doi:10.

1093/brain/awr220 Brain 2011: 134; 3310–3325 | 3310

BRAIN
A JOURNAL OF NEUROLOGY

Acute visual neglect and extinction: distinct

functional state of the visuospatial
attention system
Roza M. Umarova,1,2 Dorothee Saur,2,3 Christoph P. Kaller,1,2 Magnus-Sebastian Vry,1,2
Volkmar Glauche,1,2 Irina Mader,2,4 Jürgen Hennig5 and Cornelius Weiller1,2

Downloaded from http://brain.oxfordjournals.org/ by guest on November 14, 2015

1 Department of Neurology, University Medical Centre Freiburg, Breisacherstr. 64, 79106 Freiburg, Germany
2 Freiburg Brain Imaging, University Medical Centre Freiburg, Breisacherstr. 64, 79106 Freiburg, Germany
3 Department of Neurology, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany
4 Department of Neuroradiology, University Medical Centre Freiburg, Breisacherstr. 64, 79106 Freiburg, Germany
5 Department of Radiology, Medical Physics, University Medical Centre Freiburg, Breisacherstr. 60a, 79106 Freiburg, Germany

Correspondence to: Roza M. Umarova,

Department of Neurology,
University Medical Centre Freiburg,
Breisacher Strasse 64, 79106 Freiburg,
Germany
E-mail: roza.umarova@uniklinik-freiburg.de

The neural mechanisms underlying spatial neglect are still disputed. Abnormal left parietal hyperactivation is proposed to lead
to the rightward attentional bias, a clinical hallmark of neglect. Extinction, another deficit of visuospatial attention, is regarded
as either a ‘mild’ form of neglect or a distinct syndrome. Although both neglect and extinction are typical syndromes of acute
right hemispheric stroke, all imaging studies investigating these syndromes were conducted at least several weeks after stroke
onset, in a phase when brain reorganization has already progressed. The present study aimed at comparing the activation
patterns in acute stroke patients with neglect and extinction during visuospatial processing. Using functional magnetic reson-
ance imaging, we examined the functional state of the attention system in 33 patients with a first ever stroke (53  5 h after
stroke onset) and age-matched healthy subjects (n = 15). All patients had embolic infarcts within the territory of the right middle
cerebral artery. Patients were divided into three groups: (i) normal visuospatial processing (control patients, n = 11); (ii) patients
with visual extinction but with no signs of neglect (n = 9); and (iii) patients with visual neglect (n = 13). While undergoing
functional magnetic resonance imaging, patients performed a Posner-like task for visuospatial attention with detection of the
targets in the left and right visual hemifields. Patients with neglect showed the expected imbalance in the left versus right
parietal activation, which however, was present also in control and extinction patients, thus representing an epiphenomenon of
the acute structural lesion in the right hemisphere. Compared with control patients, neglect was characterized by reduced
activation in the right parietal and lateral occipital cortex, as well as in the left frontal eye field. In contrast, the activation
pattern in patients with extinction differed from all other groups by an increased activation of the left prefrontal cortex. In both
patients with neglect and extinction, detection of targets in the left hemifield correlated with an activation in the left prefrontal
and parietal cortex. Thus at least in acute stroke, a relative hyperactivation of the left parietal cortex is not a particular
characteristic of neglect. The specific signature of neglect is represented by the dysfunction of the right parietal and lateral
occipital cortex. The function of the left attentional centres might provide a compensatory role after critical right hemisphere
lesions and be relevant for the contralesional spatial processing.

Received January 2, 2011. Revised June 26, 2011. Accepted July 1, 2011. Advance Access publication September 23, 2011
ß The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
Acute visual neglect and extinction
Keywords: neglect; extinction; visuospatial attention; parietal hyperactivation
Introduction
Neglect is a visuospatial attention deficit, which is characterized
by the failure to report, respond or orient to novel or meaningful
stimuli presented to the contralesional side, when this failure
cannot be attributed to either sensory or motor deficits (Brain,
1941; Critchley, 1949; Heilman et al., 2003). It occurs in 70%
of patients with stroke with a right hemisphere lesion (Gottesman
et al., 2008) and has a significant negative impact on functional
outcome and rehabilitation (Buxbaum et al., 2004; Jehkonen
et al., 2006). Neglect is considered to be provoked by a structural
lesion of the inferior parietal lobule, the temporoparietal junction
or the inferior frontal cortex in the right hemisphere (Vallar and
Perani, 1986; Husain and Kennard, 1996; Marshall et al., 2002;
Mort et al., 2003). In addition, the right superior temporal cortex
is shown to be crucial for neglect (Karnath et al., 2001). This
syndrome is discussed as a disconnection syndrome (Mesulam,
1990), which may be provoked by a disruption of association
tracks connecting the parietal and the frontal lobes (Bartolomeo
et al., 2007; Urbanski et al., 2007; Doricchi et al., 2008; Shinoura
et al., 2009; Umarova et al., 2010) or the parahippocampal
gyrus with the angular one (Bird et al., 2006). Although basal
ganglia lesions may also be critical for the occurrence of
neglect (Karnath et al., 2004; Ringman et al., 2004), such infarcts
lead to neglect mainly through hypoperfusion of the cortical re-
gions mediating attention (Bogousslavsky et al., 1988; Weiller
et al., 1993; Hillis et al., 2005). The various aspects of lesion
anatomy may determine the heterogeneity of neglect: ego- or
allocentred; for personal-, peri- or extrapersonal space; in the
visual, sensory or motor modalities (Hillis et al., 2005, 2006;
Committeri et al., 2007; Verdon et al., 2009) and reflects its
complexity.
Extinction represents another type of visuospatial attention def-
icit. It is characterized by the failure to respond to contralesional
stimulus, if it is presented simultaneously with an ipsilesional one.
While there are a number of studies investigating the anatomy of
visual neglect, the morphological correlates of extinction are less
known. Animal studies (Lynch and McLaren, 1989) and experi-
ments with healthy subjects (Cicek et al., 2007) identified the right
inferior parietal cortex as an anatomical substrate for simultaneous
processing of the targets in the left and right visual hemifield.
In humans, a lesion or hypoperfusion of the right temporoparietal
cortex were related to extinction (Karnath et al., 2003; Hillis et al.,
2006; Ticini et al., 2010). The pattern of lesions causing extinction
is therefore similar to that of neglect. However, the relationship
between neglect and extinction is still not fully understood.
Whether extinction is a ‘mild’ form of neglect or a separate
form of attentional deficit is still an open question. Some data
show that these syndromes are dissociable (Vallar et al., 1994;
Hillis et al., 2006; Vossel et al., 2011). On the other hand,
extinction is also described as a part of a neglect syndrome, es-
pecially when the lesions are clustered in the inferior parietal
Brain 2011: 134; 3310–3325 | 3311
lobule (Posner et al., 1984; Vallar et al., 1994; Rees et al.,
2000; Vuilleumier and Rafal, 2000).
The cognitive and neural mechanisms underlying spatial neglect
and extinction are reflected in the theories of spatial attention.
According to the theory of hemispheric rivalry, each hemisphere
represents the contralateral space and inhibits another one
through transcallosal pathways (Kinsbourne, 1970). Under
normal conditions, the activation of both hemispheres is balanced.
In case of a structural lesion, the undamaged hemisphere is disin-
hibited from the damaged one and suppresses it. This functional
imbalance between ipsi- and contralesional hemispheres would
provoke an attentional bias towards the ipsilesional space, and
thus neglect.
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Another model of neglect reflects the limited attentional cap-
acity after damage to the right hemisphere. The right hemisphere
is considered to span the attentional functions for both hemi-
spaces, while the left hemisphere seems to provide visuospatial
processing mostly of the contralateral space (Heilman and Van
Den Abell, 1980; Mesulam, 1981). According to this model, uni-
lateral lesions of the left hemisphere are unlikely to result in neg-
lect, since the intact right hemisphere can take over the task of
attending to the right side. In contrast, in the absence of similar
compensatory mechanisms in the left hemisphere, right hemi-
sphere lesions will result in a marked unilateral neglect
(Mesulam, 1981). This model considers extinction as a ‘mild’
form of neglect, which follows less severe parietal lesions
(Mesulam, 1981).
A neglect model that is postulated by Corbetta and Shulman
(2002) includes elements of both theories: hemispheric rivalry
and right hemisphere dominance for spatial processing. Based on
the results from neuroimaging studies, they subdivide the cortical
centres for spatial attention into a dorsal and a ventral attention
network (Corbetta and Shulman, 2002). The ventral attention
network is located predominantly in the right hemisphere and
centred in the temporoparietal junction, anterior insula and ventral
frontal cortex. It is specialized for target detection, particularly
when they are salient or unexpected (Corbetta and Shulman,
2002). The dorsal attention network includes bilaterally the intra-
parietal sulcus, the frontal eye field and lateral occipital complex
(Corbetta and Shulman, 2002). It is activated by directional cues
and is involved in attention orientation: preparing and applying
goal-directed selection for stimuli and responses. Lesions of the
ventral network provoke a dysfunction in the structurally intact
dorsal network in the right hemisphere, resulting in a functional
imbalance—a push-pull pattern—of evoked responses in the left
(hyperactive) and right (hypoactive) dorsal parietal cortex
(Kinsbourne, 1970; Corbetta et al., 2005). This parietal imbalance
correlates with the degree of the rightward attentional bias and is
postulated as the pathomechanism of neglect. However, it is un-
clear whether the functional parietal imbalance is causative for
neglect or reflects cortical reorganization that follows the large
right hemispheric lesions. To answer this question, it is necessary
3312 | Brain 2011: 134; 3310–3325
to compare patients with right hemisphere lesions with and with-
out neglect.
Differences between neglect and extinction in terms of brain
activation pattern can be predicted from the models of spatial
attention. The model of hemispheric rivalry predicts a left–right
parietal imbalance in both visual neglect and extinction. Since in
neglect the spatial deficit is present during unilateral stimulation,
and in extinction only during bilateral stimulation, the functional
left–right imbalance in neglect should be more severe than in ex-
tinction. In contrast, in the theory of the right hemisphere dom-
inance in spatial processing (Mesulam, 1981), the problem is the
limited attentional capacity after right hemispheric lesions.
Therefore, the activation in the left hemisphere may account for
a compensatory mechanism by assuming either a much weaker
but existent spatial representation of both hemispaces in the left
attentional centres or an incomplete dominance of the right hemi-
sphere for spatial processing. Extinction might differ from neglect
by having a greater compensatory effect of the left hemisphere. In
other words, while (absolute or relative) increased left hemispheric
activation would be seen as rather deleterious in the hypothesis of
hemispheric rivalry, it may be seen as favourable in the second
model.
There are several neuroimaging and neurophysiological studies
in the field of visuospatial attention, but only few neuroimaging
experiments are performed in patients with neglect and extinction
(Rees et al., 2000, 2002; Vuilleumier et al., 2001, 2002, 2008;
Corbetta et al., 2005; Koch et al., 2008; Thimm et al., 2008). In
these studies, patients with neglect are compared with healthy
subjects (Corbetta et al., 2005) or include only a small number
of patients (Thimm et al., 2008). Critically, the patients are exam-
ined at least several weeks after stroke onset, when major adap-
tive and reorganizational processes have progressed substantially.
Although the results of these studies are crucial, important ques-
tions concerning the functional neuroanatomy of acute neglect
were not answered.
The purpose of our study was to investigate: (i) if acute visual
neglect is characterized by the hyperactivation of the left parietal
cortex; (ii) if acute stroke patients with visual extinction but with-
out neglect have similar but less pronounced dysfunction of the
visuospatial attention system compared with neglect, i.e. if extinc-
tion is a ‘mild’ form of neglect; and (iii) since patients with neglect
vary in the left-sided performance, what is the functional correlate
of the detection of targets in the contralesional visual hemifield.
To answer these questions, we investigated and compared three
groups of patients with acute right hemispheric stroke and
age-matched healthy subjects. Patients had either visual neglect,
visual extinction without neglect or no visuospatial attention def-
icit. The last group of patients represented the most valid control
group, since they had lesions in the same vascular territory and
were matched by age, time after stroke and stroke severity.
Patients were investigated within the first 2–4 days after stroke,
before the onset of major reorganization processes. All groups of
patients were examined with a neglect test battery and a func-
tional MRI experiment of visuospatial attention (Umarova et al.,
2010). The functional MRI paradigm was designed to be: (i)
simple and short enough to study acute stroke patients; (ii) well
established and include both visual orienting and target detection
R. M. Umarova et al.
components of the visuospatial processing; and (iii) efficient
enough to be sensitive for effects in acute stroke patients. We
chose a Posner-like visual orienting and target detection task
(Posner et al., 1984) that involves the dorsal and ventral attention
systems in healthy subjects and patients with neglect (Corbetta
and Shulman, 2002; Corbetta et al., 2005). Neuronal activations
in both hemispheres with right-hand button press for the targets
detection served as a control condition to ensure a preservation of
blood oxygen level-dependent response and to show that changes
in the attentional system are specific. We expected a wide range
in patients’ performance allowing a correlation analysis between
functional MRI activation and behavioural performance. The block
design of the paradigm ensured the high efficiency for detecting
effects in acute stroke patients (Friston et al., 2007).
Subject and methods
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Subjects
Patients were recruited from the stroke unit of the Department of
Neurology, University Medical Centre, Freiburg, Germany. For a
period of 18 months (January 2007–June 2009), we screened all
patients with ischaemic stroke in the right hemisphere. Inclusion
criteria consisted of ischaemic first-ever stroke in the right middle
cerebral artery territory confirmed by MRI. Exclusion criteria were
as follows: (i) age 580 years; (ii) hemianopia and severe sight
defects that prevented subjects from performing the functional
MRI task (object detection and recognition at a distance of at
least 2 m without glasses); (iii) inability to maintain alertness, low
conscious or arousal level; (iv) inability to tolerate the functional
MRI examination owing to reduced general health status; (v) pro-
nounced small vessel disease or additional structural brain lesions;
(vi) general contraindications for MRI examination; (vii) other
neurological or psychiatric conditions that precluded active par-
ticipation in research and/or altered the interpretation of the
behavioural/imaging data (e.g. dementia, schizophrenia); (viii)
severe stenosis (470%) of the carotid arteries and/or of the
middle cerebral arteries; and (ix) left-handedness.
Fifteen age-matched healthy right-handed subjects (eight
males), 70  2 years old (mean  SEM) without any neurological
or psychiatric history served as an additional control group.
Written informed consent was obtained from each subject in ac-
cordance with the Declaration of Helsinki. The Ethics Committee
of the University Medical Centre Freiburg approved the study.
Clinical and behavioural testing
All patients were examined for extinction and neglect on the day
of scanning. Visual fields were assessed by standardized neuro-
logical bedside examination, since an instrumental perimeter
examination was not feasible due to the early inclusion of the
patients in the study. Visual neglect was diagnosed based on the
clinical signs (e.g. when the patient oriented towards the ipsile-
sional side, when addressed from the front or the left side and/or
ignored contralesionally located persons or objects) and the results
of the neuropsychological testing. The following tests were used.
Acute visual neglect and extinction
Visual extinction
The presence of extinction was tested clinically by wiggling fingers
for 2 s in one or both visual fields while controlling central gaze
fixation. Fifteen trials were given in a fixed pseudo-randomized
sequence including 10 unilateral trials (five on each side) and
five simultaneous bilateral trials. Extinction was considered if a
patient failed to report at least two contralesional stimuli during
bilateral simultaneous presentation, while accurately detecting uni-
lateral stimuli (Beis et al., 2004).
All patients performed standardized paper and pencil tests of
visuospatial neglect in the peripersonal space (Neglect Test; Fels
and Geissner, 1997), which is an adapted version of the
Behavioural Inattention Test (Wilson et al., 1987). Visual neglect
was diagnosed when the patients failed to perform at least two
of the following clinical tests: (i) the line cancellation test; (ii) the
letter cancellation test; (iii) the star cancellation test; (iv) text read-
ing; and (v) picture copying task. Patients also performed the line
bisection task, but the results were not taken into account, be-
cause this test was reported as non-specific to neglect (Rorden
et al., 2006). All visual tests were performed with the targets
distributed on an A4 sheet of paper, which was centred in front
of the patients.
The line cancellation test
This test consists of 40 lines each with a length of 25 mm, which
are distributed into three columns each on the right and left side
(each with six lines), and one column in the centre (four lines).
All lines have to be cancelled. Patients were classified to fail the
test in case of (i) omitting at least four left-side targets; or (ii) if
right-side targets were also omitted, the difference between omis-
sions on the left and right side was 44.
The letter cancellation test
Patients were presented with five rows of different letters, con-
sisting of 34 letters per row. The task was to cancel the letters ‘E’
and ‘R’, which are randomly distributed among other irrelevant
letters that represented distractors. The interpretation of the re-
sults was the same as in the line cancellation test.
Star cancellation test
The target stimuli are 56 small stars, which are interspersed be-
tween distracters that are represented by 52 large stars, 13 letters
and 10 short words. The task was to cross out the small stars. The
interpretation of the results was the same as in the line cancella-
tion test.
Reading
The patient is prompted to read a short text, which is set out in
three columns (46, 47 and 46 words in the left, central and right
columns, respectively). The number of words read is assessed. If
one or more sentences were read incompletely on the left but not
on the right side, patients were considered to fail.
Copying of the presented pictures
Three pictures are presented to a patient (a four cornered star, a
rhomb and a flower), which are drawn on the left half of the
sheet. The task is to copy the figures on the right half of the
Brain 2011: 134; 3310–3325 | 3313
sheet. Correctness of the general contour (1 score), details (1
score) and their order (1 score) on the copied pictures are as-
sessed. The maximal score for every figure is 3. A sum score
56 was defined as deficient.
Analysis
All patients were divided into three groups: patients with visual
neglect (neglect group), who failed to perform in at least two
neglect tests; patients with visual extinction (extinction group),
who did not show visual neglect clinically nor in the neglect
tests (only two patients of the group failed in one neglect test—
copying of the presented pictures, all other patients succeeded in
all tests); and patients without neglect or extinction, who repre-
sented the group of control patients, with normal performance in
both extinction and neglect tests. Patients’ clinical data are pre-
sented in Table 1. We used a one-way ANOVA to compare the
clinical characteristics between groups of patients (age, time after
stroke onset, stroke severity in terms of NIH Stroke Scale assessed
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on admission). As the variance within neglect group was incom-
parable with those within other groups of patients, we used the
Kruskal–Wallis test to detect the differences between groups in
neglect tests.
Functional magnetic resonance imaging
paradigm
We used a Posner-like paradigm in a mixed block design
(Umarova et al., 2010). Stimuli were presented visually with the
software Presentation (http://nbs.neuro-bs.com). Task blocks
(32 s), which consisted of 12 trials, were alternated with rest
(16 s). During a trial, a centrally located arrow (visual angle, 4 )
was presented for 800 ms, which pointed to the right or left side
indicating the location of the target (size, 1.3 ). For two-thirds of
the trials, the target appeared at the indicated location for 400 ms
(at 11 of visual angle from the fixation cross). The remaining
one-third of the trials were null events, in which after the
cueing, no target appeared. The trials were separated by a fixation
cross hair (visual angle 1.4 ) for a jittered period of 1000–2000 ms.
Each task block contained 12 randomly intermixed trials, from
which eight were ‘valid’ (four events with targets in the right
and four in the left visual hemifield) and four were null-events
(two with left- and two with rightward arrow). A total of 192
stimuli were distributed over two sessions, each with eight task
blocks. Between sessions we assessed the subject’s performance.
The task was to detect left and right targets as fast as possible by
pressing a single button with the right non-paretic and
non-neglected hand. In this way, the right arm and hand were
positioned in the right non-neglected hemispace to ensure that the
response button would not be neglected. Subjects were also in-
structed to fixate on the cross-hair between trials.
Patients and healthy controls performed the same cued visuo-
spatial functional MRI experiment. Before functional MRI examin-
ation, all patients were trained on the task outside the scanner. In
case of severe neglect, the training was first performed with the
display screen positioned in the right hemispace, thus patients
were aware of both the left and right targets. Then the training
was continued with the display positioned in the centre. Inside the
3314 | Brain 2011: 134; 3310–3325 R. M. Umarova et al.

Table 1 Clinical characteristics of patients and behavioural test results (all results are given in median and range unless
stated otherwise)

Control Patients with Patients with neglect

patients extinction (n = 13)
(n = 11) (n = 9)
Age (years), mean  SEM 67  2.8 69  3.3 65  3.0
Sex (female/male) 7/4 2/7 5/8
Time after stroke onset to functional MRI (h), 53  8.7 40  9.3 62  8.1
mean  SEM
NIHSS score, mean  SEM 91 61 81
Lesion volume* (ml) mean  SEM 29.8  4.3 35.1  9.2 62.4  9.0
Personal neglect (n) 0 0 2
Anosognosia (n) 1 1 9
Detected stimuli in extinction test# max. 5 5; –/5; –/5; – 5; 3–5/5; –/0; 0–3 0; 0–5/5; –/0; 0–5
(left/right/both)
Line bisection*, max 9 9; 6–9 7; 3–9 3; 0–9
Coping of drawings#, max 9 9; 6–9 9; 2–9 2; 0–8
Lines cancelation#, max 18 (left/right) 18; 16–18/18; 17–18 18; 17–18/18; – 5; 0–18/18; 5–18
Star cancelation#, max 27 (left/right)

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27; 22–27/26; 22–27 26; 22–27/26; 22–27 0; 0–23/19; 6–26
Letters cancelation#, max 20 (left/right) 20; 16–20/19; 17–20 20; 18–20/19; 16–20 5; 0–19/15; 4–20
Reading#, max 47/46/47 words 47; 45–47/46; 45–46/47; – 47; 46–47/46; 43–46/47; 45–47 0; 0–47/44; 0–46/47; 10–47
(left/centre/right)

*Significant group effect in a one-way ANOVA; #significant group effect in the Kruskal–Wallis test.
NIHSS = NIH Stroke Scale.

scanner, the patients were first checked for the ability to fixate the
gaze on the cross hair between trials. Thereafter, they were asked
to perform a training session to ensure correct understanding of
the task.
Behavioural performance was assessed by detection of right tar-
gets and non-responses to ‘null events’. We assumed efficient
visuospatial processing if a patient detected overall 470%
(445) of the right targets and had 510% (56) false alarms.
Two-way mixed ANOVA was computed to examine reaction
time for left and right targets between groups. Reaction times of
detected targets in the left and right visual hemifield were treated
as dependent variables (two levels: right and left) with group as a
between-subject factor (four levels: healthy subjects, control pa-
tients, extinction group, neglect group). Conditional on significant
F-test results, we investigated the rightward processing bias in
terms of reaction time differences for left versus right targets
(left reaction time right reaction time) between groups
(one-way ANOVA) with further contrasting of reaction time
lateralization between control patients and other groups. The sig-
nificance level was set at P 5 0.05. Because the behavioural per-
formance was perfect in healthy subjects and nearly perfect in
control patients, the variance of data in them was skewed; there-
fore, hit rates were compared between groups using the Kruskal–
Wallis test and the Mann–Whitney rank test for pairwise compari-
sons. The control patients were contrasted with healthy subjects
and then with extinction and neglect groups, since we expected
the performance in healthy subjects and in control patients to be
superior to that of patients with visuospatial attention deficit.
A Bonferroni correction was applied, thus all effects are reported
at a 0.05/4 = 0.0125 level of significance.
Magnetic resonance imaging data
acquisition
Structural and functional MRI data were acquired on a 3 T
TIM-TRIO MRI System (Siemens) with a standard head coil.
Diffusion weighted imaging and anatomical scan
From all patients, we obtained a diffusion weighted imaging and
T1 anatomical scan. Diffusion weighted imaging was obtained with
a T2*-weighted echoplanar images (EPI) sequence (repetition
time = 3100 ms, echo time = 79 ms, b1 = 0 s/mm2, b2 = 1000 s/
mm2; matrix size = 64  64, voxel size 1.8  1.8  5 mm3,
23 slices) with three diffusion directions. Anatomical scans were
acquired with a sagittal magnetization-prepared rapid-acquisition
gradient-echo sequence (repetition time = 2200 ms, echo
time = 2.15 ms, flip angle = 12 , matrix = 256  256 pixel, voxel
size = 1  1  1 mm3, 176 slices).
Lesion mapping
The lesions were delineated on the diffusion weighted images
using MRIcron Toolbox http://www.cabiatl.com/mricro/mricron/
index.html. Lesion maps were normalized into the standard
Montreal Neurological Institute (MNI) space using normalization
parameters from the coregistered anatomical T1 scans (Ashburner
and Friston, 2005). Since the optimal algorithms for spatial nor-
malization of structurally damaged brains are implemented in
the current SPM8 version (Crinion et al., 2007), we did not
mask the structural lesions. The lesion overlap was computed
using MRIcron.
Acute visual neglect and extinction
Functional magnetic resonance imaging scan
acquisition and data analysis
During two functional MRI sessions, we acquired 330 axial
slices covering the whole brain using a T2*-weighted echoplanar
images with blood oxygen level-dependent contrast (repetition
time = 2190 ms, echo time = 30 ms, flip angle 75 , matrix
size = 64  64 pixel, voxel size = 3  3  3 mm3, 36 slices, no
gap). The functional MRI data were corrected for motion and
distortion across runs using a reference volume acquired in a pre-
vious scan (Zaitsev et al., 2004, 2006). The first four volumes
were discarded to allow for T1 equilibration effects. The subse-
quent image processing and statistical analysis of the functional
MRI data were performed with SPM8 (http://www.fil.ion.ucl.ac.
uk/spm/software/spm8/). The images were corrected for different
acquisition times between slices with reference to the middle slice.
Spatial normalization parameters were computed from the T1 scan
as detailed above and applied to the images, which were then
smoothed with an isotropic Gaussian kernel of 9 mm full-width
at half maximum. A general linear model analysis was performed
with a block design of the functional runs using the canonical
haemodynamic response function. The task blocks were modelled
as one main regressor to analyse the main effect of interest at the
single-subject level. To capture the extra variance introduced by
the motor response, it was modelled as a stick function orthogo-
nalized with respect to the main regressor of interest. The contrast
images of the motor response were further used as a control con-
dition for the analysis of the blood oxygen level-dependent signal
between groups. Six movement parameters were used as addition-
al regressors. Data were high-pass filtered at 1/128 Hz. For the
further second-level analysis, we used the images of the main
effect of interest, i.e. taking into account activation related to
the visuospatial processing.
To evaluate the functional MRI activation in each group, we
performed a random-effect analysis treating subjects as a
random variable. Group-specific main effects were characterized
using a one-sample t-test. To detect differences in the attentional
activation between groups, they were contrasted with each other
using two-sample t-tests. To identify the regional differences in
task-related activations between all groups, we performed a
between-group ANOVA, modelling group condition as an inde-
pendent factor (four levels: healthy subjects, control patients, ex-
tinction group, neglect group) and calculated the main effect of
group as F-contrast. In additional analyses, we were interested in
correlates of differences in functional MRI performance in the
contralesional space in patients with visuospatial attention deficit.
To this end, we performed a whole brain voxel-wise regression
analysis using the individual performance data as covariates (reac-
tion time, hit rate). The anatomical location of the activated
clusters was obtained using the Anatomy toolbox implemented
in SPM8: http://www.fz-juelich.de/ime/spm_anatomy_toolbox
(Eickhoff et al., 2005).
Since the current hypothesis of neglect assumes an imbalance
between activity of the left and right parietal cortex, we explored
the functional MRI activation in the dorsal attention centres
and primary visual cortex using a region of interest analysis
(see Supplementary Material). Additionally, we calculated a
Brain 2011: 134; 3310–3325 | 3315
laterality index (LI) between individual left (L) and right (R) intra-
parietal sulcus activations: LI = (L R)/(L + R). Furthermore, the
blood oxygen level-dependent response related to the button
press was explored and compared between groups (see
Supplementary Material).
The behavioural data and region of interest analysis were per-
formed using the Statistical Package for the Social Sciences
(SPSS, v.17) software.
Results
A total of 37 patients met the inclusion and exclusion criteria.
Two patients had a haemorrhagic transformation of the infarct
in the frontal and parieto-temporo-occipital junction, i.e. the re-
gions of interest. They were excluded from further analysis be-
cause of the possible false negative functional MRI group results in
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the area of haemorrhage. Two further patients were excluded due
to poor behavioural performance: one pressed the button in
410% of null events, another detected 570% of targets in the
right visual hemifield. From the remaining 33 patients, 11 patients
did not have any signs of visuospatial attention deficit and they
formed the group of control patients, nine patients presented with
visual extinction (extinction group) and 13 patients had visual neg-
lect (neglect group). All patients were examined in the acute stage
of stroke; the mean time between stroke onset and functional MRI
examination was 53  5 h (  SEM).
Demographic and clinical data from all included patients are
presented in Table 1. The three groups of patients did not differ
with respect to age [one-way ANOVA, F(2,32) = 0.40, P = 0.675]
and time interval between the stroke onset and functional MRI
examination [F(2,32) = 1.58, P = 0.222]. Stroke severity on
admission, measured with the NIH Stroke Scale, did not distinguish
between groups [F(2,32) = 0.96, P = 0.395], neither did the
frequency of contralateral motor and somatosensory deficits
[F(2,32) = 1.92, P = 0.163 and F(2,32) = 2.40, P = 0.108,
respectively].
Lesion anatomy
The location of the lesions was comparable in all groups,
although lesions of patients with neglect were significantly
larger than those of all other patients’ groups [F(2,30) = 5.33,
P = 0.010] (Table 1). In control patients, the infarcts were located
in right fronto-temporo-parietal regions including the posterior
part of the inferior frontal gyrus [Brodmann area (BA) 44],
insula, frontal operculum, putamen and superior and middle tem-
poral gyrus with adjacent white matter (Fig. 1). Patients with ex-
tinction had either large cortico-subcortical infarcts with
involvement of the right insula, superior temporal gyrus and infer-
ior parietal lobule (six patients) or cortical inferior parietal lesions
(three patients) (Fig. 1). Patients with neglect had infarcts within
the posterior middle and inferior frontal gyri (BA 44), frontal oper-
culum, insula, middle and superior temporal gyri and inferior par-
ietal lobe (Fig. 1). All patients had an intact left hemisphere and
right occipital lobe. The optic radiation was also intact.
3316 | Brain 2011: 134; 3310–3325 R. M. Umarova et al.

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Figure 1 Lesion overlap of control, extinction and patients neglect. Colour bar indicates the number of overlapping lesions.

Table 2 Hit rates and reaction times during functional MRI experiment for the targets presented in the left and right visual
hemifield

Healthy subjects Control patients Extinction patients Neglect patients

Left Right Left Right Left Right Left Right
Hits rate (%) median; range 100; – 100; – 98; 70–100 100; 80–100 92; 65–100 97; 92–100 25; 0–98 84; 75–100
Reaction time (ms) mean  SEM 324  9 320  9 516  37 477  39 522  56 420  29 641  63 543  36

Performance during functional magnetic
resonance imaging
The behavioural performance during functional MRI examination
was assessed by hit rates, reaction time and number of false
alarms (see Supplementary Material). Hit rates and reaction time
are shown in Table 2. Detection of the right targets was accurate
(470%) in all groups. In contrast, the detection of the targets in
the left hemifield was more heterogeneous. In neglect group,
hit rates for the targets in the left visual hemifield varied be-
tween 0 (four patients) and 98.4% (one patient), whereas
patients of all other groups detected almost all of them
(Table 2). All three groups of patients but not healthy subjects
were slower in response to the targets in the left than visual in
the right hemifield (paired t-test, P 5 0.01). Control patients
did not differ from healthy subjects in left versus right
Acute visual neglect and extinction Brain 2011: 134; 3310–3325 | 3317

reaction time lateralization (reaction time for the left detected tar-
gets reaction time for the right ones; t = 1.17, P = 0.25),
whereas patients extinction compared with control ones showed
a strong trend for processing the left targets slower than the right
ones (t = 1.81, P = 0.078), and patients with neglect compared
with control patients had a significant left–right reaction time lat-
eralization (t = 2.86, P 5 0.01) (Fig. 2). Thus, there was a congru-
ency between behavioural performance in the functional MRI task
and behavioural neglect testing: patients showed a rightward at-
tentional bias of the visual processing that increased from control
to patients with neglect and manifested with more missed targets
and slower reaction time in the contra- than the ipsilesional visual
field.

Functional magnetic resonance

imaging results
Functional MRI activations within and between groups are shown
in Figs 3–7. The coordinates of peaks of cluster activation are
listed in Supplementary Table 1. Healthy subjects revealed a
widespread bilateral activation of the visuospatial attention

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Figure 2 Differences in reaction time (RT) between targets
detected in the left versus right visual hemifield (mean  SEM).
There were no differences between healthy subjects and control
patients. Compared with controls, patients with extinction
showed a tendency to process targets in the left visual hemifield
slower than in the right one (P = 0.078); this difference was
significant in patients with neglect compared with control
ones (**P 5 0.01).
system (Fig. 3). Activation within the visual system included bilat-
eral primary and visual association areas, including fusiform gyrus
and the lateral occipital cortex. Bilateral activation of the attention
system included intraparietal sulcus, frontal eye field, pre-
supplementary motor area, insula, supramarginal gyrus, posterior
inferior frontal gyrus and temporoparietal junction. The activation
was lateralized to the right hemisphere in the lateral occipital
cortex, supramarginal gyrus and temporoparietal junction.

Figure 3 Task activations (red) and lesion projections (black) in groups, one-sample t-test (healthy subjects P 5 0.01, family-wise error
corrected; in groups of patients P 5 0.001, uncorrected, extent threshold 10 voxels). While activation associated with the motor response
was similar in all groups (positive control), the pattern of activation in attention-relevant areas was distinct. All peaks of cluster activation
are listed in Supplementary Table 1. FEF = frontal eye field; IPS = intraparietal sulcus; LOC = lateral occipital complex; M1/S1 = primary
motor and sensory cortex; pre-SMA = pre-supplementary motor area; SMG = supramarginal gyrus; TPJ = temporoparietal junction.
3318 | Brain 2011: 134; 3310–3325
In addition to the whole brain contrasts, the activation in the
dorsal attention system and primary visual areas was estimated
using a region of interest analysis of parameter estimates in a
one-way ANOVA and a post hoc two sample t-tests with
Bonferroni correction in case of a significant main effect of
group. We restricted the analysis to regions preserved from
lesions and thus excluded right temporoparietal junction as
well as the right posterior inferior frontal gyrus, which
were damaged in five and four patients of neglect and extinc-
tion groups correspondingly. We found a significant group
effect for all left and right regions of interest of the dorsal
attention system except for the left lateral occipital cortex:
for the left intraparietal sulcus [F(3, 44) = 2.95, P 5 0.05],
left frontal eye field [F(3, 44) = 8.09, P 5 0.001], right lateral
occipital cortex [F(3, 44) = 5.85, P 5 0.01], right intraparietal
sulcus [F(3, 44) = 4.23, P = 0.01] and right frontal eye field
[F(3, 44) = 3.59, P 5 0.05] (Fig. 5). For the primary visual
areas, there was a significant group effect only for the right
hemisphere [F(3, 44) = 7.86, P 5 0.001], but not for the left
[F(3, 44) = 0.68, P = 0.57].
Control patients and healthy subjects did not differ in the acti-
vation pattern according to both the whole brain and region of
interest analysis, except for the higher activation in the left extra-
striate visual cortex (Fig. 6). Thus, in spite of the structural lesion
in control patients, the key nodes of the attention system in them
were activated comparably to healthy subjects.
Patients with neglect demonstrated a generally reduced activa-
tion in almost all regions relevant for attention (Figs 3 and 4),
Figure 4 Contrasts between groups (two-sample t-test, P 5 0.001, uncorrected, extent threshold 10 voxels). There was no significant
difference between healthy subjects and control patients, healthy subjects 4 patients with extinction, control patients 4 patients with
extinction and patients with neglect 4 control patients.
R. M. Umarova et al.
although their visuospatial performance in the right visual field
was accurate and did not differ from patients with extinction.
Patients with neglect compared with healthy subjects showed a
small cluster of higher activation in the right gyrus angularis (peak
in 51, 69, 30, Fig. 4) that might reflect the perilesional activation
as the sign of early reorganization. We would like to emphasize
that there was no increase of contralesional activation in patients
with neglect compared with control ones and healthy subjects
according to both the whole brain and region of interest analyses
(Figs 4, 5 and 6). The whole-brain comparison between healthy
subjects and neglect groups revealed a reduced activation in the
last one not only in the right-hemispheric attention network, but
also in the left lateral occipital cortex and left posterior inferior
frontal gyrus (Fig. 4). The main difference between control and
neglect patients was hypoactivation of the right lateral occipital
cortex (Fig. 4). The region of interest analysis showed reduction of
activation in the left frontal eye field, right lateral occipital cortex
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and right intraparietal sulcus compared with control patients
(t = 3.22, P 5 0.05; t = 3.55, P 5 0.01; and t = 2.75, P 5 0.05, re-
spectively; Figs 5 and 6). Neglect patients had a tendency to
reduced activation in the left intraparietal sulcus compared with
the control ones (t = 1.94, P = 0.059) and a significantly lower
activation in the right primary visual area compared with patients
with extinction (t = 4.16, P 5 0.01) and healthy subjects (t = 4.12,
P 5 0.01; Supplementary Fig. 1).
In the whole-brain analysis, patients with extinction did not
differ from control ones in the activation of the dorsal attention
system, but they contrasted from all other groups by showing an
Acute visual neglect and extinction Brain 2011: 134; 3310–3325 | 3319

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Figure 5 Between group comparison in a region of interest analysis of activation in the left (L) and right (R) dorsal attention systems
(mean  SEM, *P 5 0.05; **P 5 0.01, ***P 5 0.001, after Bonferroni correction). FEF = frontal eye field; IPS = intraparietal sulcus;
LOC = lateral occipital complex.

Figure 6 The whole brain analysis of the main group effect: brain regions that show differences between groups in task-related blood
oxygen level-dependent signal changes during visuospatial processing (between-subject ANOVA, the main effect of group, F-contrast,
P 5 0.001, uncorrected; mean  SEM). IFG L = left posterior inferior frontal gyrus; IPS R = right intraparietal sulcus; LOC L/R = left/right
lateral occipital complex; MFG L = left posterior middle frontal gyrus; preSMA L = left pre-supplementary motor area.
3320 | Brain 2011: 134; 3310–3325
increased activation of the left prefrontal cortex, including poster-
ior middle frontal gyrus (BA 6/8, peak in 21, 12, 48), posterior
inferior frontal gyrus (BA 44, peak in 42 12 33) and bilateral
pre-supplementary motor area (BA 6) (Figs 4 and 6). In the region
of interest analysis, patients extinction had a significantly higher
activation of the left frontal eye field compared with both healthy
subjects and patients with neglect (t = 3.30, P 5 0.05 and
t = 4.55, P 5 0.001, respectively), and higher activation of the
right frontal eye field compared with neglect patients (t = 3.15,
P 5 0.05; Figs 4 and 5), while the right intraparietal sulcus and
right lateral occipital cortex activation did not differ significantly
from control patients. Thus, patients with extinction were charac-
terized by a preserved activation of the dorsal attention system in
the right hemisphere and abnormal hyperactivation of the left
dorsolateral prefrontal cortex.
At present, neglect is understood as the result of an imbalance
between hyperactive left parietal cortex and structurally or func-
tionally impaired right parietal one. To investigate this hypothesis,
we compared the activation in these regions in each group. The
left parietal cortex was activated significantly stronger than the
right in all groups of patients, including control patients without
visuospatial deficit (paired t-tests, for control patients t = 4.10,
P 5 0.01; patients with extinction t = 3.84, P 5 0.01; patients
with neglect t = 3.90, P 5 0.01), but not in healthy subjects
(paired t-tests, t = 1.04, P = 0.314). Further, we calculated the lat-
erality index between left and right intraparietal sulcus activations
(Supplementary Fig. 2). There was no significant difference in be-
tween groups [one-way ANOVA, F(3, 44) = 1.393, P = 0.257],
probably due to the high variability particularly in patients with
neglect. Correlation analysis (Pearson correlation) between lateral-
ity indices and left or right hit rates or with left versus right reac-
tion time lateralization also did not reveal any significant results.
Since the functional MRI behavioural performance in patients
with attentional deficit varied substantially, we performed an ex-
ploratory whole-brain voxel-wise correlation analysis with the be-
havioural parameters (left hit rate and left versus right reaction
time lateralization) across extinction and neglect groups. There
was no significant correlation with the left versus right reaction
Figure 7 Whole brain voxel-wise correlation in patients with
attentional deficit between blood oxygen level-dependent re-
sponse and hit rate for the targets presented in the left hemifield
(P 5 0.001, uncorrected, extent threshold 10 voxels). The left
hit rate in extinction and neglect patients correlated with acti-
vation in the contralesional left hemisphere: posterior middle
frontal gyrus (BA 6/8), posterior inferior frontal gyrus (BA 44/
45), pre-supplementary motor area, intraparietal sulcus and
prefrontal cortex (BA 10).
R. M. Umarova et al.
time lateralization. However, the hit rate for targets presented in
the left hemifield correlated with activation in the contralesional
left hemisphere: posterior middle frontal gyrus (BA 6/8, peak in
42, 0, 45, Spearman correlation r2 = 0.70, P 5 0.001,
Supplementary Fig. 3), inferior frontal gyrus (BA 44/45 peak in
48, 18, 27), prefrontal cortex (BA 10, peak in 30, 48, 9),
pre-supplementary motor area (BA 6, peak in 6, 6, 48) and
left intraparietal sulcus (Fig. 7).
It is critical to ensure that reduced activation within the atten-
tion system in neglect group was not caused by an altered blood
oxygen level-dependent response in the right middle cerebral
artery territory owing for example to impaired neurovascular
coupling in acute stroke. To compare the blood oxygen
level-dependent response between groups, we analysed the
motor activation evoked by the right-handed button press for tar-
gets detection. This motor effect showed an involvement of the
contralateral motor cortex, and also of the ipsilateral putamen and
premotor cortex (between-group full-factorial ANOVA, Fig. 8).
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The latter two regions belong to the territory of the right middle
cerebral artery. We extracted the parameter estimates of the right
premotor cortex, right putamen and left primary motor cortex. For
each region of interest, parameter estimates were compared be-
tween groups using a one-way ANOVA. For the latter two re-
gions, there were no significant group effects. We found a
significant group effect for the right premotor cortex [F(3,
44) = 2.96, P = 0.043]. However, separate post hoc two sample
t-tests comparing healthy subjects against each group of patients
Figure 8 (A) Motor activation by button press during functional
MRI experiment (main contrast of interest, between-subject
full-factorial ANOVA, family-wise error corrected, P 5 0.05). (B)
Plot of the per cent signal changes in the right premotor cortex,
right putamen and left primary motor cortex (mean  SEM).
There were no significant differences between groups in the
activation within the left primary motor cortex and right puta-
men (one-way ANOVA). Though there was a significant group
effect for the right premotor cortex, the t-test comparing those
with and without stroke did not yield a significant difference.
PM = premotor cortex; M1 = primary motor cortex.
Acute visual neglect and extinction
did not yield a significant difference (control patients t = 1.01,
P = 0.32; patients with extinction t = 1.58, P = 0.12; patients
with neglect t = 1.65, P = 0.12). This provides evidence for a pre-
served blood oxygen level-dependent response in the undamaged
territory of the right and left middle cerebral artery in all groups of
patients.
Discussion
This is the first study assessing the functional state of the visuo-
spatial attention system in patients with acute stroke before major
reorganization processes have progressed. We investigated pa-
tients with comparable right hemisphere infarcts, who differed in
the degree of visuospatial attention deficit: (i) no deficit (control
patients); (ii) extinction; or (iii) neglect, and age-matched healthy
volunteers. In accordance with the behavioural neglect testing, the
rightward attentional bias in the functional MRI experiment
increased from control patients over those with extinction to pa-
tients with neglect, while processing of targets in the right hemi-
field was almost preserved in all groups (470%). Although
neglect patients detected fewer targets in the right hemifield com-
pared with control ones, they did not differ in the rightward spa-
tial processing from patients with extinction. This demonstrates a
behavioural continuum in visuospatial abilities in these groups and
indicates that the functional MRI experiment probed into a clinic-
ally relevant feature of all examined groups. The functional MRI
paradigm aimed at activating the visuospatial attention system as
a whole, including both orientation and target detection compo-
nents. The obtained activation in healthy subjects and control pa-
tients is generally in line with the results of the previous studies
(Corbetta et al., 2000; Perry and Zeki, 2000). On the other hand,
we used a Posner-like paradigm that did not examine the visual
competition between targets and distractors, which might be con-
trolled by the distinct brain structures (Vandenberghe et al.,
2005). Thus, the attention network, which is examined in the
present study, might not be completely identical to that one,
which is pathologically impaired during neglecting of targets that
presented with distractors. Although this issue may be addressed
in future works, the absence of functional MRI studies with visual
competition in patients with neglect points to the experimental
difficulties especially in acute stroke patients. Furthermore, patients
with neglect did show the phenomenon of neglect during the
present functional MRI experiment even without visual
competition.
All three groups of patients were comparable in lesion anat-
omy: they had embolic infarcts in the right middle cerebral
artery territory. Control patients had lesions in the right fronto-
temporal cortex including the adjacent white matter, i.e. they
showed lesions typically associated with neglect (Husain and
Kennard, 1996; Karnath et al., 2004). The lesions found in
patients with extinction were in line with the literature findings
(Lynch and McLaren, 1989; Ticini et al., 2010; Vossel et al.,
2011). In line with the previous data, in the present study, pa-
tients with neglect had significantly larger infarcts than other
groups of patients.
Brain 2011: 134; 3310–3325 | 3321
Left parietal hyperactivation is not
specific for acute neglect
For a long time, neglect was believed to be a result of a functional
imbalance between undamaged left and impaired right parietal
cortices that biases attention towards the ipsilesional side of
space (Kinsbourne, 1970). This model was supported by a func-
tional MRI study of Corbetta et al. (2005) showing an abnormal
pattern of activation in patients with neglect with increased acti-
vation in the left parietal cortex compared with the right. Further,
in this study the left parietal cortex showed a relatively higher
response in patients, who detected fewer targets in the left
visual field and responded slower to left as compared with right
visual field targets (Corbetta et al., 2005). It was concluded that
the relative hyperactivity of the left intraparietal sulcus provoked
such attentional imbalance and consequently a poor left-sided
performance.
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The present data are in line with those of Corbetta and Shulman
(2002), as neglect was provoked by a lesion of the ventral atten-
tion system with the resulting relative imbalance between activa-
tions in the left and right parietal regions (Corbetta et al., 2005).
However, first, all patients groups, including those without neg-
lect, demonstrated such a ‘push-pull’ pattern of parietal activation.
Moreover, groups of patients did not differ between each other in
the laterality indices. Secondly, the laterality indices of the parietal
activation did not correlate with severity of the right attentional
bias. And finally, the left parietal activation was not higher in pa-
tients with neglect than in other groups and even tended to be
less pronounced than in control patients. Taken together, the rela-
tive left–right parietal imbalance alone did not sufficiently explain
the rightward attentional bias, but rather represented a conse-
quence of the acute severe right hemisphere structural damage,
in other words an epiphenomenon but not the cause of neglect.
Reduced activation of right parietal cortex and right lateral occipi-
tal cortex were more specific neural correlates of neglect (Figs 3, 5
and 6).
In patients with neglect, activation of the left frontal eye field
was also reduced. This may explain why not only the responses to
left targets, but also those to right ones, become progressively
slower as severity of neglect increases (Bartolomeo and Chokron,
1999); and why patients with left hemispatial neglect may also
present the additional neglect in extreme right space (Ellis et al.,
2006). The bilateral hypoactivation of the attentional centres may
reflect a pathomechanism of the non-lateralized deficits in patients
with neglect. For example, the non-spatial selective attention and
spatial working memory deficits, which are present in neglect, do
not necessarily worsen towards one side of space (Husain et al.,
1997; Malhotra et al., 2005). At the same time, there are reports
of a pathological over-excitability of the left hemisphere in neglect
but not in control patients several weeks after stroke (Koch et al.,
2008). This may potentially be explained through the differences
in the lesion size between patients with and without neglect: pa-
tients without large structural lesions and without neglect tend to
recover faster. This might be associated with better restoration and
rebalancing of brain activation in control patients compared with
neglect ones.
3322 | Brain 2011: 134; 3310–3325
Distinct pattern of activation in
extinction
The activation pattern in patients with extinction was distinct from
all other examined groups and showed an increased activation
and additional involvement of the dorso- and ventrolateral pre-
frontal cortex in the left hemisphere, including posterior middle
frontal gyrus, posterior inferior frontal gyrus and bilateral
pre-supplementary motor area. At the same time according to
the region of interest analysis, patients with extinction did not
differ from control patients in the state of the dorsal attention
system including the left intraparietal sulcus. Compared with pa-
tients with neglect, those with extinction had a stronger activation
of bilateral frontal eye field and left posterior inferior frontal gyrus.
These findings suggest that extinction group was characterized by
a distinct state of the attention system and not by its ‘milder’
dysfunction compared with neglect. It may be argued that add-
itional activation of the left prefrontal cortex in patients with ex-
tinction reflected the transcallosal disinhibition with resulting
hyperactivity of the left hemisphere. That would be in line with
the theory of hemispheric rivalry: the activation of undamaged
hemisphere suppresses the weaker, damaged one (Kinsbourne,
1970). In this case, the contralesional prefrontal hyperactivation
might represent a pathomechanism of extinction. However, ac-
cording to this assumption, a greater release of the left hemisphere
and more severe left–right imbalance are to be expected after the
larger right-sided strokes typical for neglect. But patients with neg-
lect did not show any absolute hyperactivation within the left
hemisphere. Thus, visual extinction in the present study may not
be explained through the increased contralesional activation.
The question remains as to what happens during bilateral stimu-
lation, which is specifically impaired in extinction. Does the hyper-
function of the left prefrontal cortex suppress the perception of
the contralesional stimuli during bilateral stimulation? The func-
tional MRI paradigm in the present study was not specific for an
extinction deficit, since there were no trials with bilateral visual
stimulation. But the previous data with bilateral presentation of
other kind of stimuli (faces) demonstrated that the conscious per-
ception of faces in the left visual field increased activity in the left
frontal and parietal areas besides the right visual areas (Vuilleumier
et al., 2001, 2002; Rees et al., 2002). Bilateral trials with an ex-
tinguished faces in the left visual field did not show activation of
the left parietal or left frontal areas; in other words, activity in the
left attentional centres was not associated with the phenomenon
of extinction.
In light of the theory of the limited attentional capacity after
right hemisphere damage, the contralesional activation might rep-
resent some residual visuospatial function sustaining contralesional
visuospatial processing. In the present study, the left-lateralized
activation correlated positively and strongly with the rate of re-
sponses to the left targets (Fig. 7). This could not be explained by
Kinsbourne’s hemispheric rivalry hypothesis and indicates a com-
pensatory nature of the contralesional activations. The left hemi-
sphere functional compensation might fail in neglect due to the
large lesions that provoke an extensive diaschisis and result in a
transhemispheric downregulation in acute stroke. In addition,
R. M. Umarova et al.
insufficient time for such compensation or insufficient individual
neuroplastic resources might prevent patients with neglect in
acute stroke to recruit the left hemisphere for impaired attentional
functions. Thus, we argue that the additional activation of the left
prefrontal cortex in patients with extinction was not the effect of
transcallosal disinhibiton, but rather reflected the functional com-
pensation after critical damage of the attentional centres in the
right hemisphere. We cannot exclude that the additional pre-
frontal activation in the left hemisphere modulated the right
dorsal attention network and thus supported the contralesional
visual processing. This is in line with the previous studies demon-
strating that spontaneous recovery from neglect in the later stage
was associated with increase of neural activity not only in the
right parietal cortex but also in the left dorsolateral prefrontal
and left parietal cortex (Corbetta et al., 2005; Thimm et al.,
2008) or left temporo-occipital and medial temporal cortex
(Luaute et al., 2006).
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Several studies demonstrated a positive effect of the contrale-
sional activation on the motor and language recovery in stroke
patients (Weiller et al., 1992, 1995; Musso et al., 1999;
Johansen-Berg et al., 2002; Gerloff et al., 2006; Saur et al.,
2006; Schaechter and Perdue, 2008; Bestmann et al., 2010;
Riecker et al., 2010). As for the motor and language systems,
similar mechanisms may apply to recovery of visuospatial atten-
tion. We argue that the activity of the left hemisphere structures
may be functionally relevant for the recovery of visuospatial at-
tention and may be a substrate for a functional compensation
after the large right hemispheric lesion.
Activation of the visual cortex in spatial
attention deficit
In the present study, the right lateral occipital cortex and V1,
which were spared and remote from lesions, had a pathologically
reduced activation in patients with neglect. Similar results were
demonstrated in the previous studies (Lumer et al., 1998; Driver
et al., 2001; Vuilleumier et al., 2001, 2008; Rees et al., 2002;
Corbetta et al., 2005). Studies on attentional modulation of
early visual areas (V1/V2) in healthy subjects showed that con-
scious perception of stimuli is possible only through a functional
interaction between the visual and frontoparietal cortex (Buchel
et al., 1998; Lumer et al., 1998; Lumer and Rees, 1999). In neg-
lect and extinction patients, V1 was activated without visual
awareness, but this activation was stronger for consciously de-
tected versus extinguished stimuli (Rees et al., 2000, 2002;
Driver et al., 2001; Vuilleumier et al., 2001, 2002). The abnormal
top–down modulation from the frontoparietal cortex in neglect
might decrease both stimulus-evoked responses and spatial select-
ivity of visual neurons, weakening the relative salience of stimuli
presented in the left visual field (Corbetta et al., 2005).
The study of Vuilleumier et al. (2008) also demonstrated
attention-dependent modulation of the extra- and striate visual
cortex in patients with visual neglect. When the attention load
was high, the right visual cortex showed pathologically reduced
responses particularly in the right V4/TEO to task-irrelevant
checkerboards in the contralateral left hemifield, whereas left
Acute visual neglect and extinction
visual areas showed no such reduction in their contralateral re-
sponse. Thus, the extrastriate areas, supporting higher order
visual processing, became ‘blind’ to the visual stimuli. Similarly in
animal studies, the different attentional loads under the same
visual input modulated the neuronal activity in the lateral occipi-
tal cortex (Treue and Maunsell, 1996, 1999). Hypoactivation
of the right extrastriate area, labelled as lateral occipital cortex,
as the most consistent correlate of neglect in the present
study was not previously described. Our data confirmed that
lateral occipital cortex is a necessary node in the visuospatial
processing, through which the high-order attentional centres
modulate and receive bottom–up inputs from V1, and the lesion
of which may provoke neglect (Payne et al., 1996; Saalmann
et al., 2007).
Functional magnetic resonance
imaging in acute stroke
Functional MRI examination of acute stroke patients and its inter-
pretation are difficult (Saur et al., 2006). In our study, several
measures were taken to reduce the danger of misinterpretations
due to the blood oxygen level-dependent response changes in
ischaemic stroke. First, strict exclusion criteria were applied, so
that patients with severe vessel stenosis or occlusion were not
included in the study. Secondly, we used an adequate reference
sample, since the structural lesion in acute stroke leads to a chain
of metabolic and vascular brain changes in distant, undamaged
and even contralesional regions, which may also be an effect of
diaschisis (Monakow, 1906; Baron, 1989). We therefore included
a control group of patients without any visuospatial deficit but
with acute territorial right middle cerebral artery stroke, which
demonstrated a strong and spared blood oxygen level-dependent
response and a pattern of activation similar to that of healthy
subjects.
On the other hand, patients with neglect had larger infarcts
that might provoke an abnormal blood oxygen level-dependent
response in undamaged tissue of the right middle cerebral artery
territory and vascular ischaemic effects might mimic a true hypo-
function. Therefore, we investigated the blood oxygen
level-dependent response in the right middle cerebral artery terri-
tory to right-handed button presses. As was previously shown
(Weiller et al., 1992, 1996; Johansen-Berg et al., 2002; Witt
et al., 2008), active movements (i.e. the button press) were asso-
ciated with activation of ipsilateral premotor cortex and basal
ganglia besides the contralateral motor areas (Fig. 8). The absence
of differences between patients and healthy subjects provides evi-
dence for a preserved blood oxygen level-dependent response and
indicates a true hypofunction of the bilateral attention system in
the present study.
Funding
Postdoctoral fellowship of the German Academic Exchange Service
(DAAD).
Brain 2011: 134; 3310–3325 | 3323
Supplementary material
Supplementary material is available at Brain online.
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