RESEARCH ARTICLE

Evidence for Gender-Specific Endophenotypes in High-Functioning

Autism Spectrum Disorder During Empathy
Karla Schneider, Christina Regenbogen, Katharina D. Pauly, Anna Gossen, Daniel A. Schneider,
Lea Mevissen, Tanja M. Michel, Ruben C. Gur, Ute Habel, and Frank Schneider

Despite remarkable behavioral gender differences in patients with autism spectrum disorder (ASD), and growing evidence
for a diminished male : female ratio for the putative “male disorder” ASD, aspects of gender are not addressed accordingly
in ASD research. Our study aims at filling this gap by exploring empathy abilities in a group of 28 patients with
high-functioning ASD and 28 gender-, age- and education-matched non-autistic subjects, for the first time by means of
functional neuroimaging (fMRI). In an event-related fMRI paradigm, emotional (“E”) and neutral (“N”) video clips
presented actors telling self-related short stories. After each clip, participants were asked to indicate their own emotion
and its intensity as well as the emotion and intensity perceived for the actor. Behaviorally, we found significantly less
empathic responses in the overall ASD group compared with non-autistic subjects, and inadequate emotion recognition
for the neutral clips in the female ASD group compared with healthy women. Neurally, increased activation of the
bilateral medial frontal gyrus was found in male patients compared with female patients, a pattern which was not present
in the non-autistic group. Additionally, autistic women exhibited decreased activation of midbrain and limbic regions
compared with non-autistic women, whereas there was no significant difference within the male group. While we did not
find a fundamental empathic deficit in autistic patients, our data propose different ways of processing empathy in autistic
men and women, suggesting stronger impairments in cognitive aspects of empathy/theory of mind for men, and
alterations of social reciprocity for women. Autism Res 2013, 6: 506–521. © 2013 International Society for Autism
Research, Wiley Periodicals, Inc.

Keywords: autism; empathy; gender differences; fMRI; social interactions

Introduction 1976], it is still commonly seen as a “male disorder”

The diagnostic guidelines of the 10th revision of the
International Statistical Classification of Diseases and
Related Health Problems (ICD-10) and the 4th edition of
the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV) classify autism spectrum disorder (ASD) as a
pervasive developmental disorder with serious impact on
nearly all aspects of social functioning causing daily
obstacles even for (very) high-functioning ASD patients.
Supported by the “extreme male brain theory”
[Baron-Cohen, 2002], which assigns an extremely system-
izing “male” cognitive style to patients with ASD, and
influenced by prior data on the sex ratio in ASD [Baird,
2000; Fombonne, 2005; Wing, Yeates, Brierly, & Gould,
[Baron-Cohen, 2002]. Though indeed all epidemiological
surveys confirm overrepresentation of men in ASD
[Fombonne, 2005], the estimation of the sex ratio shows a
broader variety [Baird, 2000; Fombonne, 2005] than pre-
viously expected, with an estimated mean male : female
ratio of 4.3:1 [Fombonne, 2005]. For high-functioning
ASD, this ratio declines for females to 6–8:1 [Baird, 2000;
Fombonne, 2005]. However, several studies in line with
clinical experience [Attwood, 2008] suggest a more mod-
erate male : female ratio of 4:1 [Ehlers & Gillberg, 1993] or
even 2.6:1 [Bartley, 2006; Tepest et al., 2010].
A few studies approached potential female-specific ASD
traits and, on a behavioral level, suggested females to be
more severely affected by ASD-typical cognitive deficits

From the Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical School, RWTH Aachen University, Aachen (K.S., C.R., K.D.P., A.G., D.S.,
L.M., T.M.M., U.H., F.S.); JARA-Translational Brain Medicine, Aachen-Jülich (K.S., C.R., K.D.P., A.G., D.S., U.H., F.S.); Department of Psychiatry, Perelman
School of Medicine, University of Pennsylvania and the Philadelphia Veterans Administration Medical Center, Philadelphia (R.G., F.S.); Department of
Psychiatry and Psychotherapy, University of Rostock, Rostock (T.M.M.)
Received November 9, 2012; accepted for publication June 13, 2013
Address for correspondence and reprints: Dr. Karla Schneider, Department of Psychiatry, Psychotherapy, and Psychosomatics, RWTH Aachen
University, Pauwelsstraße 30, 52074 Aachen, Germany, E-mail: karla.schneider@rwth-aachen.de
Grant sponsors:
1. Grant sponsor: German Research Foundation (DFG, International Research Training Group 1328: “Brain-behavior relationship of emotion and social
cognition in schizophrenia and autism”)
Grant Number: KFO 112 and HA 3202/7-1
2. Grant sponsor: Interdisciplinary Center for Clinical Research of the Medical Faculty of the RWTH Aachen University
Grant number: IZKF, N2-6
Published online 18 July 2013 in Wiley Online Library (wileyonlinelibrary.com)
DOI: 10.1002/aur.1310
© 2013 International Society for Autism Research, Wiley Periodicals, Inc.

506 Autism Research 6: 506–521, 2013 INSAR

[Nydén, Hjemlquist, & Gillberg, 2000]. Likewise, Lemon,
Gragaro, Enticott, and Rinehart [2011] found stronger
impairments in girls on the level of executive functions
during a behavioral stop task, in line with Kopp, Beckung,
and Gillberg [2010], who also reported a lower level of
global functioning in girls with ASD compared with autis-
tic boys.
Nonetheless, there seems to be broad consensus that
girls with ASD commonly exhibit a better level of social
adjustment [Attwood, 2008; Bartley, 2006; Kopp, Kelly, &
Gillberg, 2010]. Putatively, those social adaption skills
might make girls/women less likely to be correctly iden-
tified as autistic according to the current diagnostic cri-
teria, and hence leaves them “invisible” to prevalence
studies despite an equivalently high-level of autistic traits
as compared with boys/men [Dworzynski, Ronald,
Bolton, & Happé, 2012]. Thus, Kopp and Gillberg [2007]
even proposed a female autistic phenotype sui generis.
So far, there are only few studies exploring gender-
specific morphological brain characteristics in patients
with ASD, most of them either focusing on one sex
[i.e. Bloss & Courchesne, 2007; Calderoni et al., 2012;
Craig et al., 2007] or contrast patients solely with their
respective gender-matched non-autistic control group
[Schumann et al., 2010; Schumann, Carter Barnes, Lord, &
Courchesne, 2009]. They, however do not provide analy-
ses of gender effects within the autistic group. Nonethe-
less, following their results brain morphology of female
patients relative to non-autistic women seems to be char-
acterized by increases in brain volume particularly in the
right temporoparietal junction and the bilateral superior
frontal gyri [Calderoni et al., 2012] as well as in the amyg-
dala [Schumann et al., 2009], altered gray and white
matter density especially in limbic regions and frontotem-
poral cortices [Craig et al., 2007], or frontal and temporal
cortical gray matter enlargement [Bloss & Courchesne,
2007; Schumann et al., 2010].
However, Sparks et al. [2002] and Nordahl et al. [2011]
could not confirm overall brain enlargement in girls with
autism but rather found increased brain size as an indi-
cator for the level of regression in autistic boys [Nordahl
et al., 2011]. Beacher et al. [2011] in line with Tepest et al.
[2010] even suggested a reduced gender dimorphism in
patients with ASD compared with non-autistic control
subjects.
Convergent evidence of behavioral studies and clinical
impression led to the question whether—irrespective of
their putative impairments in executive and/or other cog-
nitive functions [Nydén et al., 2000]—females with ASD
might have a higher “socio-emotional intelligence” than
men resulting in a more preserved higher level of social
functioning [Barkley, 1998].
Empathy constitutes a core feature of social interac-
tions. Despite the heterogeneity in definitions of
empathy, it seems to be broad consensus that empathy
INSAR Schneider et al./Gender-specific endophenotypes in autism
comprises both, affective components, thus the ability to
affectively respond to another person, and cognitive ele-
ments, hence to cognitively take the perspective of one’s
counterpart [Lamm, Batson, & Decety, 2007]. Addition-
ally, several studies assume a close relation to social judg-
ments involving the understanding of other’s minds and
the ability to transfer one’s own inner-life [Farley, Lopez,
& Saunders, 2010; Zahavi, 2010].
On a neural level, empathic processing has been found
to be in close association with the mirror neuron
system (MNS) including the inferior frontal gyrus (IFG)
[Hooker, Verosky, Germine, Knight, & D’Esposito, 2010;
Shamay-Tsoory, 2011]. It has also been related to the
theory of mind (ToM) network [Völlm et al., 2006], includ-
ing the anterior cingulate cortex (ACC), insula, amygdala,
and hippocampus [Phillips, Drevets, Rauch, & Lane,
2003]. Additionally, empathy and deep social emotions
were linked to more basal areas of emotion processing, the
periaqueductal gray (PAG) in particular [Bartels & Zeki,
2004].
While not necessarily reflected in the effective behav-
ioral results, in empathy-associated tasks women impute
themselves a higher performance level than men
[Buddeberg-Fischer, Klaghofer, Abel, & Buddenberg,
2003], accompanied by increased brain activation in
emotion-related areas such as the amygdala [Koch et al.,
2007; Kohn, Kellermann, Gur, Schneider, & Habel, 2011;
Schulte-Rüther, Markowitsch, Shah, Fink, & Piefke, 2008],
the IFG [Schulte-Rüther, Markowitsch, Fink, & Piefke,
2007; Schulte-Rüther et al., 2008], and a stronger interac-
tion between insula and posterior cingulate gyrus
[Harenski, Antonenko, Shane, & Kiehl, 2008]. Addition-
ally, women in contrary to men were found to display
significantly larger gray matter volume in core areas of the
MNS, i.e. the inferior parietal lobule [Cheng et al., 2008,
2009]. A recent study [Whittle, Yücel, Yap, & Allen, 2011]
proposed gender-specific neural networks involved in
emotion processing and linked this finding to different
behavioral patterns in daily life.
Though evidence is inconclusive regarding the extent
and specific characteristics of empathy impairments in
patients with autism [Bird et al., 2010; Castelli, 2005;
Narzisi, Muratori, Calderoni, Fabbro, & Urgesi, in press],
occasionally suggesting their widely assumed deficits to be
a “function” of (in-)adequate contextual cues [Narzisi
et al., in press], there seems to be substantial convergence
that high-functioning patients with ASD exhibit at least
subtle difficulties in empathy. Hence, empathy deficits and
structural and/or functional alterations of emotion- and
empathy-related brain areas encompassing the ACC
[Dichter, Felder, & Bodfish, 2009], the IFG [Schulte-Rüther
et al., 2010], and the fusiform gyrus [Schultz, 2005] are
commonly reported for ASD patients.
Nonetheless, so far no study has explicitly addressed
gender differences in empathy in patients with ASD. We
507
aimed to fill this gap by analyzing the impact of gender
on behavioral and/or cerebral (dys-)functions in ASD
patients during an ecologically valid empathy task based
on emotional or neutral video presentations.
We hypothesized that: (a) females with high-
functioning autism would show higher levels of
empathy compared to autistic males, as they tend to
show a better socio-emotional functioning level [Baird,
2000; Nydén et al., 2000]. Irrespective of group, we
expected females to show increased task-relevant neural
activation patterns in empathy-related areas, such as the
amygdala, insula, and areas of the MNS, when compar-
ing emotional to neutral task conditions. Furthermore,
across gender we expected ASD patients to show less
empathic responses and less intense ratings of the
emotion displayed by their counterpart in the video as
compared with healthy participants. (b) As men are
assigned a more cognitive style of processing empathy
and emotional tasks reflected by activation of cognition-
related areas [Kohn et al., 2011] such as the dorsal ACC
[Phillips et al., 2003], while women would rather rely on
limbic regions [Kohn et al., 2011], we expected patients’
behavioral alterations to be accompanied by reduced
activation of more cognition-related brain areas in male
patients, and of more empathy- and emotion-related
regions in female patients, each relative to their gender-
matched healthy control group.
Methods
Participants
Thirty patients (17 males) with high-functioning ASD
were recruited at the in- and outpatient facilities of the
Department of Psychiatry, Psychotherapy, and Psychoso-
matics, RWTH Aachen University, as well as at local self-
help groups and therapy centers. Inpatients (n = 9) were
diagnosed at a special facility for patients with ASD at the
University Hospital Aachen. Patients from self-help
groups and therapy centers (n = 21) were included, if they
had received a pre-diagnosis of ASD by experienced
psychiatrists.
All participants met the following criteria: age between
18 and 55 years, no neurological disorders or other
medical conditions affecting cerebral metabolism, and no
MRI contraindications (metal implants, pregnancy, etc.).
All participants were native German speakers, and
screened for mental disorders by means of the Structured
Clinical Interview for DSM-IV [Wittchen, Wunderlich,
Gruschitz, & Zaudig, 1997]. Patients had no current psy-
chiatric comorbidities, nor a history of psychosis, person-
ality or eating disorders.
Four participants had to be excluded from data analysis
due to movement artifacts (n = 2), a failure to verify the
pre-diagnosis of an Asperger’s syndrome (n = 1), or
508 Schneider et al./Gender-specific endophenotypes in autism
because of an accidental finding of neuroanatomical
abnormality (n = 1). Thus, the final sample included 28
autistic patients and 28 gender-, age-, and education-
matched healthy controls (Con; 15 males).
Four ASD patients and two healthy subjects were left-
handed. All of the other participants were right-handed
according to the Edinburgh Handedness Inventory
[Oldfield, 1971]. Six patients were medicated with anti-
depressants (tricyclics: n = 1, selective serotonin reuptake
inhibitors (SSRI): n = 5).
Subjects also performed a task on moral reasoning
described elsewhere [Schneider et al., in press].
Neuropsychological and Psychopathological Testing
Participants completed the Toronto Alexithymia Scale
(TAS20) [Bagby, Parker, & Taylor, 1994] and the Autism
Quotient (AQ) [Baron-Cohen, Wheelwright, Skinner,
Martin, & Clubley, 2001]. Additional psychopathological
testing in patients included the Autism Diagnostic Obser-
vation Schedule—Generic (ADOS-G), Module 4 [Lord,
Rutter, DiLavore, & Risi, 1999] rated by at least two
trained clinicians, the Hamilton Depression Scale
[Hamilton, 1960], and the short version of the Inventory
for Interpersonal Problems (self rating) [Horowitz, Strauß,
& Kordy, 2000]. Fourteen patients (eight males) fulfilled
the ADOS criteria for ASD (cutoff >7), 14 did not (seven
males). Diagnosis of the latter was confirmed by addi-
tional information of relatives and therapists in accor-
dance with the diagnostic criteria of the DSM-IV.
Furthermore, a neuropsychological test battery was
applied in order to control for the sources of
interindividual variances unrelated to the main task: a
German vocabulary test for crystallized intelligence esti-
mation [“Wortschatztest”—WST; Schmidt & Metzler,
1992], the German version of the digit span of the
Wechsler Intelligence Scale for Adults (WIE) [Von Aster,
Neubauer, & Horn, 2006], a test for verbal fluency
(Regensburger Wortflüssigkeitstest, RWT) Aschenbrenner
et al. 2001], the Trail Making Test [TMT-A/-B, Reitan,
1958], and the NEO-Five Factor Inventory (NEO-FFI)
[Borkenau & Ostendorf, 1993]. Patients’ ability to recog-
nize static emotional faces was tested using the Penn
Emotion Recognition Test (PERT40) [Kohler et al., 2004].
Additionally, a test for the tendency to exhibit social
desirable behavior was applied to all participants [Stocké,
2009].
Detailed information on demographic and neuropsy-
chological data is shown in Table 1 (for additional infor-
mation on each group subdivided by gender see Tables S1
and S2 of the supplementary material).
After complete description of the study protocol,
written informed consent of each participant was
obtained. All participants received monetary compensa-
tion after study completion.
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Table 1. Demographic and Neuropsychological Data of Healthy Control Subjects (Con) and Patients With Autism Spectrum Disorder (ASD)

Males Females

Con ASD Con ASD

n Mean ± SD Mean ± SD t df P n Mean ± SD Mean ± SD t df P

Age (in years) 15/15 34.27 ± 9.73 32.73 ± 9.97 −0.67 28 0.670 13/13 27.85 ± 7.02 29.85 ± 8.02 −0.68 24 0.505
Education (in years) 15/15 12.93 ± 0.26 12.73 ± 0.80 0.92 28 0.364 13/13 12.85 ± 0.38 12.62 ± 0.87 0.88 24 0.388
WST 15/15 115.07 ± 11.35 109.87 ± 7.88 1.46 28 0.156 13/12 112.85 ± 7.22 108.08 ± 10.75 1.31 23 0.203
Digit span forward 12/15 8.93 ± 1.34 8.83 ± 2.59 0.13 25 0.898 12/7 9.75 ± 1.49 9.43 ± 0.79 0.53 17 0.605
Digit span backward 12/15 8.40 ± 2.26 8.42 ± 2.81 0.02 25 0.987 12/7 11.83 ± 10.62 8.14 ± 1.68 0.90 17 0.380
RWT lexical 12/15 15.60 ± 4.50 15.25 ± 7.35 0.15 25 0.880 11/7 18.09 ± 6.24 18.43 ± 4.76 0.12 16 0.904
RWT lexical flexibility 12/15 15.33 ± 4.30 16.00 ± 3.95 0.41 25 0.682 11/7 18.36 ± 5.28 18.29 ± 4.46 −0.03 16 0.975
RWT semantic 12/14 18.36 ± 4.70 16.42 ± 4.64 1.06 24 0.302 11/7 16.82 ± 4.56 21.71 ± 5.19 −2.12 16 0.051
RWT semantic flexibility 12/14 16.43 ± 2.41 16.33 ± 4.77 −0.07 24 0.948 11/5 18.36 ± 3.11 20.33 ± 2.16 −1.37 15 0.190
TMT-A (in seconds) 12/14 19.44 ± 6.14 27.99 ± 11.27 −2.45 24 0.022* 12/7 18.42 ± 5.81 24.04 ± 3.98 −2.26 17 0.037*
TMT-B (in seconds) 12/14 35.33 ± 7.78 45.84 ± 18.60 −1.93 24 0.065 12/7 31.71 ± 7.93 42.43 ± 8.74 −2.74 17 0.014*
AQ 15/14 11.93 ± 7.11 34.86 ± 9.19 −7.55 27 <0.001** 12/13 7.92 ± 3.28 41.00 ± 4.24 −21.92 23 <0.001**
TAS 20 15/14 41.47 ± 10.78 60.57 ± 11.60 −4.60 27 <0.001** 13/11 37.00 ± 8.62 59.09 ± 12.04 −5.23 22 <0.001**
NEO-FFI (N) 14/14 15.86 ± 6.69 29.43 ± 6.12 −5.56 26 <0.001** 13/12 15.38 ± 6.56 31.58 ± 9.29 −5.07 23 <0.001**
NEO-FFI (E) 14/14 29.43 ± 5.67 17.00 ± 7.67 4.88 26 <0.001** 13/12 32.08 ± 5.66 14.75 ± 6.20 7.31 23 <0.001**
NEO-FFI (O) 14/14 32.14 ± 5.22 26.07 ± 5.66 2.95 26 0.007* 13/12 36.69 ± 6.71 29.00 ± 5.48 2.81 23 0.781
NEO-FFI (V) 14/14 32.07 ± 5.08 25.50 ± 6.75 2.91 26 0.007* 13/12 36.08 ± 3.25 27.42 ± 6.22 4.42 23 <0.001**
NEO-FFI (G) 14/14 31.50 ± 7.27 20.00 ± 7.13 1.29 26 0.210 13/12 30.46 ± 9.27 29.17 ± 7.71 0.38 23 0.709
NSAd 15/15 4.73 ± 2.76 3.67 ± 1.95 1.22 28 0.232 13/13 4.77 ± 2.28 5.15 ± 1.86 0.47 54 0.642

Schneider et al./Gender-specific endophenotypes in autism

SD, standard deviation; WST, German vocabulary test for crystalline intelligence estimation (“Wortschatztest”); RWT, verbal fluency (“Regensburger Wortflüssigkeitstest”); TMT-A/-B, Trail Making Test
Version A/B; AQ, Autism Quotient; TAS20, Toronto Alexithymia Scale; NEO-FFI (N)/(E)/(O)/(V)/(G), NEO-Five Factor Inventory Neuroticism/Extraversion/Openness/Agreeableness/Conscientiousness; NSAd,
scale for socially desirable behavior.
t-test for independent samples, *P < 0.05; Bonferroni-corrected **P < 0.003.

509
 The local Institutional Review Board of the RWTH
Aachen University approved the protocol, and the design
fulfilled the guidelines of the Declaration of Helsinki
(2008).
Empathy Task
In order to investigate empathic abilities, we used 32
short video sequences (MDuration = 11.8 sec) depicting
ten different lay actors (five males, five females) who told
a self-related short story.
Video sequences included 16 emotional stories with
emotional semantic content, emotional facial expression
and prosody (“E” condition) comprising the emotion cat-
egories disgust, happiness, fear, and anger (four video
clips each), as well as 16 neutral control videos (“N”) with
neutral semantic content, facial expression, and prosody
(for examples see Fig. 1). All video clips and spoken sen-
tences had been thoroughly validated and previously
applied by our group [Regenbogen et al., 2012a, 2012b;
Schneider et al., 2012]. After each clip, participants were
asked to indicate by button press how they felt (“SELF”),
and what they thought the other person would
feel (“OTHER”) on a seven-point visual analogue scale
Figure 1. Examples of video clip stimuli; above: emotional (disgust), below: neutral.
510 Schneider et al./Gender-specific endophenotypes in autism
(−3 = very negative, . . . 0 = neutral, . . . +3 = very posi-
tive). If the participants’ SELF- and OTHER-ratings both
matched the target valence with regard to its nuance, e.g.
−3 up to +3 (self-matching-target, SMT; and other-matching-
target, OMT), this was defined as empathic behavior (self-
other-matching-target, SOMT).
Between ratings and the next video clip, a white
fixation cross was shown on a black screen (variable
inter-stimulus interval, M = 6.29 s, SD = 11.42 s). Stimuli
were presented in an event-related design in a pseudo-
randomized order using Presentation® 14.0 software
(Neurobehavioral Systems, Inc., Albany, CA, USA).
Data Analysis: Behavioral Data
Behavioral data were analyzed using IBM® SPSS Statis-
tics 20 (IBM Deutschland GmbH, Ehningen, Germany).
The sample size of 56 participants allowed for a
2 × 2 × 2 repeated-measures analysis of variance
(ANOVA) with group (Con, ASD) and gender (male,
female) as between-subject factors, and condition
(emotional, neutral) as a within-subject factor, per-
formed separately for the SMT-, OMT- and SOMT-rating,
respectively.
INSAR
 For the analysis of the intensity ratings, the responses
on the 7-point rating scales were transformed to absolute
values from 0 (neutral) to 3 (intensively good/intensively
bad).
These transformed data were introduced into a 2 × 2 × 2
repeated-measures ANOVA, computed separately for the
“SELF”- and “OTHER”-rating, with group (Con, ASD) and
gender (male, female) as between-subjects factors, and
condition (E/N) as within-subject factor.
ANOVAs were followed by post hoc t-tests (P < .05).
Data Acquisition and Analysis: Functional Data
Images were acquired on a 3 Tesla Siemens® Trio MR
scanner (Siemens AG, München, Germany) at the
RWTH Aachen University Hospital. A 4-min
magnetization-prepared rapid acquisition gradient
echo image (MP-RAGE) T1-weighted sequence was
applied to obtain structural images (TR = 1,900 msec,
TE = 2.52 msec, TI = 900 msec, matrix = 256 × 256, 176
slices, FoV: 250 × 250 mm2, flip angle = 90°, voxel
size = 1 × 1 × 1 mm3).
Functional data of the whole brain (420 volumes) were
acquired using an echo-planar imaging sequence sensitive
to the blood oxygenation level dependent (BOLD)
effect (T2*, TR/TE = 2000/30 msec, FoV = 200 × 200 mm2,
matrix = 64 × 64, 36 slices, flip angle = 76°, voxel size:
3.1 × 3.1 × 3.1 mm3, slice thickness/gap = 15%). This
resulted in a total scanning time of 19 min.
Functional data were processed and analyzed using
SPM8 (Wellcome Department of Cognitive Neurology,
London, UK) running on a Matlab 10 (The Mathworks,
Inc., Natick, MA, USA) platform. The first three images
were excluded to allow for scanner equilibrium stabiliza-
tion effects. Accordingly, 417 images of each participant
were included in the final analyses.
Images were aligned to the first remaining image of the
run. Realignment parameters were included as covariates
of no interest. The session mean was regressed on a con-
stant term. Realigned images were normalized to the
standard anatomical Montreal Neurological Institute
coordinate space resulting in a voxel size of 3 × 3 × 3 mm3
and smoothed with a Gaussian kernel of 8 mm (isotropic)
full width at half maximum.
On a single-subject level, three regressors (one for each
condition and one modeling the rating period) were
created by convolving the respective boxcar functions
with the canonical hemodynamic response function. A
1/128 Hz high-pass filter was applied to remove slow
scanner drifts. To handle within-subject autocorrelations,
an approximate AR{1} model was estimated.
Contrast estimates of each participant were used in a
general linear model (GLM) modeling random effects
[factors: group (Con Males/Con Females/ASD Males/ASD
Females) × condition × subject]. Violations of sphericity
INSAR Schneider et al./Gender-specific endophenotypes in autism
assumptions were accommodated using nonsphericity
correction (assuming unequal variance components and
independence for factors group and subject, and depen-
dence for factor condition).
Within this model, to investigate the processing of
dynamic emotional video clips (E>N) in patients and
control subjects separately we applied a threshold of
P < 0.05 family wise error corrected for multiple compari-
sons with an extent threshold of 20 voxels.
For group comparisons (representing a less robust dif-
ference of a difference), a more liberal Monte-Carlo cor-
rected threshold was chosen. Monte-Carlo simulations
were computed using AlphaSim by Ward [2000] imple-
mented in AFNI 2011 [Cox, 2012]. Assuming a per-voxel
probability threshold of P = 0.001, after 1,000 simula-
tions a cluster size of 19 contiguous resampled voxels
was indicated to correct for multiple comparisons at
P < 0.05.
Additionally, as Bird et al. [2010] suggested a confound-
ing influence of alexithymia in studies with ASD patients,
we introduced the score of the TAS20 as a covariate of no
interest into the group analysis subdivided into men and
women [in order to avoid gender as a potential confound
in alexithymia analysis; Levant, Hall, Williams, & Hasan,
2009].
Anatomical localization was performed using the WFU
Pick Atlas (Wake Forest University, Winston-Salem, NC)
implemented in SPM.
Results
Behavioral Data
Empathy and emotion recognition in ASD patients
and control subjects. Regarding OMT ratings, the
2 × 2 × 2 repeated-measures ANOVA yielded a significant
main effect of group (F(1,52) = 10.28, P < 0.01) with less
target-matching answers in the ASD group (76.70% vs.
87.33% in the control group). Another significant main
effect was found for condition (F(1,52) = 57.22, P < 0.01).
Analyses also revealed significant interactions for group
× condition (F(1,52) = 6.86, P = 0.01), group × gender
(F(1,52) = 5.03, P = 0.03), and group × gender × condition
(F(1,52) = 4.53, P = 0.04) indicating significantly less
target-matching answers for ASD women during the
N condition, as compared with their healthy counterparts.
All other comparisons remained nonsignificant
(Table 2a)).
For SMT ratings, the ANOVA revealed a significant
main effect of group (F(1,52) = 32.28, P < 0.01) with ASD
patients showing significantly less target-matching
responses than control participants (57.34% vs. 77.95%
in the control group).
For empathy (SOMT), again, a significant main effect of
group was found (F(1,52) = 510.89, P < 0.01) with ASD
511
Table 2. Post Hoc t-Tests of the Behavioral Data (Responses to the Video Clips)

(a) OMT-ratings: % of target-matching answers (= correct identification of the presented emotion) for each of the four groups separately

MCON (± SD) MASD (± SD) t df P

N Males 71.07 (± 24.78) 65.93 (± 24.09) 0.58 28 0.57

Females 86.31 (± 11.85) 50.15 (± 36.84) 3.37 24 <0.01*
E Males 96.73 (± 5.22) 95.13 (± 6.24) 0.76 28 0.45
Females 96.31 (± 5.22) 94.38 (± 6.92) 0.80 24 0.43

(b) Intensity ratings during the “OTHER”-rating

MCON (± SD) MASD (± SD) t df P

N Males 0.31 (± 0.30) 0.35 (± 0.28) −0.33 28 0.75

Females 0.14 (± 0.15) 0.57 (± 0.53) −2.82 24 0.01*
E Males 1.38 (± 0.23) 1.25 (± 0.21) 1.60 28 0.12
Females 1.27 (± 0.15) 1.22 (± 0.18) 0.80 24 0.05

(c) Intensity ratings during the “SELF”-rating

MCON (± SD) MASD (± SD) t df P

“N” condition 0.16 (± 0.24) 0.98 (± 0.36) −2.39 54 0.02*

“E” condition 0.98 (± 0.36) 0.76 (± 0.42) 2.09 54 0.04*

t-test for independent samples, *P < 0.05.

patients giving less empathic responses compared with
control participants (49.45% vs. 70.75% in the control
group) (Fig. 2).
Intensity ratings. For the “OTHER”-rating, a signifi-
cant main effect of condition (F(1,52) = 382.61, P < 0.01)
was found with the intensity ratings reflecting more
neutral answers during the N condition.
Significant interactions for group × condition (F(1,52) =
11.36, P < 0.01) and group × gender (F(1,52) = 4.25,
P = 0.04) indicated significantly more (inappropriate)
emotional answers during the “N” condition in autistic
women compared with their healthy control group
(Table 2b).
For the “SELF”-rating, there was a also a significant
main effect of condition (F(1,52) = 173.82, P < 0.01).
A significant interaction was found for group × condi-
tion (F(1,52) = 17.97, P < 0.01) yielding significantly
more emotional answers in the ASD group than in the
control participants for the N condition, and significantly
less emotional answers for the E condition (Table 2c).
Functional Imaging Data
Gender effects in ASD patients and healthy partici-
pants. While no gender effects emerged in the group of
non-autistic participants, in the group of ASD patients we
found activation increases for male patients compared
with autistic women in the medial frontal gyrus bilater-
ally (Table 3, Fig. 3).
Group comparisons of patients and healthy par-
ticipants subdivided by gender. No significant acti-
vation changes were present for either contrasts in the
male group (healthy males > ASD males as well as ASD
males > healthy males).
In females, we found decreased activation when com-
paring patients to non-autistic women in the midbrain
encompassing also limbic regions (left amygdala) with an
activation peak in the right PAG compared with healthy
females (Table 3 and Fig. 4). The reverse contrast (ASD
females > healthy females) did not result in any signifi-
cant BOLD changes.
Introducing the TAS20 score as covariate in the group
comparisons separated for gender yielded no significant
results.
One-sample analyses of patients and control subjects
are provided in the supplementary material (Table S3).
Discussion
The aim of the study was to elucidate gender-specific
empathy-related dysfunctions on a behavioral and a cere-
bral level in a gender-mixed group of high-functioning
ASD patients relative to a gender-matched control group
by means of functional neuroimaging.
Behaviorally, data were not significantly affected by
gender except the OMT-rating (“How did the actor feel”)
of the neutral (“N”) condition, which yielded signifi-
cantly less target-matching answers (in terms of more

512 Schneider et al./Gender-specific endophenotypes in autism INSAR

Figure 2. Behavioral data—rating correctness for SMT (at the top), OMT (in the middle), SOMT (at the bottom). SMT, self-matching
target; OMT, other-matching target; SOMT, empathy (self- and other-matching target).

INSAR Schneider et al./Gender-specific endophenotypes in autism 513

Table 3. Group Comparisons and Gender Differences in Brain Activation in Response to Emotional vs. Neutral Video Clips
Region
Con Males > Females N.S.
Females > Males N.S.
ASD Males > Females Medial frontal gyrus
Females > Males N.S.
Males Con > ASD N.S.
ASD > Con N.S.
Females Con > ASD Periaqueductal gray
ASD > Con N.S.
Note. Whole-brain analysis, flexible-factorial ANOVA, P < 0.05 Monte-Carlo corrected.
ASD, patients with autism spectrum disorder; Con, healthy control subjects; BA, Brodmann’s Area; L, left; R, right; N.S., no significant activation
increases.
inadequate emotional ratings) for the group of autistic
women compared with non-autistic women.
On a neural level, analyzing gender effects revealed
increased medial frontal gyrus activation in autistic men
compared with autistic women, a pattern of brain activa-
tion, which was not present in the group of non-autistic
participants.
Subsequent comparisons of men and women with ASD
with their respective control subjects yielded patterns of
neural hypoactivations for autistic women compared
with their non-autistic counterparts. As hypothesized,
those hypoactivations in female patients compared with
their control group were distributed over midbrain
regions extending to parts of the limbic system.
Potentially due to the relatively small sample size of
each of the four groups, we did not find significant BOLD
signal changes when comparing male patients to non-
autistic men. However, there was a remarkable tendency
to hyperactivation of the medial frontal gyrus in the male
patient group compared with non-autistic men, as
depicted by the parameter estimates (Fig. 3).
Gender Effects Within the Groups of ASD Patients and
Non-Autistic Subjects
In line with the literature [Farley et al., 2010; Hervé,
Razafimandimby, Vigneau, Mazoyer, & Tzourio-Mazoyer,
2012; Kennedy, Redcay, & Courchesne, 2006; Masten,
Morelli, & Eisenberger, 2011] and our hypotheses, our
data suggest autism-specific gender differences on brain
level during processing (social) information.
In terms of social functioning, the medial frontal gyrus,
for which we found significantly increased activation in
the group of autistic men relative to autistic women, and
in terms of a tendency also when comparing autistic and
non-autistic male subjects (Fig. 3, parameter estimates),
was linked to aspects of ToM. It particularly seems to be
involved in affective speech comprehension [Hervé et al.,
514 Schneider et al./Gender-specific endophenotypes in autism
BA Hemisphere k t x y z
9 L 50 3.92 −21 35 28
R 81 4.03 24 35 31
R 176 4.81 3 −28 −5
2012]. Thus, its atypical activation in male ASD patients
might point to alterations in the processing of those
functions.
However, fundamental deficits of ASD patients regard-
ing the level of ToM and (affective) empathy have con-
sistently been questioned [Frith & Happé, 1994; Narzisi
et al., in press]. Particularly, as autistic patients seem to be
able to successfully pass tasks involving social perception,
when they include a sufficient amount of information as
i.e. complete social situations, contextual cues were
assumed to facilitate social capacities in ASD patients
[Narzisi et al., in press]. Nonetheless, there seems to be
substantial convergence that patients with ASD show at
least subtle difficulties during higher-level ToM tasks
[Senju, Southgate, White, & Frith, 2009]. Particularly, a
recent study [Eigsti, Schuh, Mencl, Schultz, & Paul, 2012]
applying a video paradigm linked emotional speech
detection, and ToM abilities, and in line with the findings
of others [Chevallier, Noveck, Happé, & Wilson, 2011]
demonstrated impaired voice tone recognition in a group
of high-functioning autistic adult patients, when chal-
lenged with high cognitive load. Simultaneously
recorded brain activation yielded hyperactivation of
right-sided medial-prefrontal regions, which was inter-
preted in the light of an increased effort of ASD patients
to correctly identify emotional prosody [Eigsti et al.,
2012]. Moreover, the authors suggested those
hyperactivations as compensatory mechanism in the
patient group for their putative impairments on the level
of ToM [Eigsti et al., 2012].
As our video task especially challenged the ability to
integrate multimodal social information, which includes
to identify prosody, increased activation of the medial
frontal gyrus in our autistic men relative to our autistic
women might hence be interpreted in the light of male-
specific alterations in the processing of ToM-related tasks.
Particularly, men with an ASD might exhibit specific
weaknesses in identifying and integrating (multimodal)
INSAR
Figure 3. Emotional > neutral and parameter estimates—autistic men > autistic women including parameter estimates (axial: medial
frontal gyrus bilaterally); flexible-factorial ANOVA; P < 0.05 Monte-Carlo corrected.

INSAR Schneider et al./Gender-specific endophenotypes in autism 515

Figure 4. Emotional > neutral and parameter estimates—healthy women > autistic women including parameter estimates (sagittal:
periaqueductal gray; coronal: amygdala); flexible-factorial ANOVA; P < 0.05 Monte-Carlo corrected.

516 Schneider et al./Gender-specific endophenotypes in autism INSAR

information [Lai et al., 2012], emotional speech in par-
ticular [Eigsti et al., 2012], as its underlying factor.
Given the above assumption of compensation strate-
gies during ToM tasks [Eigsti et al., 2012], increased acti-
vation of the medial frontal gyrus might hypothetically
be the neural reflection of the increased effort of autistic
men in solving such tasks [Eigsti et al., 2012], while at the
same time the respective features of ToM might widely be
preserved in autistic females [Lombardo et al., 2012,
Poster Presentation at IMFAR). Clinically, such predomi-
nantly unaffected ToM abilities might allow autistic
females to better reflect their (social) behavior, and to
camouflage their autistic impairments by copying social
behavior [Attwood, 2008; Bartley, 2006; Kopp & Gillberg,
2007].
However, at the same time for the ASD group parameter
estimates of the E>N contrast for amygdala activation
surprisingly depict a remarkable tendency to decreased
amygdala activation in the female ASD group relative to
male patients as well as relative to both groups of non-
autistic participants (Fig. 4, parameter estimates). This
finding is rather unexpected, as women are commonly
supposed to exhibit increased activation of limbic regions
during empathy and emotional tasks [Baron-Cohen et al.,
1999; Buddeberg-Fischer et al., 2003; Harenski et al.,
2008; Koch et al., 2007; Kohn et al., 2011; Whittle
et al., 2011], and as clinically, autistic females are widely
accredited with a better social conduct compared with
male patients [Attwood, 2008; Bartley, 2006; Kopp, Kelly
& Gillberg, 2010; Kopp & Gillberg, 2007]. With it, the
finding seems to contradict the clinical descriptions of
social capabilities of autistic men and women [Lai et al.,
2011; Nydén et al., 2000]. Moreover, it challenges the
idea of autism as the extreme variant of the male brain
[Baron-Cohen, 2002].
So far, there is no fundamental explanation to that
[Bejerot et al., 2012]. However, we propose two interpre-
tations:
Taking our overall data into account, brain activation
of male patients with an ASD relative to all other three
groups is characterized by pronounced hyperactivation of
“cognitive” areas as the medial frontal gyrus, while autis-
tic women reveal specific alterations in more affective
parts of the brain, namely midbrain structures as the PAG,
extending to the amygdala.
Thus, first and in line with our hypotheses these
gender-specific alterations of brain activation in men and
women with an ASD might mirror common gender char-
acteristics [Phillips et al., 2003] in the processing of social
stimuli that we used for our task. As its consequence,
female ASD patients might exhibit increased impair-
ments in the respective “affective” parts of the brain,
while autism in men might affect more “cognitive”
regions. Nonetheless, we did not find the particularly
decreased amygdala activation in autistic females com-
INSAR Schneider et al./Gender-specific endophenotypes in autism
pared with all of the other groups reflected on a behav-
ioral and/or neuropsychological level, i.e. by lower
emotion recognition rates in autistic women.
Second, in view of recent studies [Bejerot et al., 2012;
De Vries, Noens, Cohen-Kettenis, van Berckelaer-Onnes,
& Doreleijers, 2010] amygdala activation in autistic males
might—rather hypothetically—also be interpreted in
terms of a neural reflection of a suggested “masculiniza-
tion” of autistic females, and a concurrent “feminization”
of male ASD patients [Beacher et al., 2011; Bejerot et al.,
2012]. According to those studies, autistic females tend to
display various male-like features such as face shape and
voice quality, while at the same time, autistic men seem
to exhibit rather female characteristics [Bejerot et al.,
2012]. Consequently, ASD is occasionally proposed a
gender defiant disorder [Bejerot et al., 2012], which
might also be in line with the finding of an increased rate
of gender identity disorder among autistic patients [De
Vries et al., 2010].
Group Comparisons—Subdivided into Gender
While we did not find significant differences within the
male group, autistic women relative to non-autistic
women yielded a pattern of hypoactivations of areas of
the midbrain, namely the PAG, expanding to limbic
regions such as the left amygdala.
Structures of the midbrain, the PAG in particular, have
been related to deep social emotions such as compassion-
ate attitude toward others’ suffering [Kim et al., 2009] and
maternal love [Bartels & Zeki, 2004). Additionally, these
structures comprise oxytocin and dopamine receptors,
and support the “brain-internal” reward system [Fields,
Hjemlstad, Margolis, & Nicola, 2007; Lee, Gallagher, &
Holland, 2010]. In case of non-autistic subjects, the reward
system, its midbrain structures in particular, has also been
proposed to be crucially engaged in the evaluation of
incentive salience of social stimuli like (smiling) faces [Lin,
Adolphs, & Rangel, 2012], as depicted by our videos.
Remarkably, for autistic patients atypical behavioral and
neural responses to rewarding stimuli have been suggested
[Kohls et al., 2011]. Reduced neural responses to social
cues in brain areas related to reward processing might
hence reflect the idea of the so-called “social motivation
theory of autism” [Chevallier, Kohls, Troinai, Brodkin, &
Schultz, 2012], which assigns autistic symptoms to a lack
of motivation in building social relationships [Chevallier
et al., 2012; Kohls et al., 2011; Schultz, 2005]. Significantly
decreased activation in the PAG in ASD females compared
with healthy women might hence point to reduced social
interests and/or less emotional contagion in autistic
females.
Additionally, there was a tendency to hypoactivation of
the left amygdala in autistic women compared with their
non-autistic counterparts (Fig. 4, parameter estimates). As
517
the left amygdala was proposed to be involved in the
evaluation of complex social input [Bzdok et al., 2012],
its hypoactivation in autistic females might indicate that
females with an ASD in contrary to healthy women
exhibit specific impairments in emotional reciprocity
during complex social situations [Nydén et al., 2000], as
depicted by our video clips.
Behaviorally, autistic women’s reduced activation in
empathy-related brain areas relative to non-autistic
females and also to autistic males in combination with
putatively spared ToM abilities in autistic women (rela-
tive to male patients) might result in an “over-
compensatory” emotional overrating of neutral stimuli
(“N” condition, Table 2c and Fig. 2).
Limitations and Conclusions
Our study has some limitations. The video stimuli we
used have the advantage of a realistic combination of
three different input channels, the content, the facial
expressions, and the tone of voice. However, we could
not analyze the different effects of every modality sepa-
rately due to a limited amount of stimuli in order to keep
the scanning time acceptable for patients. We also col-
lapsed our analyses across all four emotion categories and
were thus not able to focus on emotion-specific aspects.
Additionally, we used basic emotions and simple inten-
sity rating scales, which might neither disclose the subtle
difficulties of adult high-functioning ASD patients in
emotion recognition and empathy completely [Castelli,
2005], nor potential subtle differences between males and
females in either groups.
However, autistic men and women seem to exhibit
differential patterns of cerebral dysfunctions. Particu-
larly, our study supports the idea of autism as “gender
defiant disorder” [Bejerot et al., 2012], indicating
specific cognitive deficits for autistic men, and impair-
ments on the level of emotional empathy in autistic
women.
These findings implicate the necessity for further
research in order to meet the specific needs of autistic
men and women in diagnostic and therapeutic settings.
Acknowledgments
This study was supported by the German Research Foun-
dation (DFG, International Research Training Group
1328: “Brain-behavior relationship of emotion and social
cognition in schizophrenia and autism,” KFO 112 and HA
3202/7-1), as well as the Interdisciplinary Center for
Clinical Research of the Medical Faculty of the RWTH
Aachen University (IZKF, N2-6).
We would also like to thank all our subjects and the
participating self-help groups and therapy centers for
supporting this study.
518 Schneider et al./Gender-specific endophenotypes in autism
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Supporting Information
Additional Supporting Information may be found in the
online version of this article at the publisher’s web-site:
Figure S1. Watching Emotional vs. Neutral Video
Clips: activation in healthy subjects (green) and
ASD patients (red); flexible-factorial analysis (P < 0.05
Family Wise Error corrected, extent threshold = 20
voxels).
Table S1. Demographical and neuropsychological data
for autistic patients and healthy control subjects sepa-
rated for gender.
Table S2. Additional neuropsychological data for
autistic patients separated for gender.
Table S3. Brain activations when watching emotional
vs. neutral video clips (E>N contrast) in healthy control
subjects (Con) and ASD patients (ASD)—One-sample
analyses.
521