Visually Driven Activation in Macaque Areas V2 and V3 without Input from the Primary Visual Cortex

Abstract

Creating focal lesions in primary visual cortex (V1) provides an opportunity to study the role of extra-geniculo-striate pathways for activating extrastriate visual cortex. Previous studies have shown that more than 95% of neurons in macaque area V2 and V3 stop firing after reversibly cooling V1. However, no studies on long term recovery in areas V2, V3 following permanent V1 lesions have been reported in the macaque. Here we use macaque fMRI to study area V2, V3 activity patterns from 1 to 22 months after lesioning area V1. We find that visually driven BOLD responses persist inside the V1-lesion projection zones (LPZ) of areas V2 and V3, but are reduced in strength by approximately 70%, on average, compared to pre-lesion levels. Monitoring the LPZ activity over time starting one month following the V1 lesion did not reveal systematic changes in BOLD signal amplitude. Surprisingly, the retinotopic organization inside the LPZ of areas V2, V3 remained similar to that of the non-lesioned hemisphere, suggesting that LPZ activation in V2, V3 is not the result of input arising from nearby (non-lesioned) V1 cortex. Electrophysiology recordings of multi-unit activity corroborated the BOLD observations: visually driven multi-unit responses could be elicited inside the V2 LPZ, even when the visual stimulus was entirely contained within the scotoma induced by the V1 lesion. Restricting the stimulus to the intact visual hemi-field produced no significant BOLD modulation inside the V2, V3 LPZs. We conclude that the observed activity patterns are largely mediated by parallel, V1-bypassing, subcortical pathways that can activate areas V2 and V3 in the absence of V1 input. Such pathways may contribute to the behavioral phenomenon of blindsight.

Full text

Visually Driven Activation in Macaque Areas V2 and V3
without Input from the Primary Visual Cortex
Michael C. Schmid
1
*, Theofanis Panagiotaropoulos
1
, Mark A. Augath
1
, Nikos K. Logothetis
1,2
, Stelios M.
Smirnakis
1,3
*
1Max Planck Institut fu
¨r biologische Kybernetik, Tu
¨bingen, Germany, 2Imaging Science and Biomedical Engineering, University of Manchester, Manchester, United
Kingdom, 3Departments of Neuroscience and Neurology, Baylor College of Medicine, Houston, Texas, United States of America
Abstract
Creating focal lesions in primary visual cortex (V1) provides an opportunity to study the role of extra-geniculo-striate
pathways for activating extrastriate visual cortex. Previous studies have shown that more than 95% of neurons in macaque
area V2 and V3 stop firing after reversibly cooling V1 [1,2,3]. However, no studies on long term recovery in areas V2, V3
following permanent V1 lesions have been reported in the macaque. Here we use macaque fMRI to study area V2, V3
activity patterns from 1 to 22 months after lesioning area V1. We find that visually driven BOLD responses persist inside the
V1-lesion projection zones (LPZ) of areas V2 and V3, but are reduced in strength by ,70%, on average, compared to pre-
lesion levels. Monitoring the LPZ activity over time starting one month following the V1 lesion did not reveal systematic
changes in BOLD signal amplitude. Surprisingly, the retinotopic organization inside the LPZ of areas V2, V3 remained similar
to that of the non-lesioned hemisphere, suggesting that LPZ activation in V2, V3 is not the result of input arising from
nearby (non-lesioned) V1 cortex. Electrophysiology recordings of multi-unit activity corroborated the BOLD observations:
visually driven multi-unit responses could be elicited inside the V2 LPZ, even when the visual stimulus was entirely
contained within the scotoma induced by the V1 lesion. Restricting the stimulus to the intact visual hemi-field produced no
significant BOLD modulation inside the V2, V3 LPZs. We conclude that the observed activity patterns are largely mediated
by parallel, V1-bypassing, subcortical pathways that can activate areas V2 and V3 in the absence of V1 input. Such pathways
may contribute to the behavioral phenomenon of blindsight.
Citation: Schmid MC, Panagiotaropoulos T, Augath MA, Logothetis NK, Smirnakis SM (2009) Visually Driven Activation in Macaque Areas V2 and V3 without Input
from the Primary Visual Cortex. PLoS ONE 4(5): e5527. doi:10.1371/journal.pone.0005527
Editor: Mark W. Greenlee, University of Regensburg, Germany
Received December 8, 2008; Accepted March 17, 2009; Published May 13, 2009
Copyright: ß2009 Schmid et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: MPG, NIH, HHMI, DoD, DAAD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: schmidmicha@gmail.com (MCS); ssmirnakis@cns.bcm.edu (SMS)
Introduction
The flow of visual information from the retina to the higher
cognitive and motor areas contains a series of transformation steps
involving a number of subcortical and cortical brain areas. The
finding that, along this path, the receptive fields of neurons
increase in size, become step by step more invariant to physical
dimensions, and come to reflect, in part, perceptual processes has
contributed to the view that visual information processing is
largely organized in a serial hierarchical fashion. The primary
visual cortex (V1) is considered to be the major entry point for
cortical visual processing and activity in subsequent ‘‘higher’’
visual areas is generally interpreted as arising primarily from a
transformation of V1 input. Although this model has been highly
successful for studying how visual information is transformed
across areas, it is clear that it provides only a partial description of
the actual information flow. This is corroborated by anatomical
studies, which have revealed the existence of numerous parallel
and feedback inter-areal connections [4] whose functional
significance remains largely unknown. For example, in addition
to V1 input, most extra-striate areas receive direct, V1-bypassing,
input from the thalamic nucleus of the Pulvinar as well as from the
lateral geniculate nucleus (LGN). To date the role that these
pathways play in visual processing is at best poorly understood.
The importance of parallel, V1-bypassing, pathways for
mediating residual visual function following striate cortical lesions
has become evident from the large number of studies on human
patients and monkeys with area V1 lesions that exhibit so-called
‘‘blindsight’’-behavior (see reviews [5,6]): Despite the presence of a
scotoma in the lesion affected part of the visual field, subjects of
both species perform above chance on certain visual detection and
discrimination tasks under forced choice conditions
[7,8,9,10,11,12], and at times are even able to report the
perceptual qualities of the stimulus [13,14]. Studying the patterns
of activity that persist in extrastriate areas following area V1
lesions is a first step in trying to understand how the visual cortex
adjusts to injury, and in trying to identify candidate areas that
might mediate the residual visual behavior observed in the
phenomenon of ‘‘blindsight’’.
All cortical visual areas studied so far (V2, V3, V3A, V4, V5/
MT, MST, STP, IT) are clearly dependent on V1 input, so that,
upon lesioning or inactivating V1 the majority of cells in these
areas either cease to respond or show a markedly reduced response
to the visual stimulus [1,2,3,15,16,17,18,19,20,21,22,23,24].
Neuronal responses in areas V2, V3, depend particularly strongly
on V1 input as more than 95% of recording sites in these areas
lose visual modulation following transient V1 inactivation by
cooling [1,3,25]. Areas V4 [18] and IT [21] are similar to V2,V3
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in this regard, whereas V3A [3], V5/MT+[15,19,22,23] (but see
[16,17,24]), and STP [26] retain considerable visual responsive-
ness following V1 lesions. Although these studies [1,2,3,18] suggest
that early extra-striate areas V2 and V3 get effectively silenced
immediately following V1 inactivation, it remains unknown
whether visual responsiveness can return in these areas over time
following a permanent V1 lesion.
Neuroimaging studies confirmed the preservation of V5/MT+
activity in two highly studied human patients who exhibit
‘‘blindsight’’ [27,28,29] following V1+lesions. By contrast, results
describing the function of visual areas V2 and V3 after long-
standing V1 lesions are limited: 1) there are no electrophysiological
studies addressing directly this issue in monkeys, and 2)
neuroimaging studies of human ‘‘blindsight’’ patients have not
produced definitive results: On the one hand, the fMRI study of
hemianopic patients FS and GY by Goebel et al., appears to
confirm results from primate electrophysiology suggesting that
visually driven activity in areas V2, V3 is strictly dependent on V1
input [29]. In contrast, Baseler et al., report that visually driven
activity persists in areas V2, V3 and V3A [30] of patient GY, and
argue that this is likely the result of cortical reorganization. The
difference in these reports underscores how difficult it is to derive
definitive conclusions by studying naturally occurring human V1
lesions, which tend to be highly variable, extending typically into
the underlying white matter and into areas V2, V3 while
potentially leaving ‘‘islands’’ of V1 cortex intact. In particular,
the lesion of patient GY suffers from both these problems [30],
complicating the interpretation of the findings described above.
These important isolated reports notwithstanding, no study to
date has systematically followed how the strength of visual
modulation in primate extrastriate cortex evolves in time from
pre-lesion levels following isolated V1 lesions. Here we use
functional magnetic resonance imaging (fMRI) blood oxygen level
dependent (BOLD) signal measurements to serially monitor the
activity patterns seen after isolated V1 lesions in the retinotopically
corresponding locations of macaque areas V2 and V3 (V2, V3
lesion projection zones or LPZs). Macaque BOLD signal
measurements are well suited for addressing this issue because
they are non-invasive, they can provide a high spatial (,1 mm)
resolution picture of global brain activity [31,32] and co-localize to
within ,1 mm with recorded multi-unit activity [33]. In what
follows we will try to address the following questions: 1) do areas
V2, V3 display visually driven modulation in the absence of V1
input (i.e. are they in principle capable of mediating aspects of
‘‘blindsight’’ behavior), 2) if so, what can we say about the V1-
bypassing pathways that give rise to the persisting activity, and 3)
does the pattern of the observed activity change in time suggesting
that cortical reorganization takes place? Although currently at a
premature stage, information gathered by studies of this type may
in the future be helpful for designing interventions that may
accelerate recovery following visual system injury.
Results
To examine the dependence of visually driven activity in areas
V2 and V3 on input from V1, we performed fMRI experiments in
two anesthetized monkeys (L02 & Q02) with area V1 lesions
induced by aspiration (Materials and Methods). A standard phase
encoding expanding ring stimulation paradigm was used to map
the retinotopic (eccentricity) organization in areas V2 and V3.
Baseline experiments were performed prior to lesioning, and
subsequently the animals were scanned starting at 1 month post
lesioning and reaching up to 277 days (Q02) and 681 days (L02)
post-lesioning.
Characterization of the V1 lesion
In both monkeys, lesions were located in the right dorsal V1
sandwiched between the lunate (LS) and the external calcarine
(eCS) sulci (Figure 1A). Care was taken to aspirate gray matter
completely while leaving white matter as unaffected as possible.
Histological analysis in one monkey (Q02) confirmed that the
lesion was complete with no residual gray matter found inside the
border of the lesion (Figure 1B), while white matter remained
largely intact. Note that damage in the white matter could
potentially undercut additional input pathways to V2 (or V3) and
could potentially cause the loss of BOLD signal there. However,
complete loss of the BOLD signal is not what we observed. Gray
matter immediately (within 1 mm) surrounding the V1 lesion was
histologically (Q02) and radiologically (Q02 and L02) intact and
showed reliable visually driven BOLD responses (see below). The
loss of V1 gray matter was clearly detectable in the MR
anatomical images (0.5 mm
3
resolution anatomical Mdeft scan
[34,35]; Figure 1C), so that the lesioned area could be selected
independently of functional activity as an ROI for further analysis.
The cortical gray matter ribbon lining the lunate sulcus, including
the lesion projection zone of areas V2 and V3, was intact. To
measure the extent of the lesion and the lesion projection zone in
pre-striate areas, we reconstructed 3D renderings of the surface of
the visual cortex (Figure 1D) and converted them into cortical flat
maps (Figure 1E). The extent of the lesion was similar in both
monkeys: Along the lateral-to-medial axis the lesion started at
16 mm (L02) or 14 mm (Q02) from the foveal representation
extending laterally by 16 mm (L02) or 13 mm (Q02), up to the lip
of the calcarine sulcus (area V1 of Q02 was smaller than L02).
Along the dorsal-to-ventral axis the lesions were situated between
the lunate and the external calcarine sulcus covering a distance of
,17 mm in both monkeys. This resulted in a lower quadrant
visual field scotoma extending from ,2–7ufor both monkeys L02
and Q02. The distance of the lesion from the lunate sulcus was
,1–2 mm and may therefore have affected a small portion of the
opercular part of area V2. Independent experiments using a
meridian mapping paradigm as in [36] confirmed that the lesion
included the horizontal meridian which ensures that the entire
dorsal portion of V1 was lesioned at the specified eccentricities.
The V1 area covered by the lesions was 235 mm
2
for L02 and
198 mm
2
for Q02, representing approximately 50% of the area of
the dorsal part of central (0–7u) V1 (Figure S1). This was
confirmed histologically in monkey Q02. Histological (Figure 1B)
and radiological (Figure 1C) examination effectively ruled out the
possibility that visually driven responses in areas V2, V3 might be
due to surviving gray matter tissue within the area of the V1 lesion
itself.
During the pre-lesion experiments visual stimulation with an
expanding ring paradigm resulted in strong and reliable activation
of the entire visual cortex (areas V1, V2, V3, V4, V5/MT) with
single voxel coherence levels .0.7 and z-scores usually reaching
values of .15 (Figure 2A). Specifically the gray matter in the part
of area V1 to be lesioned showed reliable pre-lesion baseline
activity (mean z-scores of 15.6 and 17.1 for monkeys L02 and
Q02, respectively). Moreover, for both monkeys pre-lesion visually
driven modulation was strong in the retinotopically corresponding
areas of V2 (mean z-score 21.2 for L02, 17.5 for Q02) and V3
(20.4 for L02, 23.6 for, Q02), i.e. in the future lesion projection
zones. The extent of the V1 lesion (Figure S1) and its effect on the
activation of the LPZs in areas V2, V3 and on the activation of the
non-lesioned part of V1 was assessed in each subsequent
experiment, starting one month post lesion. As expected, strong
activation of non-lesioned parts of V1 was preserved throughout
the course of our experiments, whereas inside the lesioned V1 area
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coherence remained consistently at noise levels (,0.3760.13) for
all post-lesion time points (Figure S1B). It is important to note that
in both monkeys, the V1 lesion remained stable and inactive
throughout the course of all experiments.
BOLD-fMRI responses in areas V2 and V3
In the macaque monkey, the dorsal parts of areas V2 and V3
are located in the lunate sulcus [37,38,39], immediately anterior to
dorsal V1, which provides their primary input. To examine the
influence of the V1 lesion on V2 and V3 activity, we identified
retinotopically the V1-lesion projection zones (LPZ) in these areas
(i.e. we selected the regions in dorsal V2, V3 that in pre-lesion
retinotopy contain the same eccentricity information as the V1
area to be lesioned). We confirmed the accuracy of the LPZ
selections by measuring the distance of the defined V2, V3 LPZ
borders from the foveal representation and comparing them to the
predicted values derived from the extent of the V1 lesion and
previously published magnification factors for V2 and V3 [37,38].
Figure 1. Characterization of the V1 Lesion. A Picture of Macaque Q02’s brain post-mortem. The area of completely denuded gray matter and
exposed white matter, is highlighted in the picture by black dots. The dorsal border of the lesion approaches the lunate sulcus (LS) and the ventral
border reaches up to the external calcarine (eCS). Major ticks of the scale bar are in centimetres. BNissl stained axial section (100 mm thick) through
the center of Q02’s V1 lesioned cortex. Arrows point to the borders of the V1 lesion, which completely destroyed gray matter but largely spared the
underlying white matter. Note the characteristic line of Gennari indicating the border between V1 and V2 (red arrow). The V1 cortex surrounding the
lesion and the lunate sulcus (LS) containing areas V2 and V3 are not affected by the lesion. CAxial MRI slice through the visual cortex of macaque
Q02. The lesioned area is evident in the MR image due to the absence of gray matter. D3-D reconstruction of the surface of the visual cortex of
macaque Q02. The 3D rendering represents the border between gray and white matter. Some of the prominent anatomical landmarks are color
coded for easier visualization in the flat map view (see panel E). The V1 lesion shown in black was reconstructed by manually selecting the area
devoid of gray matter (panel C). Dorso-ventrally, it starts 1–2 mm ventral to the lunate reaching up to the external calcarine sulcus, and medio-
laterally from the edge of the internal calcarine sulcus to ,14 mm from the intersection of the lunate and inferior occipital sulci (*, fovea). EFlat map
of the visual cortex of Macaque Q02. Sulci and gyri are shown as dark and light regions respectively. Sulci and gyri of visual cortex are color-coded in
the same way as in the 3-D reconstruction of panel D. Abbreviations: LS: lunate sulcus, eCS: external calcarine sulcus, CS: internal calcarine sulcus, IOS:
inferior occipital sulcus, OG: occipital gyrus, STS: superior temporal sulcus Les: Lesion.
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Figure 2. Visually elicited activation of the lesion projection zones (LPZ) in areas V2 and V3. A In a pre-lesion experiment, an expanding
ring checkerboard stimulus (see Materials and Methods, gray inset) was used to obtain an eccentricity map of macaque visual cortex. Voxels within
gray matter whose coherence was at least one standard deviation above noise level (coherence .0.5, see Materials and Methods) were color-coded
according to the stimulus eccentricity that elicited the BOLD response (colored inset) and overlaid on anatomical images acquired after lesioning V1.
An axial MR-slice through the early visual cortex of macaque L02 is shown here. For display purposes, the functional data were spatially smoothed
with a 2D-Gaussian filter (FWHM =2 mm), but this was not used in the analysis and does not affect the results. White arrowheads mark the border of
the V1 lesion as seen on the anatomical scan. White bars mark the borders of the area V2, V3 LPZs. There is strong and retinotopically organized
visually driven activity throughout areas V1, V2, V3 prior to the lesion. BTo measure functional activation in the LPZ after lesioning V1, a full-field
rotating checkerboard pattern alternating with periods of background illumination was used (data from monkey L02 obtained 188 days post-
lesioning). Data display conventions are as in A, except now it is the value of the MR coherence measure that is color coded and overlaid on the
anatomical slice. As expected, the area corresponding to the anatomical V1 lesion, outlined by the white arrowheads, is devoid of significant
functional activation. However, surprisingly, visually driven activity is seen to persist inside the LPZs of both area V2 and V3. CMean percent BOLD
signal modulation (left) and mean amplitude spectrogram (right) over all voxels inside the area V2 LPZ. The stimulation frequency is displayed in red
(12 cycles). Note that there is a significant stimulus driven BOLD modulation (,0.6% peak to peak amplitude, z-score = 7.0). DSimilar to C for the V3
LPZ (z-score = 33.3).
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Similar to the extent of the V1 lesion, the LPZs in V2 and V3
covered an area equal to ,50% of the central (0–7u) dorsal V2
and V3 respectively. Figure 2A shows the baseline (pre-lesion)
retinotopic eccentricity map for an axial slice through the
macaque visual cortex overlaid on the corresponding anatomical
slice taken after lesioning. Note the excellent correspondence
between the eccentricities in the part of V1 to be lesioned (V1
region between the arrowheads) and the LPZ in area V2. The
same holds for V3, though some phases are not seen in Figure 2A
because they are out of the slice plane.
As expected, prior to lesioning the entire central sectors of areas
V1, V2, and V3 were strongly activated by the retinotopic
stimulus. This included the V1 area intended for lesioning
(Figure 2A, between the white arrows) and its corresponding
LPZs in areas V2 and V3. Figure 2B shows a map of coherence
obtained using the full-field checkerboard stimulus approximately
6 months post-lesioning. As expected there is no visually driven
activity inside the V1 lesion zone (outlined by the white arrows),
since the grey matter is absent there. However, despite lack of V1
input significant visually driven BOLD signal modulation
continues to be present inside the area V2, V3 lesion projection
zones (outlined by the white bars). Figures 2C, D (left) plot the
average time course of the mean BOLD signal, over all voxels
inside the V2, V3 LPZ respectively. Stimulation is with the
rotating full field checkerboard alternating with uniform back-
ground illumination. Note that despite the V1 lesion, significant
visually driven modulation remains in both the V2 and V3 LPZ.
This is reinforced by the mean amplitude spectrograms (Figure 2C,
D – right), which show a large amplitude peak at the stimulation
frequency (color red, 12 cycles per scan) that is significantly above
noise (z-score = 7.0 and 33.3 for V2 and V3, respectively).
We used the retinotopic stimulation paradigm to monitor the
visually driven BOLD signal modulation strength in the LPZ of
areas V2 and V3 following the V1 lesion and to compare it with
pre-lesion values. Post lesion scans shown started one month
following the lesion and proceeded up to ,22.5, ,9 months for
monkeys L02, Q02 respectively. As can be seen from the post-
lesion time points (Figure 3), although diminished, visually driven
BOLD signal modulation remains significant inside the area V2,
V3 lesion projection zones. Interestingly, activity levels did not
change systematically over time during this observation period.
We could therefore group together all time points following the
lesion in estimating the change in BOLD modulation strength that
occurs in the V2, V3 LPZ following the V1 lesion. We found that
the mean percent BOLD modulation strength inside the area V2
LPZ dropped to 17.663.2% and 31.363.2% of its pre-lesion
value for macaques L02 and Q02 respectively. The corresponding
values for the area V3 LPZ were 28.364.1% and 36.067.5% for
macaques L02 and Q02 respectively. Although clearly much
weaker than pre-lesion levels, even this reduced modulation
strength is surprising given the results from electrophysiology,
which suggest that the vast majority (.95%) of V2, V3 neurons
become inactive following transient V1 inactivation by cooling
[1,3]. There are several potential reasons for this difference which
Figure 3. Analysis of changes in signal amplitude over time. BOLD activity (Mean6SEM) inside the LPZs of area V2 (upper panels) and V3
(lower panels) are plotted up to 681 days (L02, left panels) and 277 days (Q02, right panels) post-lesioning. To account for inevitable variability in the
precise experimental/stimulation conditions across time points, BOLD signal strength is reported as percent modulation with respect to the
corresponding cortical region in the unlesioned hemisphere, and is normalized by the pre-lesion value of this quantity (see Materials and Methods).
Visually driven activity persists inside the LPZs of area V2 and V3 following the V1 lesions, though it is significantly reduced compared to pre-lesion
levels. On average activity drops to ,20–30% of pre-lesion levels. We observed no consistent increase of the visually driven activity over time from
one month post-lesion until the last point checked (681 days).
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we will discuss in more detail below (see Discussion), including the
different potential sources of the electrophysiological versus the
BOLD signal, as well as the potential manifestation of cortical
reorganization processes that are not present in the transient
cooling studies. In any event, we can conclude that: 1) as expected,
area V2, V3 activity is strongly dependent on area V1 input, yet 2)
both areas V2 and V3 can be visually modulated even in the
absence of retinotopically corresponding V1 input.
To understand how the V2, V3 LPZ activity arises independent
of retinotopically matching V1 input, we studied the eccentricity
organization of the lesioned hemisphere and compared it to the
non-lesioned hemisphere. We used the expanding ring stimulus
paradigm (Figure 4A, Materials and Methods) to derive eccen-
tricity maps in areas V1, V2, V3. The eccentricity maps of these
areas in the non-lesioned hemisphere (Figure 4B) proved to be
stable over time and remained commensurate to the maps
obtained pre-lesion (Figure 2A), as well as to maps reported in
the literature [40]. Figures 4C and 4D show the eccentricity map
in the lesioned hemisphere of monkeys L02 and Q02 respectively,
overlaid on the anatomical flat map (Materials and Methods). The
lesion area has been defined anatomically by the absence of gray
matter (as well as functional signal). Confirming the observation of
a preserved cortical organization in a human blindsight subject
[30], our data from V1 lesioned monkeys also demonstrate that
the retinotopic structure of V1 cortex surrounding the lesion has
not changed (Figure 4). Figures 4C,D show further that the BOLD
signal inside the LPZs of both areas V2 and V3 remains
retinotopically organized and, surprisingly, contains eccentricities
corresponding to the lesioned V1 region (see also Figure 5). That
is, eccentricity information not present in the lesioned portion of
dorsal V1 (green and cyan phases corresponding to ,3–5u
eccentricity) is preserved inside the LPZs of areas V2 and V3
Figure 4. Eccentricity maps in non-lesioned versus lesioned cortex. A Expansion of the rotating checkerboard ring stimulus (gray inset) over
time results in a phase shift of the BOLD response, which can be used to extract eccentricity information (Materials and Methods). Voxels with similar
eccentricity information are color-coded (colored inset) and superimposed on the anatomical flat maps. BOrganization of macaque L02’s left, non-
lesioned visual cortex 681 days post-lesion. For display purposes all data in this Figure have been spatially smoothed with a 2D-Gaussian filter (2 mm
FWHM). Only voxels in gray matter with coherence exceeding one standard deviation above the single-voxel noise level of coherence (Materials and
Methods) are displayed. This stimulus proved effective in evoking phase-locked responses from the fovea (red, * sign) up to about 9u(purple)
eccentricities in V1, V2/V3, V3A, V4, and V5/MT+. Boundaries between dV1 dV2, dV3 and V3A were derived by mapping the visual meridians in
independent experiments and are indicated here by the black lines. COrganization of macaque L02’s lesioned (right) visual cortex 681 days post-
lesion. Visual areas were identified as described in panel B. The lesion could be easily identified by the absence of gray matter as seen in a high
resolution anatomical sequence MRI scan (Figure 1). It is located in the dorsal part of V1 representing the lower part of visual space in the
contralateral quadrant and extending from ,2to7ueccentricities. The lesion projection zones (LPZ) could be also easily identified in the dorsal parts
of V2 and V3, using retinotopic correspondence criteria (Figure 2A, Materials and Methods). Note that despite the absence of direct retinotopically
corresponding area V1 input, voxels in the LPZs of areas V2 and V3 exhibit retinotopically organized responses. DOrganization of macaque Q02’s
lesioned (right) visual cortex 277 days post-lesioning. Extent of the lesion and retinotopically organized responses inside the LPZ of V2 and V3 are
similar to monkey L02.
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despite missing from their direct area V1 input. To further
illustrate the relationship between V1, V2, and V3 in representing
the visual field containing the lesion, we quantified the percentage
of voxels between 2uand 7uwith coherence .0.5 relative to the
total number of voxels per area and compared these measures for
the lesion-ipsilateral (red bars) and lesion-contralateral (black bars)
hemispheres (Figure 5). Across monkeys and visual areas between
50 and 75% of the voxels representing the visual space between 2u
and 7uexceeded coherence .0.5 in the non-lesioned hemisphere.
The lesion in V1 resulted in the virtual absence (,3%) of supra-
threshold voxels in this part of the visual field. Yet despite lacking
direct dorsal V1 input from within this eccentricity range, 12 to
68% of voxels between 2uand 7uin areas V2 and V3 reached
coherence .0.5. Therefore, information about the visual world
not represented in the preserved portion of dorsal area V1,
nevertheless reaches dorsal areas V2 and V3. This suggests that: 1)
the activity observed inside the area V2, V3 LPZs cannot arise as a
result of input arising from dorsal V1 locations that lie outside the
lesion (as might occur if the observed activity were due to a
subpopulation of V2, V3 cells with large receptive fields reaching
outside the lesioned area), and 2) the observed visual modulation
in the LPZ of areas V2, V3 must be driven by retinotopically
organized cortical or subcortical areas.
To investigate whether the retinotopic organization of areas V1,
V2, V3 is changed (e.g. reorganized) after V1 lesioning, we
compared visual eccentricity versus cortical distance plots
(Materials and Methods) across these areas both in the lesioned
and the intact hemispheres. Figure 6A shows these plots in area V1
for monkeys L02 and Q02. The V1 lesion starts at the dashed lines
(.2ueccentricity), and the color of the graph denotes whether the
plot is derived from the lesioned (red) or the non-lesioned (black)
hemisphere. There is excellent overlap of the eccentricity versus
distance curves in foveal V1, outside the area of the lesion,
suggesting that the magnification factor remains unchanged in
nearby V1 cortex following the lesion. As in area V1 little, if any,
magnification factor change is seen outside the LPZs in areas V2,
V3. Overall, the eccentricity versus distance plots in area V2, V3
of the lesioned hemisphere follow the trend seen in the intact
hemisphere, though small but significant deviations are noted from
the expected pattern inside the region of the LPZs (Figure 6B).
Note that although eccentricity information arising beyond ,2uis
absent from dorsal area V1 after the lesion (Figure 6A), it
nevertheless persists in the LPZ of areas V2, V3 (Figure 6B, 6C).
Figure 5. Percentage of supra-threshold voxels within 2–7ueccentricities across dorsal V1, V2, V3. A Data from macaque L02, 681 days
post-lesioning. The bar height corresponds to the percentage of voxels within eccentricities 2–7uwith coherence at least one standard deviation
above the noise levels (Materials and Methods) relative to the total number of voxels sampled per area 0–7u. Black versus red bars correspond to data
derived from the non-lesioned versus lesioned hemispheres, respectively. The effect of the lesion is manifest by the nearly complete absence of
significantly activated voxels between eccentricities 2–7uin V1 of the lesioned hemisphere. The percentage of voxels within the same eccentricity
range in areas V2 and V3 LPZs (red bars) remains below normal levels (black bars), but is markedly increased compared to the percentages measured
in the lesioned part of V1. BSimilar bar plot for macaque Q02, 188 days post-lesioning. Note that this animal had a weaker but still clear visual
modulation response inside the V2, V3 LPZ.
doi:10.1371/journal.pone.0005527.g005
Figure 6. Eccentricity versus cortical distance plotted across
areas V1, V2, V3, in both the lesioned (red lines) and the non-
lesioned (black lines) hemisphere. Data were obtained from
macaques L02, 681 days (left panels) and Q02, 188 days (right panels)
post-lesioning. AEccentricity versus distance curves in dorsal area V1.
The dashed line indicates the foveal border of the lesion. In both
monkeys, beyond ,2uno eccentricity information is present in dorsal
V1. Data represent Mean+/2SEM from 10 iso-angle, radial ROIs
(Materials and Methods). BEccentricity versus distance curves in area
V2. Conventions are as in (A). Data represent Mean+/2SEM from 10 iso-
angle radial ROIs. CEccentricity versus distance curves in area V3. Data
represent Mean+/2SEM from 4 iso-angle, radial ROIs. Note that the V1-
Lesion projection zones in areas V2, V3 retain the representation of
eccentricities that are not present in their dorsal V1 input.
doi:10.1371/journal.pone.0005527.g006
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This suggests that the observed responses are mediated via
retinotopically organized subcortical or cortico-cortical (feedback
or callosal) connections, which continue to have access to the
appropriate eccentricity information.
In an fMRI study on human blindsight subjects, Goebel et al.
reported that responses in areas V4 and V5/MT of the lesioned
(but not the non-lesioned) hemisphere could be driven by
stimulation in the ipsi-lesional visual field [29], which suggests
that callosal input may play a role. However, callosal input is not
likely to play a major role in our study since in areas V2, V3 it
tends to concentrate near the vertical meridians [39,41,42] while
the responses displayed in Figure 4 appear to occur over the entire
V2, V3 LPZ regions spanning the cortex from vertical to
horizontal meridians. In addition, visual stimulation restricted to
the ipsi-lesional visual field (visual field projecting to the intact
hemisphere) did not evoke significant activity inside the area V2,
V3 LPZs, despite being able to drive retinotopically corresponding
regions in the intact hemisphere (Figure 7) This strongly suggests
that callosal input does not play a critical role in the generation of
the observed patterns of activity.
The amplitude of visually driven BOLD signal modulation
inside the V2, V3 LPZ (20–30% of pre-lesion levels) is surprising in
light of transient inactivation studies [1,2,3], which report that
neuronal activity is suppressed in more than 95% of sampled V2,
V3 sites. Since, under usual stimulation conditions the BOLD
signal correlates well with multi-unit activity in the neocortex
[32,33,43,44,45,46], one might have expected the strength of the
BOLD signal modulation inside the V2, V3 LPZ to fall to less than
5% of its pre-lesion value, as opposed to the ,20–30% we report
here. However, the BOLD signal does not simply reflect multi-unit
activity, but it also depends on sub-threshold synaptic currents, as
reflected in the local field potential [32]. It therefore remains
possible that the BOLD signal responses we observe here may in
part reflect subthreshold synaptic events, not directly reflected in
the recordings of prior transient inactivation studies [1,2,3].
Multi-unit activity in area V2
To directly confirm that the observed BOLD signal responses
accurately reflect modulation in the underlying multi-unit spiking
activity we performed two electrophysiology experiments in the
one remaining animal L02 (monkey Q02 was euthanized for
histological evaluation of the lesion). The position of the electrode
in the posterior bank of the lunate sulcus (LS) was directly
monitored in relation to the V2 LPZ by MRI. In the first
experiment, we recorded from 7 sites along 3 different electrode
tracks (Figure 8A, B), all located deep in the interior of the V2
LPZ. In the second experiment (Figure 8C) we recorded from 7
cortical locations spanning the V2 LPZ border (5 inside, 2 outside
the V2 LPZ), at two cortical depths per electrode (one superficial,
one deep separated by ,500 mm). Two additional sites, two
depths each, were recorded from the V2 of a non-lesioned animal
at eccentricities commensurate to the V2 LPZ (Figure 8C, right
lower quadrant, Exp #3). Remarkably, multi- unit activity
minimal response fields could be mapped manually at each site
inside the V2 LPZ (Figure 8B, C), using small (0.5
0
61
0
) bar stimuli
at different orientations flashing or moving perpendicular to their
axis. There receptive fields were more weakly driven but much
larger than corresponding receptive fields obtained in non-
deafferented V2: for example, receptive field #4 (8B) is
approximately 6
0
65
0
, while receptive field #7 (8C) is not only
large but bipartite. It is important to point-out that visual
responses could be elicited even when the stimulus lay entirely
inside the scotoma induced by the V1 lesion, strongly suggesting
that activity inside the V2 LPZ arises through subcortical channels
that bypass the V1 input. We also measured the multi-unit activity
modulation elicited by the full field (26
0
620
0
) checkerboard
stimulation we used in the fMRI experiments (Materials and
Methods). Figure 8D plots the mean multi-unit activity modulation
at one representative penetration in the interior of the V2 LPZ.
The amplitude of the mean visually driven multi-unit activity
modulation across all recording sites in the interior of the LPZ (17
Figure 7. Activation maps obtained by restricting the stimulus to the unaffected (ipsilateral to the lesion) visual field. A rotating
checkerboard stimulus extending from 3uto 13uwas presented for 30 seconds in the ipsi-lesional visual field alternating with 30 second periods of
uniform illumination. The data presented here were obtained from one scan in monkey L02. AFunctional activation map of the left, non-lesioned
hemisphere. Note that the stimulus was effective in evoking significant activity in the retinotopically matched control areas corresponding to the area
V2, V3 LPZs. BActivation map of the right, lesioned hemisphere. The stimulus did not evoke significant visual modulation responses inside the LPZs
of areas V2 and V3.
doi:10.1371/journal.pone.0005527.g007
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Figure 8. Electrophysiological measurements inside the V2 LPZ. A The left panel shows a parasagittal slice of an anatomical MR scan of
macaque L02. The red arrows show the borders of the V1 lesion in this plane. The red-dashed line represents the position of the image plane shown
on the right. In the right panel, the recording electrode can be seen to penetrate the lesioned portion of area V1 and lie with its tip (brown arrow)
located in V2 near the fundus of the lunate sulcus (LS), where the horizontal meridian representation separates areas V2 and V3. The red arrow tips
mark the boundary of the V1 lesion in this plane (from ,2
0
eccentricity to near the midline, see Figure 2). The white dotted line outlines the cortical
gray matter located in the lunate sulcus, whose posterior bank corresponds to area V2. The yellow dotted line outlines the dural boundary. Note that
the yellow and the white dotted line come together near the lateral red arrow, marking the end of V1 gray matter and the beginning of the lesion.
During the penetration shown, multi-unit activity (MUA) was recorded from 4 different electrode positions (positions 1 to 4 shown in panel b).
Recordings were first performed in position 1 (brown arrow in the lunate fundus) and then the electrode was stepwise withdrawn 500 mm at a time,
until it exited gray matter (total distance travelled ,2 mm). Positions 2, 3, and 4 traverse the posterior bank of the lunate, positioned solidly inside
the V2 LPZ. Retracting the electrode beyond position 4 led it to exit gray matter, a further confirmation that the corresponding portion of V1 had
been completely lesioned (this has also been visualized anatomically with a high resolution MR image, and confirmed functionally –see Figure 1C, 2B,
4C). (*) marks the foveal representation in V1. LS =Lunate Sulcus, STS = Superior Temporal Sulcus, A = Anterior, P = Posterior, D = Dorsal, V = Ventral. B
Receptive field (RF) maps of multi-unit activity (MUA) recorded during the penetrations illustrated in panel A, (positions 1–4 in panel B), and during
two separate, more lateral penetrations inside the V2 LPZ (receptive fields 5, 6). RFs were mapped manually using small oriented bars
(width6length = 0.5
0
61
0
); see Materials and Methods). Note that electrode location #1 yields a receptive field map close to the horizontal meridian
(as expected from the electrode position in the lunate fundus near the border between V2, V3). Locations 2,3,4 of the same tract were situated
squarely in area V2, on the posterior bank of the lunate sulcus and the corresponding multi-unit receptive fields lie closer to the vertical meridian.
Note that receptive fields overlap with the LPZ of fMRI maps (Figures 4 & 6), but are not necessarily confined to it. Importantly, responses could be
elicited even when visual stimulation was entirely restricted within the scotoma confirming that they arise via a subcortical pathway that bypasses
area V1. CMulti-unit RF-plot obtained from a linear array of 8 electrodes during a separate experiment from the same V1-lesioned animal as in panel
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sites from two experiments) was ,30% (p = 0.01, one tailed,
paired samples t-test) compared to baseline (Figure 8E). It is then
clear that the difference between our observations and the results
of transient inactivation studies based on electrophysiology [1,2,3]
cannot be discounted based on the BOLD signal’s sensitivity to
subthreshold synaptic activity.
In summary, our results confirmed that activity in areas V2 and
V3 is strongly dependent on input from area V1. Despite this
however, both areas V2 and V3 show significant visual modulation
following the chronic absence of retinotopically matched V1 input.
This contrasts with reports from transient V1 inactivation studies
[1,2,3], suggesting that visually driven activity inside the V2, V3
LPZ may be the result of neural reorganization (for example
increased gain control in subcortical pathways projecting to areas
V2, V3) following chronic V1 lesions. If so, this likely occurs within
the first month post-lesion since BOLD signal modulation strength
does not change systematically from 1 to 22 months post lesion.
Surprisingly, V1-lesion projection zones in areas V2, V3 retain the
representation of eccentricities eliminated from their direct V1
input. Inputs from the intact dorsal V1-lesion surround or from
the contralateral hemisphere through the corpus callosum do not
appear to mediate the residual responses.
Discussion
We monitored visually driven responses in macaque areas V2
and V3 over several months following the induction of area V1
lesions. In contrast to previous studies that examined single- or
multi-unit activity in dorsal V2, V3 following reversible cooling of
V1 [1,3,25], we found that visually driven activity in V2 and V3
deprived of input from retinotopically corresponding V1 locations
was not completely silenced, though it dropped to ,20–30% of
pre-lesion levels. This level of activation did not change
systematically during the period examined here (1 to 22 months
post-lesioning). Interestingly, in spite of the observed reduction in
BOLD response amplitude, the retinotopic organization of areas
V2, V3 remained similar to before the lesion. Electrophysiological
recordings of multi-unit activity inside the V2 LPZ corroborated
the return of significant visual modulation that was observed using
the BOLD signal. In what follows, we discuss our results in the
context of the existing literature and speculate on what pathways
mediate the activity that persists following the V1 lesions.
V2 and V3 activity in the absence of V1 input
The persistence of V2 and V3 responses despite missing V1
input may not be surprising from an anatomical point of view:
There are several V1-bypassing connections to macaque areas V2
and V3 which originate in subcortical (for example: LGN or
inferior and lateral Pulvinar nuclei) as well as cortical (for example:
callosal input, V4 or V5/MT feedback) structures
[41,42,47,48,49,50,51,52,53,54,55,56]. Nevertheless, studies in
which single- or multi-unit activity was recorded in the minutes
following transient inactivation of V1 by cooling report that .95%
of V2, V3 sites stop responding entirely to the visual stimulus
[1,3,25]. This contrasts with the 20–30% residual BOLD signal
amplitude modulation we report here. Electrophysiology experi-
ments in one animal corroborated the fMRI results, confirming a
different picture than transient inactivation studies: i) all 17 multi-
unit sites recorded inside the V2 LPZ could be visually modulated
using small (0.5
0
61
0
) oriented bar stimuli, and ii) the resulting
multi-unit receptive fields were all unexpectedly large, and in one
occasion bipartite (Figure 8). While these results seem at odds with
earlier studies of V2 and V3 responses following transient V1
inactivation [1,3,25], similar results have been obtained for area
V5/MT [19,22]. There are at least two factors that may explain
the differences between the earlier V2/V3 findings and the results
of the present study:
1. The positive V2/V3 responses we report here were first
observed 1 month after lesioning area V1 whereas the earlier
studies report V2/V3 responses immediately (minutes to hours)
after V1 cooling [1,3,25]. Therefore the stronger V2/V3
activation observed in our study may reflect a degree of
reorganization occurring within the first month following the V1
lesion (see also Figure S2). This postulated reorganization might be
due to a strengthening of V1-bypassing inputs (e.g. from the
thalamus or the Pulvinar) from modulatory to driving. Early
reorganization notwithstanding, our data argue that little if any
spontaneous reorganization occurs after one month post lesion:
Specifically, we did not observe a significant systematic increase in
the strength of the visual responses recorded inside the lesion
projection zones of neither V2 nor V3, from 1 month up to 22
months post-lesioning (Figure 3). Moreover, during this time, there
was no systematic change in the eccentricity versus cortical
distance curves of the lesioned compared to the non-lesioned
hemisphere, which is another way that plasticity may manifest
[23,57]. 2. On a more technical note, it is possible that the cooling
inactivation applied in the earlier electrophysiological studies may
have inadvertently inactivated V1-bypassing fiber connections
coming to V2/V3 from subcortical structures, which might in
effect have resulted in double de-afferentiation of these areas and
may have contributed to rendering V2, V3 cells unresponsive.
Although our lesioning method (aspiration) may also in principle
undercut direct inputs to V2, V3 this would tend to decrease V2,
V3 responses, rendering the measurements we report here an
underestimate of the true visual modulation strength.
Flow of visual information in the absence of V1
Human patients and monkeys with area V1 lesions, despite
reporting being blind within the affected part of the visual field,
can nevertheless retain certain visual capacity under specific
B. Electrode number 3 broke on entry and recorded no multi-unit activity. Multi unit receptive fields from the interior of the LPZ (sites 4–8) are
represented by solid lines, whereas receptive fields obtained outside the LPZ, in non-deafferented V2, by dashed lines (control sites 1,2). Two multi-
unit receptive fields illustrated in the right inferior quadrant were obtained from a monkey without a V1 lesion (control exp #3). Note that multi unit
receptive fields obtained inside the V2 LPZ are much larger than those obtained at similar eccentricities in non-deafferented V2 cortex, and on one
occasion (electrode #7) bipartite. Receptive fields obtained at a second cortical depth (500 mm away) for each electrode penetration were found to
be commensurate. Here only one set is illustrated. DMulti unit activity peri-stimulus-time-histogram (PSTH) centered at the onset of full-field visual
stimulation (Materials and Methods) recorded from electrode position 5 (panel B). The signal was high-pass filtered at 312 Hz and thresholded at 3
standard deviations beyond the mean. Each bar height corresponds to the spike rate calculated within 100 ms bins, and averaged over 10 stimulation
cycles. The multi-unit firing rate at this position increases by more than 50% when the stimulus is on. ESummary of multi unit activity elicited from all
recording locations shown in panels B and C inside the V2 LPZ. To elicit visual responses under the same conditions as in the fMRI experiments
(Figure 2 B), the same full field rotating checkerboard stimulus was alternated with periods of background illumination. On average, MUA increased
by ,30% during visual stimulation (p = 0.01, one-tailed paired-samples t-test) compared to baseline.
doi:10.1371/journal.pone.0005527.g008
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conditions (‘‘blindsight’’) [6,58]. This raises the question of how
such ‘‘blindsight’’ might be mediated in the brain. One step in
trying to map potential neural pathways that may mediate various
aspects of the phenomenon of blindsight is to study the patterns of
extrastriate cortical activity in the absence of V1 input, as was
done here. Although the prevalent view is that blindsight may be
mediated by activity in higher cortical areas such as V5/MT
[27,28,29], it is clear from the data we present here that, visually
driven activity in the absence of V1 input also persists in early
extrastriate areas V2 and V3, which may therefore contribute to
this phenomenon.
Although our data strongly argue that areas V2 and V3 are
capable of contributing to V1 independent visual processing, the
specific pathways that mediate the V1-independent responses in
these areas remain unclear. One possibility is that the residual
visual modulation is mediated via callosal connections [41,42,56]
from the non-lesioned hemisphere. However, activity in the V2
and V3 LPZs could not be evoked when restriciting visual
stimulation to the intact visual hemifield (Figure 7). Thus it
appears that activity in early extrastriate cortex devoid of V1 input
must come about through V1-bypassing subcortical channels,
potentially also involving feedback from higher areas. The
strongest argument that V1-bypassing subcortical channels must
be involved in generating the observed V2, V3 activity is provided
by multi-unit receptive field maps recorded inside the V2 LPZ
(Figure 8). Specifically, multi-unit activity at recorded V2 sites was
clearly modulated by the visual stimulus (0.5
0
61
0
oriented bars)
even when the latter was entirely contained within the scotoma
corresponding to the V1 lesion.
The superior colliculus receives input from ,10% of the retinal
ganglion cells in its superficial layers [59], and has been shown to
be important for mediating activation in extrastriate cortex.
Residual responses observed in V5/MT [60] and STP [26]
following V1 lesions could be completely silenced by lesioning the
ipsilateral superior colliculus. The lateral geniculate nucleus (LGN)
and the Pulvinar both receive collicular input and show retinotopic
organization [61,62]. LGN cells project directly to areas V2, V4,
and V5/MT [51,52,54,63]. Specifically for area V2, recent
evidence suggests that projecting cells in the LGN are primarily
located in the intercalated layers, in which cells of the koniocellular
type predominate [51,63] and which receive at least part of their
input from the superficial layers of the superior colliculus [64].
Alternatively, or perhaps additionally, residual extra-striate activity
could be mediated through the Pulvinar. The importance of the
Pulvinar for extrastriate cortex activation is still not entirely clear,
yet anatomical projections from the Pulvinar to areas V2, V3,
V3A, V4, V5/MT, and V5/MT [47,48,65,66] suggest that it
plays a potentially important role in visual processing. With
respect to V2 and V3, not much is known, though it has been
shown that the responses of V2 neurons can be modulated by
input from the Pulvinar [67]. It remains to be seen however
whether Pulvinar input is capable of activating area V2, V3
neurons in the absence of V1 input.
An important question that remains is whether higher cortical
areas, particularly those with fast response latencies (such as V5/
MT or FEF) play a role in generating the persisting activity in
areas V2, V3 after V1 lesions. For example, activation of area V5/
MT mediated by superior collicular inputs [60] through the
Pulvinar [68] or the LGN might, through existing feedback
projections to V2 and V3 [49,53], generate the activity patterns we
observe there. Such a scenario is theoretically possible also for area
V4 given the existence of feedforward anatomic connections from
LGN [54] and Pulvinar [47,65] to this area, as well as feedback
connections from V4 to V2, V3 [50,55]. At present we cannot
definitively distinguish between i) direct, V1-bypassing, subcortical
inputs to V2, V3 versus ii) indirect, V1-bypassing, subcortical
inputs reaching V2, V3 via feedback pathways from higher areas,
as a source of the observed activity.
Finally, we would like to note that time elapsed following the
lesion may turn out to be of critical essence: Although our results
suggest that activation levels in V2 and V3 remain stable from 1 to
22 months post-lesioning, when compared to the results of
transient inactivation studies [1,3,25] they also suggest that
plasticity processes operating within the first month post lesion
likely play a role in modulating the gain of cortical networks
responsible for the observed activity. Furthermore, these processes
may be strongly dependent on behavioral training [8,10], which
we did not explore here.
In summary, our results reveal that V2 and V3 can process
visual information in the absence of retinotopically corresponding
V1 input, and point to V1-bypassing subcortical structures as the
likely pathway for generating the persisting patterns of activity in
early extrastriate cortex. Defining the precise pathways involved
and how plastic or amenable to behavioral modification they are
will be the aim of future studies. The cortical networks mediating
the phenomenon of blindsight remain to a large extent a mystery
to date, but our results lend credence to the belief that areas as
early as V2 and V3 may potentially contribute to this
phenomenon. Finally our study demonstrates the potential
promise of macaque fMRI for the serial, non-invasive, in-vivo,
monitoring of cortical organization following controlled nervous
system injury.
Materials and Methods
Mri data collection
Measurements were made on a vertical 4.7 T scanner with a
40 cm diameter bore (Biospec 47/40v, Bruker Medical, Ettlingen,
Germany). The system was equipped with a 50 mT/m (180 ms
rise time) actively shielded gradient coil (Bruker, B-GA 26) of
85 mm inner diameter. A radiofrequency coil with an inner
diameter of 85 mm was placed over the monkey’s occiput to
acquire images from visual cortex. To optimize homogeneity of
the MR signal from the visual cortex, Fastmap-shimming [69] of
this area was performed using an 18618618 mm
3
box.
Acquisition of functional data was performed using 8-shot
gradient-recalled EPI [70,71] with a voxel resolution of
16162mm
3
(17 slices, FOV = 128 mm6128 mm, Ma-
trix = 1286128, TR = 8 shots6750 ms, TE = 20 ms, FA = 40
deg). Within-session anatomical images (0.560.562mm
3
resolu-
tion) were acquired using either IR-Rare (Hahn Spin-Echo with
Rare-Factor) or Mdeft sequences [35]. Whole-brain anatomical
images were acquired using the 3D-Mdeft sequence [34] (128
slices, 0.560.560.5 mm
3
resolution) and were used for co-
registering data from different experiments.
Animal Preparation
Two healthy adult macaca mulatta (Q02, L02), older than 4
years (weight: 6–8 kg), were used for the experiments. All sessions
were in full compliance with the guidelines of the European
community for the care and use of the laboratory animals (EUVD
86/609/EEC) and were approved by the local authorities
(Regierungspra¨sidium).
Surgical operations were performed following standard surgical
procedures described elsewhere [31]. To lesion V1, the skull was
opened under sterile conditions over the occipital gyrus, and the
dura was reflected. Pial vessels over the intended lesion area were
coagulated and low suction aspiration was applied via a 20 gauge
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catheter until white matter was reached (,1.8 mm from the
cortical surface). The lesions reached medially to within ,2mmof
the internal calcarine sulcus, dorsally to ,2 mm from the lunate
sulcus, and exended ventrally to include the external calcarine
fissure. The extent of the lesions was 13617 mm (monkey Q02)
and 16617 mm (monkey L02) along the medial to lateral and
dorsal to ventral axes, respectively. After waiting for hemostasis to
set in, the dural flap was sutured back in place. Finally the bone
flap was put in place and secured via sutures and CalcibonH
(Biomet, Merck, Berlin, Germany).
FMRI experiments were done under general anesthesia
according to previously published protocols [31,33]. In brief, the
animal was intubated after induction with fentanyl (31 mg/kg),
thiopental (5 mg/kg) and succinylcholine chloride (3 mg/kg) and
anesthesia was maintained with remifentanyl (35 mg/kg/h).
Mivacurium chloride (6 mg/kg/h) was used after induction to
ensure complete paralysis of the eye muscles. Lactate Ringers with
2.5% glucose was infused at 30 ml/h. For monkey L02 10 mg
Phenylephrine were diluted in 500 ml Lactate Ringer and dialled
at ,10 ml/h (0.2 mg/h) to maintain systolic blood pressure at
constant levels (Mean6Std for systolic/diastolic: 101612/5469)
throughout the experiment. The temperature was maintained at
38–39.5 Cu. After achieving mydriasis with two drops of 1%
cyclopentolate hydrochloride, each eye was fitted with hard
contact lenses (Harte PMMA-Linsen Firma Wo¨ hlk, Kiel, Ger-
many) to bring it to focus on the stimulus plane (,2 diopters).
Following the end of the fMRI experiments animal Q02 was
sacrificed by a lethal injection (60 mg/kg) of Pentobarbibal (the
second animal (L02) is still involved in follow up experiments so
the extent of its lesion was confirmed radiologically). After
transcardial in vivo perfusion (0.4% paraformaldehyde pH 7.4,
in 0.1 M phosphate buffer solution), the brain was quickly
removed and placed in 30% sucrose solution in phosphate buffer.
100 mm thick sections were cut on a cryotome, mounted on slides
and dried overnight at 39uC. Sections were then stained in Cresyl
Violet solution for 1–2 min and dehydrated in a series of ethanol
(50–100%), Butanol and Xylene for 5 minutes each. Finally they
were coverslipped with DePex (SERVA, Heidelberg, Germany)
and studied under a microscope.
Two electrophysiology experiments were performed, under
anesthesia, on animal L02 at the end of the fMRI experiments (.2
years post-lesioning). An MR-compatible recording chamber
made of PEEK was implanted over the monkey’s primary visual
cortex to overlap extensively with the V1 lesion. In experiment 1,
electrodes (Platinum-Iridium, 1–2 MVimpedance), were lowered
under direct MRI visualization to reach the interior of the V2 LPZ
in the posterior bank of the lunate sulcus. During this experiment,
recordings were made from 7 different sites with 3 different
recording tracks. In a second experiment a linear array of 8
electrodes (Tungsten, 1–2 MVimpedance), spaced at 1 mm
intervals, was placed across the LPZ border through a recording
grid whose positioning was later confirmed in a separate MRI
session. Two cortical depths (one superficial, one 500 mm deeper)
were mapped per penetration. Receptive field maps at different
depths were commensurate.
Visual stimulation
Visual stimuli were presented using an SVGA fiber-optic system
(AVOTEC, Silent Vision) with 6406480 resolution and a 60 Hz
frame rate. The field of view was 26uhorizontal620uvertical
visual angle. All stimulation was done monocularly. Care was
taken to align the center of the stimulus to the fovea.
The basic stimulus pattern used in all experiments consisted of a
polar checkerboard pattern (,3.5 Hz visual modulation at 100%
contrast). The direction of rotation reversed every 1.5 sec to avoid
adaptation. A full-field (26uhorizontal620uvertical) version of this
stimulus (30 s presentation) alternating with periods of uniform
illumination (30 s) was used for the data presented in Figure 2B.
Retinotopic mapping was done using the expanding rings
paradigm [40,72]: We used annuli with a width of 1.5uwhose
outer radius expanded from 1.5uto 9u(11 annuli) in steps of 0.75u
(Figure 2A). Each annulus was presented for 6.0 s ( = 1 TR) and
the entire sequence of annuli was repeated 12 times per scan. This
stimulus paradigm has been shown to activate well early visual
areas in the macaque [33,40]. For the data presented in Figure 7,
the checkerboard stimulus extended from 3uto 13uand was
restricted to the intact (ipsilateral to the lesion) visual field. This
stimulus was presented for 30 s alternating with 30 s periods of
uniform intensity (background) illumination.
For electrophysiological recordings, minimal multi-unit re-
sponse fields were mapped manually using oriented bar stimuli
(width6length = 0.5
0
61
0
). Mapping was performed after waiting
for 30–60 minutes for the signal to stabilize. Finally we also
applied the same full-field checkerboard stimulation paradigm as
during the fMRI-sessions (see Materials and Methods), albeit with
shorter (10 s) stimulation (ON) and background (OFF) periods.
Data analysis
We used the mrVista software (http://white.stanford.edu/
software) for data analysis. In a typical experiment 5 to 10 repeats
of the expanding ring stimulation paradigm were performed and
the average BOLD signal time course was generated. Using the
average time course, we then assessed the strength of the BOLD
signal in each voxel independently by using the measure of
coherence [33,40,72]:C~Af
0
ðÞ
P
f0zDf=2
f0{Df=2
AfðÞ
2
!
1=2, where f
0
is the
stimulation frequency, A(f
0
) the amplitude of the BOLD signal
at that frequency, and Df (noiseband) a range of frequencies
around the fundamental (f
0
). For the stimuli that we used, f
0
corresponded to 12 cycles per scan and Df was chosen to be a
bandwidth of 6 cycles (that is from 9 to 15 cycles) centered at f
0
.
Note that the noise level of coherence depends on the chosen
bandwidth. So that for Df = 6 cycles under the assumption of a
white noise distribution, the noise level of coherence (the
coherence value in the absence of visual modulation) is expected
to be 1/(Df+1)
0.5
= 0.38. In agreement with this estimate, the noise
level measured in a rectangular ROI outside the brain, in muscle,
or in non-stimulated parts of cortex reached a coherence level of
0.3760.13 (mean6std). This noise level proved to be stable across
monkeys and experiments.
Functional activation maps were plotted using a coherence
threshold of 0.5 corresponding to 1 standard deviation above the
mean single-voxel noise level, and were co-registered with and
overlaid on high-resolution anatomical maps. To visualize activity
located in cortical sulci, cortical flat maps were constructed by
using the mrGray software to segment gray/white matter and
flatten the visual cortex [73]. The functional activity of gray matter
voxels was overlaid onto the flat maps. For display purposes (but
not for the quantitative analysis), functional data shown in
Figures 2, 4, and 6 have also been smoothed with a 2D-Gaussian
spatial filter (FWHM = 2 mm, i.e. 2 voxels).
In order to quantify the strength of visual stimulation inside the
area V2, V3 LPZs (Figure 3), the amplitude of the mean BOLD
signal over the LPZ at the stimulation frequency (f
0
) minus the
mean amplitude in the noiseband (excluding the stimulation
frequency) was normalized using a retinotopically matched control
V2/V3 Activation without V1
PLoS ONE | www.plosone.org 12 May 2009 | Volume 4 | Issue 5 | e5527

ROI in the intact hemisphere:
Anorm:LPZ~
ALPZ f0
ðÞ{P
Noiseband
ALPZnNoiseband

AControl f0
ðÞ{P
Noiseband
AControl nNoiseband

In the expanding ring paradigm the visual stimulus is displayed
in different spatial locations over time which translates into a
BOLD signal phase shift in correspondingly activated cortical
voxels. Information about the maximum stimulus expansion (9u)in
one cycle of stimulation (2p) was used to convert the radian phase
value (W) of each voxel into the corresponding eccentricity
information:
Ecc~90|
W
2p
The eccentricity information over all active voxels could then be
used to plot the representation of eccentricity information in visual
cortex as a function of distance (Figures 2, 4–6). To plot the
eccentricity versus cortical distance functions (Figure 6) for visual
areas V1, V2, and V3, we selected from the smoothed flat maps
(Figure 4) 4 (V3) or 10 (V1, V2) iso-angle, radial, ROIs extending
from the fovea to 4–5ueccentricity near the center of the lesion,
and sorted the contributing voxels according to their distance from
the foveal representation.
To measure multi-unit activity (MUA) the recorded signal was
high-pass filtered at 312 Hz and thresholded at 3 standard
deviations beyond the mean. Spike rates were measured in bins of
100 ms (Figure 8D). To compare the mean MUA between
stimulus (ON) versus background (OFF) periods (Figure 8E), for
each experimental run the spike rate 3 seconds before and after
stimulus onset were averaged across 10 stimulation cycles.
Supporting Information
Figure S1 Stability of the V1 lesion. The V1 lesion could be
easily identified in each experiment from the anatomical
(MDEFT) MR images by the absence of gray matter. A..The
number of voxels defining the lesion was plotted over time for
monkeys L02 (left) and Q02 (right). B. The mean coherence over
all voxels within the lesion was plotted over time for monkeys L02
(left) and Q02 (right). The dashed line corresponds to a coherence
level of 1 std.mean noise levels (see methods). The lesion
remained stable and inactive over the entire time period.
Found at: doi:10.1371/journal.pone.0005527.s001 (0.14 MB TIF)
Figure S2 A Comparison of fMRI activity hours versus 39 days
post-lesioning. A representative axial slice from the macaque visual
cortex with overlaid coherence (left column) and phase (right
column) activation maps. The top row represents data obtained on
day 1 (,12 hours after the V1 aspiration lesion), the second row
data obtained on day 39. In this slice, the lesion spares a small
portion of V1 near the lunate sulcus (which explains the small
focus of activity seen outside the foveal border of the V2 LPZ in
the upper panels) and extends medially nearly to the midline. Note
that on day #1 the V2 LPZ is not significantly modulated by the
visual stimulus, in contrast to the strong area V2 modulation seen
in the contralateral (intact hemisphere). By day 39, it is clear that
weak but significant modulation has returned to the V2 LPZ. B
Mean percent signal modulation inside the V2 LPZ during
presentation of a ring stimulus centered at 4u. Signal modulation,
absent at the first day post-lesioning (red line), recovers within 39
days post-lesioning (black line).
Found at: doi:10.1371/journal.pone.0005527.s002 (0.26 MB TIF)
Acknowledgments
We would like to thank Drs Alyssa Brewer and Alex Wade for advice
regarding the VistaSoft software, Drs David Sheinberg and Yusuke
Murayama for providing visual stimulation software, and Drs Andreas
Tolias and David Leopold for helpful discussions.
Author Contributions
Conceived and designed the experiments: MS NKL SS. Performed the
experiments: MS TP MA. Analyzed the data: MS. Contributed reagents/
materials/analysis tools: MS. Wrote the paper: MS SS.
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