NeuroImage: Clinical 11 (2016) 73–80

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NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl

Hurt but still alive: Residual activity in the parahippocampal cortex
conditions the recognition of familiar places in a patient with
topographic agnosia☆
Mitsouko van Assche a,b,⁎, Valeria Kebets a,b, Ursula Lopez b,c, Arnaud Saj a,b, Rachel Goldstein a,b,
Françoise Bernasconi b,c, Patrik Vuilleumier a, Frédéric Assal a,b
a

Faculty of Medicine, University of Geneva, Geneva, Switzerland
Department of Neurology, Geneva University Hospitals, Geneva, Switzerland
c
Faculty of Psychology, University of Geneva, Geneva, Switzerland
b

a r t i c l e

i n f o

Article history:
Received 27 July 2015
Received in revised form 16 December 2015
Accepted 2 January 2016
Available online 8 January 2016
Keywords:
Landmark agnosia
Human navigation
fMRI
Case
Stroke
Hemispheric laterality

a b s t r a c t
The parahippocampal cortex (PHC) participates in both perception and memory. However, the way perceptual
and memory processes cooperate when we navigate in our everyday life environment remains poorly understood. We studied a stroke patient presenting a brain lesion in the right PHC, which resulted in a mild and quantifiable topographic agnosia, and allowed us to investigate the role of this structure in overt place recognition.
Photographs of personally familiar and unfamiliar places were displayed during functional magnetic resonance
imaging (fMRI). Familiar places were either recognized or unrecognized by the patient and 6 age- and
education-matched controls in a visual post-scan recognition test. In fMRI, recognized places were associated
with a network comprising the fusiform gyrus in the intact side, but also the right anterior PHC, which included
the lesion site. Moreover, this right PHC showed increased connectivity with the left homologous PHC in the intact hemisphere. By contrasting recognized with unrecognized familiar places, we replicate the finding of the
joint involvement of the retrosplenial cortex, occipito-temporal areas, and posterior parietal cortex in place recognition. This study shows that the ability for left and right anterior PHC to communicate despite the neurological
damage conditioned place recognition success in this patient. It further highlights a hemispheric asymmetry in
this process, by showing the fundamental role of the right PHC in topographic agnosia.
© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Neuroimaging studies in healthy participants have pointed out the
specificity of the region of the posterior parahippocampal cortex
(PHC), since the discovery of its high sensitivity to places and buildings
as opposed to other stimulus categories (Aguirre et al., 1998; Epstein
and Kanwisher, 1998). This place-sensitive area supports the coding of
the spatial layout of scenes, a necessary step before their encoding and
later recognition (review in Epstein, 2008), and a challenging task
given the number of places that we cross every day. A related function
is the coding of objects-place associations, particularly on the right
hemisphere (Owen et al., 1996). However, the contribution of PHC to
the visual recognition process itself remains unclear (Sewards, 2011;
Spiers and Maguire, 2007), since previous neuroimaging studies yielded
mixed findings in neurologically healthy participants (Epstein, 2008;
☆ Place recognition in topographic agnosia.
⁎ Corresponding author at: Department of Neurology, Geneva University Hospital, rue
Gabrielle-Perret-Gentil 4, 1211, Geneva, Switzerland.
E-mail address: mitsouko.vanassche@unige.ch (M. van Assche).

Epstein et al., 2007), see also (Epstein and Higgins, 2007) and supported
a clearer role of the retrosplenial complex (RSC) in this function
(Epstein, 2008; Spiers and Maguire, 2007; Sugiura et al., 2005). Thus,
it is uncertain to which extent the PHC is implicated during place recognition, beyond its role in perceptual processing.
More insights may be gained with the study of brain-lesioned patients, by determining whether a target area is necessarily required for
place analysis, or whether this function can be shouldered by a any
other brain region. Topographic agnosia or disorientation is a neurological condition in which patients become unable to find their way in the
environment following a focal brain damage (Aguirre and D'Esposito,
1999; De Renzi, 1982). In a specific form of this disorder called landmark
agnosia (Aguirre and D'Esposito, 1999), a lesion around the right posterior PHC — the region of the right anterior lingual gyrus/PHC/medial
fusiform gyrus — usually impairs spatial orientation in familiar environments, but spares the ability to describe them (e.g. Busigny et al., 2014;
Habib and Sirigu, 1987; Landis et al., 1986; Takahashi and Kawamura,
2002). This condition arises as a failure to recognize typical landmarks
known before the lesion occurrence (Incisa della Rocchetta et al.,
1996; Landis et al., 1986; Pallis, 1955; Rainville et al., 2005; Whiteley

http://dx.doi.org/10.1016/j.nicl.2016.01.001
2213-1582/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80

and Warrington, 1978), disrupting the interaction between perceptual
and memory processes (Brunsdon et al., 2007). However, the specific
study of the relationships between landmark agnosia, place familiarity,
and the location of the lesion in patients with peri-hippocampal lesions
has yielded mixed findings, with patients either showing preserved
(Habib and Sirigu, 1987; Takahashi and Kawamura, 2002) or altered
recognition of known places (Habib and Sirigu, 1987; Hecaen et al.,
1980; Incisa della Rocchetta et al., 1996; Pallis, 1955; McCarthy et al.,
1996; Takahashi and Kawamura, 2002; Whiteley and Warrington,
1978). A common feature of patients with preserved topographic abilities in familiar environments is the sparing of visual areas located posterior to the PHC (review in Sewards, 2011). On the other hand,
disconnection following a focal lesion of the PHC may play a role in
this particular neurological disorder (Ffytche et al., 2010; see also
Kleinschmidt and Vuilleumier, 2013). Indeed, successful navigation in
familiar environments not only involves the PHC, but also a wide
range of occipital, medial parietal, temporal and frontal areas (metaanalysis in Boccia et al., 2014). Thus, a disconnection between the
right PHC and other areas of this network may also play a role in this
disorder.
Our goal was to investigate place recognition mechanisms in a stroke
patient with damage including mainly the right PHC/hippocampus and
part of the medial fusiform cortex. The location and extent of the lesion
caused a severe prosopagnosia and a partial landmark agnosia (see
Hecaen et al., 1980; McCarthy et al., 1996; Pallis, 1955; for similar
cases of combined prosopagnosia and topographic agnosia following
analogous lesions), providing the unique opportunity to disentangle
successful versus unsuccessful place recognition mechanisms in the
same participant. Photographs of personally familiar and unfamiliar
places were displayed during event-related fMRI of an incidental categorization task (van Assche et al., 2016). An additional post-scan visual
recognition test allowed classifying recognized versus unrecognized familiar places. We first examined the functional integrity of the right and
left PHC during basic visualization of places, checking that the left but
not right PHC region remained functionally active after the lesion.
Then, we assessed the involvement of the PHC during the analysis of
recognized (familiar) scenes as compared with unrecognized (familiar
or unfamiliar) scenes by means of direct comparison, to specifically
probe for brain processes associated with overt place recognition. Moreover, task-based functional connectivity was performed to illuminate
the role of functional interactions during overt place recognition. If the
PHC plays a fundamental role in this process, then it should be more recruited for recognized places in the patient, either in the contralesional
and/or ipsilesional side. If not, the patient should show compensatory
activity elsewhere during the recognition process.

agnosia and verbal episodic memory difficulties had disappeared.
Concerning visual episodic memory, his performance improved and
was within the normal range, however from a clinical standpoint, immediate recall was estimated to be insufficient given his high educational level. At this time, PR continued working full-time as a business
expert.
Ten months later, the patient was admitted again in the same unit
due to unprecedented and acute visual complaints consisting in an inability to recognize close family members as well as slight difficulties
in orientating himself in his neighborhood. The neurological status
was normal, except a left superior quadranopsia which did not affect
the following testing. During a third neuropsychological examination
(Supplementary Table 1), PR was alert and fully cooperative. His expression was fluent, and his verbal comprehension intact. No visuoconstructive apraxia, neglect, or any other generalized visuo-spatial impairment was observed. Verbal episodic memory was intact. With reference to executive and attentional functions, PR showed mild difficulties
in cognitive flexibility and selective attention (Bells' test). With regard
to visuo-perceptive abilities, signs of associative agnosia were observed
(Visual Object and Space Perception Battery; Birmingham Object Recognition Battery). For the evaluation of prosopagnosia, we used a standard
battery from the Geneva University Hospital in addition to standard
neuropsychological testing (Benton Face Recognition Test). The patient
performed significantly worse than a control group (t-test Crawford &
Garthwaite, 2007) at the recognition of famous faces (patient = 54%
correct; control group = 77 ± 12% correct; p b 0.01), famous faces occupation sorting (matching semantic and visual inputs; patient: 56%
correct; control group: 90 ± 9% correct; p b 0.01), gender identification
(patient = 66%; control group = 92 ± 5% correct; p b 0.01), and at a
short version of the Jane task (patient: 50% correct; control group =
80 ± 15% correct; p b 0.01; Mondloch et al., 2002; Supplementary
Table 2).
Concerning the topographical domain (Table 1), the patient presented some difficulties in the identification of famous buildings (hesitation,
latency, utilization of verbal strategies to facilitate the identification),
and a significantly impaired ability to recognize places that are highly
familiar for him (26/40 recognized familiar places; see post-scan procedure and results section). In contrast, tests assessing spatial representations were intact as judged by his normal performance on tests
evaluating specific spatial abilities (i.e. landscape perspective test, cognitive map recall test, map drawing). Moreover, his capacity to navigate
in the hospital was adequate (using both verbal and spatial strategies).
In sum, PR presented a mild landmark agnosia, a severe prosopagnosia,
signs of associative agnosia and very mild executive and attentional
difficulties.

2. Material and methods

Table 1
Neuropsychological assessment of the patient's topographical abilities (impaired performance in bold).

2.1. Case report
Patient PR is a right-handed male, 68 years of age at the time of the
present evaluation. He graduated from a university-level business
school and is a businessman in the finance domain. One year prior to
the current study, he had been admitted to the Neurology Unit of the
Geneva University Hospital following a first minor cardio-embolic ischemic stroke involving the right parietal cortex and the occipital cortex
bilaterally. The neurological status did not reveal any particular visual
field defect. On this occasion, he underwent a series of standard neuropsychological tests assessing language, praxis, executive, memory, attention and visual-perceptual abilities (see Supplementary Table 1).
This first neuropsychological testing revealed signs of associative visual
agnosia, difficulties in verbal and visual episodic memory, and a mild
executive impairment. All other assessed cognitive functions were unimpaired. In a second evaluation one month later (Supplementary
Table 1), only verbal working memory difficulties and a mild executive
impairment (inhibition) were observed. Signs of associative visual

Landmark identification
Identification of famous buildings
Egocentric space
Landscape Perspective Test1
Rotational movement
Translational movement
Road-Map Money test2
Allocentric space
Localization of landmarks on a map
Spatial cognition about familiar environments
Identification of personally familiar places
(see results section)
Familiar egocentric space: Route description
Familiar allocentric space:
Cognitive Map Recall test1
Map and route drawing
Spatial cognition about unfamiliar environments
Navigational abilities in the hospital
1

Descloux et al. (2015).
2
Money et al. (1965).

19/23, hesitations, latencies

6/7
4/6
32/32
Ok
26/40
Ok
17/24
Ok
Ok

M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80

Structural MRI revealed an acute occipito-temporal stroke involving
the right PHC along the posterior–anterior axis, the posterior part of the
hippocampus and the medial portion of the adjacent fusiform gyrus,
sparing the most lateral part of the right fusiform gyrus (Fig. 1). The
damage was compatible with a lesion of the right parahippocampal
place-sensitive area and an impaired ability to recognize personally familiar places in our experiment.
2.2. Participants
Recognition performance and brain activity in the patient was compared with a group of 6 elderly controls (3 males; 5 right-handed; mean
age = 68.8 ± 2.1 years old; mean education years = 16.8 ± 2.9), without previous or current neurological or psychiatric disease. This protocol
was approved by the Ethic Central Commission of the University Hospital of Geneva. Informed consent was obtained from the participants following the ethical principles of the Declaration of Helsinki.
In this study, we followed strictly the same procedure as described
previously (van Assche et al., 2016).
2.3. Pre-scan selection of personally familiar and unfamiliar place stimuli
A few weeks before the fMRI session, the patient was asked to enumerate places he knew well in and around Geneva, as well as to describe
some typical routes in the city which he used to take several times a
week. His descriptions followed a route-based strategy describing how
to go from one place/street to the next to reach a particular destination,
and included street names. We selected these personally relevant locations with Google Street view and used them as stimuli for the familiar

75

places condition in the fMRI experiment. The same procedure was applied for the control group.
2.4. Post-scan recognition test
After scanning, the patient was submitted to a self-paced surprise
place recognition test. All photographs of familiar places were presented
again. The patient had to indicate the name and/or the location of the
place shown. A place was considered as Familiar Recognized whenever
its name was correctly retrieved, or at least when it was correctly localized. In all other cases, the familiar place was classified as Familiar Unrecognized. The same procedure was conducted in the control group.
2.5. MRI procedure
2.5.1. Activation task
We used an incidental categorization task, which required no explicit recognition abilities (van Assche et al., 2016). Photographs of familiar
and unfamiliar places were displayed during fMRI scanning. The participant had to indicate whether the places shown in the photographs
were “lively” (e.g. imagining noise or traffic jam) or “calm” compared
with a place of reference. Familiar places in the city were named as
the reference. Photographs were presented in series of four, shown
each in turn during 2 s at the centre of the screen (Fig. 2). Each picture
of a given series was a particular viewpoint of the same place. In addition to personal familiarity with places, the succession of the viewpoints
within each series was manipulated. In the Sequential Order of presentation, the sequence of four pictures could mimic a point of view similar to
one turning gradually his head from left to right or the reverse.

Fig. 1. T2-weighted MRI (top row) and T1-weighted MRI (bottom row) of the stroke patient (neurological convention). The right occipito-temporal stroke damaged the right
parahippocampal cortex along the posterior–anterior axis, posterior part of the hippocampus and medial part of the fusiform gyrus, sparing the most lateral part of the fusiform gyrus
and the anterior medial temporal lobe (including the hippocampus and perirhinal cortex). R = Right side.

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M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80

Fig. 2. Categorization task. At each trial, viewpoints of familiar or unfamiliar places were presented in series of four, shown each in turn during 2 s at the center of the screen. Each picture of
a given series was a different viewpoint of the same place.

Alternatively, in the Scramble Order of presentation, pictures were presented in a non-progressive order. There were also two unfamiliar control conditions, one in which the same picture was repeated four times
within a series (repeated condition), the other in which all pictures of a
series were taken from different places (different condition). The participant indicated his categorical judgment after each series of four pictures, by pressing one of two buttons of a response box at the end of
each series. There were 20 trials per condition.
2.5.2. Equipment
Data were acquired on a 3T MRI system (Trio TIM, Siemens,
Germany) with a 12 channel head coil. Visual stimuli were back
projected on a screen (E-prime 1.0, Psychology Software Tools Inc.,
Pittsburgh). Head movements were prevented using an ergonomic air
head cushion.
2.5.3. Scanning protocol
Whole brain functional images were collected using a susceptibility
weighted EPI sequence (TR/TE = 1810/30 ms; flip angle = 90 degrees;
PAT factor = 2; FOV = 255 mm; matrix size = 64 × 64 pixels). 32 transversal slices were acquired in an interleaved descending manner (slice
thickness = 4 mm, interslice gap = 1 mm, voxel size = 4 mm isotropic). High-resolution anatomical images were acquired using a T1weighted, 3D sequence (MPRAGE; TR/TI/TE = 1900/900/2.32 ms; flip
angle = 9 degrees; voxel size = 0.9 mm isotropic; 256 × 256 × 192
voxels).
2.6. Imaging data analysis
Anatomical volumes of the patient were normalized to a T1 template
of elderly individuals (Rorden et al., 2012) using a lesion cost function
masking (Brett, Leff, Rorden, & Ashburner, 2001). The lesion was manually delineated to create a mask that excluded the lesion from the nonlinear transformation during the normalization step.
Functional images were pre-processed and analyzed using a standard procedure implemented in Statistical Parametric Mapping
(SPM8; Wellcome Trust Centre for NeuroImaging London). All volumes
were first temporally realigned and resampled to the acquisition time of
the middle slice. The data were then spatially realigned to the first slice.
The anatomical volumes were spatially coregistered to the mean functional image resulting from the spatial realignment. Functional images
were then normalized to the MNI EPI template, resampled to 3 mm isotropic voxels and smoothed with a Gaussian kernel (8 mm full-width at
half-maximum).
In the patient, data were modeled according to the General Linear
Model (GLM) which modeled all conditions across recognition states
and head movements. In controls, the GLM modeled all task conditions,
plus occasionally unrecognized places (as described in van Assche et al.,
2016), as well as head-movements. Each regressor was convolved to a

canonical hemodynamic function. A high-pass filter (cut off = 128 s)
and a first-order autoregressive function were applied to account for
temporal autocorrelation. Statistical parametric maps (t-maps) were
obtained by comparing each condition with baseline activity. Functional
connectivity analyses were performed using the generalized PPI approach (McLaren et al., 2012). Whole-brain analyses were performed
on a voxel-wise basis, at a threshold p b 0.001 uncorrected (minimal
cluster size = 5) for within-subject comparisons and p b 0.005 (minimal cluster size = 10) for between-subject comparisons, unless specified differently.
For the sake of clarity and simplicity, only data related to the manipulation of familiarity are presented in this paper.
2.7. Scene localizer scan
The response of the right scene-sensitive area around the PHC was
investigated in the patient, in order to check how brain responses to pictures of unfamiliar places were impacted by the lesion. Four blocks of
scenes, buildings or scrambled stimuli were presented in alternation.
In each block, 18 stimuli of the same category were displayed for
750 ms with an interval of 500 ms. The patient performed a one-back
task in which he had to press a right button at each stimulus repetition.
The scanning parameters were identical as in the main experiment. For
the analyses, the GLM modeled all conditions plus head-movements.
The region of the posterior PHC was functionally localized using the
Scenes N Scrambled Scenes t-contrast at the whole-brain level at a liberal threshold (p b 0.05 uncorrected, k N 5), in order to maximize the possibility to observe activity around the lesion site.
3. Results
3.1. Behavioral data
First, recognition performance in the patient confirmed a partial agnosia for personally familiar places despite the extended lesion. He was
able to visually recognize 26 out of 40 familiar places (65% correct). His
recognition abilities still contrasted with the performance achieved by
the Control group (97.92% correct recognitions; SD = 1.88), and this difference was statistically significant (one-tailed p b 0.001; effect size =
17.491; 95% CI = 7.095–28.038; Crawford and Garthwaite, 2007).
3.2. Scene localizer
Consistent with the lesion site in the right hemisphere, the patient
showed activation of the left but not right scene-sensitive area, around
the posterior PHC/fusiform gyrus (MNI coordinates: peak 1: -21, −40,
−2, t = 2.37; peak 2: -24, −55, −14; t = 2.29; cluster size: 100 voxels;
Fig. 3). In the right temporal lobe, brain activity was instead observed
laterally to the lesion site, much more laterally than in the left

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77

Fig. 3. The Scenes N Scrambled Scenes contrast shows that only the left posterior parahippocampal cortex remains functionally active and sensitive to pictures of places after the right
occipito-temporal stroke (p b 0.05 uncorrected). Instead, activity in the right side is observed laterally to the lesion. Brain activity is superimposed on the anatomical T1 of the patient.

hemisphere (MNI coordinates: peak 1: 45, −55, −14; t = 2.44; peak 2:
45, −55, −23, t = 2.22; cluster size: 111 voxels). This confirms that the
lesion site has become functionally irresponsive to randomly presented
places. However, the lateral activity in the right side might indicate a
form of functional reorganization related to place processing or the mobilization of other processes to perform this function.
3.3. Imaging data
We first compared brain activity in patient and controls, to check the
functionality of the lesion area and more globally, to highlight areas of
hypo- and/or hyper-activity in the patient during the visualization of
personally familiar and unfamiliar places.
3.3.1. Patient – Control comparison
3.3.1.1. Familiar places. For Familiar places, the Controls N Patient
contrast notably revealed differential activity in the right PHC, including
around the lesion site (including in the anterior and posterior portions
of the lesioned tissue), as well as in the right posterior fusiform gyrus
region (p b 0.005; Table 2, upper panel). The reverse contrast
(Patient N Controls) revealed enhanced activity in the anterior insula bilaterally in the patient, as well as right temporo-parietal junction, left
precentral and middle cingulate gyrus.
3.3.1.2. Unfamiliar places. The Controls N Patient comparison again revealed decreased activity in the right posterior fusiform region in the
patient (including in the posterior portion of the lesioned tissue). The
reverse contrast, Patient N Controls, showed the same brain areas as
for familiar recognized, with the additional recruitment of the right
opercular IFG and left orbital IFG (p b 0.005; Table 2, lower panel).
The comparison of brain activity between the patient and the control
group thus confirms that the lesion area was systematically hypoactivated in the patient, for both familiar and unfamiliar places.
3.3.2. Familiar place processing according to recognition in the patient
A first analysis compared brain activity for Recognized places against
Unrecognized and Unfamiliar places jointly, to characterize the key
areas involved in place recognition irrespective of place familiarity.
This comparison (Recognized N (Unrecognized + Unfamiliar)) not
only revealed an implication of the fusiform gyrus, inferior temporal
gyrus and lingual gyrus in the intact side, but also an involvement of
the PHC in the anterior portion of the lesion (p b 0.001; Fig. 4, top;
Table 3, upper panel). This cluster of activity encompassed both lesioned
and perilesional (spared) tissue. The bilateral orbital inferior frontal

gyrus (IFG), cerebellum, and left middle orbito-frontal cortex (midOFC)
were additionally recruited.
To better understand the association between right PHC and successful recognition, we investigated its functional connectivity by defining it as a seed region (sphere, 10 mm radius) in the following PPI
analysis. In the Recognized N Unrecognized comparison, functional
coupling increased between the right anterior PHC in the lesion side,
and the left anterior PHC in the intact side (p b 0.001, Table 3, middle
panel). Interestingly, this region was located in the homologous region
of the lesion site, adjacent to the one observed in the scene localizer
(Fig. 4, bottom). Importantly, increased functional coupling was also
observed with the infero-temporal cortex bilaterally, and right dorsolateral PFC. In marked contrast with the previous comparison, the
Recognized N Unfamiliar contrast (PPI analysis) revealed enhanced coupling between the right anterior PHC and the left cerebellum only, without any coupling with the left PHC. Altogether, the findings indicate a
Table 2
Activation peaks (MNI peak coordinates) for the comparison between Controls and
the Patient for Familiar Recognized places (upper panel) and Unfamiliar places
(lower panel); p b 0.005 uncorrected, minimal cluster size = 10. L = Left, R =
Right, PHC = parahippocampal cortex, IFG = inferior frontal gyrus.
MNI coordinates

Familiar Recognized: Patient vs. Controls
Controls N Patient
R Cerebellum
PHC
Inferior occipital/posterior Fusiform
R gyrus
Patient N Controls
R Temporo-parietal junction
R Anterior Insula/Putamen
L Anterior Insula
L Precentral Gyrus
L Middle cingulate gyrus
Unfamiliar: Patient vs. Control
Controls N Patient
R Posterior fusiform gyrus
Patient N Controls
R Putamen/Anterior insula
L Anterior insula/Putamen
L Posterior insula
R opercular IFG
L orbital IFG
L Postcentral gyrus
L Middle cingulate gyrus

T value

Cluster
size

x

y

z

24
24

−37 −26 8.515
−40 −14 6.562

20

42

−64 −14 7.236

31

45
33
−30
−45
−9

−22
11
11
−7
20

7
−11
7
40
34

7.534
13.866
7.733
6.959
5.742

24
48
49
17
10

27

−70 −8

5.784

28

21
−27
−36
30
−39
−48
−18

14
14
−22
8
20
−7
−19

−5
7
−8
34
−14
40
40

15.771
7.793
5.892
9.067
6.303
6.425
12.583

100
23
11
16
16
10
15

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M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80

Fig. 4. Top. The region of the right parahippocampal cortex (PHC) located in the anterior portion lesion site activates for recognized familiar places (p b 0.001). MNI peak coordinates: 30, −34,
−20. Brain activity is overlaid on the normalized anatomical T1 of the patient. Bottom. Functional connectivity analysis showing enhanced functional coupling between the right PHC in the
lesion side (seed region) and left PHC in the intact side for the comparison between recognized and unrecognized familiar places (p b 0.001; MNI peak coordinates: 30, −37, −17).

crucial contribution of the anterior PHC in both hemispheres in the recognition of familiar places.
We next compared activity between recognized and unrecognized
familiar places with standard contrasts in the patient, to isolate the
brain areas enabling visual recognition in the case of personally familiar
places. The Recognized N Unrecognized places comparison globally
revealed more left-sided activity, with activations in bilateral middle
occipital gyri, left cuneus, RSC, inferior parietal lobule (IPL), and right
lingual gyrus (p b 0.001; Table 3, lower panel). Finally, for the reverse
contrast (Unrecognized N Recognized), increased activity was observed
in the left fusiform gyrus and bilateral orbital gyrus (p b 0.005).
To summarize, the right anterior PHC was clearly activated
when personally familiar places were recognized, indicating a crucial
implication in the analysis of personally familiar places. This region
showed increased functional connectivity with the anterior PHC in the
contralesional side for recognized compared with unrecognized familiar
places. Moreover, joint recruitment of visual areas, left occipito-parietal,
left retrosplenial and anterior PFC differentiated between successfully
and unsuccessfully recognized places in the patient during the display
of familiar information.

3.3.3. Familiar vs. unfamiliar places in controls
The Familiar N Unfamiliar places contrast revealed a widespread network of activity, including postero-medial areas bilaterally, left PHC, bilateral lateral temporal areas and VMPFC (see Supplementary Table 3 and
Supplementary Fig. 1; p b 5 × 10−4). These findings are in line with our
previous data obtained in a group of young participants (van Assche
et al., 2016).

4. Discussion
We studied a patient with an extended lesion in the right HC/PHC/
medial fusiform gyrus, to investigate the functional role of the PHC in
the context of a quantifiable landmark agnosia. This represented a
unique opportunity to characterize the brain areas that are necessarily
involved in overt place recognition. First, a comparison of brain activity
with controls indicated ubiquitous hypo-activation of the right PHC for
both familiar and unfamiliar places, confirming that the right PHC was
dysfunctional. Secondly, the possibility to access place identity explicitly
was associated with increased activity in the right ipsilesional PHC, in a
region overlapping with the anterior portion of the lesion site, as well as
left fusiform and lingual gyrus in the intact side. Crucially, for personally
familiar places, functional connectivity was increased between the PHC
in the lesion (right) side, and the PHC in the contralesional side. This last
region was located in the homologous region of the lesion in the healthy
side, anterior to a scene-sensitive parahippocampal region observed in
an independent localizer. Moreover, neural correlates of place recognition were observed in a set of areas comprising bilateral visual areas,
the RSC and inferior parietal lobule in the intact hemisphere, and the
right IFG.
A key result was the finding of residual activity in the PHC on the lesion side, together with the recruitment of the fusiform gyrus in the intact side, when familiar places were recognized and despite the lesion.
This suggests that the right PHC is mandatory in the processing stream
leading to visual place recognition. This finding is in accordance with
previous lesion studies highlighting the fundamental role of the right
PHC in spatial memory (Aguirre and D'Esposito, 1999; Bohbot et al.,
1998; Ploner et al., 2000), as well as clinical descriptions of much

M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80
Table 3
Upper panel: Activation peaks (MNI peak coordinates) for Recognized places in patient PR,
characterizing brain activity associated with successful recognition irrespective of place familiarity (p b 0.001 uncorrected). Middle panel: Activation peaks of the PPI analysis with
right anterior PHC as seed region (sphere, 10 mm radius; p b 0.001 uncorrected, minimum
cluster size = 20 voxels). Lower panel: Activation peaks for recognized compared with unrecognized places in the patient, highlighting the brain areas supporting the recognition of
familiar places (p b 0.001 uncorrected).L = Left, R = Right, PHC = parahippocampal cortex, IFG = inferior frontal gyrus, RSC = retrosplenial complex.
MNI coordinates
x

T value cluster size

y

z

30
−36
−33
−12
−48
15
−9
−42
48

−34
−58
−19
−43
−43
−49
59
44
47

−20
−11
−32
−5
−26
−38
−14
17
−17

4.19
4.73
3.59
3.53
4.46
4.38
3.88
4.33
4.78

36
24
6
8
6
86
6
14
24

−30
−39
−24
57
12
15

−37
−22
−46
−13
−85
65

−17
−26
−35
−23
−41
22

3.91
3.66
3.65
4.15
4.01
3.72

151

−9
48
57

−85
32
23

−41 3.93
28
3.85
34
3.42

48
43

18
−36
39
9
−33
−15
−30

−103
−82
−76
−82
−91
−55
53

13
13
10
−5
31
10
−8

3.46
3.93
3.61
3.88
3.62
3.67
3.58

9
30
27
54
9
26
8

−42
−15
12

−67
59
53

−14 2.948
−14 3.231
−8
2.960

5
11
24

Familiar Recognized N (Unrecognized +
Unfamiliar)
R
PHC
L
posterior Fusiform gyrus
L
anterior Fusiform gyrus
L
Lingual gyrus
L
Inferior temporal gyrus
R
Cerebellum
L
Superior orbital gyrus
L
orbital IFG
R
orbital IFG
Functional connectivity: right PHC as
seed
Recognized N Unrecognized
L
Posterior PHC
L
Inferior temporal gyrus
L
Cerebellum
R
Inferior temporal gyrus
R
Cerebellum
R
Frontal pole
Recognized N Unfamiliar
L
Cerebellum
R
Middle frontal gyrus
R
triangular IFG
Familiar Recognized N Unrecognized
L
Cuneus
L
Middle Occipital Gyrus
R
Middle Occipital Gyrus
R
Lingual Gyrus
L
Middle Occipital Gyrus/IPL
L
RSC
L
Lateral midOFC
Familiar Unrecognized N Recognized
L
Fusiform gyrus
L
Superior orbital gyrus
R
Mid-orbital gyrus

21
20
37

more severe landmark agnosia following brain damage in this area (e.g.
Aguirre and D'Esposito, 1999; Busigny et al., 2014; Habib and Sirigu,
1987; Landis et al., 1986; Takahashi and Kawamura, 2002). Nonetheless,
our results go beyond, by specifying a neural mechanism for this type of
agnostic disorder. Indeed, a related and important result was the increased functional connectivity between the PHC in the lesioned tissue
and the PHC in the intact side associated with the recognition of personally familiar information (Recognized N Unrecognized contrast). This
was not the case when looking at the effect of familiarity
(Recognized N Unfamiliar contrast). This left anterior PHC region was located close to a functionally preserved place-sensitive area shown to be
functionally preserved in a functional localizer, and homotopic to the lesion site.
Together with adjacent occipito-temporal structures, the posterior
aspect of the right PHC is known to form a functional complex dedicated
to the analysis of the spatial layouts of scenes (Epstein, 2008). Moreover,
it has been suggested that the visuo-spatial function of posterior PHC
contrasts with a memory-related function in more anterior sites within
this region (Aminoff et al., 2013; Epstein, 2008), in line with recent
fMRI data highlighting an anterior–posterior functional segregation
expressed by greater functional connectivity with occipital and
retrosplenial areas respectively (Baldassano et al., 2013; Nasr et al.,
2013). Our findings are in accordance with this proposal. Interestingly,

79

the PHC is involved in the reinstatement of specific episodic memories
triggered by single stimuli previously paired with scenes (Hayes et al.,
2007; Staresina et al., 2012). Such anterior/posterior PHC interactions
may perhaps not be necessary in case of verbal instead of visual stimulation (Willment and Golby, 2013); but see (Kennepohl et al., 2007), as
this rather depends on the hippocampal complex in the left side
(Burgess, 2002) and/or top-down influences by prefrontal cortex
(Preston and Eichenbaum, 2013). Thus, it may be hypothesized that
the ability to access place identity in the context of landmark agnosia
is conditioned by the capacity for scenes, after their visual processing
in the posterior PHC, to activate reinstatement of personal and/or semantic memories in a more anterior memory-related region of PHC.
The study of a patient with unilateral brain lesion also allowed investigating whether the right and left PHC are equally involved in place recognition. Because the implication of the right PHC was predictive of
recognition success in this patient, the data suggest a preponderant
role of the right PHC in this process. Further studies are however required to understand whether this specific region is specialized in the
retrieval of scene context (e.g. Aminoff et al., 2013), the recognition of
objects in scenes (Hayes et al., 2007; Martin et al., 2013), or both
(Harel et al., 2013). In addition, a gradient from abstract to concrete object response has been described in the PHC (Baldassano et al., 2013).
Here, the patient notably failed to recognize familiar places when they
lacked salient or unique landmarks, as described in Mendez and
Cherrier (2003), that is, when the he was unable to analyze spatial configurations properly. Moreover, the right PHC showed increased functional coupling with the inferior temporal gyrus bilaterally, known for
its role in visual object recognition at the terminal portion of the ventral
pathway (Mishkin et al., 1983). Thus and despite pathological scores at
object recognition as measured by conventional neuropsychological
tests, the experimental data suggest that object recognition problems
do not fully account for the topographic agnosia here.
Finally, another finding was that successful place recognition in the
patient was associated with the recruitment of a distributed network
beyond PHC, implicating visual occipito-temporal areas bilaterally, the
left RSC, and lateral midOFC. The RSC is particularly known to be strongly sensitive to place familiarity (Epstein, 2008; Sugiura et al., 2005; van
Assche et al., 2016) and involved during mental navigation in a familiar
environment (Ino et al., 2002; Rosenbaum et al., 2004). Also, previous
work strongly implicates visual areas in patients with deficits of topographical memory (Aguirre and D'Esposito, 1999; Busigny et al., 2014;
Takahashi and Kawamura, 2002). A similar network of occipitotemporal and parieto-medial areas was recently reported to be strongly
mobilized during the visualization of familiar environments in healthy
participants (Boccia et al., 2014; Nemmi et al., 2015). Our data corroborate these findings, by showing similar key areas at work in a patient
with dysfunctional right posterior hippocampal complex.
4.1. Limitations of the study
The data may be limited by the possibility to generalize the current
patient's functioning to similar patients with occipito-temporal lesions.
Many factors may modify brain functioning after a lesion, such as the
time between the infarct and the study, age of the patient or extent of
the lesion. Nonetheless, the data are in line with previous reports of
landmark agnosia. Moreover, because prosopagnosia and landmark agnosia were not equally affected in this patient, it was not possible to reliably assess whether compensatory processes that accompany the
recognition of familiar places also extend to other stimulus categories
such as faces. More studies are necessary to better understand the role
the intact hemisphere can play in preserved processes.
5. Conclusions
In summary, the study of a patient with a mild landmark agnosia due
to right occipito-temporal lesion has revealed the fundamental role of

80

M. van Assche et al. / NeuroImage: Clinical 11 (2016) 73–80

the right PHC in the analysis of familiar places that leads to recognition.
Importantly, successful recognition was associated with increased functional connectivity between both anterior PHC in each hemisphere.
These interactions between homologous regions of PHC may provide a
fundamental mechanism enabling perceptual inputs to activate corresponding representations held in long-term memory. Finally, successful
recognition was accompanied by the recruitment of a network implicating occipito-temporal, retrosplenial and posterior parietal areas, similarly as in neurologically intact subjects.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.nicl.2016.01.001.

Conflict of interest
No conflict of interest.

Acknowledgments
This work was funded by the Swiss National Science Foundation
under grant n°320030_138163 (FA); and the Société académique de
Genève (NAC 08-025 to FA). We are grateful to Bruno Bonet and Lore
Legrand for assistance during data collection and Benoit Musel for helpful discussions. We also thank the anonymous reviewers for their useful
suggestions.

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