Skip to main content Accessibility help
×
Home

Information:

  • Access
  • Cited by 25

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Deficits in Social Cognition: An Unveiled Signature of Multiple Sclerosis
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Deficits in Social Cognition: An Unveiled Signature of Multiple Sclerosis
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Deficits in Social Cognition: An Unveiled Signature of Multiple Sclerosis
        Available formats
        ×
Export citation

Abstract

Background and Objectives: Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system, representing the primary cause of non-traumatic disability in young adults. Cognitive dysfunction can affect patients at any time during the disease process and might alter the six core functional domains. Social cognition is a multi-component construct that includes the theory of mind, empathy and social perception of emotions from facial, bodily and vocal cues. Deficits in this cognitive faculty might have a drastic impact on interpersonal relationships and quality of life (QoL). Although exhaustive data exist for non-social cognitive functions in MS, only a little attention has been paid for social cognition. The objectives of the present work are to reappraise the definition and anatomy of social cognition and evaluate the integrity of this domain across MS studies. We will put special emphasis on neuropsychological and neuroimaging studies concerning social cognitive performance in MS. Methods:Studies were selected in conformity with PRISMA guidelines. We looked for computerized databases (PubMed, Medline, and Scopus) that index peer-reviewed journals to identify published reports in English and French languages that mention social cognition and multiple sclerosis, regardless of publication year. We combined keywords as follows: (facial emotion or facial expression or emotional facial expressions or theory of mind or social cognition or empathy or affective prosody) AND multiple sclerosis AND (MRI or functional MRI or positron emission tomography or functional imaging or structural imaging). We also scanned references from articles aiming to get additional relevant studies. Results: In total, 26 studies matched the abovementioned criteria (26 neuropsychological studies including five neuroimaging studies). Available data support the presence of social cognitive deficits even at early stages of MS. The increase in disease burden along with the “multiple disconnection syndrome” resulting from gray and white matters pathology might exceed the “threshold for cerebral tolerance” and can manifest as deficits in social cognition. Admitting the impact of the latter on patients’ social functioning, a thorough screening for such deficits is crucial to improving patients’ QoL. (JINS, 2017, 23, 266–286)

INTRODUCTION

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) representing the primary cause of non-traumatic disability in young adults (Compston & Coles, Reference Compston and Coles2008). Its precise etiology remains unclear and includes a constellation of mechanisms. Its most common type is the relapsing-remitting (RR) which usually shifts to a secondary progressive (SP) fate (Compston & Coles, Reference Compston and Coles2008). Primary progressive (PP) MS is a third form which still does not have approved disease-modifying therapies and is considered to have a poor prognosis (Gajofatto & Benedetti, Reference Gajofatto and Benedetti2015; Segal & Stüve, Reference Segal and Stüve2016). The disease course can be very heterogeneous, through which patients may develop sensorimotor, cerebellar, emotional, and cognitive symptoms (Compston & Coles, Reference Compston and Coles2008).

Cognitive decline occurs in approximately 40–65% of MS patients at some point during their life (Benedict et al., Reference Benedict, Cookfair, Gavett, Gunther, Munschauer, Garg and Weinstock-Guttman2006; Rao, Leo, Bernardin, & Unverzagt, Reference Rao, Leo, Bernardin and Unverzagt1991; Sanfilipo, Benedict, Weinstock-Guttman, & Bakshi, Reference Sanfilipo, Benedict, Weinstock-Guttman and Bakshi2006) and may involve any of the six core functional domains: are perceptual-motor functions, language, learning and memory, executive functions, complex attention, and social cognition (5th ed.; DSM–5; American Psychiatric Association, 2013). Working memory and information processing speed (IPS) are the most frequently impaired areas in MS, followed by learning, memory, and executive functions (Benedict et al., Reference Benedict, Cookfair, Gavett, Gunther, Munschauer, Garg and Weinstock-Guttman2006; Rao, Leo, Bernadin, et al., Reference Rao, Leo, Bernardin and Unverzagt1991; Sanfilipo et al., Reference Sanfilipo, Benedict, Weinstock-Guttman and Bakshi2006).

Although these domains have been well studied in MS (Mohr & Cox, Reference Mohr and Cox2001), little attention has been paid for social cognition, which defines the individual’s ability to understand others’ mind and feelings (Sebastian et al., Reference Sebastian, Fontaine, Bird, Blakemore, De Brito, McCrory and Viding2012; Uekermann, Channon, Winkel, Schlebusch, & Daum, Reference Uekermann, Channon, Winkel, Schlebusch and Daum2007; Uekermann & Daum, Reference Uekermann and Daum2008; Uekermann et al., Reference Uekermann, Kraemer, Abdel-Hamid, Schimmelmann, Hebebrand, Daum and Kis2010; Vistoli, Brunet-Gouet, Baup-Bobin, Hardy-Bayle, & Passerieux, Reference Vistoli, Brunet-Gouet, Baup-Bobin, Hardy-Bayle and Passerieux2011; Wolkenstein, Schonenberg, Schirm, & Hautzinger, Reference Wolkenstein, Schonenberg, Schirm and Hautzinger2011). It is a multi-component construct that includes theory of mind (ToM) (Abdel-Hamid et al., Reference Abdel-Hamid, Lehmkämper, Sonntag, Juckel, Daum and Brüne2009; Koelkebeck, Abdel-Hamid, Ohrmann, & Brune, Reference Koelkebeck, Abdel-Hamid, Ohrmann and Brune2008), empathy (Carr, Iacoboni, Dubeau, Mazziotta, & Lenzi, Reference Carr, Iacoboni, Dubeau, Mazziotta and Lenzi2003; Decety & Jackson, Reference Decety and Jackson2004; Leslie, Johnson-Frey, & Grafton Reference Leslie, Johnson-Frey and Grafton2004; Seitz, Nickel, & Azari, Reference Seitz, Nickel and Azari2006; Vollm et al., Reference Vollm, Taylor, Richardson, Corcoran, Stirling, McKie and Elliott2006), and social perception of emotions from prosody, facial expressions, and bodily gestures (Calder & Young, Reference Calder and Young2005; Ethofer et al., Reference Ethofer, Anders, Erb, Herbert, Wiethoff, Kissler and Wildgruber2006; Heikkinen et al., Reference Heikkinen, Jansson-Verkasalo, Toivanen, Suominen, Vayrynen, Moilanen and Seppanen2010; Ross, Thompson, & Yenkosky, Reference Ross, Thompson and Yenkosky1997; Wheaton, Thompson, Syngeniotis, Abbott, & Puce, Reference Wheaton, Thompson, Syngeniotis, Abbott and Puce2004; Uekermann & Daum, Reference Uekermann and Daum2008; Uekermann, Abdel-Hamid, Lehmkamper, Vollmoeller, & Daum, Reference Uekermann, Abdel-Hamid, Lehmkamper, Vollmoeller and Daum2008).

The integrity of social cognitive functions is crucial for proper retrieval of information from social stimuli, to establish an appropriate social interaction and cope with chronic diseases such as MS (Montel & Bungener, Reference Montel and Bungener2007). In this perspective, deficits in social cognition might have a drastic impact on quality of life (QoL) and interpersonal communication. Interestingly, altered social interactions have been frequently reported in MS patients (Buhse, Reference Buhse2008; Kesselring & Klement, Reference Kesselring and Klement2001; Rao, Leo, Elllington, et al., Reference Rao, Leo, Ellington, Nauertz, Bernardin and Unverzagt1991) and could be reflected by high rates of divorce and unemployment (Julian, Vella, Vollmer, Hadjimichael, & Mohr, Reference Julian, Vella, Vollmer, Hadjimichael and Mohr2008; Langdon, Reference Langdon2011; Pfleger, Flachs, & Koch-Henriksen, Reference Pfleger, Flachs and Koch-Henriksen2010; Rao, Leo, Elllington, et al., Reference Rao, Leo, Ellington, Nauertz, Bernardin and Unverzagt1991) and increased level of social anxiety (Poder et al., Reference Poder, Ghatavi, Fisk, Campbell, Kisely, Sarty and Bhan2009).

The main objective of the present work is to review the available data concerning social cognition in MS. First, we will reappraise terms defining social cognition, particularly social perception of emotions, theory of mind and empathy. This section will also include the neuroanatomy of social cognition in healthy brain. The second section will examine neuropsychological studies regarding social cognition in MS. This will be followed by a third section that puts emphasis on neuroimaging studies of social cognition in this population. Finally, findings will be discussed in the light of the “cognitive reserve” hypothesis. The clinical assessment of social cognition is developed elsewhere (for reviews, see Henry, von Hippel, Molenberghs, Lee, & Sachdev, Reference Henry, von Hippel, Molenberghs, Lee and Sachdev2016) and is beyond the scope of this review.

NEUROANATOMICAL CORRELATES OF SOCIAL COGNITION

In the past few years, tremendous advances in neuroimaging have unveiled many cerebral hubs that take part in brain networks dedicated to social cognition. Although social cognitive domains might recruit different cerebral areas, an overlapping seems to occur among their networks.

Social Perception

Social perception of emotions from facial expressions

A chief element in social interaction is the ability to recognize facial expressions and their emotional significance (Brothers, Reference Brothers1990; Van Kleef, Reference Van Kleef2009). A large-scale network and a complex processing have been suggested by this skill. The first step consists of early visual processing of faces, which entails a relatively shared neural pathway for facial identity discrimination and facial emotion recognition (Calder & Young, Reference Calder and Young2005; LaBar, Crupain, Voyvodic, & McCarthy, Reference LaBar, Crupain, Voyvodic and McCarthy2003; Palermo & Rhodes, Reference Palermo and Rhodes2007; Vuilleumier & Pourtois, Reference Vuilleumier and Pourtois2007). In the following steps, distinct cortical regions would intervene. For instance, the fusiform face area (FFA) plays a key role in recognizing invariant or neutral facial aspect that defines identity (Kanwisher & Yovel, Reference Kanwisher and Yovel2006). Other areas, such as the superior temporal sulcus (STS), are more specialized in changeable facial features (i.e., perception of eyes and mouth movements; Allison, Puce, & McCarthy, Reference Allison, Puce and McCarthy2000). The amygdala is an essential element in automatic attentional capture by emotionally relevant facial expressions (Vuilleumier & Pourtois, Reference Vuilleumier and Pourtois2007). The orbitofrontal cortex (OFC) is crucially involved in processing non-conscious aspects of facial expressions (Adolphs, 2006; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009). To note, non-conscious perception of emotional stimuli is an intrinsic property of the healthy brain. Through this process, emotionally relevant visual stimuli that are not perceived consciously can induce behavioral responses manifesting as changes in emotional states (Tamietto & de Gelder, Reference Tamietto and de Gelder2010).

Of interest, observing facial emotions is known to trigger an affective reaction which subsequently leads to adaptive changes in the observer’s behavior (Van Kleef, Reference Van Kleef2009). Such a reaction depends on the generation of an “emotional state” and a “motivation state.” The former is mainly created by the anterior insula that integrates environmental cues with viscero-reception of internal body state (Adolphs, Reference Adolphs2002). The latter is completed via the action of the anterior cingulate cortex (ACC; Critchley, Reference Critchley2005).

Social perception of vocal cues: Affective prosody

Prosody is an aspect of language represented by acoustic characters such as the pattern of intonation (i.e., timing, pitch, rhythm, stress, and pausing; Heikkinen et al., Reference Heikkinen, Jansson-Verkasalo, Toivanen, Suominen, Vayrynen, Moilanen and Seppanen2010; Uekermann & Daum, Reference Uekermann and Daum2008; Uekermann, Abdel-Hamid et al., Reference Uekermann, Abdel-Hamid, Lehmkamper, Vollmoeller and Daum2008). Among the subdivisions of prosody, the most relevant here are the linguistic and affective components (Ross et al., Reference Ross, Thompson and Yenkosky1997; Uekermann & Daum, Reference Uekermann and Daum2008). While processing linguistic prosody seems to involve left-sided brain regions, perception of affective prosody is a dominant function of the right hemisphere and encompasses many steps (Ethofer et al., Reference Ethofer, Anders, Erb, Herbert, Wiethoff, Kissler and Wildgruber2006; Uekermann & Daum, Reference Uekermann and Daum2008; Uekermann, Abdel-Hamid, et al., Reference Uekermann, Abdel-Hamid, Lehmkamper, Vollmoeller and Daum2008; Wildgruber, Ackermann, Kreifelts, & Ethofer, Reference Wildgruber, Ackermann, Kreifelts and Ethofer2006).

For example, primary and higher order right-hemispheric acoustic areas deal with extracting suprasegmental acoustic information whose meaningful representation mainly involves the right STS. Bilateral inferior frontal regions maintain an explicit assessment of affective prosody. Lastly, the corpus callosum (CC) participates by ensuring the inter-hemispheric integration of language functions (Ross et al., Reference Ross, Thompson and Yenkosky1997); this seems crucial to understanding emotional prosody, especially when the latter is not in agreement with the linguistic component. In this situation, a proper understanding requires a successful prioritization of the affective aspect over the linguistic one (Uekermann et al., Reference Uekermann, Kraemer, Abdel-Hamid, Schimmelmann, Hebebrand, Daum and Kis2010).

Theory of Mind

ToM, also known as “mentalizing,” suggests understanding and predicting mental states of others, based on (i) their emotions and feelings (affective ToM) and/or (ii) their intentions, thoughts, and beliefs (cognitive ToM; Stone, Baron-Cohen, & Knight, Reference Stone, Baron-Cohen and Knight1998; Uekermann et al., Reference Uekermann, Channon, Winkel, Schlebusch and Daum2007; Uekermann, Channon, et al., Reference Uekermann, Channon, Lehmkamper, Abdel-Hamid, Vollmoeller and Daum2008). ToM is a key aspect of social cognition and constitutes an important prerequisite for adequate social interactions. The two extremes of ToM abnormalities are known as “undermentalizing” (insufficient ToM) and “overmentalizing” (excessive ToM), which, respectively, refer to deficits commonly encountered in patients with autism (Baron-Cohen, Reference Baron-Cohen2000) and schizophrenia (Frith, Reference Frith2004).

ToM recruits a complex neural network which includes the ACC, OFC, amygdala and many areas of the temporal lobe (i.e., posterior STS, temporal pole, and temporoparietal junction [TPJ]; Adolphs et al., Reference Adolphs, Baron-Cohen and Tranel2002; Frith & Frith, Reference Frith and Frith2006; Herold et al., Reference Herold, Feldmann, Simon, Tényi, Kövér, Nagy and Fekete2009; Kuperberg et al., Reference Kuperberg, Broome, McGuire, David, Eddy, Ozawa and Fischl2003; Schulte-Rüther et al., Reference Schulte-Rüther, Greimel, Markowitsch, Kamp-Becker, Remschmidt, Fink and Piefke2011; Stone et al., Reference Stone, Baron-Cohen and Knight1998; Uekermann et al., Reference Uekermann, Channon, Winkel, Schlebusch and Daum2007, Reference Uekermann, Kraemer, Abdel-Hamid, Schimmelmann, Hebebrand, Daum and Kis2010). Remarkably, available data suggest that ToM subcomponents be modulated by distinct frontal circuits. Saying differently, while the ventromedial prefrontal cortex (VMPFC) appears to be particularly involved in processing affective ToM (Shamay-Tsoory & Aharon-Peretz, Reference Shamay-Tsoory and Aharon-Peretz2007); the ventrolateral prefrontal (VLPFC) and dorsolateral prefrontal cortices (DLPFC) seem to be chiefly implicated in mediating cognitive ToM (Shamay-Tsoory & Aharon-Peretz, Reference Shamay-Tsoory and Aharon-Peretz2007).

Empathy

Empathy lies in the individual’s ability to reason, predict the consequences of emotions, and have a compassionate response accordingly (Decety & Jackson, Reference Decety and Jackson2004; Ruby & Decety, Reference Ruby and Decety2004; Uekermann & Daum, Reference Uekermann and Daum2008; Uekermann, Channon, et al., Reference Uekermann, Channon, Lehmkamper, Abdel-Hamid, Vollmoeller and Daum2008; Uekermann et al., Reference Uekermann, Kraemer, Abdel-Hamid, Schimmelmann, Hebebrand, Daum and Kis2010). Such a skill consists of taking another person’s perspective (other-oriented emotions), which often leads to altruistic helping behavior. In contrast, self-oriented emotions, such as personal distress, primarily focus on the empathizer’s feelings in a way that it might interfere with prosocial behavior and, therefore, are not considered empathy (Davis, Reference Davis1983; Tangney, Stuewig, and Mashek, Reference Tangney, Stuewig and Mashek2007). The empathy network includes anterior insula and regions of the prefrontal and frontal cortices (i.e., dorsal and middle parts of the ACC, supplementary motor areas; Decety & Jackson, Reference Decety and Jackson2004; Fan, Duncan, de Greck, & Northoff, Reference Fan, Duncan, de Greck and Northoff2011; Gallese, Keysers, & Rizzolatti, 2004; Seitz et al., Reference Seitz, Nickel and Azari2006; Vollm et al., Reference Vollm, Taylor, Richardson, Corcoran, Stirling, McKie and Elliott2006).

STUDY SELECTION

For the aims of this review, studies were selected in conformity with PRISMA guidelines (Moher et al., Reference Moher, Liberati, Tetzlaff and Altman2009). First, we searched for computerized databases that index peer-reviewed journals (PubMed, Medline, and Scopus) to identify published reports, in English and French languages, mentioning social cognition and multiple sclerosis, regardless of publication year. For the section dealing with neuropsychological studies, we combined keywords as follows: (facial emotion or facial expression or emotional facial expressions or theory of mind or social cognition or empathy or affective prosody) AND multiple sclerosis. Second, for the section dedicated to neuroimaging underpinnings of social cognitive performance in MS, our combination consisted of the previous keywords AND [MRI/functional MRI (fMRI)/positron emission tomography (PET)/functional imaging/structural imaging]. In both researches, we scanned references from articles aiming to get additional relevant studies. Twenty-six neuropsychological studies matched these criteria (25 in English, 1 in French), of which five also contained neuroimaging data.

SOCIAL COGNITION ACROSS MULTIPLE SCLEROSIS STUDIES

After defining social cognition and its neuroanatomical substrates in healthy humans, we will continue by reviewing the neuropsychological studies assessing social cognition in MS patients.

Social Perception

Social perception of facial emotions in multiple sclerosis

In the past two decades, there was a growing interest in understanding the abilities of MS patients to recognize emotional facial expressions (EFE). The earliest insight into this topic came from a pioneering study by Beatty and colleagues (Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989). Patients with chronic progressive MS and age and education matched healthy controls (HCs) performed the Benton Facial Recognition Test (BFRT) for facial identity discrimination (Benton, Sivan, Hamsher, Varney, & Spreen, Reference Benton, Sivan, Hamsher, Varney and Spreen1994) and an affective judgment task that evaluates the ability to recognize the six basic facial emotions (i.e., happiness, sadness, anger, fear, disgust and surprise; Ekman and Friesen, Reference Ekman and Friesen1976).

Compared to HCs, patients had worse cognitive performance and lower accuracy in both facial identity discrimination and facial emotion recognition. The deficits in emotion recognition were not restricted to a particular emotional state. Furthermore, correlation analysis revealed a positive correlation between scores on BFRT and those on affective judgment task. This made the authors consider the observed deficits in EFE recognition as secondary to those in facial identity discrimination which can somewhat reflect visuoperceptual deficits. Concurrently, the authors included a group of RR MS patients who, unlike their progressive counterparts, had preserved abilities to recognize EFE but were “slightly” impaired on BFRT test. Based on these findings, one would assume that clinical and demographic differences between both patient groups accounted for the observed differences in recognizing EFE. Unfortunately, the RR MS group was not included in the remaining statistical analyses.

Consistent with the first report, Parada-Fernández et al. considered a mixed cohort of RR and progressive MS patients and healthy subjects (2015). The authors used BFRT and Facially Expressed Emotion Labeling task (Kessler, Bayerl, Deighton, & Traue, Reference Kessler, Bayerl, Deighton and Traue2002) which, respectively, evaluate facial identity discrimination and facial emotion recognition. To further eliminate any bias that might result from visual impairment, the authors excluded patients who had visual difficulties which disable them from reading and/or writing. This study showed that patients had difficulties in facial emotion recognition and identity discrimination. Moreover, a stepwise multiple regression analysis revealed that disease type and non-social cognitive abilities were the main contributors to the observed deficits in recognizing EFE. Facial identity discrimination did not seem to contribute to social cognitive deficits in this study.

Similarly, Berneiser et al. applied the facial affect task of Florida Affect Battery (Bowers, Blonder, & Heilman, Reference Bowers, Blonder and Heilman1991, Reference Bowers, Blonder and Heilman2001) to evaluate EFE recognition abilities in patients with different MS subtypes and HCs (2014). Compared to HCs, patients had worse performance in all subsets of the facial affect task, even after exclusively considering those with intact abilities to discriminate facial identity. This stands with what Parada-Fernández et al. stated (Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015) and is against the earlier suggestion by Beatty et al. (Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989). Again, Berneiser et al. found more pronounced deficits among SP MS patients compared to those suffering from RR MS. In addition, emotion recognition scores were directly correlated with cognitive performance and indirectly correlated with each of depression and fatigue scores, disease duration, and level of physical disability based on the Expanded Disability Status Scale score (EDSS).

Analogously, in the study by Cecchetto et al., patients had poorer performance than HCs on tasks assessing the recognition of all of the six basic facial emotions but had intact abilities to discriminate facial identity (2014). When patients were subdivided based on physical disability (EDSS scores), only highly disabled ones were impaired in labeling EFE. The latter was further correlated with disease characteristics (i.e., disease duration and EDSS scores) and non-social cognitive performance.

In the same perspective, Phillips et al. have assessed emotions’ recognition skills using static (Ekman & Friesen, Reference Ekman and Friesen1976) and dynamic measures (videos featuring frustration, excitement, annoyance, and boredom by Sullivan & Ruffman, Reference Sullivan and Ruffman2004) (2011). Compared to HCs, patients had worse mood and cognitive scores and showed deficits in recognizing facial emotions without differences in facial identity discrimination. The deficits remained significant even after accounting for depression and cognitive decline. In addition, EFE recognition was associated with social and psychological aspects of QoL (Phillips et al., Reference Phillips, Henry, Scott, Summers, Whyte and Cook2011).

Unlike the above-mentioned studies that brought out social cognitive deficits in all of the six basic facial emotions, others rather found an isolated pattern of impairment in recognizing EFE. For instance, two MS trials documented exclusive deficits in identifying the emotions “fear” and “anger” (Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011). These results are in line with those of a third study comparing HCs and two groups of MS patients with or without altered abilities to recognize EFE (Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009). Here, compared to HCs and the preserved MS group, affected patients had deficits in recognizing “sadness,” “fear,” and “anger” but were able to discern positive emotions. Moreover, in a fourth study, patients with intact abilities to discriminate facial identity had significant impairment in identifying “fear,” “sadness,” “anger,” and “surprise” (Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011). More interestingly, when considering physical disability as a variable, severely disabled patients had worse cognitive performance and displayed an additional deficit in the emotion “disgust.” Thus, higher disability levels seem to contribute to the emergence of other deficits.

The isolated involvement of negative emotions in the latter studies (Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011) might be explained as follows: One of the possibilities is that positive emotions might be relatively easier to process than negative ones and could hence be more compensated (Skowronski & Carlston, Reference Skowronski and Carlston1989). This idea is supported by one MS study in which “happiness,” for example, was better recognized than “fear” or “sadness” (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014). Another reason is that MS patients might express low sensitivity toward aversive stimuli (Di Bitonto et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011). Indeed, these patients were found to have reduced emotional reactivity to negative stimuli (i.e., sounds and pictures) compared to HCs but had normal reactivity to positive ones (Di Bitonto et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011).

Functional neuroimaging data can provide a third explanation. In fact, the normal processing of each emotion seems to induce a selective pattern of brain activation (Jehna, Neuper, et al., Reference Jehna, Neuper, Ischebeck, Loitfelder, Ropele, Langkammer and Enzinger2011). For example, some cerebral areas (i.e., VLPFC, ACC, and superior temporal gyri) are more activated during processing of “sadness,” while others (i.e., DLPFC, cingulate gyrus, inferior temporal gyrus, and cerebellum) appear to be more specific for “happiness” (Habel, Klein, Kellermann, Shah, & Schneider, Reference Habel, Klein, Kellermann, Shah and Schneider2005). This idea can be exemplified by one fMRI study in MS where the selective deficit in recognizing negative emotions was associated with hypoactivation of cortical areas devoted to processing negative emotions (i.e., ACC, fSTS, and VLPFC) (Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009).

Finally, five studies found intact EFE recognition abilities in MS patients (Di Bitonto et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010; Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012). This is not surprising given that four of them recruited exclusively (Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009; Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Di Bitonto et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011) or predominantly (Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012) RR MS patients. Once more, the cohort of the fifth study consisted mostly of preserved patients with clinically isolated syndrome and RR MS (Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010). Here, the authors assessed the accuracy and reaction time during EFE recognition task. Although accuracy did not differ between both groups, patients were slower than HCs. The observed slowing might not reflect deficits in emotion recognition, but could rather hint to a general delay in IPS which is frequent in MS (Vázquez-Marrufo et al., Reference Vázquez-Marrufo, Galvao-Carmona, González-Rosa, Hidalgo-Muñoz, Borges, Ruiz-Peña and Izquierdo2014) or an age-related slowing (Knight & Mather, Reference Knight and Mather2013) since HCs were significantly younger than patients.

The above-mentioned studies are summarized in Table 1. The differences in their outcomes might be explained by the disparity in clinical and demographic characteristics of their cohorts (e.g., Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011), differences in adopted assessment tools (dynamic vs. static tasks) and presence of confounding variables such as mood and affective disturbances, cognitive deficits, and MS fatigue, all of which might contribute to deficits in identifying EFE.

Table 1 Studies assessing facial emotion recognition in multiple sclerosis

Note. Demographic and clinical data were expressed as mean unless indicated otherwise. Age and disease duration were expressed in years.

ADS-L=Allgemeine Depressions-Skala; BDI=Beck Depression Inventory; BEAST=Bodily Expressive Action Stimulus Test; BERT=Behavioral Emotion Recognition Test; BFRT=Benton Facial Recognition Test; BRB-N=Brief Repeatable Battery of Neuropsychological Tests; CIS=clinically isolated syndrome; CMDI=Chicago Multiscale Depression Inventory; DD=disease duration; FAB=Florida Affect Battery; FEEL=Facially Expressed Emotion Labeling; FEEST=Facial expressions of emotions, stimuli and tests; FSS=Fatigue Severity Scale; FST=Faces Symbol Test; GDS=Geriatric Depression Scale; HADS=Hospital Anxiety and Depression Scale; HAM-A=Hamilton Rating Scale Anxiety; HCs=healthy controls; IADS=International Affective Digitized Sounds and Picture System; IAPS=International Affective Picture System; IPS=information processing speed; MFIS=Modified Fatigue Impact Scale; MMSE=Mini Mental Status Exam; MS=multiple sclerosis; NP=not provided; PASAT=Paced Auditory Serial Attention Test; PCFAE=Test of Perceptual Competence of Facial Affect Recognition; PP=primary progressive; RAVLT=Rey Auditory-Verbal Learning Test; ROCFT=Rey–Osterrieth Complex Figure Test; RR=relapsing remitting; RT=reaction time; SART=Sustained Attention to Response Task; SD=standard deviation; SDMT=Symbol Digit Modalities Test; SEFCI=Screening Examination for Cognitive Impairment; SP=secondary progressive; TAS- 20=Toronto Alexithymia Scale; TMT=Trail Making Test; WAIS-R=Wechsler Adult Intelligence Scale-Revised; WCST=Wisconsin Card Sorting Test; WHOQoL-BREF=World Health Organization quality of life questionnaire.

Starting with disease characteristics, patients with higher physical disabilities seem to be the most affected on tasks assessing EFE recognition (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011). In this context, some studies were for a correlation between EDSS scores (Kurtzke, Reference Kurtzke1983) and deficits in judging EFE (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014), while others denied it (Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010). As for disease subtypes, progressive MS patients seem to suffer from more pronounced deficits compared to RR MS patients (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010; Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012). Regarding disease duration, it was found to be associated with deficits in labeling EFE in some (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014) but not all studies (Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010).

Facial identity discrimination remains the main confounding variable in the recognition of EFE (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Di Bitonto et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012) since both processes share early common neural processing pathways. Although some MS studies suggest that deficits in the former be behind those in the latter (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Di Bitonti et al., Reference Di Bitonto, Longato, Jung, Fleury, Marcel, Collongues and Blanc2011), most of the remaining data are not in favor of this assumption (Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Phillips et al., Reference Phillips, Henry, Scott, Summers, Whyte and Cook2011; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011).

MS fatigue is another frequent symptom that can be defined as a reversible alteration of cognitive task performance (Chalah et al., Reference Chalah, Riachi, Ahdab, Créange, Lefaucheur and Ayache2015). Up until now, only a few studies evaluated its relationship with EFE recognition. While one study found it to be associated with EFE task performance (Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014), others were not able to detect any significant relationship (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011).

Importantly, an interaction was previously found among emotions, mood, and cognition (Leppanen, Reference Leppanen2006; Pessoa, 2008). In some studies, MS patients with deficits on EFE recognition tasks had also high depression scores (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Parada Fernandez et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Phillips et al., Reference Phillips, Henry, Scott, Summers, Whyte and Cook2011; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011) and poor cognitive abilities (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Phillips et al., Reference Phillips, Saldias, McCarrey, Henry, Scott, Summers and Whyte2009; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011). However, the correlation of EFE recognition with cognitive and mood scores remains controversial. While some studies are in favor of this relationship (Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012), others failed to detect any significant association (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011).

Alexithymia is an additional variable that might interfere here (Grynberg et al., Reference Grynberg, Chang, Corneille, Maurage, Vermeulen, Berthoz and Luminet2012). By definition, it is a personality trait characterized by difficulties in emotional identification, understanding, and description (Franz et al., Reference Franz, Popp, Schaefer, Sitte, Schneider, Hardt and Braehler2008). Alexithymia was tackled in two MS trials evaluating EFE recognition. Although one of them featured higher levels of alexithymia in MS patients compared to HCs (Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011), the other did not find any group difference (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014), and neither of them detected an association between alexithymia and deficits in EFE recognition.

All in all, deficits in facial emotion recognition might occur early during MS, and do not seem to be restricted to progressive disease subtypes. However, disease characteristics and concomitant symptoms may contribute to such deficits. Heterogeneity in MS lesions location might be behind the different patterns of EFE recognition deficits encountered in various studies. One might speculate that during disease course, clinical and radiological MS progression can also be mirrored by a shift from an intact abilities to recognize EFE (Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010, Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012), to an isolated pattern of deficits (Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011), and finally to a global deficit (Beatty et al., Reference Beatty, Goodkin, Weir, Staton, Monson and Beatty1989; Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015).

Social perception of affective prosody in multiple sclerosis

In advanced MS stages, visual deficits can become very pronounced, and patients might depend on the perception of affective prosody for a successful social interaction. Only two MS studies have addressed this issue. In the first one, the authors used the comprehension and discrimination portions of Aprosodia battery (Ross et al., Reference Ross, Thompson and Yenkosky1997) in a cohort of chronic MS patients (Beatty, Orbelo, Sorocco, & Ross, Reference Beatty, Orbelo, Sorocco and Ross2003). Compared to HCs, patients had worse performance on affective prosody, mood, and cognitive scales. Measures of affective prosody were positively correlated with cognitive scores but were not associated with mood disturbance, hearing loss, aphasia, treatment profile, or education. Unfortunately, patients’ clinical characteristics were not provided and their impact on prosody was not assessed.

In contrast with the first study, the second one included patients with early stage of RR MS (Kraemer, Herold, Uekermann, Kis, et al., Reference Kraemer, Herold, Uekermann, Kis, Daum, Wiltfang and . . .Abdel-Hamid2013). Compared to HCs, patients had higher depression scores but did not differ on most of the cognitive scores. They poorly discriminated affective prosody, had lower accuracy in matching affective prosody to the facial expression for “anger,” but were able to recognize “happiness.” This finding is in line with the isolated pattern of deficits seen in some EFE studies (anger and fear in Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; anger, sadness, and fear in Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; anger, sadness, fear, and surprise in Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011). The observed deficits were unrelated to mood, cognitive performance, or physical disability. Unlike the cohort examined by Beatty et al. (Reference Beatty, Orbelo, Sorocco and Ross2003), patients seen here performed better than HCs on matching affective prosody to facial expression for the emotion “fear.” This finding might be due to an increased sensitivity for recognizing “fear” in a population of young patients recently shocked by the diagnosis of a chronic disabling disease such as MS (Kraemer, Herold, Uekermann, Kis, et al., Reference Kraemer, Herold, Uekermann, Kis, Daum, Wiltfang and . . .Abdel-Hamid2013).

ToM in MS

The majority of ToM studies in MS have adopted the Faces test (Baron-Cohen, Jolliffe, Mortimore, & Robertson, Reference Baron-Cohen, Jolliffe, Mortimore and Robertson1997; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, Reference Baron-Cohen, Wheelwright, Hill, Raste and Plumb2001), Reading the Mind in the Eyes test and Faux Pas test (Baron-Cohen, O’Riordan, Stone, Jones, & Plaisted, Reference Baron-Cohen, O’Riordan, Stone, Jones and Plaisted1999) (for a summary, see Table 2). Faces test consists of 20 photographs of the same actress portraying different complex mental states (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Baron-Cohen et al., Reference Baron-Cohen, Jolliffe, Mortimore and Robertson1997, Reference Baron-Cohen, Wheelwright, Hill, Raste and Plumb2001; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). During Reading the Mind in the Eyes test, also simply known as Eyes test, patients are asked to observe and comment on feelings or thoughts expressed in 36 face photographs depicting only the eye region (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Baron-Cohen et al., Reference Baron-Cohen, O’Riordan, Stone, Jones and Plaisted1999; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). Both are non-verbal tasks that evaluate “affective” ToM based on visual cues. The third one, Faux Pas test, is a verbal task that assesses “cognitive” ToM.

Table 2 Studies reporting deficits in the theory of mind in multiple sclerosis

Note. Demographic and clinical data were expressed as mean unless indicated otherwise. Age and disease duration were expressed in years.

BDI=Beck Depression Inventory; C&I=Conversations and Insinuations video-taped task; DD=disease duration; GDS=Geriatric Depression Scale; HADS=Hospital Anxiety and Depression Scale; HCs=healthy controls; IPS=information processing speed; MASC=Movie for the Assessment of Social Cognition; MFIS=Modified Fatigue Impact Scale; MS=multiple sclerosis; NP=not provided; PASAT=Paced Auditory Serial Attention Test; PP=primary progressive; RR=relapsing remitting; SDMT=Symbol Digit Modalities Test; SEFCI=Screening Examination for Cognitive Impairment; SP=secondary progressive; STAI=Spielberger Trait Anxiety Inventory; TASIT=The Awareness of Social Inference Test; TMT=Trail Making Test; ToM=theory of mind; WAIS=Wechsler Adult Intelligence Scale-Revised; WCST=The Wisconsin Card Sorting Test.

Some authors used exclusively verbal or non-verbal ToM tasks and found pronounced ToM deficits in their MS cohorts (Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014). Others combined several tools that assess both ToM aspects (affective and cognitive) and obtained heterogeneous results. For instance, in two studies, patients were evaluated by the means of Reading the Mind in the Eyes test, Faces test, and Faux Pas test (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). Patients had an altered performance on the first (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013) and second (Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013) tests, but had normal scores on the third one.

At a first glance, the absence of abnormality on the Faux Pas test appears surprising. However, this test seems to have low sensitivity to detect mentalization deficits as seen in some MS trials (Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013; Ouellet et al., Reference Ouellet, Scherzer, Rouleau, Metras, Bertrand-Gauvin, Djerroud and Duquette2010). For instance, in one study, MS patients had ToM deficits according to the Strange Stories task (Happé, Winner, & Brownell, Reference Happé, Winner and Brownell1998), yet they had normal performance on the Faux Pas test (Baron-Cohen et al., Reference Baron-Cohen, O’Riordan, Stone, Jones and Plaisted1999). Such a discrepancy might be due to the fact that the Strange Stories task assesses a diversity of mental states and, unlike the Faux Past test, is not limited to detecting a “faux pas” in social interaction (Ouellet et al., Reference Ouellet, Scherzer, Rouleau, Metras, Bertrand-Gauvin, Djerroud and Duquette2010). Another plausible explanation is that MS patients may be more prone to mentalization deficits that depend on visual information processing than verbal processing (Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). This might be due to a selective involvement of emotional networks at some point during the disease course. This assumption is supported by data from a fMRI study where verbal and non-verbal social information elicited different patterns of neural activation, respectively, in the precuneus/posterior cingulate cortex (PC/PCC) and amygdala (Kuzmanovic et al., Reference Kuzmanovic, Bente, von Cramon, Schilbach, Tittgemeyer and Vogeley2012).

Besides classical static ToM tasks used in the aforementioned works, some authors used dynamic videotaped tasks presenting social interactions and obtained similar results (Genova, Cagna, Chiaravalloti, DeLuca, & Lengenfelder, Reference Genova, Cagna, Chiaravalloti, DeLuca and Lengenfelder2016; Kraemer, Herold, Uekermann, Kis Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013; Ouellet et al., Reference Ouellet, Scherzer, Rouleau, Metras, Bertrand-Gauvin, Djerroud and Duquette2010; Pöttgen, Dziobek, Reh, Heesen, & Gold, Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013). Interestingly, in the study by Pöttgen et al., MS patients further exhibited insufficient mentalization abilities (Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013), similar to those documented in autism (Baron-Cohen, Reference Baron-Cohen2000). Dynamic tests such as the one used here necessitate online complex processing abilities for an adequate interpretation of the exposed scenes. This might make of them better simulator of daily life events compared to the static written tests.

Last but not least, cognitive and affective ToM deficits in pediatric-onset MS patients have been documented by Charvet et al. (Reference Charvet, Cleary, Vazquez, Belman and Krupp2014). The observed deficits were correlated with visuospatial attention and IPS scores (Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014) and remained significant after accounting for cognitive functions.

As seen in EFE section, ToM studies enclosed several confounding factors such as MS fatigue (Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011), low intelligence quotient (Pöttgen et al., Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013), high mood scores (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015), and cognitive deficits (Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010; Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014; Genova et al., Reference Genova, Cagna, Chiaravalloti, DeLuca and Lengenfelder2016; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009, Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014).

While ToM scores were significantly associated with non-social cognitive performance (Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014; Genova et al., Reference Genova, Cagna, Chiaravalloti, DeLuca and Lengenfelder2016; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009; Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013; Ouellet et al., Reference Ouellet, Scherzer, Rouleau, Metras, Bertrand-Gauvin, Djerroud and Duquette2010; Pöttgen et al., Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014) and clinical characteristics in some studies (EDSS scores in Pöttgen et al., Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013; progression rate in Banati et al., Reference Banati, Sandor, Mike, Illes, Bors, Feldmann and Illes2010); other studies did not detect any significant association between ToM performance and each of demographic or clinical characteristics (Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014; Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011), cognitive profiles (Henry et al., Reference Henry, Tourbah, Chaunu, Rumbach, Montreuil and Bakchine2011; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014), and mood scores (Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013; Pöttgen et al., Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014), or MS fatigue (Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014).

Empathy in MS

Two studies reported low levels of empathy in MS patients (Gleichgerrcht, Tomashitis, & Sinay, Reference Gleichgerrcht, Tomashitis and Sinay2015; Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013). In the first one, patients also had mood disturbance and cognitive decline (Kraemer, Herold, Uekermann, Kis, Wiltfang, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013). In the second, they had high levels of alexithymia and altered moral judgment (Gleichgerrcht et al., Reference Gleichgerrcht, Tomashitis and Sinay2015). It is noteworthy that alexithymia could modulate empathy (Bird et al., Reference Bird, Silani, Brindley, White, Frith and Singer2010). Hence, the observed low levels of empathy and high levels of alexithymia might have contributed to an altered moral judgment (Gleichgerrcht et al., Reference Gleichgerrcht, Tomashitis and Sinay2015).

Differently, other studies have documented high levels of empathy among MS patients. For instance, Benedict, Priore, Miller, Munschauer, and Jacobs detected a discrepancy between the levels of empathy as reported by patients and their informants (family members or friends) (2001). While informants reported low levels of empathy among patients, patients themselves generated high self-reporting. These results were substantiated by another report by Banati et al. who found higher empathy levels in patients with greater physical disability and shorter disease duration, both of which characterize a rapid disease progression (2010).

The findings of both studies might be explained by different views. For instance, severely impaired patients may exhibit more profound emotional misjudgment compared to relatively preserved patients, which can appear as high levels of empathy. Another possibility is that MS-related emotional stress might lead to a more focused emotional processing which can emerge as a higher estimate of empathy. The phenomenon of benefit finding can also account for the observed results (Pakenham & Cox, Reference Pakenham and Cox2009). It provides an explanation on how constant challenges, such as those seen during MS course, might lead to positive learning and experiencing psychological growth (Pakenham & Cox, Reference Pakenham and Cox2009).

Of interest, one study included a cohort of pediatric-onset MS patients and HCs but did not detect any significant group differences based on empathy questionnaires filled by parents (Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014). However, one should keep in mind that parents-filled questionnaires do not necessarily reflect the patients’ impression.

The papers mentioned above are summarized in Table 3.

Table 3 Studies reporting alteration of empathy in multiple sclerosis

Note. Demographic and clinical data were expressed as mean unless indicated otherwise. Age and disease duration were expressed in years.

BDI=Beck Depression Inventory; DD=disease duration; HCs=healthy controls; HES=Hogan Empathy Scale; MS=multiple sclerosis; NP=not provided; PASAT=Paced Auditory Serial Attention Test; RR=relapsing remitting; SDMT=Symbol Digit Modalities Test; SP=secondary progressive; STAI=Spielberger Trait Anxiety Inventory; TAS-20=Toronto Alexithymia Scale; TMT=Trail Making Test; WAIS=Wechsler Adult Intelligence Scale; WCST=The Wisconsin Card Sorting Test.

NEURAL UNDERPINNINGS OF SOCIAL COGNITIVE DEFICITS IN MULTIPLE SCLEROSIS

Five MRI studies (Table 4) investigated the neural basis of social cognitive deficits in MS (Beatty et al., Reference Beatty, Orbelo, Sorocco and Ross2003; Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009).

Table 4 MRI Studies evaluating social cognition in multiple sclerosis

Note. Demographic and clinical data were expressed as mean unless indicated otherwise. Age and disease duration were expressed in years.

CC=corpus callosum; DD=disease duration; DSM-IV=Diagnostic and Statistical Manual for Mental Disorders, 4th edition; FFA=fusiform facial area; fSTS=facial area of the superior temporal sulcus; GCC=genu of corpus callosum; GM=gray matter; LL=lesion load; LV=lesion volume; MS=multiple sclerosis; NP=not provided; PP=primary progressive; RR=relapsing remitting, SCC=splenium of corpus callosum; SP=secondary progressive; PCC=posterior cingulate cortex; UF=uncinated fasciculus; VLPFC=ventrolateral prefrontal cortex; WM=white matter.

STRUCTURAL NEUROIMAGING DATA

Concerning facial emotion perception, Krause et al. performed voxel-based lesion symptom mapping in MS patients with or without deficits in EFE recognition (Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009). Although lesion volume did not statistically differ between both patient groups, poor performance on facial affect task was correlated with lesions in left temporal WM (Figure 1), an area containing several connections between the OFC and the STS (Cavada, Company, Tejedor, Cruz-Rizzolo, & Reinoso-Suarez, Reference Cavada, Company, Tejedor, Cruz-Rizzolo and Reinoso-Suarez2000). Therefore, the observed impairment in EFE recognition might be due to interruption of the fibers responsible for visual processing of emotionally relevant stimuli. To note, this study also contained fMRI data that will be analyzed in the following section.

Fig. 1 (a, b) Axial and (c) sagittal brain views illustrating the structural correlates of social cognitive deficits in multiple sclerosis. FFA: left fusiform facial area; R: right; SCC: splenium of the corpus callosum; TP: left temporal pole; *: left temporal white matters lesions; left uncinated fasciculus not shown.

Our insight into ToM in MS arises from the study by Mike et al. who compared structural MRI data between MS patients and healthy controls (Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). In addition to the observed social cognitive deficits in the patients’ group, inverse correlations were found between each of the Faces and Reading the Mind in the Eyes tests and total T1 lesion volume (tT1LV). More interestingly, patients’ performance on the Faces test was inversely associated with regional T1 lesion volume (rT1LV) of CC (genu and splenium) and several fasciculi (bilateral uncinated fasciculus, right inferior longitudinal and fronto-occipital fasciculi); with regional T2 lesion volume of CC (genu) and left fornix, and with cortical thinning of many areas (i.e., bilateral FFA, right entorhinal cortex).

Second, performance on Reading the Mind in the Eyes test was inversely correlated with rT1LV of the CC (splenium) and cortical thinning of left anterior inferior temporal gyrus (temporal pole), left FFA and right caudal middle frontal gyrus (right premotor frontal eye field, FEF). However, performance on the Faux Pas test did not correlate with any of the studied parameters. The multiple regression analysis also revealed several issues. For instance, rT1LV of left uncinated fasciculus was an independent predictor of the Faces test performance. Besides, performance on Reading the Mind in the Eyes test was predicted by rT1LV of the splenium of CC and cortical thickness of left FFA and left temporal pole (Figure 1).

Of interest, all of these structures are neural nodes which take parts of social cognitive networks. For instance, the genu and splenium of CC links, respectively, identical anterior (prefrontal and premotor) and posterior cortical areas (occipital, parietal, and temporal lobes) involved in emotional, cognitive, and visual processing (Park et al., Reference Park, Kim, Lee, Seok, Chun, Kim and Lee2008). The role of FFA has been already seen in facial identity discrimination and emotion recognition (Haxby, Hoffman, & Gobbini, Reference Haxby, Hoffman and Gobbini2000, Reference Haxby, Hoffman and Gobbini2002; Zaki, Hennigan, Weber, & Ochsner, Reference Zaki, Hennigan, Weber and Ochsner2010). The temporal pole enables the confrontation of perceived social and emotional cues (visual information) with stored general knowledge (contextual information) (Frith & Frith, Reference Frith and Frith2006).

As for affective prosody, the available data are derived from only one study in which the comprehension of affective prosody did not correlate with any studied parameters, namely the CC size and the extent of right or left hemispheric lesions (Beatty et al., Reference Beatty, Orbelo, Sorocco and Ross2003). The absence of correlations might be due to the use of basic MRI measures which could have been different with the adoption of non-conventional MRI techniques (Rovaris, Comi, & Filippi, Reference Rovaris, Comi and Filippi2001).

Functional Neuroimaging Data

The available fMRI studies in MS patients focused on EFE recognition. The first one included early stage RR MS patients with intact social cognitive abilities and healthy controls (Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). The imaging acquisition took place during the execution of an active task that consisted of processing facial emotions relative to neutral stimuli (geometric shapes such as circles, or horizontal and vertical ellipses) (Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). Compared to their healthy counterparts, patients exhibited a hyperactivation within bilateral prefrontal areas (VLPFC) and left posterior cortices (PC, superior parietal cortex) (Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). They also displayed a reduced pattern of functional connectivity between prefrontal cortices (ventrolateral and medial parts) and left amygdala (Figure 2).

Fig. 2 (a, b) Axial and (c) sagittal brain views illustrating the functional changes during social cognitive performance in multiple sclerosis. AMY: left amygdala; mPFC: medial prefrontal cortex; R: right; SPC: superior parietal cortex; vlPFC: ventrolateral prefrontal cortex; upward arrows: hyperactivation pattern seen in multiple sclerosis patients with preserved social cognitive abilities compared to healthy controls; downward arrows: hypoactivation pattern seen in multiple sclerosis patients with social cognitive deficits compared to those with intact abilities; dashed lines: reduced functional connectivity in the tagged networks; left superior parietal cortex not shown.

It is noteworthy that a lateralization pattern of amygdalar activation exists in the normal human brain during emotional processing, with the left amygdala being more activated than the right one (Baas, Aleman, & Kahn, Reference Baas, Aleman and Kahn2004). In fact, by communicating with posterior brain regions that are involved in visual processing, the amygdala has a pivotal role in decoding emotionally significant sensory stimuli and by doing so, it participates in the formation of emotional memory. Also, the dialogue between the amygdala and prefrontal cortex is crucial in the processing of emotional information (Ghashghaei, Hilgetag, & Barbas, Reference Ghashghaei, Hilgetag and Barbas2007).

The findings of this study were supported soon after by another one in which early stages RR MS patients had normal performance on cognitive and facial affect recognition tasks compared to healthy controls (Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011), yet they exhibited a hyperactivation within fusiform gyri and other right cortical areas (i.e., fontral pole, ACC, and paracingulate cortex) during the performance of neutral faces (facial identity); and hyperactivation of PC and PCC during the performance of “anger” (left activation) and “disgust” (right activation) contrasted to neutral faces (Figure 2).

In addition to the above-stated role of the amygdala, PCC is implicated in mediating the interactions between emotional and memory-related processes (Maddock, Garrett, & Buonocore, Reference Maddock, Garrett and Buonocore2003). More interestingly, The PC seems to be divided into two parts, an anterior one dealing with self-centered mental imagery strategies and a posterior one in charge of episodic memory retrieval (Cavanna & Trimble, Reference Cavanna and Trimble2006).

A third study by Krause et al. provides additional evidence. MS patients with or without deficits in facial affect recognition underwent functional imaging (Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009). Compared to the preserved MS group, the impaired group showed a hypoactivation in the facial area of STS, left VLPFC and insula, all of which are normally implicated in the social perception of EFE (Figure 2). In the whole patients group (impaired and preserved), the accuracy on facial affect task was correlated with the increased activation within the left anterior insula and left VLPFC.

To sum up, all of the three studies, featured a hyperactivation pattern in MS patients with preserved social cognitive abilities (Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). To explain these findings, one can speculate that compensatory processes occur early in the disease course to restrain the social cognitive deficits that might arise from MS-related gray (GM) and white (WM) matter pathologies (Mainero et al., Reference Mainero, Caramia, Pozzilli, Pisani, Pestalozza, Borriello and Pantano2004; Mainero, Pantano, Caramia, & Pozzilli, Reference Mainero, Pantano, Caramia and Pozzilli2006; Pantano et al., Reference Pantano, Iannetti, Caramia, Mainero, Di Legge, Bozzao and Lenzi2002; Rocca et al., Reference Rocca, Absinta, Ghezzi, Moiola, Comi and Filippi2009; Sumowski, Wylie, Deluca, & Chiaravalloti, Reference Sumowski, Wylie, Deluca and Chiaravalloti2009; Staffen et al., Reference Staffen, Mair, Zauner, Unterrainer, Niederhofer, Kutzelnigg and Ladurner2002; Sweet, Rao, Primeau, Durgerian, & Cohen, Reference Sweet, Rao, Primeau, Durgerian and Cohen2006; Wegner et al., Reference Wegner, Filippi, Korteweg, Beckmann, Ciccarelli, De Stefano and Matthews2008). These mechanisms could radiologically manifest as increased regional activation patterns (Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009) or reduced functional connectivity of some brain networks (Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). Saying so, the increase in lesions load and subsequent diffuse neural disorganization might lead to reduced or maladaptive plasticity processes (Citri & Malenka, Reference Citri and Malenka2008; Morgen et al., Reference Morgen, Kadom, Sawaki, Tessitore, Ohayon, McFarland and Cohen2004). This would cause poor social cognitive performance and lead to regional hypoactivation on fMRI as seen with the impaired MS group of the third study (Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009).

SOCIAL COGNITIVE DEFICITS IN MULTIPLE SCLEROSIS: A PRIMARY OR SECONDARY SIGNATURE

Several cognitive domains could be altered in MS patients, and this population commonly suffers from mood disturbances, fatigue, alexithymia, and sleep problems. Hence, one might ask whether social cognitive deficits in MS constitute a primary phenomenon or rather result from the previously described confounders. Although this issue is still a matter of debate, the influence of these variables on social cognition was addressed in some studies and deserves to be mentioned here.

For instance, despite the high prevalence of alexithymia in MS patients (Bodini et al., Reference Bodini, Mandarelli, Tomassini, Tarsitani, Pestalozza, Gasperini and Pozzilli2008; Chahraoui et al., Reference Chahraoui, Pinoit, Viegas, Adnet, Bonin and Moreau2008, Chahraoui, Duchene, Rollot, Bonin, & Moreau, Reference Chahraoui, Duchene, Rollot, Bonin and Moreau2014; Gay, Vrignaud, Garitte, & Meunier, Reference Gay, Vrignaud, Garitte and Meunier2010), only few studies controlled for this factor (Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Gleichgerrcht et al., Reference Gleichgerrcht, Tomashitis and Sinay2015; Prochnow et al., Reference Prochnow, Donell, Schäfer, Jörgens, Hartung, Franz and Seitz2011). It is worth noting that patients with alexithymia were found to have social cognitive deficits (Grynberg et al., Reference Grynberg, Chang, Corneille, Maurage, Vermeulen, Berthoz and Luminet2012) and display abnormal pattern of brain activation during EFE processing (Kano et al., Reference Kano, Fukudo, Gyoba, Kamachi, Tagawa, Mochizuki and Yanai2003).

Moreover, alexithymia was associated with decreased GM volume in regions such as the ACC, amygdala, and insula (Ihme et al., Reference Ihme, Dannlowski, Lichev, Stuhrmann, Grotegerd, Rosenberg and Suslow2013), which had abnormal activation pattern in fMRI studies assessing social cognition in MS (Jehna, Langkammer, et al., Reference Jehna, Langkammer, Wallner-Blazek, Neuper, Loitfelder, Ropele and Enzinger2011; Krause et al., Reference Krause, Wendt, Dressel, Berneiser, Kessler, Hamm and Lotze2009; Passamonti et al., Reference Passamonti, Cerasa, Liguori, Gioia, Valentino, Nisticò and Fera2009). These facts altogether should prompt screening for alexithymia in future assessment of social cognition.

Depression also appears to be a frequent symptom in MS patients (Feinstein, Reference Feinstein2011) and is linked to pathological changes in bilateral frontal regions which are key components in social cognitive processing (Gobbi, Rocca, Riccitelli, et al., Reference Gobbi, Rocca, Riccitelli, Pagani, Messina, Preziosa and Filippi2014). Admitting the influence of mood on social cognition in MS (Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012; Parada-Fernández et al., Reference Parada-Fernández, Oliva-Macias, Amayra, Lopez-Paz, Lazaro, Martinez and Perez2015) and other clinical settings (Asthana, Mandal, Khurana, & Haque-Nizamie, Reference Asthana, Mandal, Khurana and Haque-Nizamie1998; Leppanen, Reference Leppanen2006; Persad & Polivy, Reference Persad and Polivy1993; Suslow et al., Reference Suslow, Dannlowski, Lalee-Mentzel, Donges, Arolt and Kersting2004), an optimal evaluation of social cognition should account for this variable.

As for MS fatigue per se, its underlying pathophysiology lies in the so-called “cortico-striato-thalamo-cortical loop” (for reviews, see Chalah et al., Reference Chalah, Riachi, Ahdab, Créange, Lefaucheur and Ayache2015), which includes pathological alterations of many cerebral tracts such as UF, CC, and IFOF (Bisecco et al., Reference Bisecco, Caiazzo, d’Ambrosio, Sacco, Bonavita, Docimo and Gallo2016; Gobbi, Rocca, Pagani, et al., Reference Gobbi, Rocca, Pagani, Riccitelli, Pravatà, Radaelli and Filippi2014). Importantly, abnormalities in these brain structures are also documented in social cognition studies and were inversely correlated with MS patients’ performance on ToM tasks (Mike et al., Reference Mike, Strammer, Aradi, Orsi, Perlaki, Hajnal and Illes2013). The fact that both fatigue and social cognitive deficits in MS share several anatomical pathologies should pave the way for a better control of MS fatigue in upcoming trials.

Furthermore, MS patients commonly suffer from cognitive symptoms (Ayache et al., Reference Ayache, Palm, Chalah, Nguyen, Farhat, Créange and Lefaucheur2015; Kesselring & Klement, Reference Kesselring and Klement2001; Vázquez-Marrufo et al., Reference Vázquez-Marrufo, Galvao-Carmona, González-Rosa, Hidalgo-Muñoz, Borges, Ruiz-Peña and Izquierdo2014) and significant correlations were found in MS patients between social cognitive performance and several non-social cognitive abilities, such as attention, processing speed, working memory, learning, and executive functions (Benedict et al., Reference Benedict, Priore, Miller, Munschauer and Jacobs2001; Berneiser et al., Reference Berneiser, Wendt, Grothe, Kessler, Hamm and Dressel2014; Cecchetto et al., Reference Cecchetto, Aiello, D’Amico, Cutuli, Cargnelutti, Eleopra and Rumiati2014; Charvet et al., Reference Charvet, Cleary, Vazquez, Belman and Krupp2014; Genova et al., Reference Genova, Cagna, Chiaravalloti, DeLuca and Lengenfelder2016; Henry et al., Reference Henry, Phillips, Beatty, McDonald, Longley, Joscelyne and Rendell2009; Jehna et al., Reference Jehna, Neuper, Petrovic, Wallner-Blazek, Schmidt, Fuchs and Enzinger2010; Kraemer, Herold, Uekermann, Kis, et al., Reference Kraemer, Herold, Uekermann, Kis, Wiltfang, Daum and Abdel-Hamid2013b; Ouellet et al., Reference Ouellet, Scherzer, Rouleau, Metras, Bertrand-Gauvin, Djerroud and Duquette2010; Pinto et al., Reference Pinto, Gomes, Moreira, Rosa, Santos, Silva and Cavaco2012; Pöttgen et al., Reference Pöttgen, Dziobek, Reh, Heesen and Gold2013; Roca et al., Reference Roca, Manes, Gleichgerrcht, Ibáñez, González de Toledo, Marenco and Sinay2014). For these reasons, evaluating non-social cognitive abilities in forthcoming works might help better understand their relationship with social cognition.

Nevertheless, altered moral judgment could also co-occur with social cognitive deficits and has been related to pathological changes within the TPJ, the latter region being an important component of the ToM circuit (Samson, Apperly, Chiavarino, & Humphreys, Reference Samson, Apperly, Chiavarino and Humphreys2004; Young, Camprodon, Hauser, Pascual-Leone, & Saxe, Reference Young, Camprodon, Hauser, Pascual-Leone and Saxe2010). Lastly, sleep disorders, frequently encountered in MS, might as well influence social cognition and deserve to be taken into consideration (Beattie, Kyle, Espie, & Biello, Reference Beattie, Kyle, Espie and Biello2015).

CONCLUSION

Taken together, these data provide convergent evidence on the occurrence of social cognitive deficits even at early stages of MS. Deficits in recognizing negative emotions seem to be more pronounced that those of positive ones among MS patients.

Here, two questions might arise: (i) how individuals with MS could preserve their social cognitive performance early in the disease process despite the continuous accumulation of brain lesions and then, at a certain point in their life, start experiencing deficits; and (ii) why an inhomogeneity in social cognitive performance was observed across MS studies. The hypothesis of “functional brain reorganization” could answer the first question. In fact, in front of the neural damage encountered in MS, compensatory neuroplasticity mechanisms and functional reorganization would take place in an attempt to limit subsequent behavioral deficits that might arise from MS-related pathologies. Later on, the increase in disease burden may exhaust the adaptive mechanisms and functional reserves (Cader, Cifelli, Abu-Omar, Palace, & Matthews, Reference Cader, Cifelli, Abu-Omar, Palace and Matthews2006; Pantano et al., Reference Pantano, Mainero, Lenzi, Caramia, Iannetti, Piattella and Pozzilli2005) leading to poor social cognitive performance.

The second question could be addressed in light of “cognitive reserve hypothesis.” Cognitive reserve is thought to be a moderator between the amount of brain damage and the extent of clinical outcome (Stern, Reference Stern2012). This could apply to MS patients in a way that those with higher cognitive reserve might experience less social cognitive deficits than others with similar extent of brain lesions (Sumowski et al., Reference Sumowski, Wylie, Deluca and Chiaravalloti2009; Sumowski & Leavitt, Reference Sumowski and Leavitt2013).

Other important issues remain unresolved and need a careful assessment in future studies. First, the prevalence of social cognitive deficits in MS is still undetermined. In fact, a large number of reported trials dealt with heterogeneous MS cohorts with different disease subtypes, wide ranges of physical disability and advanced stages, which make them more prone to social and non-social cognitive deficits.

Second, whether the social cognitive deficits constitute a primary impairment, or they result from cognitive deficits, or other MS-related symptoms is still a matter of debate. Henceforth, future in-depth assessment of social cognition should focus on confounding factors and the onset of these deficits.

Third, neural components of social cognition need further deciphering. Thus, coupling non-conventional neuroimaging and neurophysiological modalities with more detailed neuropsychological testing could be of particular help.

Fourth, the evaluation of social cognition might benefit from combining static, and dynamic assessment tools since videotaped tasks seem to have better accuracy than classical static tests in evaluating social cognition (Dziobek et al., Reference Dziobek, Fleck, Kalbe, Rogers, Hassenstab, Brand and Convit2006).

In summary, these considerations would shed the light on the social cognitive deficits in MS and may open a venue for an optimal multidisciplinary approach in MS patient care. By doing so, affected patients will be able to overcome their interpersonal difficulties and improve their QoL.

ACKNOWLEDGMENT

Both authors declare no conflict of interest.

REFERENCES

Abdel-Hamid, M., Lehmkämper, C., Sonntag, C., Juckel, G., Daum, I., & Brüne, M. (2009). Theory of mind in schizophrenia: The role of clinical symptomatology and neurocognition in understanding other people’s thoughts and intentions. Psychiatry Research, 165(1-2), 1926. doi: 10.1016/j.psychres.2007.10.021
Ackerer, A.W. (2003). Emotional intelligence, academic intelligence and speed of mind: The case of emotion perception. Munich: GRIN Verlag.
Adolphs, R. (2002). Neural systems for recognizing emotion. Current Opinion in Neurobiology, 12(2), 169177.
Adolphs, R. (2006). How do we know the minds of others? Domain-specificity, simulation, and enactive social cognition. Brain Research, 1079(1), 2535.
Adolphs, R., Baron-Cohen, S., & Tranel, D. (2002). Impaired recognition of social emotions following amygdala damage. Journal of Cognitive Neuroscience, 14(8), 12641274.
Allison, T., Puce, A., & McCarthy, G. (2000). Social perception from visual cues: Role of the STS region. Trends in Cognitive Sciences, 4(7), 267278.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.) Washington, DC: American Psychiatric Association.
Asthana, H.S., Mandal, M.K., Khurana, H., & Haque-Nizamie, S. (1998). Visuospatial and affect recognition deficit in depression. Journal of Affective Disorders, 48(1), 5762.
Auyeung, B., Wheelwright, S., Allison, C., Atkinson, M., Samarawickrema, N., & Baron-Cohen, S. (2009). The children’s empathy quotient and systemizing quotient: Sex differences in typical development and in autism spectrum conditions. Journal of Autism and Developmental Disorders, 39(11), 15091521. doi: 10.1007/s10803-009-0772-x
Ayache, S.S., Palm, U., Chalah, M.A., Nguyen, R., Farhat, W.H., Créange, A., &Lefaucheur, J.P. (2015). Orienting network dysfunction in progressive multiple sclerosis. Journal of the Neurological Sciences, 351(1-2), 206207. doi: 10.1016/j.jns.2015.02.044
Baas, D., Aleman, A., & Kahn, R.S. (2004). Lateralization of amygdala activation: A systematic review of functional neuroimaging studies. Brain Research. Brain Research Reviews, 45(2), 96103.
Bagby, R.M., Parker, J.D., & Taylor, G.J. (1994). The twenty-item Toronto alexithymia scale-I. Item selection and cross-validation of the factor structure. Journal of Psychosomatic Research, 38, 2332.
Banati, M., Sandor, J., Mike, A., Illes, E., Bors, L., Feldmann, A., & Illes, Z. (2010). Social cognition and theory of mind in patients with relapsing-remitting multiple sclerosis. European Journal of Neurology, 17(3), 426433. doi: 10.1111/j.1468-1331.2009.02836.x
Baron-Cohen, S. (2000). Theory of mind and autism: A review. International Review of Research in Mental Retardation, 23, 169184.
Baron-Cohen, S., Leslie, A.M., & Frith, U. (1985). Does the autistic child have a “theory of mind”? Cognition, 21(1), 3746.
Baron-Cohen, S., O’Riordan, M., Stone, V., Jones, R., & Plaisted, K. (1999). Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism. Journal of Autism and Developmental Disorders, 29(5), 407418.
Baron-Cohen, S., & Wheelwright, S. (2004). The empathy quotient: An investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. Journal of Autism and Developmental Disorders, 34(2), 163175.
Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., & Plumb, I. (2001). The “Reading the Mind in the Eyes” test revised version: A study with normal adults, and adults with Asperger syndrome or high-functioning autism. Journal of Child Psychology and Psychiatry, 42(2), 241251.
Baron-Cohen, S., Jolliffe, T., Mortimore, C., & Robertson, M. (1997). A further advanced test of theory of mind: Evidence from very high functioning adults with autism or Asperger syndrome. Journal of Child Psychology and Psychiatry, 38(7), 813822.
Beattie, L., Kyle, S.D., Espie, C.A., & Biello, S.M. (2015). Social interactions, emotion and sleep: A systematic review and research agenda. Sleep Medicine Reviews, 24, 83100. doi: 10.1016/j.smrv.2014.12.005
Beatty, W.W., Goodkin, D.E., Weir, W.S., Staton, R.D., Monson, N., & Beatty, P.A. (1989). Affective judgments by patients with Parkinson’s disease or chronic progressive multiple sclerosis. Bulletin of the Psychonomic Society, 27(4), 361364.
Beatty, W.W., Orbelo, D.M., Sorocco, K.H., & Ross, E.D. (2003). Comprehension of affective prosody in multiple sclerosis. Multiple Sclerosis, 9(2), 148153.
Benedict, R.H., Cookfair, D., Gavett, R., Gunther, M., Munschauer, F., Garg, N., & Weinstock-Guttman, B. (2006). Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). Journal of the International Neuropsychological Society, 12(4), 549558.
Benedict, R.H., Priore, R.L., Miller, C., Munschauer, F., & Jacobs, L. (2001). Personality disorder in multiple sclerosis correlates with cognitive impairment. The Journal of Neuropsychiatry and Clinical Neurosciences, 13(1), 7076.
Benton, A.L., Sivan, A.B., Hamsher, K., Varney, N.R., & Spreen, O. (1994). Contributions to neuropsychological assessment. New York: Oxford University Press.
Berneiser, J., Wendt, J., Grothe, M., Kessler, C., Hamm, A.O., & Dressel, A. (2014). Impaired recognition of emotional facial expressions in patients with multiple sclerosis. Multiple Sclerosis and Related Disorders, 3(4), 482488. doi: 10.1016/j.msard.2014.02.001
Bird, G., Silani, G., Brindley, R., White, S., Frith, U., & Singer, T. (2010). Empathic brain responses in insula are modulated by levels of alexithymia but not autism. Brain, 133(Pt 5), 15151525. doi: 10.1093/brain/awq060
Bisecco, A., Caiazzo, G., d’Ambrosio, A., Sacco, R., Bonavita, S., Docimo, R., & Gallo, A. (2016). Fatigue in multiple sclerosis: The contribution of occult white matter damage. Multiple Sclerosis, 22, 16761684.
Bodini, B., Mandarelli, G., Tomassini, V., Tarsitani, L., Pestalozza, I., Gasperini, C., & Pozzilli, C. (2008). Alexithymia in multiple sclerosis: Relationship with fatigue and depression. Acta Neurologica Scandinavica, 118(1), 1823.
Bowers, D., Blonder, L.X., & Heilman, K.M. (1991). The Florida affect battery. Gainesville, FL: Center for Neuropsychological Studies, University of Florida.
Bowers, D., Blonder, L.X., & Heilman, K.M. (2001). The Florida affect battery, manual (revised). Gainesville, FL: Center for Neuropsychological Studies, University of Florida.
Bradley, M.M., & Lang, P.J. (2007). The International Affective Digitized Sounds (IADS-2): Affective ratings of sounds and instruction manual. Technical report B-3, (2nd ed.). Gainesville, FL: University of Florida.
Brothers, L. (1990). The social brain: A project for integrating primate behavior and neurophysiology in a new domain. Concepts in Neuroscience, 1, 2751.
Buhse, M. (2008). Assessment of caregiver burden in families of persons with multiple sclerosis. Journal of Neuroscience Nursing, 40(1), 2531.
Cader, S., Cifelli, A., Abu-Omar, Y., Palace, J., & Matthews, P.M. (2006). Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis. Brain, 129(Pt 2), 527537.
Calder, A.J., & Young, A.W. (2005). Understanding the recognition of facial identity and facial expression. Nature Reviews Neuroscience, 6(8), 641651.
Carr, L., Iacoboni, M., Dubeau, M.C., Mazziotta, J.C., & Lenzi, G.L. (2003). Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas. Proceedings of the National Academy of Sciences of the United States of America, 100(9), 54975502.
Cavada, C., Company, T., Tejedor, J., Cruz-Rizzolo, R.J., & Reinoso-Suarez, F. (2000). The anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cerebral Cortex, 10(3), 220242.
Cavanna, A.E., & Trimble, M.R. (2006). The precuneus: A review of its functional anatomy and behavioural correlates. Brain, 129(Pt 3), 564583.
Cecchetto, C., Aiello, M., D’Amico, D., Cutuli, D., Cargnelutti, D., Eleopra, R., & Rumiati, R.I. (2014). Facial and bodily emotion recognition in multiple sclerosis: The role of alexithymia and other characteristics of the disease. Journal of the International Neuropsychological Society, 20(10), 10041014. doi: 10.1017/S1355617714000939
Chahraoui, K., Duchene, C., Rollot, F., Bonin, B., & Moreau, T. (2014). Longitudinal study of alexithymia and multiple sclerosis. Brain and Behavior, 4(1), 7582. doi: 10.1002/brb3.194
Chahraoui, K., Pinoit, J.M., Viegas, N., Adnet, J., Bonin, B., & Moreau, T. (2008). Alexithymie et liens avec la dépression et l’anxiété dans la sclérose en plaques. Revue Neurologique, 164(3), 242245. doi: 10.1016/j.neurol.2007.09.006
Chalah, M.A., Riachi, N., Ahdab, R., Créange, A., Lefaucheur, J.P., & Ayache, S.S. (2015). Fatigue in multiple sclerosis: Neural correlates and the role of non-invasive brain stimulation. Frontiers in Cellular Neuroscience, 9, 460. doi: 10.3389/fncel.2015.00460
Chartrand, T.L., & Bargh, J.A. (1999). The chameleon effect: The perception-behavior link and social interaction. Journal of Personality and Social Psychology, 76(6), 893910.
Charvet, L.E., Cleary, R.E., Vazquez, K., Belman, A.L., & Krupp, L.B., US Network for Pediatric M.S.. (2014). Social cognition in pediatric-onset multiple sclerosis (MS). Multiple Sclerosis, 20(11), 14781484. doi: 10.1177/1352458514526942
Citri, A., & Malenka, R.C. (2008). Synaptic plasticity: Multiple forms, functions, and mechanisms. Neuropsychopharmacology, 33(1), 1841.
Compston, A., & Coles, A. (2008). Multiple sclerosis. Lancet, 372(9648), 15021517. doi: 10.1016/S0140-6736(08)61620-7
Costa, P.T., & McCrae, R.R. (1992). Professional Manual for the Revised NEO Personality Inventory and NEO Five-Factor Inventory. Odessa, FL: Psychological Assessment Resources.
Critchley, H.D. (2005). Neural mechanisms of autonomic, affective, and cognitive integration. Journal of Comparative Neurology, 493(1), 154166.
Davis, M.H. (1983). Measuring individual differences in empathy: Evidence for a multidimensional approach. Journal of Personality and Social Psychology, 44, 113126.
Decety, J., & Jackson, P.L. (2004). The functional architecture of human empathy. Behavioural and Cognitive Neuroscience Reviews, 3(2), 71100.
Di Bitonto, L., Longato, N., Jung, B., Fleury, M., Marcel, C., Collongues, N., & Blanc, F. (2011). [Reduced emotional reactivity to negative stimuli in multiple sclerosis, preliminary results]. Revue Neurologique, 167(11), 820826. doi: 10.1016/j.neurol.2011.01.024
Dziobek, I., Fleck, S., Kalbe, E., Rogers, K., Hassenstab, J., Brand, M., & Convit, A. (2006). Introducing MASC: A movie for the assessment of social cognition. Journal of Autism and Developmental Disorder, 36(5), 623636.
Ekman, P., & Friesen, W.V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press.
Ethofer, T., Anders, S., Erb, M., Herbert, C., Wiethoff, S., Kissler, J., & Wildgruber, D. (2006). Cerebral pathways in processing of affective prosody: A dynamic causal modeling study. Neuroimage, 30(2), 580587. doi: 10.1016/j.neuroimage.2005.09.059
Fan, Y., Duncan, N.W., de Greck, M., & Northoff, G. (2011). Is there a core neural network in empathy? An fMRI based quantitative meta-analysis. Neuroscience & Biobehavioral Reviews, 35(3), 903911. doi: 10.1016/j.neubiorev.2010.10.009
Feinstein, A. (2011). Multiple sclerosis and depression. Multiple Sclerosis, 17(11), 12761281. doi: 10.1177/1352458511417835
Franz, M., Popp, K., Schaefer, R., Sitte, W., Schneider, C., Hardt, J., & Braehler, E. (2008). Alexithymia in the German general population. Social Psychiatry and Psychiatric Epidemiology, 43, 5462.
Frith, C.D. (2004). Schizophrenia and theory of mind. Psychological Medicine, 34(3), 385389.
Frith, C.D., & Frith, U. (2006). The neural basis of mentalizing. Neuron, 50(4), 531534.
Gajofatto, A., & Benedetti, M.D. (2015). Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World Journal of Clinical Cases, 3(7), 545555.
Gallese, V., Keysers, C., & Rizzolatti, G. (2004). A unifying view of the basis of social cognition. Trends in Cognitive Sciences, 8(9), 396403.
Gay, M.C., Vrignaud, P., Garitte, C., & Meunier, C. (2010). Predictors of depression in multiple sclerosis patients. Acta Neurologica Scandinavica, 121(3), 161170. doi: 10.1111/j.1600-0404.2009.01232.x
Genova, H.M., Cagna, C.J., Chiaravalloti, N.D., DeLuca, J., & Lengenfelder, J. (2016). Dynamic assessment of social cognition in individuals with multiple sclerosis: A pilot study. Journal of the International Neuropsychological Society, 22(1), 8388. doi: 10.1017/S1355617715001137
Ghashghaei, H.T., Hilgetag, C.C., & Barbas, H. (2007). Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage, 34(3), 905923.
Gleichgerrcht, E., Tomashitis, B., & Sinay, V. (2015). The relationship between alexithymia, empathy and moral judgment in patients with multiple sclerosis. European Journal of Neurology, 22(9), 12951303. doi: 10.1111/ene.12745
Gobbi, C., Rocca, M.A., Pagani, E., Riccitelli, G.C., Pravatà, E., Radaelli, M., & Filippi, M. (2014). Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis. Multiple Sclerosis, 20(12), 16331640. doi: 10.1177/1352458514530022
Gobbi, C., Rocca, M.A., Riccitelli, G., Pagani, E., Messina, R., Preziosa, P., & Filippi, M. (2014). Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. Multiple Sclerosis, 20, 192201. doi: 10.1177/1352458513493684
Greene, J., Nystrom, L.E., Engell, A.D., Darley, J.M., & Cohen, J.D. (2004). The neural bases of cognitive conflict and control in moral judgment. Neuron, 44(22), 389400.
Greene, J., Sommerville, R.B., Nystrom, L.E., Darley, J.M., & Cohen, J.D. (2001). An fMRI investigation of emotional engagement in moral judgment. Science, 293(5537), 21052108.
Grynberg, D., Chang, B., Corneille, O., Maurage, P., Vermeulen, N., Berthoz, S., & Luminet, O. (2012). Alexithymia and the processing of emotional facial expressions (EFEs): Systematic review, unanswered questions and further perspectives. PLoS One, 7(8), e42429. doi: 10.1371/journal.pone.0042429
Habel, U., Klein, M., Kellermann, T., Shah, N.J., & Schneider, F. (2005). Same or different? Neural correlates of happy and sad mood in healthy males. Neuroimage, 26(1), 206214.
Happé, F.G.E., Winner, E., & Brownell, H. (1998). The getting of wisdom: Theory of mind in old age. Developmental Psychology, 34(2), 358362.
Haxby, J.V., Hoffman, E.A., & Gobbini, M.I. (2000). The distributed human neural system for face perception. Trends in Cognitive Sciences, 4(6), 223233.
Haxby, J.V., Hoffman, E.A., & Gobbini, M.I. (2002). Human neural systems for face recognition and social communication. Biological Psychiatry, 51(1), 5967.
Heikkinen, J., Jansson-Verkasalo, E., Toivanen, J., Suominen, K., Vayrynen, E., Moilanen, I., & Seppanen, T. (2010). Perception of basic emotions from speech prosody in adolescents with Asperger’s syndrome. Logopedics, Phoniatrics, Vocology, 35(3), 113120. doi: 10.3109/14015430903311184
Henry, J.D., Phillips, L.H., Beatty, W.W., McDonald, S., Longley, W.A., Joscelyne, A., & Rendell, P.G. (2009). Evidence for deficits in facial affect recognition and Theory of Mind in multiple sclerosis. Journal of the International Neuropsychological Society, 15(2), 277285. doi: 10.1017/S1355617709090195
Henry, A., Tourbah, A., Chaunu, M.-P., Rumbach, L., Montreuil, M., & Bakchine, S. (2011). Social cognition impairments in relapsing remitting multiple sclerosis. Journal of the International Neuropsychological Society, 17(6), 11221131. doi: 10.1017/S1355617711001147
Henry, J.D., von Hippel, W., Molenberghs, P., Lee, T., & Sachdev, P.S. (2016). Clinical assessment of social cognitive function in neurological disorders. Nature Reviews Neurology, 12(1), 2839. doi: 10.1038/nrneurol.2015.229
Herold, R., Feldmann, A., Simon, M., Tényi, T., Kövér, F., Nagy, F., & Fekete, S. (2009). Regional gray matter reduction and theory of mind deficit in the early phase of schizophrenia: A voxel-based morphometric study. Acta Psychiatrica Scandinavica, 119(3), 199208.
Hogan, R. (1969). Development of an empathy scale. Journal of Consulting and Clinical Psychology, 33(3), 307316.
Ihme, K., Dannlowski, U., Lichev, V., Stuhrmann, A., Grotegerd, D., Rosenberg, N., & Suslow, T. (2013). Alexithymia is related to differences in gray matter volume: A voxelbased morphometry study. Brain Research, 1491, 6067. doi: 10.1016/j.brainres.2012.10.044
Jehna, M., Langkammer, C., Wallner-Blazek, M., Neuper, C., Loitfelder, M., Ropele, S., & Enzinger, C. (2011). Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces. Brain Imaging and Behavior, 5(4), 241251. doi: 10.1007/s11682-011-9128-1
Jehna, M., Neuper, C., Ischebeck, A., Loitfelder, M., Ropele, S., Langkammer, C., & Enzinger, C. (2011). The functional correlates of face perception and recognition of emotional facial expressions as evidenced by fMRI. Brain Research, 1393, 7383. doi: 10.1016/j.brainres.2011.04.007
Jehna, M., Neuper, C., Petrovic, K., Wallner-Blazek, M., Schmidt, R., Fuchs, S., & Enzinger, C. (2010). An exploratory study on emotion recognition in patients with a clinically isolated syndrome and multiple sclerosis. Clinical Neurology and Neurosurgery, 112(6), 482484. doi: 10.1016/j.clineuro.2010.03.020
Julian, L.J., Vella, L., Vollmer, T., Hadjimichael, O., & Mohr, D.C. (2008). Employment in multiple sclerosis. Exiting and reentering the work force. Journal of Neurology, 255(9), 13541360. doi: 10.1007/s00415-008-0910-y
Kano, M., Fukudo, S., Gyoba, J., Kamachi, M., Tagawa, M., Mochizuki, H., & Yanai, K. (2003). Specific brain processing of facial expressions in people with alexithymia: An H2 15O-PET study. Brain, 126(Pt 6), 14741484.
Kanwisher, N., & Yovel, G. (2006). The fusiform face area: A cortical region specialized for the perception of faces. Philosophical Transactions of the Royal Society B: Biological Sciences, 361(1476), 21092128.
Kesselring, J., & Klement, U. (2001). Cognitive and affective disturbances in multiple sclerosis. Journal of Neurology, 248(3), 180183.
Kessler, H., Bayerl, P., Deighton, R., & Traue, H. (2002). Facially Expressed Emotion Labeling (FEEL): PC-gestützer Test zur Emotionserkennung. Verhaltenstherapie und Verhaltensmedizin, 23, 297306.
Knight, M., & Mather, M. (2013). Look out-it’s your off-peak time of day! Time of day matters more for alerting than for orienting or executive attention. Experimental Aging Research, 39(3), 305321. doi: 10.1080/0361073X.2013.779197
Koelkebeck, K., Abdel-Hamid, M., Ohrmann, P., & Brune, M. (2008). Theory of mind in schizophrenia: Clinical aspects and empirical research. Fortschritte der Neurologie Psychiatrie, 76(10), 573582. doi: 10.1055/s-2008-1038250
Kraemer, M., Herold, M., Uekermann, J., Kis, B., Daum, I., Wiltfang, J., & . . .Abdel-Hamid, M. (2013). Perception of affective prosody in patients at an early stage of relapsing-remitting multiple sclerosis. Journal of Neuropsychology, 7(1), 91106. doi: 10.1111/j.1748-6653.2012.02037.x
Kraemer, M., Herold, M., Uekermann, J., Kis, B., Wiltfang, J., Daum, I., & Abdel-Hamid, M. (2013). Theory of mind and empathy in patients at an early stage of relapsing remitting multiple sclerosis. Clinical Neurology and Neurosurgery, 115(7), 10161022. doi: 10.1016/j.clineuro.2012.10.027
Krause, M., Wendt, J., Dressel, A., Berneiser, J., Kessler, C., Hamm, A.O., & Lotze, M. (2009). Prefrontal function associated with impaired emotion recognition in patients with multiple sclerosis. Behavioural Brain Research, 205(1), 280285. doi: 10.1016/j.bbr.2009.08.009
Kuperberg, G.R., Broome, M.R., McGuire, P.K., David, A.S., Eddy, M., Ozawa, F., & Fischl, B. (2003). Regionally localized thinning of the cerebral cortex in schizophrenia. Archives of General Psychiatry, 60(9), 878888.
Kurtzke, J.F. (1983). Rating neurological impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology, 33(11), 14441452.
Kuzmanovic, B., Bente, G., von Cramon, D.Y., Schilbach, L., Tittgemeyer, M., & Vogeley, K. (2012). Imaging first impressions: Distinct neural processing of verbal and nonverbal social information. Neuroimage, 60(1), 179188. doi: 10.1016/j.neuroimage.2011.12.046
LaBar, K.S., Crupain, M.J., Voyvodic, J.T., & McCarthy, G. (2003). Dynamic perception of facial affect and identity in the human brain. Cerebral Cortex, 13(10), 10231033.
Lang, P.J., Bradley, M.M., & Cuthbert, B.N. (2005). International affective picture system (IAPS): Affective ratings of pictures and instruction manual. Technical report A-6. Gainesville, FL: University of Florida.
Langdon, D.W. (2011). Cognition in multiple sclerosis. emotion. Current Opinion in Neurology, 24(3), 244249. doi: 10.1097/WCO.0b013e328346a43b
Leppanen, J.M. (2006). Emotional information processing in mood disorders: A review of behavioral and neuroimaging findings. Current Opinion in Psychiatry, 19(1), 3439.
Leslie, K.R., Johnson-Frey, S.H., & Grafton, S.T. (2004). Functional imaging of face and hand imitation: Towards a motor theory of empathy. Neuroimage, 21(2), 601607.
Maddock, R.J., Garrett, A.S., & Buonocore, M.H. (2003). Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task. Human Brain Mapping, 18(1), 3041.
Mainero, C., Caramia, F., Pozzilli, C., Pisani, A., Pestalozza, I., Borriello, G., & Pantano, P. (2004). fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis. Neuroimage, 21(3), 858867.
Mainero, C., Pantano, P., Caramia, F., & Pozzilli, C. (2006). Brain reorganization during attention and memory tasks in multiple sclerosis: Insights from functional MRI studies. Journal of the Neurological Sciences, 245(1–2), 9398.
McDonald, S., Bornhofen, C., Shum, D., Long, E., Saunders, C., & Neulinger, K. (2006). Reliability and validity of The Awareness of Social Inference Test (TASIT): A clinical test of social perception. Disability and Rehabilitation, 28(24), 15291542.
McDonald, S., Flanagan, S., Rollins, J., & Kinch, J. (2003). TASIT: A new clinical tool for assessing social perception after traumatic brain injury. The Journal of Head Trauma Rehabilitation, 18(3), 219238.
Mike, A., Strammer, E., Aradi, M., Orsi, G., Perlaki, G., Hajnal, A., & Illes, Z. (2013). Disconnection mechanism and regional cortical atrophy contribute to impaired processing of facial expressions and theory of mind in multiple sclerosis: A structural MRI study. PLoS One, 8(12), e82422. doi: 10.1371/journal.pone.0082422
Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., & Group PRISMA. (2009). Preferred reporting items for systematic reviews and metaanalyses: The PRISMA statement. BMJ, 339, b2535.
Mohr, D.C., & Cox, D. (2001). Multiple sclerosis: Empirical literature for the clinical health psychologist. Journal of Clinical Psychology, 57(4), 479499.
Montel, S.R., & Bungener, C. (2007). Coping and quality of life in one hundred and thirty-five subjects with multiple sclerosis. Multiple Sclerosis, 13(3), 393401. doi: 10.1177/1352458506071170
Morgen, K., Kadom, N., Sawaki, L., Tessitore, A., Ohayon, J., McFarland, H., & Cohen, L.G. (2004). Training-dependent plasticity in patients with multiple sclerosis. Brain, 127(Pt 11), 25062517.
Ouellet, J., Scherzer, P.B., Rouleau, I., Metras, P., Bertrand-Gauvin, C., Djerroud, N., & Duquette, P. (2010). Assessment of social cognition in patients with multiple sclerosis. Journal of the International Neuropsychological Society, 16(2), 287296. doi: 10.1017/S1355617709991329
Pakenham, K.I., & Cox, S. (2009). The dimensional structure of benefit finding in multiple sclerosis and relations with positive and negative adjustment: A longitudinal study. Psychology and Health, 24(4), 373393. doi: 10.1080/08870440701832592
Palermo, R., & Rhodes, G. (2007). Are you always on my mind? A review of how face perception and attention interact. Neuropsychologia, 45(1), 7592.
Pantano, P., Iannetti, G.D., Caramia, F., Mainero, C., Di Legge, S., Bozzao, L., & Lenzi, G.L. (2002). Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain, 125(Pt 7), 16071615.
Pantano, P., Mainero, C., Lenzi, D., Caramia, F., Iannetti, G.D., Piattella, M.C., & Pozzilli, C. (2005). A longitudinal fMRI study on motor activity in patients with multiple sclerosis. Brain, 128(Pt 9), 21462153.
Parada-Fernández, P., Oliva-Macias, M., Amayra, I., Lopez-Paz, J.F., Lazaro, E., Martinez, O., & Perez, M. (2015). Accuracy and reaction time in recognition of facial emotions in people with multiple sclerosis. Revue Neurologique, 61(10), 433440.
Park, H.J., Kim, J.J., Lee, S.K., Seok, J.H., Chun, J., Kim, D.I., &Lee, J.D. (2008). Corpus callosal connection mapping using cortical gray matter parcellation and DT-MRI. Human Brain Mapping, 29(5), 503516.
Passamonti, L., Cerasa, A., Liguori, M., Gioia, M., Valentino, P., Nisticò, R., & Fera, F. (2009). Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain, 132(Pt 12), 33803391. doi: 10.1093/brain/awp095
Persad, S.M., & Polivy, J. (1993). Differences between depressed and nondepressed individuals in the recognition of and response to facial emotional cues. Journal of Abnormal Psychology, 102(3), 358368.
Pessoa, L. (2008). On the relationship between emotion and cognition. Nature Reviews Neuroscience, 9(2), 148158.
Pfleger, C.C., Flachs, E.M., & Koch-Henriksen, N. (2010). Social consequences of multiple sclerosis. Part 2. Divorce and separation: A historical prospective cohort study. Multiple Sclerosis, 16(7), 878882. doi: 10.1177/1352458510370978
Phillips, L., Henry, J., Scott, C., Summers, F., Whyte, M., & Cook, M. (2011). Specific impairments of emotion perception in multiple sclerosis. Neuropsychology, 25(1), 131136. doi: 10.1037/a0020752
Phillips, L.H., Saldias, A., McCarrey, A., Henry, J.D., Scott, C., Summers, F., & Whyte, M. (2009). Attentional lapses, emotional regulation and quality of life in multiple sclerosis. British Journal of Clinical Psychology, 48(Pt 1), 101106. doi: 10.1348/014466508X379566
Pinto, C., Gomes, F., Moreira, I., Rosa, B., Santos, E., Silva, A.M., &Cavaco, S. (2012). Emotion recognition in multiple sclerosis. Journal of Eye Tracking, Visual Cognition and Emotion, 2(1), 7681.
Poder, K., Ghatavi, K., Fisk, J.D., Campbell, T.L., Kisely, S., Sarty, I., & Bhan, V. (2009). Social anxiety in a multiple sclerosis clinic population. Multiple Sclerosis, 15(3), 393398. doi: 10.1177/1352458508099143
Pöttgen, J., Dziobek, I., Reh, S., Heesen, C., & Gold, S.M. (2013). Impaired social cognition in multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 84(5), 523528. doi: 10.1136/jnnp-2012-304157
Prochnow, D., Donell, J., Schäfer, R., Jörgens, S., Hartung, H., Franz, M., & Seitz, R. (2011). Alexithymia and impaired facial affect recognition in multiple sclerosis. Journal of Neurology, 258(9), 16831688. doi: 10.1007/s00415-011-6002-4
Rao, S.M., Leo, G.J., Bernardin, L., & Unverzagt, F. (1991). Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology, 41(5), 685691.
Rao, S.M., Leo, G.J., Ellington, L., Nauertz, T., Bernardin, L., & Unverzagt, F. (1991). Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology, 41(5), 692696.
Roca, M., Manes, F., Gleichgerrcht, E., Ibáñez, A., González de Toledo, M.E., Marenco, V., & Sinay, V. (2014). Cognitive but not affective theory of mind deficits in mild relapsing-remitting multiple sclerosis. Cognitive and Behavioral Neurology, 27(1), 2530. doi: 10.1097/WNN.0000000000000017
Rocca, M.A., Absinta, M., Ghezzi, A., Moiola, L., Comi, G., & Filippi, M. (2009). Is a preserved functional reserve a mechanism limiting clinical impairment in pediatric MS patients? Human Brain Mapping, 30(9), 28442851. doi: 10.1002/hbm.20712
Ross, E.D., Thompson, R.D., & Yenkosky, J. (1997). Lateralization of affective prosody in brain and the callosal integration of hemispheric language functions. Brain and Language, 56(1), 2754. doi: 10.1006/brln.1997.1731
Rovaris, M., Comi, G., & Filippi, M. (2001). The role of non-conventional MR techniques to study multiple sclerosis patients. Journal of the Neurological Sciences, 186(Suppl. 1), S3S9.
Rowe, A.D., Bullock, P.R., Polkey, C.E., & Morris, R.G. (2001). Theory of mind impairments and their relationship to executive functioning following frontal lobe excisions. Brain, 124(Pt 3), 600616.
Ruby, P., & Decety, J. (2004). How would you feel versus how do you think she would feel? A neuroimaging study of perspective-taking with social emotions. Journal of Cognitive Neuroscience, 16(6), 988999.
Samson, D., Apperly, I.A., Chiavarino, C., & Humphreys, G.W. (2004). Left temporoparietal junction is necessary for representing someone else’s belief. Nature Neuroscience, 7(5), 499500.
Sanfilipo, M.P., Benedict, R.H., Weinstock-Guttman, B., & Bakshi, R. (2006). Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology, 66(5), 685692. doi: 10.1212/01.wnl.0000201238.93586.d9
Schulte-Rüther, M., Greimel, E., Markowitsch, H.J., Kamp-Becker, I., Remschmidt, H., Fink, G.R., & Piefke, M. (2011). Dysfunctions in brain networks supporting empathy: An fMRI study in adults with autism spectrum disorders. Social Neuroscience, 6(1), 121. doi: 10.1080/17470911003708032
Sebastian, C.L., Fontaine, N.M., Bird, G., Blakemore, S.J., De Brito, S.A., McCrory, E.J., &Viding, E. (2012). Neural processing associated with cognitive and affective Theory of Mind in adolescents and adults. Social Cognitive and Affective Neuroscience, 7(1), 5363. doi: 10.1093/scan/nsr023
Segal, B.M., & Stüve, O. (2016). Primary progressive multiple sclerosis--why we are failing. Lancet, 387(10023), 10321034.
Seitz, R.J., Nickel, J., & Azari, N.P. (2006). Functional modularity of the medial prefrontal cortex: Involvement in human empathy. Neuropsychology, 20(6), 743751.
Shamay-Tsoory, S.G., & Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: A lesion study. Neuropsychologia, 45(13), 30543067.
Skevington, S.M., Lotfy, M., & O’Connell, K.A. (2004). The World Health Organisation’s WHOQOL-BREF quality of life assessment: Psychometric properties and results of the international field trial. A report from the WHOQOL group. Quality of Life Research, 13(2), 299310.
Skowronski, J.J., & Carlston, D.E. (1989). Negativity and extremity biases in impression formation: A review of explanations. Psychological Bulletin, 105, 131142.
Staffen, W., Mair, A., Zauner, H., Unterrainer, J., Niederhofer, H., Kutzelnigg, A., & Ladurner, G. (2002). Cognitive function and fMRI in patients with multiple sclerosis: Evidence for compensatory cortical activation during an attention task. Brain, 125(Pt 6), 12751282.
Stern, Y. (2012). Cognitive reserve in ageing and Alzheimer’s disease. The Lancet Neurology, 11(11), 10061012.
Stone, V.E., Baron-Cohen, S., & Knight, R.T. (1998). Frontal lobe contribution to theory of mind. Journal of Cognitive Neuroscience, 10(5), 640656.
Sullivan, S., & Ruffman, T. (2004). Social understanding: How does it fare with advancing years? British Journal of Psychology, 95(Pt 1), 118.
Sumowski, J.F., Wylie, G.R., Deluca, J., & Chiaravalloti, N. (2009). Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: Functional magnetic resonance imaging evidence for cognitive reserve. Brain, 133(Pt 2), 362374. doi: 10.1093/brain/awp307
Sumowski, J.F., & Leavitt, V.M. (2013). Cognitive reserve in multiple sclerosis. Multiple Sclerosis, 19(9), 11221127.
Suslow, T., Dannlowski, U., Lalee-Mentzel, J., Donges, U.S., Arolt, V., & Kersting, A. (2004). Spatial processing of facial emotion in patients with unipolar depression: A longitudinal study. Journal of Affective Disorders, 83(1), 5963.
Sweet, L.H., Rao, S.M., Primeau, M., Durgerian, S., & Cohen, R.A. (2006). Functional magnetic resonance imaging response to increased verbal working memory demands among patients with multiple sclerosis. Human Brain Mapping, 27(1), 2836.
Tamietto, M., & de Gelder, B. (2010). Neural bases of the non-conscious perception of emotional signals. Nature Reviews Neuroscience, 11(10), 697709.
Tangney, J.P., Stuewig, J., & Mashek, D.J. (2007). Moral emotions and moral behavior. Annual Review of Psychology, 58, 345372.
Tottenham, N., Tanaka, J., Leon, A., McCarry, T., Nurse, M., Hare, T., & Nelson, C. (2009). The NimStim set of facial expressions: Judgments from untrained research participants. Psychiatry Research, 168(3), 242249. doi: 10.1016/j.psychres.2008.05.006
Uekermann, J., Abdel-Hamid, M., Lehmkamper, C., Vollmoeller, W., & Daum, I. (2008). Perception of affective prosody in major depression: A link to executive functions? Journal of the International Neuropsychological Society, 14(4), 552561. doi: 10.1017/S1355617708080740
Uekermann, J., Channon, S., Lehmkamper, C., Abdel-Hamid, M., Vollmoeller, W., & Daum, I. (2008). Executive function, mentalizing and humor in major depression. Journal of the International Neuropsychological Society, 14(1), 5562. doi: 10.1017/S1355617708080016
Uekermann, J., Channon, S., Winkel, K., Schlebusch, P., & Daum, I. (2007). Theory of Mind, humour processing and executive functioning in alcoholism. Addiction, 102(2), 232240. doi: 10.1111/j.1360-0443.2006.01656.x
Uekermann, J., & Daum, I. (2008). Social cognition in alcoholism: A link to prefrontal cortex dysfunction? Addiction, 103(5), 726735. doi: 10.1111/j.1360-0443.2008.02157.x
Uekermann, J., Kraemer, M., Abdel-Hamid, M., Schimmelmann, B.G., Hebebrand, J., Daum, I., & Kis, B. (2010). Social cognition in attention-deficit hyperactivity disorder (ADHD). Neuroscience and Biobehavioral Reviews, 34(5), 734743. doi: 10.1016/j.neubiorev.2009.10.009
Van Kleef, G.A. (2009). How emotions regulate social life. The Emotions as Social Information (EASI) model. Current Directions in Psychological Sciences, 18, 184188.
Vázquez-Marrufo, M., Galvao-Carmona, A., González-Rosa, J.J., Hidalgo-Muñoz, A.R., Borges, M., Ruiz-Peña, J.L., & Izquierdo, G. (2014). Neural correlates of alerting and orienting impairment in multiple sclerosis patients. PLoS One, 12(9), e97226. doi: 10.1371/journal.pone.0097226
Vistoli, D., Brunet-Gouet, E., Baup-Bobin, E., Hardy-Bayle, M.C., & Passerieux, C. (2011). Anatomical and temporal architecture of Theory of Mind: A MEG insight into the early stages. Neuroimage, 54(2), 14061414. doi: 10.1016/j.neuroimage.2010.09.015
Vollm, B.A., Taylor, A.N., Richardson, P., Corcoran, R., Stirling, J., McKie, S., &Elliott, R. (2006). Neuronal correlates of theory of mind and empathy: A functional magnetic resonance imaging study in a nonverbal task. Neuroimage, 29(1), 9098.
Vuilleumier, P., & Pourtois, G. (2007). Distributed and interactive brain mechanisms during emotion face perception: Evidence from functional neuroimaging. Neuropsychologia, 45(1), 174194.
Wegner, C., Filippi, M., Korteweg, T., Beckmann, C., Ciccarelli, O., De Stefano, N., & Matthews, P.M. (2008). Relating functional changes during hand movement to clinical parameters in patients with multiple sclerosis in a multi-centre fMRI study. European Journal of Neurology, 15(2), 113122. doi: 10.1111/j.1468-1331.2007.02027.x
Wheaton, K.J., Thompson, J.C., Syngeniotis, A., Abbott, D.F., & Puce, A. (2004). Viewing the motion of human body parts activates different regions of premotor, temporal, and parietal cortex. Neuroimage, 22(1), 277288.
Williams, J.H. (2008). Self-other relations in social development and autism: Multiple roles for mirror neurons and other brain bases. Autism Research, 1(2), 7390. doi: 10.1002/aur.15
Wildgruber, D., Ackermann, H., Kreifelts, B., & Ethofer, T. (2006). Cerebral processing of linguistic and emotional prosody: fMRI studies. Progress in Brain Research, 156, 249268. doi: 10.1016/S0079-6123(06)56013-3
Wolkenstein, L., Schonenberg, M., Schirm, E., & Hautzinger, M. (2011). I can see what you feel, but I can’t deal with it: Impaired Theory of Mind in depression. Journal of Affective Disorders, 132(1-2), 104111. doi: 10.1016/j.jad.2011.02.010
Young, L., Camprodon, J.A., Hauser, M., Pascual-Leone, A., & Saxe, R. (2010). Disruption of the right temporoparietal junction with transcranial magnetic stimulation reduces the role of beliefs in moral judgments. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 67536758. doi: 10.1073/pnas.0914826107
Young, A., Perrett, D., Calder, A., Sprengelmeyer, R., & Ekman, P. (2002). Facial expressions of emotion - Stimuli and tests (Software Manual v2.1 Ed.), Bury St Edmunds, England: Thames Valley Test Company.
Zaki, J., Hennigan, K., Weber, J., & Ochsner, K.N. (2010). Social cognitive conflict resolution: Contributions of domain-general and domain-specific neural systems. Journal of Neuroscience, 30(25), 84818488. doi: 10.1523/JNEUROSCI.0382-10.2010