.

Fig. 6. Conduction velocities of feedforward, feedback and horizontal connections. These were deduced from latencies to orthodromic stimulation,

because of the small sample of antidromically activated horizontal connections. For feedforward and feedback connections, conduction velocities

measured from antidromic latencies return similar values [32]. Note that feedback connections are as rapid as feedforward connections (no significant

differences between the distributions) and are much faster than horizontal connections.


These results therefore disprove common assump-

tions on the slow effects of feedback connections, and

instead point to the slow nature of horizontal connec-

tions. This is consistent with the large caliber of feed-

back axons [77] and the thin unmyelinated character of

most horizontal connections. It is clear, therefore, thatfeedback connections are much better suited than hori-

zontal connections to fast transfer of signals between

neurons with distant receptive fields.

5. Conclusions

There is thus evidence for involvement of feedbackconnections as well as horizontal connections in center–

surround interactions in area V1 neurons. The different

extents of the divergences of horizontal and feedback

connections from different areas (Fig. 7) provide a

progressive tiling of the surround by horizontal and

feedback connections from areas located further and

further away from V1. This extensive overlap between

the different feedback connections may explain why ef-fects of V2 inactivation on center–surround interactions

have not been observed in V1 with suprathreshold

stimuli [41]. In that case, it is likely that feedback con-

nections from areas other than V2 were able to provide

unchanged center–surround interactions during V2 in-

activation. The reason why we observed strong effects of

MT inactivation on center–surround interactions at low

salience (Fig. 5) is probably that we used low contrast

stimuli that activate area MT more than other corticalsources of feedback connections [86,99]. It is therefore

important when testing the effects of feedback from one

cortical area to use appropriate visual stimuli to isolate

the contribution of the inactivated area.

Both horizontal and feedback connections impose

a non-linear control on the responses of the center

mechanism. There are several questions that need to be

resolved: how do feedback connections coming fromdifferent areas interact with each other and with hori-

zontal connections at the level of the target neuron? Do

feedback connections simply converge on the same type

of network as horizontal connections or is the interac-

tion more complex? Do feedback connections modify

the gain of horizontal connections?

We have proposed a model of how feedback and

horizontal connections might mediate modulation ofcenter mechanism responses [5]. In this model, the out-

put of each excitatory pyramidal neuron (e.g. the center

recorded neuron) in V1 is controlled by a local inhibi-

Fig. 7. Summary diagram showing the spatial scales of V1 horizontal

and feedback connections relative to the spatial scales of empirically

measured summation receptive field and modulatory surround field of

V1 neurons. Gray area: region over which presentation of stimuli at the

same orientation as the center stimulus can suppress the center re-

sponse to an optimally oriented high contrast stimulus (proxi-

mal + distal surround). White area: region over which presentation of

optimally oriented high contrast stimuli evokes or facilitates a response

from the neuron (hsRF). Hatched gray annulus: region over which

presentation of stimuli at the same orientation as the center stimulus

can suppress or facilitate the center response to an optimally oriented

stimulus, depending on the center stimulus’ contrast (i.e. proximal

surround). Horizontal connections within V1 (red) extend beyond the

high contrast summation RF (hsRF; solid black circle) and are com-

mensurate with the low contrast summation RF (lsRF; dashed black

circle) of the V1 neurons from which they arise. Feedback connections

(FB; blue) from extrastriate cortex to V1 are commensurate with the

full spatial scale of summation RF and surround field. Feedback from

‘‘higher’’ cortical areas is more extensive than feedback from ‘‘lower’’

areas. Scale bar: 1�. Modified from [4].


tory neuron having higher response gain and contrast

threshold than the pyramid (see also [59,93]). Feedback

and horizontal inputs contact directly both neuron

types, while feedforward inputs drive only the pyramid.

The divergent/convergent organization of feedback and

horizontal axons is such that these two systems overlapin space and are active for any stimulus diameter, even

for stimuli confined to the RF center. At low contrast,

RF excitation predominates; horizontal and feedback

input to the pyramid can be summed from more distant

cortical (and visual space) locations before inhibition

begins to rise. Suppression of the center neuron response

would result from increasing the weight of excitation

onto the pyramid and its local inhibitory neuron, eithervia high contrast feedforward drive, or via horizontal

and feedback inputs, such as by increasing stimulus di-

ameter. A number of experiments will be necessary to

test this model to determine whether it captures the es-

sential aspects of the interactions between feedback and

horizontal connections.

Acknowledgements

This work was supported by: European Community

Grant Viprom Biomed 2, Wellcome Trust Grant061113, and Research to Prevent Blindness, Inc., New

York, INSERM, CNRS, GIS Cognisciences.

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