The left amygdala: A shared substrate of alexithymia and empathy

    The left amygdala: A shared substrate of alexithymia and empathy Katharina Sophia Goerlich-Dobre, Claus Lamm, Juergen Pripfl, Ute Habel, Mikhail Votinov PII: DOI: Reference:

S1053-8119(15)00723-5 doi: 10.1016/j.neuroimage.2015.08.014 YNIMG 12492

To appear in:

NeuroImage

Received date: Accepted date:

14 May 2015 5 August 2015

Please cite this article as: Goerlich-Dobre, Katharina Sophia, Lamm, Claus, Pripfl, Juergen, Habel, Ute, Votinov, Mikhail, The left amygdala: A shared substrate of alexithymia and empathy, NeuroImage (2015), doi: 10.1016/j.neuroimage.2015.08.014

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ACCEPTED MANUSCRIPT The left amygdala: A shared substrate of alexithymia and empathy

Germany 2

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Department of Psychiatry and Psychotherapy, Medical Faculty, RWTH Aachen University, Aachen,

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Katharina Sophia Goerlich-Dobre1, Claus Lamm2, Juergen Pripfl2, Ute Habel1,3, Mikhail Votinov1,2

Social, Cognitive and Affective Neuroscience Unit, Department of Basic Psychological Research

JARA – Translational Brain Medicine, Aachen & Jülich, Nordrhein-Westfalen, Germany

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Abstract: 303 words

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Manuscript: 6,734 words

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and Research Methods, Faculty of Psychology, University of Vienna, Vienna, Austria

Please address correspondence to:

Katharina Sophia Goerlich-Dobre, PhD Department of Psychiatry and Psychotherapy RWTH Aachen University Hospital Pauwelsstr. 30, 52074 Aachen, Germany Phone: +49 (0)241 80 80279 Email: [email protected]

ACCEPTED MANUSCRIPT Abstract Alexithymia, a deficit in emotional self-awareness, and deficits in empathy, which encompasses the awareness of other’s emotions, are related constructs that are both associated with a range of

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psychopathological disorders. Neuroimaging studies suggest that there is overlap between the

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neural bases of alexithymia and empathy, but no systematic comparison has been conducted so far.

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The aim of this structural magnetic resonance imaging study was to disentangle the overlap and differences between the morphological profiles of the cognitive and affective dimensions of

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alexithymia and empathy, and to find out to what extent these differ between women and men. High-resolution T1 anatomical images were obtained from 125 healthy right-handers (18 - 42 years),

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70 women and 55 men. By means of voxel-based morphometry, region of interest (ROI) analyses were performed on gray matter volumes of several anatomically defined a-priori regions previously

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linked to alexithymia and empathy. Partial correlations were conducted within the female and male

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group using ROI parameter estimates as dependent variables and the cognitive and affective

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dimensions of alexithymia and empathy, respectively, as predictors, controlling for age. Results were considered significant if they survived Holm-Bonferroni correction for multiple comparisons. The left amygdala was identified as a key substrate of both alexithymia and empathy. This

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association was characterized by an opposite pattern: The cognitive alexithymia dimension was linked to smaller, the two empathy dimensions to larger left amygdala volume. While sex-specific effects were not observed for empathy, they were evident for the affective alexithymia dimension: Men - but not women - with difficulty fantasizing had smaller gray matter volume in the middle cingulate cortex. Moreover, structural covariance patterns between the left amygdala and other emotion-related brain regions differed markedly between alexithymia and empathy. These differences may underlie the complex patterns of deficits in emotional self- and other-awareness observed across a range of psychopathological conditions.

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ACCEPTED MANUSCRIPT 1.

Introduction

Alexithymia (‘no words for feelings’) is a dimensional psychological construct referring to individuals with difficulty identifying their feelings, distinguishing them from physiological

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sensations of arousal, and describing feelings to others. In addition, alexithymic individuals lack

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imaginative abilities and exhibit an externally oriented thinking style devoid of introspection

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(Sifneos, 1973; Vorst & Bermond, 2001). Alexithymia is considered a risk factor for a variety of psychiatric conditions, including schizoid personality disorder, psychopathy, borderline personality

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disorder, and schizophrenia (e.g., Moormann et al., 2008; Taylor, Bagby, & Parker, 1999; van der Meer, van't Wout, & Aleman, 2009). The alexithymia construct comprises two separable dimensions.

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Its cognitive dimension consists of the facets (difficulties) identifying, analyzing, and verbalizing feelings and thus refers to deficiencies in emotion processing at a cognitive level. In contrast, its

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affective dimension refers to the extent to which emotions are subjectively experienced and

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comprises the facets emotionalizing (the extent to which an individual is emotionally aroused by

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emotion-inducing experiences) and fantasizing (the extent to which an individual is inclined to imagine, daydream etc).

Clinical observations indicated that alexithymia is concomitant with a specific style of social

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interaction (Grabe, Spitzer, & Freyberger, 2001; Nemiah & Sifneos, 1970; Taylor et al., 1999), and empirical research confirmed that individuals scoring high on this personality trait approach others in a cold and detached manner (De Rick & Vanheule, 2006; Guttman & Laporte, 2002). In a study specifically examining interpersonal problems associated with alexithymia, a stable association between alexithymia and cold and distant social behavior was observed (i.e., low degrees of affection for and connection with others), both in healthy individuals (n = 157) and in clinical outpatients (n = 404) (Vanheule, Desmet, Meganck, & Bogaerts, 2007), underlining descriptions of the ‘cold-blooded’ personality of alexithymic individuals. In line with these reports of compromised social behavior, several studies showed that alexithymia is associated with reduced empathy for others (Bird et al., 2010; Delphine Grynberg, 3

ACCEPTED MANUSCRIPT Luminet, Corneille, Grèzes, & Berthoz, 2010; Guttman & Laporte, 2002; Moriguchi et al., 2007; Silani et al., 2008). Like alexithymia, empathy can be subdivided into a cognitive and an affective dimension. Perspective taking, i.e. one’s ability to arrive at a cognitive understanding of what

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another person thinks or feels, and fantasy, a person’s ability to project themselves into fictional

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situations, can occur without a simultaneous emotional response and are thus considered part of the

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cognitive empathy dimension. Empathic concern, i.e. a person’s emotional response to observing someone else suffering, and personal distress, emerging when observing someone else becoming

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agitated or emotionally distraught, do not require a cognitive understanding of the other’s suffering, and thus form the affective empathy dimension. Note, however, that both alexithymia and empathy

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are complex concepts, and the distinction into an affective and a cognitive dimension in each of them is not considered unequivocal: A study by Bagby and colleagues failed to confirm the

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existence of two distinct alexithymia subtypes based on these two dimensions (Bagby et al., 2009),

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and due to the extensive interaction between cognitive and affective aspects of empathy, several

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researchers have either rejected the idea of these being separable concepts (Baron-Cohen & Wheelwright, 2004; Duan & Hill, 1996; Singer, 2006), or proposed to conceive of them in terms of different yet inherently interacting mechanisms contributing to different aspects of empathic

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resonance (Lamm & Majdandzic, 2015). Previous research indicates that individuals with high levels of alexithymia have pronounced deficits in both perspective taking and empathic concern (Berthoz, Wessa, Kedia, Wicker, & Grezes, 2008; Feldmanhall, Dalgleish, & Mobbs, 2013; Grynberg et al., 2010; Guttman & Laporte, 2002; Silani et al., 2008; Vanheule et al., 2007; see Grynberg et al., 2012 for a review). This strong link can be explained in light of alexithymia being a deficit in the self-awareness of one’s own feelings. Emotional self-awareness is a fundamental aspect of empathy, because an individual’s access to their own feelings is the basis for being able to identify the feelings of others (Decety, Jackson, Sommerville, Chaminade, & Meltzoff, 2004; Gallup & Platek, 2002). According to simulation models of empathy, an observer understands the emotional experience of another by activating 4

ACCEPTED MANUSCRIPT similar brain regions that are engaged when they experience the perceived emotional state themselves (e.g., Gallese, 2003; Goldman, 2006). In alexithymia, neural activity in brain regions necessary for successful emotion processing is compromised, suggesting impaired abilities to

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efficiently recruit those same regions when attempting to process other people’s feelings.

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Although no systematic comparison exists yet, structural and functional imaging studies on

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empathy on the one hand and alexithymia on the other suggest that there is significant overlap between their neural bases. The anterior cingulate cortex (ACC), middle cingulate cortex (MCC),

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and insulae are consistently activated in tasks that require empathizing with other people’s feelings (Fan, Duncan, de Greck, & Northoff, 2011) and pain (Lamm, Decety, & Singer, 2011) and are thus

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considered to constitute the core empathy network. Importantly, these regions are also key correlates of alexithymia (for a review, see Wingbermühle, Theunissen, Verhoeven, Kessels, &

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Egger, 2012). The ACC shows aberrant activation during socio-affective tasks in relation to

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alexithymia (e.g., Feldmanhall et al., 2013; Moriguchi et al., 2007); for a meta-analysis, see (van

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der Velde et al., 2013), and its volume seems to be reduced in individuals scoring high on the cognitive alexithymia dimension (van der Velde et al., 2014). Regarding the empathy dimensions, lesion studies also suggest a role of the ACC in affective empathy (for a review, see Hillis, 2014).

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The medial prefrontal cortex (mPFC) and MCC are involved in mentalizing (Lombardo et al., 2010; for a meta-analysis, see Schurz et al., 2014) and the regulation and integration of affect based on their intrinsic connections with the insula (for reviews, see Lamm & Singer, 2010; Medford & Critchley, 2010) and could thus be involved in either empathy dimension. Moreover, its volume seems to be linked to the affective dimension of alexithymia (Goerlich-Dobre, Bruce, Martens, Aleman, & Hooker, 2014a). Insular volume has been reported to correlate with the affective empathy facets personal distress and empathic concern (Banissy, Kanai, Walsh, & Rees, 2012). With respect to alexithymia, volume differences in the insulae have been found in relation to both the cognitive (e.g., Borsci et al., 2009; Goerlich-Dobre et al., 2015; Grabe et al., 2014; Ihme et al., 2013; Karlsson, Naatanen, & Stenman, 2008) and the affective dimension (Goerlich-Dobre et al., 5

ACCEPTED MANUSCRIPT 2014a), and when contrasting different alexithymia subtypes (Goerlich-Dobre et al., 2015). Taken together, the ACC appears to be involved in the cognitive dimensions of both alexithymia and empathy as well as in the affective empathy dimension. The MCC appears to be

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linked to the affective dimension of alexithymia and may be associated with either empathy

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dimension, and the insulae may be implicated in the cognitive and affective dimensions of both

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constructs.

Furthermore, the precuneus, the amygdalae, and the orbitofrontal cortex (OFC) have been

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reported as correlates of both empathy and alexithymia. The precuneus has been found to be consistently involved in (cognitive) alexithymia (for a meta-analysis, see (van der Velde et al.,

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2013), and precuneus volume was reported to correlate negatively with empathic concern, part of affective empathy (Banissy et al., 2012). The amygdalae have been implicated in affective aspects

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of empathy including affective arousal (for a review, see Decety, 2010; Derntl et al., 2010) and

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personal distress (Ho, Konrath, Brown, & Swain, 2014), whereas they have been suggested to be

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specifically linked to the cognitive dimension of alexithymia (Wingbermühle et al., 2012). Finally, reduced OFC volume has been reported in relation to affective alexithymia (van der Velde et al., 2014). Patients with OFC lesions and individuals with psychopathy showed impaired performance

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in an affective, but not a cognitive theory of mind task, implicating the OFC in affective empathy (Shamay-Tsoory, Harari, Aharon-Peretz, & Levkovitz, 2010). Taken together, the OFC seems to be involved in the affective dimensions of alexithymia and empathy, whereas the precuneus and the amygdalae appear to be linked to the cognitive dimension of alexithymia, but the affective dimension of empathy. To understand the relationship between the alexithymia and empathy constructs and their neural bases, a direct comparison is necessary, but has not been performed so far. Therefore, the present study used voxel-based morphometry (VBM) aiming to disentangle specific links between the cognitive and affective alexithymia and empathy dimensions with gray matter volumes of the ACC, MCC, OFC, precuneus, insulae, and amygdalae by means of a region of interest (ROI) 6

ACCEPTED MANUSCRIPT approach. Sex differences have been frequently reported for empathy (Baron-Cohen & Wheelwright, 2004; Berthoz et al., 2008; Davis & Association, 1980; Grynberg et al., 2010). Furthermore, they are evident in alexithymia (Levant, Hall, Williams, & Hasan, 2009). Thus, the study participants

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were subdivided into a female and a male group in order to examine sex-specific overlap and

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differences between the neural bases of the cognitive and affective empathy and alexithymia

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dimensions.

Based on the previous imaging literature on alexithymia and empathy, we hypothesized the

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cognitive alexithymia dimension to be associated with gray matter volume differences in the ACC, precuneus, and amygdala, and the affective alexithymia dimension to be linked to MCC and OFC

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volume differences, while insula volume differences could occur in relation to either alexithymia dimension. Regarding the empathy dimensions, we hypothesized that the affective empathy

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dimension might be linked to gray matter volume differences in the amygdala, precuneus, and the

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OFC. ACC, MCC, and insula volume differences could be observed in relation to either empathy

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dimension. Lastly, given the negative correlation between the cognitive alexithymia and empathy dimensions, we hypothesized these to affect gray matter volumes of shared neural structures in

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opposite directions.

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ACCEPTED MANUSCRIPT 2.

Material and methods

2.1.

Participants

Structural T1-weighted images of 125 (55 male) healthy subjects aged between 18 and 42 years

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were selected from two previous studies: Seventy-five (60%) from a previous genetic neuroimaging

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study (Votinov et al., 2014), and 50 (40%) from another neuroimaging study, both performed at the

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University of Vienna 1 . However, samples were not genetically homogeneous as the sample in Votinov et al. (2014) comprised three different and equal-sized groups with high, intermediate, and

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low prodynorphin gene expression, while the second study did neither collect genetic information nor perform a screening for genetic differences. All 125 participants were right-handed, as

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determined by the Edinburgh Handedness Inventory, native speakers of German with normal or corrected-to-normal vision, and no hearing problems. None had a psychiatric or neurological

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disorder in present or past according to self-report. Participants gave informed consent prior to the

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respective study they participated in and received compensation for participation. Both studies were

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approved by the ethics committee of the Medical University of Vienna and conducted in accordance with the Declaration of Helsinki.

Alexithymia and empathy scales

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2.2.

Before MRI scanning, all participants filled in two questionnaires assessing empathy and alexithymia. Alexithymia was assessed by means of a validated German version (Müller et al., 2004) of the Bermond-Vorst Alexithymia Questionnaire (BVAQ, (Vorst & Bermond, 2001). The BVAQ is a 40-item self-report scale that comprises five subscales which eight items each: Identifying, verbalizing, analyzing, emotionalizing and fantasizing defined by Nemiah and Sifneos (Nemiah & Sifneos, 1970). Answers are rated on a 5-point Likert scale from 1 to 5, with higher scores indicating more pronounced alexithymic characteristics. Previous studies have confirmed the fivefactor structure of the BVAQ and its good psychometric properties (Berthoz, Ouhayoun, Perez-Diaz,

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Using TMS to treat smoking addiction: behavioral and neural effects. 8

ACCEPTED MANUSCRIPT Consoli, & Jouvent, 2000; Vorst & Bermond, 2001). In contrast to the Toronto Alexithymia Scale (TAS-20), which assesses only the cognitive alexithymia dimension, the BVAQ makes it possible to assess both the affective and the cognitive alexithymia dimension: The factors Identifying (I),

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Verbalizing (V), and Analyzing (A) are grouped into the cognitive dimension (possible scores: 10 –

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80), and the factors Emotionalizing (E) and Fantasizing (F) into the affective dimension of

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alexithymia (possible scores: 15 – 120). The validity of this two-factor structure has been confirmed through factor analyses (Bailey & Henry, 2007; Bekker, Bachrach, & Croon, 2007; Bermond et al.,

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2007; but see Bagby et al., 2009 for failure to support the two-factor structure). The correlation between the cognitive BVAQ factor and the total score of the TAS-20 is high (r = 0.80), indicating

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that they assess the same alexithymic features (Vorst & Bermond, 2001). Empathy was assessed by means of a validated German version (Kanske, Schönfelder, &

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Wessa, 2013) of the Interpersonal Reactivity Index (IRI, Davis, 1980), a widely used empathy scale

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that consists of four subscales: Perspective Taking (PT), Fantasy (F), Empathic Concern (EC), and Personal Distress (PD). The subscales of the original American version possess good psychometric

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properties with Cronbach’s α coefficients of internal consistency ranging from 0.71 to 0.77 and test–retest reliability coefficients ranging from 0.61 to 0.81 (Davis, 1980). The psychometric quality

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of the German translation used here was comparable (Cronbach’s α coefficients: F, 0.79; PT, 0.82; PD, 0.78; EC, 0.68).

Each IRI subscale comprises seven items that are scored on a 5-point Likert scale from 0 (‘Does not describe me well’) to 4 (‘Describes me very well’), resulting in a possible score of 0 to 28 per subscale. PT is a form of cognitive empathy that describes one’s ability to arrive at a cognitive understanding of what another person thinks or feels, which may occur apart from an emotional response. F assesses a person’s ability to project themselves into fictional situations, for example while reading or watching movies. EC may manifest as a sudden emotional response to observing someone in distress and does not necessarily require a cognitive understanding of why the other is suffering. PD occurs when an observer of someone else’s distress becomes agitated or 9

ACCEPTED MANUSCRIPT emotionally distraught him/herself, which may occur in the absence of a cognitive understanding of the other’s distress. Accordingly, PT and F were grouped into the cognitive dimension of empathy (possible score: 0 – 56), and EC and PD into the affective dimension (possible score: 0 – 56), as

MRI procedure

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2.3.

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done in previous studies (e.g., Rankin, Kramer, & Miller, 2005; Ze, Thoma, & Suchan, 2014).

MRI scanning was conducted on a 3 Tesla TIM Trio whole body scanner (Siemens, Germany) at the

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MR Center of Excellence, Medical University of Vienna. Participants were scanned using the manufacturer’s 32-channel head coil. For anatomical registration, we obtained high-resolution 3D

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T1 anatomical images (magnetization prepared rapid gradient echo sequence, repetition time (TR) = 2.3 s, echo time (TE) = 4.21 ms, 1-mm3 isotropic voxels, 1.1 mm slice thickness, 900 ms inversion

Preprocessing

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2.4.

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time, 9° flip angle).

Imaging data were preprocessed using the SPM8 software (Wellcome Department of Imaging Neuroscience Group, London, UK; http://www.fil.ion.ucl.ac.uk/spm) running under MATLAB

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2012b (The MathWorks, Natick, MA, USA) and the VBM8 toolbox (Mietchen & Gaser, 2009). Within the same generative model (Ashburner & Friston, 2005) images were reoriented to the intercommissural plane, corrected for field intensity inhomogeneities, and spatially normalized into standard space using the DARTEL default template of VBM8. The images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). The segmented tissue was then modulated with Jacobian determinants. In modulated images, the total volume of gray matter is the same as in the original images as modulation scales by the same amount of expansion or contraction that is applied during normalization. The modulated gray matter volumes were smoothed with a Gaussian kernel of 8 mm full width at half maximum (FWHM), which is the optimal kernel for detecting morphometric differences in small as well as larger neural structures 10

ACCEPTED MANUSCRIPT (Honea, Crow, Passingham, & Mackay, 2005; White et al., 2001). No outliers were identified via a homogeneity check, thus the normalized, modulated, and smoothed gray matter segments of all 125

Questionnaire analyses

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2.5.

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subjects were included in the statistical analyses.

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Demographic data were analyzed using SPSS 20 (SPSS Inc, Chicago, Illinois). A one-way analysis of variance (ANOVA) tested for differences in cognitive and affective alexithymia and empathy

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scores, age, and total intracranial volume (TIV) between the female and male groups. Validation of the two-factor structure of the BVAQ and IRI and associations between the cognitive and affective

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dimensions of alexithymia and empathy within the two groups were tested by means of partial correlations controlling for age. Significance was set at p < 0.05 (one-tailed for the two-factor

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validation due to the hypothesized correlation between subscales, two-tailed for the within-group

2.6.

ROI analyses

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comparisons).

First, whole-brain multiple correlations of the alexithymia and empathy dimensions with gray

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matter volume were performed for visualization, controlling for age. Then, VBM ROI analyses were performed on eight a priori defined regions (see Figure 1): the ACC, MCC, OFC, precuneus, amygdalae (left and right), and insulae (left and right). Masks for these anatomical ROIs were used as defined by the WFU Pickatlas toolbox (Wake Forest School of Medicine, Winston Salem. Mean parameter estimates of each ROI for each subject were then extracted using MarsBaR (http://marsbar.sourceforge.net/) for analysis in SPSS 20 (SPSS Inc, Chicago, Illinois). To test associations between ROI gray matter volumes and the cognitive and affective dimensions of alexithymia and empathy, partial correlations were conducted within the female and male group using the ROI parameter estimates as dependent variables and the cognitive and affective dimensions of alexithymia and empathy, respectively, as predictors, while controlling for age. TIV 11

ACCEPTED MANUSCRIPT was not used as a covariate as the non-linear images represent volume of gray matter that is already corrected for individual brain sizes. Because of the high negative correlation between alexithymia and empathy and their associated covariance, separate analyses were performed to avoid variance

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inflation.

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Given functional and cytoarchitectonic differences between subregions of the ACC

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(Beckmann, Johansen-Berg, & Rushworth, 2009; Palomero-Gallagher, Vogt, Schleicher, Mayberg, & Zilles, 2009; Palomero-Gallagher, Eickhoff, Hoffstaedter, Schleicher, Mohlberg, Vogt, Amunts,

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Zilles, 2015; Vogt, 2005) and insula (Kurth, Zilles, Fox, Laird, & Eickhoff, 2010) and the involvement of these regions in empathy as well as alexithymia, additional analyses were performed

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for the dorsal (d), pregenual (pg), and subgenual (sg) ACC, and for the left and right anterior and posterior insulae (Figure 2). Masks for these ROIs were created using a modified version of the

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automated anatomical labeling (AAL) atlas that contains a higher level of parcellation for the

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cingulate and insular cortex (Lord, Horn, Breakspear, & Walter, 2012). Mean parameter estimates of

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each ROI for each subject were extracted, and additional partial correlations were performed within the female and male group with ROI parameter estimates as dependent variables and the cognitive

age).

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and affective dimensions of alexithymia and empathy, respectively, as predictors (controlling for

For all ROI analyses, the Holm-Bonferroni correction for multiple comparisons was applied. This correction controls the family-wise error rate at a given level of α to minimize type I errors while performing multiple Bonferroni tests at each intersection (Holm, 1979). This method was chosen because it minimized the type II errors inherent in a Bonferroni correction, which would have been too conservative for the present data. In the Holm-Bonferroni method, uncorrected P values are ordered, with the smallest value compared with 0.05/n (where n = number of comparisons). If this value is lower, the null hypothesis is rejected, and the next smallest is compared with 0.05/(n–1). This process continues until the null hypothesis cannot be rejected and all p values above this level are considered non-significant. Applied to the current data, the initial 12

ACCEPTED MANUSCRIPT significance threshold for the main ROI analysis (n = 8) was p = 0.006; the initial threshold for the parcellated ROI analysis (n = 7) was p = 0.007. Moreover, whole-brain analyses were performed in order to detect gray matter volume

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differences in relation to the alexithymia and empathy dimensions outside of our a-priori ROIs.

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Whole-brain analyses were run both for the entire sample (controlling for age and sex) and for the

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female and male groups separately (controlling for age). The significance threshold for these analyses was pFWE < 0.05 cluster level, correcting for multiple comparisons using random Gaussian

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field theory implemented in SPM (Ashburner & Friston, 2000).

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ACCEPTED MANUSCRIPT 3.

Results

3.1.

Alexithymia and empathy

Validation analyses of the two-dimensional character of empathy and alexithymia showed that the

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two cognitive empathy subscales PT and F were significantly correlated (r = 0.36, p < 0.001), as

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were the two affective subscales EC and PD (r = 0.20, p < 0.05). The three cognitive alexithymia

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subscales I, V, and A were highly correlated with one another (I and V, r = 0.49, p < 0.001; I and A, r = 0.50, p < 0.001; V and A, r = 0.54, p < 0.001). However, the two affective alexithymia subscales

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E and F were not significantly correlated (r = 0.07, p < 0.001). Therefore, analyses regarding the affective alexithymia dimension were performed for E and F separately.

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Table 1 lists the means, standard deviations (SD), and range (minimum – maximum) of scores on the cognitive and affective dimensions of alexithymia and empathy in the female and the

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male group. Moreover, the table indicates the results of a one-way ANOVA between the two groups,

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which revealed no significant differences in age and alexithymia levels between women and men

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(p > 0.05). Confirming sex differences with respect to empathy (Davis & Association, 1980), women had more affective empathy than men (p < 0.01), whereas cognitive empathy levels did not differ between sexs (p > 0.05).

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Partial correlations between the alexithymia and empathy dimensions showed that the cognitive alexithymia dimension was negatively correlated with cognitive empathy (women: r = 0.75, p < 0.001; men: r = -0.59, p < 0.001) and with affective empathy (women: r = -0.68, p < 0.001; men: r = -0.43, p < 0.001), demonstrating that empathy was significantly reduced in individuals with higher cognitive alexithymia. Fisher’s r-to-z transformation additionally revealed a significant effect of sex, suggesting that the link between cognitive alexithymia and the two empathy dimensions was stronger in women than in men (p < 0.05). The affective alexithymia dimension (E and F) was not significantly related to either empathy dimension, neither in women nor in men (p > 0.05).

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ACCEPTED MANUSCRIPT 3.2.

ROI analysis

Table 2 lists the results of sex-specific partial correlations between the cognitive and affective dimensions of alexithymia and empathy with ROI gray matter volumes.

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The cognitive dimensions of alexithymia and empathy were significantly associated with left

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amygdala volume in opposite directions: Higher levels of cognitive alexithymia were linked to

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reduced left amygdala volume, higher levels of cognitive empathy to larger left amygdala volume, irrespective of sex. This effect was also observed for the affective empathy dimension, which was

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also related to larger left amygdala volume, but this association survived our corrected significance threshold p < 0.006 only in women, while it was only significant at an uncorrected threshold p <

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0.05 in men. Fisher’s r-to-z transformation revealed eventually that the correlation coefficients of this association did not significantly differ between women and men, suggesting that sex did not

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mediate the link between the affective empathy dimension and left amygdala volume. In contrast,

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for the affective alexithymia dimension a significant effect of sex was found: The difficulties

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fantasizing (F) subscale of the affective alexithymia dimension was associated with reduced gray matter volume in the MCC in men only. These results suggest that alexithymia and empathy have one neural substrate, the left

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amygdala, in common, with whose volumes they are associated in opposite directions. They further indicate that, regarding the structural manifestation of the affective alexithymia dimension, sex plays a significant role.

Several other ROIs showed some associations with cognitive alexithymia (right amygdala, OFC, precuneus), affective alexithymia (ACC, left insula, precuneus), and cognitive empathy (right amygdala, right insula), but these correlations did not survive the Holm-Bonferroni correction. For a more complete assessment, uncorrected results are listed in Supplementary Table 1.

3.3.

Parcellated ROI analysis: ACC and insula subregions

Additional ROI analyses on the parcellated subregions of the ACC (dACC, pgACC, sgACC) and 15

ACCEPTED MANUSCRIPT the insulae (left and right anterior and posterior) revealed no gray matter volume differences surviving the threshold p = 0.007. At an uncorrected threshold p < 0.05, however, the fantasizing subscale of the affective alexithymia dimension was linked to volumes of the pgACC, dACC, and

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the left anterior and posterior insula, whereas both empathy dimensions were associated with dACC

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volumes. These uncorrected results are listed in Supplementary Table 2.

3.4. Whole-brain analyses

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Results of the whole-brain analyses for the entire sample are visualized in Figure 3 for alexithymia and in Figure 4 for empathy, revealing a large cluster comprising the left amygdala, thalamus,

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hippocampus and parahippocampal gyrus common to the cognitive dimensions of both constructs. Overall, alexithymia was mainly related to reductions in gray matter volume, while empathy was

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predominantly related to increased gray matter volumes. While there was substantial overlap

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between the neural substrates of the two empathy dimensions, no overlap was observed between the

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two alexithymia dimensions, confirming their distinct neuroanatomical bases. All results of the whole-brain analyses for the entire sample are listed in Table 3. Results of the sex-specific whole-brain analyses are visualized in Figure 5 for alexithymia

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and in Figure 6 for empathy. Overall, these results suggest distinct effects of sex on the neural substrates of particularly the affective alexithymia dimension, for which there was virtually no overlap between sexes. All results of the sex-specific whole-brain analyses are listed in Table 4. Taken together, both ROI and whole brain analyses identified the left amygdala as a key correlate of alexithymia and empathy. Left amygdala volume was significantly correlated with both empathy dimensions (cognitive: r = 0.47, p < 0.001; affective: r = 0.38, p < 0.001) and showed a high negative correlation with the cognitive alexithymia dimension (r = -0.50, p < 0.001), while it was unrelated to its affective dimension (E: r = -0.09, p = 0.17; F: r = -0.09, p = 0.14). A conjunction analysis (significance threshold pFWE < 0.05) confirmed the left amygdala as a common substrate of the two empathy dimensions and the cognitive alexithymia dimension (Figure 7). 16

ACCEPTED MANUSCRIPT 3.5. The left amygdala: A shared substrate of alexithymia and empathy 3.5.1. Hierarchical correlation To examine the relative contributions of the cognitive alexithymia dimension and the empathy

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dimensions to the observed volume differences of the left amygdala, hierarchical correlation

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analyses were performed. The affective empathy dimension (r = 0.38) was entered in the first step,

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the cognitive empathy dimension (r = 0.47) in the second, and the cognitive alexithymia dimension (r = -0.50) in the third. Adding the cognitive alexithymia dimension significantly increased the fit of

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the model by 4.5% from 23.6% to 28.1% (F(1,124) = 7.61, p = 0.007), suggesting that the cognitive alexithymia dimension predicted left amygdala volume change above and beyond both empathy

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dimensions. A second (comparison) model, in which the cognitive alexithymia and empathy dimensions were entered in reversed order (i.e., the cognitive alexithymia dimension in step 2, the

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cognitive empathy dimension in step 3) resulted in a non-significant change of the model fit by

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1.6% (F(1,124) = 2.72, p = 0.101), demonstrating that the cognitive empathy dimension did not

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contribute to left amygdala volume differences beyond the cognitive alexithymia dimension. Taken together, the cognitive alexithymia dimension had the strongest effect on left amygdala volume.

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3.5.2. Structural covariance

The previous analyses implicated the left amygdala as a key correlate of the cognitive alexithymia dimension and both empathy dimensions. However, they do not provide further information such as whether volume differences in this region are linked to volume differences in other structures and whether such covariance patterns would differ between alexithymia and empathy. We thus decided to explore this question by means of a structural covariance analysis. First, a conjunction analysis (see above) masked with the AAL mask of the left amygdala identified the peak voxel of the three clusters as the seed region. A 4-mm sphere was then created around this seed voxel, and mean parameter estimates of gray matter volumes within the sphere were extracted (for more details on this procedure, see Li et al., 2013). To define the interactions of volumes of the left amygdala seed 17

ACCEPTED MANUSCRIPT region with alexithymia and empathy, parameter estimates of the seed region were mean-centered, and three interaction terms were calculated between the left amygdala (seed) parameter estimates and the mean-centered empathy dimensions as well as the mean-centered cognitive dimension of

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alexithymia. The resulting three interaction terms were then entered as covariates in separate whole-

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brain structural covariance correlation analyses across the entire sample, controlled for age and sex.

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Due to the exploratory nature of this analysis, results were considered significant at p < 0.001 uncorrected.

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A markedly different pattern of the left amygdala’s whole brain connectivity for empathy compared to alexithymia emerged, and also for the two empathy dimensions (see Table 5). In

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relation to higher levels of cognitive alexithymia, left amygdala volume reductions covaried with reduced gray matter volume in the right amygdala and the left insula. Relative to higher levels of

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cognitive empathy, larger left amygdala volume was linked to larger MCC volume and to reduced

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gray matter volume in the left thalamus and the left postcentral gyrus (somatosensory cortex). A yet

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different pattern was observed for higher levels on affective empathy: Here, larger left amygdala volume was associated with larger gray matter volumes in the left inferior temporal and fusiform gyrus and in the right DLPFC, as well as with reduced gray matter volume in the right putamen.

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Figure 8 depicts these distinct structural covariance patterns.

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ACCEPTED MANUSCRIPT 5.

Discussion

The aim of the present study was to disentangle the overlap and differences between the neuroanatomical profiles of the cognitive and affective dimensions of alexithymia and empathy, and

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to reveal to what extent their structural manifestations differ between sexes. Our results identified

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the left amygdala as a shared substrate of the cognitive alexithymia dimensions and both empathy

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dimensions. Confirming our hypothesis, left amygdala volume was related to alexithymia and empathy in opposite directions, showing a negative relationship with the cognitive alexithymia

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dimension but a positive correlation with the affective and cognitive empathy dimension. In line with our hypothesis of sex-specific effects, men - but not women - with difficulty fantasizing, part

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of the affective alexithymia dimension, showed reduced MCC volumes. For empathy, no sexspecific effects on ROI volumes were observed. These results show that alexithymia and empathy

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share a common neural basis and indicate a significant role of sex on the structural correlates of the

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affective alexithymia dimension. Moreover, the present findings provide evidence for separable

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neuroanatomical profiles of the cognitive and affective dimensions of alexithymia, whereas comparatively little structural differences were observed between the cognitive and affective dimensions of empathy.

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This study identified the left amygdala as a key correlate of both alexithymia and empathy, independent from age. This is not surprising given the crucial role of this structure in a broad range of emotional processing (for a recent review, see Armony, 2013). Our finding of reduced left amygdala volume with higher levels of cognitive alexithymia confirms previous findings of amygdala volume reductions in alexithymia (e.g., Grabe et al., 2014; Ihme et al., 2013), and is in line with Wingbermühle’s hypothesis of a specific involvement of the amygdala in cognitive aspects of alexithymia (Wingbermühle et al., 2012). Gray matter volume reduction in the amygdala may thus underlie the frequently observed hypo-responsiveness of this structure to visual (e.g., Kugel et al., 2008; Reker et al., 2010; for a review, see Grynberg et al., 2012) and auditory (Goerlich-Dobre et al., 2014b) socio-affective stimuli in individuals with high levels of cognitive alexithymia. The 19

ACCEPTED MANUSCRIPT amygdala has been mostly implicated in affective aspects of empathy (e.g., Blair, 2008; Decety, 2010; Ho et al., 2014; Schneider, Pauly, Gossen, Mevissen, Michel, Gur, Schneider, Habel, 2013; see Bzdok et al., 2012 for a meta-analysis of fMRI studies on morality, theory of mind, and

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empathy). Moreover, a recent study demonstrated its central importance in empathic regulation

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dimensions are linked to larger volumes of the left amygdala.

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towards others’ emotional pain (Bruneau et al., 2015). Our results indicate that both empathy

In addition to affecting amygdalar volumes in opposite directions, the pattern of amygdala

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connectivity was also markedly different between alexithymia and empathy. Structural covariance analysis revealed that volume changes associated with this region were qualitatively different

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between the two constructs, suggesting that alexithymia and empathy are marked by distinct patterns of network connectivity. Future studies could apply diffusion tensor imaging to determine

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the strength and directions of fiber pathways that connect the left amygdala with the regions

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indicated by the structural covariance analysis. Such studies might provide more insight into the

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neural networks that underlie the alexithymia and empathy dimensions. Interestingly, a significant structural covariance of the insula with amygdala volume was identified only in relation to the cognitive alexithymia dimension, but not in relation to empathy.

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The insula is involved in the evaluation and experience of emotions and in interoceptive awareness (for a review, see Craig, 2009), and alexithymia has frequently been linked to aberrant insula activity during emotion processing (Bird et al., 2010; Kano et al., 2003; Karlsson et al., 2008; Moriguchi et al., 2007; Reker et al., 2010; for a meta-analysis, see van der Velde et al., 2013). Previous VBM studies reported reduced left insula volume in high- versus low-scorers on the cognitive alexithymia dimension (Borsci et al., 2009; Goerlich-Dobre et al., 2014a; Ihme et al., 2013) and in 844 male participants with difficulty identifying feelings, part of the cognitive alexithymia dimension (Grabe et al., 2014). The present result of reduced left insula volume in covariance with reduced left amygdala volume confirms this association but suggests that reduced left insula volume may be a more indirect marker of the cognitive alexithymia dimension: The 20

ACCEPTED MANUSCRIPT extent of volume reduction in the insular cortex may be linked to volumes of the amygdala, with which it has strong anatomical connections, giving rise to an intense crosstalk between the amygdalae and insulae and shared functions during emotion processing (Moraga-Amaro & Stehberg,

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2012).

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Surprisingly, significant insula volume differences were not observed in relation to empathy

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in this study, although the insula is considered a key correlate of empathy (e.g., Fan et al., 2011; Lamm et al., 2011) and insula volume differences in relation to empathy have previously been

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reported in female participants (Mutschler, Reinbold, Wankerl, Seifritz, & Ball, 2013). In a VBM study using the same self-report empathy scale as in the present study (Banissy et al., 2012), insula

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volume was reported to correlate with personal distress and to be smaller with increasing scores on empathic concern in male and female participants. However, this discrepancy can be explained by

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different significance thresholds: While the current study applied a strict correction for multiple

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comparisons by using anatomical ROI masks and FWE correction at the cluster level, Banissy and

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coworkers employed small volume correction with a 10-mm sphere around the peak voxel of their observed clusters, which results in a much smaller search space and thus represents a much more lenient threshold. In fact, applying their same threshold, we also observed two small insula clusters

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(one anterior, 25 voxels; one posterior, 39 voxels) in relation to the affective empathy dimension, which however just failed to survive our significance threshold. To sum up, insula volume differences in relation to empathy may be rather small and their reliability as a structural marker of affective empathy should be further investigated. Note that a recent meta-analysis on the functional correlates of explicit emotional evaluation found that the insula was specifically linked to the evaluation of one’s own emotion, an aspect of alexithymia, rather than to the evaluation of other people’s emotion, an aspect of empathy (Lee & Siegle, 2009). The cingulate cortex is considered a key correlate of both alexithymia and empathy (for meta-analyses of fMRI studies, see Fan et al., 2011; Lamm et al., 2011 for empathy; van der Velde et al., 2013 for alexithymia). In the present study, ACC volume differences were not observed for 21

ACCEPTED MANUSCRIPT the entire ACC or for its separate subregions. However, men with difficulty fantasizing, a part of the affective alexithymia dimension, had significantly smaller gray matter volume in the MCC. The present finding of a link between the affective alexithymia dimension and MCC volume confirms

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the results of a previous study, in which such a relationship was also identified (Goerlich-Dobre et

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al., 2014a). Interestingly, in the previous study a positive relationship between MCC volume and the

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affective alexithymia dimension was observed, whereas the current study identified a negative relationship. However, this can be explained by the fact that the present study observed reduced

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MCC volumes only in relation to the fantasizing subscale of the affective alexithymia dimension (and only in men), while in the previous study larger MCC volumes were observed in relation to the

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emotionalizing factor of the affective alexithymia dimension, independent of sex. Although the precise relationship between the affective alexithymia dimension and MCC volume differences

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requires further research, these findings suggest that MCC volume differences may underlie

Limitations

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reduced emotional experience and awareness characteristic of affective alexithymia.

It should be kept in mind that alexithymia and empathy were assessed by means of self-report scales

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in this study, which rely on the participants’ self-evaluation accuracy; and while the German version of the BVAQ has a demonstrated validity, its reliability needs to be improved (Müller et al., 2004). It would thus be worthwhile to replicate our results in the future using more objective measures, such as observer-rated interviews. Moreover, as noted in the introduction, the distinction of alexithymia and empathy into an affective and a cognitive dimension is not unequivocal. In the case of empathy, the affective dimension as defined here may aggregate different components such as affective arousal, emotion understanding, and emotion regulation, which may involve different brain regions. Similarly, the affective alexithymia dimension, particularly its emotionalizing subscale, has been criticized to be closely related to physiological arousal (Bagby et al., 2009), thus also involving other processes distinct from the core alexithymia concept of a lack of emotional 22

ACCEPTED MANUSCRIPT awareness. Moreover, we observed here as well as in one of our previous studies (Goerlich-Dobre et al., 2014a) that the emotionalizing and fantasizing subscales of the affective alexithymia dimension were not correlated with one another, even though this should be the case if they were to constitute

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a common (affective) dimension of alexithymia. Also the correlations between the two affective and

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the two cognitive subscales of empathy were found to be lower here than one would expect. These

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ambiguities regarding the definitions of the affective alexithymia and empathy dimensions might contribute to the lack of a clear-cut differentiation between the neural correlates of cognitive and

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affective empathy in the present study, and may partly explain inconsistent results of previous studies using the affective alexithymia dimension without further differentiation between its

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separate subscales. Neuroimaging studies such as the present one might help overcome these

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limitations by identifying biological markers of empathy and alexithymia.

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Conclusions

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In summary, the present results provide evidence for a common neural basis of alexithymia and empathy in the left amygdala, while the neuroanatomical manifestations of the affective alexithymia dimension appears to be critically linked to sex. Moreover, the findings of this study

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corroborate the notion of distinct neural systems underlying the cognitive and affective dimensions of alexithymia (Goerlich-Dobre et al., 2014a, 2015; van der Velde et al., 2014). The cognitive and affective empathy dimensions showed comparatively more overlap in their structural correlates, in line with the notion of close interactions between the two processes (Heberlein & Saxe, 2005; Lamm & Majdandzic, 2015, see Lamm et al., 2007 and Shamay-Tsoory, 2011, for reviews). Considering these results, both alexithymia dimensions as well as sex should be considered in clinical applications in the future, for example during neuropsychiatric assessments of individuals at risk for a psychiatric disorder. Furthermore, the present findings strongly indicate structural abnormalities in the amygdala in alexithymia and empathy. Similar findings have been reported for psychopathic traits (e.g., Yang et al., 2009; Vieira et al., 2015) antisocial personality disorder (e.g., 23

ACCEPTED MANUSCRIPT Hyde et al., 2014, see Glenn & Raine, 2014 for a review), and conduct disorder (e.g., Raine, 2011), all of which are – like alexithymia and lack of empathy – linked to social dysfunction. Together, these findings substantiate the role of the amygdala as a critical hub in social networks (Bickart et

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al., 2014) and suggest a causal relationship between this region and dysfunctions in social behavior

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(for a review, see Glenn & Raine, 2014). Thus, pharmacological manipulations targeting the

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amygdala may be a promising endeavor to improve social behaviour in future research. In conclusion, the present findings may contribute to a better understanding of the complex patterns of

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deficits in the awareness of one’s own emotions and those of others associated with a range of

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psychopathological conditions.

Funding

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This work was supported by the Austrian Science Fund (FWF, project number: P22813-B09) and

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the Österreichische Nationalbank (Anniversary Fund, project number: 14350).

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ACCEPTED MANUSCRIPT Table legends Table 1. Means, standard deviation (SD), and range (minimum – maximum) of age, TIV, and the cognitive and affective dimensions of alexithymia and empathy, for women (n = 70) and men (n = 55). Significance threshold p < 0.05. n.s. – not significant.

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Table 2. Partial correlations between ROI gray matter volumes and the cognitive and affective dimensions of alexithymia and empathy, in women (n = 70) and men (n = 55), controlled for age and corrected for multiple comparisons at p < 0.006 (Holm-Bonferroni). n.s. – not significant.

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Table 3. Whole-brain gray matter volume differences in relation to the cognitive and affective alexithymia and empathy dimensions across the entire sample, controlled for age and gender (pFWE-corr < 0.05 cluster level). n.s. – not significant. Table 4 Sex-specific (70 women ♀, 55 men ♂) whole-brain gray matter volume differences in relation to the cognitive and affective alexithymia and empathy dimensions, controlled for age. Significance threshold pFWEcorr < 0.05 cluster level. n.s. – not significant.

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Table 5. Structural covariance between left amygdala volume and gray matter volumes in relation to the cognitive alexithymia dimension and the cognitive and affective empathy dimensions across the entire sample, controlled for age and gender. MCC – middle cingulate cortex, DLPFC – dorsolateral prefrontal cortex. Significance threshold pFWE < 0.05 cluster level.

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ACCEPTED MANUSCRIPT Figure Legends Figure 1. A priori regions of interest (ROIs) included in the gray matter ROI analyses. ACC – anterior cingulate cortex, MCC – middle cingulate cortex, mOFC – medial orbitofrontal cortex.

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Figure 2. Parcellation of anterior cingulate cortex (ACC) and bilateral insular cortex following a modified version of the automated anatomical labeling (AAL) atlas (Lord et al., 2012). dACC – dorsal ACC, pgACC – pregenual ACC, sgACC – subgenual ACC.

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Figure 3. Whole-brain correlations with the cognitive (blue) and affective (red) alexithymia dimensions across the whole sample. Results are displayed at p < 0.001 uncorrected.

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Figure 4. Whole-brain correlations with the cognitive (blue) and affective (red) empathy dimensions across the whole sample. Results are displayed at p < 0.001 uncorrected. Figure 5. Sex-specific whole-brain correlations with the cognitive (top) and affective (bottom) alexithymia dimensions. Results are displayed at p < 0.001 uncorrected.

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Figure 6. Sex-specific whole-brain correlations with the cognitive (top) and affective (bottom) empathy dimensions. Results are displayed at p < 0.001 uncorrected.

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Figure 7. A – Whole-brain conjunction in the left amygdala between the cognitive alexithymia dimension and the cognitive and affective empathy dimensions, at p < 0.001 uncorrected (top) and at p FWE < 0.05 corrected (bottom). B – Whole-sample correlations of the cognitive (blue) and affective (red) dimensions of alexithymia (top) and empathy (bottom) with left amygdala volume.

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Figure 8. Structural covariance patterns between gray matter volumes of the left amygdala seed region and volumes of other (whole-brain) regions in relation to the cognitive dimension of alexithymia and the cognitive and affective dimensions of empathy. Up arrows indicate more gray matter volume, down arrows less gray matter volume. Results are displayed at p < 0.001 uncorrected.

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ACCEPTED MANUSCRIPT Table 1. Women

Men Range

Mean ± SD

Range

Age

25.2 ± 5.6

19 – 42

25.6 ± 5.6

19 – 40

n.s

TIV

1358 ± 102

1174 – 1609

1530 ± 96

1337 – 1808

0.001

60.3 ± 17.0

28 – 98

28 – 88

n.s.

Emotionalizing Fantasizing

23.2 ± 3.7 19.7 ± 6.7

14 – 30 8 – 34

23.3 ± 4.5 19.1 ± 6.5

16 – 32 8 – 38

n.s. n.s.

Cognitive Dimension

33.8 ± 9.3

11 – 52

32.4 ± 9.6

9 – 48

n.s.

Affective Dimension

28.5 ± 7.7

11 – 52

24.8 ± 7.5

10 – 44

0.01

Cognitive Dimension

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Empathy

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61.1 ± 14.6

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Alexithymia

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Mean ± SD

pvalue

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Men

Alexithymia Cognitive Dimension L Amygdala r = -0.49

IP

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r = -0.43 Affective dimension Emotionalizing Fantasizing

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no significant correlations MCC

Empathy Cognitive Dimension

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n.s.

r = -0.36

L Amygdala

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r = 0.34 Affective Dimension

L Amygdala r = 0.28

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r = 0.39

r = 0.47

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ACCEPTED MANUSCRIPT Table 3. Cluster size

Brain area (aal)

x

y

z

T-score

Alexithymia

11759

-17 17 -26 -24 -11

-18 -15 -6 -3 0

13 12 -23 -23 -21

8.91 6.83 6.79 6.71 4.77

n.s.

8454

-17 -24 17 -12

-18 -4 -13 2

13 -23 13 -23

8.81 6.10 5.54 4.49

7128

-18 -26 17 -18

-22 -3 -16 -22

12 -21 7 -18

6.24 4.63 3.92 3.72

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Affective dimension

L Thamalus R Thalamus L Hippocampus L Amygdala L Parahippocampal Gyrus

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Negative correlation

n.s.

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Positive correlation

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Cognitive dimension

Empathy

n.s.

Affective dimension

L Thalamus L Amygdala R Thalamus L Parahippocampal Gyrus

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Positive correlation

D

Negative correlation

L Thalamus L Amygdala R Thalamus L Parahippocampal Gyrus

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Positive correlation

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Cognitive dimension

n.s.

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Negative correlation

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ACCEPTED MANUSCRIPT Table 4. Cluster size

Brain area (aal)

x

y

z

T-score

Alexithymia

♂ Positive correlation

n.s.

IP

n.s.

♀ Negative correlation

L Thamalus R Thalamus L Amygdala R Thalamus L Parahippocampal Gyrus

♂ Negative correlation

L Thamalus L Hippocampus L Amygdala L Parahippocampal Gyrus

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♀ Positive correlation

T

Cognitive dimension

-15 17 -26 12 -9

-18 -15 -4 -7 -3

6 7 -23 7 -20

7.25 6.39 6.31 3.96 3.51

2500

-17 -27 -25 -17

-18 -7 -5 2

13 -21 -25 -20

6.15 6.39 6.29 4.37

761

-51

-67

15

5.13

1456

17

-13

13

5.28

998

-12 5 2

-70 -66 -75

-5 4 13

4.48 3.73 3.49

L Thalamus R Thalamus

3257

-17 18

-18 -12

13 -13

6.08 4.19

L Superior Temporal Pole

1034

-56

9

-16

5.96

L Hippocampus L Parahippocampal Gyrus

2005

-23 -17

-10 2

-20 -21

4.80 4.18

3682

-15 18 -27

-19 -16 -1

4 9 -21

6.05 4.02 3.94

MA

NU

5480

L Middle Temporal Gyrus

D

R Thalamus

Empathy Cognitive dimension

n.s.

CE P

Affective dimension

TE

L Lingual Gyrus R Lingual Gyrus R Cuneus

AC

♀ Positive correlation ♂ Positive correlation

Negative correlation

n.s.

Affective dimension ♀ Positive correlation

L Thalamus R Thalamus L Amygdala

♂ Positive correlation

n.s.

Negative correlation

n.s.

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ACCEPTED MANUSCRIPT Table 5. x

y

z

T-score

T

Cluster size

Brain area (AAL)

-41

-1

-6

4.47

24

-3

-21

3.68

155

11 11

6 17

40 39

3.66 3.56

182

-41

-37

66

4.00

277

-9 -12

-10 -18

4 10

3.72 3.68

320

-47 -39

-52 -64

-11 0

5.23 4.95

1150

20 20 14

36 45 44

40 31 40

4.66 4.40 4.00

111

-42

-52

-12

4.46

88

32

-15

-5

3.53

Alexithymia

Positive correlation

L Insula

367 43

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R Amygdala

Empathy

MCC

Negative correlation

L Postcentral gyrus L Thalamus

D

Affective dimension

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Positive correlation

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Cognitive dimension

L Inferior temporal lobe

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Positive correlation

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R DLPFC

L Fusiform gyrus R Putamen

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Negative correlation

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Cognitive dimension

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Highlights 1) The left amygdala is a common substrate of alexithymia and empathy 2) The cognitive alexithymia dimension is linked to smaller left amygdala volume 3) The empathy dimensions are linked to larger left amygdala volume 4) Sex-specific effects are evident for the affective alexithymia dimension 5) Alexithymia and empathy exhibit distinct patterns of structural covariance

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