Brain Advance Access published July 9, 2013
doi:10.1093/brain/awt185
Brain 2013: Page 1 of 12
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BRAIN
A JOURNAL OF NEUROLOGY
The orbitofrontal cortex is involved in emotional
enhancement of memory: evidence from the
dementias
Fiona Kumfor,1,2,3 Muireann Irish,1,3,4 John R. Hodges1,2,3 and Olivier Piguet1,2,3
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, the University of New South Wales, Sydney, Australia
ARC Centre of Excellence in Cognition and its Disorders, the University of New South Wales, Sydney, Australia
School of Psychology, the University of New South Wales, Sydney, Australia
Correspondence to: Olivier Piguet,
Neuroscience Research Australia,
PO Box 1165,
Randwick,
NSW,
Australia
E-mail: [email protected]
The enhancing effect of emotion on subsequent memory retrieval is well established. Patients with frontotemporal dementia
show profound emotion processing difficulties, yet the extent to which such deficits attenuate emotional enhancement of
memory remains unknown. Here, we studied the intersection between emotion and memory using a visual forced-choice
recognition test for negative and neutral stimuli in 34 patients with frontotemporal dementia compared with 10 patients
with Alzheimer’s disease and 15 control subjects. Control subjects and patients with Alzheimer’s disease recognized more
emotional than neutral items, as demonstrated by a significant interaction between emotion and memory for true recognition.
This emotional enhancement effect was notably absent in the frontotemporal dementia cohort, with comparable recognition
performance regardless of emotional content. Voxel-based morphometry analyses revealed distinct neural substrates for overall
memory versus emotional memory performance. Overall memory performance correlated with the hippocampus, precuneus and
posterior cingulate, regions crucial for successful episodic memory performance. Emotional enhancement of memory, by contrast, was associated exclusively with the integrity of the right orbitofrontal and subcallosal cortex. Our findings demonstrate
differential disruption of emotional enhancement of memory in neurodegenerative disorders, and point toward the potentially
pivotal role of the orbitofrontal cortex in supporting the successful retrieval of emotionally charged negative stimuli.
Keywords: Alzheimer’s disease; frontotemporal dementia; episodic memory; orbitofrontal cortex, emotion
Abbreviations: FTD = frontotemporal dementia; PNFA = progressive non-fluent aphasia
Introduction
Memories for emotional events are typically more vivid than memories for non-emotional events (Heuer and Reisberg, 1990;
LeDoux, 1993; Hamann, 2001). This emotional enhancement of
memory is observed under different forms, including ‘flashbulb’
memories (Brown and Kulik, 1977), such as the memory of 11
September 2001, as well as recollections of personal emotional
events, such as one’s wedding day or graduation. This effect
has been investigated experimentally with a range of stimuli
Received March 14, 2013. Revised May 9, 2013. Accepted May 27, 2013.
ß The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
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memory measures (reviewed by Klein-Koerkamp et al., 2012).
Highly arousing stimuli (e.g. pictures rather than words) and stimuli that provide emotional information from multiple modalities
(e.g. real-life events) in combination with less demanding memory
tasks, are thought to be more likely to elicit the emotional enhancement of memory effect in patients with Alzheimer’s disease
(Kensinger et al., 2004).
Of particular interest to this study is the dementia syndrome of
frontotemporal dementia (FTD), a neurodegenerative brain disorder affecting primarily the frontal and temporal lobes (GornoTempini et al., 2011; Rascovsky et al., 2011). Emotion processing
difficulties have been found in all three main subtypes of FTD:
behavioural variant FTD, semantic dementia and progressive
non-fluent aphasia (PNFA) (Lavenu et al., 1999; Rosen et al.,
2002b; Seeley et al., 2008; Rohrer et al., 2010; Kumfor et al.,
2011), which are due to atrophy in emotion-specific brain regions
in the frontal and temporal lobes (Kumfor et al., 2013). In direct
contrast to Alzheimer’s disease, these emotion processing deficits
are present in the context of relatively intact performance in other
cognitive domains, including visuoperception and item recognition
(Graham et al., 1999; Pasquier et al., 2001). The interaction between emotion and memory, however, has not been investigated
in FTD, despite these patients showing progressive neurodegeneration in key regions essential for emotion processing, including
the medial and orbitofrontal cortex, amygdala and insula (Rosen
et al., 2002a; Gorno-Tempini et al., 2004; Seeley, et al., 2008).
To date, investigations of emotion processing disturbance in
FTD have been limited to aspects of emotion recognition and
reactivity (reviewed by Kumfor and Piguet, 2012). The evidence
reviewed here suggests that emotional enhancement of memory is
likely to be differentially affected in FTD and Alzheimer’s disease.
To address this issue, we investigated the effects of emotion on
memory in Alzheimer’s disease and FTD using visually arousing
pictures in a recognition memory test. Based on the existing evidence, we hypothesized that in patients with Alzheimer’s disease,
emotional enhancement of memory would be preserved, in contrast to patients with FTD where emotional enhancement of
memory would be compromised. In addition, we predicted that
medial temporal lobe structures, including the hippocampus would
be critical for episodic memory, irrespective of emotional content,
whereas, emotional memory retrieval would be dependent on the
integrity of temporal and frontal lobe regions including the amygdala and orbitofrontal cortex.
Materials and methods
Participants
Thirty-four patients with FTD (11 behavioural variant FTD, 13 semantic dementia and 10 PNFA) and 10 patients with Alzheimer’s disease
were recruited into the study from FRONTIER, the frontotemporal
dementia clinical research group at Neuroscience Research Australia,
Sydney. All patients underwent a clinical assessment with an experienced behavioural neurologist and neuropsychological assessment. All
patients were diagnosed by consensus and met current clinical diagnostic criteria (Gorno-Tempini, et al., 2011; McKhann et al., 2011;
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(e.g. stories, words, pictures) and testing conditions (e.g. recall and
recognition paradigms) (Bradley et al., 1992; Cahill et al., 1995;
Kensinger et al., 2002; Mickley and Kensinger 2008), and is
observed across the age spectrum (Comblain et al., 2005).
Irrespective of the methodology, a robust effect is observed
where the retrieval of emotionally charged stimuli is more readily
and vividly remembered than neutral stimuli.
Among the brain structures involved in emotional enhancement
of memory, the amygdala appears critical for the enhancement
effect. Patients with amygdala lesions show an attenuation of
emotional enhancement of memory, although memory for neutral
information remains unchanged (Adolphs et al., 1997). Functional
neuroimaging studies indicate that increased amygdala activity
during encoding is linked to emotional enhancement of memory
(Canli et al., 2000; Dolcos et al., 2005; Kensinger and Schacter,
2006). The involvement of the amygdala appears important for
both encoding and consolidation of emotionally arousing information, through its interactions with regions necessary for the encoding of sensory information (e.g. the fusiform gyrus), and for the
long-term consolidation of information (e.g. the hippocampus), by
mediating the release of stress hormones in response to emotionally arousing stimuli (McGaugh, 2004; Kensinger, 2009).
Although the role of the amygdala is not disputed, emotional
enhancement of memory likely depends upon the integrity of additional brain structures within the frontal and temporal lobes. Brain
activation in regions necessary for emotion processing, such as the
orbitofrontal cortex, ventral striatum and anterior cingulate, is
associated with memory for details of negative stimuli (Kensinger
et al., 2007). The orbitofrontal cortex is suggested to play a modulatory role whereby orbitofrontal cortex activity will enhance
amygdala and hippocampal activation (Smith et al., 2006).
Despite the wealth of information arising from functional neuroimaging studies in attempting to understand the cognitive and
neural underpinnings of emotional memory enhancement, corroborative lesion studies are scant and have mostly focused on
patients with focal amygdala or hippocampal lesions (Adolphs
et al., 1997, 2005; Phelps et al., 1997). Apart from Alzheimer’s
disease, the effects of progressive neurodegenerative conditions
on the brain structures associated with emotional enhancement
of memory have received relatively little attention. This lack of
research is somewhat surprising in light of the disturbance in
both general emotion processing abilities and of memory performance, observed in dementia syndromes.
The predominant clinical feature of Alzheimer’s disease is an
impairment of episodic memory, which is attributable to pathological processes taking place in the medial temporal lobes, notably the hippocampus (Scheltens et al., 1992; McKhann et al.,
2011). Relevant to this study is the fact that aspects of emotion
processing remain relatively intact in Alzheimer’s disease (Lavenu
et al., 1999), despite severe deficits in the retrieval of emotional
aspects of personally relevant autobiographical memories
(Irish et al., 2011a). Nevertheless, investigations of emotional enhancement of memory in Alzheimer’s disease have produced
mixed results, with intact emotional enhancement of memory
reported in some studies (Ikeda et al., 1998; Kazui et al., 2000),
but not others (Kensinger et al., 2002, 2004). The variability in
findings may be due in part to patients performing at floor on
F. Kumfor et al.
Role of the OFC in emotional memory
Design and materials
Stimuli were selected from the International Affective Picture System
(Lang et al., 1997) and were supplemented with images from the
Geneva Affective Picture Database (Dan-Glauser and Scherer, 2011),
as the International Affective Picture System has a limited number of
neutrally rated images. Two sets of stimuli (A and B) were created,
each comprising 40 negative and 40 neutral images. Sets were
matched for valence and arousal according to normative ratings
(Supplementary Table 1). Negative items were selected to be low in
valence and high in arousal, whereas neutral items were selected to be
mid-range in valence and low in arousal. Positive stimuli were not
included because more robust enhancement effects are seen for negative than for positive stimuli (Dewhurst and Parry, 2000; Ochsner,
2000; Kensinger, 2009). Sets A and B were counterbalanced across
participants so that for half the participants, Set A were target items
and Set B were foils, and for the other half this was reversed. All
stimuli were presented electronically on a 15-inch colour computer
screen using E-Prime 2.0 software (Psychology Software Tools).
Practice phase
Participants viewed three images presented one at a time on the computer screen for 1 s. After each image, participants were asked: ‘Is this
bigger than a shoebox?’ This perceptual question was included to
ensure that participants were attending to the stimuli and to encourage incidental encoding. Participants registered their response by clicking the ‘Yes’ or ‘No’ button on the screen using a mouse or, for those
unfamiliar with the use of a mouse, verbally or by pointing to the
selected option on the screen. Participants received feedback on
their responses and an additional check was included to ensure understanding of task demands. Participants who did not understand the
task requirements were not included in the study.
Study phase
Participants viewed images in pseudorandom order so that no more
than two images of the same valence were presented in succession.
Four buffer stimuli (two negative and two neutral) were included at
the beginning and end of the study phase to reduce primacy and
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recency effects. As described in the practice phase, participants were
asked ‘Is this bigger than a shoebox?’ and their responses were recorded. During the study phase no feedback on their response was
provided. The ‘Yes’ and ‘No’ buttons occasionally switched sides, to
reduce the potential for participants’ to habitually respond ‘yes’ or ‘no’
(Fig. 1).
Recognition phase
After a 1-h delay, during which participants were assessed on unrelated neuropsychological tasks, participants completed an incidental
yes/no recognition memory task. Participants were asked, ‘Have you
seen this picture before?’ The procedure to respond was the same as
during the study phase. Again, the ‘Yes’ and ‘No’ buttons occasionally
switched sides. Participants were encouraged to respond as quickly as
possible, however, accuracy was emphasized over speed. Images were
presented in pseudorandom order so that no more than six targets or
foils were presented in succession. Three practice images were shown
to familiarize participants with the recognition procedure (Fig. 1).
Ratings phase
Immediately after completing the recognition phase, participants rated
all items for valence using the Self-Assessment Manikin (Lang et al.,
1997). Participants were asked ‘How does this picture make you feel?’
and responded by selecting from five cartoon pictures depicting a
manikin whose expression ranges from sad to happy. A subset of
participants also rated all items for arousal using the Self-Assessment
Manikin. For the arousal ratings, five similar cartoon pictures were
shown, which varied from calm/relaxed to excited/agitated, for participants to select from. Three practice ratings familiarized participants
with the procedure. Time to respond was unlimited, and the image
remained on the screen until the response was recorded (Fig. 1).
Participants’ valence ratings of the stimuli according to diagnosis are
provided in Supplementary Table 2.
Image acquisition
Participants underwent whole brain structural MRI with a 3 T Phillips
MRI scanner. High resolution coronal plane T1-images were obtained
using the following protocol: 256 256, 200 slices, 1 mm2 in-plane
resolution, 1 mm slice thickness, echo time/repetition time = 2.6/
5.8 ms, flip angle = 19 . Brain scans were available for 38 patients
(nine behavioural variant FTD, 10 semantic dementia, nine PNFA
and 10 Alzheimer’s disease) and 10 healthy control subjects. Five participants (one behavioural variant FTD, three semantic dementia, one
control) could not be scanned due to MRI contraindications and MRI
data for six participants (one behavioural variant FTD, one PNFA, four
controls) were not available because of technical difficulties. No significant differences in age [F(1,57) = 1.009, P 4 0.05], sex (2 = 2.118,
P 4 0.05) or level of education [F(1,57) = 0.745, P 4 0.05] were present between participants included in the scanned group and those
whose scans were unavailable.
Data preprocessing
FSL voxel-based-morphometry, part of the FMRIB software library
package (http://www.fmrib.ox.ac.uk/fsl/fslvbm/index.html; Smith
et al., 2004) was used to analyse the MRI data (Ashburner and
Friston 2000; Mechelli et al., 2005; Woolrich et al., 2009).
Structural images were brain-extracted using BET, then tissue segmentation was conducted with automatic segmentation (FAST) (Zhang
et al., 2001). Grey matter partial volume maps were aligned to
Montreal Neurological Institute standard space (MNI152) using nonlinear registration (FNIRT) (Andersson et al., 2007a, b), which uses a
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Rascovsky et al., 2011). In addition, 15 age- and education-matched
healthy control participants were recruited from local community
clubs. Controls scored 488/100 on the Addenbrooke’s Cognitive
Examination–Revised (Mioshi et al., 2006) and 0 on the Clinical
Dementia Rating Scale.
All participants underwent a comprehensive neuropsychological
assessment and structural MRI. The cognitive assessment included a
measure of general cognitive ability, (Addenbrooke’s Cognitive
Examination–Revised) (Mioshi et al., 2006), and tasks of attention
(Digit Span Forwards, maximum span) (Wechsler, 1997), working
memory (Digit Span Backwards, maximum span) (Wechsler, 1997),
visual recall memory (Rey Complex Figure) (Meyers and Meyers,
1995), confrontation naming (Savage et al., 2013), and letter fluency
(Controlled Oral Word Association Test; Spreen and Strauss, 1998).
Exclusion criteria for control subjects and patients included concurrent
psychiatric disturbance or neurological disorder, history of substance
abuse, and/or use of medications with CNS effects.
Participants or their person responsible provided informed consent
for participation in the study in accordance with the Declaration of
Helsinki. The Southeastern Sydney and Illawarra Area Health Service
and the University of New South Wales’ ethics committees approved
the study. Participants volunteered their time and were reimbursed for
any travel costs incurred.
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b-spline representation of the registration warp field (Rueckert et al.,
1999). A study-specific template was created and the native grey
matter images were non-linearly re-registered. Modulation of the
registered partial volume maps was carried out by dividing them by
F. Kumfor et al.
the Jacobian of the warp field, and the modulated, segmented images
were smoothed with an isotropic Gaussian kernel with a sigma of
3 mm.
Behavioural analyses
Voxel-based morphometry analyses
Figure 1 Experimental design and procedure. Black squares
represent negative images. Grey squares represent neutral
images. An example screen view is shown for each phase of the
experiment. T = target; F = foil. During encoding, participants
viewed images one at a time, and were asked whether the main
object in the picture was bigger than a shoebox. During recognition, participants were asked whether they had seen the
picture before. During the ratings phase, participants rated each
picture for valence and arousal using the Self-Assessment
Mannikin (SAM).
A voxel-wise general linear model was applied to investigate grey
matter intensity differences, using permutation-based, non-parametric
statistics, with 5000 permutations per contrast (Nichols and Holmes,
2002). Differences in grey matter intensities between patients (behavioural variant FTD, semantic dementia, PNFA and Alzheimer’s disease)
and controls were assessed using t-tests.
Next, correlations between recognition performance and grey
matter intensity were conducted. True recognition scores for emotional
and neutral items were entered simultaneously into the design matrix.
Contrasts investigated correlations averaged across Emotional and
Neutral items (1,1) and correlations for Emotional memory performance, taking into account Neutral memory performance (1,0). Age was
included as a nuisance variable for all contrasts. Correlations between
recognition performance and grey matter intensity were investigated
combining all participants (behavioural variant FTD, semantic dementia, PNFA, Alzheimer’s disease, controls). Then, correlations for overall
memory and emotional memory were investigated using the same
analyses described above, in each patient group combined with controls, to identify neural correlates of emotional memory specific to
each patient group. This approach has been shown to achieve greater
variance in scores, increasing the statistical power to detect behavioural correlations (Sollberger et al., 2009; Irish et al., 2012). Finally,
region of interest analyses were conducted to examine associations
between the amygdala and emotional memory performance. A
region of interest mask was created for the right and left amygdala
using the Harvard-Oxford subcortical atlas. For all analyses, the statistical threshold was set at P 5 0.005 uncorrected for multiple comparisons. In addition, a conservative cluster extent threshold of 100
voxels was used to reduce the likelihood of false positives.
Anatomical locations of significant results were overlaid on the
Montreal Neurological Institute (MNI) standard brain, with maximum
coordinates provided in MNI stereotaxic space. Anatomical labels were
determined with reference to the Harvard-Oxford probabilistic cortical
and subcortical atlases.
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Data were analysed using SPSS 20.0 (SPSS Inc.). All variables were
checked for normality of distribution using the Kolmogorov-Smirnov
tests. Clinical and demographic variables were analysed using univariate ANOVA, with post hoc analyses comparing differences across
groups, using Sidak correction for multiple comparisons. Analyses
investigating the effect of emotion on memory were conducted
using each participant’s subjective valence ratings. Items subjectively
rated as emotional were compared with items rated as neutral. This
approach was taken to ensure that the lack of emotional enhancement
was not due to patients failing to perceive stimuli as emotional. True
recognition rate (i.e. number correct responses; ‘yes’ to studied items/
total number of studied items) and false recognition rate (i.e. number
incorrect responses; ‘yes’ to novel items/total number of novel items)
for emotional and non-emotional images were log transformed to
normalize. Separate repeated-measures ANOVAs with Sidak post hoc
tests were conducted for true and false recognition scores to investigate main effects of diagnosis (behavioural variant FTD, semantic dementia, PNFA, controls) and condition (emotional, neutral), as well as
interactions.
Role of the OFC in emotional memory
Brain 2013: Page 5 of 12
Results
Demographics and clinical
characteristics
True recognition
P = 0.047], revealing that the effect of emotion on true recognition differed across diagnostic groups. Within group comparisons
indicated that this condition diagnosis interaction was driven by
the significantly greater recognition of emotional compared with
neutral images in control subjects (P = 0.037), and patients with
Alzheimer’s disease (P 5 0.001). In contrast, no difference in true
recognition between emotional and neutral items was seen in the
behavioural variant FTD, semantic dementia or PNFA groups (all
P-values 4 0.05). Overall level of recognition did not differ across
groups (all P-values 4 0.05) (Fig. 2).
To check that differences in emotional enhancement of memory
were not confounded by impaired coding of stimuli as emotional
or neutral, the same analyses described above were repeated using
each item’s objective rating (International Affective Picture System
and Geneva Affective Picture Database normative ratings). For
these analyses, a main effect of condition was present, indicating
Figure 2 Proportion of true recognition for the control, be-
A significant main effect of condition emerged [F(1,54) = 10.990,
P = 0.002], indicating that true recognition was higher for emotional than neutral images. No main effect of diagnosis was
present [F(4,54) = 0.887, P = 0.478]. A significant interaction between condition and diagnosis was observed [F(4,54) = 2.589,
havioural variant FTD (bvFTD), semantic dementia (SD), PNFA
and Alzheimer’s disease (AD) groups on emotional and neutral
items based on subjective ratings. Error bars represent standard
error of the mean. Significant within group differences are
indicated *P 5 0.05; **P 5 0.01.
Table 1 Demographics and neuropsychological test performance for the study cohorts
bvFTD n = 11
M/F
Age, years
Education, years
Duration, months
ACE-R (100)
Digits-F (8)c
Digits-B (8)c
RCF delay (36)b
Naming (30)c
Fluencyb,c,d
8/3
66.7 9.8
11.2 2.2
73.5 41.9
77.7 13.3
5.5 0.8
3.7 1.1
9.8 6.8
22.1 3.8
20.6 14.2
SD n = 13
10/3
63.9 4.5
12.7 3.2
66.2 23.9
67.3 17.7
7.5 2.6
5.4 1.7
15.7 4.7
8.5 5.3
28.0 10.9
PNFA n = 10
4/6
67.4 9.9
13.5 3.3
41.9 18.1
78.8 10.7
4.5 1.2
3.1 1.2
17.0 6.0
22.0 6.8
17.0 13.2
AD n = 10
8/2
67.5 7.8
11.5 2.6
64.8 31.8
70.7 21.5
6.4 1.1
4.4 1.5
4.9 6.8
21.0 5.8
34.8 16.7
Control n = 15
8/7
69.5 6.1
13.9 3.5
–
94.8 3.9
7.4 1.1
5.6 1.2
17.7 5.5
25.9 2.5
50.7 13.4
Post hoc
F
ns
ns
ns
ns
*
*
*
*
*
*
a
bvFTD, SD, AD 5 Controls
bvFTD, PNFA 5 SD, Controls
bvFTD, PNFA, AD 5 SD, Controls
bvFTD, AD 5 SD, Controls; AD 5 SD
SD 5 bvFTD, PNFA, AD, Controls
bvFTD, SD, PNFA 5 Controls
Scores are means standard deviation. Maximum scores where applicable are provided next to each test name. Sidak correction used for post hoc multiple comparisons.
*P 5 0.05; ns P 4 0.05. bvFTD = behavioural-variant FTD; SD = semantic dementia; AD = Alzheimer’s disease.
ACE-R = Addenbrooke’s Cognitive Examination-Revised; RCF = Rey Complex Figure.
a
Chi-square value.
b
Scores missing for one patient with Alzheimer’s disease on Rey Complex Figure and Fluency tests.
c
Scores on the Addenbrooke’s Cognitive Examination-Revised, Digit Span, and Fluency, removed for one participant with PNFA because of significant expressive language
deficit.
d
Scores missing for two additional PNFA participants on Fluency test.
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Groups were well matched for age, education and sex (all
P-values 4 0.05). On the general cognitive screening measure,
the Addenbrooke’s Cognitive Examination–Revised, a significant
effect of diagnosis was present [F(4,53) = 7.64, P 5 0.001], with
behavioural variant FTD, semantic dementia and Alzheimer’s disease performing worse than control subjects (behavioural variant
FTD: P = 0.039; semantic dementia: P 5 0.001; Alzheimer’s disease: P = 0.001). Neuropsychological testing revealed deficits characteristic of each patient group (Table 1). Compared with controls,
behavioural variant FTD showed impaired attention (Digits
Forwards: P = 0.039), working memory (Digits Backwards:
P = 0.004), visual memory (Rey complex figure: P = 0.016), and
letter fluency (P 5 0.001), indicative of attention deficits and
executive dysfunction. Patients with semantic dementia were
impaired on confrontation naming (P 5 0.001), and verbal fluency
(P = 0.001), reflecting their semantic deficits. In contrast, PNFA
displayed reduced verbal output on verbal measures of attention
(Digits Forwards: P = 0.001), working memory (Digits Backwards:
P 5 0.001) and fluency (P 5 0.001). Finally, Alzheimer’s disease
showed reduced verbal working memory (Digits Backwards:
P = 0.008) and visual episodic memory (Rey Complex Figure:
P 5 0.001) (Table 1).
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F. Kumfor et al.
that true recognition was higher for emotional than non-emotional
items, although this effect was weak, with no within-group
differences observed. Importantly, the FTD groups showed no
differences in true recognition of emotional or neutral items
when analyses were conducted based on either subjective or objective ratings, indicating that abnormal emotional enhancement in
these groups was not solely due to an inability to perceive the
stimuli as emotional. Behavioural scores and complete analyses
based on objective ratings are provided in Supplementary Table 3.
False recognition
Voxel-based morphometry
Patterns of atrophy
Voxel-based morphometry analyses revealed a pattern of grey
matter atrophy typical of each patient group (Supplementary
Fig. 1). Briefly, patients with behavioural variant FTD showed
characteristic widespread grey matter intensity decrease involving
frontal (orbitofrontal cortex, frontal pole, lateral frontal cortices,
paracingulate gyrus), temporal and medial temporal regions (inferior temporal gyrus, temporal pole, parahippocampal gyrus, hippocampus, and amygdala) bilaterally. In contrast, patients with
semantic dementia showed bilateral grey matter intensity decrease
Figure 3 Proportion of false recognition for the control, behavioural variant FTD (bvFTD), semantic dementia (SD), PNFA
and Alzheimer’s disease (AD) groups on emotional and neutral
items based on subjective ratings. Error bars represent standard
error of the mean. Significant within group differences are
indicated *P 5 0.05; **P 5 0.01.
in the lateral temporal cortices and temporal poles, including the
hippocampus and amygdala, with more severe atrophy seen on
the left compared with the right hemisphere. Patients with PNFA
showed grey matter intensity decrease predominantly in left frontotemporal regions including the frontal operculum cortex, inferior,
middle and superior frontal gyrus, insula and putamen. Finally, in
Alzheimer’s disease widespread regions of grey matter intensity
decrease were evident in lateral and medial temporal regions
(hippocampus, parahippocampal gyrus), frontal, parietal, and
occipital cortices. These patterns of atrophy are consistent with
those reported previously in the literature for the FTD (Rosen
et al., 2002a; Nestor et al., 2003; Mion et al., 2010) and
Alzheimer’s disease cohorts (Dickerson et al., 2001)
(Supplementary Fig. 1).
Neural correlates of emotional enhancement of memory
Investigation of correlations between behavioural performance on
the recognition memory task and grey matter intensity revealed
that overall memory performance (averaged across emotional and
neutral items) for all participants combined (behavioural variant
FTD, semantic dementia, PNFA, Alzheimer’s disease and control
subjects) was associated with a broad network of regions (Fig. 4
and Table 2). The brain regions implicated included the left hippocampus and parahippocampal gyrus, together with posterior
regions including the lateral occipital cortex bilaterally, the precuneus and posterior cingulate, and regions in the right middle and
superior temporal gyrus and planum polare.
In contrast, emotional memory performance (accounting for
memory for neutral items) was associated with a set of brain
regions that were distinct from those identified in the overall
memory performance contrast. Emotional memory performance
was associated with grey matter intensity of the right orbitofrontal
and subcallosal cortex, together with the right middle and inferior
frontal gyri, revealing that integrity of these frontal regions is critical for the emotional enhancement of memory effect. The region
of interest analyses specific to the amygdala revealed only two
clusters (two and seven voxels in size) that were associated with
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A significant main effect of condition was present
[F(1,54) = 5.167, P = 0.027], indicating that incorrect endorsement
of novel items was higher for emotional than neutral images. A
main effect of diagnosis also emerged [F(4,54) = 2.814,
P = 0.034], demonstrating that overall level of false recognition
differed across diagnostic groups. The interaction between condition and diagnosis on false recognition was not significant
[F(4,54) = 2.219, P = 0.079]. Post hoc between-group analyses revealed that the effect of diagnosis was driven by increased false
recognition in the behavioural variant FTD and Alzheimer’s disease
groups. For emotional items, only the Alzheimer’s disease group
showed increased false recognition compared with controls
(P = 0.029), whereas behavioural variant FTD, semantic dementia
and PNFA groups did not statistically differ from controls
(all P-values 4 0.05) (Fig. 3). In contrast, for neutral items, only
the behavioural variant FTD group showed increased false recognition compared to controls (behavioural variant FTD: P = 0.018;
semantic dementia, PNFA, Alzheimer’s disease: P 4 0.05). Withingroup post hoc comparisons indicated that false recognition was
significantly more frequent for emotional than neutral novel items
in Alzheimer’s disease (P = 0.012), but not in the other groups
(all P-values 4 0.05) (Fig. 3).
Together these results indicate that the effect of emotion on
memory differs across dementia subtypes. For true recognition,
the enhancing effect of emotion was seen in control and
Alzheimer’s disease groups only, with no significant enhancing
effect of emotion on memory in any of the FTD subtypes. For
false recognition, emotion also tended to increase errors in the
Alzheimer’s disease group. Whereas patients with behavioural
variant FTD showed elevated levels of false recognition compared
to controls for neutral items, the presence of emotion was not
found to influence their false recognition rates.
Role of the OFC in emotional memory
Brain 2013: Page 7 of 12
| 7
Figure 4 Voxel-based morphometry analyses showing brain regions, which correlated with memory for emotional items (red), and
memory averaged across emotional and neutral items (green) in all participants combined. Coloured voxels show regions that were
significant in the analyses at P 5 0.005 uncorrected for multiple comparisons. Age included as a covariate in all voxel-based morphometry
analyses. All clusters reported t 4 2.72. Clusters are overlaid on the standard MNI brain.
Regions
Hemisphere
Overall true recognition
Lateral occipital cortex, superior division extending into occipital pole
Middle temporal gyrus, posterior division extending into superior temporal
gyrus, posterior division
Planum polare extending into superior temporal gyrus anterior division
Lateral occipital cortex, inferior division extending into superior division
Cerebellum
Postcentral gyrus
Precuneus, extending into lateral occipital cortex, superior division
Posterior cingulate
Occipital pole
Lateral occipital cortex, superior division
Parahippocampal cortex, posterior division extending into hippocampus
Postcentral gyrus
Emotional true recognition
Orbitofrontal cortex, extending into subcallosal cortex
Frontal operculum cortex, extending into inferior frontal gyrus
Middle frontal gyrus
MNI Coordinates
Number
of Voxels
x
y
z
Left
Right
32
56
88
34
12
4
611
589
Right
Right
Left
Right
Left
Left
Right
Right
Left
Left
58
56
42
38
12
10
14
30
14
54
0
66
84
26
58
28
90
78
26
16
2
10
32
56
34
38
28
16
22
42
345
303
300
275
249
232
211
145
128
122
Right
Right
Right
10
38
26
24
20
30
26
10
28
633
516
130
Age included as a nuisance variable in all contrasts. Clusters significant at P 5 0.005 uncorrected for multiple comparisons. Only clusters 4100 contiguous voxels reported.
All clusters t 4 2.72.
emotional memory performance. No clusters in the amygdala were
associated with overall memory performance.
Additional voxel-based morphometry analyses to investigate the
brain correlates of memory and emotional memory performance
separately in each patient group combined with controls yielded
similar patterns of findings. Briefly, in behavioural variant FTD, the
left hippocampus and parahippocampal gyrus, left lateral occipital
cortex, as well as the right frontal pole and middle frontal gyrus,
were associated with overall memory performance. In addition,
the right amygdala and orbitofrontal cortex were associated with
memory for emotional items (Fig.5 and Supplementary Table 4). In
semantic dementia, overall memory was associated with the right
frontal medial and lateral temporal cortices, the inferior temporal
cortex bilaterally, as well as a small region surrounding the left
central sulcus. Emotional memory was associated with the right
orbitofrontal cortex and frontal pole, as well as regions in the right
posterior temporal cortex (Fig. 5 and Supplementary Table 5). In
PNFA, overall memory was associated with frontotemporal regions
bilaterally, but more so on the left. Emotional memory performance was associated with clusters in the left lingual gyrus, the right
inferior frontal and left middle frontal gyri, as well as regions in the
precuneus and posterior cingulate (Fig. 5 and Supplementary
Table 6). Finally, in Alzheimer’s disease, overall memory was associated with the right hippocampus, bilateral frontal cortex, and left
medial and lateral parieto-temporal cortices. Emotional memory
was associated with similar regions as overall memory but also
included the orbitofrontal cortex, extending into the right amygdala (Fig. 5 and Supplementary Table 7).
Downloaded from http://brain.oxfordjournals.org/ at University of New South Wales on July 9, 2013
Table 2 Voxel-based morphometry analyses showing significant correlations between grey matter intensity and True
Recognition for all participant groups (behavioural variant FTD, semantic dementia, PNFA, Alzheimer’s disease and controls)
8
| Brain 2013: Page 8 of 12
F. Kumfor et al.
controls. Alzheimer’s disease (blue), behavioural variant FTD (green), semantic dementia (yellow) and PNFA (red) at MNI coordinates:
x = 2, y = 15, z = 24. Coloured voxels show regions that were significant in the analyses at P 5 0.005 uncorrected for multiple comparisons. Age included as a covariate in all voxel-based morphometry analyses. All clusters reported t 4 2.72. Clusters are overlaid on the
standard MNI brain. A = anterior; L = left; P = posterior; R = right.
Discussion
This study is the first to investigate the interplay between emotion
and memory, and the underlying neural substrates in Alzheimer’s
disease and FTD. A robust emotional enhancement of memory
effect was observed in Alzheimer’s disease for true recognition,
similar to that seen in healthy control subjects, accompanied by
an increased false recognition for emotional items. In contrast, an
absence of the emotional enhancement effect was revealed in all
FTD subtypes. The dissociable effects of emotion on memory in
Alzheimer’s disease and FTD is in keeping with the divergent patterns of neurodegeneration seen in these dementia syndromes.
Importantly, voxel-based morphometry analyses confirmed that
regardless of group membership, overall memory performance
was associated with a distinct set of brain regions that included
the left hippocampus, posterior cingulate, precuneus, right superior and middle temporal gyri and postcentral gyrus, regions classically associated with successful episodic memory performance
(reviewed by Dickerson and Eichenbaum, 2010; Ranganath and
Ritchey, 2012). Importantly, atrophy in these brain regions has
recently been shown to differentially contribute to episodic
memory disturbances in both Alzheimer’s disease and behavioural
variant FTD (Irish et al., 2013). In contrast, emotional enhancement was associated with a separate set of frontal lobe structures,
which included the right orbitofrontal and subcallosal cortex, the
right frontal operculum cortex and the inferior and middle frontal
gyri, with the largest cluster present in the right orbitofrontal
cortex. These results provide strong evidence for the specialization
of distinct frontal and temporal lobe regions for overall memory
and emotional enhancement of memory. Our findings are further
corroborated by the dissociation in behavioural performance
observed in Alzheimer’s disease and FTD groups, with emotional
enhancement of memory attenuated in FTD but not Alzheimer’s
disease. Here, we discuss how our neuroimaging and behavioural
findings inform our understanding of the mechanisms by which
emotion facilitates subsequent memory.
Neural correlates supporting memory
and emotional enhancement
The hippocampus undoubtedly plays a crucial role during encoding
and consolidation of episodic memory (Squire, 2004; Moscovitch
et al., 2006). Extra-hippocampal structures, however, also contribute to successful retrieval of information (Buckner et al., 2008;
Ranganath and Ritchey, 2012). In this study, the precuneus and
posterior cingulate, as well as occipital regions necessary for visual
processing, were associated with true recognition, irrespective of
emotional content. These posterior regions are activated during
visual inspection of emotional and neutral scenes in healthy
adults, with the degree of activation varying according to emotional content (i.e. increased activation for emotional than neutral
stimuli) (Sabatinelli et al., 2007). By combining across emotional
and neutral stimuli in order to determine common brain regions
involved in memory, we confirmed the importance of the hippocampus, together with posterior regions, in processing and
remembering visual stimuli, irrespective of emotional content.
In contrast with overall memory, memory for emotional stimuli
involved different brain regions and was associated with the orbitofrontal cortex predominantly. The orbitofrontal cortex shares
strong bidirectional connections with the hippocampus and amygdala (Cavada et al., 2000; Ranganath et al., 2005; Stein et al.,
2007) but it does not appear to be critically involved in declarative
memory per se. Rather, the orbitofrontal cortex is thought to play
a specialized role in the processing of unexpected or unpleasant
Downloaded from http://brain.oxfordjournals.org/ at University of New South Wales on July 9, 2013
Figure 5 Voxel-based morphometry analyses showing regions correlated with emotional memory in each patient group combined with
Role of the OFC in emotional memory
Dissociable effects of emotion on
memory across dementia syndromes
Our neuroimaging results reflected the differential effects of emotion on memory in Alzheimer’s disease and FTD, with emotion
modulating memory in Alzheimer’s disease but not FTD.
Equivocal results of emotional enhancement of memory in
Alzheimer’s disease have been reported previously (Ikeda et al.,
1998; Mori et al., 1999; Kensinger et al., 2004). Disease severity
and methods of investigation (i.e. recollection versus recognition;
reviewed by Klein-Koerkamp et al., 2012) likely account for discrepancies across studies. In this study, we used a recognition
paradigm to elucidate mechanisms of emotional enhancement.
In a group of patients with relatively mild Alzheimer’s disease
we revealed that emotional content produces a striking increase
in item endorsement, irrespective of the accuracy of those responses. In other words, patients with Alzheimer’s disease
showed an increased tendency to ‘recognize’ emotional items,
whether they had seen them previously or not. This pattern of
results suggests a reliance on gist rather than detail processing in
Alzheimer’s disease with a more liberal response bias evident for
emotional than neutral items, leading to a trade-off in memory
performance (Gallo et al., 2006). Depending on how memory is
tested, gist processing may give rise to emotional enhancement
(e.g. during free recall or semi-structured interviews), although this
effect may be negated when response bias is taken into account.
This finding is consistent with the view that emotion tends to
boost the likelihood of endorsing an item, without necessarily improving overall accuracy (Sharot et al., 2004). In the current context, we have demonstrated that despite their memory deficits and
associated hippocampal damage, emotion exerts a significant
effect on memory performance in Alzheimer’s disease. The finding
of an appreciable benefit to memory performance in patients with
well documented medial temporal lobe atrophy is noteworthy, and
suggests that at an early stage in the disease course, patients with
Alzheimer’s disease can harness emotional aspects of stimuli to
facilitate subsequent retrieval.
By contrast no significant effect of emotion on subsequent
memory recognition was evident in FTD, irrespective of subtype.
It is unlikely that the attenuation of emotional enhancement of
| 9
memory in these patients is due to a failure to appreciate the
emotional content of the stimulus, as items were classified as emotional or neutral based on individuals’ subjective ratings, and analyses based on objective ratings showed a similar absence of
emotional enhancement in the FTD groups. Rather, the results
indicate that despite patients with FTD rating the stimuli as emotional, this appraisal had no influence on memory. One explanation for this apparent contradiction is the decoupling between
patients’ cognitive appraisal and the emotional experience of a
stimulus in patients with FTD. Whereas these patients may
retain the capacity to appropriately rate the emotional content
of a stimulus in a cognitive manner (e.g. a snake is negative),
the associated increase in physiological arousal in response to
emotional stimuli may be disturbed. Indeed, physiological responding to a highly aversive noise is reportedly abnormal in FTD, and
this is associated with orbitofrontal, anterior cingulate, amygdala
and insula atrophy (Hoefer et al., 2008; Sturm et al., 2013). A
similar discrepancy is observed in healthy adult participants who
rate the emotionality of a story appropriately, yet fail to show any
appreciable emotional enhancement of memory, following betablocker administration (reducing physiological arousal) (Cahill
et al., 1994). Further, evidence from the autobiographical
memory literature, suggests that the emotional intensity of an
event robustly predicts subsequent retrieval and the subjective
recollective experience (Talarico et al., 2004; Irish et al., 2011b).
Our results suggest that emotional enhancement of memory is
dependent on changes in physiological arousal in FTD, although
this will require confirmation. Crucially, our findings support the
proposal that the identification of emotional valence alone is not
sufficient to produce an emotional enhancement of memory effect
(McGaugh, 2004; Van Stegeren, 2008).
The neuroimaging results revealed divergent neural contributions to the emotional enhancement of memory in FTD and
Alzheimer’s disease groups, confirming the dissociable effects
seen behaviourally. In behavioural variant FTD and semantic dementia, emotional enhancement of memory was associated with
the orbitofrontal cortex, and in PNFA emotional memory was
associated with the right inferior frontal cortex. Despite their divergent patterns of atrophy, all three FTD subtypes show a degree
of orbitofrontal and inferior frontal atrophy (Seeley, et al., 2008;
Rohrer et al., 2009) (Supplementary Fig. 2). These frontal regions
associated with emotional memory performance are distinct from
those associated with overall memory performance in these patient groups, suggesting that attenuation of emotional enhancement of memory is attributable to degradation of frontal lobe
regions necessary for processing emotional stimuli. In contrast, a
discrete set of regions including the hippocampus, posterior cingulate cortex, precuneus, frontal pole and lateral occipital cortex
correlated with both overall memory and emotional memory performance in Alzheimer’s disease. This overlap of regions in the
classic episodic memory network, irrespective of emotional content, indicates that disruption to episodic memory, rather than
emotional processing deficits, contributes solely to Alzheimer’s disease participants’ performance on this type of task. Accordingly,
our behavioural and neuroimaging findings converge to suggest
that fundamentally different neurobiological mechanisms underpin
Downloaded from http://brain.oxfordjournals.org/ at University of New South Wales on July 9, 2013
stimuli (reviewed by Petrides, 2007). This region appears to influence memory via its role in evaluating information from the environment and integrating this knowledge with information from
the internal state (i.e. physiological arousal) (Petrides, 2007;
Viskontas et al., 2007). Our neuroimaging results therefore suggest that the integrity of the amygdala alone is not sufficient for
the emotional enhancement of memory effect to occur. Functional
imaging studies have indicated that increased activation of both
the amygdala and orbitofrontal cortex is present during emotional
memory tasks (e.g. Kensinger and Corkin, 2004; Kensinger and
Schacter, 2005). Our results provide corroborative lesion evidence
of the contribution of the orbitofrontal cortex to emotional enhancement of memory. Further, our findings reveal for the first
time that damage to this structure underlies the attenuation of
emotional enhancement of memory in FTD.
Brain 2013: Page 9 of 12
10
| Brain 2013: Page 10 of 12
Acknowledgements
The authors thank the participants and their families for their support of our research.
Funding
This work was supported in part by an Australian Research Council
(ARC) Discovery Grant (DP1093279) and by the ARC Centre of
Excellence in Cognition and its Disorders (CE110001021). F.K. is
supported by an Australian Postgraduate Award (APA); M.I. is
supported by an ARC Discovery Early Career Researcher Award
(DE130100463); J.R.H. is supported by an ARC Federation
Fellowship (FF0776229); O.P. is supported by a National Health
and Medical Research Council Clinical Career Development
Fellowship (APP1022684).
Supplementary material
Supplementary material is available at Brain online.
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