Neuropsychologia 104 (2017) 31–47

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Neuropsychologia
journal homepage: www.elsevier.com/locate/neuropsychologia

Review article

Alexithymia in multiple sclerosis: A systematic review of literature MARK

a,b a,b,c,⁎
Moussa A. Chalah , Samar S. Ayache
a
EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, France
b
Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, 94010 Créteil, France
c
Lebanese American University Medical Center, Rizk hospital (LAUMC-RH), Beirut, Lebanon

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

Keywords: Background: Alexithymia is a multidimensional personality construct characterized by difficulties identifying

Multiple sclerosis and describing one’s feelings, and externally oriented thinking. Although extensively reported in psychiatric
Alexithymia patients, little attention has been paid regarding its occurrence and its pathophysiology in the context of multiple
Toronto Alexithymia Scale-20 sclerosis (MS).
Bremond-Vorst Alexithymia Questionnaire
Methods: A research was conducted according to the PRISMA guidelines aiming to identify original research
MRI
articles in English and French languages about alexithymia in MS. Computerized databases (MEDLINE, PubMed,
Imaging
Scopus) were consulted. The key terms used were the following: (‘multiple sclerosis’ OR ‘MS’) AND (‘alexithymia’
OR ‘alexithymic’ OR ‘emotion processing’ OR ‘emotion awareness’ OR ‘Toronto Alexithymia Scale’ OR ‘Bermond-
Vorst Alexithymia Questionnaire’) AND (‘imaging’ OR ‘neuroimaging’ OR ‘magnetic resonance imaging’ or
‘MRI’). References of the retrieved papers were scanned manually aiming to get additional sources.
Results: 14 papers matched the above criteria. The prevalence of alexithymia in MS ranges from 10% to 53%. It
seems to be associated with anxiety, depression, fatigue, and some social cognitive aspects. Its relationship with
clinical and classical cognitive variables was rarely assessed. Finally, only one study has addressed its patho-
physiology and has suggested an aberrant interhemispheric transfer.
Conclusion: Admitting the prevalence of alexithymia in MS and its potential negative impact on the quality of life
and interpersonal communication, screening for it is relevant for a better management. Its relationship with
clinical, emotional and cognitive confounders merits to be further evaluated. Large-scale studies, employing
neuroimaging techniques, are greatly needed in order to disentangle the neural underpinnings of this trait in MS.

1. Introduction
Multiple sclerosis (MS) is a chronic inflammatory and neurodegen-
erative disease of the central nervous system (CNS) that usually appears
between 20 and 40 years of age. From a pathophysiological perspective,
the disease is characterized by demyelination and axonal loss.
Depending on the location and extent of lesions, patients would ex-
perience various symptoms such as motor weakness, sensory deficit,
impaired balance, and urinary disturbance. Recent years have seen a
growing interest in studying the emotional and cognitive deficits in MS
population (Pelletier et al., 2000).
In fact, psychiatric comorbidities can affect up to 95% of MS pa-
tients at some point during their life time (Chalah and Ayache, 2017a).
As for cognitive decline, it would occur in up to 65% of patients (Rao
et al., 1991a, 1991b; Benedict et al., 2006; Sanfilipo et al., 2006; Chalah
and Ayache, 2017b). Whereas most of the studies have investigated the
domains of working memory, information processing speed, attention,
learning and executive function (Rao et al., 1991a, 1991b; Mohr and
Cox, 2001; Ayache et al., 2015; Van Schependom et al., 2015), only a
little attention has been paid to social cognition (Chalah and Ayache,
2017b). The latter is an umbrella term that entails the individual’s
ability to recognize emotional facial expressions (EFE), to perceive and
understand others’ thoughts and emotions (which is known as menta-
lizing or theory of mind [ToM]), and subsequently to have a compas-
sionate response which characterizes empathy (Chalah and Ayache,
2017b). Of equal importance to the individuals’ capacity to process
other’s emotions, is their ability to perceive and comprehend their
proper emotions, the alteration of which is referred to as ‘alexithymia’.
The integrity of these cognitive and affective functions is crucial for
an appropriate social interaction (Cacioppo and Decety, 2011; Chalah
and Ayache, 2017b), and is particularly important to cope with chronic
disabling diseases such as MS. Therefore, difficulties in understanding
one’s (alexithymia) and others’ emotions (social cognitive deficits) may
have drastic impact on interpersonal communication (Bird and Cook,
2013; Chalah and Ayache, 2017b). This might contribute to the fact
that MS patients frequently report altered social interaction, high rates

⁎
Corresponding author at: EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, France.
E-mail address: samarayache@gmail.com (S.S. Ayache).

http://dx.doi.org/10.1016/j.neuropsychologia.2017.07.034
Received 13 April 2017; Received in revised form 28 July 2017; Accepted 29 July 2017
Available online 29 July 2017
0028-3932/ © 2017 Elsevier Ltd. All rights reserved.
M.A. Chalah, S.S. Ayache
of unemployment and divorce, and high levels of social anxiety (Chalah
and Ayache, 2017a). Most importantly, alexithymia seems to be a risk
factor for affective disorders (Conrad et al., 2009; Luminet, 2010).
A better understanding of alexithymia and social cognition, espe-
cially in this population, seems crucial for an ideal medical manage-
ment. We have previously addressed the social cognition deficits in MS
studies (Chalah and Ayache, 2017b), and hence they are beyond the
scope of the present review. Also, regarding alexithymia treatment, a
limited number of studies are available and applied psychotherapies
(e.g. psychodynamic, cognitive behavioral, skilled-based therapies).
However, only few of them were controlled (Beresnevaite, 2000;
Tulipani et al., 2010), and none included MS patients. For this reason,
they will not be discussed in this work. The purpose here is to analyze
the available data on alexithymia in MS. First, a definition of alex-
ithymia is provided along with its classification and assessment mod-
alities. This is followed by an overview of the studies which assessed
alexithymia in MS. The possible underlying mechanisms of alexithymia
in MS are addressed in the light of the available immune, anatomical,
physiological, and neurochemical findings. Finally, some re-
commendations are provided for future studies aiming to increase our
understanding of this trait.
2. Study selection
A research was conducted independently by both authors according
to PRISMA guidelines (Moher et al., 2009) in order to identify original
research articles published till July 2017 in English and French lan-
guages about alexithymia in multiple sclerosis. Computerized databases
(MEDLINE, PubMed, Scopus) were consulted. The key terms used were
as follows: (‘multiple sclerosis’ OR ‘MS’) AND (‘alexithymia’ OR ‘alex-
ithymic’ OR ‘emotion processing’ OR ‘Toronto Alexithymia Scale’ OR
‘Bermond-Vorst Alexithymia Questionnaire’) AND (‘imaging’ OR ‘neu-
roimaging’ OR ‘magnetic resonance imaging’ or ‘MRI’). The references
of the retrieved articles were also scanned manually in order to get
additional sources. Admitting the paucity of MS studies addressing
alexithymia, all of them were included regardless of the study design or
primary endpoints. Initially, 12 studies (10 in English and 2 in French
Languages) were detected on the computerized databases. Two addi-
tional relevant citations were found among the papers’ references. One
was available online (Fernández-Jiménez et al., 2013) and the other
was provided by the original authors (Montreuil and Lyon-Caen, 1993).
Hence, a total of 14 studies were included in this review. A summary of
the all these studies is provided in Table 1.
3. Definition and classification
3.1. Definition of alexithymia
‘Alexithymia’ derives from Greek language where ‘a’, ‘lexis’ and
‘thymos’ means the ‘absence’ of ‘words’ for ‘emotion’. The term was first
introduced by Sifneos in 1972 to describe the symptomatology of pa-
tients with psychosomatic disorders who experience somatic symptoms
in the absence of any identifiable organic etiology (Sifneos, 1973;
Nemiah et al., 1976). Although sometimes referred to as ‘blunted
feeling’ (Goerlich-Dobre et al., 2014b), alexithymia is a multifaceted
construct that is not considered a disorder but rather a personality trait
according to the diagnostic and statistical manual for mental disorders
(5th ed.; DSM–5; American Psychiatric Association, 2013). Briefly, it
entails difficulties in experiencing and analyzing emotions. Its char-
acteristics are: (a) difficulty in identifying feelings (DIF) and distin-
guishing between feelings and bodily sensations related to emotional
arousal, (b) difficulty in describing feelings to others (DDF), which
might be reflected by ‘acting out’ or having a ‘circumstantial speech’,
(c) low inner emotional and fantasy life (LFL), (d) externally oriented
thinking (EOT) which is reality-based, concrete, literal and devoid of
introspection (e) and tendency to avoid active conflict resolution
32
Neuropsychologia 104 (2017) 31–47
(Bagby et al., 1994a; Taylor, 2000; Vorst and Bermond, 2001).
It is important to mention that, several years prior to the term in-
troduction by Sifneos, some features of alexithymia were described by
the Psychosomatic French School in the early sixties when referring to
the ‘pensée opératoire’. The term employed by Marty and de M’Uzan
refers to a cognitive style characterized by a preoccupation with the
smallest details of an external event and lack of fantasy life (Marty and
de M’Uzan, 1963).
3.2. Classification of Alexithymia
After Sifneos, Freyberger distinguished between primary alex-
ithymia which could arise from neurophysiological or neuroanatomical
abnormalities, and secondary alexithymia which might be encountered
in the context of psychiatric disorders (e.g. anxiety or depression) or be
the result of psychodynamic factors such as enormous employment of
defense mechanisms (e.g. repression, regression or denial) (Freyberger,
1977; Smith et al., 1992). Another way of classifying alexithymia would
be by considering it either a stable ‘trait’ over time (Sifneos, 1973) or a
conditional ‘state’ that might arise as a defensive strategy in front of
stressful events (Parker et al., 1998).
In the context of alexithymia, growing evidence supports the pre-
sence of two dimensions: affective and cognitive. While the former
refers to hampered levels of emotion experience, the latter represents
deficits in cognitive processing of emotions (Bermond et al., 2007). In
the light of their proposition, Bermond and colleagues hypothesized
that alexithymia may manifest in different subtypes (2007). Contrarily
to ‘lexithymia’ or ‘non-alexithymia’ which refers to the absence of im-
pairment of either dimension, type I alexithymia represents deficits in
both dimensions, type II alexithymia denotes intact or even heightened
emotionality but impaired cognitive dimension, and type III stands for
intact cognitive processing but altered levels of emotional experience
(Bermond et al., 2007).
3.3. Alexithymia and emotion processing
Emotion processing comprises three main steps. While the first two
steps are referred to as ‘emotion perception’ and designate (1) paying
attention to an emotional stimulus and identifying its emotional re-
levance and (2) generating an affective state; the third one deals with
‘emotion regulation’ (Phillips et al., 2003). Emotion regulation re-
presents the strategies adapted to inhibit or modulate affective states
(Gross, 1998; Phillips et al., 2003). The most studied strategies are
‘suppression’ and ‘reappraisal’ which respectively refer to inhibiting the
expressive behavior of emotion (e.g. hiding feelings) or decreasing the
initial emotional response in an attempt to restrain its influence (e.g.
decreasing the negativity of a stimuli) (Gross, 1998). The available
literature suggests an aberrant emotion perception (the first two steps)
behind the manifestation of alexithymia (Roedema and Simons, 1999;
Mueller et al., 2006; Swart et al., 2009; Grynberg et al., 2012; Bermond
et al., 2010; van der Velde et al., 2015). However, regarding emotion
regulation (the third step), its involvement in the occurrence of alex-
ithymia is still debatable with some studies being with (Taylor et al.,
1999; Taylor and Bagby, 2004; Swart et al., 2009; Walker et al., 2011;
Pollatos and Gramann, 2012; Venta et al., 2013; Wingbermühle et al.,
2012) or against this idea (van der Velde et al., 2015). In this context,
some authors have found that, compared to lexithymics, alexithymic
individuals employ less efficient strategies like ‘suppression’ and rely
less on more efficient strategies such as ‘reappraisal’ (Swart et al., 2009;
Kessler et al., 2010; Wingenfeld et al., 2011; Stasiewicz et al., 2012).
However, this association was not replicated in other studies (Geenen
et al., 2012; Weiss et al., 2012). The relationship between alexithymia
and emotion regulation in MS will be presented later in this work.
 Table 1
Studies evaluating alexithymia in multiple sclerosis.

Authors (Years) Population Alexithymia measure Variables Prevalence Correlation and other analyses

Montreuil and Lyon- 60 MS BIQ (cutoff score N/A) Depression: N/A > 50.0% of patients presented – Inverse correlation between alexithymia
Caen (1993) Details N/A PVIPT Anxiety: N/A alexithymic features scores and reduced affect display (blunted
M.A. Chalah, S.S. Ayache

(French) No HCs Fatigue: N/A affect) which includes anhedonia.

Cognition: N/A – No correlation between alexithymia scores
and cognitive functions
– No correlation between alexithymia and
sociodemographic data or disease
characteristics.
Bodini et al. (2008) 58 RR MS TAS-20 Depression: BDI 13.8% alexithymic – Correlation between alexithymia scores
(Italian) (age: 34.8 ± 9.3; DD: 9.1 ± 5.5; EDSS (North-American cutoff Anxiety : N/A 27.6% borderline alexithymic and each of fatigue and depression
median: 1.5) score > 60 for alexithymia) Fatigue: FSS 58.6% non-alexithymic – Data on correlation between alexithymia
No HCs Cognition: N/A * Higher levels of fatigue and depression scores and demographic or disease
in alexithymic compared to non- characteristics are N/A
alexithymic patients – Alexithymia significantly contributes to the
severity of fatigue and depression
– DIF was a predictor for fatigue
– TAS total, DIF and FSS scores were
predictors for depression
Chahraoui et al. 46 RR/9 PP/6 SP MS TAS- 20 Depression: BDI 42.6% alexithymic – Correlation between alexithymia scores
(2008) (French) (age:41.1 ± 10.8; DD: 9.3 ± 7.5 years; (French cutoff score > 55 for Anxiety: STAI 32.8% borderline alexithymic and each of anxiety (DIF and DDF
EDSS: 2.9 ± 2.2) alexithymia) Fatigue: N/A 24.6% non-alexithymic subscales) and depression (DIF subscale).
No HCS Cognition: N/A * Alexithymic patients were younger, No correlation between EOT subscale and
more anxious and more depressed than any of mood scores.
non-alexithymic patients. No group – No correlations between alexithymia scores
difference on disease characteristics. and disease characteristics

33
Gay et al. (2010) 115 MS (type N/A) TAS- 20 Depression: Depression Self-Rating Scale 38.2% vs. 23.3% alexithymic using the – Correlation between alexithymia scores
(French) (age 47.2 ± 10.9; DD: 15.3 ± 10.1; (French and North-American Anxiety: STAI French and the North-American and each of depression, anxiety and self-
EDSS: 4.8 ± 2.5; DD: 15.3 ± 10.1) cut-off scores were Fatigue: VAS thresholds, respectively esteem (but not fatigue)
No HCs simultaneously used for Cognition: N/A – No correlation between alexithymia and
comparison) Others: EDSS score
– Data on correlation between alexithymia
– Self-Esteem Inventory scores and demographic or other disease
– Social Support Questionnaire characteristics are N/A
– Coping : CHIP
Fernández-Jiménez 172 RR/10 PP/39 SPMS TAS- 20 Depression: N/A 18.1% alexithymic – Data on correlation analysis between
et al. (2013) (age: 40.6 ± 9.7; DD: 8.5 ± 6.3; EDSS: (North-American cutoff Anxiety: N/A 20.4% borderline alexithymic alexithymia and other measures are N/A
(Spanish) 3.0 ± 1.8) score > 60 for alexithymia) Fatigue: N/A 61.5% non-alexithymic
No HCs Cognition: N/A
Prochnow et al. 5 RR/ 1 PP/ 29 SP MS TAS- 20 Depression: BDI 25.7% had high alexithymia – No correlations between alexithymia and
(2011) (age 48.2 ± 10.2; DD: 9.2 ± 8.4; (the 66th percentile for the Anxiety: N/A 37.1% had moderate alexithymia social cognition scores
(German) median EDSS: 6.0) identification of high Fatigue: N/A 37.1% had low alexithymia – Data on correlation between alexithymia
61 HCs alexithymics (Franz et al., Cognition: MMSE/FST * Compared to HCs, patients were older, scores and demographic or disease
2008) Others: more alexithymic, had higher depression characteristics are N/A
scores, worse cognitive performance, and – Data on correlation between alexithymia
– Facial emotion recognition: PCFAE and significant deficits in facial emotions and cognitive measures are N/A
Ekman-60-Faces Test recognition – Data on correlation between alexithymia
– Facial identity recognition: BFRT and depression are N/A
Chahraoui et al. At baseline (T1): TAS-20 Depression: BDI at T1: – Correlation between TAS−20 scores
(2014) (French) 50 RR/12 P MS (age:41.4 ± 10.9; DD: (North-American cutoff Anxiety: STAI 30.6% alexithymic (total, DIF, DDF but not EOT) and each of
10.9 ± 8.7; EDSS: 3.1 ± 2.2) score > 60 for alexithymia) Fatigue: N/A 30.6% borderline alexithymic anxiety and depression at T1 and T2
5 years later (T2): 30 RR/12 P MS Cognition: N/A 38.7% nonalexithymic – Correlation between EOT scores and the
(age:46.2 ± 11.3; DD: 16.5 ± 8.2; at T2: number of relapses at 5 years
EDSS: 3.8 ± 2.4) 29.5% alexithymic – No correlation between alexithymia scores
No HCs 31.8% borderline alexithymic and demographic or other disease
(continued on next page)
Neuropsychologia 104 (2017) 31–47
 Table 1 (continued)

Authors (Years) Population Alexithymia measure Variables Prevalence Correlation and other analyses

38.6% non-alexithymic characteristics

At T2, alexithymia (total, DIF and DDF
subscales) and anxiety scores remained
M.A. Chalah, S.S. Ayache

constant. Conversely, EOT subscale and

depression scores decreased.
Cecchetto et al. 30 RR MS TAS-20 Depression: BDI 10.0% alexithymic – Correlation between alexithymia total
(2014) (age: 34.2 ± 6.2; DD: 9.1 ± 6.7; EDSS: (North-American cutoff Anxiety : N/A 13.3% borderline alexithymic scores and depression but not fatigue
(Italian) 2.0 ± 1.0) score > 60 for alexithymia) Fatigue: FSS 76.7% non-alexithymic* scores
30 HCs Cognition: BRB-N, TMT, phonemic verbal Compared to HCs, patients have deficits – No correlation between alexithymia scores
fluency, verbal and spatial span in recognizing all of facial emotions but and social cognitive measures
Others: not identity. – Data on correlation between alexithymia
No group differences in alexithymia or and demographic or disease characteristics
– Facial emotion recognition task: bodily emotional postures recognition are N/A
ERT derived from the Nim Set collection of – Multiple linear regression analysis:
facial expressions alexithymia could not account for social
– Facial identity recognition: BFRT cognitive deficits
– Bodily emotion recognition task: BEAST
Mosson et al. (2014) 13 RR/10 PP/14 SP MS BVAQ Form B Depression & Anxiety: HADS Prevalence N/A – Inverse correlation between cognitive
(French) (age: 50.2 ± 9.0; DD: N/A; EDSS≤4.0) (cut-off score not applicable Fatigue: FIS * Compared to patients with low levels of alexithymia scores and cognitive
No HCs since grouping was based on Cognition: N/A physical activity, those with high/ (particularly ID) and psychosocial fatigue
physical activity) Others: moderate levels did not differ on scores (social role with ANL, ID; social
alexithymia total or affective dimension relationships with all except ANL)
– Physical acitivity: Short version of the scores, but were significantly better in – Direct correlation between cognitive
International Activity Questionnaire analyzing emotions, and tended to have alexithymia scores and each of depression
– Coping: CHIP better cognitive dimension scores (except ANL) and anxiety (particularly ID)
– Inverse correlation between the affective

34
dimension of alexithymia (as well as EMO
subscale) and emotional regulation
– Correlations between alexithymia scores and
disease characteristics N/A
Gleichgerrcht et al. 38 RR MS TAS-20 Depression: N/A 31.6% alexithymic – Inverse correlation between alexithymia
(2015) (age: 42.3 ± 11.3; DD: 1.6 ± 8.7; (North-American cutoff Anxiety: N/A 26.3% borderline alexithymic and empathy scores.
North/South EDSS:1.7 ± 1.6) score > 60 for alexithymia) Fatigue: N/A 42.1% non-alexithymic – Direct correlation between alexithymia and
American 38 HCs Cognition: N/A * Compared to HCs, patients showed moral permissibility scores
Others: significantly higher scores on all aspects – No correlation between alexithymia and
of alexithymia and lower levels of disease characteristics (i.e. EDSS, DD or
– Empathy: Interpersonal Reactivity Index empathy, and altered moral judgment number of relapse)
– Moral judgement: dilemmas measuring * No group difference in demographic – Data on correlation between alexithymia
moral permissibility, moral relativity and data scores demographic data are N/A
emotional reactivity
Patil et al. (2016b) 38 RR MS TAS-20 Depression: N/A 31.6% alexithymic – No correlation between alexithymia scores
North/South (age: 42.3 ± 11.3; DD: 10.6 ± 8.7; (North-American cutoff Anxiety: N/A 26.3% borderline alexithymic and disease characteristics (i.e. EDSS, DD
American and EDSS: 1.7 ± 1.6) score > 60 for alexithymia) Fatigue: N/A 42.1% non alexithymic or number of relapse) or moral judgement
Italian 38 HCs Cognition: inclusion only if MMSE > 24 * Compared to HCs, patients had higher – Data on correlation between alexithymia
Others: rates of alexithymia, lower scores of and empathy scores or demographic data
some aspects of empathy, and altered are N/A.
– Empathy: Interpersonal Reactivity Index moral judgment
– Moral judgement task * No group difference in demographic
data
Gay et al. (2017) 107 RR/ 28 PP/ 54 SP MS BVAQ Form B Depression & Anxiety: HADS 53.0% alexithymic – No correlation between alexithymia scores
(French) (age: 47.2 ± 12.5; DD: 15.0 ± 9.3; (cutoff score for Fatigue: N/A Cognition: N/A * No significant differences between and each of anxiety, depression or disease
EDSS: 4.7 ± 2.4) alexithymia > 52) Others: depressed and non-depressed or between characteristics (i.e. EDSS).
No HCs Emotion: Emotional Processing Scale, Positive anxious and non-anxious patients in – Data on correlation between alexithymia
and Negative Emotionality Scale terms of alexithymia scores scores and socio-demographic
Coping: CHIP characteristics are N/A
(continued on next page)
Neuropsychologia 104 (2017) 31–47
 Table 1 (continued)

Authors (Years) Population Alexithymia measure Variables Prevalence Correlation and other analyses

Dulau et al. (2017) 30 RR/ 15 PP/ 15 SP MS BVAQ Form B (cutoff score N/ Depression: BDI 12.0% alexithymic in the whole patient – No correlation between alexithymia scores
(French) (age 46.5 ± 10.6; DD: 14.4 ± 9.4; A) Anxiety: STAI group; 27.0% alexithymic PP MS (details and each of disease characteristics, mood
median EDSS: 4.0) Fatigue: N/A N/A) scores, or non-social cognitive scores
M.A. Chalah, S.S. Ayache

65 HCs Cognition: Cognitive alexithymia: 17.0–20.0% – Data on correlation between alexithymia

according to MS phenotypes and social cognitive domains or
– Episodic memory: French adapation of the Affective alexithymia: 7.0% demographic characteristics are N/A
Grober and Buschke Free, Cued Selective * Compared to HCs, the whole patient
Reminding Test and forward digit span group was significantly more depressed,
– Working memory: backward and forward scored significantly lower on the Reading
digit span and PASAT 3s the Mind in the Eyes Test (but not the
– IPS: digit symbol, CSCT, D2 Test, a letter other social cognitive tests), and did not
cancellation test (numbers of items differ on anxiety scores or demographic
analyzed), Stroop 45- colour denomination; data.
Stroop 45-reading
– Attention: D2 Test, a crossing test
measuring selective and sustained attention
and visual scanning speed (error
percentage)
– Executive functions: verbal fluency, WCST,
and Stroop 45 inhibition score
Others:

– Theory of mind: The Faux Pas Test, the

Attribution of Intentions Test, and the
Reading the Mind in the Eyes Test
– Facial emotion recognition: The Faces Test

35
– Emotional awareness: LEAS
– Emotional fluency task of the PECS-B
Raimo et al. (2017) 29 RR/2 PP/2 SP MS TAS- 20( Depression: HDRS Prevalence N/A – Inverse correlation between alexithymia
(Italian) (age: 40.6 ± 11.5; DD: 98.8 ± 89.8; cutoff score not applicable) Anxiety: STAI * Compared to HCs (matched on and theory of mind scores (Reading the
EDSS: 2.4 ± 1.5) Fatigue: FSS demographic data), patients had higher Mind in the Eyes Test)
40 HCs Cognition: alexithymia and depression scores, worse – Data on correlations between alexithymia
– MMSE cognitive performance (IPS, visuospatial scores and each of demographic, clinical and
– BRB-N learning and memory), and significant cognitive data are N/A
Others: deficits in theory of mind

– Theory of mind: Reading the Mind in the

Eyes Test, modified version of the Emotion
Attribution Task, Theory of Mind Picture
Sequencing Task, and Advanced Test of
Theory of Mind
– Apathy: Apathy Evaluation Scale

ANL: Analyzing; BDI: Beck Depression Inventory; BEAST: Bodily Expressive Action Stimulus Test; BFRT: Benton Facial Recognition Test; BIQ: Beth Israel Questionnaire; BRB-N: The Brief Repeatable Battery of Neuropsychological Tests; BVAQ:
Bermond-Vorst Alexithymia Questionnaire; CHIP: Coping about Health Injuries and Problems questionnaire; CSCT: Computerized Speed Cognitive Test; DIF: Difficulty Identifying Feelings; DD: Disease duration; DDF: Difficulty Describing Feeling;
EMO: Emotionalizing; ERT: Emotion recognition task; EDSS: Expanded Disability Status Scale; EOT: Externally Oriented Thinking; FIS: Fatigue Impact Scale; FSS: Fatigue Severity Scale; FST: Faces Symbol Test; HADS: Hospital Anxiety and
Depression Scale; HCs: Healthy controls; HDRS: Hamilton Depression Rating Scale; ID: Identifying; IPS: Information processing speed; LEAS: Levels of Emotional Awareness Scale; MMSE: Mini Mental Status Exam; MS: Multiple sclerosis; N/A: Not
available; PASAT: Paced Auditory Serial Attention Test; PCFAE: Test of Perceptual Competence of Facial Affect Recognition; PECS-B: Bordeaux Social Cognition Evaluation Protocol; P: Progressive; PP: Primary Progressive; PVIPT: Parallel Visual
Information Processing Test; RR: Relapsing Remitting; SP: Secondary progressive; STAI: State-Trait Anxiety Inventory; TAS- 20: Toronto Alexithymia Scale; TMT: Trail Making Test; VAS: Visual Analogue Scale; WCST: The Wisconsin Card Sorting
Test. Age and disease duration are expressed in years. All quantitative variables are shown as mean ± SD unless indicated otherwise.
Neuropsychologia 104 (2017) 31–47
M.A. Chalah, S.S. Ayache
4. Assessment tools for alexithymia
The most primitive instruments to measure alexithymia included
the Schalling Sifneos Personality Scale (SSPS) and the Minnesota
Multiphasic Personality Inventory Alexithymia Scale (MMPI) (Kleiger
and Kinsman, 1980; Taylor et al., 1999) which were limited by their
lack of reliability and validation (Parker et al., 1991; Bertagne et al.,
1992). Since then, the utility of different tools has been tested and
several are now available for the evaluation of alexithymia, including
projective tests, observer-rated and self-reported questionnaires. For
the sake of this review, only the most common tools, particularly those
used in MS studies, will be revisited. The Beth Israel Questionnaire
(BIQ) created by Sifneos is a 17-item forced choice questionnaire filled
out by the examiner (Sifneos, 1973) and consists of an initial period of
unstructured dialogue followed by questions that assess alexithymia
(describing feelings and reporting fantasies) (Nemiah et al., 1976).
Eight of these questions were found to be closely linked to alexithymia
and were therefore used to classify patients as alexithymics or not based
on an arbitrary cutoff score of 6. The test was found to have sufficient
psychometric properties (Smith et al., 1992). However, its validity was
not derived from the ability to distinguish alexithymics from non-
alexithymics, but was rather based on comparative studies which
documented higher scores in psychosomatic patients compared to
psychoneurotic patients or those with other psychiatric diagnoses
(Sifneos, 1973). Few years later, a revised version was introduced and
aimed to enhance the psychometric properties of BIQ. It consists of 12
items (four new items added, nine were eliminated) that had 7-likert
type format contrarily to the dichotomous format adapted in the initial
version (Bagby et al., 1994b). Its initial evaluation yielded a satisfactory
interrater agreement and a significant correlation with the 20-item
Toronto Alexithymia Scale (Bagby et al., 1994b). Such a correlation was
more significant than that obtained when using BIQ version.
The Toronto Alexithymia Scale is the most popular tool to measure
the symptom and is currently available in numerous languages (Taylor
et al., 1985). When it was first introduced by the Canadian team, it
consisted of 26 items that evaluate the four facets of alexithymia: DIF (7
items), DDF (5 items), EOT (8 items) and LFL (6 items). It is a self-
reported measure that consists of a 5-choice scale (from ‘strongly agree’
to ‘strongly disagree’). Later in time, a revised version came out ac-
counting only for the first three components (DIF, DDF, and EOT), since
the fourth one was found to be of low coherence with the other three
factors. This resulted in the 20-item Toronto Alexithymia scale (TAS-
20) which was shown to have good predictive validity and internal
consistency (Bagby et al., 1994b; Loas et al., 2001; Culhane et al.,
2003). The North American and French cut-offs are respectively as
follows: non-clinical alexithymic [scores ≤51 (American cut-off)
vs. < 44 (French cut-off)], borderline alexithymic (scores of 52–60 vs.
44–55), or alexithymic (scores > 60 vs. > 55) (Bagby et al., 1994a;
Loas et al., 1996a, 1996b).
Some authors consider the first two constructs (DIF, DDF) and the
third one (EOT) as the affective and cognitive dimensions respectively
(Zackheim, 2007; Grynberg et al., 2010; Moriguchi and Komaki, 2013).
However, a Dutch team argues that these TAS-20 subscales represent
only cognitive alexithymia and do not take into account the affective
component, a fact that pushed them to put into place a scale which
contains two parallel sets of twenty items each (Form A comprising
items 1–20, and Form B comprising items 21–40). This gave birth to the
so-called 40-item ‘Bermond-Vorst Alexithymia Scale’ (BVAQ) which
was found to have good reliability and validity (Bermond and Vorst,
1994; Zech et al., 1999; Vorst and Bermond, 2001; Farges et al., 2004;
Morera et al., 2005). Similar to TAS-20, BVAQ items are of 5-point
Likert-type ranging from ‘this definitely applies to me’ to ‘this in no way
applies to me’. Most importantly, it is a 5-component contrast (vs. 3
components in TAS-20) which takes into consideration the cognitive
and emotional components of alexithymia. Its five dimensions (8 items
each) are as the following: (1) the capacity to identify one’s emotional
36
Neuropsychologia 104 (2017) 31–47
arousal states (Identifying, [ID] which corresponds to DIF in TAS-20),
(2) the tendency to describe one’s emotions (Verbalizing [VER] which
corresponds to DDF in TAS-20), (3) the interest in finding explanation
for one’s emotional reaction (Analyzing [ANL] which corresponds to
EOT in TAS-20), (4) the extent of arousal by an emotional event
(Emotionalizing, [EMO]) and finally (5) the individual’s tendency to
have daydreams, fantasies or other imaginative thoughts (Fantasizing,
[FANT]). As per the original authors, the affective (1–28: clearly non-
alexithymic, 29 – 41: modal, 42–80: alexithymic) and cognitive (1–42:
clearly non-alexithymic, 43–61: modal, 62–120: alexithymic) dimen-
sions are scored separately.
The originality of this new scale lies in the last two facets (EMO and
FANT) (Vorst and Bermond, 2001; Bermond et al., 2010). This might
provide a more global view on alexithymia by representing the two
forgotten elements that were present in the initial definition of Taylor
and colleagues (Taylor et al., 2000). This was highlighted by the fact
that total TAS-20 score correlates with the cognitive (ID, VER, ANL) but
not the affective (EMO, FANT) dimension of BVAQ (Zech et al., 1999;
Vorst and Bermond, 2001). However, some authors argue that BVAQ
might not be superior to TAS-20 since the conceptualization of alex-
ithymia remains debatable. In other terms, they consider the additional
affective aspects as correlates of alexithymia rather than core facets of
it. For this reason, some authors only employ the 20-item BVAQ Form B
admitting its convergent validity and the high correlation found be-
tween its items and those of TAS-20 (Morera et al., 2005). The cut-off
scores of the BVAQ Form B are derived from studies in healthy young
adults (lexithymia: 43–45, alexithymia: 50–53) (Loas et al., 2015), al-
cohol abuse (alexithymia: 52) (Sauvage and Loas, 2006), eating dis-
orders (lexithymia: 43, alexithymia: 53) (Deborde et al., 2008), and
multiple sclerosis (alexithymia: 52) (Gay et al., 2017).
5. The neuroanatomical underpinnings of alexithymia
Ever since the description of alexithymia, a considerable amount of
neuropsychological and imaging works has addressed its neural un-
derpinnings, but a prominent inconsistency and even a contradiction
exist among their findings. In MS, alexithymia might result from de-
myelinating lesions and neurodegenerative processes that usually ac-
cumulate throughout the disease course. In fact, such pathological
changes have been reflected by structural and functional brain ab-
normalities on magnetic resonance imaging (MRI) and have been found
to be associated with cognitive, psychiatric and emotional disturbances
commonly observed in MS population (Chalah et al., 2015; Chalah and
Ayache, 2017a; Chalah and Ayache, 2017b). Remarkably, among the 14
papers that have dealt with alexithymia in MS, none has addressed the
neural underpinning of this trait by the means of imaging modalities.
Therefore, this section will reappraise the underlying mechanisms in
the light of the most accepted models that derive from studies per-
formed in healthy subjects and patients with neuropsychiatric com-
plaints (other than MS).
5.1. Emotion processing networks and Alexithymia
One of the compelling models considers alexithymia to arise from a
dysfunction in emotion processing networks. To start, emotion per-
ception is an early step of emotion processing that involves a ventral
neural system made of amygdala, insula, anterior cingulate cortex
(ACC), prefrontal cortex (PFC) and striatum, amongst others (Phillips
et al., 2003; Bermond et al., 2006; Fusar-Poli et al., 2009; van der Velde
et al., 2013; 2015). The amygdala and insula play an important role in
automatic emotion processing. Upon the presentation of an emotion-
ally-relevant stimulus, the amygdala is in charge of automatically di-
recting the bottom-up attention of the occipital cortex towards the
stimulus via a feedback loop involving the fusiform gyrus (Phillips
et al., 2003; Vuilleumier, 2005; Jacobs et al., 2012). In addition, the
insula, as well as the precuneus, are key elements in the process of
M.A. Chalah, S.S. Ayache
emotional insight which requires the transformation of an interoceptive
information (insula) into a subjective affective state (precuneus)
(Critchley et al., 2004; Tsuchiya and Adolphs, 2007; Terasawa et al.,
2013). Following attention capture, the retrieval of conceptual knowl-
edge about emotion and the generation of affective reactions involve
the superior temporal cortex and hippocampal formation (Adolphs,
2002a, 2002b). Other important cerebral areas are the motor and so-
matosensory cortices which are involved in emotional awareness and
recognition (Adolphs, 2002a, 2002b), parts of the ventromedial pre-
frontal cortex -particularly ACC and orbitofrontal cortex (OFC)- which
participate in emotional learning through their connections with limbic
structures (Kandel et al., 1991; Malloy and Duffy, 1994), and the basal
ganglia which contribute to emotional experience through the dorso-
lateral prefrontal cortex (dlPFC) and the OFC circuits (Alexander et al.,
1990).
That is to say, alexithymia was associated in many studies with
structural or functional abnormalities in the abovementioned regions,
namely the amygdalae, basal ganglia, ACC, insula, precuneus, fusiform
gyrus, PFC, and occipital cortex (Berthoz et al., 2000; Hornak et al.,
2003; Kano and Fukudo, 2013; Karlsson et al., 2008; Kugel et al., 2008;
Eichmann et al., 2008; Paradiso et al., 2008; Borsci et al., 2009; Pouga
et al., 2010; Reker et al., 2010; Kubota et al., 2011; Sturm and
Levenson, 2011; Zhang et al., 2011; Liemburg et al., 2012;
Wingbermühle et al., 2012; Kano and Fukudo, 2013; Moriguchi and
Komaki, 2013; Kano and Fukudo, 2013; Ihme et al., 2013; Moriguchi
and Komaki, 2013; Kano and Fukudo, 2013; van der Velde et al., 2013;
Grabe et al., 2014; Goerlich-Dobre et al., 2015b; van der Velde al.,
2014; Suslow et al., 2016).
5.2. The Neuroanatomical profiles of alexithymia dimensions and subtypes
5.2.1. Hemispheric specialization and Alexithymia
Most of the available hypotheses arise from the bi-dimensional
nature of alexithymia and its theoretical subtypes as initially proposed
by the Dutch team (Vorst and Bermond, 2001; Larsen et al., 2003;
Bermond et al., 2006). For instance, in one of their works, Bermond and
colleagues discussed the possibility of a left hemispheric preference or a
right hemispheric negligence in alexithymics during the processing of
visual emotional information compared to non-alexithymics who pro-
cess the stimulus in the hemisphere that receives it (Bermond et al.,
2005). In another work (Larsen et al., 2003), they proposed a kind of
hemispheric specialization in line with the connexionist theory initially
proposed by McClelland and colleagues (McClelland et al., 1987). Here,
the right and left hemispheres would be respectively more specialized
in the processing of global, nonverbal and unconscious information
(emotional experience) (Gazzaniga, 1989; Kolb and Whishaw, 1990)
versus verbal, serial, and conscious one (high explicit emotional cog-
nition) (Tucker, 1981; Gainotti, 1989; Joseph, 1992; Hoppe, 1988;
Gainotti et al., 1993; Bear, 1983; Larsen et al., 2003; Bermond et al.,
2006). In this framework, the corpus callosum (CC) - the largest in-
terhemispheric white matter bundle - could be the bridge through
which the cognitive component of an emotional stimulus presented to
the right ‘affective’ hemisphere would reach the left ‘cognitive’ one
(Gazzaniga and LeDoux, 1978). In this context, alexithymia might occur
due to a dysfunction in (1) the right hemisphere (Parker et al., 1993;
Jessimer et al., 1997), (2) the interhemispheric affective-cognitive
communication mediated by the CC (Hoppe and Bogen, 1976;
TenHouten et al., 1985a, 1985b, 1985c, 1986; TenHouten et al., 1987,
1988; Houtveen et al., 1997; Parker et al., 1999), or (3) the left
hemisphere. Following this proposition, one might assume that the lo-
cation of brain pathology would result in phenotypic differences among
the theoretical subtypes of alexithymia (Bermond et al., 2006). Inter-
estingly, right-sided hemispheric lesions were found in some studies to
engender an alteration of emotional experience and subsequently an
absence of cognitive emotion processing (Ross et al., 1984; Fricchione
and Howanitz, 1985; Gainotti, 1989; Borod, 1992; Borod, 1993; Borod
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Neuropsychologia 104 (2017) 31–47
et al., 1992, 1998; Mandal et al., 1999). Following the same logic, a CC
dysfunction may result in an intact emotion experiencing but altered
cognitive emotion processing (Bermond, 1995; 1997), an idea that was
supported later in time by several clinical and imaging studies including
those performed on patients with CC transections (Sperry et al., 1979;
Buchanan et al., 1980a, 1980b; Larsen et al., 2003; Habib and Joly-
Pottuz, 2003; Kubota et al., 2012; Goerlich-Dobre et al., 2015b). Some
authors have labeled this mechanism as a right-to-left unidirectional
deficit in interhemispheric transfer (IHT) (Hoppe and Bogen, 1976;
Houtveen et al., 1997; Parker et al., 1999; Zeitlin et al., 1989; Dewaraja
and Sasaki, 1990). Moreover, in the same model, frontal lobe dys-
function was suggested to be behind the occurrence of both dimensions
(Damasio and van Hoesen, 1983; Alexander et al., 1990; de Bruin,
1990; Neafsey, 1990; Kandel et al., 1991; Devinsky et al., 1995; Hornak
et al., 1996; Berthoz et al., 2000; van der Velde et al., 2013; Lane et al.,
1997; Wingbermühle et al., 2012; Milad et al., 2007; Phan et al., 2002;
Larsen et al., 2003). The strict hemispheric specialization of this model
constitutes its major shortcoming since more recent studies failed to
demonstrate a typical left and right hemispheric specializations with
regards to the different dimensions and types of alexithymia (Goerlich-
Dobre et al., 2015b).
In fact, three years after the introduction of the hemispheric spe-
cialization model, a tuned and more flexible version of it was presented
by the same authors, where the implicated structures are inter-
connected in a way that they can influence one another (Bermond et al.,
2006). The orbito/medial-prefrontal cortices, more on the right side,
seem to be mainly implicated in affective alexithymia. Modules of the
right temporal cortex, are primarily involved in the cognitive dimen-
sion, but also play a role in the affective one via their connections with
the orbito-prefrontal cortices. These structures are linked, via CC and/
or anterior commissure, to left-hemispheric areas that ensure emotional
cognition. The model also proposes the specialization of ventral and
caudal ACC subparts in the affective and cognitive alexithymia di-
mensions respectively. In addition, it suggests the involvement of
amygdalae in the cognitive dimension via their connections with neo-
cortical regions and in the affective dimension by the means of their
links with PFC.
More importantly, authors advocate the presence of a reciprocal
inhibition between brain parts involved in the cognitive and affective
aspects of emotions (for example, between the subparts of ACC, be-
tween PFC and amygdalae, etc.). This means that the processing of
emotional versus non-emotional stimuli would primarily activate the
regions dedicated to the affective facet versus those in charge of the
cognitive aspect of emotions, respectively.
Based on this assumption, the authors conceived four possible ways
of emotion management: (a) the exclusive activation of neural regions
involved in non-emotional cognitive processing would result in a total
negation of emotions (low affective and cognitive capacities char-
acterizing alexithymia type I), (b) the exclusive activation of affective
neural modules would lead to intense emotional experience without
cognitive processing (high affective and low cognitive capacities de-
fining alexithymia type II) (c) the exclusive activation of neural circuits
involved in emotion cognitive processing would result in emotionally
detached emotion-related cognition (high cognitive and low affective
capacities denoting alexithymia type III), and finally an adequate ac-
tivation of the affective followed by cognitive processing of emotional
information would result in a normal emotion processing (high affec-
tive and cognitive capacities hallmarking lexithymia). Finally, in the
most recent report, Lane and colleagues have attempted to expand the
alexithymia construct by proposing a new concept based on Freud’s
perception of agnosia (Freud, 1891; Lane et al., 2015). According to
Freud, recognizing an object (i.e. somatomotor and visceromotor ex-
pression of emotional responses) relies on a multi-step process con-
sisting of (1) sensory perception, (2) mental representation (i.e. emo-
tional awareness), and (3) verbal labeling (i.e. naming or expressing
emotions). In this context, a deficit in the second step rather than in the
M.A. Chalah, S.S. Ayache
third one would result in impaired ability to mentally represent emo-
tions, a concept which Lane et al. refer to as a type of agnosia: ‘affective
agnosia’. However, Taylor and colleagues argue that, early since the
description of alexithymia, the construct included deficits in emotional
awareness as a central core (Taylor et al., 2016). They also added that
the newly described concept does not take into account the pensée
opératoire (operative thinking) which constitutes a central aspect of
alexithymia.
5.2.2. Neuroimaging data and neural substrates of alexithymia:
shortcomings and drawbacks
The important advances in neuroimaging techniques could be of
great help in clarifying the current speculations and disentangling the
neural substrates of alexithymia. However, some discrepancies exist
among the available studies.
For instance, the gray matter volume of ACC was found to be larger
(Gundel et al., 2004), smaller (Borsci et al., 2009; Grabe et al., 2014;
van der Velde et al., 2014; Ihme et al., 2013; Koven et al., 2011;
Paradiso et al., 2008; Sturm and Levenson, 2011), or alike (Heinzel
et al., 2012) in alexithymics compared to lexithymics. The same applies
to the amygdalar volumes (smaller in Grabe et al., 2014; Ihme et al.,
2013 vs. similar in Borsci et al., 2009; Heinzel et al., 2012; Kubota
et al., 2011) and insular volumes (larger in Zhang et al., 2011; Goerlich-
Dobre et al., 2014a vs. smaller in Borsci et al., 2009; Pouga et al., 2010;
Grabe et al., 2014; Ihme et al., 2013 vs. similar in Heinzel et al., 2012;
Kubota et al., 2011; Sturm and Levenson, 2011), and the list goes on.
This inconsistency might be partly attributed to the difference in the
adapted structural MRI methods. Some studies used surface area mea-
surements (Gundel et al., 2004) while others relied on automated voxel-
based morphometry (Borsci et al., 2009; Grabe et al., 2014; Ihme et al.,
2013; Koven et al., 2011; Paradiso et al., 2008; Sturm and Levenson,
2011).
Another illustration of inconsistent results come from fMRI data. For
instance, various pattern of ACC activation was found in alexithymics
patients compared to lexithymic ones. Here, several reasons might ex-
plain such divergent results.
First, in the context of alexithymia, the hyperactivation pattern
would imply (1) a great need to recruit neural resources in face of in-
creased cognitive demands (compensatory mechanisms), (2) a hy-
persensitivity to the physical aspect of emotional stimuli or (3) an
amplification of physical sensation which constitutes one of the cores of
alexithymia (Koch et al., 2012; Mulert et al., 2005; Urry et al., 2009;
Pollatos & Gramann, 2012; Kano and Fukudo, 2013; Moriguchi and
Komaki, 2013). Conversely, the hypoactivation pattern can be ex-
plained by the inverted U-shape hypothesis which was observed while
increasing the task load (Koch et al., 2012). In other words, during the
initial increase in task load, patients exhibited a hyperactivation in the
concerned brain region, and this would be followed by a hypoactivation
with a further increase in the task load.
Second, the difference in the adapted tasks and stimuli types might
be behind the incongruent findings of fMRI studies (Pouga et al., 2010;
Kano and Fukudo, 2013). Here, it is worth noting that valence-depen-
dent pattern of brain activation exists in alexithymia (van der Velde
et al., 2013). That it to say, negative and positive emotion processing
elicit different pattern of brain activation and might explain the dif-
ferences across studies employing tasks that assess positive versus ne-
gative emotions.
Third, the difference in the assessment tools (i.e. TAS-20 vs. BVAQ-
40 vs. BVAQ- Form B) might account for the incongruent data of the
existing trials. In fact, a large number of the earliest studies have used
TAS-20 while relatively little number have employed the BVAQ, which
might constitute an important source of bias.
5.2.3. Neuroimaging data and neural substrates of Alexithymia: Current
perspectives
Despite the above discussed inconsistency among MRI studies, a
38
Neuropsychologia 104 (2017) 31–47
pattern of cerebral (non-hemispheric) specialization in alexithymia di-
mensions remains suitable till these days (Larsen et al., 2003; Bermond
et al., 2010; Pouga et al., 2010; Goerlich et al., 2012; Goerlich-Dobre
et al., 2014a).
In reality, there is a certain degree of agreement on the presence of
emotion processing networks. This includes the interhemispheric con-
nections (i.e. CC) and the fronto-parietal regions (e.g. precuneus,
frontal and prefrontal cortices), as well as the limbic and paralimbic
areas, namely insula, amygdala, parahippocampal gyrus, and the cin-
gulate cortex. (Lane et al., 1997; Singer et al., 2009; Etkin et al., 2011;
Kano et al., 2003; Kubota et al., 2012; Ihme et al., 2013; van der Velde
et al., 2013; Grabe et al., 2014; Goerlich-Dobre et al., 2015b). Con-
cerning the latter, it is now accepted that the ventral-rostral subgenual
(sgACC) and the dorso-caudal ACC (dcACC) are respectively involved in
affective and cognitive alexithymia (Devinsky et al., 1995; Bush et al.,
2000; Bermond et al., 2006; Etkin et al., 2011). Through its association
with limbic and orbito-prefrontal regions, the sgACC could influence
the generation of emotional responses, which justifies its inference in
the affective dimension of alexithymia (Bermond et al., 2006; Pouga
et al., 2010; Goerlich-Dobre et al., 2015b). In addition, via its functional
connectivity with the amygdala among other emotion processing areas,
the dcACC could take part in the cognitive reappraisal (Amaral et al.,
1992; Giuliani et al., 2011) which explains its contribution to the
cognitive dimension.
6. The neuroimmune and neurochemical substrates of
Alexithymia
An association between immune dysregulation and alexithymia has
been suggested based on several studies documenting pro-inflammatory
imbalance (e.g. interleukins (IL)−1, −2, −6, −8 and tumor necrosis
factor-⍺ (TNF-⍺)) in the context of alexithymia (Uher, 2010; Guilbaud
et al., 2003; Uher et al., 2010; De Berardis et al., 2014). For example,
high serum levels of IL-6 and TNF-α were found in alexithymic com-
pared to non-alexithymic patients with rheumatoid arthritis (Bruni
et al., 2006; Vadacca et al., 2008). Another illustration would be the
significant correlation between alexithymia scores and cerebrospinal
fluid (CSF) levels of IL-8 in a cohort of non-inflammatory neurological
disorders (Uher and Bob, 2011) or serum levels of IL-18 in alexithymic
patients during an acute stroke (Bossù et al., 2009).
Importantly, CNS inflammation is the pathophysiological hallmark
of MS. The inflammatory milieu would activate the microglia which
would result in the release of pro-inflammatory mediators such as TNF-
α, interferon-γ, and IL-1-β (Block and Hong, 2005; Kawanokuchi et al.,
2006; Muzio et al., 2007) which were remarkably found to be at high
levels in the CSF of MS patients (Chalah et al., 2015; Ayache and
Chalah, 2017a). Although no MS study till present has assessed the
relationship between alexithymia and inflammatory markers, the con-
tribution of the latter in alexithymia deserves to be verified.
Besides the inflammation itself, other factors, such as neurochem-
ical imbalance, might also contribute to alexithymia in MS. For in-
stance, inflammation-induced synaptopathy in the context of MS seems
to be the link between inflammatory and neurodegenerative processes
(Chalah et al., 2015). The inflammatory mediators can result in a
neurochemical imbalance, mainly an upregulation of the excitatory
glutamatergic transmission (Stellwagen et al., 2005; Lai et al., 2006;
Mizuno et al., 2008), and a down regulation of the inhibitory G-
ABAergic transmission (Stellwagen et al., 2005). This idea is supported
by molecular, imaging and neurophysiological studies documenting
aberrant glutamatergic, GABAergic as well as dopaminergic metabolism
in the CNS of MS patients (Chalah et al., 2015; Ayache and Chalah,
2017b). Although no studies have addressed this issue in this popula-
tion, some evidence are available from other clinical and healthy co-
horts and might be applicable to MS. For instance, Larsen and collea-
gues have suggested that alexithymia be related to a deficient
dopaminergic transmission in ACC or OFC which are connected to basal
M.A. Chalah, S.S. Ayache
ganglia and therefore may contribute to the emotional experience
(Larsen et al., 2003). This assumption has its roots in studies in patients
with Parkinson’s disease, where the reduction in the function of dopa-
minergic nigrostriatal networks was accompanied by numbness in
motivation and affect which characterizes alexithymia (Berman and
Weinberger, 1990; Costa et al., 2010). Contemporary evidence also
arises from genetic studies which have suggested the implication of
Catechol-O-Methyltransferase, brain-derived neurotrophic factor and
DRD2/ANKK1 genes - all of which are involved in dopaminergic
pathways – in alexithymia (TAS-20) (Ham et al., 2005; Walter et al.,
2011; Koh et al., 2016).
Moreover, preliminary findings on the involvement of other neu-
rotransmitters derive from a proton magnetic resonance spectroscopy
by Ernst and colleagues (Ernst et al., 2014) where alexithymia scores
(TAS-20) were correlated with glutamate levels in the left insula and
GABA levels in the ACC (Ernst et al., 2014).
Taken together, these data suggest that the CNS neurochemical
imbalance seen in MS patients contribute to the occurrence of alex-
ithymia in this population.
7. The neuroendocrine correlates of Alexithymia
The hypothalamo-pituitary-adrenal axis (HPA) gets usually acti-
vated in response to stressful conditions or physiological states.
Inflammatory mediators can influence HPA activity via a cytokine-HPA
axis feedback network model (Marques et al., 2009; Kern et al., 2014).
For instance, positive correlation was documented between IL-6 serum
levels and cortisol increment (Zarković et al., 2008). Another case in a
point would be the increase in serum cortisol levels following in-
travenous administration of IL-1b and TNF-α (Sharp et al., 1989;
Gwosdow et al., 1990).
In the context of MS, several studies have demonstrated an HPA axis
dysregulation, a finding that could be associated with the disease pro-
gression, cognitive decline and fatigue (Michelson et al., 1994;
Fassbender et al., 1998; Then Bergh et al., 1999; Huitinga et al., 2004;
Gold et al., 2005; Ysrraelit et al., 2008; Melief et al., 2013; Huitinga
et al., 2004; Ayache and Chalah, 2017a). While numerous studies have
reported HPA hyperactivity (Michelson et al., 1994; Fassbender et al.,
1998; Then Bergh et al., 1999; Gold et al., 2005; Ysrraelit et al., 2008;
Melief et al., 2013; Huitinga et al., 2004), few studies have found to a
hypoactivity pattern (Huitinga et al., 2004). These divergent findings
could be explained by the results of Kern and colleagues who docu-
mented, in MS patients, a time-dependent variability of HPA axis re-
sponse. Expressed differently, the response becomes blunted in ad-
vanced stages of the disease (Kern et al., 2014). Nonetheless, none of
the available studies has assessed the association between HPA axis
activity and alexithymia.
Regarding the relationship between alexithymia and HPA axis ac-
tivity, inconsistency exists among alexithymia studies with some trials
reported no association (McCaslin et al., 2006; Pedrosa Gil et al., 2008)
while others documented a positive correlation between alexithymia
and the activation pattern of HPA axis (hypoactivity in Alkan Härtwig
et al., 2013; and hyperactivity in de Timary et al., 2008 and Hua et al.,
2014). Such findings could be explained in the light of the stress-alex-
ithymia hypothesis which implies the association between alexithymia
and chronic stress (Martin and Pihl, 1985; Friedlander et al., 1997; De
Berardis et al., 2014). Given this background, chronic stressful experi-
ence, such as in the context of MS, might result in HPA hyperactivation
which, in case of a persisting stress, could shift into a hypoactivation
pattern (Fries et al., 2005) and might engender alexithymia.
8. Neurophysiological findings in Alexithymia
Physiologically speaking, alexithymia seems to be associated with
autonomic dysfunction. In fact, it was found to be associated with high
tonic sympathetic arousal and a decoupling between physiological and
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Neuropsychologia 104 (2017) 31–47
emotional arousal (Papciak et al., 1985; Martin and Pihl, 1986;
Rabavilas, 1987; Friedlander et al., 1997; Infrasca, 1997; Fukunishi
et al., 1999; Stone and Nielson, 2001; Gundel et al., 2002). At baseline,
alexithymic individuals were found to have continuous autonomic hy-
peractivity which might be similar to that observed in chronic stress
states. Conversely, during the exposure to arousing stimuli, alex-
ithymics were found to have normal or lower sympathetic activity
(Fukunishi et al., 1999; Wehmer et al., 1995; Linden et al., 1996;
Friedlander et al., 1997; Roedema and Simons, 1999; Roedema and
Simons, 1999; Stone and Nielson, 2001). The unusual alexithymic re-
sponse to psychosocial stress may reflect aberrant channels for emo-
tional discharge, and might explain the observed emotional-physiolo-
gical decoupling. The documented neurophysiological findings seem to
share the same neural mechanisms of alexithymia, namely abnormal-
ities in cortical and subcortical regions (e.g. ACC, PFC, insula, amyg-
dala, CC) linked to brainstem and spinal autonomic centers (Barbas
et al., 2003; Simpson et al., 2001; Gainotti, 2001; Larsen et al., 2003;
Bermond et al., 2006).
9. Prevalence of alexithymia in multiple sclerosis
In the last three decades, alexithymia has gained more attention in
the field of MS. The first evidence on alexithymia in this population
comes from studies dating back to the eighties of the last century. In
1983, Pavlo and Stefoski reported that some of their patients had dif-
ficulties in elaborating their feelings or discriminating between the
latter and their physical sensations. Therefore, they tend to express this
reality by their somatic or bodily complaints (Pavlou and Stefoski,
1983). Afterwards, Grant published in 1986 his experience with some
of his patients who describe a sensation of ‘dysconnection’ between
their interior/inner experience and the expression of their affect. For
instance, they would feel sad or depressed, but their facial mimicry
would not reveal or reflect these feelings (Grant, 1986). Both studies
feature a contrast between a weak ability to analyze inner emotions and
a huge amount of somatic complaints in this population.
Montreuil and Lyon-Caen were the first to concretely address alex-
ithymia in MS in 1993. These French researchers reported, based on
their clinical experience, a pattern of dissociation between what pa-
tients subjectively report regarding their emotions and what is clinically
perceived in their facial mimicry, bodily gestures and speech (Montreuil
and Lyon-Caen, 1993). For this purpose, they assessed alexithymia in a
cohort of 60 MS patients (clinical and demographic characteristics were
not mentioned) using BIQ. Alexithymia was found in 50% of their pa-
tients and was correlated with blunted affect -which occurs in the
context of anhedonia- but not with education, gender, disease duration
or cognitive function (details were not provided). Interestingly, based
on the abovementioned connexionist theory (right ‘holistic’ versus left
‘analytical’ hemispheres) and previous works documenting deficient
IHT in MS (Rubens et al., 1985; Lindeboom & ter Horst, 1988; Rao et al.,
1989; Pelletier et al., 1993), the authors also performed a visual task,
the Parallel Visual Information Processing Test (PVIPT), to assess the
capacity of visual holistic (involuntary) attention during the perfor-
mance of logical distraction task (Montreuil and Jouvent, 1989). In
other words, PVIPT tests the individual’s ability to consciously retrieve
the emotional component of photographs which are simultaneously
presented during the performance of a dual task. Interestingly, perfor-
mance on PVIPT was significantly correlated with BIQ scores, pleading
for a possible role of IHT in the occurrence of alexithymia. Nowadays,
extensive data exist on aberrant IHT and CC pathologies in the context
of MS (Rao et al., 1989; Pelletier et al., 2001; Wishart et al., 1995;
Brown et al., 2003, 2010; Warlop et al., 2008; Bonzano et al., 2011).
Hence, further investigations are greatly needed to understand the
contribution of such an aberrant transfer to the generation of alex-
ithymia in this disease.
Ever since Montreuil and Lyon-Caen’s work, the available literature
consists of 14 studies, 10 using TAS-20 (Bodini et al., 2008; Chahraoui
M.A. Chalah, S.S. Ayache
et al., 2014; Gay et al., 2010; Prochnow et al., 2011; Fernández-Jiménez
et al., 2013; Cecchetto et al., 2014; Gleichgerrcht et al., 2015; Patil
et al., 2016b), 3 employing BVAQ Form B (Mosson et al., 2014; Dulau,
Feb 20 et al., 2017; Gay et al., 2017; Raimo et al., 2017), and 1 using
BIQ (Montreuil and Lyon-Caen, 1993). Although the prevalence of
alexithymia in the general population varies between 10% and 20.7%
(Salminen et al., 1999; Guilbaut et al., 2002), it seems to be higher in
MS patients where it ranges from 10% to as high as 53% (Bodini et al.,
2008; Chahraoui et al., 2014; Gay et al., 2010; Prochnow et al., 2011;
Fernández-Jiménez et al., 2013; Cecchetto et al., 2014; Gleichgerrcht
et al., 2015; Patil et al., 2016b; Dulau, Feb 20 et al., 2017; Gay et al.,
2017). The prevalence of each alexithymia dimension was not reported
in the majority of MS studies except one (Dulau et al., 2017), where
cognitive dimension was found to be more frequent (around 20%) than
the affective one (7%).
Such a disparity in alexithymia prevalence might be partly attrib-
uted to the difference in the adapted TAS-20 cut-offs which might have
accounted for the relatively high prevalence reported by some French
studies (Chahraoui et al., 2008; Gay et al., 2010). This is particularly
illustrated in the work of Gay and colleagues, where the rate of alex-
ithymia changed from 23% to 38.2% when using the North-American
and French cutoff scores, respectively (TAS-20 total > 60 vs. > 55)
(Gay et al., 2010).
Another reason might be the cultural difference, a finding that was
previously documented in healthy cohorts where alexithymia rates
differed among ethnic origins (Le et al., 2002; Dere et al., 2013). Here,
it is important to mention that the available MS studies were mainly
performed in European populations (French (n = 7), Italian (n = 3),
Spanish (n = 1) and German (n = 1)) with only two works done in
American populations. Demographic differences might have also im-
pacted the results of various studies. Notably, gender and age differ-
ences were previously described in the context of alexithymia (Mattila
et al., 2006; Goerlich-Dobre et al., 2015a; Colic et al., 2016). In fact, the
selected studies varied in their gender and age compositions, with
women participation ranging from 34.3% (Prochnow et al., 2011) to
87.3% (Gleichgerrcht et al., 2015) and mean age ranging from 34.2
(Cecchetto et al., 2014) to 50.2 years (Mosson et al., 2014). Methodo-
logical differences, mainly the adopted scale, might have also inter-
fered, knowing that 11/14 studies used TAS-20 while only two adopted
BVAQ Form B (Dulau et al., 2017: Gay et al., 2017). Finally, clinical and
neuropsychological variables such as disease type, disease duration,
expanded disability status scale scores (EDSS, Kurtzke, 1983), mood
and cognitive functions might have also contributed to the observed
difference in alexithymia rates. The relationship between alexithymia
and the stated variables will be explored in the following section.
9.1. Alexithymia, clinical and demographic characteristics
As stated above, alexithymia could be associated with clinical and
sociodemographic characteristics (Mattila et al., 2006; Goerlich-Dobre
et al., 2015a; Colic et al., 2016). Concerning MS studies, one should
bear in mind that only few of them assessed such an association. For
instance, one study showed that alexithymic patients were younger
than non-alexithymic ones (Chahraoui et al., 2008). Another one found
that the prevalence of alexithymia was higher in patients with primary
progressive MS (27%) compared to the whole group (12%) (Dulau
et al., 2017). Other works did not find any difference in these variables
(age, gender, education, disease duration, EDSS, or number of relapses)
between alexithymic and non-alexithymic MS patients (Chahraoui
et al., 2008; Bodini et al., 2008) or between MS patients and healthy
controls (HCs) (Gleichgerrcht et al., 2015; Patil et al., 2016b; Dulau
et al., 2017).
Moreover, alexithymia was found to be inversely correlated with
age in one study (Chahraoui et al., 2008) and directly correlated with
the number of relapse at 5 years in another study (Chahraoui et al.,
2014). The remaining works did not detect any correlation between
40
Neuropsychologia 104 (2017) 31–47
alexithymia and demographic data (particularly gender and education)
(Montreuil and Lyon-Caen, 1993; Chahraoui et al., 2014), or clinical
characteristics, namely EDSS (Chahraoui et al., 2014; Gay et al., 2010;
Gleichgerrcht et al., 2015; Patil et al., 2016b; Dulau, Feb 20 et al., 2017;
Gay et al., 2017), disease duration (Montreuil and Lyon-Caen, 1993;
Chahraoui et al., 2014; Gleichgerrcht et al., 2015; Patil et al., 2016b;
Dulau, Feb 20 et al., 2017), disease type (Chahraoui et al., 2014), or
number of relapses (Chahraoui et al., 2008; Gleichgerrcht et al., 2015;
Patil et al., 2016b).
9.2. Alexithymia and neuropsychological variables
MS patients commonly suffer from cognitive deficits (Rao et al.,
1991a, 1991b; Benedict et al., 2006; Sanfilipo et al., 2006; Ayache
et al., 2015; Van Schependom et al., 2015; Cotter et al., 2016; Chalah
and Ayache, 2017b). Alexithymia has been associated sometimes with
neuropsychological performance such as executive function in healthy
individuals (Santorelli and Ready, 2015), visuospatial processing in
Parkinson’s disease (Costa et al., 2007) and elderly populations (Onor
et al., 2010), and verbal abilities in healthy veterans (Lamberty and
Holt, 1995). In some populations, like traumatic brain injury (TBI),
diverging results exist with regards to such a relationship (e.g. execu-
tive function: positive in Henry et al., 2006; negative in Wood and
Williams, 2007).
In MS, the first evidence on this matter was provided by Montreuil
and Lyon-Caen who briefly mentioned that alexithymia did not differ
between cognitively preserved and impaired MS patients (Montreuil
and Lyon-Caen, 1993). After that, only one study by Dulau et al. has
extensively evaluated the relationship between alexithymia and cog-
nitive measures (Dulau et al., 2017). No association was found between
alexithymia and each of attention, information processing speed,
memory, and executive function. The remaining studies neither as-
sessed cognitive functions (Chahraoui et al., 2014; Mosson et al., 2014;
Bodini et al., 2008; Gay et al., 2017; Fernández-Jiménez et al., 2013;
Gleichgerrcht et al., 2015; Patil et al., 2016b) nor studied their corre-
lation with alexithymia (Prochnow et al., 2011; Cecchetto et al., 2014;
Raimo et al., 2017).
9.3. Alexithymia and mood disorders
A bidirectional relationship seems to exist between immune dysre-
gulation-the main pathophysiological mechanism of MS- and mood
disorders (Irwin & Miller, 2007). Regarding MS, several psychiatric
comorbidities could be encountered in this disease (José Sá, 2008).
Depression is the most prevalent one affecting up to 50% of patients,
followed by anxiety with a prevalence ranging from 14% to 41%
(Chalah and Ayache, 2017a).
Admitting the established relationship between alexithymia and
mood based on the available literature (Berthoz et al., 1999; Wood and
Williams, 2007), MS studies on alexithymia also accounted for anxiety
and depression in their evaluation.
9.3.1. Alexithymia and depression
With regards to depression, high rates of the latter (26.9–47.1%)
were observed among MS cohorts screened for alexithymia (Chahraoui
et al., 2008; 2014; Gay et al., 2010, 2017; Prochnow et al., 2011),
among alexithymics compared to lexithymic MS patients (Bodini et al.,
2008; Chahraoui et al., 2008) or among MS patients compared to HCs
(Dulau et al., 2017). Concerning the correlation between depression
and alexithymia, it was not assessed in four trials (Fernández-Jiménez
et al., 2013; Gleichgerrcht et al., 2015; Patil et al., 2016b; Raimo et al.,
2017), was negative in two (Dulau et al., 2017; Gay et al., 2017) and
positive in the remaining studies (Bodini et al., 2008; Chahraoui et al.,
2008; 2014; Gay et al., 2010; Cecchetto et al., 2014; Mosson et al.,
2014). Inerestingly, one study found that DIF subscale of alexithymia is
the strongest factor associated with depression (Bodini et al., 2008).
M.A. Chalah, S.S. Ayache
More interestingly, alexithymia was found to be a major predictor to
the development of depression based on causal path analysis models
(Gay et al., 2010). Conversely, Chahraoui et al. failed to identify de-
pression as a predictor for alexithymia (Chahraoui et al., 2008).
9.3.2. Alexithymia and anxiety
In the context of MS, data on the presence of anxiety and its re-
lationship with alexithymia come from only few studies, which detected
high rates of anxiety (20.6 – 45.5%) among MS patients evaluated for
alexithymia (Chahraoui et al., 2008, 2014; Gay et al., 2010, 2017). In
addition, anxiety was found to be more frequent in alexithymic com-
pared to lexithymic patients (Chahraoui et al., 2008). However, alex-
ithymia did not differ between anxious and nonanxious MS patients
(Gay et al., 2017).
As for the correlation between alexithymia and anxiety, it was po-
sitive in four studies (Chahraoui et al., 2008, 2014; Gay et al., 2010;
Mosson et al., 2014), weak in one (Gay et al., 2017) and negative in one
(Dulau et al., 2017).
9.3.3. Alexithymia and coping strategies
It is of high importance here to analyze the studies performed by
Chahraoui and colleagues which assessed the relationship between the
different subscales of TAS-20 (DIF, DDF, EOT) (Chahraroui et al., 2008;
2014), and presented for the first time a longitudinal follow up of
alexithymia in MS (Chahraoui et al., 2014). In their first work, DIF was
significantly correlated with both anxiety and depression, DDF was only
correlated with anxiety, and EOT was not correlated with any of the
mood scales (Chahraoui et al., 2008). Based on these findings, EOT
seems to be a specific feature of alexithymia. In fact, by externally or-
ienting their thinking and preoccupations, MS patients might find a way
to deny or avoid facing their interior feelings, particularly the extreme
anxiety which could arise from the stressful course of the disease.
Whether EOT represents a stable factor linked to personality or occurs
as a coping mechanism in the context of MS could not be answered
based on this unique cross-sectional study but needs to be further ad-
dressed in a longitudinal one. For this reason, Chahraoui and colleagues
followed an MS cohort over 5 years aiming to better understand the
course of alexithymia and its dimensions (Chahraoui et al., 2014). At 5
years, TAS-20 total scores and its DIF and DDF subscales remained
constant. Both subscales were also correlated with depression and an-
xiety as seen in the first study. However, EOT subscale decreased over
time, was correlated with relapse rate, and most importantly was in-
dependent from anxiety and depression. In addition, anxiety did not
significantly change while depression fell five years later. Therefore,
EOT seems to be a defensive coping strategy aiming to refute or evade
from the distressing feelings that would accompany a heterogeneous
disease such as MS. Indeed, MS patients need to survive the traumatism
of sudden and unexpected relapses, the uncertainty of functional status
following such events, and the unpredictable nature of disease pro-
gression. During the remission phase, their fear would focus on ex-
periencing a new relapse. During a relapse, they would try to anticipate
the possible functional deficits heralded by the event. And during the
progressive phase, the concrete functional decline would present an
additional source of worry about the future. Therefore, the reduction in
EOT, as well as depression scores, at the study end-point might in fact
reflect a better acceptance of the disease, a better adjustment to its
frightening consequences, and thus a lesser necessity to a coping
strategy such as EOT.
9.4. Alexithymia and fatigue
In the context of MS, fatigue is known to be a frequent and difficult
to treat symptom (Chalah et al., 2015; José Sá, 2008; Ayache and
Chalah, 2017a). The frequency of fatigue and its relationship with
alexithymia were addressed in only three studies (Bodini et al., 2008;
Cecchetto et al., 2014; Mosson et al., 2014). Higher rates of fatigue
41
Neuropsychologia 104 (2017) 31–47
were found among MS patients screened for alexithymia (53.8% in
Cecchetto et al., 2014) or in alexithymic compared to lexithymic ones
(Bodini et al., 2008). In addition, fatigue was significantly correlated
with alexithymia in only two trials (Bodini et al., 2008; Mosson et al.,
2014). The third one failed to show such a correlation (Cecchetto et al.,
2014) and this might be attributed to its relatively small sample size (n
= 26 in Cecchetto et al., 2014 vs. n = 37 in Mosson et al., 2014 and n
= 58 in Bodini et al., 2008). Finally, a stepwise regression analysis
identified the DIF alexithymia subscale as a predictor for the occurrence
of fatigue (Bodini et al., 2008). This finding sheds the light on the au-
tonomic hyperarousal and heightened attention to bodily sensations,
which are usually described in the context of alexithymia. In other
words, enhanced arousal might increase MS patients’ tendency to in-
tensify bodily sensations, and hence to exaggerate their perception of
fatigue (Lumley et al., 1996; Larsen et al., 2003).
9.5. Alexithymia and emotion regulation
Some data propose that MS patients have difficulties in regulating
their emotions and infrequently use the emotional reappraisal strategy
(Phillips et al., 2009, 2014). Only two studies have simultaneously as-
sessed alexithymia and emotion regulation (Mosson et al., 2014; Gay
et al., 2017). Emotion regulation was inversely correlated with alex-
ithymia total and EMO scores (weak: r = −0.33 and r = −0. 35,
respectively) in the first one (Mosson et al., 2014), and with the ID,
ANL, and EMO scores (very weak correlations ranging from 0.15 to
0.16) in the second one (Gay et al., 2017). The results of these studies
would further support the implication of emotion regulation as an un-
derlying mechanism in the development of alexithymia. However, the
dearth of data on this topic and the observed weak/very weak corre-
lations prompt further investigations to decipher the origins of alex-
ithymia and its relationship with emotional dysregulation in MS.
9.6. The Alexithymia hypothesis and social cognition
Growing evidence supports the existence of a relationship between
understanding one's own and other's emotional states. The ‘alexithymia
hypothesis’ or the ‘simulationist hypothesis’ implies that the ability to
understand our own mental states is important to be able to understand
those of others (Parker et al., 2005; Goldman and Sripada, 2005;
Barsalou, 2008; Prkachin et al., 2009; Jessimer et al., 1997; Swart et al.,
2009; McDonald et al., 1990; Moriguchi et al., 2006, 2007; Guttman
and Laporte, 2002; Grynberg et al., 2012 ; FeldmanHall et al., 2012;
Bird and Cook, 2013; Prochnow et al., 2013; Bogdanov et al., 2013;
Neumann et al., 2014 ; Aaron et al., 2015). In addition, the recent
concept of ‘shared emotional representation between self and other’
implies that, when emphasizing with someone, the individual empathic
reaction is grounded in his/her own emotion experience (Lamm et al.,
2016). Here, the individual may co-represent the affect of others by
putting into action cerebral and bodily functions that underlie the first-
hand experience of the concerned emotion. Althought different, all
these ideas suggest that alexithymia can be behind deficits in social
cognition. The available data from clinical studies point to low social
cognitive abilities in patients with alexithymia (Guttman and Laporte,
2002; Swart et al., 2009; Grynberg et al., 2012) as well as abnormal
pattern of cerebral activation during social cognitive processing (Kano
et al., 2003). Remarkably, both processes seem to activate common
brain areas such as medial PFC, superior temporal gyrus, posterior
cingulate cortex and precuneus (Ochsner et al., 2004). Only five studies
have assessed alexithymia in the context of social cognition in MS pa-
tients (Prochnow et al., 2011; Cecchetto et al., 2014; Gleichgerrcht
et al., 2015; Patil et al., 2016b; Dulau et al., 2017).
9.6.1. Facial emotion recognition & theory of mind
Two of the earliest studies have assessed alexithymia and facial
emotion recognition. In one of them, compared to HCs, MS patients
M.A. Chalah, S.S. Ayache
exhibited higher rates of alexithymia, depression and cognitive decline,
and deficits in recognizing facial emotions (Prochnow et al., 2011). The
other one failed to document any difference on alexithymia between
patients and their healthy counterparts; although the former were im-
paired on facial emotion recognition and to a lesser extent (non-sig-
nificant) on bodily emotion recognition (Cecchetto et al., 2014).
Moreover, in both studies, no correlation was found between alex-
ithymia and facial emotion recognition (Prochnow et al., 2011, 2014)
or bodily emotion recognition (Cecchetto et al., 2014).
In a third work, the authors attempted to overcome the previous
limitations and provided an extensive assessment of mood, neu-
ropsychological/cognitive functions, social cognition and alexithymia
(Dulau et al., 2017). Compared to HCs, MS patients had higher de-
pression scores, deficits in ToM, but showed no difference in facial
emotion recognition or alexithymia (Dulau et al., 2017). Interestingly,
at patients’ level, alexithymia was higher in primary progressive pa-
tients compared to the whole group (27% vs. 12%), with higher pre-
valence of the cognitive dimension compared to the affective one
(around 20% vs. 7%, respectively) (Dulau et al., 2017). Although sig-
nificant correlations were detected between ToM and some cognitive
functions (i.e. executive functions, working memory and episodic
memory), alexithymia scores were not correlated with any cognitive
variable. Nevertheless, the authors considered alexithymia as a social
cognitive domain and its correlation with facial emotion recognition or
ToM was not assessed in this study (Dulau et al., 2017). The latter
limitation was recently addressed by Raimo and colleagues who eval-
uated their MS cohort by means of a comprehensive neuropsychological
battery which included ToM tests (Raimo et al., 2017). Compared to
HCs, patients had higher alexithymia and depression scores, worse
cognitive performance (i.e. IPS, visuospatial learning and memory), and
significant deficits in ToM tasks. Intrestingly, a significant inverse
correlation was found between the latter (i.e. Reading the Mind in the
Eyes Test) and alexithymia.
Therefore, based on these studies, the alexithymia hypothesis does
not seem to apply in MS patients with regards to facial emotion re-
cognition, a finding that is in line with some studies in psychiatric
patients (e.g. substance abuse in Mann et al., 1995; eating disorders in
Kessler et al., 2006). Deficits in facial emotion recognition might
therefore be a social cognitive signature of MS independent from
alexithymia. One might also propose that the easiness of facial emotion
recognition tasks might be behind the lack of correlation. However,
although the study by Cecchetto and colleagues employed an easy task,
Prochnow and colleagues used a relatively advanced task and still could
not establish such a relationship (Prochnow et al., 2011; Cecchetto
et al., 2014). Regarding ToM, the only study that addressed this issue
supports the existence of a relationship between alexithymia and ToM
(Raimo et al., 2017), a finding that merits to be addressed in further
works.
9.6.2. Empathy
The relationship between alexithymia and empathy has been al-
ready reported in the literature (Bird et al., 2010; Bogdanov et al.,
2013; Al Ain et al., 2013; Lockwood et al., 2013). Only two MS studies
have assessed the association between alexithymia and empathy. They
also included measures for moral cognition (Gleichgerrcht et al., 2015;
Patil et al., 2016b) based on evidence supporting the presence of a
relationship between moral cognition, empathy and alexithymia
(Koven, 2011; Patil and Silani, 2014; Patil et al., 2016a; Cecchetto
et al., 2017). In both studies, relative to the controls, patients exhibited
higher alexithymia scores (TAS-20 total and subscales), lower levels of
empathy and an altered moral judgment. In one of them, significant
inverse correlation was found between alexithymia and empathy scores
as well as a positive correlation between abnormal moral judgment and
alexithymia (Gleichgerrcht et al., 2015). Both studies reported positive
correlation between empathy and altered moral judgment
(Gleichgerrcht et al., 2015; Patil et al., 2016b).
42
Neuropsychologia 104 (2017) 31–47
Hence, low empathic abilities and high alexithymia seem to con-
tribute to altered moral judgment capacities in MS patients
(Gleichgerrcht et al., 2015). In fact, moral cognition involves high order
mental processes that are crucial for healthy social interactions. The
observed moral judgment features in MS could be interpreted in the
light of the dual-process model of moral cognition initially proposed by
Greene and colleagues (Greene et al., 2001, 2004, 2008; Koenigs et al.,
2007; Gleichgerrcht et al., 2011; Gleichgerrcht and Decety, 2013a;
Gleichgerrcht et al., 2013b). Here, facing a moral dilemma would result
in a conflict between the ventromedial PFC (vmPFC) which is in charge
of the automatic emotional aversion to harm and the dlPFC which en-
sures a controlled cognitive ability to maximize aggregate welfare at
any cost. In this model, the ACC would interplay in monitoring the
conflict resolution. Based on this model, vmFPC might be more acti-
vated than dlPFC in MS patients, a finding that merits being addressed
in future studies.
10. Conclusion
These data altogether hint to a high prevalence of alexithymia in
patients with MS. Etiologically speaking, the only available study pro-
poses a crucial role of IHT in the development of this trait (Montreuil
and Lyon-Caen, 1993). Some evidence suggests an association between
alexithymia and anxiety, depression, fatigue and social cognitive mea-
sures. Admitting the shortage of data regarding its relationship with
sociodemographic variables, disease characteristics, and neuropsycho-
logical measures, it is premature to draw any conclusion on the matter
and further investigations are highly required. One should pay attention
to the major limitations of the present studies. The cross-sectional de-
sign of most of them does not allow to establish any causality between
alexithymia and other variables. Another shortcoming is the absence of
healthy controls in the majority of trials. Furthermore, the scarcity of
correlation analysis done with regards to the disease characteristics
does not allow to understand the course of alexithymia in relation to the
natural history of MS.
The following questions might be raised: Is alexithymia a trait or a
state? Is it a primary feature or a secondary phenomenon in MS po-
pulation? And finally, does it get aggravated or change over time?
Obviously, these questions require further consideration in future
longitudinal studies. Concerning alexithymia per se, it is still unclear
whether it occurs primarily as a result of MS pathological changes
themselves, or it is secondary to the psychological distress generated by
a chronic disease, or it is due to both factors. Nowadays, it is difficult to
solve this dilemna, since we are faced by the lack of imaging studies and
the paucity of neuropsychological investigations in this context. At the
same time, little evidence exists on the progression of alexithymia over
time. It seems to have a stable pattern, at least in what concerns the
ability to identify and describe feelings. The EOT appears to be a coping
strategy upon which patients rely to overcome their suffering, espe-
cially at the beginning of their illness. Later, their stress would ease as
they become more accustomed to the disease, accept their fate and thus
experience less fear towards their future.
Future studies would benefit from adapting a longitudinal design
and enrolling patients with different MS subtypes in order to under-
stand the occurrence of alexithymia across different phenotypes and to
assess the stability of this trait over time. Admitting the lack of data on
its pathophysiology, it would be helpful for researchers to integrate
different neuroimaging and neurophysiological techniques in their
studies, notably the resting-state functional connectivity and diffusion
tensor imaging tractography. The latter would help in identifying the
strength and direction of fibers that constitute CC, for example.
Magnetic resonance spectroscopy is a third imaging technique that
would provide additional information on aberrant neurochemical
transmissions, which may pave the way for developing pharmacological
therapies. Furthermore, non-invasive brain stimulation techniques
might play a key role in the exploration of neurophysiological
M.A. Chalah, S.S. Ayache
correlates of alexithymia and in the modulation of the functioning of
various cortical areas involved in its pathophysiology.
Declaration of interest
This work did not receive any specific grant. SSA declares having
received travel grants or compensation from Genzyme, Biogen, Novartis
and Roche. MAC declares no conflict of interest.
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