Medial perirhinal cortex disambiguates confusable objects

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DOI: 10.1093/brain/aws277 · Source: PubMed
Abstract
Our brain disambiguates the objects in our cluttered visual world seemingly effortlessly, enabling us to understand their significance and to act appropriately. The role of anteromedial temporal structures in this process, particularly the perirhinal cortex, is highly controversial. In some accounts, the perirhinal cortex is necessary for differentiating between perceptually and semantically confusable objects. Other models claim that the perirhinal cortex neither disambiguates perceptually confusable objects nor plays a unique role in semantic processing. One major hurdle to resolving this central debate is the fact that brain damage in human patients typically encompasses large portions of the anteromedial temporal lobe, such that the identification of individual substructures and precise neuroanatomical locus of the functional impairments has been difficult. We tested these competing accounts in patients with Alzheimer's disease with varying degrees of atrophy in anteromedial structures, including the perirhinal cortex. To assess the functional contribution of each anteromedial temporal region separately, we used a detailed region of interest approach. From each participant, we obtained magnetic resonance imaging scans and behavioural data from a picture naming task that contrasted naming performance with living and non-living things as a way of manipulating perceptual and semantic confusability; living things are more similar to one another than non-living things, which have more distinctive features. We manually traced neuroanatomical regions of interest on native-space cortical surface reconstructions to obtain mean thickness estimates for the lateral and medial perirhinal cortex and entorhinal cortex. Mean cortical thickness in each region of interest, and hippocampal volume, were submitted to regression analyses predicting naming performance. Importantly, atrophy of the medial perirhinal cortex, but not lateral perirhinal cortex, entorhinal cortex or hippocampus, significantly predicted naming performance on living relative to non-living things. These findings indicate that one specific anteromedial temporal lobe region-the medial perirhinal cortex-is necessary for the disambiguation of perceptually and semantically confusable objects. Taken together, these results support a hierarchical account of object processing, whereby the perirhinal cortex at the apex of the ventral object processing system is required to bind properties of not just perceptually, but also semantically confusable objects together, enabling their disambiguation from other similar objects and thus comprehension. Significantly, this model combining a hierarchical object processing architecture with a semantic feature statistic account explains why category-specific semantic impairments for living things are associated with anteromedial temporal lobe damage, and pinpoints the root of this syndrome to perirhinal cortex damage.

Figures

BRAIN
A JOURNAL OF NEUROLOGY
Medial perirhinal cortex disambiguates
confusable objects
Sasa L. Kivisaari,
1,2
Lorraine K. Tyler,
3
Andreas U. Monsch
1,2
and Kirsten I. Taylor
1,2,3
1 Memory Clinic, Department of Geriatrics, University Hospital Basel, University of Basel, Basel, CH, Switzerland
2 Faculty of Psychology, University of Basel, Basel, CH, Switzerland
3 Centre for Speech, Language and the Brain, Department of Experimental Psychology, University of Cambridge, Cambridge, UK
Correspondence to: Kirsten I. Taylor
Schanzenstrasse 55,
CH-4031, Basel,
Switzerland
E-mail: ktaylor@uhbs.ch
Our brain disambiguates the objects in our cluttered visual world seemingly effortlessly, enabling us to understand their
significance and to act appropriately. The role of anteromedial temporal structures in this process, particularly the perirhinal
cortex, is highly controversial. In some accounts, the perirhinal cortex is necessary for differentiating between perceptually and
semantically confusable objects. Other models claim that the perirhinal cortex neither disambiguates perceptually confusable
objects nor plays a unique role in semantic processing. One major hurdle to resolving this central debate is the fact that brain
damage in human patients typically encompasses large portions of the anteromedial temporal lobe, such that the identification
of individual substructures and precise neuroanatomical locus of the functional impairments has been difficult. We tested these
competing accounts in patients with Alzheimer’s disease with varying degrees of atrophy in anteromedial structures, including
the perirhinal cortex. To assess the functional contribution of each anteromedial temporal region separately, we used a detailed
region of interest approach. From each participant, we obtained magnetic resonance imaging scans and behavioural data from a
picture naming task that contrasted naming performance with living and non-living things as a way of manipulating perceptual
and semantic confusability; living things are more similar to one another than non-living things, which have more distinctive
features. We manually traced neuroanatomical regions of interest on native-space cortical surface reconstructions to obtain
mean thickness estimates for the lateral and medial perirhinal cortex and entorhinal cortex. Mean cortical thickness in each
region of interest, and hippocampal volume, were submitted to regression analyses predicting naming performance. Importantly,
atrophy of the medial perirhinal cortex, but not lateral perirhinal cortex, entorhinal cortex or hippocampus, significantly pre-
dicted naming performance on living relative to non-living things. These findings indicate that one specific anteromedial tem-
poral lobe region—the medial perirhinal cortex—is necessary for the disambiguation of perceptually and semantically confusable
objects. Taken together, these results support a hierarchical account of object processing, whereby the perirhinal cortex at the
apex of the ventral object processing system is required to bind properties of not just perceptually, but also semantically
confusable objects together, enabling their disambiguation from other similar objects and thus comprehension. Significantly,
this model combining a hierarchical object processing architecture with a semantic feature statistic account explains why
category-specific semantic impairments for living things are associated with anteromedial temporal lobe damage, and pinpoints
the root of this syndrome to perirhinal cortex damage.
Keywords: semantic; category-specificity; perirhinal cortex; transentorhinal cortex; Alzheimer’s disease; declarative memory
doi:10.1093/brain/aws277 Brain 2012: 135; 3757–3769 | 3757
Received January 26, 2012. Revised August 13, 2012. Accepted August 20, 2012
ß The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/),
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
The functional role of the perirhinal cortex is a highly controversial
issue in current models of anterior medial temporal lobe function.
Most of the debate focuses on two major claims of perirhinal
cortex function. In one account, the perirhinal cortex is necessary
for differentiating between perceptually and semantically ambigu-
ous objects (Murray and Bussey, 1999; Tyler et al., 2004; Taylor
et al., 2011). An alternative, unitary model claims that the peri-
rhinal cortex is neither required for complex perceptual discrimin-
ations (Levy et al., 2005; Shrager et al., 2006) nor plays a unique
role in semantic processing (Squire et al., 2004); instead, the entire
anterior medial temporal lobe (perirhinal cortex, entorhinal cortex
and hippocampus) subserves the acquisition and recall of semantic
memories (Manns et al., 2003; Squire et al., 2004). The testing of
these opposing views of perirhinal cortex function has been ham-
pered by the fact that in humans, lesions including the perirhinal
cortex typically encompass large expanses of the anterior and
anteromedial temporal lobe, such that the precise neuroanatomical
locus of the functional impairments is difficult to determine. In the
present study, we tested these competing accounts by relating the
structural integrity of detailed native-space regions of interest for
the perirhinal cortex, entorhinal cortex and hippocampus to pic-
ture naming performance using stimuli in which we varied the
perceptual and semantic confusability of the objects. Participants
included patients with Alzheimer’s disease and amnestic mild cog-
nitive impairment, a putative Alzheimer’s disease prodrome
(Petersen, 2004), who are known to exhibit various degrees of
anterior medial temporal lobe atrophy (Braak and Braak, 1991;
Lerch et al., 2005).
The claim that perirhinal cortex is important for discriminating
between visually confusable objects derives from the hierarchical
account of object processing developed in non-human primates.
This model of object processing claims that the complexity of
neural representations increases from posterior occipital areas
through ventral temporal to the anterior and anteromedial tem-
poral regions (Ungerleider and Mishkin, 1982; Mishkin et al,.
1983). The perirhinal cortex represents the culmination of this
object processing pathway, performing the most complex feature
computations required to discriminate confusable objects, espe-
cially those with a high degree of visual feature overlap (Bussey
and Saksida, 2002; Buckley and Gaffan 2006; Saksida and Bussey,
2010). For example, Buckley et al., (2001) presented simultaneous
visual discrimination trials to unoperated control and perirhinal
cortex-lesioned monkeys. The authors found that lesioned mon-
keys performed normally in shape or size oddity discriminations,
but performed worse than control monkeys in perceptually de-
manding trials with e.g. degraded stimuli (see also Buckley and
Gaffan, 1998; Bussey et al., 2002, 2003, 2005). In extending
this model to humans, functional MRI studies have shown
increased activity in the perirhinal cortex during demanding
object discriminations, indicating that the perirhinal cortex is nor-
mally engaged for these tasks (Tyler et al., 2004; Lee et al., 2008;
O’Neil et al., 2009; Barense et al., 2010). Evidence for the ‘ne-
cessity’ of the human perirhinal cortex for complex perceptual
discriminations is provided by studies in patients with large anterior
medial temporal lobe lesions including the perirhinal cortex. These
patients are impaired in demanding perceptual discriminations (Lee
et al., 2005a, b) and discriminations between visually ambiguous
stimuli (Barense et al., 2005, 2007) in non-mnemonic tasks. Thus,
these latter studies suggest that the human anterior medial tem-
poral lobe is critical for fine-grained visual discriminations, but do
not demonstrate that the perirhinal cortex specifically is required
for this perceptual function.
The perirhinal cortex receives and integrates uni- and polymodel
input (Suzuki and Amaral, 1994a; Murray et al., 1998), leading
authors to claim that it facilitates the construction of coherent
multimodal object representations corresponding to our ‘semantic’
object memories (Eacott et al., 1994; Murray and Richmond,
2001). Based on this pattern of connectivity, a feature-based hier-
archical model of human semantic memory claims that the peri-
rhinal cortex is necessary for discriminating between not only
perceptually ambiguous objects but also semantically ambiguous
objects (Tyler et al., 2004; Moss et al., 2005; Taylor et al., 2006).
The degree to which a concept is semantically ambiguous can be
quantified on the basis of data from large-scale property norm
studies, where healthy participants list all features they can think
of that belong to a concept (Cree and McRae, 2003; Randall
et al., 2004; McRae et al., 2005; Vinson and Vigliocco, 2008).
Although this methodology has its drawbacks (McRae, 2004), the
regularities in the statistical properties of object features have
been shown to affect behaviour on a variety of conceptual tasks
(see Taylor et al ., 2011 for a review). A critical feature statistic is
‘distinctiveness’, that is, the inverse of the number of the concepts
in which the feature occurs, which reflects the extent to which a
feature is shared by many concepts or is distinctive to a particular
concept. Although shared features are informative about the cat-
egory to which a concept belongs (e.g. an object with four legs
and eyes is likely to be a living thing, an animal), distinctive fea-
tures (e.g. has humps) are further required to determine the
object’s unique identity. Indeed, Taylor et al. (2012) demonstrated
that basic-level picture naming latencies were significantly facili-
tated for objects with relatively more distinctive features compared
with objects with relatively more shared features. Importantly,
living and non-living things systematically differ with respect to
the statistical characteristics of their features. Specifically, living
things are naturally ambiguous because they share many features
with their category members (e.g. many animals have eyes,
legs and live on farms) and have relatively few distinctive features
(e.g. few animals have stripes) compared with non-living things,
which consist of fewer features overall and a higher proportion of
distinctive features (Humphreys and Forde, 2001; Tyler and Moss,
2001; Cree and McRae, 2003; Randall et al., 2004; Moss et al.,
2007; Taylor et al., 2007). These differences in feature statistics
render living things more confusable with respect to basic-level
identity.
Based on the hierarchical model of human semantic memory
and the noted differences in feature statistics, Taylor et al.
(2006) predicted that the processing of living things requires
more complex feature computations underpinned by the perirhinal
cortex than the processing of non-living things. Consistent with
this hypothesis, greater perirhinal cortex activity was found during
the crossmodal integration of living things’ compared with
3758 | Brain 2012: 135; 3757–3769 S. L. Kivisaari et al.
non-living things’ features (Taylor et al., 2006). Evidence consist-
ent with the notion that the perirhinal cortex is necessary for the
disambiguation of perceptually and semantically confusable ob-
jects comes from neuropsychological studies showing that wide-
spread anterior medial temporal lobe lesions, most typically those
associated with herpex simplex encephalitis, are associated with
disproportionate impairments with processing the meaning of
living compared with non-living things (Warrington and Shallice,
1984; Pietrini et al ., 1988; Moss et al., 1998, 2005; Gainotti,
2000; Brambati et al., 2006; Taylor et al., 2009; see Humphreys
and Forde, 2001 for a review). Critically, the specificity of the
relationship between perirhinal cortex damage and difficulty iden-
tifying confusable living compared with less confusable non-living
objects has not yet been shown in patients, as their lesions typic-
ally extend throughout the anterior medial temporal lobe and an-
terolateral temporal lobe (Gainotti, 2000).
An alternative, unitary model argues that the perirhinal cortex
plays no special role in the disambiguation of perceptually confus-
able objects (Squire et al ., 2004; Levy et al., 2005; Shrager et al.,
2006; Suzuki et al., 2009; Squire and Wixted, 2011), that is, ‘the
perirhinal cortex is not necessary for making difficult visual dis-
criminations, including discriminations between stimuli with a
high degree of feature ambiguity’ (Levy et al., 2005, p. 64). For
example, Shrager et al. (2006) found that patients with anterior
medial temporal lobe lesions were unimpaired relative to control
participants in visual discrimination tasks with perceptually
ambiguous stimuli. These authors suggest that previous findings
supporting the involvement of perirhinal cortex in the processing
of confusable objects may be accounted for by poor control for
lesion location, which may have extended anteriorly and laterally,
outside the anterior medial temporal lobe (Shrager et al., 2006;
Squire and Wixted, 2011; but see Lee and Rudebeck, 2010).
However, with respect to semantic processing, the unitary account
claims that the entire anterior medial temporal lobe complex
(i.e. the hippocampus, entorhinal cortex and perirhinal cortex) is
required for accessing semantic memories (Manns et al., 2003;
Squire et al., 2004) and that ‘structures of the medial temporal
lobe are richly interconnected (Lavenex and Amaral, 2000), and
attempts to differentiate between the hippocampal region and the
adjacent cortex based on sharp dichotomies ...are unlikely to be
successful’ (Manns et al., 2003, p. 131). Thus, although the uni-
tary account claims that the perirhinal cortex is not necessary for
disambiguating perceptually confusable objects, it predicts that the
perirhinal cortex, together with the entorhinal cortex and hippo-
campus, is involved in accessing semantic memories. As semantic-
ally confusable concepts are expected to engage the semantic
system more than semantically less confusable concepts, and as
all anterior medial temporal lobe structures are claimed to support
semantic retrieval (Manns et al., 2003; Squire et al., 2004), this
account predicts that all anterior medial temporal lobe structures
will show an effect of semantic confusability.
The present study aims to test these competing accounts of
perirhinal cortex function with respect to the disambiguation of
perceptually and semantically confusable objects using stringent
anatomical criteria. Alzheimer’s disease provides a disease model
with which to test these issues, as neurofibrillary pathology asso-
ciated with cognitive dysfunction begins in the medial perirhinal
cortex (‘transentorhinal cortex’) before spreading to downstream
anterior medial temporal lobe structures and on to the rest of the
cortex (Braak and Braak, 1991; Taylor and Probst, 2008). As the
anterior medial temporal lobe is an anatomically highly variable
region, we use a priori defined anatomical regions of interest,
and individually quantify these in native space for each participant
to acquire estimates of perirhinal cortex and entorhinal cortex
thickness and hippocampal volume (Kivisaari et al., in press). To
obtain measures of object confusability, we used the semantic
feature-based statistic data described previously (Gonnerman
et al., 1997; Tyler et al., 2000; Tyler and Moss, 2001; McRae
et al., 2005). Specifically, living things tend to have many
shared features (i.e. those that occur in many concepts, e.g. has
four legs) and relatively few distinctive features (i.e. those that
occur in few concepts, e.g. has wool) compared with non-living
things (Cree and McRae, 2003; Randall et al., 2004; for reviews
see Tyler and Moss, 2001; Taylor et al., 2007). Thus, living things
are inherently more perceptually and semantically confusable at
the basic-level than non-living things. This relationship is predicted
to be modulated by the number of features in a concept and
degree of global brain damage (Pexman et al., 2002, 2003; see
Plaut and Shallice, 1993 for a computational account); specifically,
as non-living things have fewer features than living things (Tyler
and Moss, 2001; Randall et al., 2004; Taylor et al., 2007), global
brain damage is predicted to disproportionately affect the repre-
sentations of low number of features non-living things, rendering
non-living things more difficult to identify at the basic-level (Moss
and Tyler, 2000; Moss et al., 2002). As successful object identifi-
cation depends both on the integrity of the representations and
the neuroanatomical disambiguation processes available, the basic-
level identification of impoverished representations of non-living
things because of higher levels of global brain damage is expected
to require more fine-grained analyses for their basic-level identifi-
cation (compare Moss and Tyler, 2000; Moss et al., 2005).
Integrating the assumptions of the feature statistic account with
the hierarchical model leads to the prediction that at low levels of
global brain damage, perirhinal cortex atrophy will be associated
with disproportionately poorer performance with living compared
with non-living objects. In the presence of higher levels of global
brain atrophy, perirhinal cortex thinning is expected to be add-
itionally associated with increasingly worse basic-level identifica-
tion performance with non-living things whose representations
have been degraded by global brain damage. In contrast, the
unitary model predicts that the perirhinal cortex is neither involved
in discriminating perceptually ambiguous objects (Levy et al.,
2005; Shrager et al., 2006) nor does it play a unique role in
accessing semantic object memories (Manns et al., 2003; Squire
et al., 2004). Instead, the entire anterior medial temporal lobe
complex is expected to support access to declarative (semantic)
memory (Manns et al., 2003; Squire et al., 2004). Thus, as the
recognition of semantically confusable objects is expected to
engage the semantic system more than the recognition of seman-
tically less confusable objects, all anterior medial temporal lobe
structures are predicted to be associated with this process. We
tested these competing predictions in a basic-level picture
naming task with matched sets of living and non-living pictures
by relating relative naming performance to the integrity of detailed
Perirhinal cortex and confusable object Brain 2012: 135; 3757–3769 | 3759
native-space neuroanatomical regions of interest for the perirhinal
cortex, entorhinal cortex and hippocampus while taking into
account the level of global atrophy.
Materials and methods
Participants
Forty native Swiss–German or German speaking adults participated in
this study [mean age = 73.1 years, standard deviation (SD) = 6.7 years;
mean education = 11.8 years, SD = 2.8 years; 50% were female sub-
jects]. Fourteen participants were healthy control individuals recruited
from two longitudinal research studies on ageing and dementia at the
Memory Clinic, Department of Geriatrics at the University Hospital
Basel (Monsch et al., 2000). Eleven participants were diagnosed with
amnestic mild cognitive impairment, a putative prodrome of
Alzheimer’s disease, according to the Winblad et al. (2004) criteria.
Fifteen individuals were diagnosed with Alzheimer’s disease according
to the Diagnostic and Statistical Manual of Mental Disorders, fourth
edition (American Psychiatric Association, 1994) and NINCDS-ADRDA
criteria (McKhann et al., 1984). The demographic characteristics and
Mini-Mental State Examination scores (Folstein et al., 1975) of all
groups are shown in Table 1. The groups did not differ with respect
to educational attainment or the percentage of female participants.
Group differences approached significance with respect to mean age;
therefore, age was covaried in all statistical participant analyses. As
expected, the groups differed significantly with respect to their
Mini-Mental State Examination scores. We note that patients with
Alzheimer’s disease were in mild stages of the disease according to
this measure (Monsch et al., 1995). This study was approved by the
ethics committee of both the University of Basel and University
Hospital Basel, and informed consent was obtained from each partici-
pant. A summary of participants’ neuropsychological test performance
is provided in Supplementary Table 1.
Picture naming task
Stimuli
Sixty realistic colour pictures were selected for the experiment. Half of
the pictures represented objects from the living domain (i.e. animals,
fruits/vegetables) and half from the non-living domain (i.e. vehicles,
tools; see Supplementary Table 2 for complete list of stimuli). The
stimuli were matched as closely as possible across domain on the fol-
lowing psycholinguistic and visual variables: concept agreement, famil-
iarity, H-statistic, age of acquisition, lemma frequency, number of
phonemes, number of letters, subjective visual complexity and two
objective measures of visual complexity, that is, file size and number
of pixels in the digital picture file (Supplementary material). Because
different categories of objects differ with respect to visual complexity
and familiarity measures, that is, vehicles and animals contain more
visual information and tend to be rated as less familiar than fruits and
tools, we split each domain into two groups, such that half of the
objects were visually complex (animals, vehicles) and half visually
simple (fruits/vegetables, tools). Two of the test items (spade, van)
were excluded from the statistical analyses because they were correctly
named by 550% of the healthy control participants (i.e. 7 and 47%,
respectively). Thus, the final stimulus set consisted of 15 objects each
in the animal and fruit/vegetable categories, and 14 objects each in
the vehicle and tool categories. Living and non-living domains differed
only with respect to the H-statistic (Supplementary Table 3).
Procedure
The behavioural task began with five novel practice items (not
included in the statistical analyses) followed by the 60 test stimuli.
The order of items from different categories was pseudo-randomized
such that there were no more than three consecutive pictures from the
same domain or category and no more than four consecutive pictures
from the same visual complexity level. All stimuli were presented in the
centre of a computer monitor. Each trial started with a 200 ms signal
tone followed by 1500 ms of silence. The picture then appeared on the
computer monitor for 1000 ms, after which the participants had
3000 ms to name the picture. An intertrial interval of 2000 ms followed
the response or time-out. The participants were instructed to say the
name of the pictured object out loud as quickly and as accurately as
possible, and to press a response key once they had begun saying the
name. The experimenter recorded the participant’s verbal response.
Two judges scored all verbal responses as correct or incorrect, and
conflicting ratings were resolved in a consensus conference. DMDX
software controlled presentation timings and participant responses
(Forster and Forster, 2003).
Behavioural variables and statistical analyses
As the domains had unequal numbers of items, all statistical analyses
used proportion correct. To test the key predictions outlined in the
‘Introduction’ section, we created a domain index representing the
relative performance on living compared with non-living things: [(pro-
portion correct living proportion correct non-living)/(proportion cor-
rect living + proportion correct non-living)] 100. On this measure,
positive scores indicated poorer performance with non-living than
living things, and negative scores indicated poorer performance with
living than non-living things. We analyzed the behavioural data using
SPSS version 19 (SPSS Inc. and IBM company, 2010). Age was used as
a covariate in all statistical analyses. The pairwise comparisons for
Table 1 Demographic characteristics and Mini-Mental State Examination scores of the healthy control, amnestic mild
cognitive impairment and Alzheimer’s disease groups
Demographic and neuropsychological
screening variables
Diagnosis
F
/
2
P
-value
Healthy control Amnestic mild cognitive impairment Alzheimer’s disease
n 14 11 15
Age (years) 71.6 (6.1) 70.8 (6.3) 76.0 (6.9) 2.6 0.09
Education (years) 12.1 (2.2) 10.5 (2.4) 12.3 (3.4) 1.7 0.2
Percentage of female subjects 35.7 54.4 60.0 1.8
a
0.4
Mini-Mental State Examination score 29.3 (0.7) 27.8 (1.3) 25.9 (2.8) 11.5 50.001
a
2
-test; values are mean (SD).
3760 | Brain 2012: 135; 3757–3769 S. L. Kivisaari et al.
group were Bonferroni-corrected by the number of pairwise compari-
sons conducted (with a corrected of 0.05/3 = 0.017).
Magnetic resonance imaging
acquisition and processing
Image acquisition
MRI scanning and behavioural testing were conducted on average
within a 3-month period (mean interval = 2.4 months, SD = 2.4
months). All structural scans were acquired on the same 3-T MRI
scanner (MAGNETOM Allegra, Siemens) at the University Hospital
Basel using a high-resolution T
1
-weighted 3D MPRAGE sequence
with a headcoil (inversion time = 1000 ms, repetition time = 2150 ms,
echo time = 3.5 ms, flip angle = 7
; rectangular field of view = 87.5%,
acquisition matrix = 256 224 mm, voxel size = 1.1 mm isotropic).
Cortical surface reconstructions
We focused on the following a priori defined anatomical regions of
interest in the left hemisphere to test the predictions outlined in the
‘Introduction’ section: (i) perirhinal cortex; (ii) entorhinal cortex; and
(iii) hippocampus. Only left hemisphere regions of interest are con-
sidered here because the task required a verbal response (results for
right hemisphere regions of interest are reported in the Supplementary
material). Because neurofibrillary pathology in Alzheimer’s disease
begins in the medial perirhinal cortex (corresponding to the transen-
torhinal cortex: Braak and Braak, 1991; Taylor and Probst, 2008), we
quantified the lateral and medial perirhinal cortex separately (see later
in the text).
Cortical thickness measurements for the key anteromedial temporal
lobe regions of interest were based on surface reconstructions of MP-
RAGE images created in FreeSurfer (Massachusetts General Hospital,
Boston, MA; http:/surfer.nmr.mgh.harvard.edu; Dale et al., 1999;
Fischl et al., 1999) followed by anatomical surface tracings described
later in the text. FreeSurfer segments the MPRAGE volumes into grey
and white matter in a semi-automatic processing stream. It builds a
subcortical mass to model the white matter surface, and extends it
outwards by tracking the grey matter intensity gradient to form the
pial surface (Dale et al., 1999). The white matter and pial surfaces are
represented as two meshes of connected vertices, and the thickness of
the cortical mantle is defined as the distance between corresponding
vertices on the two surfaces. The tissue next to the anterior medial
temporal lobe structures, which interfered with the cortical surface
reconstructions, was manually removed. In contrast to the cortical
thickness measurements for the key anterior medial temporal lobe
structures, the volume of the hippocampus (which has no meaningful
thickness) was acquired with the automatic subcortical registration
procedure in FreeSurfer (Fischl et al., 2002).
Anatomical surface tracings
We manually labelled anatomic regions of interest for the lateral peri-
rhinal cortex, medial perirhinal cortex (i.e. transentorhinal cortex) and
entorhinal cortex on the cortical surface reconstructions described pre-
viously. Labelling followed a surface-volumetric protocol (Goncharova
et al., 2001; Feczko et al., 2009) using the landmarks from anatom-
ical and pathological studies of the parahippocampal gyrus (Insausti
et al., 1998; Taylor and Probst, 2008; Kivisaari et al., in press). As
surface reconstructions are susceptible to inaccuracies in the most
anteromedial regions of the temporal lobe (compare Feczko et al.,
2009), we restricted labelling to the posterior portions of the entorh-
inal cortex and perirhinal cortex at the anterior border of the hippo-
campus (see later in the text). Surface tracings were not conducted for
one healthy control and one participant with Alzheimer’s disease be-
cause of the inferior quality of their medial temporal lobe surface re-
constructions. These participants were removed from all region of
interest analyses.
Definition of anatomical boundaries
All landmarks were localized on coronal slices of volumes reoriented
along the anterior commissure–posterior commissure axis (Fig. 1).
Moving from rostral to caudal levels, the anterior border of lateral
and medial perirhinal cortex used in this study (see earlier in the
text) was the midpoint (i.e. largest extent) of the mamillary bodies
along their rostrocaudal axis. Because of the inaccuracies in reconstruc-
tion of the angular bundle (compare Feczko et al., 2009), the anterior
border of the entorhinal cortex was conservatively defined as 3 mm
posterior to the slice where the posterior end of the mamillary bodies
was last visible. The posterior border of the lateral and medial peri-
rhinal cortex and the entorhinal cortex was 2 mm posterior to the apex
of the intralimbic gyrus (Insausti et al., 1998). As the regions of inter-
est were drawn posterior to the rostral tip of the hippocampus, the
uncal notch was used as the medial border of the entorhinal cortex
(Insausti et al., 1998). The shoulder of the medial bank of the collat-
eral sulcus always served as the border between the entorhinal
cortex and medial perirhinal cortex (Taylor and Probst, 2008;
Dickerson et al., 2009b). Because the location of the transentorhinal
cortex depends on the shape and depth of the collateral sulcus (Taylor
and Probst, 2008), we adjusted the label borders accordingly. In the
majority of cases where the collateral sulcus was 41.5 cm deep
(n = 87%), the border between the medial perirhinal cortex and the
lateral perirhinal cortex was defined as the fundus of the collateral
sulcus (Fig. 1A). The lateral border of the lateral perirhinal cortex
was then the shoulder of the lateral bank of the collateral sulcus. If
the collateral sulcus was 41.5 cm deep (n = 13%), the border
between the medial and lateral perirhinal cortex was the midpoint
between the shoulder of the medial bank of the collateral sulcus and
the midpoint of the lateral bank of the collateral sulcus (Fig. 1B;
Insausti et al., 1998; Taylor and Probst, 2008; Kivisaari et al., in
press). In these instances, the lateral border of the lateral perirhinal
cortex was the midpoint of the lateral bank of the collateral sulcus. In
cases of bifurcated collateral sulci (n = 13%), the criteria described
previously were applied to the medial-most sulcus (Taylor and
Probst, 2008). All manual tracings were performed by one of the
authors blind to diagnosis (S.L.K.).
Estimates of global atrophy level
To estimate the overall reduction in grey matter with respect to a fixed
baseline, we related the volume of the grey matter to the volume of the
whole cranium. For this purpose, we used Statistical Parametric Mapping
software (SPM8, Wellcome Institute of Cognitive Neurology, www.fil.
ion.ucl.ac.uk) running in MATLAB 2010 (Mathworks Inc.). The images
were segmented into grey matter with bias correction. Masks were
manually drawn on the tissue misclassified as grey matter, and these
areas were removed from the native space T
1
images. These corrected
native space T
1
images were then segmented into grey matter, white
matter and CSF while masking the voxels with zero intensity. Volumes
of each tissue type were extracted (get_totals65.m; http://www.cs.ucl.
ac.uk/staff/G.Ridgway/vbm/), and each grey matter volume was
divided by the corresponding total intracranial volume (i.e. sum of grey
matter, white matter and CSF volumes) to create a ‘grey matter index’.
Finally, these ratios were dichotomized to create a binomial ‘atrophy’
variable for use in the regression analyses, in which zero values indicated
a grey matter index in the uppermost 26th–100th percentile (i.e. no/mild
atrophy), and a value of 1 indicated a grey matter index in the bottom
Perirhinal cortex and confusable object Brain 2012: 135; 3757–3769 | 3761
quartile (i.e. moderate atrophy). This cut-off was chosen because the
majority of our sample was either healthy or only mildly affected (i.e.
healthy control and amnestic mild cognitive impairment participants),
who were a priori assumed to have relatively low levels of global atrophy.
This cut-off score resulted in the categorization of two healthy control
(14%), three amnestic mild cognitive impairment (27%) and five Alz-
heimer’s disease (33%) participants as members of the moderate atrophy
group. The group means on the grey matter index are presented in Table
2.
Validity of volumetric and cortical thickness estimates
To confirm the validity of the volumetric and cortical thickness esti-
mates, we performed two sets of global analyses. First, we correlated
overall proportion correct with signal intensities in each voxel across all
participants’ preprocessed grey matter volumes in SPM8 (Wellcome
Institute of Cognitive Neurology, www.fil.ion.ucl.ac.uk) running in
MATLAB 2010 (Mathworks Inc.). Second, we correlated overall pro-
portion correct with cortical thickness estimates across the entire left
hemisphere and right hemisphere in two independent analyses in
FreeSurfer (Massachusetts General Hospital, Boston, MA; http:/
surfer.nmr.mgh.harvard.edu; Dale et al., 1999; Fischl et al., 1999).
Both sets of analyses revealed similar patterns of results, thus, con-
firming the quality of the data and preprocessing. The corresponding
methods and results are provided as Supplementary material.
Region of interest statistical analyses
Four separate stepwise linear regression analyses were conducted to
predict overall naming performance and domain index scores, one for
each anatomic region of interest. Both healthy controls’ and patients’
data were included in the same regression analysis because clinical-
neuropathological studies show that cognitively healthy mature indi-
viduals can exhibit Alzheimer’s disease-related neurofibrillary path-
ology in the anterior medial temporal lobe (Braak and Braak, 1997;
Polvikoski et al., 2001; Riley et al., 2002; Knopman et al., 2003; Braak
et al., 2011), which are assumed to affect the associated functions.
Indeed, cortical thinning in clinically healthy controls may signal pre-
clinical Alzheimer’s disease-related pathological changes (Dickerson
et al., 2009a). Variables were entered into each model in two steps.
The first step included only the nuisance covariates: age and left hemi-
sphere mean thickness for models of region of interest thickness; age
and grey matter volume for the model of hippocampal volume; and
additionally overall naming scores in models of the domain index. The
variables of interest (anatomic region of interest, atrophy variable and
the interaction of these two variables) were entered into the model in
the second step. The results for partial regression models are reported;
thus, F - and P-values reflect whether the model (R
2
) significantly im-
proved when the covariates of interest were added to the initial
model. Finally, to reduce the likelihood of a Type I error, we used
an adjusted -level that was Bonferroni-corrected by the number of
independent region of interest regression analyses conducted to test
the main hypotheses of the study (adjusted level = 0.05/4 = 0.013).
Statistical analyses of the region of interest data were conducted with
IBM SPSS Statistics, version 19 (SPSS Inc. and IBM company, 2010).
Results
Behavioural results
To determine whether domain influenced each group’s naming
performance, we performed a 3 (diagnostic group) 2 (domain)
ANOVA across participants and over the two categories in each
domain. The ANOVAs revealed a main effect of group
[F(2,153) = 22.8, P 5 0.001], with healthy control participants
performing better than patients with amnestic mild cognitive im-
pairment [t(98) = 3.4, P 5 0.017] and patients with Alzheimer’s
disease [t(114) = 7.3, P 5 0.017], and patients with amnestic
mild cognitive impairment performing better than patients with
Alzheimer’s disease [t(102) = 3.7, P 5 0.017]. The effect of
domain [F(1,153) = 8.1, P = 0.001] was significant, reflecting a
living things disadvantage for all groups. Although this main
effect seemed to be driven by the two patient groups
(Supplementary Table 4), the interaction between group and
domain was non-significant [F(2,153) = 1.4, P = 0.2], indicating
that the patient groups did not exhibit a significantly pronounced
Figure 1 Anatomical border definitions of lateral perirhinal cortex (PRc), medial perirhinal cortex and entorhinal cortex (ERc) in two
coronal MRI slices. The anatomical borders are indicated with solid lines perpindicular to the cortical surface. The dashed lines represent the
collateral sulcus measurement (Taylor and Probst, 2008). Anatomical borders were adjusted according to the depth of the collateral sulcus,
that is, (A) collateral sulcus 51.5 cm or (B) collateral sulcus 41.5 cm (see text for details). CS = collateral sulcus; D = dorsal; FG = fusiform
gyrus; HC = hippocampus; ITG = inferior temporal gyrus; L = lateral; M = medial; MTG = middle temporal gyrus; PHG = parahippocampal
gyrus; STG = superior temporal gyrus; Un = uncal notch; V = ventral.
3762 | Brain 2012: 135; 3757–3769 S. L. Kivisaari et al.
domain-specific naming impairment relative to the healthy control
participants. The groups’ overall naming performance, naming
scores in each domain, and corresponding domain indices are pre-
sented in Supplementary Table 4.
Brain–behaviour correlations
Overall basic-level naming performance
For completeness, we report the extent to which each anterior
medial temporal lobe area was associated with overall naming
performance. To examine this question, we conducted four inde-
pendent stepwise linear regression analyses predicting the overall
proportion correct score with each region of interest. We found
that only hippocampal volume significantly predicted overall
naming performance [F(1,34) = 7.8, P = 0.009; b = 0.5, t = 2.8,
P = 0.009]. The lateral perirhinal cortex [F(1,34) = 0.08, P = 0.8],
medial perirhinal cortex [F(1,34) = 1.4, P = 0.2] and entorhinal
cortex [F(1,34) = 2.0, P = 0.2] models were non-significant.
Relative basic-level naming performance for living and
non-living things
To disentangle the contribution of the perirhinal cortex, entorhinal
cortex and hippocampus to the identification of perceptually and
semantically confusable compared with less confusable objects, we
conducted stepwise linear regression analyses predicting domain
index scores with the four anatomic regions of interest. To deter-
mine the relationship between relative performance in the living
and non-living domains (domain index) and the integrity of the
region of interest at mild to more moderate levels of global atro-
phy, we included the atrophy variable and an interaction term
(region of interest atrophy). The regression models below test
whether inclusion of these three terms (region of interest, atrophy,
region of interest atrophy) improved the initial model with only
nuisance covariates. The descriptive statistics of all regions of inter-
est are reported in Table 2.
Only the medial perirhinal cortex thickness model significantly
predicted domain index scores at the Bonferroni-corrected level
[F(3,31) = 4.7, P = 0.008]. For all other regions of interest, the
inclusion of the covariates of interest did not statistically improve
the model: lateral perirhinal cortex thickness [F(3,31) = 2.1,
P 4 0.013], entorhinal cortex [F(3,31) = 2.9, P 4 0.013] and
hippocampus [F(3,31) = 2.2, P 4 0.013]. Therefore, only the ef-
fects of individual predictors from the medial perirhinal cortex
thickness model are reported below. For completeness, the results
of all individual predictors from all models are reported in Table 3.
The regression analysis with the medial perirhinal cortex thick-
ness revealed that at no/mild levels of atrophy, medial perirhinal
cortex thickness significantly positively correlated with domain
index scores, indicating that thinner medial perirhinal cortices
were associated with fewer correctly named living relative to
non-living things. Importantly, global atrophy level significantly
interacted with medial perirhinal cortex thickness: at no/mild
levels of global atrophy, thinner medial perirhinal cortices were
associated with poorer performance with living compared with
non-living things, whereas at moderate levels of global atrophy,
this effect reversed, such that thinner medial perirhinal cortices
were associated with increasingly poorer naming performance
with non-living compared with living things (Table 3 and Fig. 2).
To ensure that these results were not driven by potential eccen-
tricities of the healthy control group, we repeated the analysis
excluding the healthy control participants. In this analysis, the
effect of medial perirhinal cortex thickness (b = 0.5, t = 2.7,
P = 0.02) and the interaction between medial perirhinal cortex
thickness and the level of global atrophy (b = 1.9, t = 2.4,
P = 0.03) remained significant. We note that 8 of 10 participants
in the moderate atrophy had an overall disadvantage for living
Table 2 Means and standard deviations of left hemisphere cortical thicknesses estimates (mm) of the lateral and medial
perirhinal cortex and entorhinal cortex, hippocampal volume estimates (cm
3
), and the global atrophy variable
Diagnostic group
n
Lateral perirhinal
cortex
Medial perirhinal
cortex
Entorhinal
cortex
Hippocampus Grey matter
index
n 38 38 38 40 40
Healthy control subjects 14 2.8 (0.5) 2.3 (0.5) 3.5 (0.2) 3.8 (0.4) 0.36 (0.03)
Amnestic mild cognitive impairment 11 2.8 (0.5) 2.2 (0.5) 2.9 (0.3) 3.2 (0.5) 0.35 (0.03)
Alzheimer’s disease 15 2.9 (0.6) 2.0 (0.5) 2.9 (0.5) 2.7 (0.4) 0.33 (0.03)
Table 3 Results of five stepwise linear regression models predicting domain index scores with cortical thickness estimates
of lateral perirhinal cortex, medial perirhinal cortex and entorhinal cortex and the volume of the hippocampus. We note that
only the regression model with the medial perirhinal cortex was significant
Covariate Lateral perirhinal cortex Medial perirhinal cortex Entorhinal cortex Hippocampus
b
tP
b
tP
b
tP
b
tP
Region of interest 0.3 2.1 0.05 0.5 3.1 0.004 0.6 2.7 0.01 0.6 2.3 0.03
Atrophy 1.6 1.5 0.1 1.9 2.6 0.01 1.0 1.1 0.3 0.2 0.3 0.8
Region of interest atrophy 1.8 1.7 0.1 2.0 2.8 0.008 1.1 1.2 0.2 0.04 0.05 1.0
The predictive strengths of the corresponding regions of interest and global atrophy and the interaction region of interest atrophy, are listed for each model. The nuisance
variables were entered in the first step and are not shown in this table.
Perirhinal cortex and confusable object Brain 2012: 135; 3757–3769 | 3763
things, as indicated by negative index scores (Fig. 2), such that
their overall naming performance was poorer in the living than
non-living domain (percentage living and non-living things correct:
74 and 84%, respectively). That is, despite an overall living things
impairment within the moderate atrophy group, thinner medial
perirhinal cortices were significantly associated with poorer
naming of non-living compared with living things. These findings
are in line with the hierarchical account, as medial perirhinal cortex
thickness was specifically associated with the ability to identify
concepts that are either inherently ambiguous (living things) or
impoverished (non-living things in the presence of moderate
global atrophy).
Two participants had low domain index scores and relatively low
cortical thickness values (Fig. 2). To ensure that the results
reported previously were not driven by these two participants,
we repeated all regression analyses excluding the two outlying
participants. We found that the medial perirhinal cortex regression
model remained significant at a standard level of 0.05
[F(3,29) = 3.7, P = 0.02], as did the effects for medial perirhinal
cortex thickness (b = 0.4, t = 2.0, P = 0.05), atrophy (b = 1.7,
t = 2.0, P = 0.05) and the medial perirhinal cortex atrophy
interaction (b = 1.9, t = 2.4, P = 0.02) within this model. By
comparison, the models with the lateral perirhinal cortex
[F(3,29) = 2.1, P = 0.1], entorhinal cortex [F(3,29) = 1.8, P = 0.2]
and hippocampus [F(3,29) = 2.0, P = 0.1] remained non-
significant, as did the predictors of interest within these models
(all region of interest main effects P 4 0.2, all region of inter-
est atrophy interactions P 4 0.1). Boxplots for each region of
interest further ruled out the possibility that the pattern of results
reported previously emerged because of a truncation in range for
the non-significant regions of interest (Supplementary Fig. 1).
Taken together, these analyses suggest that the medial perirhinal
cortex supports the basic-level identification of perceptually and
semantically confusable living things, and that medial perirhinal
cortex integrity and the level of global atrophy indeed interact
to determine the direction of the domain naming disadvantage
in Alzheimer’s disease. Significantly, these patterns were specific
to the medial perirhinal cortex and not to the surrounding anterior
medial temporal lobe areas.
Discussion
Medial perirhinal cortex thinning was associated with a dispropor-
tionate difficulty in naming living things at no/mild levels of global
atrophy, and at moderate levels of global atrophy, with increasing
difficulty in naming impoverished representations of non-living
things, in the context of overall living things impairment. Thus,
the present study demonstrated that the medial perirhinal cortex
(i.e. transentorhinal cortex, Braak and Braak, 1991; Taylor and
Probst, 2008) is necessary for identifying perceptually and seman-
tically confusable concepts. Importantly, although similar behav-
ioural performance patterns have been related to widespread
anterior and anteromedial temporal lobe lesions (e.g. Taylor
et al., 2009), the anatomically defined region of interest approach
used here showed that the impairments in distinguishing percep-
tually and semantically ambiguous objects were specifically related
to the medial perirhinal cortex, but not the lateral perirhinal
cortex, entorhinal cortex or hippocampus. Moreover, these find-
ings extend former reports on the involvement of the human
perirhinal cortex in the disambiguation of perceptually complex
objects by demonstrating that perceptually and semantically con-
fusable objects require the perirhinal cortex for their discrimination
and recognition. These findings, therefore, support a hierarchical
account of anterior medial temporal lobe functioning (Bussey
et al., 2003, 2005; Tyler et al., 2004; Taylor et al., 2011;
Barense et al., 2010), in which the perirhinal cortex, at the apex
of the ventral visual object processing stream and site of conver-
gence of multimodal perceptual information, supports discrimin-
ations between perceptually and semantically confusable objects,
thereby enabling the appreciation of their unique significance.
Consistent with the hypothesized role of the perirhinal cortex in
disambiguating and thereby identifying perceptually and seman-
tically ambiguous objects (Buckley and Gaffan, 1998, 2006;
Buckley et al., 2001; Bussey and Saksida, 2002; Saksida and
Bussey, 2010; Taylor et al., 2011), medial perirhinal cortex thin-
ning was associated with a disproportionate difficulty in naming
living things at no/mild levels of atrophy. This result indicates that
perirhinal cortex atrophy disrupts the disambiguation of inherently
confusable living things, which consist of a large number of shared
features and few distinctive features, compared with non-living
things, which consist of fewer features overall and a greater pro-
portion of distinctive to shared features (Tyler and Moss, 2001;
Cree and McRae, 2003; Randall et al., 2004). However, sparser
representations of non-living things are expected to be more
Figure 2 The scatterplot represents the relationship between
estimated medial perirhinal cortex (PRc) thickness and the
domain index for no/mild and moderate global atrophy levels
separately (all covariates held at their mean). At no/mild levels of
global atrophy, thinner medial perirhinal cortices are associated
with worse performance with living than non-living things (grey
line). At moderate levels of global atrophy, this relationship re-
verses, such that thinner medial perirhinal cortices are associated
with worse performance with non-living than living things (black
line). The dashed line represents equivalent performance in both
domains.
3764 | Brain 2012: 135; 3757–3769 S. L. Kivisaari et al.
susceptible to moderate levels of global atrophy than rich repre-
sentations of living things, as probabilistically, the sparse represen-
tations of the non-living things lose a greater proportion of their
features from global damage (Moss and Tyler, 2000; Moss et al.,
2000; see also Plaut and Shallice, 1993; Pexman et al., 2003).
Indeed, global atrophy interacted with medial perirhinal cortex
thickness: medial perirhinal cortex thinning was associated with
an increasing disadvantage for non-living things at moderate
levels of atrophy in the context of general living things impair-
ment. These effects remained significant even after excluding the
healthy control group from the analysis, demonstrating that the
primary findings were not driven by factors specific to the healthy
control participants. Thus, these findings indicate that the peri-
rhinal cortex is not involved in the identification of living things
per se, but the identification of perceptually and semantically con-
fusable objects, whether they are inherently confusable living
things or the degraded representations of non-living things.
The unitary model of anterior medial temporal lobe function pos-
tulates that the perirhinal cortex alone does not support the per-
ceptual discrimination of ambiguous objects (Levy et al., 2005;
Shrager et al., 2006; Suzuki, 2009). Rather, all anterior medial tem-
poral lobe structures are predicted to be involved in accessing se-
mantic memory (Manns et al., 2003; Squire et al., 2004). As
semantically confusable objects are expected to engage the seman-
tic system more than semantically simple objects, the unitary view
predicts that the integrity of all anterior medial temporal lobe struc-
tures should be associated with a disadvantage for semantically
confusable objects (compare Manns et al., 2003; Squire et al.,
2004). The present results based on strict anatomic differentiation
within the anterior medial temporal lobe do not support this pre-
diction: only the integrity of the medial perirhinal cortex, but not
that of the lateral perirhinal cortex, entorhinal cortex or hippocam-
pus, was significantly associated with a disproportionate impair-
ment in naming confusable objects. A recent formulation of the
unitary account allows for the relatively greater involvement of
the perirhinal cortex (i.e. relative to the entorhinal cortex and
hippocampus) in visual object memory: ‘Based on anatomy, it
seems reasonable to suppose that perirhinal cortex plays an import-
ant role in ...visual recollection (e.g. when a visual stimulus is used
as a retrieval cue to recollect its visual paired associate)’ (Wixted
and Squire, 2011, p. 212). This claim would be consistent with a
greater involvement of the perirhinal cortex than the entorhinal
cortex and hippocampus in overall picture naming performance.
However, the present results demonstrate that overall picture
naming was significantly related to hippocampal, not perirhinal
cortex or entorhinal cortex integrity. Thus, the perirhinal cortex
does not seem to play a special role in object recognition per se,
but in the disambiguation and, thus, recognition of perceptually
and semantically complex objects, consistent with a hierarchical
account of object representations (Tyler et al ., 2004; Moss et al.,
2005; Saksida and Bussey, 2010; see also Winters et al., 2008).
Studies of patients with semantic dementia localize general se-
mantic processing to the anterolateral temporal lobe structures,
such as the temporal pole (Mummery et al., 2000; Levy et al .,
2004; Hodges and Patterson, 2007). These observations are not
incompatible with the claims made here. Specifically, the antero-
lateral structures and the perirhinal cortex may be involved in
semantic processing, but may make qualitatively different contri-
butions. To test this possibility and to ensure that the present
findings were not driven by pathology extending into the antero-
lateral areas (Levy et al., 2004; Squire et al., 2004; Squire and
Wixted, 2011), we conducted additional region of interest ana-
lyses. We used FreeSurfer’s automatic surface parcellation
(Desikan et al., 2006) to acquire the thicknesses of the temporal
poles and inferotemporal gyri of each participant, and we used
analogous regression models (see ‘Materials and methods’ section)
to examine whether the thickness of these regions predicts picture
naming performance (Supplementary material). These analyses
revealed that the thickness of the temporal poles, but not inferior
temporal gyri, was indeed associated with the proportion of over-
all correctly named objects, but not with the domain index scores.
Thus, although the anterolateral temporal lobe areas may play a
general role in processing semantic knowledge as suggested by
findings from patients with semantic dementia (Mummery et al.,
2000; Levy et al., 2004; Squire et al., 2004; Hodges and
Patterson, 2007), they do not seem to play a specific role in pro-
cessing perceptually and semantically ambiguous objects (see also
Moss et al., 2005).
Because the medial perirhinal cortex is the first region affected
by neurofibrillary pathology in Alzheimer’s disease (Braak and
Braak, 1991; Taylor and Probst, 2008), the present result suggests
that a relative difficulty naming living compared with non-living
things in the context of relatively mild overall atrophy may serve
as a specific early cognitive marker of the disease. Furthermore,
the reverse naming pattern at moderate levels of global atrophy
suggests that the living things naming impairment may be transi-
tory. Taken together, these patterns may account for the mixed
results in earlier behavioural studies of category-specific semantic
impairments in Alzheimer’s disease (Gonnerman et al., 1997;
Garrard et al., 1998; Moreno-Martı
´
nez and Laws, 2008; see
Laws et al., 2007 for a meta-analysis) and the present behavioural
results, which showed no significant group by domain interactions.
Specifically, the heterogeneity in the degree and distribution of
atrophy may generate competing domain effects, thereby attenu-
ating differences between diagnostic groups. This heterogeneity is
not surprising given that some cognitively healthy mature individ-
uals exhibit early stage Alzheimer’s disease pathology on post-
mortem neuropathological examination (Braak and Braak, 1997;
Polvikoski et al., 2001; Riley et al. , 2002; Knopman
et al., 2003;
Braak et al., 2011). Thus, the integrity of the semantic system
globally (indexed here by global atrophy) and the medial perirhinal
cortex more focally, should be considered as mechanisms driving
category-specific semantic impairments (Moss and Tyler, 2000;
Moss et al., 2000; compare Moss et al., 2005).
Our findings may seem to be at odds with a study by Lee et al.
(2006), which investigated visual discrimination performance with
faces and simple computerized scenic images in seven patients
with Alzheimer’s disease. Using an odd-one-out task, these au-
thors found that participants with Alzheimer’s disease performed
significantly poorer than their control participants on scene, but
not face, discriminations. However, the ventral stream network
involved in human face processing only partially overlaps with
that required for non-face object processing (e.g. Kanwisher
et al., 1997), suggesting that face recognition relies on specialized
Perirhinal cortex and confusable object Brain 2012: 135; 3757–3769 | 3765
neural circuitry (Nelson, 2001; Pascalis and Kelly, 2009). Thus,
patients’ performance with faces cannot be generalized to
non-face object processing. Moreover, Lee et al. (2006) neither
explicitly manipulated the degree of feature overlap in their visual
stimuli nor did they relate performance specifically to perirhinal
cortex integrity. Thus, object processing impairments in their pa-
tients with Alzheimer’s disease may have emerged if real and
meaningful objects had been used, the extent of feature overlap
manipulated and specific functional–neuroanatomical relationships
tested. Interestingly, a follow-up study by the same group (Lee
et al., 2007) implemented these stimulus factors. In this study,
(i) a lion and a dog; and (ii) a guitar and a cello, were morphed
together to create different levels of visual overlap, and partici-
pants decided whether the morphed lion–dog and guitar–cello
pairs were the same or different. Consistent with the present find-
ings, the participants with Alzheimer’s disease committed numer-
ically more errors than control participants on the object
discrimination trials with the highest degree of visual overlap
(see Lee et al., 2007, p. 2141), although this difference was not
statistically tested.
The results presented here are consistent with a hierarchical
view of object processing, whereby perirhinal cortex at the top
of the object processing hierarchy binds perceptual and semantic
features of confusable objects together to enable their identifica-
tion (Murray and Richmond, 2001). Information processed in the
perirhinal cortex is forwarded to the entorhinal cortex, which pre-
sumably integrates it with visuospatial information from the para-
hippocampal cortex and higher-order information from other
association cortices (Insausti et al., 1987; Suzuki and Amaral,
1994b; Canto et al., 2008), and transmits its output to the hippo-
campus (Witter and Amaral, 1991). Lavanex and Amaral (2000)
conceived this system as a hierarchy of associativity, in which in-
creasingly more elaborate representations are computed (see also
Mishkin et al., 1997; Eichenbaum, 2000; Cowell et al., 2009). In
this context, the finding that hippocampal integrity predicted over-
all naming performance can be interpreted as reflecting recall of
higher-order associative information from semantic memory, a
process common to the basic-level naming of many different
types of concepts.
To our knowledge, the present study is the first to show that
the human medial perirhinal cortex is necessary for the disambigu-
ation of perceptually and semantically confusable objects and,
importantly, that this function distinguishes it from more medial
anterior medial temporal lobe areas and lateral temporal cortex.
The present results, therefore, extend those reported by Davies
et al. (2004), who demonstrated that performance on two
common clinical tests of semantic memory—animal fluency and
picture naming—significantly correlated with left and right peri-
rhinal cortex volumes, but not the volumes of the entorhinal
cortex and hippocampi, in eight patients with semantic dementia
(see also Hirni et al., 2011). Moreover, although numerous studies
have demonstrated a relationship between the perirhinal cortex
and the disambiguation of perceptually confusable objects, we
show here that the disambiguation capabilities of the perirhinal
cortex extend to non-perceptual, semantically confusable objects.
Feature-based statistical models (e.g. Tyler and Moss, 2001) pro-
vide the theoretical grounds on which to determine and, therefore,
generate predictions about an object’s semantic confusability and,
thus, dependence on the perirhinal cortex for disambiguation. The
role of the perirhinal cortex may be characterized in terms of the
processes it performs on ambiguous patterns of input (Moss et al.,
2005), the representations of specific types of content (Cowell
et al., 2010; Saksida and Bussey, 2010) or a combination of
these two factors. Given that living things tend to be more per-
ceptually and semantically ambiguous compared with non-living
things, as demonstrated by feature statistic accounts (e.g. Tyler
and Moss, 2001), the present results additionally provide an
explanation of why the syndrome of category-specific semantic
impairments for living things are associated with anterior medial
temporal lobe damage (see also Moss et al., 2005), and critically,
pinpoint the root of this syndrome to perirhinal cortex damage.
Acknowledgements
The authors would like to thank Professor Manfred Berres for
statistical assistance and Professor emeritus Alphonse Probst for
his anatomical advice.
Funding
Swiss National Science Foundation Ambizione Fellowship (to
K.I.T.), the Swiss Alzheimer’s Association (PZ00P1_126493; to
K.I.T.), Swiss Foundation for Ageing Research (financed by the
Loterie Romande) (to K.I.T.), a Young Clinical Researcher Grant
from the University of Basel (to K.I.T.), a Tilma Hainari Jubilee
Grant from the Finnish Concordia Fund (to S.L.K.), the Swiss
Federal Commission for Scholarships for Foreign Students (Berne)
(to S.L.K.), European Research Council Advanced Investigator
grant (249640; to L.K.T.). The MRI scans were financed by
grants from the Novartis Foundation (to A.U.M.) and
GlaxoSmithKline (to A.U.M.).
Supplementary material
Supplementary material is available at Brain online.
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    • "Thus, NFT-induced functional mPRC impairments appear early in the preclinical course of AD, offering clinicians an inexpensive, early and specific additional AD biomarker. The challenge to future studies will be to develop more specific cognitive measures of mPRC functioning than the current clinical neuropsychological tools [14, 15, 23] by taking advantage of the wealth of primarily non-human primate research on these structures [8]. "
    [Show abstract] [Hide abstract] ABSTRACT: Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.
    Full-text · Article · Mar 2016
    • "The perirhinal cortex ablation has been shown to impair visual object identification (Buckley and Gaffan, 1998). Furthermore, recent studies suggested that the perirhinal cortex contributes to perceptual processing (Devlin and Price, 2007) and that it is necessary for the disambiguation of perceptually and semantically confusable objects (Kivisaari et al., 2012). The parahippocampus was damaged in DLB patients but not in AD patients. "
    [Show abstract] [Hide abstract] ABSTRACT: The hippocampus and adjacent extra-hippocampal structures are organized in distinct and specialized regions which process heterogeneous functions, including memory, and visuospatial functions. Specific alterations of the different hippocampal subfields and adjacent extra-hippocampal structures could differently contribute to the pathophysiology of AD and DLB. Based on visual symptoms which characterize DLB patients, the hippocampal subfields and the adjacent extra-hippocampal structures which are mainly involved in the visual functions could be impaired in DLB and preserved in AD. To test this hypothesis, we performed structural magnetic resonance imaging on 19 DLB, 15 AD and 19 age-matched healthy controls. FreeSurfer’s pipelines were used to perform parcellation of hippocampus and adjacent extra-hippocampal structures and to assess the structural changes within each region. The cornu ammonis and subiculum were bilaterally damaged in AD and preserved in DLB. The perirhinal cortex and parahippocampus were damaged in DLB but not in AD. Our findings demonstrate that the hippocampal subfields and adjacent extra-hippocampal structures were differently altered in AD and DLB. Particularly, DLB patients showed a more focused alteration of the extra-hippocampal structures linked to visual functions.
    Article · Jan 2016
    • "However, common clinical tests of semantic memory, such as semantic fluency, may not be sensitive enough to specific kinds of disturbances in semantic object processing associated with PRC dysfunction that have been described in recent years (see e.g. Hirni et al., 2013; Kivisaari et al., 2012 Kivisaari et al., , 2013a Moss et al., 2005; Tyler et al., 2004). More specific cognitive tasks based on cognitive neuroscience models of PRC functioning should be developed to take advantage of the progress made in this domain and translate it to the clinical research setting. "
    [Show abstract] [Hide abstract] ABSTRACT: The stereotypical pattern of neurofibrillary tangle (NFT) spreading in the earliest stages of typical Alzheimer’s dementia (AD) predicts that medial perirhinal cortex (mPRC) atrophy precedes entorhinal cortex (ERC) atrophy, while the status of the parahippocampal cortex (PHC) remains unclear. Atrophy studies have focused on more advanced rather than early AD patients, and usually segment the entire perirhinal cortex (PRC) as opposed to the mPRC vs. lateral PRC (lPRC) . The present study therefore determined the extent of ERC, mPRC, (lPRC and PHC atrophy in very early AD (mean MMSE=26) patients and its presumed prodrome amnestic mild cognitive impairment (aMCI; mean MMSE=28) compared to demographically-matched controls. PHG structures were manually segmented (blinded rater) and cortical thicknesses extracted. ERC and mPRC were similarly atrophied in both patient groups. The lPRC was atrophied in the AD group only. Thus, atrophic changes in very early AD broadly map onto the pattern of NFT spreading, and suggest that mPRC, ERC, and lPRC, but not PHC-associated functional impairments, characterize very early-stage AD.
    Full-text · Article · Nov 2015
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