Neuroscience Letters 658 (2017) 108–113

Contents lists available at ScienceDirect

Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Research article

Theory of mind in multiple sclerosis: A neuropsychological and MRI study MARK

a,b a,c a,b a,c a,d
Moussa A. Chalah , Paul Kauv , Jean-Pascal Lefaucheur , Jérôme Hodel , Alain Créange ,
⁎
Samar S. Ayachea,b,e,
a
EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, Créteil, France
b
Service de Physiologie—Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, Créteil, France
c
Service de Neuroradiologie, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, Créteil, France
d
Service de Neurologie, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, Créteil, France
e
Neurology Division, Lebanese American University Medical Center Rizk Hospital, Beirut, Lebanon

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: Social cognition stands among the most frequently affected yet the least studied cognitive domains in
Multiple sclerosis multiple sclerosis (MS). Theory of mind (ToM) is a social cognitive facet that implies the one’s ability to predict
Theory of mind others’ mental states. The objective of this study was to assess the relationship between ToM and neu-
Mentalizing ropsychological and neuroimaging data.
Social cognition
Methods: Thirty-eight consecutive MS patients completed the Reading the Mind in the Eyes test (RMET). They
Magnetic resonance imaging
underwent a neuropsychological evaluation and a 3 T T1-weighted brain MRI. A fully automated volume-based
Alexithymia
morphometry algorithm (MorphoBox) was applied to calculate regional brain volumes. Correlation analysis was
performed using Spearman’s test.
Results: Among the sociodemographic and clinical data, significant correlations were found between RMET
scores and each of years of education (r = 0.54; p < 0.01) and the duration of the disease progressive phase
(r = −0.46; p < 0.01). Regarding neuropsychological measures, RMET scores were directly correlated with
information processing speed (r = 0.58; p < 0.01) and empathy (r = 0.46; p < 0.01) scores. As for brain
volumes, RMET scores were directly correlated with parietal (left: r = 0.39; right: r = 0.46; p < 0.05) and
temporal (left: r = 0.36; right: r = 0.40; p < 0.05) white matter volumes, as well as with cingulate (left:
r = 0.32; right: r = 0.44; p < 0.05) gray matter volumes.
Conclusion: These results highlight the relationship between ToM and some of the disease characteristics and
cognitive domains. Importantly, ToM performance in MS is associated with brain volumes of key areas in social
cognitive networks. Further works are needed to enhance the current knowledge on the underlying mechanisms
of ToM deficits in this population.

1. Introduction
Multiple sclerosis (MS) is a neurodegenerative and inflammatory
disease of the central nervous system (CNS) and constitutes one of the
leading causes of disability in young adults. Through its course, the
location and extent of CNS lesions would dictate the appearance of
various sensory, motor and cerebellar symptoms, but also emotional,
cognitive and behavioral ones. For instance, fatigue and psychiatric
comorbidities, could concern up to 90% and 95% of MS patients, re-
spectively [1,2]. Also, recent evidence supports the frequent occurrence
of alexithymia – a personality trait characterized by difficulties in
identifying and describing one’s own emotions – in this disease [3]. Of
great importance, cognitive deficits could occur among MS patients and
affects between 40 and 70% of this population [4–7]. In this context,
the great majority of studies have focused on assessing attention,
working memory, information processing speed (IPS), learning and
executive functions [4–7]. However, only few reports have addressed
social cognition (For reviews see [2,8,9]).
Social cognition refers to the mental operations that underlie social
interactions [8,9]. Such abilities may impact employment as well as
relationships with friends, family members and caregivers. Therefore,
they are potentially of particular importance to MS patients whose peer

Abbreviations: CNS, central nervous system; EQ, empathy quotient; ESS, Epworth sleepiness scale; GM, gray matter; HADS, hospital anxiety and depression scale; IPS, information
processing speed; MFIS, modified fatigued impact scale; MPRAGE, magnetization-prepared rapid acquisition gradient-echo; MRI, magnetic resonance imaging; MS, multiple sclerosis; PP,
primary progressive; QoL, quality of life; RMET, reading the mind in the eyes test; RR, relapsing remitting; SDMT, Symbol digit modalities test; SP, secondary progressive; TAS, Toronto
alexithymia scale; TIV, total intracranial volume; ToM, theory of mind; WM, white matter
⁎
Corresponding author at: Samar Ayache, Service de Physiologie—Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, 94010, Créteil, France.
E-mail address: samarayache@gmail.com (S.S. Ayache).

http://dx.doi.org/10.1016/j.neulet.2017.08.055
Received 16 July 2017; Received in revised form 17 August 2017; Accepted 23 August 2017
0304-3940/ © 2017 Elsevier B.V. All rights reserved.
M.A. Chalah et al.
support represents one of the major determinants of quality of life
(QoL) [8,9]. That is to say, social cognitive deficits may be overlooked
in MS but seem to constitute an important aspect of cognitive decline in
this population [2,8,9]. A key aspect of social cognition is the theory of
mind (ToM), also known as mentalizing, which implies the individual’s
ability to understand and predict others’ mental states based on their
emotions, feelings, thoughts and beliefs [2,8,9]. An adequate ToM
performance is critical for establishing proper social interaction and
coping with chronic and stressful conditions like MS. In particular, one
study has reported an association between social cognitive deficits and
poor psychological and social QoL in MS patients, a finding that re-
mained significant after accounting for patients’ demographic, clinical
and neuropsychological variables [10].
Therefore, it is of importance to understand the underlying me-
chanisms of ToM performance in MS. Only few MS studies have as-
sessed ToM and its relationship with the neuropsychological data (For
reviews see [2,8,9]) and even fewer works have included MRI measures
in their evaluation [11–13]. The main objective of the present study
was to examine the neural underpinnings of ToM performance in pa-
tients with MS. The secondary objective was to assess the relationship
between ToM and clinical, sociodemographic and neuropsychological
variables in this context.
2. Experimental procedures
2.1. Subjects
Thirty-eight consecutive patients were enrolled from the neurology
department of Henri Mondor Hospital, Créteil, France. Patients were
included if they (i) were between 18 and 75 years of age, (ii) had a
confirmed MS diagnosis according to 2010 revised McDonald’s criteria
[14], and (iii) had not experienced any relapse or treatment modifica-
tion in the last three months prior to inclusion. Patients were excluded
if they had (i) severe visual or motor impairments that might interfere
with testing, (ii) intellectual impairment as per mini mental status exam
score < 24 [15], (iii) other neuropsychiatric diseases, or (iv) contra-
indications to MRI. All patients underwent a full neurological exam by
experienced neurologists (SSA and AC), and the Expanded Disability
Status Scale (EDSS) scores were calculated [16]. Sociodemographic and
clinical data were collected including age, gender, education level, re-
lationship status, medications, MS subtypes, duration of the disease,
and duration of the progressive phase of illness. The latter is defined as
an objectively documented neurological dysfunction/disability which
has been steadily increasing without unequivocal recovery over a cer-
tain period of time (e.g. 1 year) [17]. To note, the progressive phase
duration was calculated for all patients and corresponds to a value of 0
in patients with relapsing remitting (RR) MS.
2.2. Ethics statement
The local ethical committee has approved the study protocol which
was performed in conformity with the declaration of Helsinki. All pa-
tients voluntarily gave their written informed consent prior to inclu-
sion.
2.3. Neuropsychological and cognitive measures
2.3.1. Theory of mind
ToM was evaluated using the French version of ‘Reading the Mind in
the Eyes test’ (RMET) [18]. The test contains 36 photos depicting only
the eyes regions of Caucasian actors (19 actors and 17 actresses). Pa-
tients were asked to observe each photograph and select among four
descriptors the best that describes the feeling or thought of the actor/
actress. Scores can range from 0 to 36 (lowest to highest mentalizing
abilities). A control task consisted of guessing the gender of actors
featured in the photos to check for possible impairments in facial
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Neuroscience Letters 658 (2017) 108–113
perception which might interfere with facial emotion recognition.
2.3.2. Empathy
The ability to understand others’ mental state -ToM- may influence
the individual’s ability to empathize with others and have a compas-
sionate response [2,8]. For this reason, empathy was considered in the
evaluation and was assessed using the French version of the 60-item
Empathy Quotient (EQ) [19]. It consists of 40 scored empathy items
and 20 filler items that do not enter the scoring. One can score 2, 1, or 0
on each item. The total EQ score can range from 0 denoting lack of
empathy to 80 designating the highest empathic ability.
2.3.3. Visuospatial attention and information processing speed
Patients were evaluated using the oral version of the Symbol Digit
Modalities Test (SDMT) which assesses the visuospatial attention and
IPS [20]. The test consists of a simple substitution task, where patients
refer to a reference key to match a sequence of geometric figures with
their corresponding numbers, as fast as possible. The test is usually
performed during 90 s and the total score represents the number of
correct answers (each correct answer gives one point).
2.3.4. Alexithymia
Considering the relationship between the individual’s ability to
understand his/her own emotions and the ability to understand others’
mental states [2], alexithymia was evaluated by means of the French
version of the 20-item Toronto Alexithymia Scale (TAS) [21]. TAS items
are rated using a 5-point Likert scale from 1 (strongly disagree) to 5
(strongly agree). Scores can range from 20 to 100. Higher scores design
worse abilities.
2.3.5. Anxiety and depression
Anxiety and depression were assessed by means of the French ver-
sion of the 14-item Hospital Anxiety and Depression Scale (HADS) [22].
It contains two subscales each consisting of 7 items that evaluates an-
xiety (HADSanxiety) and depression (HADSdepression). The score can range
between 0 (normal mood) and 21 (severe anxiety or depressive symp-
toms) on each subscale.
2.3.6. Fatigue
Fatigue was assessed using the French version of the Modified
Fatigue Impact Scale (MFIS) [23], which includes 21 items and assesses
the physical, cognitive and psychosocial dimensions of fatigue. The
score of each item can range from 0 to 4, with a total MFIS score ran-
ging from 0 (absence of fatigue) to 84 (maximal fatigue).
2.3.7. Excessive daytime sleepiness
Excessive daytime sleepiness was evaluated by means of the French
version of the 8-item Epworth Sleepiness Scale (ESS) [24]. Each item
represents a situation in which the individual might have recently
dozed and is graded from 0 (would never doze) to 3 (high chance of
dozing). Scores can range from 0 to 24, the latter indicates excessive
daytime sleepiness.
2.4. MRI protocol
2.4.1. Sequence acquisition
A T1-weighted three-dimensional magnetization-prepared rapid
acquisition gradient-echo (MPRAGE) MRI sequence was obtained for
each patient using a 3 T scanner 64-channel head coil (Magnetom
Skyra, Siemens Healthcare, Erlangen, Germany). The MPRAGE protocol
introduced by a Swiss team was adapted (the Alzheimer’s Disease
Neuroimaging Initiative; www.adni-info.org), with a 2-fold accelera-
tion, yielding 256 × 240 × 176 voxels with slightly anisotropic size
(1 × 1 × 1.2 mm3) [25].
M.A. Chalah et al. Neuroscience Letters 658 (2017) 108–113

2.4.2. Fully-automated volume-based morphometry
A brain volumetry algorithm ‘MorphoBox’ (http://brain-morpho.
epfl.ch) which combines simple and fast methods of image analysis
without hardware optimization was implemented. By splitting the
segmentation process in two steps, MorphBox enables a reduced com-
putation time compared to other available algorithms. In addition, by
assigning voxels to tissue weights (soft tissue labeling), MorphoBox
accounts to some extent for partial volume effects. The first step con-
sists of labeling the total intracranial volume (TIV) voxels in brain tissue
(gray matter (GM), cerebrospinal fluid (CSF) and whiter matter (WM))
of each patient without atlas-based prior. The second step entails seg-
menting the brain structures via a combination of tissue maps resulting
from the first step and anatomical masks derived from a single control
template by means of non-rigid registration. Regional volume estimates
are obtained by combining the tissue probability maps with the masks
resampled from the template via the transformation applied in the re-
gistration step. The GM probabilities were summed up over the tem-
plate-based parcels to compute lobe-wise GM volumes. The ventricular
volumes were obtained from CSF probabilities using the same ap-
proach. GM and WM probabilities were summed up over relevant masks
in order to compute hippocampal, basal ganglia, and cerebellar vo-
lumes. The final outcomes are regional GM and WM normalized vo-
lumes that are expressed as % of TIV. For a more detailed description of
the volumetry method (Manual construction of the template, template-
to-subject registration, bias field correction, skull stripping, brain tissue
classification) please review Schmitter et al. [25].
2.5. Statistical analyses
All statistical analyses were performed with GraphPad software
(GraphPad Prism 7, San Diego, CA). Since not all data followed normal
distribution according to the Kolmogorov-Smirnov test, Spearman rank
correlation coefficients was applied to assess the relationship between
RMET scores and clinical, sociodemographic, neuropsychological and
neuroimaging data. Data are displayed as median [1st quartile; 3rd
quartile]. P values < 0.05 were considered statistically significant.
Because of the small sample size (low statistical power), the large
number of studied variables and the exploratory nature of the study, no
corrections for multiple comparisons were applied.
3. Results
3.1. ToM, sociodemographic and clinical data
The present cohort consisted of 20 men and 18 women, with a
median age of 56.00 [45.75; 65.25] years. Their median education
duration was 15.00 [13.00; 16.00] years. Regarding their relationship
status, 23 patients were married, 2 were in a relationship, 3 were wi-
dowed, 7 were single, and 3 were divorced.
As for the disease characteristics, 18 patients had a primary pro-
gressive (PP) form, 17 had a secondary progressive (SP) form, and 3 had
a RR form. Their median EDSS score was 6.50 [5.50; 6.50]. Their
median duration of illness was 12.00 [6.00; 18.00] years. Their median
duration of the progressive phase was 7.00 [4.00; 11.00] years.
Regarding patients’ treatment, it consisted of dimethyl-fumarate
Moreover, a tendency toward significant inverse correlation was found
between RMET and EDSS scores (r = −0.32, p = 0.0508). No other
significant correlation was observed between social cognitive perfor-
mance and clinical or sociodemographic variables.
3.2. ToM and neuropsychological data
The median EQ score was 40.00 [32.00; 47.00]. The median SDMT
score was 43.00 [31.00; 53.00]; the median TAS score was 50.50
[44.75; 56.25]; the median HADSanxiety and HADSdepression scores were
5.50 [2.00; 7.00] and 6.00 [3.00; 8.00], respectively; the median MFIS
score was 49.50 [36.75; 61.00]; and the median ESS score was 4.00
[1.00; 8.25].
A direct correlation was found between RMET and EQ scores
(r = 0.46; p = 0.0039). In addition, RMET scores were directly corre-
lated with SDMT scores (r = 0.58, p = 0.0002). No correlations were
observed between RMET scores and TAS, MFIS, HADSdepression,
HADSanxiety, or ESS scores.
3.3. ToM and volume-based morphometry data
The brain volumes that were significantly correlated with ToM
scores are presented in Table 1. RMET scores were directly correlated
with parietal WM volume (left side: r = 0.39, p = 0.0156; right side:
r = 0.46, p = 0.0038), temporal WM volume (left side: r = 0.36,
p = 0.0277; right side: r = 0.40, p = 0.0122), and cingulate GM vo-
lume (left side: r = 0.32, p = 0.0498; right side: r = 0.44,
p = 0.0061).
4. Discussion
4.1. ToM, sociodemographic and clinical data
Regarding sociodemographic data, the only significant correlation
was found between RMET scores and the years of education. As for
clinical factors, RMET scores were inversely correlated with progressive
phase duration and tended to inversely correlate with EDSS scores.
To start, the relationship between education and social cognition
varies among studies with some of them supporting this association
[26] and others standing against it [12,13]. This divergence might be
related to the cohorts’ characteristics which consisted of relatively
younger patients with lower disability scores and majorly suffering
from RR forms in the studies who failed to show such a relationship
compared to those who documented positive findings. To understand
the relationship between education and ToM performance, one could
refer to the ‘cognitive reserve hypothesis’. In fact, the cognitive reserve
hypothesis might explain how similar amount of brain lesions can lead
Table 1
Normalized gray and white matter volumes in patients with multiple sclerosis. Results are
displayed as median [1st quartile; 3rd quartile]. RMET: reading the mind in the eyes test;
*: p < 0.05; **: p < 0.01.
Cerebral regions Normalized volumes Correlation coefficient (with
(%) RMET scores)

(n = 5), fingolimod (n = 3), natalizumab (n = 4), teriflunomide Left parietal white 3.23 [2.83; 3.51] 0.39*
(n = 2), glatiramer acetate (n = 1), interferon-β (n = 1), methotrexate matter
(n = 1), rituximab (n = 1), tacrolimus and mycophenolate mofetil Right parietal white 3.08 [2.75; 3.30] 0.46**
(n = 1) or no treatment (n = 19). 8 patients were also receiving fam- matter
Left temporal white 1.91 [1.71; 2.10] 0.36*
pridine treatment. matter
The median RMET score was 23.00 [20.00; 26.00]. Patients had no Right temporal white 2.08 [1.75; 2.28] 0.40*
difficulties on RMET control task. matter
A significant direct correlation was found between RMET scores and Left cingulate gray 0.54 [0.51; 0.60] 0.32*
matter
the number of years of education (r = 0.54, p = 0.0034). In addition, a
Right cingulate gray 0.54 [0.51; 0.59] 0.44**
significant inverse correlation was found between RMET scores and the matter
duration of the progressive phase of illness (r = −0.46, p = 0.0047).

110
M.A. Chalah et al.
to different degrees of cognitive deficit [27]. In other words, for the
same extent of brain damage, performance on neuropsychological tests
(i.e. ToM task) would be better in patients with higher cognitive re-
serve. The latter is known to depend on several factors, such as in-
telligence, life experiences, occupational attainment and educational
level, among others [27]. This applies to various neurological disorders,
such as dementia, traumatic brain injury, and MS. In the latter, edu-
cation has been described as ‘a proxy of cognitive reserve’ and seems to
act as a protector from cognitive decline [4,7,27].
Apart from the protective factors, other variables are known to
contribute to the various neurological deficits, and thus the cognitive
deficits encountered in MS patients. Although demyelinating lesions are
considered the hallmark of MS, it is now widely accepted that the
amount of axonal degeneration is the major governor of permanent
neurological decline [28]. The degree of axonal loss increases with the
evolution of MS, is more prominent in the later stages of the illness and
is more pronounced in progressive subtypes [28,29]. Indeed, the more
severe levels of cognitive deficits tend to happen in the progressive
phase of illness, and the decline seems to be most pronounced in pro-
gressive patients (For review see [4]). These data could explain our
current findings on the relationship between RMET scores and the
progressive phase duration. Such findings are also consistent with those
of a previous work which found an association between ToM perfor-
mance and the progression rate in MS [30].
Concerning the relationship between ToM task performance and
physical disability, although the results of this study tended to support
such a relationship, an inconstancy exists in the available literature. In
fact, cognitive status in general seems to be only loosely related to
physical disability in MS (for reviews see [4]). With regards to ToM,
some reports were in favor [30,31] and others were against such an
association [12,13]. Hence, to decide on the existence or not of a re-
lationship between ToM and physical disability, further investigations
are obviously needed.
As for the remaining variables, no significant associations were
observed which is in line with previous reports regarding age, gender or
the duration of illness [12,13].
4.2. ToM and neuropsychological data
A direct correlation was found between RMET and EQ scores. This
finding is supported by previous studies in healthy subjects and other
clinical populations, and support the idea that the individual’s ability to
understand others’ emotions would influence his/her ability to em-
pathize with them [2].
A direct correlation was found between RMET and visuospatial at-
tention and IPS according to SDMT, a finding that is consistent with the
majority of the available studies [31,32] (for reviews see [2,8,9]). In
fact, deficits in visuospatial attention and IPS are frequently reported in
MS [2]. The observed correlation suggests an interaction between social
cognition and non-social cognitive domains (e.g. attention) and merits
to be addressed in future works.
The remaining variables were not correlated with ToM perfor-
mance. To start, no correlation was found between ToM and alex-
ithymia, a personality trait of high prevalence in MS [3]. This finding
stands against what Raimo et al. recently reported [32]. A plausible
explanation for such a discrepancy lies in the difference of the cohorts
used in both works (the present and that of Raimo et al.). In fact,
compared to the present study, Raimo et al.’s cohort consisted pre-
dominantly of RR MS patients with relatively younger age, shorter
disease duration, and lower EDSS scores.
In addition, similar to studies that assessed fatigue [12,13], anxiety
and depression [12,13,31,32], the correlation between ToM and these
measures did not reach statistical significance in the present work. Al-
though MS patients are frequently fatigued, depressed or anxious [1,2],
ToM performance does not seem to be associated with this sympto-
matology.
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Neuroscience Letters 658 (2017) 108–113
In the same direction, no significant correlation was found between
RMET and ESS scores. To the best of our knowledge, this relationship
was not previously addressed in MS patients. Admitting the frequency
of sleep disorders in MS [1] and their possible impact on cognitive
functions, we thought that sleep symptoms would be related to ToM
performance, but our results were not in favor of such an association.
The lack of studies on this topic warrants further research to be able to
examine this relationship.
4.3. ToM and volume-based morphometry data
ToM puts into action a complex neural network involved in visual,
cognitive and emotional processing (For reviews see [2]). The corre-
lations between RMET scores and GM and WM volumes will be dis-
cussed in the following sections.
4.4. ToM and WM volumes
A direct relationship was found between ToM task performance and
temporal WM volumes. The available reports, including one study done
in MS, propose a major role played by many temporal lobe regions in
social cognitive performance (i.e. amygdala, entorhinal cortex, fusiform
gyrus, and superior temporal gyrus [12]). For instance, the fusiform
facial area embedded in the fusiform gyrus enables facial identity dis-
crimination and emotion recognition [2]. The temporal pole per se en-
sures the confrontation of perceived social and emotional visual in-
formation with contextual information (stored general knowledge
about the world) [2]. The amygdala plays a pivotal role in this context
and is an essential element in attentional capture by emotional stimuli
[2]. Through its links with the posterior cerebral areas of visual pro-
cessing, the temporal pole enables the decoding of emotionally relevant
stimuli and subsequently assists in emotional memory formation. Also,
it participates in emotional processing via its connections with the
prefrontal cortex [2]. In one MS study by Mike et al., ToM task per-
formance was correlated with cortical thickness of the left temporal
pole in the anterior inferior temporal gyrus and the left fusiform facial
area [11]. In our study, ToM scores were correlated with temporal WM
volumes. Interestingly, many fasciculi course in the temporal WM and
convey emotional information. For instance, the uncinate fasciculus,
located in the rostral part of the temporal lobe, connects the temporal
pole with the orbitofrontal cortex and is thought to be involved in
several emotional processes such as attributing emotional valence to
visual stimuli [33]. In this context, two of the three studies on ToM in
MS have included WM measures and found convergent results. Mike
et al. found an inverse association between ToM task performance and
regional T1 lesion volume of the uncinate fasciculus in MS patients
[11]. Similarly, Batista et al. found a correlation between ToM task
performance and abnormalities in several WM tracts including the
uncinate fasciculus [13].
Besides the temporal lobe, the role of the parietal lobe is of great
importance. By responding to visual, auditory and somatosensory sti-
muli, the parietal lobe constitutes one of the backbones of social cog-
nition [2]. Interestingly, the superior longitudinal fasciculus (sub-
component III) which passes through the parietal operculum WM is
involved in many processes including those involved in the monitoring
of facial actions [33] and was found to be implicated in ToM perfor-
mance in some clinical populations (e.g. Parkinson’s disease [34]).
Another relevant tract, the middle longitudinal fasciculus, is situated in
the WM of the caudal inferior parietal lobule and is responsible for
linking high-level paralimbic and association areas (e.g. cingulate,
parahipoccampal, inferior parietal and prefrontal areas) [33]. In line
with these data, our results support the implication of parietal WM in
ToM performance. The key role of parietal lobe in social cognition was
also demonstrated in a study by Batista et al. [12].
M.A. Chalah et al.
4.5. ToM and GM volumes
In addition to the above discussed results, a direct correlation was
found between ToM and the cingulate cortex volume which is con-
sistent with the data of Batista et al. [12]. To mention, the anterior
cingulate cortex is a part of an attentional circuit involved in regulating
cognitive and emotional processing and is involved in the autonomic
responses, conditioned emotional learning, and emotional valence at-
tribution to internal and external stimuli [2]. As for the posterior cin-
gulate cortex, it is involved in mediating the interaction between
memory-related and emotional processes via its reciprocal connections
with the medial temporal lobe memory structures (i.e. entorhinal and
parahippocampal cortices) and emotional processing areas such as the
orbital frontal and anterior cingulate cortices [35]. These facts would
provide an explanation for the implication of the cingulate cortex in
ToM performance in MS.
4.6. Study limitations
It is worth noting that the current study presents some limitations.
First, the absence of a control group does not allow drawing a formal
conclusion regarding the neuropsychological and cognitive evaluation
of the patients group. Second, the sample size is small and might not be
adequately powered to detect significant association between ToM and
many of the assessed variables. Third, the heterogeneity of clinical
presentation could make it difficult to generalize the results since the
examined cohort consisted majorly of PP and SP phenotypes. Therefore,
the reported findings might not apply to RR patients.
5. Conclusion
These data altogether suggest that, through the course of MS, ToM
deficits might emerge due to alteration of brain networks devoted to
social cognitive processing. This may occur due to the processes of (1)
demyelination and axonal loss which yield a ‘multiple disconnection
syndrome’ and (2) neurodegeneration in specific brain areas of ToM
networks. Large-scale studies are needed to replicate those findings and
enhance the current knowledge on the underlying mechanisms of ToM
deficits in MS patients. To overcome the current limitations, a multi-
disciplinary approach needs to be adapted. This could be achieved by a
thorough screening for these deficits in clinical wards. In addition,
coupling structural and functional MRI techniques could allow a better
understanding of the underlying mechanisms of ToM in this population.
Moreover, since ToM is usually assessed using static tools (e.g. RMET),
combining static and dynamic tasks (e.g. videotapes) might constitute a
better simulator of daily life events. In addition, in the absence of suf-
ficient data on the relationship between ToM and QoL in this popula-
tion, future works would benefit from including QoL questionnaires in
order to examine the potential impact of ToM deficits on MS patients’
daily life. Finally, adapting a longitudinal design would be of interest to
understand the course of ToM in MS and its relationship with clinical
and neuropsychological variables.
Conflicts of interest statement
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors. SSA de-
clares having received travel grants or compensation from Genzyme,
Biogen, Novartis and Roche. AC gave expert testimony for CSL Behring,
Novartis, received grants from Biogen, Novartis, CSL Behring, GE
Neuro, Octapharma, and gave lectures for Genzyme. The remaining
authors declare no conflict of interest.
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