This article was downloaded by: [Colin Dourish]

On: 03 August 2015, At: 03:02

Publisher: Routledge
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: 5 Howick Place, London, SW1P 1WG

Aging, Neuropsychology, and Cognition:

A Journal on Normal and Dysfunctional
Development
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/nanc20

Investigating virtual reality navigation

in amnestic mild cognitive impairment
using fMRI
a a ab a
E.M. Migo , O. O’Daly , M. Mitterschiffthaler , E. Antonova , G.R.
c c c ade f
Dawson , C.T. Dourish , K.J. Craig , A. Simmons , G.K. Wilcock ,
f g a a
E. McCulloch , S.H.D. Jackson , M.D. Kopelman , S.C.R. Williams
a
& R.G. Morris
a
Click for updates King’s College London, Institute of Psychiatry, Psychology and
Neuroscience, London, UK
b
Department for Psychotherapy and Psychosomatics, Campus
Innenstadt, Ludwig-Maximilians-University, Munich, Germany
c
P1vital, Wallingford, UK
d
NIHR Biomedical Research Centre for Mental Health at South
London and Maudsley NHS Foundation Trust and Institute of
Psychiatry, Psychology and Neuroscience, King’s College London,
London, UK
e
NIHR Biomedical Research Unit for Dementia at South London
and Maudsley NHS Foundation Trust and Institute of Psychiatry,
Psychology and Neuroscience, King’s College London, London, UK
f
Nuffield Department of Clinical Neurosciences, University of
Oxford, John Radcliffe Hospital, Oxford, UK
g
Clinical Age Research Unit, King’s College Hospital, London, UK
Published online: 03 Aug 2015.

To cite this article: E.M. Migo, O. O’Daly, M. Mitterschiffthaler, E. Antonova, G.R. Dawson, C.T.
Dourish, K.J. Craig, A. Simmons, G.K. Wilcock, E. McCulloch, S.H.D. Jackson, M.D. Kopelman,
S.C.R. Williams & R.G. Morris (2015): Investigating virtual reality navigation in amnestic mild
cognitive impairment using fMRI, Aging, Neuropsychology, and Cognition: A Journal on Normal and
Dysfunctional Development, DOI: 10.1080/13825585.2015.1073218

To link to this article: http://dx.doi.org/10.1080/13825585.2015.1073218

 PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
Downloaded by [Colin Dourish] at 03:02 03 August 2015

and-conditions
 AGING, NEUROPSYCHOLOGY, AND COGNITION, 2015
http://dx.doi.org/10.1080/13825585.2015.1073218

Investigating virtual reality navigation in amnestic mild

cognitive impairment using fMRI
E.M. Migoa, O. O’Dalya, M. Mitterschiffthalera,b, E. Antonovaa, G.R. Dawsonc,
C.T. Dourishc, K.J. Craigc, A. Simmonsa,d,e, G.K. Wilcockf, E. McCullochf, S.H.D. Jacksong,
M.D. Kopelmana, S.C.R. Williamsa and R.G. Morrisa
a
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; bDepartment
for Psychotherapy and Psychosomatics, Campus Innenstadt, Ludwig-Maximilians-University, Munich,
Germany; cP1vital, Wallingford, UK; dNIHR Biomedical Research Centre for Mental Health at South London
and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King’s
College London, London, UK; eNIHR Biomedical Research Unit for Dementia at South London and
Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King’s College
Downloaded by [Colin Dourish] at 03:02 03 August 2015

London, London, UK; fNuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe
Hospital, Oxford, UK; gClinical Age Research Unit, King’s College Hospital, London, UK

ABSTRACT ARTICLE HISTORY

Spatial navigation requires a well-established network of brain Received 14 April 2015
regions, including the hippocampus, caudate nucleus, and retro- Accepted 11 July 2015
splenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a KEYWORDS
condition with predominantly memory impairment, conferring a Mild cognitive impairment;
high predictive risk factor for dementia. aMCI is associated with fMRI, navigation; spatial
hippocampal atrophy and subtle deficits in spatial navigation. We memory; hippocampus
present the first use of a functional Magnetic Resonance Imaging
(fMRI) navigation task in aMCI, using a virtual reality analog of the
Radial Arm Maze. Compared with controls, aMCI patients showed
reduced activity in the hippocampus bilaterally, retrosplenial cor-
tex, and left dorsolateral prefrontal cortex. Reduced activation in
key areas for successful navigation, as well as additional regions,
was found alongside relatively normal task performance. Results
also revealed increased activity in the right dorsolateral prefrontal
cortex in aMCI patients, which may reflect compensation for
reduced activations elsewhere. These data support suggestions
that fMRI spatial navigation tasks may be useful for staging of
progression in MCI.

Introduction
Spatial navigation is the mechanism by which we move around an environment,
determining a route between places and moving along it. It is complex, requiring
perceptual identification and use of both self-centered (egocentric) and non-self-cen-
tered (allocentric) frames of reference. Much of our understanding of the neurobiology
of immersive spatial navigation has come from rodent work in artificial mazes, such as
the Morris Swim Maze (Morris, Garrud, Rawlins, & O’Keefe, 1982), Olton Radial Arm

CONTACT: E.M. Migo ellen.migo@kcl.ac.uk

© 2015 Taylor & Francis
 2 E.M. MIGO ET AL.

Maze (Olton & Samuelson, 1976), and cross mazes (O’Keefe & Conway, 1980). This has
shown the critical role of the hippocampus, especially for allocentric processing
(Devan, Goad, & Petri, 1996), as well as non-medial temporal structures such as the
caudate nucleus (Devan et al., 1996) and retrosplenial cortex (Vann, Aggleton, &
Maguire, 2009). More recently, the role of the prefrontal cortex in navigation has
been highlighted in terms of the problem-solving component associated with spatial
navigation (Spiers & Gilbert, 2015).
Examining spatial navigation in humans has required innovative real-world tests,
including the use of virtual reality (see Bohil, Alicea, & Biocca, 2011 for a review). This
allows navigational tasks to be performed in an imaging environment, where functional
activations are found in similar key regions to those identified in animal work. Across a
variety of tasks, hippocampal activation is reliably seen in young healthy participants
(Antonova et al., 2009; Baumann, Chan, & Mattingley, 2012; Iaria, Chen, Guariglia, Ptito, &
Petrides, 2007; Iaria, Petrides, Dagher, Pike, & Bohbot, 2003; Maguire et al., 1998; Marsh
et al., 2010; Parslow et al., 2004; Shipman & Astur, 2008). A number of studies have
Downloaded by [Colin Dourish] at 03:02 03 August 2015

shown a right lateralized effect across multiple imaging modalities, including functional
imaging tasks (Hartley, Maguire, Spiers, & Burgess, 2003; Iaria et al., 2003; Maguire et al.,
1998; Wolbers, Wiener, Mallot, & Büchel, 2007) and when looking at associations
between right hippocampal structure and navigation performance (Bohbot, Lerch,
Thorndycraft, Iaria, & Zijdenbos, 2007; Iaria, Lanyon, Fox, Giaschi, & Barton, 2008;
Schinazi, Nardi, Newcombe, Shipley, & Epstein, 2013; Wegman et al., 2014).
Although the role of the hippocampus in spatial memory is clearly established,
navigation tasks also activate a consistent range of other brain regions, including the
parahippocampal place area and retrosplenial cortex (see Epstein, 2008 for a review),
as well as the precuneus (Cavanna & Trimble, 2006). The retrosplenial cortex may
have a specific role processing landmarks and permanent features (e.g., Auger,
Mullally, & Maguire, 2012), whereas the parahippocampal place area appears to be
involved in encoding the local scene for later memory (Epstein, 2008). The precuneus
appears to be important for episodic retrieval as well as visuospatial imagery
(Cavanna & Trimble, 2006).
In line with animal work, functional Magnetic Resonance Imaging (fMRI) activity
during spatial navigation tasks is found in the caudate nucleus when participants
use egocentric or response strategies (Hartley et al., 2003; Iaria et al., 2003), as
opposed to allocentric strategies. Caudate gray matter density is significantly
positively correlated with participants spontaneously choosing to use a response
learning strategy in an Olton Radial Arm Maze task (Bohbot et al., 2007) and,
showing the opposite pattern to the hippocampus, negatively correlated with
assessments of allocentric learning in a real-world navigation task (Schinazi et al.,
2013). This interaction between hippocampal- and caudate-mediated spatial strate-
gies has also been highlighted in a study using a virtual reality Morris Water Maze
procedure, the Arena task, where a pharmacological challenge (scopolamine) was
used to disrupt normal hippocampal function (Antonova et al., 2011).
Administration of scopolamine compared with placebo led to significant compen-
satory recruitment of the caudate during the task. Most spatial tasks will require the
use of both egocentric and allocentric representations, although this will be influ-
enced by participants' strategies and can change with practice on the task (Iaria
 AGING, NEUROPSYCHOLOGY, AND COGNITION 3

et al., 2003). Another interpretation of caudate activity relates it to learning about

landmarks within navigation (Doeller, King, & Burgess, 2008).
Amnestic Mild Cognitive Impairment (aMCI) is a condition characterized by a
relatively selective decline in memory over and above what is expected in normal
aging (Petersen, 2004). Having the condition is widely considered to be a highly
predictive risk factor for the development of Alzheimer's Disease (AD; Morris et al.,
2001; Petersen, 2004) and there is therefore diverse research into identifying aMCI
patients, understanding their cognitive impairments, and predicting later conversion
to dementia (Blennow, Hampel, Weiner, & Zetterberg, 2010; Prvulovic, Bokde,
Faltraco, & Hampel, 2011; Sperling, 2011; Wolk & Detre, 2012). There has been a
recent emphasis on investigating spatial navigation in normal and pathological aging
(Gazova et al., 2012; Iachini, Iavarone, Senese, Ruotolo, & Ruggiero, 2009; Lithfous,
Dufour, & Després, 2013; Moffat, 2009). Spatial navigation impairments occur early in
the progress of AD, where patients can be disoriented even in familiar surroundings
(Henderson, Mack, & Williams, 1989; Monacelli, Cushman, Kavcic, & Duffy, 2003).
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Hippocampal atrophy is well established in aMCI (Shi, Liu, Zhou, Yu, & Jiang, 2009;
Yang et al., 2012), making tests that are sensitive to hippocampal damage/dysfunc-
tion appropriate for investigation, and a number of behavioral studies have investi-
gated navigation performance in these patients.
Work with a real-world navigation task based on the Morris Water Maze has shown
that aMCI patients can be impaired, especially when an allocentric strategy is required
(Hort et al., 2007; Laczó et al., 2010, 2009). When using navigation tasks in a functional
imaging setting, the use of virtual reality tasks is critical. Such tasks have been validated
in studies demonstrating highly correlated performance between real-world and virtual
navigation within an MCI population (Cushman, Stein, & Duffy, 2008; Nedelska et al.,
2012). Using virtual tasks, work has shown impairments in aMCI on route learning, but
not landmark recognition (DeIpolyi, Rankin, Mucke, Miller, & Gorno-Tempini, 2007), and
in navigating through a virtual park and maze (Weniger, Ruhleder, Lange, Wolf, & Irle,
2011). However, these behavioral impairments in navigation in aMCI are not universal
(Cushman et al., 2008) and where multiple patient groups have been studied, single-
domain and purely aMCI patients show much milder impairments than the multi-
domain MCI groups (Hort et al., 2007). These performance differences are therefore
mild and often do not reach statistical significance.
Some studies have used structural imaging to look for associations between naviga-
tion performance and regional brain volume in aMCI patients. When combining MCI, AD,
and healthy controls, correlations have been seen between performance and the right
hippocampus (DeIpolyi et al., 2007; Nedelska et al., 2012). Other work has shown an
association between precuneus volume and performance within aMCI (Weniger et al.,
2011). Using a broader MCI group, associations between navigation performance on
objective tasks and subjective questionnaires have been seen in a range of brain regions
including the middle and medial frontal gyrus, superior temporal gyrus, and cuneus
(Mitolo et al., 2013).
Here we investigate spatial navigation in aMCI using fMRI for the first time.
Virtual reality navigation tasks are highly suitable for use in an MRI environment,
and the widespread use of navigation tasks in healthy controls has identified
regions that are reliably activated. We present data from a group of aMCI patients
 4 E.M. MIGO ET AL.

and matched controls on a virtual reality Olton Radial Arm Maze analog. Given the
variation in the literature on existing navigation task performance in aMCI patients,
we expected only relatively mild performance impairments, if any, in these patients
compared with the control group. Much work using fMRI in MCI has been focussed
on episodic and working memory tasks (Li et al., 2015), with a few studies on
visuospatial processing and none using a navigation task on which to base any
predictions. We expected that the control group would show blood-oxygen-level
dependent (BOLD) task-related activations in areas known to be important for
navigation, such as the hippocampus, retrosplenial cortex, and caudate nucleus.
We predicted decreases in BOLD activity in the aMCI patients in regions affected by
early dementia processing, most notably in the hippocampus.

Materials and methods

Downloaded by [Colin Dourish] at 03:02 03 August 2015

Participants
The patient group was composed of eight patients (5 male) with aMCI, recruited
from specialized memory clinics. All patients met the criteria for aMCI as defined in
Petersen et al. (2001), including subjective memory complaints, objective memory
impairments, normal general cognitive function, and intact activities of daily living.
All scored 0.5 on the Clinical Dementia Rating Scale, as measured during this study
(CDR; J. C. Morris, 1993), indicating that none had advanced to dementia. A control
group of 10 healthy volunteers (6 male), age and IQ matched to the patients, were
recruited from existing databases of research volunteers or in response to locally
placed adverts.
Participants were aged between 61 and 80 years of age and were all native English
speakers. For both groups, a full medical history and medical examination was carried
out by a clinician employed for the study, with blood tests and urinalysis, to ensure that
all participants were healthy with no history of head injury, alcoholism, or any psychiatric
or neurological condition (other than memory problems in the aMCI group). No parti-
cipants were excluded based on their medical history or examination; no alternative
conditions to explain memory problems in the aMCI group were indicated. Informed
written consent was obtained from all participants and the study was approved by the
National Hospital for Neurology and Neurosurgery and Institute of Neurology Research
Ethics Committee.

Apparatus
The fMRI paradigm software was programmed by Third Dimension (Dorset, UK)
using Superscape Virtual Reality software (Superscape, Hampshire, UK). The experi-
ment was presented on a 450 MHz microprocessor fitted with an 8 MB, three-
dimensional graphics card. The image was displayed via a projector onto a Perspex
screen at the foot of the scanning table. To navigate in the virtual reality task,
participants used a trackerball. Participants who had corrected vision wore contact
lenses or used MR-compatible vision-correcting goggles, to ensure they could
accurately see the screen.
 AGING, NEUROPSYCHOLOGY, AND COGNITION 5

Procedure
Participants completed a screening visit and a scanning visit. On the screening visit,
they completed a neuropsychological assessment and had a medical examination,
with full medical history taken. The neuropsychological assessment covered tests of
memory, executive function, and intelligence. The neuropsychological tests used
were the Wechsler Abbreviated Scale of Intelligence (WASI) two subtest form
(Wechsler, 1999), the California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan,
& Ober, 2000), the Logical Memory and Visual Reproduction Subtests of the
Wechsler Memory Scale-III (WMS-III; Wechsler, 1998), the Hayling and Brixton
Tasks (Burgess & Shallice, 1997), and the National Adult Reading Test (NART;
Nelson & Willison, 1991). Participants also underwent training on the platform
task (see below). On the scanning visit, the vital signs for participants were checked
and an alcohol breath test was administered. For the aMCI group, the CDR was
administered and all participants completed the Trail Making Task (TMT; Delis,
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Kaplan, & Kramer, 2001). All participants completed a computerized N-back task
as an fMRI study; the behavioral data reported here indicate working memory
performance, while fMRI data are reported elsewhere (Migo et al., 2015).

Task
Participants moved in a virtual circular arena containing a randomly arranged array of
circular platforms positioned on the floor. Surrounding the arena were visual cues to
help the participants navigate around the central space using a trackerball; see Figure 1
for a plan view of the arena with four platforms and an example of the participants' eye
view during the task. The visual cues were buildings, people, vehicles, and trees.
Participants could select platforms using a cursor on the screen using a trackerball to
navigate and select platforms.
The task was to visit each platform in turn, without going back to the same
platform twice. Once a platform is selected, the participant is automatically moved
to stand on it and turned to face the center of the arena. Other platforms are now
visible from a different perspective, requiring an allocentric strategy linking plat-
forms with landmarks. To avoid the use of simple egocentric strategies (e.g., always

Figure 1. Platform task. A: Plan view of arena space with landmarks: 1, wind turbine; 2, cottage with
car outside; 3, stone formation; 4, group of three houses; 5, statue; 6, castle; 7, fire engine; 8, bus
with passengers; 9, tower block; 10, church. B: Participant’s view of task with two platforms, one of
which can be selected. The statue, castle, and fire engine landmarks can be seen, as well as the cross
hair controlled by participants with the trackerball. C: Visual control image.
 6 E.M. MIGO ET AL.

turning right), not every platform could be selected on any given choice. Platforms
could only be selected when they were yellow; they could not be selected when
they were red. This color change was independent of whether or not the platforms
had been selected before (although there was always at least one correct available
platform per choice). Participants received feedback in the form of a green tick or
red cross after each choice. The task was self-paced and continued until all plat-
forms had been selected. Before and after each trial there were 10 s periods of
blank screen (rest) and 10 s of a visual control image, which participants passively
viewed (see Figure 1). Task difficulty could be manipulated by changing the
number of platforms on each trial. Here, we used three trials of four platforms
and three trials of six platforms in a fixed order for all participants.
Participants were trained on the task on a separate visit where the neuropsychologi-
cal assessment was completed. After trials introducing the trackerball and the task, they
completed a full practice run of the experiment, comprising three trials at four platforms
and three trials at six platforms. On the day of the scan, each participant was reintro-
Downloaded by [Colin Dourish] at 03:02 03 August 2015

duced to the task and completed another full dry run before entering the scanner.

Image acquisition
Images were acquired using a 3.0-Tesla, GE Signa HDx system running 14m4 software
(General Electric, Milwaukee, WI, USA) at the Institute of Psychiatry, Psychology and
Neuroscience Department of Neuroimaging. Image volumes (each consisting of 38 near-
axial slices) were collected using a gradient-echo echo planar imaging sequence with a
repetition time (TR) of 2000 ms, an echo time (TE) of 30 ms, and a 75° flip angle. The
slices were positioned parallel to the AC-PC line. The body coil was used for radio-
frequency (RF) transmission and an 8-channel head coil for RF reception. Each image
slice was acquired using a 64 × 64 image matrix over a 24 cm field of view. The resulting
in-plane pixel size of the images was 3.75 mm × 3.75 mm. The image slices had a
thickness of 3.0 mm with a 0.3 mm gap. Head movement was limited by foam padding
within the head coil and a restraining band across the forehead. At the same session a
60-slice, high-resolution gradient-echo echo planar sequence was acquired in both the
coronal and axial planes with the same acquisition parameters apart from a 128 × 128
matrix, giving 1.875 × 1.875 in-plane resolution. Data quality was assured using an
automated quality control procedure (Simmons, Moore, & Williams, 1999). A high-
resolution 3D T1 weighted SPGR image was acquired in the coronal plane, with
1.1 mm isotropic voxels using a 256 × 256 × 196 matrix with a TI of 450 ms, TR of
7.1 ms, TE of 2.8 ms. and a flip angle of 20°.

Imaging data processing

Functional MRI data were preprocessed and analyzed using SPM8 (Wellcome
Department of Cognitive Neurology, London, UK; www.fil.ion.ucl.ac.uk/spm). Images
were preprocessed using the following steps: images were first spatially realigned to
the mean image from the series and then resliced. The mean functional image was co-
registered to each subject's T1 structural scan. Spatial normalization into Montreal
Neurological Institute (MNI) stereotactic space was carried out using Diffeomorphic
 AGING, NEUROPSYCHOLOGY, AND COGNITION 7

Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) (Ashburner, 2007),

using a sample template generated from all participants' structural scans. The functional
images were resampled into 1.5 mm3 voxels and spatially smoothed with an 8 mm full-
width half-maximum Gaussian kernel.
At the single-subject level, the data were modeled by splitting responses into
pairs of choices (i.e., a regressor encoding choices one and two at four platforms,
regressors encoding choices three and four at four platforms, etc.). Error trials,
visual control epochs, and a resting baseline condition were modeled separately.
In each case the regressor encoded the relevant epochs (i.e., blocks), modeled
using a boxcar, convolved with the canonical hemodynamic response function in
SPM. Importantly, for each trial the duration of the modeled epoch was dependent
upon subject performance, and therefore varied among epochs. Six regressors
encoding movement parameters (i.e., translations and rotations around the x-, y-,
z-axes) created during the realignment stage were included as covariates in all first-
level models to control for residual motion-related signal intensity variation. In the
Downloaded by [Colin Dourish] at 03:02 03 August 2015

second-level analysis, age and IQ (WASI) were included as covariates of no

interest to account for variance associated with these factors in both groups. A
number of separate group-level random effects analyses were carried out to iden-
tify task-related activation. Separate one-sample t-tests for patients and controls
were conducted using the first-level contrast of (i) all task-related activity (i.e.,
across four- and six-platform trials) versus resting baseline; (ii) activity during the
four-platform trials alone, compared to the resting baseline; (iii) activity during the
six-platform trials alone, compared to the resting baseline; and (iv) to identify load
effects, the first-level contrast of activity during the four-platform was compared to
the six-platform trials. Finally, a group-level three-way analysis of variance (ANOVA)
was created with the following factors: group (patient versus control), task
level (four versus six platforms), and trial (first pair of choices versus last pair of
choices).
The results were considered significant if they survived stringent family-wise
error correction for multiple comparisons on the basis of cluster extent (p < .05
corrected) using a cluster-forming height threshold of p < .001. For region of
interest (ROI) analysis of the hippocampus/parahippocampal gyrus, we used a
small volume correction limited to an anatomical mask, defined a priori in the
WFU Pickatlas (Wake Forest University, Winston-Salem, North Carolina). Statistical
significance was defined at the voxel level (p < .05) corrected for multiple
comparisons.
Structural data were processed for voxel-based morphometry (VBM) analysis
using the VBM8 toolbox within SPM8 (http://dbm.neuro.uni-jena.de/vbm/). Default
settings in VBM8 were used, which included normalization via DARTEL and seg-
mentation into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF).
Total intracranial volume (ICV) was calculated for each participant by summing
global tissue volume (i.e., GM, WM, and CSF) within VBM8. Images were smoothed
with an 8 mm full-width half-maximum Gaussian kernel. Statistical analysis used
unpaired t-tests in SPM8 to compare GM differences between healthy controls and
aMCI patients. Age and ICV were included as variables of no interest. The threshold
 8 E.M. MIGO ET AL.

of significance for this analysis was set to p < .001 (uncorrected) with an extent
threshold of 200 voxels.

Results
Neuropsychological assessment
The performance of both groups of participants is shown in Table 1. The control and
aMCI groups were matched for age, years in education, IQ, and executive function. The
aMCI group were significantly impaired on all measures of memory performance, with
no group differences on other measures.

Platform task performance

Both groups performed well at the task. The mean errors per trial (i.e., returning to a
Downloaded by [Colin Dourish] at 03:02 03 August 2015

previously visited platform) and total time taken per trial are shown in Table 2. Both
groups made errors at both levels of task difficulty and although aMCI patients
made numerically slightly more errors, a two-way repeated measures ANOVA with
group as a between-subject factor and a number of platforms as a within-subject
factor showed no significant effect of group (F(1,16) = 1.470, p = .243, f = .302). The

Table 1. Performance on neuropsychological test battery.

Control aMCI p
N (male) 10 (6) 8 (5) >.999#
Age 70.3 (6.5) 69.6 (5.8) .822
Years in education 16.0 (4.2) 17.0 (4.2) .622
IQ NART 121.3 (6.3) 119.8 (9.3) .679
WASI 124.4 (15.9) 116.8 (16.7) .474
Executive function Hayling 6.0 (1.0) 6.0 (0.0) .740*
Brixton 4.2 (2.5) 3.8 (2.1) .690
Trails B Time 74.0 (34.8) 88.4 (29.2) .365
Memory CVLT T Score 56.0 (10.5) 35.9 (15.1) .004
Logical Memory Immediate 11.9 (3.0) 7.6 (4.2) .022
Logical Memory Delayed 13.1 (2.1) 9.5 (3.7) .018
Visual Reproduction Immediate 12.7 (3.0) 8.9 (4.0) .033
Visual Reproduction Delayed 14.9 (2.7) 8.8 (4.2) .002
Attention Trails A Time 39.4 (11.4) 35.8 (10.3) .492
Working memory N-Back 2-back d’ 3.8 (1.0) 3.8 (0.6) .721*
N-Back 2-back RT 570.8 (107.0) 594.8 (94.7) .626
Values represent means for each group (SD) except for counts of participants, Hayling test, and N-Back 2-back d’ (Mdn
with IQR presented). p-Values represent independent t-tests except for #Chi squared with Fisher’s exact test and
*Mann–Whitney U-test.

Table 2. Platform performance.

Control aMCI
Errors per trial 4 Platforms 0.57 (.35) 0.83 (.44)
6 Platforms 1.90 (.74) 2.13 (.62)
Time per trial (seconds) 4 Platforms 59.7 (18.4) 84.3 (32.6)
6 Platforms 92.5 (19.6) 103.0 (31.8)
Mean errors or trial times are presented with standard deviation in parentheses.
 AGING, NEUROPSYCHOLOGY, AND COGNITION 9

main effect of number of platforms was significant, with more errors being made at six
platforms, (F(1,16) = 58.898, p < .001, f = 1.916), but the interaction of group and number
of platforms was not significant (F(1,16) = .015, p = .905, f = .032). The results from the
time taken per trial showed the same pattern, with a significant main effect of number
of platforms (F(1,16) = 15.399, p = .001, f = .980) and non-significant results for the main
effect of group (F(1,16) = 2.820, p = .107, f = .423) and interaction (F(1,16) = 1.147,
p = .300, f = .268).
To investigate more subtle performance differences, errors and reaction time for
correct choices were broken down within each trial (i.e., choices 1, 2, 3, and 4 at four
platforms and choices 1–6 at six platforms). For the reaction time data for four platforms,
a two-way repeated measures ANOVA was carried out, with group as a between-subjects
factor and choice as a within-subjects factor; there was no significant main effect of
group (F(1,15) = 2.843, p = .112, f = .435), but the main effect of choice was significant (F
(3,45) = 3.941, p = .014, f = .512). There was a trend for an interaction between platform
choice and group (F(3,45) = 2.500, p = .072, f = .408) due to the aMCI group being slower
Downloaded by [Colin Dourish] at 03:02 03 August 2015

as the number of choices increased. Planned post hoc t-tests showed no significant
differences between reaction time for the first two choices (smallest p = .392), but trends
for the last two choices (Choice 3 p = .115, d = .875; Choice 4 p = .058, d = 0.970).
Although the results of the ANOVA tests were marginal, the effect sizes indicate strong
effects of the aMCI group being slower on the later trials. This pattern was not present at
six platforms (smallest p = .343 for ANOVA). Errors were compared at each choice with
separate Mann–Whitney U-tests, but no significant differences were seen (smallest
uncorrected p = .148). Finally, we investigated any learning effects in reaction time
across trials (trials 1–3 for both task levels) but none were seen for each group separately
and there were no group by trial interactions (largest F = 2.371, p = .138 for main effect
of trial number at four platforms).

fMRI results
Control group
In the control group, a large network of brain regions showed increased BOLD response
during the task compared with rest, including a large cluster with a peak in the posterior
parietal cortex that extended bilaterally into the precuneus and visual cortex. These
regions are shown in Figure 2 and in Table 3. No regions were significantly deactivated
during the task when comparing both task levels against rest or when looking at the
task levels separately. When activity at four versus six platforms was compared, the left
supramarginal gyrus showed a trend for being more active at four than six platforms
(Table 3), but no regions showed increased activity with increased task difficulty. In the
ROI analysis of the hippocampus/parahippocampus, a cluster within the right hippo-
campus was significantly activated during the task compared with rest (x y z = 24, −25,
−8; 144 voxels; Z = 3.96).

Patient group
In the aMCI group, the brain regions that were significantly active covered a similar
network, but on visual inspection showed less activation (Figure 2, Table 4). Unlike in the
control group, an area in the midline cuneus showed task-related deactivations compared
 10 E.M. MIGO ET AL.
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Figure 2. Activation patterns for task versus rest condition. Left side shows control data and right
side shows data from aMCI group.

Table 3. Task-related activations in control participants. BA = Brodmann area, L = left, R = right.

x y z BA Voxels Z p(FWE-corr)
Task > Rest
Precuneus R 21 −70 54 7 79569 6.04 <.001
Supramarginal Gyrus R 56 −19 28 40 601 4.41 .002
Insula L −51 17 −3 13 495 3.94 .005
4 Platforms > Rest
Extrastriate Cortex L −27 −72 34 19 100198 6.09 <.001
6 Platforms > Rest
Precuneus R 20 −70 56 7 50807 5.84 <.001
Precentral Gyrus R 56 11 10 6 2319 5.15 <.001
Supramarginal Gyrus R 59 −18 28 40 335 4.39 .048
Thalamus L −20 −22 0 − 552 3.54 .005
4 Platforms > 6 Platforms
Supramarginal Gyrus L −60 −51 36 40 291 4.25 .088

with rest and no regions in the hippocampal/parahippocampal ROI were significantly

activated or deactivated by the task. No regions were sensitive to a change in number of
platforms, as there were no effects when comparing activation at four versus six platforms.

aMCI versus control group

When the control group was directly compared to the aMCI group across both task
levels, a widespread network of regions was significantly more active in controls than in
aMCI Patients (Table 5, Figure 3: red). This included areas important for navigation such
as the retrosplenial cortex, bilateral precuneus, left dorsolateral prefrontal cortex
(DLPFC), and caudate nucleus, extending into the parahippocampal gyrus and hippo-
campus. It also included areas such as the left middle frontal gyrus, bilateral insula, and
occipital cortex. In the reverse contrast, two regions were significantly less active in the
controls compared with the aMCI patients (Table 5, Figure 3: blue). These regions are in
the right DLPFC, in a medial region of the superior frontal gyrus and in the primary
 AGING, NEUROPSYCHOLOGY, AND COGNITION 11

Table 4. Task-related activations and deactivations in the aMCI group.

x y z BA Voxels Z p(FWE-corr)
Task > Rest
Middle occipital gyrus L −30 −97 9 18 8692 5.34 <.001
Superior frontal gyrus L 0 32 52 8 887 4.87 <.001
Middle frontal gyrus L −33 24 22 46 354 4.00 .003
Orbital frontal gyrus R 35 33 0 47 324 3.84 .005
Supplementary motor area R 12 −19 57 6 413 4.00 .001
Precentral gyrus L −28 −15 54 6 233 3.5 .026
Postcentral gyrus L −54 −21 54 2 252 4.05 .018
Superior parietal lobule R 20 −57 67 5 284 3.85 .010
Middle temporal gyrus R 51 −64 −3 37 224 4.23 .031
4 Platforms > Rest
Middle occipital gyrus L −28 −82 28 19 529 4.43 <.001
Middle occipital gyrus L −32 −96 6 18 517 4.02 <.001
Medial frontal gyrus L −12 −3 60 6 1224 4.33 <.001
Medial frontal gyrus R 18 −6 61 6 347 3.79 .006
Superior frontal gyrus R 6 35 51 8 1189 4.21 <.001
Orbital frontal gyrus R 35 20 −14 47 529 4.73 <.001
Superior parietal lobule L −28 −67 52 7 306 3.86 .001
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Lingual gyrus R 20 −87 −14 18 1264 4.59 <.001

6 Platforms > Rest
Middle occipital gyrus L −30 −91 12 18 6385 5.64 <.001
Middle frontal gyrus R 38 9 57 8 475 4.63 <.001
Medial frontal gyrus R 4 11 48 32 404 4.47 <.001
Medial frontal gyrus R 16 −6 60 6 226 3.79 .012
Postcentral gyrus L −54 −21 52 2 3197 4.31 <.001
Precentral gyrus L −32 −3 46 6 747 4.19 <.001
Precuneus R 21 −63 48 7 1271 4.16 <.001
Supramagrinal gyrus R 52 −43 43 40 305 4.76 .002
Task < Rest
Cuneus R 6 −91 25 18 206 4.31 .045
6 Platforms < Rest
Cuneus R 3 −87 30 18 225 3.94 .013

Table 5. Significant regions for aMCI patients versus controls.

x y z BA Voxels Z p(FWE-corr)
Controls > aMCI
Inferior occipital gyrus L −39 −73 −3 19 43173 6.73 <.001
Precuneus L −30 −67 33 7 1769 5.61 <.001
Middle frontal gyrus L −24 38 24 46 6553 5.55 <.001
Retrosplenial cortex R 12 −58 13 30 633 4.00 .040
Controls > aMCI (Parahippocampal/Hippocampal ROI)
Hippocampus L −16 −25 −11 – 253 4.29 .019
Parahippocampus R 18 −42 −3 27 552 4.32 .003
Controls < aMCI
Medial frontal gyrus R 8 51 43 9 1008 5.63 .006
Precentral gyrus L −16 −28 67 4 1099 5.11 .004

Figure 3. Activation maps for controls greater than aMCI patients (red) and controls less than aMCI
patients (blue). To view this figure in color, please see the online version of this journal.
 12 E.M. MIGO ET AL.

Figure 4. Activation maps for controls greater than aMCI patients in hippocampal/parahippocampal
ROI. A: Left hemisphere peak and B: Right hemisphere peak. See also Table 5.
Downloaded by [Colin Dourish] at 03:02 03 August 2015

motor cortex, in the precentral gyrus. Using the parahippocampal/hippocampal ROI, one
cluster in the left posterior hippocampus and one in the right parahippocampal gyrus,
extending into the hippocampus, were significantly more active in the control group
than in the patients (Table 5, Figure 4).
Across both groups, a region in the right supplementary motor area (BA 6) was signifi-
cantly more active at four platforms versus six platforms (x y z = 14, −18, 55; 724 voxels;
Z = 4.21). No regions were significant in the reverse contrast. No regions showed significant
effects of choice (start of trial versus end of trial). Finally, driven by the behavioral results, we
compared activity in the aMCI group versus controls at the end of the four-platform trials,
where the only performance differences were seen. This showed significantly more activity
in the right caudate in the control group compared with the patients (x y z = 21, −9, 31; 610
voxels; Z = 4.73) and no regions for the reverse contrast.

VBM analysis
Multiple regions of reduced gray matter were seen in the aMCI group in comparison to
the controls (Table 6). This included clusters with peaks in the hippocampus bilaterally,
as well as the left perirhinal cortex. Another cluster covered the right thalamus. No
regions showed significantly higher gray matter in the aMCI group.

Table 6. Significant clusters for VBM results where reduced gray matter was found in aMCI patients
compared with controls.
Region BA Area Peak MNI Co-ordinates Cluster Size Z p(uncorrected)
Hippocampus L – −53 314 3.78 <.001
Hippocampus R – 33–12 −11 246 3.62 <.001
Perirhinal cortex L 36 −39 3–30 245 3.89 <.001
Inferior temporal gyrus L 20 −106 1354 4.45 <.001
Thalamus/vermis R – −41 1226 4.00 <.001
Gyrus rectus R 11 10 27–17 399 4.12 <.001
 AGING, NEUROPSYCHOLOGY, AND COGNITION 13

Discussion
This study used a virtual reality navigation task based on the Olton Radial Arm
Maze in an fMRI study comparing aMCI patients and healthy control participants.
Both groups performed well on the task and performance data were not sensitive
enough to differentiate patients from controls, except for a subtle deficit at the end
of the easier task-level trials. Our fMRI results showed significantly different recruit-
ment of areas known to be important for spatial navigation between the two
groups, covering widespread networks. Specifically, aMCI patients showed reduced
recruitment of the hippocampus alongside increased recruitment of the retrosple-
nial cortex, precuneus, and caudate nucleus. Lateralized differences were seen in
the DLPFC.
In this study we have demonstrated that aMCI patients can successfully com-
plete what seems on the surface to be a relatively complicated navigation task,
albeit in the context of structured and standardized training beforehand at screen-
Downloaded by [Colin Dourish] at 03:02 03 August 2015

ing and on the day of the scan. All patients (and control participants) successfully
completed a dry run outside the scanner immediately prior to the scanning session.
With this training, the patients performed as well as controls, except for a subtle
difference toward the end of the four platforms trials. This subtle performance
deficit follows previous reports in the literature, where some studies show deficits
in navigation tasks while others are unimpaired, depending on the task.
Our healthy control group showed an expected right hippocampal activation
during the task in our ROI analysis. Right hippocampal involvement in spatial
navigation is well established from previous fMRI studies (Hartley et al., 2003;
Iaria et al., 2003; Maguire et al., 1998; Wolbers et al., 2007), as well as MRI studies
linking the volume or structural integrity of the region to behavioral performance
(Bohbot et al., 2007; Iaria et al., 2008). In the present group of healthy elderly
controls, hippocampal activation was not significant in the whole-brain analysis, as
expected from results showing reduced hippocampal activity during navigation
with age (Antonova et al., 2009). In using a virtual reality Arena task, an analog
of the Morris Swim Maze, multiple replications have shown robust hippocampal
activation in young, healthy control participants (Antonova et al., 2009, 2011;
Parslow et al., 2004). However, when the same task was used with healthy older
participants, hippocampal activation was not seen in whole-brain analysis
(Antonova et al., 2009). Significantly reduced activation in the hippocampus in
older versus younger participants has been replicated in different navigation tasks
(Meulenbroek, Petersson, Voermans, Weber, & Fernández, 2004; Moffat, Elkins, &
Resnick, 2006).
Within the hippocampal/parahippocampal ROI, our aMCI group showed significantly
reduced activation compared with controls, with the peak in the hippocampus proper in
the left hemisphere and the parahippocampal gyrus in the right hemisphere.
Significantly reduced activity in this anterior region of the right parahippocampal
gyrus is frequently reported in studies of episodic memory in MCI patients, and it is
one of the few regions reliably implicated in MCI as revealed by meta-analysis
(Browndyke et al., 2013). In a separate study involving the same participants as used
in this study, as well as some additional participants, reduced hippocampal activity was
 14 E.M. MIGO ET AL.

found during a working memory N-back task (Migo et al., 2015), mirroring our results
here. This suggests that reduced hippocampal activity is present both for tasks where
hippocampal involvement is expected, as well as in those, such as the N-back, where it
not expected to be critical.
The aMCI group showed a much restricted network of task-related activity,
notably including the DLPFC. When the two groups were directly compared, a
wide network showed significantly more activation in the controls than in the
aMCI group and some restricted areas were significantly more activated in patients
than controls. These comparisons showed laterality-related dissociations within the
frontal cortex. Patients recruited the right DLPFC (BA 46) more than controls, who
instead showed greater activation of the left DLPFC (BA 46 and 9) and left
medial prefrontal cortex (BA 32). A very similar region in BA 9 has been found to
be reliability less activated in MCI than in healthy controls in a meta-analysis of
episodic memory studies (Browndyke et al., 2013), showing some consistency
across tasks. The role of the left DLPFC in verbal working memory (Owen,
Downloaded by [Colin Dourish] at 03:02 03 August 2015

McMillan, Laird, & Bullmore, 2005; Wager & Smith, 2003) may explain its activation
in controls, since participants often used a strategy of continually rehearsing which
platforms had been visited in order to complete the task, allowing working
memory to contribute to performance. In meta-analysis, the left DLPFC is more
frequently reported as being involved in verbal working memory than the right
(Wager & Smith, 2003), consistent with verbal maintenance across the task in
controls. The right DLPFC may have been additionally recruited in aMCI
patients as a result of attentional demands, a role suggested, for example, by
meta-analysis of Stroop task performance in healthy controls (Vanderhasselt,
Raedt, & Baeken, 2009).
The laterality effects in BA 46 may also reflect how demanding participants
found the task. Meta-analysis shows that for spatial and verbal working memory,
the left DLPFC is implicated for passive working memory storage whereas the right
DLPFC is implicated for executive working memory more than the left (Wager &
Smith, 2003). Whilst the procedure used in the task was designed to prevent the
emergence of organizational strategies, for the aMCI patients it may have been
sufficiently demanding to recruit more executive working memory networks. The
task is set up to limit the number of choices on specific trial to avoid strategies
such as “clustering” or “ordering” spatial information through repetitive routes,
done by using a pseudorandom method of certain locations not being accessible
for checking on each trial (see Methods). However, greater demands on spatial
working memory may have occurred in the aMCI group, with the participants
involving more central executive resources. More recently, the importance of the
prefrontal cortex interacting with the hippocampus for successful navigation has
been stressed by Spiers and Gilbert (2015). The right lateral prefrontal cortex may
be particularly important for detecting that a change in route is needed as a result
of environment alteration, with the frontopolar prefrontal cortex involved in re-
planning the route. The posterior hippocampus processes the new path while the
superior prefrontal cortex may be particularly important for dealing with conflicting
route options. This interpretation suggests that the aMCI and control participants
were differentially recruiting parts of a navigation network in order to succeed in
 AGING, NEUROPSYCHOLOGY, AND COGNITION 15

the task. If spatial navigation involves much more than just hippocampal proces-
sing in isolation, this could perhaps explain why our patients did well on the task
despite hippocampal atrophy and demonstrable episodic memory impairments
using standard tests.
Other regions that were recruited significantly more in the healthy controls than
the aMCI patients include those known to be important for spatial navigation, such
as the caudate, the precuneus, and the retrosplenial cortex. When looking at the
specific part of the task where performance differences were seen among the
groups, at the end of the four platform trials, the right caudate nucleus was
significantly more active in controls versus patients. Caudate activation is also
associated with egocentric spatial processing (Postle & D’Esposito, 2003) and over-
learning of spatial environments (Dahmani & Bohbot, 2015). In most spatial tasks,
egocentric and allocentric processing interact and are coordinated to solve a
particular task, but here the task is designed to emphasize allocentric processing.
It is notable that in a previous study in which hippocampal functioning was
Downloaded by [Colin Dourish] at 03:02 03 August 2015

suppressed using scopolamine in normal participants, the caudate nucleus became

more active, which was interpreted as involving an egocentric compensatory
mechanism (Antonova et al., 2011). Although it is possible that egocentric choices
could sometimes be successful on this task, an egocentric-based mnemonic would
tend to make responses less accurate. The caudate nucleus is also associated with
using landmarks in spatial navigation (Doeller et al., 2008), which is consistent with
the design of the task to utilize major landmarks in the virtual environment to
navigate between platforms. Studies of brain dysfunction and/or atrophy in MCI
have tended to focus on the medial temporal lobes and the hippocampus, but
caudate atrophy has also been reported (Madsen et al., 2010). Right
caudate atrophy has been particularly associated with MCI to AD conversion
(Madsen et al., 2010).
A significant reduction in recruitment of the precuneus in MCI, as found in this
study, is one of the most widely reported results in fMRI studies of MCI using
traditional memory tasks, such as associative memory (Pihlajamäki & Sperling,
2008). Disruption here is thought to occur early in the progress of degeneration
toward dementia (Pihlajamäki & Sperling, 2008). The retrosplenial cortex was also
activated more strongly in controls than in our aMCI patients. The role of the
region in navigation is thought to be centered on switching between egocentric
and allocentric frame of reference, and patients with retrosplenial damage struggle
to navigate in familiar environments, even when landmarks are recognized (Vann
et al., 2009). Hypoperfusion in the retrosplenial cortex is a key feature of MCI
(Nestor, Fryer, Ikeda, & Hodges, 2003) and is noticeable before any changes in
the parahippocampal gyrus (Minoshima et al., 1997). fMRI investigations of cogni-
tion beyond long-term episodic memory remain limited and therefore we are
cautious that we should not over-interpret group differences in regions recruited
for the task; as more studies are published it will be possible to establish which
regions show the most reliable group differences. A recent meta-analysis on all
published fMRI tasks comparing MCI patients against age-matched controls
reported not having enough studies to be conclusive as to whether there are any
significant regions implicated in visuospatial tasks (Li et al., 2015).
 16 E.M. MIGO ET AL.

Widespread differences in BOLD activity were found despite the lack of major
performance impairments in the aMCI group. Our lack of performance differences
on the platform task itself cannot be easily attributed to the sample size, since the
patient group showed significant deficits on all the standardized memory tasks. The
regions showing significantly reduced task-related activity in the patient group
cover the key regions known to be important for spatial navigation, and are
consistent with reports of early atrophy and changes in perfusion in MCI from
the literature. The additional use of prefrontal regions in the aMCI group can
presumably compensate for the lack of recruitment of other regions in the standard
network used for navigation. Outside of the expected navigation network, our
results are consistent with other studies using fMRI in MCI/aMCI patients. Some
of the regions where we see reduced activation relative to controls are reliably
reported across a variety of cognitive tasks, as indicated by meta-analysis (Li et al.,
2015), notably including the left middle frontal gyrus and right insula. It might be
concluded that reduced activation in aMCI patients reflects changes in those brain
Downloaded by [Colin Dourish] at 03:02 03 August 2015

regions as a part of an early disease process, before atrophy can be seen, not
necessarily specific in relation to disruption of particular neurocognitive systems.
Our structural imaging VBM analysis found expected loss of gray matter in the
hippocampus bilaterally in our aMCI patients compared with controls. We also found
volume reductions in the left perirhinal cortex and in a cluster extending to cover the
right thalamus. Gray matter reductions in medial temporal lobe regions are reliably
found in meta-analysis, particularly on the left side (Ferreira, Diniz, Forlenza, Busatto, &
Zanetti, 2011; Yang et al., 2012). Our results are therefore consistent with the extensive
previous literature looking at atrophy in aMCI.
There was some evidence that patients were impaired toward the end of the four-
platform trials, but not for six platforms. It might be expected that the task would be
increasingly sensitive to impairment with task difficulty. It is worth noting that this
remains a subtle deficit and that, despite showing problems with episodic memory,
our aMCI patients performed well on all other cognitive tasks, including a measure of
working memory. Since participants (both patients and controls) used verbal mainte-
nance to keep in mind which platforms they had visited, this task will not have
extensively tapped the types of anterograde memory with which they are impaired on
standardized tests.
One other potential explanation for our aMCI patients performing well on the
task is the training they received before completing the scanning session. This
training ensured that all patients, and indeed, the controls, were comfortable
with both the cognitive and practical demands of the task. Training introduced
them to the virtual spatial environment and the use of the trackerball, which was a
novel device to use for all participants. Standardized instructions, gradually intro-
ducing the task complexity, ensured that all participants, even those with little
experience of using a computer, were able to successfully complete the task. This
may explain the lack of any learning effect across the individual task trials. In other
studies, where participants are asked to navigate the same route, participants learn
their way around a virtual environment and aMCI patients show less improvement
across trials (Weniger et al., 2011). In our study, participants learned the layout of
the virtual space before entering the scanner and the task instead measured their
 AGING, NEUROPSYCHOLOGY, AND COGNITION 17

ability to navigate within a now familiar space. As more navigation tasks are used
with MCI patients, and in aMCI in particular, these differences in design and
training will be important for interpreting any performance differences between
groups.
Much of the existing data using virtual or real-world tasks of spatial navigation
shows only small impairments in MCI, particularly when the aMCI group is investi-
gated (Cushman et al., 2008; Hort et al., 2007; Tippett et al., 2009). This is partly due
to the limited numbers of existing studies, which means that making replications
and the development of novel tasks is important. Variation in results will also be
influenced by the heterogeneity in MCI patients, both within any given group and
among studies (Stephan, Matthews, McKeith, Bond, & Brayne, 2007; Stephan et al.,
2013). The outcome measures of our task, reaction time, and error rates may not be
sensitive enough to fully expose aMCI performance impairments in the same way
as tasks such as the Hidden Goal Task (Hort et al., 2007), based on the Morris Water
Maze (Morris et al., 1982), which measure distance errors. The procedure used was
Downloaded by [Colin Dourish] at 03:02 03 August 2015

designed to mimic the allocentric spatial memory demands of the Radial Arm Maze,
but for humans. In real-life situations, there is often time pressure to make a
decision and slower responding has negative consequences. Here, the experiment
was designed to be self-paced and therefore may not reflect the full nature of
everyday life task demands. A challenge for creating ecologically valid virtual reality
tasks for fMRI use is to create the real-world demands, whilst having sufficient
experimental control to ensure reliable measurement.
A limitation of our study is that our sample was relatively small, including only
eight patients with aMCI. Again, this might have resulted in the task not detecting
cognitive change if the task had low sensitivity in this respect. For activation
measurement, to try to mitigate the risk that our results represent a type I error,
our fMRI results are corrected at a whole-brain level with a height threshold of .001,
indicating a strict statistical threshold. In order to fully compare and contrast
results, the use of and full reporting of broad neuropsychological background
testing remains important. Here, our group of aMCI patients was carefully selected,
screened, and trained on the task, helping us to have a relatively homogenous
group which has allowed us to see statistically robust BOLD differences.
It should be noted that fMRI tasks like the Platform task are used experimentally
and do not currently replace standardized neuropsychological assessment used to
define aMCI. The lack of behavioral differences between the groups, although
helpful in avoiding a confound in interpreting fMRI differences (Price & Friston,
1999), indicates that this task does not separate the groups based on performance.
However, fMRI tasks such as these help us understand neural changes that precede
performance deficits and already have potential in the evaluation of pharmaceutical
treatment, using fMRI brain activations as outcome measures for drug screening
trials, as suggested for schizophrenia research (Dourish & Dawson, 2014).
In conclusion, in this study we found statistically robust fMRI differences between
healthy controls and aMCI patients. Even in the absence of profound performance deficits,
widespread differences in activation patterns were found when considering the groups
separately, but also when directly compared. We believe this to be the first use of an fMRI
spatial navigation task in aMCI, showing reduced recruitment of many regions important
 18 E.M. MIGO ET AL.

for spatial navigation in aMCI, including the hippocampus, caudate, retrosplenial cortex,
and precuneus. We also saw reduced activation in a wide network of other regions,
matching results from a variety of fMRI tasks used with this population. In contrast, we
observed significantly increased recruitment of the right prefrontal regions in the patient
group. These effects add weight to suggestions that spatial navigation tasks may be
potentially useful in staging of the disease (Gazova et al., 2012; Lithfous et al., 2013)
based on the differential activation patterns rather than performance.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
Downloaded by [Colin Dourish] at 03:02 03 August 2015

This study was supported by the P1vital CNS Experimental Medicine Consortium (members
AstraZeneca, GlaxoSmithKline, Lundbeck, Organon (a subsidiary of Merck) and Pfizer). GKW was
partly supported by the NIHR Comprehensive Biomedical Research Centre Programme, Oxford. AS
and SCRW were supported by the NIHR Biomedical Research Centre for Mental Health at South
London and Maudsley NHS Foundation Trust and King's College London, IoPPN. AS and MDK were
supported by the NIHR Biomedical Research Unit for Dementia at South London and Maudsley
NHS Foundation Trust and King's College London, IoPPN.

References
Antonova, E., Parslow, D., Brammer, M., Dawson, G. R., Jackson, S. H. D., & Morris, R. G. (2009). Age-
related neural activity during allocentric spatial memory. Memory, 17, 125–143. doi:10.1080/
09658210802077348
Antonova, E., Parslow, D., Brammer, M., Simmons, A., Williams, S., Dawson, G. R., & Morris, R. (2011).
Scopolamine disrupts hippocampal activity during allocentric spatial memory in humans: An
fMRI study using a virtual reality analogue of the Morris Water Maze. Journal of
Psychopharmacology, 25, 1256–1265. doi:10.1177/0269881110379285
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage, 38, 95–113.
doi:10.1016/j.neuroimage.2007.07.007
Auger, S. D., Mullally, S. L., & Maguire, E. A. (2012). Retrosplenial cortex codes for permanent
landmarks. PLoS ONE, 7, e43620. doi:10.1371/journal.pone.0043620
Baumann, O., Chan, E., & Mattingley, J. B. (2012). Distinct neural networks underlie encoding of
categorical versus coordinate spatial relations during active navigation. NeuroImage, 60, 1630–
1637. doi:10.1016/j.neuroimage.2012.01.089
Blennow, K., Hampel, H., Weiner, M., & Zetterberg, H. (2010). Cerebrospinal fluid and plasma
biomarkers in Alzheimer disease. Nature Reviews Neurology, 6, 131–144. doi:10.1038/
nrneurol.2010.4
Bohbot, V. D., Lerch, J., Thorndycraft, B., Iaria, G., & Zijdenbos, A. P. (2007). Gray matter differences
correlate with spontaneous strategies in a human virtual navigation task. The Journal of
Neuroscience, 27, 10078–10083. doi:10.1523/jneurosci.1763-07.2007
Bohil, C. J., Alicea, B., & Biocca, F. A. (2011). Virtual reality in neuroscience research and therapy.
Nature Reviews Neuroscience, 12, 752–762. doi:10.1038/nrn3122
Browndyke, J. N., Giovanello, K., Petrella, J., Hayden, K., Chiba-Falek, O., Tucker, K. A., . . . Welsh-
Bohmer, K. A. (2013). Phenotypic regional functional imaging patterns during memory encoding
in mild cognitive impairment and Alzheimer’s disease. Alzheimer’s & Dementia, 9, 284–294.
doi:10.1016/j.jalz.2011.12.006
 AGING, NEUROPSYCHOLOGY, AND COGNITION 19

Burgess, P., & Shallice, T. (1997). The hayling and brixton tests. Bury St Edmunds: Thames Valley Test
Company.
Cavanna, A. E., & Trimble, M. R. (2006). The precuneus: A review of its functional anatomy and
behavioural correlates. Brain, 129, 564–583. doi:10.1093/brain/awl004
Cushman, L. A., Stein, K., & Duffy, C. J. M. D. (2008). Detecting navigational deficits in cognitive
aging and Alzheimer disease using virtual reality. Neurology, 71, 888–895. doi:10.1212/01.
wnl.0000326262.67613.fe
Dahmani, L., & Bohbot, V. D. (2015). Dissociable contributions of the prefrontal cortex to hippo-
campus- and caudate nucleus-dependent virtual navigation strategies. Neurobiology of Learning
and Memory, 117, 42–50. doi:10.1016/j.nlm.2014.07.002
DeIpolyi, A. R., Rankin, K. P., Mucke, L., Miller, B. L., & Gorno-Tempini, M. L. (2007). Spatial cognition
and the human navigation network in AD and MCI. Neurology, 69, 986–997. doi:10.1212/01.
wnl.0000271376.19515.c6
Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis-Kaplan executive function system. San Antonio,
TX: Psychological Corporation.
Delis, D. C., Kramer, J., Kaplan, E., & Ober, B. (2000). The California verbal learning test. San Antonio,
TX: Psychological Corporation.
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Devan, B. D., Goad, E. H., & Petri, H. L. (1996). Dissociation of hippocampal and striatal contribu-
tions to spatial navigation in the water maze. Neurobiology of Learning and Memory, 66, 305–
323. doi:10.1006/nlme.1996.0072
Doeller, C. F., King, J. A., & Burgess, N. (2008). Parallel striatal and hippocampal systems for
landmarks and boundaries in spatial memory. Proceedings of the National Academy of
Sciences, 105, 5915–5920. doi:10.1073/pnas.0801489105
Dourish, C. T., & Dawson, G. R. (2014). Precompetitive consortium approach to validation of the next
generation of biomarkers in schizophrenia. Biomarkers in Medicine, 8, 5–8. doi:10.2217/bmm.13.89
Epstein, R. A. (2008). Parahippocampal and retrosplenial contributions to human spatial naviga-
tion. Trends in Cognitive Sciences, 12, 388–396. doi:10.1016/j.tics.2008.07.004
Ferreira, L. K., Diniz, B. S., Forlenza, O. V., Busatto, G. F., & Zanetti, M. V. (2011). Neurostructural
predictors of Alzheimer’s disease: A meta-analysis of VBM studies. Neurobiology of Aging, 32,
1733–1741. doi:10.1016/j.neurobiolaging.2009.11.008
Gazova, I., Vlcek, K., Laczó, J., Nedelska, Z., Hyncicova, E., Mokrisova, I., . . . Hort, J. (2012). Spatial
navigation-A unique window into physiological and pathological aging. Frontiers in Aging
Neuroscience, 4. doi:10.3389/fnagi.2012.00016
Hartley, T., Maguire, E. A., Spiers, H. J., & Burgess, N. (2003). The well-worn route and the path less
traveled: Distinct neural bases of route following and wayfinding in humans. Neuron, 37, 877–
888. doi:10.1016/s0896-6273(03)00095-3
Henderson, V. W., Mack, W., & Williams, B. W. (1989). Spatial disorientation in Alzheimer’s
disease. Archives of Neurology, 46, 391–394. doi:10.1001/archneur.1989.00520400045018
Hort, J., Laczó, J., Vyhnálek, M., Bojar, M., Bureš, J., & Vlček, K. (2007). Spatial navigation deficit in
amnestic mild cognitive impairment. Proceedings of the National Academy of Sciences of the
United States of America, 104, 4042–4047. doi:10.1073/pnas.0611314104
Iachini, T., Iavarone, A., Senese, V. P., Ruotolo, F., & Ruggiero, G. (2009). Visuospatial memory in
healthy elderly, AD and MCI: A review. Current Aging Science, 2, 43–59. doi:10.2174/
1874609810902010043
Iaria, G., Chen, J.-K., Guariglia, C., Ptito, A., & Petrides, M. (2007). Retrosplenial and hippocampal
brain regions in human navigation: Complementary functional contributions to the formation
and use of cognitive maps. European Journal of Neuroscience, 25, 890–899. doi:10.1111/j.1460-
9568.2007.05371.x
Iaria, G., Lanyon, L. J., Fox, C. J., Giaschi, D., & Barton, J. J. S. (2008). Navigational skills correlate with
hippocampal fractional anisotropy in humans. Hippocampus, 18, 335–339. doi:10.1002/
hipo.20400
Iaria, G., Petrides, M., Dagher, A., Pike, B., & Bohbot, V. D. (2003). Cognitive strategies dependent on
the hippocampus and caudate nucleus in human navigation: Variability and change with
practice. Journal of Neuroscience, 23, 5945–5952.
 20 E.M. MIGO ET AL.

Laczó, J., Andel, R., Vyhnalek, M., Vlcek, K., Magerova, H., Varjassyova, A., & Hort, J. (2010). Human
analogue of the Morris Water Maze for testing subjects at risk of Alzheimer’s disease.
Neurodegenerative Diseases, 7, 148–152.
Laczó, J., Vlček, K., Vyhnálek, M., Vajnerová, O., Ort, M., Holmerová, I., . . . Hort, J. (2009). Spatial
navigation testing discriminates two types of amnestic mild cognitive impairment. Behavioural
Brain Research, 202, 252–259. doi:10.1016/j.bbr.2009.03.041
Li, H.-J., Hou, X.-H., Liu, -H.-H., Yue, C.-L., He, Y., & Zuo, X.-N. (2015). Toward systems neuroscience in
mild cognitive impairment and Alzheimer’s disease: A meta-analysis of 75 fMRI studies. Human
Brain Mapping, 36, 1217–1232. doi:10.1002/hbm.22689
Lithfous, S., Dufour, A., & Després, O. (2013). Spatial navigation in normal aging and the prodromal
stage of Alzheimer’s disease: Insights from imaging and behavioral studies. Ageing Research
Reviews, 12, 201–213. doi:10.1016/j.arr.2012.04.007
Madsen, S. K., Ho, A. J., Hua, X., Saharan, P. S., Toga, A. W., Jack, C. R., . . . Thompson, P. M. (2010). 3D
maps localize caudate nucleus atrophy in 400 Alzheimer’s disease, mild cognitive impairment,
and healthy elderly subjects. Neurobiology of Aging, 31, 1312–1325. doi:10.1016/j.
neurobiolaging.2010.05.002
Maguire, E. A., Burgess, N., Donnett, J. G., Frackowiak, R. S. J., Frith, C. D., & O’Keefe, J. (1998).
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Knowing where and getting there: A human navigation network. Science, 280, 921–924.
doi:10.1126/science.280.5365.921
Marsh, R., Hao, X., Xu, D., Wang, Z., Duan, Y., Liu, J., . . . Peterson, B. S. (2010). A virtual reality-based
FMRI study of reward-based spatial learning. Neuropsychologia, 48, 2912–2921. doi:10.1016/j.
neuropsychologia.2010.05.033
Meulenbroek, O., Petersson, K. M., Voermans, N., Weber, B., & Fernández, G. (2004). Age differences
in neural correlates of route encoding and route recognition. NeuroImage, 22, 1503–1514.
doi:10.1016/j.neuroimage.2004.04.007
Migo, E. M., Mitterschiffthaler, M., O’Daly, O., Dawson, G. R., Dourish, C. T., Craig, K. J., . . . Morris, R.
G. (2015). Alterations in working memory networks in amnestic mild cognitive impairment.
Aging, Neuropsychology, and Cognition, 22, 106–127. doi:10.1080/13825585.2014.894958
Minoshima, S., Giordani, B., Berent, S., Frey, K. A., Foster, N. L., & Kuhl, D. E. (1997). Metabolic
reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Annals of
Neurology, 42, 85–94. doi:10.1002/ana.410420114
Mitolo, M., Gardini, S., Fasano, F., Crisi, G., Pelosi, A., Pazzaglia, F., & Caffarra, P. (2013). Visuospatial
memory and neuroimaging correlates in mild cognitive impairment. Journal of Alzheimer’s
Disease, 35, 75–90. doi:10.3233/JAD-121288
Moffat, S. D. (2009). Aging and spatial navigation: What do we know and where do we go?
Neuropsychology Review, 19, 478–489. doi:10.1007/s11065-009-9120-3
Moffat, S. D., Elkins, W., & Resnick, S. M. (2006). Age differences in the neural systems supporting
human allocentric spatial navigation. Neurobiology of Aging, 27, 965–972. doi:10.1016/j.
neurobiolaging.2005.05.011
Monacelli, A. M., Cushman, L. A., Kavcic, V., & Duffy, C. J. (2003). Spatial disorientation in
Alzheimer’s disease: The remembrance of things passed. Neurology, 61, 1491–1497.
doi:10.1212/WNL.61.11.1491
Morris, J. C. (1993). The clinical dementia rating (CDR): Current version and scoring rules.
Neurology, 43, 2412–2412. doi:10.1212/WNL.43.11.2412-a
Morris, J. C., Storandt, M., Miller, J. P., McKeel, D. W., Price, J. L., Rubin, E. H., & Berg, L. (2001). Mild
cognitive impairment represents early-stage Alzheimer disease. Archives of Neurology, 58, 397–
405. doi:10.1001/archneur.58.3.397
Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O’Keefe, J. (1982). Place navigation impaired in rats
with hippocampal lesions. Nature, 297, 681–683. doi:10.1038/297681a0
Nedelska, Z., Andel, R., Laczó, J., Vlcek, K., Horinek, D., Lisy, J., . . . Hort, J. (2012). Spatial navigation
impairment is proportional to right hippocampal volume. Proceedings of the National Academy
of Sciences, 109, 2590–2594. doi:10.1073/pnas.1121588109
Nelson, H. E., & Willison, J. R. (1991). National adult reading test (Part II): Test manual. Windsor:
NFER-NELSON.
 AGING, NEUROPSYCHOLOGY, AND COGNITION 21

Nestor, P. J., Fryer, T. D., Ikeda, M., & Hodges, J. R. (2003). Retrosplenial cortex (BA 29/30)
hypometabolism in mild cognitive impairment (prodromal Alzheimer’s disease). European
Journal of Neuroscience, 18, 2663–2667. doi:10.1046/j.1460-9568.2003.02999.x
O’Keefe, J., & Conway, D. H. (1980). On the trail of the hippocampal engram. Physiological
Psychology, 8, 229–238. doi:10.3758/BF03332854
Olton, D. S., & Samuelson, R. J. (1976). Remembrance of places passed: Spatial memory in rats.
Journal of Experimental Psychology: Animal Behavior Processes, 2, 97–116. doi:10.1037/0097-
7403.2.2.97
Owen, A. M., McMillan, K. M., Laird, A. R., & Bullmore, E. (2005). N-back working memory paradigm:
A meta-analysis of normative functional neuroimaging studies. Human Brain Mapping, 25, 46–
59. doi:10.1002/(ISSN)1097-0193
Parslow, D. M., Rose, D., Brooks, B., Fleminger, S., Gray, J. A., Giampietro, V., . . . Morris, R. G. (2004).
Allocentric spatial memory activation of the hippocampal formation measured with fMRI.
Neuropsychology, 18, 450–461. doi:10.1037/0894-4105.18.3.450
Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine,
256, 183–194. doi:10.1111/j.1365-2796.2004.01388.x
Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins, P. V., . . . Winblad, B. (2001).
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Current concepts in mild cognitive impairment. Archives of Neurology, 58, 1985–1992.

doi:10.1001/archneur.58.12.1985
Pihlajamäki, M., & Sperling, R. A. (2008). fMRI: Use in early Alzheimer’s disease and in clinical trials.
Future Neurology, 3, 409–421. doi:10.2217/14796708.3.4.409
Postle, B. R., & D’Esposito, M. (2003). Spatial working memory activity of the caudate nucleus is
sensitive to frame of reference. Cognitive, Affective, & Behavioral Neuroscience, 3, 133–144.
doi:10.3758/CABN.3.2.133
Price, C. J., & Friston, K. J. (1999). Scanning patients with tasks they can perform. Human Brain
Mapping, 8, 102–108. doi:10.1002/(SICI)1097-0193(1999)8:2/3<102::AID-HBM6>3.0.CO;2-J
Prvulovic, D., Bokde, A. L. W., Faltraco, F., & Hampel, H. (2011). Functional magnetic resonance
imaging as a dynamic candidate biomarker for Alzheimer’s disease. Progress in Neurobiology, 95,
557–569. doi:10.1016/j.pneurobio.2011.05.008
Schinazi, V. R., Nardi, D., Newcombe, N. S., Shipley, T. F., & Epstein, R. A. (2013). Hippocampal size
predicts rapid learning of a cognitive map in humans. Hippocampus, 23, 515–528. doi:10.1002/
hipo.v23.6
Shi, F., Liu, B., Zhou, Y., Yu, C., & Jiang, T. (2009). Hippocampal volume and asymmetry in mild
cognitive impairment and Alzheimer’s disease: Meta-analyses of MRI studies. Hippocampus, 19,
1055–1064. doi:10.1002/hipo.20573
Shipman, S. L., & Astur, R. S. (2008). Factors affecting the hippocampal BOLD response during
spatial memory. Behavioural Brain Research, 187, 433–441. doi:10.1016/j.bbr.2007.10.014
Simmons, A., Moore, E., & Williams, S. C. R. (1999). Quality control for functional magnetic
resonance imaging using automated data analysis and Shewhart charting. Magnetic
Resonance in Medicine, 41, 1274–1278. doi:10.1002/(sici)1522-2594(199906)41:6<1274::aid-
mrm27>3.0.co;2-1
Sperling, R. (2011). The potential of functional MRI as a biomarker in early Alzheimer’s disease.
Neurobiology of Aging, 32, S37–S43. doi:10.1016/j.neurobiolaging.2011.09.009
Spiers, H. J., & Gilbert, S. J. (2015). Solving the detour problem in navigation: A model of prefrontal
and hippocampal interactions. Frontiers in Human Neuroscience, 9. doi:10.3389/
fnhum.2015.00125
Stephan, B. C. M., Matthews, F. E., McKeith, I. G., Bond, J., & Brayne, C. (2007). Early cognitive
change in the general population: How do different definitions work? Journal of the American
Geriatrics Society, 55, 1534–1540. doi:10.1111/j.1532-5415.2007.01386.x
Stephan, B. C. M., Minett, T., Pagett, E., Siervo, M., Brayne, C., & McKeith, I. G. (2013). Diagnosing
mild cognitive impairment (MCI) in clinical trials: A systematic review. BMJ Open, 3. doi:10.1136/
bmjopen-2012-001909
Tippett, W. J., Lee, J.-H., Zakzanis, K. K., Black, S. E., Mraz, R., & Graham, S. J. (2009). Visually
navigating a virtual world with real-world impairments: A study of visually and spatially guided
 22 E.M. MIGO ET AL.

performance in individuals with mild cognitive impairments. Journal of Clinical and Experimental
Neuropsychology, 31, 447–454. doi:10.1080/13803390802251360
Vanderhasselt, M.-A., Raedt, R., & Baeken, C. (2009). Dorsolateral prefrontal cortex and stroop
performance: Tackling the lateralization. Psychonomic Bulletin & Review, 16, 609–612.
doi:10.3758/pbr.16.3.609
Vann, S. D., Aggleton, J. P., & Maguire, E. A. (2009). What does the retrosplenial cortex do? Nature
Reviews Neuroscience, 10, 792–802. doi:10.1038/nrn2733
Wager, T. D., & Smith, E. E. (2003). Neuroimaging studies of working memory: A meta-analysis.
Cognitive, Affective, & Behavioral Neuroscience, 3, 255–274. doi:10.3758/CABN.3.4.255
Wechsler, D. (1998). Wechsler memory scale ® - 3rd UK edition. London: Psychological Corporation.
Wechsler, D. (1999). WASI manual. San Antonio, TX: Psychological Corporation.
Wegman, J., Fonteijn, H. M., Van Ekert, J., Tyborowska, A., Jansen, C., & Janzen, G. (2014). Gray and
white matter correlates of navigational ability in humans. Human Brain Mapping, 35, 2561–2572.
doi:10.1002/hbm.22349
Weniger, G., Ruhleder, M., Lange, C., Wolf, S., & Irle, E. (2011). Egocentric and allocentric memory as
assessed by virtual reality in individuals with amnestic mild cognitive impairment.
Neuropsychologia, 49, 518–527. doi:10.1016/j.neuropsychologia.2010.12.031
Downloaded by [Colin Dourish] at 03:02 03 August 2015

Wolbers, T., Wiener, J. M., Mallot, H. A., & Büchel, C. (2007). Differential recruitment of the
hippocampus, medial prefrontal cortex, and the human motion complex during path inte-
gration in humans. Journal of Neuroscience, 27, 9408–9416. doi:10.1523/JNEUROSCI.2146-
07.2007
Wolk, D. A., & Detre, J. A. (2012). Arterial spin labeling MRI: An emerging biomarker for Alzheimer’s
disease and other neurodegenerative conditions. Current Opinion in Neurology, 25, 421–428.
doi:10.1097/WCO.0b013e328354ff0a
Yang, J., Pan, P., Song, W., Huang, R., Li, J., Chen, K., . . . Shang, H. (2012). Voxelwise meta-analysis of
gray matter anomalies in Alzheimer’s disease and mild cognitive impairment using anatomic
likelihood estimation. Journal of the Neurological Sciences, 316, 21–29. doi:10.1016/j.
jns.2012.02.010