Vestibular loss causes hippocampal atrophy and
impaired spatial memory in humans
Brain (2005), 128, 2732–2741
Thomas Brandt,1Franz Schautzer,2Derek A. Hamilton,3Roland Bru ¨ning,4Hans J. Markowitsch,5
Roger Kalla,1Cynthia Darlington,6Paul Smith6and Michael Strupp1
1Department of Neurology, Ludwig-Maximilians University, Munich, Germany,2Department of Neurology and
Psychosomatics, LKH Villach, Austria,3Department of Psychology, University of New Mexico, Albuquerque, USA,
4Department of Neuroradiology, Ludwig-Maximilians University, Munich, Germany,5Physiological Psychology,
University of Bielefeld, Bielefeld, Germany and6Department of Pharmacology and Toxicology, School of
Medical Sciences, University of Otago Medical School, Dunedin, New Zealand
Correspondence to: Thomas Brandt, MD, FRCP, Department of Neurology, Ludwig-Maximilians University,
D-81377 Munich, Germany
on the human hippocampus stresses its non-spatial memory functions, but older work in rodents and some
other species emphasized the role of the hippocampus in spatial learning and memory as well. A few human
studies also point to a direct relation between hippocampal size, navigation and spatial memory. Conversely,
the importance of the vestibular system for navigation and spatial memory was until now convincingly demon-
strated only in animals. Using magnetic resonance imaging volumetry, we found that patients (n = 10) with
acquired chronic bilateral vestibular loss (BVL) develop a significant selective atrophy of the hippocampus
patients exhibited significant spatial memory and navigation deficits that closely matched the pattern of
hippocampal atrophy. These spatial memory deficits were not associated with general memory deficits.
phylogenetically ancient—function of the archicortical hippocampal tissue is still evident in spatial aspects of
memory processing for navigation. Furthermore, these data demonstrate for the first time in humans that
spatial navigation critically depends on preserved vestibular function, even when the subjects are stationary,
e.g. without any actual vestibular or somatosensory stimulation.
Keywords: hippocampus; bilateral vestibular failure; spatial memory; navigation
Abbreviations: BVL = bilateral vestibular loss; VMWT = virtual Morris water task; GM = grey matter; WM = white matter
Received December 17, 2004. Revised July 18, 2005. Accepted July 26, 2005. Advance Access publication September 1, 2005
Input from the vestibular system is important for navigation
and spatial memory in animals; however, controversy still
surrounds the role of the hippocampus. The human hip-
pocampal formation is widely agreed to be important for
memory processing aspects, such as early encoding, consol-
idation and retrieval (Scoville and Milner, 1957; Manns et al.,
2003), but it is also thought to be involved in spatial memory
functions (e.g. see McNaughton et al., 1996; Mumby, 2001 for
reviews). Earlier research in rodents highlighted a hippocam-
pal role in spatial functions (Becker and Olton, 1981; Jarrard,
1993), while more recent research de-emphasized this role
and likewise argued for a principally non-spatial role in
memory processing as well (Bunsey and Eichenbaum, 1995;
McEchron and Disterhoft, 1999; Eichenbaum, 2003). Wood
et al. (2000), for instance, argued that the rat hippocampus,
like the human one, encodes what occurred earlier and what
will occur next, even in a spatial T-maze situation, and there-
fore plays a role similar to that of the human hippocampus
in episodic memory formation. Currently, some authors
do not consider the human hippocampus essential for
maintaining or retrieving remotely formed spatial represen-
tations of major landmarks, routes, distances and directions
#The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.org
(Rosenbaum et al., 2000). Others continue to emphasize
the direct relation between hippocampal size, navigation
and spatial memory in humans (Maguire et al., 2000;
Biegler et al., 2001). Especially the right human hippocampus
may be related to allocentric spatial memory (Feigenbaum
and Morris, 2004; Parslow et al., 2005) and proximity judge-
ments (Maguire et al., 1996), the left hippocampus may be
engaged intopokinetic memory
Several electrophysiological studies from the 1990s demon-
strated that vestibular stimulation couldmodulate the activity
of ‘head direction cells’ in the thalamus (e.g. Blair and Sharp,
hippocampus (O’Mara et al., 1994; Gavrilov et al., 1995;
Wiener et al., 1995). Using functional MRI, Vitte et al. (1996)
demonstrated in humans that caloric stimulation could
activatethehippocampal formation.Various anatomicalcon-
nections were proposed to join the vestibular nuclei to the
hippocampus via the thalamus, the dorsal tegmental nucleus
(i.e. the ‘head direction pathway’) or the pedunculopontine
tegmental nucleus (i.e. the ‘theta pathway’) (Smith, 1997;
Cuthbert et al., 2000; Horii et al., 2004). Several reports
suggested that spatial learning deficits in animals after
vestibular lesions or stimulation are linked to changes in cir-
cuitry critical for place learning and navigation. For example,
vestibular stimulation modulated ‘head direction cells’ in the
anterior thalamic nuclei (Stackman and Taube, 1997), and
location-related firing of ‘place cells’ in the hippocampus was
abolished in rats after bilateral labyrinthectomy (Stackman
et al., 2002; Russell et al., 2003a). Thus, vestibular signals
are necessary for location-specific ‘place cell’ activity in the
hippocampus, which provides a putative neural substrate for
the spatial representation also involved in human navigation
(Ekstrom et al., 2003).
Patients with bilateral vestibular deficits can execute goal-
directed linear locomotion without impairment, but they
fail to accurately negotiate corners when walking along a
triangular path (Glasauer et al., 2002). In a pilot study
we found spatial memory deficits in patients with chronic
bilateral vestibular loss (BVL; Schautzer et al., 2003). This
prompted us to test spatial and non-spatial memory
[using a virtual Morris water task (MWT) and the Wechsler
Memory Scale, respectively] and to determine the volume of
the hippocampus in 10 patients with chronic BVL due to
(i) Can MRI volumetry show morphological changes in the
hippocampus of BVL patients?
(ii) Are the BVL-related deficits in spatial memory and
navigation selective or associated with general memory
deficits? Since males had outperformed females in place
learning but not cued-navigation in previous studies
(Astur et al., 1998; Driscoll et al., 2003), sex was included
as a between-subject factor in the analysis.
Ten patients (four women, six men; mean 6 SD = 38.0 6 6.7 years)
with BVL and ten sex- and age-matched controls (mean 6 SD =
38.7 6 5.4 years) with no known neurological history participated in
the study. All patients had undergone a bilateral vestibular nerve
section 5–10 years before the test and subsequently had a complete
and control subjects were also matched for years of school education
(patients: 10.9 6 1.8 years and controls: 11.1 6 1.7 years). Neither
patients nor controls had professions requiring pronounced spatial
memory or a history of extensive experience in navigation.
Patients and controls were examined using a superconducting 1.5-T
scanner and the circular polarized head coil (Magnetom Vision?,
Siemens Medical Systems, Germany). T2-weighted images (TR/TE =
2300/20/85 ms, field of view 220 mm, 3 mm slice, 1 average) and
matched FLAIR images (TR/TE = 5000/110 ms, TI = 1850 ms) were
axis of the hippocampus. Additionally, a 3D gradient echo sequence
was measured (MPRAGE, TR/TE = 9.7/4 ms, 15 degree flip angle
with a pixel size of 1.02 · 1.02 mm). The total measurement time
took ?25 min per patient.
MRI data post-processing
Image data processing for the hippocampal volume was per-
formed on a remote Linux workstation, using FSL and MedX 3.4
(Medical Numerics, Inc. Sterling, VA, USA). Both the T1-weighted
and the T2-weighted datasets were computed by manually tracing
the outlines of the hippocampus on reformatted successive coronal
1-mm slices. The hippocampal head, body and tail were seg-
mented manually according to recently described state-of-the-art
protocols (Bernasconi et al., 2003). The ento- and the perirhinal
cortex (Bernasconi et al., 1999) and the parahippocampal
cortex (Insausti et al., 1998) were not included. The resulting
data were adapted to the imaging parameters and documented
in a protocol file.
The Sienax protocol (Version 2.2) was used on the 3D dataset for
total brain volume estimation (Smith et al., 2002). Total brain tissue
volume was estimated from a single image, after being registered to
standard (Talairach) space. The protocol runs tissue segmentation to
estimate the volume of grey matter (GM) and white matter (WM)
factor to reduce head-size-related variability between subjects.
Memory and memory-influencing functions
To estimate pre-morbid intelligence, a German-language adaptation
of the National Adult Reading Test of Nelson was selected.
Memory and attention/concentration
The Wechsler Memory Scale–Revised was used in full, since it
constitutes the most universally employed memory test battery
and allows the calculation of several indices (general memory,
attention/concentration, visual memory, verbal memory and
Vestibular loss and impaired spatial memory in humans Brain (2005), 128, 2732–27412733
delayed recall). Furthermore, the doors sub-test of the doors and
people test of Baddeley et al. (1994) was used. It allows measurement
of visual recognition memory. Colour photographs of doors have to
be memorized and then each of the presented doors has to be iden-
tified from an array of four doors, two on the upper and two on the
lower half of a sheet of paper. All tests were administered to 9 of
the 10 patients using computer-screen based visual instructions.
One patient refused to undergo the testing.
The MWT (Morris, 1981) is the gold standard for testing spatial
learning, spatial memory and navigation in rodents. Rats are trained
to navigate to an escape platform in a circular pool of water. The
escape platform is made invisible by submerging it just below
the surface of the water; however, normal rats can directly navigate
to the platform from several release points. Such behaviour is gen-
erally agreed to be related to ambient visual cues in the extra-maze
environment which remain in a fixed spatial location to the platform
The virtual MWT (VMWT) is a purely visual task that is devoid
of many forms of stimulus control involved in spatial navigation.
Accurate navigation to a hidden platform depends upon a constel-
lation of visual cues in the extra-maze environment, whereas other
ambiguous cues provided in the room and pool geometry appear
to be utilized for non-spatial strategies. The virtual environment
used here for all patients and 10 controls was described in detail
elsewhere (Hamilton et al., 2002). In brief, it consisted of a circular
pool located in the centre of a room with a square floor plan. Four
conspicuous distal cues of equal size were placed around the
distal walls. The cues were positioned so that one cue was on
each of the four walls, and the platform could not be encountered
by simply moving towards a single cue from any release point.
The platform occupied ?2% of the pool area and was in the
centre of one quadrant (N/E). A first-person view of the virtual
environment was displayed on a 17-inch PC laptop monitor with
a 45?field of view. The observer’s position was always slightly
above the surface of the water. Forward movement was controlled
by the UP (") arrow key on the keyboard, and rotation by the
LEFT ( ) and RIGHT (!) arrow keys. Backward navigation or
up–down movement within the pool was not possible. A full 360?
rotation in the absence of forward movement required ?2.5 s to
complete and the direct path from a release point to the opposite
side of the pool took ?4 s.
Design and procedure
?30 min to complete. During Phase I, participants completed five
hidden platform training blocks, each consisting of four trials. Start-
replacement from the four locations corresponding to the cardinal
compass points. The latency and path length required to navigate to
the hidden platform were measured for each trial (latency was mea-
sured from the time the first movement was made until the platform
was found; path length was measured as the total distance travelled
to find the platform, divided by the diameter of the virtual pool).
Amaximum of60swasallotted tolocatetheplatform duringPhaseI
trials, after which the platform was made visible by raising it above
the surface of the water. Phase II consisted of a single 45 s probe trial
during which the platform was removed from the environment. The
starting location for the probe trial was selected pseudo-randomly
from the two starting locations furthest from the platform location.
Two dependent measures were recorded for the probe trial: (i) initial
heading error (the angular deviation from a straight trajectory to the
platform measured 1 s after movement was initiated) and (ii) per-
centage of time spent in the platform quadrant. During Phase III the
platform was slightly raised above the water surface to make it visible
for two blocks of four trials. Starting locations were determined as in
Phase I, and the latency and path length required to navigate to the
provided a control task that did not require spatial processing, which
is intact in individuals with spatial navigation impairment (Driscoll
et al., 2003; Hamilton et al., 2003).
MRI volumetry revealed a 16.91% decrease in total hip-
pocampal volume in the BVL patients relative to controls
(see Table 1; Fig. 1). An analysis of variance (ANOVA)
with BVL status and sex as between-subject factors confirmed
a significant difference in hippocampal volume between BVL
patients and controls [F(1, 17) = 13.08, P < 0.01]. Males had
significantly greater total hippocampal volume than females
[F(1, 17) = 5.25, P < 0.05]; however, the BVL status by sex
interaction term was not significant (P = 0.92), indicating that
BVL did not differentially affect males or females in the
Table 1 Mean hippocampal, GM, WM, CSF and whole-brain volume (6 SD) measured by MRI volumetry in NF2 patients
Control (male)Control (female)BVL (male) BVL (female)
Right HPC (cm3)
Left HPC (cm3)
Total HPC (cm3)
Grey matter (cm3)
White matter (cm3)
Whole brain (GM + WM, cm3)
Right HPC/whole brain
Left HPC/whole brain
Total HPC/whole brain
HPC, hippocampus. *Measures were not obtained or could not be computed for four participants (3 BVL patients and 1 control).
2734 Brain (2005), 128, 2732–2741 T. Brandt et al.
current sample. Separate ANOVAs for each hemisphere
indicated that BVL was associated with smaller hippocampi
in both the left [F(1, 17) =10.36, P < 0.01] and right
[F(1, 17) = 13.77, P < 0.01] hemispheres, and neither of
the BVL · sex interactions reached statistical significance
(both P > 0.46).
Total GM, WM, CSF and an estimate of total parenchyma
(whole-brain volume; GM + WM) are shown in Table 1.
These measures were not obtained or could not be computed
for four participants (3 BVL patients and 1 control). There
were no significant BVL main effects for whole-brain GM
(P = 0.66), WM (P = 0.43) or whole-brain volume (P =
0.44); however, BVL was associated with increased CSF
[F(1, 14) = 11.43, P < 0.01]. Significant effects of sex were
found for WM, GM, and whole-brain volume (males >
females, all P < .005), but not for CSF (P = 0.15). The sex
· BVL interaction was significant only for GM [F(1, 14) =
9.06, P < 0.01; all other interactions P > 0.19] and was due to a
greater sex difference (males > females) in the BVL group.
To control for group differences in whole-brain volume,
analyses of covariance (ANCOVAs) were also performed for
the hippocampal measures with whole-brain volume (GM +
WM) as a single covariate. BVL patients still showed a sig-
nificant decrease relative to controls for right hippocampal
volume [F(1, 13) = 9.98, P < 0.01], left hippocampal volume
[F(1, 13) = 6.56, P < 0.05] and total hippocampal volume
[F(1, 13) = 8.93, P < 0.05]. None of the sex main effects or sex
· BVL interactions were significant for the ANCOVAs (all
P > 0.12). Although the sex · BVL interactions were not
significant, an interesting pattern was observed among sex
and BVL status. Table 1 suggests that BVL may have had a
however, this group had only four patients. While the control
subjects showed a non-significant negative correlation
(r = ?0.165) between hippocampal volume and age, which
was within the range of values in normal ageing (Raz, 2000),
BVL patients had a positive, non-significant correlation
between age and hippocampal volume (r = 0.12). All but
one of the control subjects was under 54 years of age; thus,
these correlations must be evaluated cautiously, given the
restricted age ranges (see the Methods section).
An analysis of zero-order correlations between perfor-
mance in the VMWT (see below) and hippocampal volume
in the BVL patients failed to reveal a significant correlation
[r(9) = ?0.26 (P = 0.50) for percent time in the platform
is important to note that people either solve the VMWT
efficiently or they apply a non-efficient strategy. Thus,
while a continuous relationship between hippocampal vol-
ume and spatial learning may be expected, the measure of
spatial learning used here only provides meaningful continu-
ous information if individuals are actually learning by using a
spatial strategy. If not, any variability in behaviour does not
reflect variability in spatial learning and should not be
expected to correlate with factors related to spatial learning
performance. At the group level, performance differences in
the VMWT largely reflected differences in the proportion of
individuals in each group who used a spatial strategy.
Fig. 1 In BVL patients, a 16.91% volume loss in the hippocampus (arrows) was observed in comparison to age- and sex-matched controls
(normal hippocampus: dotted arrows). Volume loss was similar for the left and right hippocampus. Analysis of variance (ANOVA) with BVL
status and sex confirmed a significant difference in hippocampal volume between BVL patients and controls [F(1, 17) = 13.08]. Shown are
examples of coronal 3 mm MRI T2-weighted images with a distance of 6 mm. (A) 39-year-old female volunteer. (B) 40-year-old female BVL
patient (for methodological details, see Methods). This patient had a total volume of 3.9 ml (left hippocampus 1939.18 mm3, right
hippocampus 2002.82 mm3).
Vestibular loss and impaired spatial memory in humans Brain (2005), 128, 2732–27412735
Pre-morbid intelligence and
Quantitative data on memory and attention/concentration of
the patients as assessed using the Wechsler Memory Scale–
Revised are presented in Table 2. The pre-morbid intelligence
level of all patients was average to above average. Only one
patient was significantly impaired in all measures of memory.
Most of the other patients were in the normal or even above-
average range. Only visual recognition memory, as measured
using the doors test, was impaired in four patients, and the
attention/concentration index was below average in two
Tests of spatial memory and place learning, however, revealed
deficits in the BVL patients.
Figure 2 shows the performance of BVL patients and con-
trols during the hidden platform place learning trial blocks
(hidden platform training). Hidden platform trials were
blocked into three levels (trials 1–4, 5–12 and 13–20),
which were included as a within-subject factor in a repeated
measures ANOVA. Overall, BVL patients took more time and
longer paths to navigate to the platform than controls. For
the path length measure, the only effects to reach statistical
significance were the Trial block by BVL status interaction
[F(2, 36) = 4.33, P < 0.05]. These effects were attributable
platform in male controls [F(1, 5) = 10.71, P < 0.05], which
was not detected in the BVL patients or female controls [all
P > 0.167]. For the latency measure, only the main effects of
Trial block [F(2, 36) = 11.28, P < 0.01] and BVL status [BVL >
control; F(1, 18) = 4.67, P < 0.05] reached statistical signifi-
cance. The Trial block effect was due to a linear decrease in
latency to navigate to the platform across the three Trial
blocks [F(1, 18) = 15.12, P < 0.01].
Since the path length measure is independent of speed, it
provides a relatively pure measure of navigation accuracy. In
contrast, a BVL-related increase in latency might have several
causes (e.g. general slowing). The group differences observed
in the first Trial block were because some patients did not find
the platform within 60 s, but were able to navigate to a visible
platform (resulting in artificial reduction in path length).
Importantly, a statistical comparison of BVL patients and
controls on path length and latency during the first trial failed
to yield significant differences (both P > 0.13). The BVL
patients showed some improvement, apparently by adopting
a better, but suboptimal, strategy; however, they still failed to
reach the level of controls. Most patients did not navigate
directly to the platform at the end of training but used
circuitous or otherwise random strategies. If they had been
given additional training, it is doubtful that they would have
reached the level of controls. Normal adults achieve this task
within 12 trials, and additional training did not appear to
improve performance in impaired individuals.
Behavioural data from the no-platform probe trial are
shown in Fig. 3. There were significant main effects of BVL
status [control > BVL; F(1, 18) = 18.07, P < 0.01] and Sex
[males > females; F(1, 18) = 8.55, P < 0.01] for percent time
spent in the platform quadrant during the probe trial. The
interaction term was not significant [P = 0.261]. There was
also a significant main effect of BVL status [BVL > control;
F(1, 18) = 8.75, P < 0.01] for initial heading error. Although
male controls had lower heading error values than female
controls, the main effects of sex and the interaction term
did not reach statistical significance [both P > 0.13]. The
pattern of means obtained during the no-platform probe
trial followed that obtained for hippocampal volume,
shown in Table 1.
Female BVL patients spent significantly less time than con-
trols or male BVL patients in searching in the platform quad-
rant during the probe trial (Table 3). If one assumes that
?25% is chance performance, then the female patients
could have had a preference for some other region of the
pool. Figure 4 shows the swim paths for all four female
BVL patients: clearly there is no systematic preference for a
quadrant of the pool other than the platform quadrant, and
the female BVL patients did not have a preference for the
platform quadrant. The amount of time spent in the release
Table 2 Results for behavioural tests of memory and intelligence
SubjectAge (years) Education Intelligence
Wechsler memory scale-revisedDoors test
GMI VisM VerbMAtt/Conc Delayed recall
Test results below average are marked in bold. Att/Conc, attention/concentration index; GMI, general memory index; IQ, intelligence
quotient; MWT-B, Mehrfach-Wahl-Wortschatztest B; VisM, visual memory index; VerbM, verbal memory index.
2736 Brain (2005), 128, 2732–2741T. Brandt et al.
the locations far from the platform. BVL females apparently
preferred one of the quadrants adjacent to the release quad-
rants as indicated by the 41.5% value for the SE quadrant;
explanation of this observation is that the BVL females spent
more time near the release point. In fact, all other groups had
values >30% for some quadrant other than the platform
quadrant (SE for BVL males and control males, and NW
for control females). Due to the small sample sizes and
pseudo-random selection of the release point in the probe
trial, these apparent preferences can be attributed to group
differences in the release location. Since the release points
were equidistant from the platform quadrant, a valid com-
parison of percent search values for each of the groups can be
made, whereas direct comparisons forthe other quadrants are
not unbiased (they are influenced by whether the release
locations are sampled equally often for all groups). Nonethe-
less, several additionalanalyseswere carried outtoaddressthe
possibility that there were group preferences for regions other
than the target quadrant. Due to the apparent preference of
BVL females for the SE quadrant, we also computed the
percentage of the overall path length spent navigating in
each quadrant. The means (SEMs) were as follows: NE (plat-
form quadrant) = 16.6% (6.4), SE = 30.6% (5.1), SW = 22.9%
(4.1) and NW = 25.8% (8.3). The percentage of the overall
path was only 30.6% for the SE, indicating that the 41.5%
value obtained for search time is related to the time spent in
the quadrant without moving.
To address this issue in more detail a comparison of BVL
and Sex effects for the non-target quadrants is also provided
along with effect sizes. For the target quadrant the effect sizes
for the BVL and Sex effects were 0.18 and 0.1, respectively
(power was 0.92 and 0.85, respectively). For the remaining
quadrants the effect sizes (power) for the BVL effect were as
follows: NW = 0.02 (0.085) [F(1, 18) < 1], SW = 0.024 (0.12)
[F(1, 18) < 1] and SE = 0.04 (0.15) [F(1, 18) < 1]. Thus, the
group effect sizes and power were the greatest for the target
quadrant. An identical pattern was observed for the Sex effect
with effect sizes (power): NW = 0.07 (0.37) [F(1, 18) = 2.90,
P > 0.1], SW = 0.03 (0.20) [F(1, 18) = 1.11, P > 0.30] and
SE = 0.04 (0.15) [F(1, 18) < 1]. Again, the greatest effect sizes
tions support the view that apparent preferences for quad-
rants other than the target quadrant were not systematically
related to BVL status or sex. Instead these apparent
Fig. 2 Mean latency and path length for male and female patients and controls to navigate to the platform during the 20 hidden platform
(place learning) and eight visible platform (cued-navigation) trials. Average values were computed for hidden platform trials 1–4, 5–12
and 13–20, and the eight visible platform trials.
Vestibular loss and impaired spatial memory in humansBrain (2005), 128, 2732–27412737
preferences only reflected variation in search time that was
due to differences in release locations.
Mean latency and path length to navigate to the visible
platform during the eight cued-navigation trials were com-
puted for each participant (see Fig. 2), and analysed with BVL
status and sex as factors. None of the main effects or inter-
action terms for the path length measure reached statistical
significance; however, the BVL status main effect approached
significance [BVL > control; F(1, 18) = 3.91, P = 0.064; all
other P > 0.14]. Compared with the training and probe trial
data, the BVL patients did not appear to be substantially
impaired in navigating to a distinct cue. Although the
paths for BVL patients during the visible platform trials
were direct and the latencies to navigate to the platform
were substantially lower than the training latencies, there
F(1, 18) = 4.70, P < 0.05], which was in part due to the
low variability in the controls. The sex main effect and inter-
action were not significant for the latency measure (for both
P > 0.18).
The main findings of our investigation are 2-fold: (i) BVL
patients had normal to superior memory performance on
standardized tests, but were deficient in the virtual maze
situation and (ii) the bilateral hippocampal volume of the
patients was reduced compared with that of sex- and age-
matched controls, who also matched the patients in years
of schooling and personal experience in navigation. Thus,
BVL patients were impaired relative to the controls in
hippocampus-dependent spatial learning in a virtual task
(on a PC) that did not require vestibular information.
It is almost a natural law that the hippocampus as the core
structure of the medial temporal lobe is the most important
1957; McNaughton et al., 1996; Maguire et al., 2000; Biegler
et al., 2001; Mumby, 2001; Whishaw et al., 2001; Etienne and
Jeffery, 2004; Ergorul and Eichenbaum, 2004). Consequently,
one would expect the patients to have considerable memory
deficits: first, because of their deficits in the virtual maze and
Fig. 3 (Top, left) Mean percentage of search time that each group
(female and male controls and NF2 patients) spent in the platform
quadrant during the no-platform probe trial of phase II. (Top, right)
Mean initial heading error for each group during the no-platform
probe trial of phase II. Error bars are 61 SEM. (Bottom) Dwell
time for BVL patients and controls during the no-platform probe
trial. Light yellow areas indicate regions where a relatively large
amount of time was spent; dark red areas indicate regions where a
relatively small amount of time was spent. The platform quadrant
is demarcated by white lines.
Table 3 Data for VMWT probe trial as percent time
spent in the four platform quadrants (means, SEM)
NE, northeast; SE, southeast; SW, southwest; NW, northwest.
Fig. 4 Original recordings of the swim paths during the VMWT
probe trial for female BVL patients. Swim paths do not indicate
any systematic bias towards a particular spatial location (grey
square represents the hidden escape platform).
2738 Brain (2005), 128, 2732–2741T. Brandt et al.
secondly, because of their hippocampal pathology. However,
only one of the nine patients tested had moderate amnesia.
Theothersperformed average oreven above thememorylevel
expected on the basis of their educational background (six
patients had at least one sub-test score significantly above
average in the WMS-R), although the WMS-R includes vari-
ous visual and verbal sub-tests and measures of recognition
memory, cued recall and free recall. Only one patient had
attention deficits. Four of the nine patients scored signifi-
cantly below average on the visual recognition test (doors
test) (Table 2). This more sensitive test—which as a recog-
nition memory test initially seems easier than most WMS-R
tests—has a spatial component as well, since there are always
four spatially arranged doors during the recognition condi-
tion, and the remembrance of spatially distributed details
helps to find the correct door. At least two patients performed
even above average on this test, probably because they used
non-spatial cues for recognition as well.
The discrepancy between spatial versus non-spatial mem-
ory deficits could be due to the special role of the hippocam-
pus in spatial functions (McNaughton et al., 1996; Bohbot
et al., 1998; Biegler et al., 2001; Mumby, 2001; Whishaw et al.,
2001; Maguire et al., 2003; Etienne and Jeffery, 2004).
Although this role may in general be attributed more to the
right (which was more severely affected in our study) than to
the left hippocampus (Curtis et al., 2000; de Toledo-Morrell
et al., 2000), deficits in topographical orientation and spatial
memory functions have been observed in patients after dam-
age to either right or left hemisphere (Kessels et al., 2001,
2004), possibly depending on tasks and strategies (Maguire
et al., 2000, 2003; Lambrey et al., 2002). Astur et al. (2002)
tested patients with unilateral hippocampus resections in a
virtual MWT. They found that when these patients are
required to use spatial cues to navigate to a hidden escape
platform in a pool, they exhibit severe impairments in spatial
navigation regardless of the side of surgery. Driscoll et al.
(2003) found that normal ageing was associated with
decreases in left and right hippocampal volume, which cor-
related with age-related deficits in place learning in
The existence of a close link between spatial memory and
superior memory in general is also supported by the finding
that outstanding memorizers usually apply spatial learning
strategies (Maguire et al., 2003). Furthermore, hippocampal
processing of spatial memory seems to rely primarily on
vestibular input (see Smith, 1997 for a review). In an elegant
single-unit recording study in rats, Stackman et al. (2002)
showed that temporary inactivation of the vestibular system
resulted in the disruption of location-specific firing in hip-
pocampal place cells. They concluded that vestibular signals
have an important influence on hippocampal spatial repre-
icits in human patients with vestibular dysfunction. Similarly,
lar lesions resulted in place cell dysfunction that lasted even
6 weeks following the lesions. FMRI studies demonstrated
that vestibular stimulation (Vitte et al., 1996) and imagined
locomotion (Jahn et al., 2004) activated the hippocampal
formation. Functional imaging studies, in which subjects
navigated in virtual environments during PET (Maguire
et al., 1997, 1998) or fMRI scanning (Gro ¨n et al., 2000;
Hartley et al., 2003), showed activation of especially the
right hippocampus in wayfinding, a navigation task defined
as ‘finding novel paths between locations’, mainly when the
subjects used spatial landmarks to navigate in the early phase
of a place-learning task in a computer-generated virtual envi-
ronment (Iaria et al., 2003). In a recent fMRI study, hip-
pocampal activation was most prominent during initial
navigational learning, pointing to its role in incorporating
new information into an emerging memory representation
(Wolbers et al., 2005). While limited data in rats indicate that
bilateral peripheral vestibular lesions produce long-term
changes in spatial learning (Russell et al., 2003b), patient
data illustrating the relation between hippocampal-based
amnesia and vestibular dysfunctions have until now been
Explanations for why bilateral vestibular damage results in
hippocampal atrophy have included chronic stress, which is
associated with vestibular dysfunction (Maclennan et al.,
1998). Several lines of evidence suggest that this explanation
is unlikely. First, our patients received their BVLs 5–10 years
previously, and although vestibular compensation for bilat-
eral vestibular damage is limited (for example, the vestibulo-
ocular reflex never recovers its normal function (Curthoys
and Halmagyi, 1995), they would have achieved a steady
state of compensation within the first year post-op. Secondly,
animal studies show that elevated salivary cortisol (in guinea
pigs; Gliddon et al., 2003) and blood corticosterone levels (in
rats; Lindsay et al., 2005) decrease rapidly following vestibular
damage and are normal within 2 weeks post-op. These results
suggest that animals subjected to BVL are not chronically
Another explanation is that hippocampal atrophy is pos-
sibly a direct or indirect result of BVL. Bilateral input of one
vestibular organ to both hippocampi has been demonstrated
by electrophysiological experiments in guinea pigs. In one
study, the right labyrinth was electrically stimulated and
evoked field potentials were recorded over the hippocampal
formation bilaterally (Cuthbert et al., 2000). Although bilat-
eral vestibular lesions abolish the tonic input from the periph-
eral vestibular system (resting discharge is ?100 Hz) as well as
its modulation by head movements, spontaneous resting
activity regenerates bilaterally in the vestibular nuclei over
time (e.g. Ris and Godaux, 1998). However, these neurons
no longer respond normally to head movement because of the
permanent loss of dynamic vestibular information (Ris and
Godaux, 1998). Whether this leads to cell death in the hip-
pocampus or tochanges in neuronal cytoarchitecture remains
to be seen. We are currently investigating these possibilities in
BVL rats. Studies of hippocampal slices, removed from rats
CA1 neurons exhibited a marked decrease in electrical
Vestibular loss and impaired spatial memory in humansBrain (2005), 128, 2732–27412739
excitability in response to stimulation of the Schaffer collat-
eral pathway, and this effect was evident both ipsilateral and
contralateral to the lesion (Zheng et al., 2003).
Thus, there is evidence that acquired chronic loss of
vestibular function can cause hippocampal atrophy. The
pattern of means for the probe trial measures in the
VMWT closely matched the pattern of hippocampal volumes
observed in the patient and control groups. Spatial navigation
requires a continuous representation of the location and
motion of the individual within a 3-dimensional environ-
ment, whose coordinates are provided mainly by vestibular
and visual cues. Hippocampal atrophy may consequently
impair complex forms of spatial memory processing, while
non-spatial functions remain well preserved. Perhaps the
ancient phylogenetic roleof thehippocampusin spatial mem-
ory processing (Kessels et al., 2001), which is based on intact
vestibular input, is more sensitive to hippocampal atrophy
than more advanced, non-spatial roles that rely additionally
on the surrounding medial temporal lobe and prefrontal tis-
sue (Dolan and Fletcher, 1997; Gaffan, 2002; Markowitsch
et al., 2003; Owen et al., 1996).
The authors thank Kirsten Labudda foradministering most of
the psychological tests (WMS-R, Doors Test, MWT-B). The
their help in calculating brain volumes, and Judy Benson for
critically reading the manuscript.
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