Durham Research Online
Durham Research Online
Deposited in DRO:
08 June 2012
Version of attached le:
Published Version
Peer-review status of attached le:
Peer-reviewed
Citation for published item:
Lewald, J. and Tegentho, M. and Peters, S. and Hausmann, M. (2012) 'Passive auditory stimulation
improves vision in hemianopia.', PLoS ONE., 7 (5). e31603.
Further information on publisher's website:
https://doi.org/10.1371/journal.pone.0031603
Publisher's copyright statement:
Copyright:
c
2012 Lewald 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.
Additional information:
Use policy
The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for
personal research or study, educational, or not-for-prot purposes provided that:
• a full bibliographic reference is made to the original source
• a link is made to the metadata record in DRO
• the full-text is not changed in any way
The full-text must not be sold in any format or medium without the formal permission of the copyright holders.
Please consult the full DRO policy for further details.
Durham University Library, Stockton Road, Durham DH1 3LY, United Kingdom
Tel : +44 (0)191 334 3042 | Fax : +44 (0)191 334 2971
http://dro.dur.ac.uk
Passive Auditory Stimulation Improves Vision in
Hemianopia
Jörg Lewald1,2*, Martin Tegenthoff3, Sören Peters4, Markus Hausmann5
1 Department of Cognitive Psychology, Faculty of Psychology, Ruhr University Bochum, Bochum, Germany, 2 Research Group Ageing and CNS Alterations, Leibniz
Research Centre for Working Environment and Human Factors, Ardeystr, Dortmund, Germany, 3 Department of Neurology, BG-Kliniken Bergmannsheil, Ruhr University
Bochum, Bochum, Germany, 4 Department of Radiology, BG-Kliniken Bergmannsheil, Ruhr University Bochum, Bochum, Germany, 5 Department of Psychology, University
of Durham, Durham, United Kingdom
Abstract
Techniques employed in rehabilitation of visual field disorders such as hemianopia are usually based on either visual or
audio-visual stimulation and patients have to perform a training task. Here we present results from a completely different,
novel approach that was based on passive unimodal auditory stimulation. Ten patients with either left or right-sided pure
hemianopia (without neglect) received one hour of unilateral passive auditory stimulation on either their anopic or their
intact side by application of repetitive trains of sound pulses emitted simultaneously via two loudspeakers. Immediately
before and after passive auditory stimulation as well as after a period of recovery, patients completed a simple visual task
requiring detection of light flashes presented along the horizontal plane in total darkness. The results showed that one-time
passive auditory stimulation on the side of the blind, but not of the intact, hemifield of patients with hemianopia induced
an improvement in visual detections by almost 100% within 30 min after passive auditory stimulation. This enhancement in
performance was reversible and was reduced to baseline 1.5 h later. A non-significant trend of a shift of the visual field
border toward the blind hemifield was obtained after passive auditory stimulation. These results are compatible with the
view that passive auditory stimulation elicited some activation of the residual visual pathways, which are known to be
multisensory and may also be sensitive to unimodal auditory stimuli as were used here.
Trial Registration: DRKS00003577
Citation: Lewald J, Tegenthoff M, Peters S, Hausmann M (2012) Passive Auditory Stimulation Improves Vision in Hemianopia. PLoS ONE 7(5): e31603. doi:10.1371/
journal.pone.0031603
Editor: Mark W. Greenlee, University of Regensburg, Germany
Received September 15, 2011; Accepted January 10, 2012; Published May 29, 2012
Copyright: ß 2012 Lewald 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: This research was supported by the Deutsche Forschungsgemeinschaft (FA 211/24-1; http://www.dfg.de). 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: [email protected]
relatively low unconscious level without acknowledged awareness)
in their anopic hemifield which has been referred to as blindsight
[5–10]. These residual abilities in HA have usually been proposed
to rely on ‘‘residual’’ visual pathways that are independent of the
damaged geniculostriate pathway to the primary occipital area
(V1). In particular, visual information may be conveyed from the
eye directly to the SC, from there to the pulvinar nucleus of the
thalamus which, in turn, projects not only to parietal but also onto
temporal (including primary auditory) cortices [6,9,11–13].
Alternatively, in cases where the lateral geniculate nucleus is left
intact, projections from this structure to extrastriate cortex may
enable V1-independent processing of visual information [14].
However, residual visual functions can also be based on surviving
visual fibres of the geniculostriate pathway [15–17]. Thus, residual
visual abilities in the anopic hemifield of HA patients can, in
principle, rely on two types of residual fibers: (1) intact fibers of the
extrastriate visual pathways and (2) surviving fibers in the partially
damaged primary visual system.
It is important to note that almost all brain regions involved in
both types of these ‘‘residual’’ pathways are multimodal structures,
which are not only involved in processing of auditory and visual
information, but also in the allocation of attention across sensory
modalities. The SC contains superimposed maps of visual and
Introduction
In the mammalian brain, auditory and visual systems are closely
interconnected. Single-neuron recordings in non-human species
have demonstrated auditory-visual bisensory responses as well as
effects of cross-modal integration in a multitude of subcortical and
cortical regions. These comprise the inferior and superior colliculi,
the thalamus and frontal, temporal, insular, parietal, and occipital
cortices which include the presumptive unimodal sensory areas.
Moreover, neuroimaging studies have indicated potential correlates of bisensory phenomena in human cortex [1,2]. These
interconnections between the senses may form the structural basis
for the remarkable capacity of spatial cross-modal plasticity which
can occur in a surprisingly short time scale (e.g., [3,4]).
Currently, the issue of cross-modal spatial plasticity attracts
growing attention with respect to patients with homonymous
hemianopia (HA). This is a visual field defect, characterized by a
loss of vision in one hemifield. It is caused by unilateral brain
lesions located contralaterally to the anopic side in postchiasmatic
optic tract, lateral geniculate nucleus, optic radiation or (in the
majority of cases) in the occipital lobe, while leaving intact the
superior colliculus (SC). The functional integrity of the SC in HA
may result in the retention of some residual visual functions (at a
PLoS ONE | www.plosone.org
1
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
auditory spaces, in particular topographically-aligned eye-centred
bisensory representations of contralateral hemispace, located in
the deep and intermediate layers [18,19]. This structure is also
known to be crucially involved in the control of both overt and
covert spatial attention [20,21]. With respect to the pulvinar
nucleus, Cappe et al. [22] recently suggested that it receives
multisensory information from the SC and, referring to the
hypothesis of Crick and Koch [23], loops between cortex and
pulvinar may be part of mechanisms involved in multisensory
integration observed in unisensory cortical areas. Neurons in the
posterior parietal cortex, that is known to receive inputs from the
pulvinar [24] and to have direct interconnections with ipsi- and
contralateral SC [25], have been shown to support the integration
of auditory and visual space [26,27] as well as the control of
auditory and visual spatial attention [28,29]. Auditory-visual
interaction has also been demonstrated in single cells in the cortex
of the superior temporal sulcus [30]. Finally, there is sufficient
evidence from human and animal research that even the primary
visual system, namely the lateral geniculate nucleus [31,32] and
the primary visual cortex [33–39], exhibits properties of auditoryvisual cross-modal interaction.
In accordance with these findings, the relevance of auditoryvisual bisensory integration of information has been demonstrated
in patients with HA. It has been found that a sound, spatially and
temporally coincident to a visual stimulus, can improve visual
perception in the blind hemifield of hemianopic patients [40]. In
addition, auditory localization performance in the blind hemifield
was markedly enhanced when a visual stimulus was coincident
with the acoustic target in both space and time [41]. Adaptation by
spatially coincident repetitive auditory-visual stimulation induced
significant improvement in auditory localization after exposure
[42]. Most importantly, systematic training with auditory spatial
stimuli presented in spatio-temporal alignment with visual stimuli,
was shown to induce long-lasting visual improvement in visual
search in the anopic hemifield [43].
As with previous approaches, the present study started from the
largely accepted basic hypothesis that sensory input from an intact
modality (audition) can improve processing of information by
spared structures of a damaged sensory system (vision). Activation
of the colliculo-pulvinar-extrastriate pathway and/or surviving
parts of the primary pathway in HA may induce an improvement
of the related residual visual abilities in the blind field, either by
more effective sensory processing of unimodal visual information
within the ‘‘residual’’ pathway, or by an increase of spatial
attentional functions. We made the assumption that auditoryvisual bimodal neurons not only respond to stimulus combinations
from different modalities, but also can show suprathreshold
responses to unimodal stimuli, thus providing a substrate for
signalling in two separate modalities, despite their potential for
integrating information from different modalities (cf. [44]). Previous
bimodal approaches to improve blind-field vision in HA (e.g., [45])
have focussed on the latter issue, correctly arguing that combining
auditory and visual stimuli may be more beneficial than unimodal
stimuli in this respect, given the known mechanisms of multisensory interaction, in particular those of multisensory enhancement
observed in SC neurons (for review, see [1]). However, while such
multisensory integrative properties may be present in a relatively
small portion of cells, it is known that the vast majority of neurons
in SC and in posterior parietal cortex show multisensory sensitivity,
that is, most neurons that are responsive to visual stimuli respond
equally well or even more strongly to unimodal auditory stimuli
(e.g., [18,27]). Thus, as separate modalities are processed by the
same neurons and the same synapses, it is reasonable to suggest
that activation of these multimodal circuits by unimodal auditory
PLoS ONE | www.plosone.org
stimuli could induce facilitating effects of unimodal visual
information within these bimodal pathways. We therefore used
unimodal auditory stimuli for activation of the multisensory
‘‘residual’’ pathways to test whether this stimulus type is suited to
induce improving effects on blind-field vision in HA.
While earlier approaches used training procedures involving the
execution of specific tasks, we employed a protocol of passive
auditory stimulation (PAS). This protocol closely follows the idea
that synchronous neural activity, necessary to drive plastic
changes, is evoked by repetitive sensory stimulation without
requiring any active task from the patient [45]. Such task-free,
passive stimulation protocols, also referred to as coactivation or
unattended activation-based learning, have been shown in several
previous studies to improve tactile and sensorimotor performance
in healthy human subjects as well as in subacute and chronic
stroke patients [46–49]. We hypothesised that PAS on the anopic
side of HA patients may induce short-term cross-modal effects,
resulting in an improvement of vision immediately after PAS.
Since the SC contains a map of the contralateral half of the
auditory space (for review, see [1]), we assumed that hemispatial
PAS on the anopic side (thus selectively activating the residual
pathway in the damaged cerebral hemisphere) would be more
effective than PAS on the side of the intact hemifield.
Materials and Methods
Ethics Statement
This study conformed to the Code of Ethics of the World
Medical Association (Declaration of Helsinki), printed in the
British Medical Journal (18 July 1964). All patients gave their
written informed consent to participate in this study, which was
specifically approved by the Ethical Committee of the Medical
Faculty of the Ruhr University Bochum.
Patients
Ten patients with brain lesions participated in this study. All of
them had received the diagnosis of persistent homonymous
hemianopia (HA) confined to one hemifield, as confirmed by
visual perimetry. HA was left-sided (LHA) in seven patients
(LHA1–LHA7) and right-sided (RHA) in three patients (RHA1–
RHA3). Age, sex, visual field defects and lesion sites are reported
in Table 1 (detailed information on lesion sites is given in Fig. 1).
All patients were congenitally right-handed, as assessed by a
German adaptation of Coren’s [50] inventory [51], with a
criterion of an individual score of $2 (range from 24 to 4) in
the hand section of this questionnaire. However, hemiparesis
prevented two patients (LHA6, RHA2) from use of their
contralesional hand, and two other patients (LHA4, LHA7)
showed mild impairment with use of the contralesional hand due
to hemiparesis. Two further patients (one LHA and one RHA
patient) were also tested, but were excluded from the study. One of
the excluded patients already showed excessive variation in the
position of the VFB (maximum difference .20 degrees) between
baseline measurements, and the other patient was unable to follow
adequately the instruction to fixate on the central fixation target
during experimental blocks (see below). All patients were naı̈ve
with respect to the purpose of the experiment.
All HA patients had circumscribed brain lesions as a result of
ischemic stroke or haemorrhage, demonstrated by magnetic
resonance imaging (MRI) or computed tomography (CT). In all
patients, lesions were unilateral (i.e., on the side contralateral to
the anopic hemifield), with the exception of patient RHA3 who
showed some minor involvement of right-hemispheric regions in
addition to the predominant left-hemispheric lesion (see Fig. 1).
2
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Table 1. Summary of clinical data and visual field defects of patients with hemianopia.
Patient
Age
Sex
Side of HA
VF border
Time since onset
Ethiology
Lesion site
LHA1
39
F
Left
21.7u
10 months
AVM
Right temporo-parieto-occipital
LHA2
61
M
Left
23.8u
7 years
ICH
Right temporal
LHA3
64
M
Left
22.3u
9 months
CI
Right temporo-occipital
LHA4
23
F
Left
25.1u
44 months
CI, ICH
Right temporo-parieto-frontal
LHA5
65
M
Left
23.4u
6 years
CI
Right occipital
LHA6
43
F
Left
20.1u
43 months
CI
Right temporal
LHA7
40
M
Left
21.8u
6 years
CI
Right occipital
RHA1
44
M
Right
+13.0u
5 months
CI
Left temporo-parieto-occipital
RHA2
48
M
Right
+0.7u
34 months
CI
Left temporo-occipital
RHA3
37
F
Right
+3.0u
8 months
CI
Left parieto-occipital, right occipital
VF borders are means across pre-PAS blocks in all three experimental conditions. Negative VF borders are to the left, positive to the right.
Abbreviations AVM, cerebral arteriovenous malformation; CI, cerebral ischemia; ICH, intracerebral hemorrhage; HA, hemianopia; PAS, passive auditory stimulation; VF,
visual field.
doi:10.1371/journal.pone.0031603.t001
To test whether HA patients suffer from spatial neglect a
neglect-test battery [52] was applied, which consisted of the
following tests: (a) Letter Cancellation task [53], which requires the
patient to cancel all target letters ‘A’ (30 on the left and 30 on the
right side) distributed amid distractors on a horizontally oriented
standard page (DIN A4). Patients are classified as suffering from
spatial neglect when they omit at least five targets on the left. (b)
Bells Test [54], which consists of seven columns each containing
five targets (bells) and 40 distractors. Three of the seven columns
( = 15 targets) are located on the left and three columns ( = 15
targets) are located on the right side of a horizontally oriented
standard page. When patients omit more than five left sided
targets, they are classified as suffering from spatial neglect. (c)
Baking Tray Test [55], which requires the patient to place 16
identical items as evenly as possible on a blank standard page (8 on
the left, and 8 on the right side). Any distribution more skewed
than seven items on the left side and nine items on the right side is
considered as a sign of spatial neglect. (d) Copying task [52,56], in
which patients are asked to copy a complex multi-object scene
consisting of four figures on a standard page (two on the left, and
two on the right side). Omission of one left-sided feature of each
figure is scored as 1, and omission of each whole figure is scored as
2, resulting in a maximum score of 8. A score higher than 1 (i.e.
.12.5% omissions) is considered as a sign of spatial neglect. None
of the HA patients exceeded the limit values in at least two of these
four tests, which has been regarded as the criterion for presence of
spatial neglect [57].
In addition, we applied a line-bisection task which comprised 17
horizontal black lines of 1 mm width on a horizontally-oriented
white standard page. The lines ranged from 100 to 260 mm long, in
steps of 20 mm. The mean length was 183.5 mm. Patients were
asked to bisect all lines into two parts of equal length by marking the
subjective midpoint of each line with a fine pencil (for details, see
e.g. [58,59]). Neglect patients typically show a large bisection bias
towards the right. Unlike that, the HA patients showed a significant
mean bisection bias of 4.05% (SE 1.70, range from 22.92% to
11.32%; t[9] = 2.38, p = 0.041) toward the side of the anopic
hemifield (LHA: mean leftward bias 6.01%, SE 1.94; RHA: mean
rightward bias 0.53%, SE 1.47). This conforms with previous
findings of a contralesional bias in patients with HA (e.g., [58–60]).
Prior to experimentation, the presence of homonymous HA was
confirmed by visual static perimetry in all patients included in this
study (see plots in Fig. 2). In addition, the azimuthal dimensions of
PLoS ONE | www.plosone.org
the visual field, and in particular the position of the binocular VFB
(see Table 1) was derived from the baseline measurements in each
experimental session, using visual stimulation by the experimental
apparatus (see below). Across all patients, the baseline VFB was
only slightly shifted toward the side of the anopic field (mean
3.48u, SE 1.16u). One of the patients (LHA7) showed incomplete
left HA, with a small peripheral area of vision lying to the left of
the anopic field.
All patients were tested for general hearing loss. For this
purpose, white-noise bursts with a duration of 1 s were presented
monaurally via headphones (K271, AKG Acoustics, Vienna,
Austria) at various sound-pressure levels (SPLs, range 10–80 dB re
20 mPa, steps of 10 dB; onset/offset time 50 ms), and patients
pressed a button as soon as they heard a sound. In this test, HA
patients did not show any superiority of the ear on the side of the
intact (contralateral) or the anopic (ipsilateral) hemifield
(t[9] = 0.00, p = 1.00).
Prior to these experiments, all HA patients had already
participated in studies in which they had been tested for spatial
hearing abilities [61,62]. In these previous studies, patients showed
statistically significant deficits in accuracy and precision of sound
localization compared with healthy controls. However, in absolute
terms, impairments were very slight, such that the patient’s general
ability to localize a sound could be considered as quasi-normal (for
details, see [61,62]). Each patient completed the first session of the
present experiment within 2 to 11 months after these investigations.
Apparatus and stimuli
The experiments took place in a sound-proof and anechoic room
(5.464.462.1 m3), which was insulated by 40 cm (height)640 cm
(depth)615 cm (width at base) fiberglass wedges on each of the six
sides. A suspended mat of steel wires served as floor. The ambient
background noise level was below 20 dB(A) SPL.
The patient sat on a comfortable chair with their head fixed by a
custom-made framework with stabilizing rests for the chin,
forehead, and occiput (see [63]). In front of the patient, at a
constant distance of 1.5 m from the centre of the head, 91 broadband loudspeakers (569 cm2, Visaton SC 5.9, Visaton, Haan,
Germany) were mounted in the patient’s horizontal plane. The
azimuth of the loudspeakers ranged from 290u (left) to 90u (right), in
steps of 2u, with the centre loudspeaker at 0u. However, only four of
the loudspeakers were used in these experiments (see Fig. 3A): two
3
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 1. Lesion sites. Series of schematic brain slices along the superior-inferior direction for each of the ten patients are depicted using
standardized templates from Damasio and Damasio [84], with black areas indicating the lesioned sites. More inferior templates are to left, more
superior templates to the right. Templates are in neurological orientation, i.e., the left side of the template refers to the left side of the brain.
doi:10.1371/journal.pone.0031603.g001
loudspeakers at 276u and 214u to the left (for left-sided PAS); and
two loudspeakers at 14u and 76u to the right (for right-sided PAS).
The PAS protocol used here has been originally developed by
J. Lewald, S. Getzmann, and H. R. Dinse (unpublished; [64]).
The PAS protocol was adopted from the previous literature on
unattended activation-based learning in the tactile modality. We
used a high-frequency stimulation protocol (10 Hz) for PAS, as
has been shown to induce improvement of sensory performance
in these previous studies. It has been suggested that this type of
sensory stimulation may evoke processes of long-term potentiation (LTP) of synaptic transmission, thus resulting in activitydependent strengthening of synaptic connections (e.g., [45]). The
PLoS ONE | www.plosone.org
acoustic stimulus used consisted of band-pass-filtered frozen noise
(lower cutoff frequency 2 kHz; upper cutoff frequency 11 kHz).
The cutoff frequencies were chosen on the basis of pilot
experiments, in order to maximize the spatial separability, as
stimuli were presented simultaneously from two locations.
Stimuli were trains of ten sound bursts (Fig. 3B). Each stimulus
train had an overall duration of 960 ms; single sound bursts had
a duration of 60 ms with triangular envelope (onset/offset time
30 ms) and were presented at a rate of 10 s21. The stimulus
trains were presented at a rate of one per 5 s (interstimulus
interval 4.04 s). PAS stimuli were always emitted simultaneously
from two loudspeakers located 14u and 76u on the same side.
4
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 2. Visual field defects of patients with left (LHA1–7) and right hemianopia (RHA1–3). The left panel shows the azimuthal
dimensions of the binocular visual fields, as were measured without PAS (mean of pre-PAS blocks 1 and 2 across all three sessions). For each patient,
the percentage of correct detections (gray bars) of visual stimuli is plotted as a function of the stimulus azimuth (steps of 2u; negative azimuths, left
hemifield; positive values, right hemifield). The right panel shows reconstructions of the monocular visual fields based on static perimetry (black
areas: anopic regions; white areas: intact regions).
doi:10.1371/journal.pone.0031603.g002
Analogously to the previous tactile studies, we presented two
stimulus locations simultaneously in order to activate large parts
of the multisensory map of contralateral hemispace that is
present in SC (for review, see [1]). In order to prevent fusion of
the two sound sources into one unified percept, we used
incoherent noise, i.e. waveforms delivered by the two loudspeaker
channels were independent. Under these conditions, normal
subjects typically hear two spatially disparate sounds, or at least a
sound image extending over a relatively broad range in azimuth
within the stimulated hemifield. Sound stimuli were generated
digitally using CoolEdit 2000 (Syntrillium Software Co., Phoenix,
AZ, USA) and converted to analog form via a computer-controlled
external soundcard (Sound Blaster Audigy 2 NX, Creative Labs,
Singapore) at a sampling rate of 96 kHz. Sound stimuli were
presented at a sound-pressure level of 60 dB(A).
For visual stimulation, at the lower edge of the chassis of each
loudspeaker a white light-emitting diode (LED) was mounted in a
central position, thus resulting in an array of 91 LEDs over 180u
azimuth centered to the patient’s head (Fig. 3A). Each of these
LEDs (diameter 10 mm; luminance about 700 cd/m2) was
mounted in a small housing impermeable to light, with a central
circular aperture of 2 mm diameter immediately in front of the
LED (resulting in a luminous intensity of about 0.003 mcd). As the
aperture resulted in a narrow viewing angle of the LED and the
optical axis of the LED was exactly oriented toward the patient’s
head, straylight was almost completely prevented. Moreover, the
experimental setup in front of the patient including loudspeakers
and LED housings were matt black, and any specular lightreflecting surfaces did not exist in the experimental room.
PLoS ONE | www.plosone.org
Visual stimuli consisted of single light flashes with rectangular
envelope (duration 50 ms). In addition, one dim red LED
(diameter 3 mm; luminance about 35 cd/m2) served as a fixation
target. The fixation LED, that was permanently on, was mounted
immediately below the central loudspeaker (0u azimuth). In order
to control for accurate fixation, eye position was monitored online
by the experimenter via an infrared video camera. The video
camera was mounted on a long-focus lens and was focussed on the
patient’s right eye. The fixation LED emitted light of wavelengths
from the visible (red) down to the infrared range, and thus also
served as the light source for the infrared video camera.
The timing of the stimuli and the recording of the patients’
responses were controlled by custom-written software. Reaction
times (RTs) were measured by a high-resolution timer interface
connected with an external response button. All experimental
blocks were conducted in total darkness, except the visual stimuli
and the fixation LED. During the PAS period, the experimental
room was dimly illuminated (background luminance ,10 cd/m2) in
order to counteract drowsiness of the patients. The room was also
illuminated during pauses between experimental blocks and patients
had their eyes open prior to the beginning of each block, in order to
keep constant the level of pre-adapting luminance. Thus, conditions
of dark adaptation were constant for each block (see below).
Procedure
Conditions of PAS. The experiment consisted of three
sessions, conducted on different days, with intervals of several
weeks to months beween sessions. Patients completed all sessions
within 2 to 7 months. Sessions were conducted following a fixed
5
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
had merely a vague impression that any event appeared in their
blind field. The next stimulus followed after a quasi-randomly
varied time interval (balanced across trials) between 1 s and 3 s
(steps of 0.5 s) after the patients’ response ( = trial onset), such that
patients were not able to predict the time of stimulus presentation.
Results of the first 10 min of the block were discarded, as this period
was considered to be necessary for sufficient dark adaptation and to
give patients adequate practice with the task. Data were collected in
a total of 273 trials, in which each of the 91 stimulus positions was
presented three times. The overall duration of each block, including
the discarded trials, was about 30 min.
PAS. Immediately following the end of pre-PAS block 2, the
PAS was begun. The patient was seated with the head fixed, as in
the experimental blocks. No specific instruction was given. A total
of 720 acoustic stimulus pairs, always emitted simultaneously from
the two loudspeakers on the same side, were presented over a
period of 1 h. In the control session, no acoustic stimuli were
presented during this period (i.e., silence). Apart from that,
experimental conditions were as in sessions with PAS.
Data analysis
Responses to light flashes were considered to be correct if the
RT was within 1.5 s (see Fig. 4). Data were corrected for false
alarms, that is, reactions not controlled by the reaction stimulus.
For this purpose, all responses in one to two time intervals (overall
duration 1.5 s) between 1 s and 4.5 s after trial onset that were not
within the adjacent ‘‘correct’’ time interval of 1.5 s after stimulus
offset, were considered as false alarms. For example, when the
flash was presented 3 s after trial onset, the 1.5-s interval from
1.55 s after trial onset to stimulus offset was used for estimating
false alarms; or when the flash was presented 1.5 s after trial onset,
the sum of the periods from 0.5 s before stimulus offset and from
1.5 s to 2.5 s after stimulus offset was used for this purpose. For
each experimental block, the mean rate of false alarms was
subtracted from the patient’s rate of correct responses prior to
further data analysis. Across all patients the mean rate of false
alarms was 3.23% (SE 1.13). The mean rates of correct detections
adjusted for false alarms were 5.84% (SE 1.58) in the anopic
hemifield and 81.87% (SE 3.89) in the intact hemifield.
For statistical comparisons, data of LHA and RHA patients were
classified according to whether they had been obtained within the
patient’s anopic or intact hemifield and were pooled. The resulting
percentages of correct responses (minus false alarms) were plotted as a
function of stimulus azimuth for each experimental block (Fig. 5).
Two different analyses were performed on the basis of these data sets.
The first analysis concentrated on changes in the rate of correct
detections depending on the sequence of the experimental blocks.
Only detections in anopic hemifield were analysed in detail. We
refrained from corresponding analyses in intact hemifield because of
the inevitable presence of a ceiling effect (with nearly 100% correct
detections in the more central parts of the visual field; see Fig. 5).
In the second analysis, the VFB depending on the sequence of
the experimental blocks was derived from the same original data
sets. For computation of the VFB, the number of correct responses
(minus false alarms) was plotted as a function of stimulus azimuth
(h) within the range of 246u on the left to 46u on the right (in order
to exclude potential effects of peripheral vision), and fitted to the
sigmoid equation:
Figure 3. Experimental procedure for passive auditory stimulation (PAS). (A) Sounds were delivered simultaneously from two
loudspeakers which were both located on the same side, either to the
left or right from the patient’s median plane. (B) During the PAS period,
trains of ten 60-ms noise bursts were presented at a rate of 0.2 s21. (C)
Prior to the PAS, baseline data were obtained in two pre-PAS blocks (Pre
1, Pre 2), with an intermittent rest of 30 min (Rest 1). Immediately after
the end of the PAS followed the post-PAS block (Post), and then the
patient was allowed to rest (Rest 2). The final block (Recovery) was
started 1.5 h after the end of the post-PAS block.
doi:10.1371/journal.pone.0031603.g003
sequence, each session with a different condition of PAS. PAS was
applied to the anopic side in Session 1 and to the intact side in
Session 2. No acoustic stimulation was presented in the final
Session 3, which was used as the control condition (see below).
Course of the experimental session. Each session was
subdivided into four identical experimental blocks in which
patients performed the visual detection task (pre-PAS 1; pre-PAS
2; post-PAS; recovery). Prior to the beginning of the session,
patients were familiarized with the experimental set-up and a
minimum of 20 practice trials was conducted. After pre-PAS block
1 was completed, the patient was allowed to rest, and pre-PAS
block 2 was started 1 h after the beginning of pre-PAS block 1.
The PAS period lay between pre-PAS-2 and post-PAS blocks
(Fig. 3C). After the end of the PAS period, the post-PAS block was
started without a break. After this block was completed, the patient
was allowed to rest for about 1.5 h. Finally, the recovery block
started 2 h after the end of the PAS period.
Visual detection task. In each trial, a white light flash was
presented in total darkness. Trials were not announced. The timing
of the trial onset was controlled by the computer. The location of the
flash changed between trials following a fixed quasi-random order
over a range from 290u on the left to 90u on the right, in steps of 2u.
Patients were instructed to fixate the central red LED, and to press a
response button as soon as a white light flash appeared. Patients
were explicitly encouraged to guess and to also respond when they
PLoS ONE | www.plosone.org
f ~100 1ze{k(h{VFB)
where f is the frequency of responses, given as percentage; VFB is
that h where f is 50%; k is the slope of the function at 50%; e the base
6
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 4. Frequency distribution of reaction times (RTs). RTs obtained in anopic (upper plot) and intact hemifield (lower plot) are shown for
the four experimental blocks of the session with PAS on the side of the anopic hemifield. Each bar shows the number of responses to light flashes
recorded in a time interval of 0.5 s (mean values across all patients; error bars, standard error; 0 s = stimulus offset). The yellow area indicates the
range of RTs within that responses were considered to be correct (1.5 s after stimulus offset). The remaining responses outside this time window
were considered to be false alarms.
doi:10.1371/journal.pone.0031603.g004
of the natural logarithm. The mean coefficient of determination (R2)
of the fit was 0.91 (range from 0.27 to 1.00; p#0.0009 in each case),
indicating analyzable boundary of the visual field for all patients.
The visual-field border determinations did not differentiate between
areas of relative or absolute defect. In both analyses (correct
detections, VFB) the mean of the data obtained in blocks 1 and 2 was
used as the pre-PAS baseline for each individual patient. In neither
case, statistical comparisons of results obtained in blocks 1 and 2
revealed any significant difference (paired t-tests; t[9]#0.60, p$0.56).
For statistical analyses, two-factor repeated-measures analyses of
variance (ANOVAs) were conducted to compare performances of
patients at three measurement points in time (pre-PAS; post-PAS;
PLoS ONE | www.plosone.org
recovery) and for three conditions of PAS (anopic hemifield; intact
hemifield; control condition). In subsequent stages of analysis, onefactor ANOVAs were used to reveal differences between measurement points in time within one session and between conditions for
each measurement point in time. For all computations, the Mauchly
test of sphericity was checked, and the Greenhouse-Geisser
correction was performed when appropriate. The a-level was
adjusted for multiple testing (Bonferroni). In particular, a-adjustments accounted for the two independent analyses (correct
detections, VFB) performed on the basis of the same set of data.
7
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 5. Mean percentage of correct detections minus false alarms, plotted as a function of visual stimulus location, for the four
experimental blocks of the session with PAS on the side of the anopic hemifield. Bars indicate mean values across all patients (error bars,
standard error). Data for the central range (646u) were fitted to a sigmoid equation (solid curve, extrapolated to 690u), and the 50 percent point of
the curve was defined as the position of the VFB (vertical solid line). In the post-PAS block, the VFB was shifted by few degrees toward the side of the
anopic hemifield compared with the other blocks. Note that the negative percentages at some positions were the result of more false alarms than
correct detections. Negative azimuths, anopic hemifield; positive azimuths, intact hemifield; vertical dotted line, median plane.
doi:10.1371/journal.pone.0031603.g005
than those of both pre-PAS (5.17%, SE 2.03; t[9] = 4.29, p = 0.0020)
and recovery (5.09%, SE 1.30; t[9] = 4.09, p = 0.0027), while the
recovery results did not differ from the pre-PAS data (t[9] = 0.07,
p = 0.95). Thus, the percentage of correct visual detections in the
post-PAS block was increased by 86.5% with reference to the mean
of the pre-PAS and recovery measurements. Further subsequent
one-way ANOVAs with ‘‘Condition’’ as factor showed a significant
effect for the post-PAS measurement (F[2,18] = 12.89, p = 0.00034,
gp2 = 0.59), but not for the remaining two measurement points in
time (F[2,18]#1.59, p$0.23, gp2#0.15). Post-hoc paired t-tests
revealed that for the post-PAS block the percentage of correct
detections after PAS on the anopic side (9.56%, SE 2.01) significantly
differed from the control condition (4.95%, SE 1.81; t[9] = 6.63,
p = 0.00010). The difference in the percentage of correct decisions
between the intact-hemifield PAS (6.91%, SE 1.55) and the anopichemifield PAS only approached significance after Bonferroni
correction (t[9] = 2.45, p = 0.037) and was not significant for the
control condition (t[9] = 2.14, p = 0.061). Thus, with reference to the
control condition, PAS on the side of the anopic hemifield increased
the percentage of correct detections by 98.1%, while after PAS of the
Results
Effect of PAS on visual detections
A two-factor (363) repeated measures ANOVA with measurement point in time (‘‘Time’’) and ‘‘Condition’’ as within-patient
factors was conducted for correct detections of light flashes in the
anopic hemifield (2–90u azimuth). The ANOVA revealed a
significant main effect of the factor ‘‘Condition’’ (F[2,18] = 4.55,
p = 0.025, gp2 = 0. 34) and a two-way interaction of ‘‘Time’’6
‘‘Condition’’ (F[4,36] = 7.80, p = 0.00012, gp2 = 0.46), but no main
effect of ‘‘Time’’ (F[2,18] = 2.65, p = 0.10, gp2 = 0.23), indicating an
effect of the experimental condition that was specific to the
measurement point in time (Figs. 6A, 7). Subsequent one-way
ANOVAs for each hemifield condition with ‘‘Time’’ as factor
showed a significant effect with PAS on the side of the anopic
hemifield (F[2,18] = 9.87, p = 0.0013, gp2 = 0.52), but not for the
remaining two conditions (F[2,18]#1.64, p$0.22, gp2#0.15). Posthoc comparisons, using paired t-tests, revealed that the mean
percentage of correct detections obtained in the post-PAS block after
PAS on the anopic side (9.56%, SE 2.01) was significantly higher
PLoS ONE | www.plosone.org
8
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 6. Effects of PAS. Rate of correct detections in the anopic hemifield (A) and VFB (B) measured prior to PAS (pre-PAS, mean of blocks 1 and 2)
are compared with data obtained immediately after PAS (post-PAS) and after a period of recovery in three experimental conditions (PAS on the anopic
side; PAS on the intact side; control condition without PAS). Plots show mean values across all patients (error bars, standard error). Statistically significant
differences (asterisk; A) were found only for the rate of correct detections with the measurement after PAS on the side of the anopic hemifield. This value
differed from both pre-PAS and recovery data of the same session, and from the related measurement point in time of the control condition.
doi:10.1371/journal.pone.0031603.g006
the main experimental sessions. Patients were tested as in the main
session with PAS of the anopic side, except that a different PAS
protocol was used: Sound bursts (duration 400 ms; onset/offset time
200 ms; sound pressure level and spectral content as in the main
experiment; see Materials and Methods) were presented at a mean
rate of of 0.2 Hz, with 3 s jitter. Instead of simultaneous
presentation of sound stimuli from two different sources, each
sound burst was presented from one loudspeaker. Sound locations
changed between presentations following a random scheme, with
positions between 14u and 76u (steps of 2u) in the patient’s anopic
hemifield. This very-low frequency stimulation protocol was applied
in order to get some hints whether the effect obtained in the main
experiment (see above) was specific to the high-frequency PAS
protocol used, or was a consequence of the lateral acoustic
stimulation per se. One-way ANOVAs for these data with ‘‘Time’’
as factor showed a significant effect in the main experiment
(F[2,6] = 7.35, p = 0.024, gp2 = 0.71), but not for the control
condition (F[2,6]#1.55, p = 0.29, gp2#0.34), thus suggesting that
the effect shown in the main experiment was critically dependent on
the specific stimulation protocol used.
intact hemifield there was a numerical, non-significant trend for an
enhancement that was about half that obtained after anopichemifield PAS and control condition.
For all conditions, significant changes in performance were
absent in the intact hemifield, with even a slight numerical
decrease in the percentage of correct detections after PAS in each
case (mean difference pre- vs. post-PAS#5.41%, SE 2.65;
t[9]#2.04, p$0.071).
Effect of PAS on visual field border
A two-factor (363) repeated measures ANOVA with ‘‘Time’’
and ‘‘Condition’’ as factors was conducted for the normalized
VFBs (Figs. 6B, 7).There was an obvious numerical trend for a
shift of the VFB toward the anopic side immediately after PAS,
even though the ANOVA did not indicate significance for the
main effects or the interaction (all F#2.90, p$0.11, gp2#0.24).
Control experiment
An additional control experiment was conducted with a subgroup
of four patients (LHA3, LHA4, LHA6, RHA3) after completion of
PLoS ONE | www.plosone.org
9
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Figure 7. Normalized percentage of correct detections for each individual subject in the post-PAS and recovery conditions of the
session with PAS on the side of the anopic hemifield. Gray bars show the difference between percentage values obtained in the respective
block and the mean percentage obtained in pre-PAS blocks 1 and 2. The azimuth of visual stimulus location (steps of 2u) is normalized for each
subject such that zero (vertical black dotted line) is the mean visual field (VF) border measured in the pre-PAS blocks 1 and 2. Thus, positive gray bars
indicate improved detections, and negative positions of the VF border (vertical red solid line) indicate a shift toward the anopic field with reference to
pre-PAS blocks. Panels with blue bars show mean changes with reference to pre-PAS blocks across total anopic or intact hemifields (non-normalized
azimuth). Note that in their anopic hemifield all patients consistently showed both an improvement of correct detections in the post-PAS block and a
decline in the recovery block. The majority of patients, but not all, also showed a shift of the VF border toward the anopic hemifield in the post-PAS
block, and in the recovery block the VF border was consistently shifted to the intact hemifield with reference to its position in the post-PAS block.
doi:10.1371/journal.pone.0031603.g007
was a non-significant trend of a shift of the VFB toward the blind
hemifield after PAS (see Figs. 5, 7). However, in sum, these results
left open the question whether the genuine effect of PAS consisted
in an enhancement of residual vision extending over large parts of
the anopic field (as would be expected with an intensification of
blindsight functions [65]) or in a dislocation of the transition zone
between blind and sighted fields [66,67], since each of these
Discussion
These results showed that one hour of PAS on the side of the
blind, but not of the intact, hemifield of patients with HA induced
an improvement in visual detections by almost 100% within
30 min after PAS. This enhancement in performance was
reversible and was reduced to baseline 1.5 h later. Also, there
PLoS ONE | www.plosone.org
10
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
Alternatively, these results can be interpreted in terms of
changes in visual attention. PAS could have increased sustained
lateralized covert attention, resulting in temporarily improved
visual detection. This interpretation seems plausible as the
multisensory brain structures of the residual visual pathways, in
particular the SC, are well-known to be crucially involved in visual
attentional functions [20,21]. Thus, PAS on the side of the anopic
hemifield could have engaged multisensory mechanisms that have
intensified visual attentional functions of the residual pathway.
This explanation might be compatible with previous studies that
have shown that visual improvements in HA patients can be
obtained immediately in an attentional cueing task [69] and after
long-term training with an attenion cue [70]. In order to shed
some light on this issue, a further control condition was conducted
in which, instead of application of two sound positions, a single
sound source was presented at randomly varying locations on the
side of the anopic hemifield. This type of PAS may have been
suited to draw the patient’s attention to the hemifield of PAS, but
without the specific (LTP-like) protocol used in the main
experiment. These results did not indicate any consistent
improvement in visual detection under these conditions of PAS,
thus arguing in favour of a specific effect induced by the PAS
protocol in the main experiment, rather than any more general
change in spatial attention. In accordance with this view, we did
not find improvements on the intact side after PAS on the same
side, as would be expected in case of an intensification of spatial
attention. Nevertheless, on the basis of these data there is no
conclusive evidence with respect to the question of whether more
basic sensory or higher-order attentional mechanisms were
temporarily changed after the PAS.
Although our initial hypothesis was primarily based on auditoryvisual cross-modal processes in the secondary (extrastriate) pathway,
one can not completely rule out that some elements of the primary
(geniculostriate) pathway to V1 have survived in the damaged
hemisphere and have preserved some residual visual functions [15–
17] that could have been intensified by the PAS. If one assumes any
role of the residual parts of the primary pathway in the effect shown
here, the results might also be interpreted in terms of the crossmodal and attentional mechanisms as discussed above for the
involvement of the secondary pathway. In particular, there is
sufficient evidence indicating multisensory convergence as well as
cross-modal effects of attention in V1, which might be mediated by
projections from auditory cortex, parietal lobe, and superior
temporal cortex (e.g., [33–39]).
Furthermore, it is possible that PAS induced an increased bias
in favour of reporting awareness of visual stimuli rather than a
genuine perceptual improvement [8]. This problem remains
unsolved as reliable data on the phenomenological quality of the
visual percept are not available. However, an analysis of responses
in the intact hemifield after PAS on the same side indicated a nonsignificant trend of a decrease in performance (probably due to
fatigue), which rather argued against this possibility.
Finally, it is conceivable that PAS induced an increase in overt,
rather than covert, attention. As the duration of the visual stimulus
(50 ms) was well below the minimum saccadic reaction times for
visual targets in healthy subjects (around 100 ms; [71,72]), the
initiation of visually-guided saccades prior to stimulus offset can be
excluded. Even though patients consistently followed the instruction of fixation on the fixation target (except one patient excluded
from the study), it might be that PAS induced a bias in the
frequency or amplitude of spontaneous self-paced saccades and/or
eccentric fixation towards the stimulated side, such that flashes
presented on this side necessarily felt more frequently in the intact
visual field. For technical reasons, namely the optimization of our
patterns was observed in some individual patients, without any
consistent trend (see Fig. 7). Thus, it remained unclear whether the
improvement in visual detections resulted from an enhancement of
blindsight or from an activation of residual vision due to partial
damage to the primary pathway.
The results are compatible with the view that the PAS used
induced some activation of the residual visual pathways, even though
the data left open the question of precisely which structures of the still
available (extrastriate or primary) ‘‘residual’’ pathways were
involved. In particular, the multimodal regions of the SC, that was
spared by lesions in HA patients, may be a candidate substrate of the
effect of PAS on visual performance. As sound stimuli were spatially
arranged such that they were approximately covering one hemifield,
one may assume that auditory or multisensory neurons in the
contralateral SC were activated during presentation and may have
driven short-term processes of synaptic plasticity of pathways
originating in the SC and of their non-lesioned target areas in
extrastriate cortex, either via the pulvinar [22,23] or via the lateral
geniculate nucleus [14]. These processes, possibly relying on a
mechanism of LTP-like facilitation at the synaptic level, may have
resulted in a reversible recruitment of the residual visual processing
resources in HA, thus significantly enhancing visual sensitivity for a
short time. In this respect, the central role of the multisensory circuits
of the SC seems plausible, as the visual task used in this study was
comparatively simple, merely requiring detection of light flashes
appearing in darkness at random points in time [9]. The result that
an effect of hemispatial PAS was only present on the anopic side (not
on the intact side) can be explained by assuming that spatial auditory
processing in the colliculo-cortical pathways of both cerebral
hemispheres is – despite the extensive bilateral projections of the
auditory system in general – contralaterally organized. On the one
hand, PAS on the anopic side may have induced a selective
activation of the intact colliculo-cortical pathway in the damaged
hemisphere. On the other hand, PAS on the side of the intact field
(ipsilateral to the lesion) may have had no significant influence on
processing in the residual pathway of the damaged hemisphere. This
finding is compatible with data from several mammalian species
indicating the existence of a neural map of the contralateral auditory
(multisensory) hemispace in the SC (for review, see [1]). In this
context, the possibility has to be taken into account that our PAS
paradigm, using synchronous presentation of two spatially disparate
sound sources (which was adopted from previous non-auditory
research), may not necessarily be essential for the result obtained
here. Future studies may have to clarify whether beneficial effects of
PAS can be elicited when only one single sound source is used.
In conclusion, it seems possible that PAS induced an
intensification of multisensory features of ‘‘residual’’ structures,
such as the SC. At the level of synaptic transmission, similar
Hebbian mechanisms may be relevant for these cross-modal
processes of plasticity as have been proposed by Dinse et al. [48]
for unattended activation-based learning in the tactile modality.
The repetitive (LTP-like) auditory stimulation on the side of the
blind field may have induced synchronous neural activity in the
circuits of the auditory and multisensory neurons in the
contralateral SC (representing the affected hemispace) and its
cortical target areas (possibly even those of the non-lesioned,
ipsilateral hemisphere), thus modifying synaptic efficacy within the
colliculo-cortical pathways, which may have resulted in improved
visual processing therein. In this respect, our findings are in
accordance with the previous studies that have demonstrated that
perceptual learning can be induced by the variation of input
statistics alone, without invocation of attention or reinforcement,
and even without awareness of stimuli (for review, see [68]).
PLoS ONE | www.plosone.org
11
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
exclude a genuine restitution of parts of the blind field, which would
bear the potential for improvement of more complex visual
abilities, such as reading or spatial orientation.
The present study was based on a conception fundamentally
different from previous approaches to change homonymous visual
field defects by visual restitution training (e.g., [43,69,70,65–
67,73–81]; for review, see [17]). Most importantly, it was shown
that substantial improvements of blind-field vision can be also
induced without requiring any active task nor explicit attention
from the patient. If it should emerge in future studies that longlasting improvement can be induced, passive stimulation may turn
out to be an effective therapeutic alternative, with potentially
higher compliance of patients to application than exhausting
training procedures. Similarly important in this respect is the
demonstration of cross-modal effects of passive stimulation.
Compared with visual abilities, spatial hearing has been shown
to be unusually robust to unilateral cortical lesions, most likely
because of the generally bilateral organization of the auditory
system, with a relatively weakly pronounced contralaterality in
cortical processing: even after hemispherectomy, sound localization performance can be approximately normal [82,83]. Crossmodal passive stimulation using sound stimuli thus could open the
possibility for therapeutic intervention even in the case that very
severe impairment of visual abilities limits the effectiveness of
visual stimuli.
set-up for PAS, it was impossible to implement fundus controlled
presentation of visual stimuli, which would have completely
excluded this possibility. In this context, it has to be emphasized
that the criticism of previous studies employing visual restitution
training (see below) may not directly apply to the present study. It
has been doubted whether the described improvements after such
training were real or were based on adaptive oculomotor
strategies, such as those mentioned above, which the patients
developed during the training phase. But if such adaptive strategies
would have played any role in our experiments, performance may
have been continuously increasing over time, unlike the reversible
improvement after PAS found here. Moreover, it is hard to
imagine that the patients were aware of our hypotheses and
changed their oculomotor behaviour accordingly between experimental blocks. Patients were naı̈ve with respect to the exact
scientific background of the experiment and our concrete
expectations. However, as the general purpose of the study might
be obvious by the procedure per se, and patients who had
completed the first session might have obtained some further
knowledge in this respect, the sequence of conditions was not
balanced, but the most critical condition (blind-field PAS) was
always conducted first. Notwithstanding, there was no increase in
performance over sessions, as would be expected if improvements
were based on explicit learning. In future studies it will,
nevertheless, be necessary to employ fundus-controlled microperimetric methods, optimally using a scanning laser ophthalmoscope,
to receive further insights into the effects of PAS on blind-field
vision.
On the one hand, these data do not allow any conclusion about
long-term effects of PAS. It was shown that the visual improvement had disappeared as soon as 1.5 h after one-time treatment.
On the other hand, it is known from previous studies that have
used passive stimulation for improving sensorimotor performance
in subacute and chronic stroke patients that daily application for
several weeks can induce long-lasting therapeutic effects [49].
Thus, it seems likely that repetition of PAS to HA patients induces
longer-lasting or even permanent improvements of blind-field
vision. The intriguing finding that already one-time application for
one hour can induce improvements by about 100% is quite
promising in this respect, but the therapeutic value of this
treatment has still to be established. In particular, it has to be
emphasized that the present data did neither demonstrate nor
Supporting Information
Trial Protocol S1
(PDF)
Acknowledgments
We thank all participants for their willing cooperation, A. Stöbener and V.
Zimmermann for help with running the experiments, P. Dillmann for
preparing the software and parts of the electronic equipment, and H. R.
Dinse, C. A. Heywood and R. W. Kentridge for valuable comments on an
earlier draft of the manuscript.
Author Contributions
Conceived and designed the experiments: JL. Performed the experiments:
JL. Analyzed the data: JL SP MH. Contributed reagents/materials/
analysis tools: JL MT. Wrote the paper: JL MT MH.
References
11. Zihl J, Werth R (1984) Contributions to the study of ‘‘blindsight’’ I. Can stray
light account for saccadic localisation in patients with postgeniculate field
defects? Neuropsychologia 22: 1–11.
12. Zihl J, Werth R (1984) Contributions to the study of ‘blindsight’ II. The role of
specific practice for saccadic localization in patients with postgeniculate visual
field defects. Neuropsychologia 22: 13–22.
13. Danckert J, Goodale MA (2000) A conscious route to unconscious vision. Curr
Biol 10: R64–67.
14. Schmid MC, Mrowka SW, Turchi J, Saunders RC, Wilke M, et al. (2010)
Blindsight depends on the lateral geniculate nucleus. Nature 466: 373–377.
15. Fendrich R, Wessinger CM, Gazzaniga MS (1992) Residual vision in a scotoma:
implications for blindsight. Science 258: 1489–1491.
16. Wüst S, Kasten E, Sabel BA (2002) Blindsight after optic nerve injury indicates
functionality of spared fibers. J Cogn Neurosci 14: 243–253.
17. Sabel BA, Fedorov A, Henrich-Noack P, Gall C (2011) Vision restoration after
brain damage: The ‘‘Residual Vision Activation Theory’’. Prog Brain Res 192:
199–262.
18. Jay MF, Sparks DL (1987) Sensorimotor integration in the primate superior
colliculus. II. Coordinates of auditory signals. J Neurophysiol 57: 35–55.
19. Wallace MT, Wilkinson LK, Stein BE (1996) Representation and integration of
multiple sensory inputs in primate superior colliculus. J Neurophysiol 76:
1246–1266.
20. Müller JR, Philiastides MG, Newsome WT (2005) Microstimulation of the
superior colliculus focuses attention without moving the eyes. Proc Natl Acad Sci
USA 102: 524–529.
1. Stein BE, Meredith MA (1993) The merging of the senses. Cambridge, Mass,
London: MIT Press.
2. Ghazanfar AA, Schroeder CE (2006) Is neocortex essentially multisensory?
Trends Cogn Sci 10: 278–285.
3. Recanzone GH (1998) Rapidly induced auditory plasticity: The ventriloquism
aftereffect. Proc Natl Acad Sci USA 95: 869–875.
4. Lewald J (2007) More accurate sound localization induced by short-term light
deprivation. Neuropsychologia 45: 1215–1222.
5. Pöppel E, Held R, Frost D (1973) Residual visual function after brain wounds
involving the central visual pathways in man. Nature 243: 295–296.
6. Weiskrantz L, Warrington EK, Sanders MD, Marshall J (1974) Visual capacity
in the hemianopic field following a restricted cortical ablation. Brain 97:
709–728.
7. Stoerig P (1996) Varieties of vision: from blind responses to conscious
recognition. Trends Neurosci 19: 401–406.
8. Kentridge RW, Heywood CA (1999) The status of blindsight: Near-threshold
vision, islands of cortex and the Riddoch phenomenon. J Consciousness Stud 6:
3–11.
9. Danckert J, Rossetti Y (2005) Blindsight in action: what can the different subtypes of blindsight tell us about the control of visually guided actions? Neurosci
Biobehav Rev 29: 1035–1046.
10. Leh SE, Johansen-Berg H, Ptito A (2006) Unconscious vision: new insights into
the neuronal correlate of blindsight using diffusion tractography. Brain 129:
1822–1832.
PLoS ONE | www.plosone.org
12
May 2012 | Volume 7 | Issue 5 | e31603
Passive Auditory Stimulation in Hemianopia
21. Schneider KA, Kastner S (2009) Effects of sustained spatial attention in the
human lateral geniculate nucleus and superior colliculus. J Neurosci 29:
1784–1795.
22. Cappe C, Rouiller EM, Barone P (2009) Multisensory anatomical pathways.
Hear Res 258: 28–36.
23. Crick F, Koch C (1998) Constraints on cortical and thalamic projections: the
nostrong-loops hypothesis. Nature 391: 245–250.
24. Asanuma C, Andersen RA, Cowan WM (1985) The thalamic relations of the
caudal inferior parietal lobule and the lateral prefrontal cortex in monkeys:
Divergent cortical projections from cell clusters in the medial pulvinar nucleus.
J Comp Neurol 241: 357–381.
25. Rushworth MF, Behrens TE, Johansen-Berg H (2006) Connection patterns
distinguish 3 regions of human parietal cortex. Cereb Cortex 16: 1418–1430.
26. Andersen RA (1997) Multimodal integration for the representation of space in
the posterior parietal cortex. Phil Trans R Soc Lond B 352: 1421–1428.
27. Schlack A, Sterbing-D’Angelo SJ, Hartung K, Hoffmann KP, Bremmer F (2005)
Multisensory space representations in the macaque ventral intraparietal area.
J Neurosci 25: 4616–4625.
28. Kastner S, Ungerleider LG (2000) Mechanisms of visual attention in the human
cortex. Annu Rev Neurosci 23: 315–341.
29. Shomstein S, Yantis S (2006) Parietal cortex mediates voluntary control of
spatial and nonspatial auditory attention. J Neurosci 26: 435–439.
30. Benevento LA, Fallon J, Davis BJ, Rezak M (1977) Auditory-visual interaction in
single cells in the cortex of the superior temporal sulcus and the orbital frontal
cortex of the macaque monkey. Exp Neurol 57: 849–872.
31. Chalupa LM, Macadar AW, Lindsley DB (1975) Response plasticity of lateral
geniculate neurons during and after pairing of auditory and visual stimuli.
Science 190: 290–292.
32. Noesselt T, Tyll S, Boehler CN, Budinger E, Heinze HJ, et al. (2010) S Soundinduced enhancement of low-intensity vision: multisensory influences on human
sensory-specific cortices and thalamic bodies relate to perceptual enhancement
of visual detection sensitivity. J Neurosci 30: 13609–13623.
33. Falchier A, Clavagnier S, Barone P, Kennedy H (2002) Anatomical evidence of
multimodal integration in primate striate cortex. J Neurosci 22: 5749–5759.
34. Clavagnier S, Falchier A, Kennedy H (2004) Long-distance feedback projections
to area V1: implications for multisensory integration, spatial awareness, and
visual consciousness. Cogn Affect Behav Neurosci 4: 117–126.
35. Lewald J, Meister IG, Weidemann J, Töpper R (2004) Involvement of the
superior temporal cortex and the occipital cortex in spatial hearing: evidence
from repetitive transcranial magnetic stimulation. J Cogn Neurosci 16: 828–838.
36. Zimmer U, Lewald J, Erb M, Grodd W, Karnath HO (2004) Is there a role of
visual cortex in spatial hearing? Eur J Neurosci 20: 3148–3156.
37. Eckert MA, Kamdar NV, Chang CE, Beckmann CF, Greicius MD, et al. (2008)
A cross-modal system linking primary auditory and visual cortices: Evidence
from intrinsic fMRI connectivity analysis. Hum Brain Mapp 29: 848–857.
38. Cate AD, Herron TJ, Yund EW, Stecker GC, Rinne T, et al. (2009) Auditory
attention activates peripheral visual cortex. PLoS ONE 4: e4645.
39. Borra E, Rockland KS (2011) Projections to early visual areas v1 and v2 in the
calcarine fissure from parietal association areas in the macaque. Front
Neuroanat 5: 35.
40. Frassinetti F, Bolognini N, Bottari D, Bonora A, Làdavas E (2005) Audiovisual
integration in patients with visual deficit. J Cogn Neurosci 17: 1442–1452.
41. Leo F, Bolognini N, Passamonti C, Stein BE, Làdavas E (2008) Cross-modal
localization in hemianopia: new insights on multisensory integration. Brain 131:
855–865.
42. Passamonti C, Bertini C, Làdavas E (2009) Audio-visual stimulation improves
oculomotor patterns in patients with hemianopia. Neuropsychologia 47:
546–555.
43. Bolognini N, Rasi F, Coccia M, Làdavas E (2005) Visual search improvement in
hemianopic patients after audio-visual stimulation. Brain 128: 2830–2842.
44. Meredith MA, Allman BL, Keniston LP, Clemo HR (2009) Auditory influences
on non-auditory cortices. Hear Res 258: 64–71.
45. Dinse HR, Kalisch T, Ragert P, Pleger B, Schwenkreis P, et al. (2005) Improving
human haptic performance in normal and impaired human populations through
unattended activation-based learning. Transaction Appl Perc 2: 71–88.
46. Kalisch T, Tegenthoff M, Dinse HR (2009) Sensory stimulation therapy. Front
Neurosci 3: 96–97.
47. Pleger B, Dinse HR, Ragert P, Schwenkreis P, Malin JP, et al. (2001) Shifts in
cortical representations predict human discrimination improvement. Proc Natl
Acad Sci USA 98: 12255–12260.
48. Dinse HR, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M (2003)
Pharmacological modulation of perceptual learning and associated cortical
reorganization. Science 301: 91–94.
49. Smith PS, Dinse HR, Kalisch T, Johnson M, Walker-Batson D (2009) Effects of
repetitive electrical stimulation to treat sensory loss in persons poststroke. Arch
Phys Med Rehabil 90: 2108–2111.
50. Coren S (1993) The lateral preference inventory for measurement of
handedness, footedness, eyedness, and earedness: norms for young adult. Bull
Psychonom Soc 31: 1–3.
51. Siefer A, Ehrenstein WH, Arnold-Schulz-Gahmen BE, Sökeland J, Luttmann A
(2003) Populationsstatistik und Assoziationsanalyse sensumotorischer Seitenbevorzugung und deren Relevanz für verschiedene berufliche Tätigkeitsfelder.
Zentralbl Arbeitsmed 53: 346–353.
PLoS ONE | www.plosone.org
52. Ferber S, Karnath H-O (2001) Size perception in hemianopia and neglect. Brain
124: 527–536.
53. Weintraub S, Mesulam M-M (1985) Mental state assessment of young and
elderly adults in behavioral neurology. In: Mesulam M-M, ed. Principles of
behavioral neurology. PhiladelphiaPA: FA Davis Company. pp 71–123.
54. Gauthier L, Dehaut F, Joanette Y (1998) The bells test: a quantitative and
qualitative test for visual neglect. Int J Clin Neuropsychol 11: 49–54.
55. Tham K, Tegnér R (1996) The Baking Tray task: a test of spatial neglect.
Neuropsychol Rehabil 6: 19–25.
56. Johannsen L, Karnath H-O (2004) How efficient is a simple copying task to
diagnose spatial neglect in its chronic phase. J Clin Exp Neuropsychol 26:
251–256.
57. Karnath H-O, Himmelbach M, Rorden C (2002) The subcortical anatomy of
human spatial neglect: putamen, caudate nucleus and pulvinar. Brain 125:
350–360.
58. Hausmann M, Waldie KE, Allison SD, Corballis MC (2003) Line bisection
following hemispherectomy. Neuropsychologia 41: 1523–1530.
59. Hausmann M, Corballis MC, Fabri M (2003) Line bisection in the split brain.
Neuropsychology 17: 602–609.
60. Barton JJ, Black SE (1998) Line bisection in hemianopia. J Neurol Neurosurg
Psychiatr 64: 660–662.
61. Lewald J, Peters S, Tegenthoff M, Hausmann M (2009) Distortion of auditory
space in hemianopia. Eur J Neurosci 30: 1401–1411.
62. Lewald J, Peters S, Tegenthoff M, Hausmann M (2009) Dissociation of auditory
and visual straight ahead in hemianopia. Brain Res 1287: 111–117.
63. Lewald J (1997) Eye-position effects in directional hearing. Behav Brain Res 87:
35–48.
64. Höller M (2007) Auditive Koaktivierung und ihre Wirkung auf Frequenz- bzw.
auditive Raumdiskrimination. Diploma Thesis, Bochum: Ruhr University
Bochum.
65. Jobke S, Kasten E, Sabel BA (2009) Vision restoration through extrastriate
stimulation in patients with visual field defects: a double-blind and randomized
experimental study. Neurorehabil Neural Repair 23: 246–255.
66. Bergsma DP, van der Wildt G (2010) Visual training of cerebral blindness
patients gradually enlarges the visual field. Br J Ophthalmol 94: 88–96.
67. Marshall RS, Chmayssani M, O’Brien KA, Handy C, Greenstein VC (2010)
Visual field expansion after visual restoration therapy. Clin Rehabil 24:
1027–1035.
68. Seitz A, Watanabe T (2005) A unified model for perceptual learning. Trends
Cogn Sci 9: 329–334.
69. Poggel DA, Kasten E, Müller-Oehring EM, Bunzenthal U, Sabel BA (2006)
Improving residual vision by attentional cueing in patients with brain lesions.
Brain Res 1097: 142–148.
70. Poggel DA, Kasten E, Sabel BA (2004) Attentional cueing improves vision
restoration therapy in patients with visual field loss. Neurology 63: 2069–2076.
71. Findlay JM (1981) Spatial and temporal factors in the predictive generation of
saccadic eye movements. Vision Res 21: 347–354.
72. Fischer B, Ramsperger E (1986) Human express saccades: effects of
randomization and daily practice. Exp Brain Res 64: 569–578.
73. Pöppel E, Stoerig P, Logothetis N, Fries W, Boergen KP, et al. (1987) Plasticity
and rigidity in the representation of the human visual field. Exp Brain Res 68:
445–448.
74. Potthoff RD (1995) Regeneration of specific nerve cells in lesioned visual cortex
of the human brain: an indirect evidence after constant stimulation with different
spots of light. J Neurosci Res 15: 787–796.
75. Schmielau F, Wong EK, Ling CA (1998) Treatment induced recovery of visual
function in hemianopia. Invest Ophthalmol Vis Sci 39: 2571.
76. Tegenthoff M, Widdig W, Rommel O, Malin J-P (1998) Visuelle Stimulationstherapie in der Rehabilitation posttraumatischer kortikaler Blindheit.
Neurol Rehabil 4: 5–9.
77. Werth R, Moehrenschlager M (1999) The development of visual functions in
cerebrally blind children during a systematic visual field training. Restor Neurol
Neurosci 15: 229–241.
78. Sahraie A, Macleod MJ, Trevethan CT, Robson SE, Olson JA, et al. (2010)
Improved detection following Neuro-Eye Therapy in patients with postgeniculate brain damage. Exp Brain Res 206: 25–34.
79. Kasten E, Wüst S, Behrens-Baumann W, Sabel BA (1998) Computer-based
training for the treatment of partial blindness. Nat Med 4: 1083–1087.
80. Huxlin KR (2008) Perceptual plasticity in damaged adult visual systems. Vision
Res 48: 2154–2166.
81. Huxlin KR, Martin T, Kelly K, Riley M, Friedman DI, et al. (2009) Perceptual
relearning of complex visual motion after V1 damage in humans. J Neurosci 29:
3981–3991.
82. Hausmann M, Corballis MC, Fabri M, Paggi A, Lewald J (2005) Sound
lateralization in subjects with callosotomy, callosal agenesis, or hemispherectomy. Cogn Brain Res 25: 537–546.
83. Lewald J, Peters S, Corballis MC, Hausmann M (2009) Perception of stationary
and moving sound following unilateral cortectomy. Neuropsychologia 47:
962–971.
84. Damasio H, Damasio AR (1989) Lesion analysis in neuropsychology. New York:
Oxford University Press.
13
May 2012 | Volume 7 | Issue 5 | e31603
Was this manual useful for you? yes no
Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Download PDF

advertisement