Neurobiology of Stress 15 (2021) 100399

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Neurobiology of Stress
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Childhood maltreatment results in altered deactivation of reward

processing circuits in depressed patients: A functional magnetic resonance
imaging study of a facial emotion recognition task
Szilvia Anett Nagy a, b, c, d, e, Zsófia Kürtös a, d, Nándor Németh a, Gábor Perlaki b, c, d,
Eszter Csernela a, Flóra Elza Lakner a, e, Tamás Dóczi b, c, d, Boldizsár Czéh a, e, *, Maria Simon a, f
a
Neurobiology of Stress Research Group, Szentágothai János Research Centre, University of Pécs, Pécs, Hungary
b
MTA-PTE, Clinical Neuroscience MR Research Group, Pécs, Hungary
c
Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary
d
Pécs Diagnostic Centre, Pécs, Hungary
e
Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
f
Department of Psychiatry and Psychotherapy, Medical School, University of Pécs, Hungary

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

Keywords: Importance and objectives: Childhood adversity is a strong risk factor for the development of various psychopa­
Adverse childhood experiences thologies including major depressive disorder (MDD). However, not all depressed patients experience early life
Child abuse trauma. Functional magnetic resonance imaging (fMRI) studies using facial emotion processing tasks have
Childhood trauma
documented altered blood-oxygen-level-dependent (BOLD) responses in specific cortico-limbic networks both in
CTQ
Major depressive disorder
MDD patients and in individuals with a history of childhood maltreatment (CM). Therefore, a history of
MRI maltreatment may represent a key modulating factor responsible for the altered processing of socio-affective
stimuli. To test this hypothesis, we recruited MDD patients with and without of maltreatment history to study
the long-term consequences of childhood trauma and examined the impact of CM on brain activity using a facial
emotion recognition fMRI task.
Methods: MDD patients with childhood maltreatment (MDD + CM, n = 21), MDD patients without maltreatment
(MDD, n = 19), and healthy controls (n = 21) matched for age, sex and intelligence quotient underwent fMRI
while performing a block design facial emotion matching task with images portraying negative emotions (fear,
anger and sadness). The history of maltreatment was assessed with the 28-item Childhood Trauma
Questionnaire.
Results: Both MDD and MDD + CM patients displayed impaired accuracy to recognize sad faces. Analysis of brain
activity revealed that MDD + CM patients had significantly reduced negative BOLD signals in their right
accumbens, subcallosal cortex, and anterior paracingulate gyrus compared to controls. Furthermore, MDD + CM
patients had a significantly increased negative BOLD response in their right precentral and postcentral gyri
compared to controls. We found little difference between MDD and MDD + CM patients, except that MDD + CM
patients had reduced negative BOLD response in their anterior paracingulate gyrus relative to the MDD group.
Conclusions: Our present data provide evidence that depressed patients with a history of maltreatment are
impaired in facial emotion recognition and that they display altered functioning of key reward-related fronto-
striatal circuits during a facial emotion matching task.

represents a global moral and health problem (Gilbert et al., 2009; Bellis
1. Introduction et al., 2014). Approximately 30–50% of the adult population experience
at least one form of adverse childhood experience (Felitti et al., 1998;
Exposure to neglect and abuse in childhood is highly prevalent and Kessler et al., 2010; Vanaelst et al., 2012). Childhood maltreatment

* Corresponding author. Department of Laboratory Medicine, Medical School, University of Pécs, H-7624, Pécs, Ifjúság út 13. Hungary.
E-mail addresses: [Link]@[Link] (S.A. Nagy), [Link]@[Link] (Z. Kürtös), nemethnandor1@[Link] (N. Németh), [Link]@
[Link] (G. Perlaki), [Link]@[Link] (E. Csernela), laknerelza@[Link] (F.E. Lakner), [Link]@[Link] (T. Dóczi), [Link]@[Link]
(B. Czéh), [Link]@[Link] (M. Simon).

[Link]
Received 17 May 2021; Received in revised form 1 September 2021; Accepted 14 September 2021
Available online 24 September 2021
2352-2895/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
([Link]
S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

related fronto-striatal neural circuits in depressed individuals (Hamil­

Abbreviations ton et al., 2012; Zhang et al., 2013). In fMRI studies, facial emotion
processing paradigms are widely used to examine functional brain ab­
BOLD blood-oxygen-level-dependent normalities in MDD patients. Typically, depressed patients display
CTQ childhood trauma questionnaire exaggerated amygdala activation in response to faces expressing nega­
CM childhood maltreatment tive emotions (Sheline et al., 2001; Dannlowski et al., 2007; Peluso et al.,
fMRI functional magnetic resonance imaging 2009; Victor et al., 2010; Palmer et al., 2015). However, exaggerated
GABA gamma-aminobutyric acid amygdala responses to negative facial expressions have also been re­
HC healthy control ported in patients with post-traumatic stress disorder (PTSD) (Shin et al.,
IQ intelligence quotient 2005) and in healthy individuals who experienced childhood maltreat­
MDD major depressive disorder ment (Dannlowski et al., 2012, 2013). Since a significant percentage of
PFC prefrontal cortex patients with MDD has been exposed to early life trauma, former neu­
PTSD post-traumatic stress disorder roimaging investigations could be confounded by this variable. Some of
the neurobiological alterations found in MDD patients could be
accredited to the difference in the history of childhood maltreatment
(Hart and Rubia, 2012). In support of this concept, childhood
(CM) is a potent risk factor for the development of a wide spectrum of maltreatment has also been associated with enhanced bilateral amyg­
physical and mental disorders and can eventually lead to premature dala reactivity to emotional faces in general (van Harmelen et al., 2013)
mortality (Felitti et al., 1998; Anda et al., 2006; Gilbert et al., 2009; and with greater activation of the prefrontal cortex and basal ganglia
Brown et al., 2009; Carr et al., 2013; Hughes et al., 2017). Individuals and increased amygdala connectivity with the hippocampus and pre­
with a history of adverse experiences display altered structural and frontal cortex during a facial emotion recognition task (Jedd et al., 2015;
functional brain development of cortico-limbic circuits (Pechtel and Demers et al., 2018). In addition to that, studies investigating maltreated
Pizzagalli, 2011; Dannlowski et al., 2012; Hart and Rubia, 2012; Lim individuals document disturbed functioning of lateral and ventromedial
et al., 2014; Teicher et al., 2016; Teicher and Samson, 2016). Further­ fronto-limbic networks which mediate affect control (Hart and Rubia,
more, a history of childhood trauma elicits a host of biological responses 2012). More recently, a hypothesis has been put forward proposing that
which in turn significantly increase the risk to develop depressive dis­ childhood maltreatment results in diminished inhibition of the amyg­
orders later in adulthood (McLaughlin et al., 2010; Heim and Binder, dala by the medial PFC during emotional processing and the consequent
2012). Among others, disturbed functioning of the hyperactivity of the amygdala may constitute a vulnerability marker for
hypothalamic-pituitary-adrenal axis (van Bodegom et al., 2017) and depressive symptoms in later life (Kessler et al., 2020). Therefore, it is
altered inflammatory responses (Danese and Lewis, 2017) have been important to understand the contribution of CM, as a key moderating
pointed out as key mechanisms, while more recently, epigenetic modi­ variable, to the pathophysiology of neural networks regulating
fications like methylation, histone modifications, and the role of small higher-order socio-cognitive processes in patients with depressive dis­
noncoding RNAs (microRNAs) have emerged as potential contributors to orders. Indeed, a robust positive correlation has been found between
the maladaptive processes associated with early life trauma (Heim and physical childhood abuse and right amygdala response to sad face
Binder, 2012; Torres-Berrío et al., 2019; Allen and Dwivedi, 2020). stimuli in depressed patients suggesting that the relationship between
Major depressive disorder (MDD) is a common and heterogeneous childhood trauma and risk for depression might be mediated by
mental disorder with complex and not fully understood pathophysiology heightened amygdala responses to negative stimuli (Grant et al., 2011;
(Otte et al., 2016). Besides depressed mood, anhedonia, and cognitive Kessler et al., 2020).
symptoms such as self-focused attention, self-referential thinking, as To further examine neurobiological correlates of childhood
well as impaired social behavior hallmark the clinical feature of MDD. maltreatment in adult patients with MDD, we designed an fMRI study,
All types of child maltreatment are considered as significant risk factors where we investigated the influence of childhood maltreatment on the
for MDD in adults (meta-analyzed by Mandelli et al., 2015; Li et al., neural processing of negative socio-affective stimuli in patients with
2016; Humphreys et al., 2020). Emotional abuse and neglect have the MDD. We compared the blood-oxygen-level-dependent (BOLD) re­
strongest association with the prevalence of MDD, although the different sponses of three groups of participants using an established facial
types of maltreatments typically co-occur. Moreover, child maltreat­ emotion recognition fMRI paradigm: 1) MDD patients who experienced
ment is associated with the occurrence of chronic, as well as a recurrent severe to extreme maltreatment; 2) MDD patients who were exposed to
course of MDD, and can predict poor treatment response and outcome moderate childhood maltreatment at most and 3) healthy, never-
(Nanni et al., 2012). depressed controls. We decided to use a well-established face match­
Neuroimaging methods have been extensively employed to study the ing emotional fMRI task, because this task reliably activates brain areas
neurobiological underpinnings of MDD (Anderson et al., 2020). Deficits involved in emotional processing (e.g. the amygdala) (Costafreda et al.,
in emotional processing are one of the most obvious clinical symptoms 2008; Sergerie et al., 2008). Furthermore, this task has been subjected to
of MDD, and neuroimaging studies document altered functioning of thorough scrutiny (McDermott et al., 2018) and recommended for
neural circuitries underlying these emotional impairments (Li and between-subject designs (Plichta et al., 2012). Several studies employed
Wang, 2021). A large body of human data from functional and structural this task and demonstrated that adults with a history of CM react
imaging studies as well as postmortem histopathological evidences differently and show greater brain activation when they perform this
indicate that a neural circuitry which connects the medial prefrontal task (Bérubé et al., 2021). For socio-affective stimuli, we used photo­
cortex to limbic structures such as the amygdala, and to subcortical graphs of faces expressing negative emotions: fear, anger, and sadness.
structures like the ventral striatum and pallidum, the medial thalamus, We used images of negative emotions because evidence suggests that
and hypothalamus, forms a neural network system which is centrally negative emotional stimuli activates the amygdala with higher proba­
involved in mood disorders (Price and Drevets, 2010; Zhang et al., 2013; bility (Costafreda et al., 2008), and because individuals with a history of
Helm et al., 2018). Furthermore, a recent meta-analysis which analyzed early adversity react to sad faces with heightened bilateral amygdala
neuroimaging studies investigating reward processing functions in MDD activity compared to other facial emotions (Saarinen et al., 2021).
reported that dysregulated corticostriatal connectivity may explain the Furthermore, it has been reported that abused children have a recog­
reward-processing abnormalities in MDD (Ng et al., 2019). nition bias for negative expressions, and that neglected children have a
Functional magnetic resonance imaging (fMRI) is a well-established shorter reaction time for recognition of negative facial expressions
method to investigate the activity of cortico-limbic as well as reward- (Assed et al., 2020).

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

We hypothesized that depressed patients with a history of childhood individuals took psychotropic medication. Only healthy control partic­
maltreatment will perceive such negative socio-affective stimuli as more ipants with no significant history of childhood maltreatment were
arousing and threatening and will display different brain activity pat­ enrolled in the study. By using cut-off values on each subscale of the
terns compared to controls and also to MDD patients. To certify this Childhood Trauma Questionnaire, we enrolled only those control sub­
hypothesis, we compared the activation and deactivation patterns of jects who did not score higher than the ‘low’ range in any trauma
neural circuits during the facial emotion matching task in the control, dimension (for the exact cut-off values used in this study, please see the
MDD, and MDD + CM groups. We also evaluated interactions and cor­ Supplementary Materials). After group assignment, MDD + CM patients
relations of the BOLD responses with the clinical data. had significantly lower median of years of education compared to MDD
and control subjects. However, there was no significant difference in
2. Material and methods general IQ between the three study groups. Hence, all three groups were
matched in IQ. All participants were Caucasian, native Hungarian
2.1. Subjects speakers living in the urban and suburban area of Pécs and provided
written informed consent.
Forty patients with major depressive disorder and 21 age-, sex- and The local Research Ethics Committee of the University of Pécs
education matched healthy controls (HC) participated in the study. We approved the study design and protocol (Ethical Approval Nr.: 2015/
set the following exclusion criteria for participation: current substance 5626).
use (i.e. abstinence for <2 years), history of internal medical or neuro­
logical disorders, head injury, hearing or visual impairment, an Intelli­
gence Quotient (IQ) < 85, and any MR scanning issues (e.g. 2.2. Clinical status and childhood trauma assessment
claustrophobia, or metal objects in the body). Moreover, no participants
exposed to traumatic life events fulfilling the DSM-5 PTSD criterion A Depression severity was evaluated by a multimethod approach: with
were enrolled in the study. the 21-item Hamilton Depression Rating Scale, and with the Beck
Patients with major depression (N = 40) were recruited from the Depression Inventory (Beck et al., 1961). Anxiety severity was assessed
Affective Disorder Unit of the Department of Psychiatry and Psycho­ with the Beck Anxiety Inventory (Beck et al., 1988.) The overall level of
therapy, University of Pécs. All patients fulfilled the DSM-5 diagnostic IQ was estimated with a four-subtest version of the Hungarian adapta­
criteria of major depression (American Psychiatric Association, 2013), tion of the Wechsler Adult Intelligence Scale-Revised (Kaufman et al.,
assessed using the Structured Clinical Interviews for DSM-5 disorders 1991, Wechsler, 1997; Nagybányai Nagy and Rózsa, 2006).
(SCID-5-CV and SCID-5-PD; First et al., 2015, 2016) by a trained psy­ Childhood maltreatment was defined as exposure to long-lasting
chiatrist (MS). Inclusion criteria for patients with major depression and/or repeated abuse and/or neglect before the age of 18. Childhood
were: (1) age 18–50 years; (2) a diagnosis of major depression in a abuse and neglect were surveyed with a self-report questionnaire: the
current major depressive episode (≥8 points on the Hamilton Depression Hungarian version of the 28-item Childhood Trauma Questionnaire-
Rating Scale, 21-item version (Hamilton, 1967). Short Form (CTQ, Bernstein, et al., 2003; Csernela et al., 2021). CTQ
Exclusion of psychiatric comorbidities, where altered brain activa­ is a widely used, 28-item, retrospective self-report questionnaire
tions during the facial emotion recognition tasks have been demon­ designed to assess the severity of five types of childhood maltreatment.
strated: Considering the available brain imaging data, patients with CTQ total score and scores for the 5 subscales (physical abuse and
comorbid borderline personality disorder and PTSD were also excluded, neglect, emotional abuse and neglect, as well as sexual abuse) of the
because they have increased sensitivity to negative environmental CTQ were calculated. By using cut-off values on each subscale,
stimuli, which is associated with increased activation of the amygdala depressed patients scoring in any trauma dimension at least above the
(New et al., 2007; Shin et al., 2005). In our sample, non-excluded psy­ ‘low’ range were assigned to the MDD + CM group. For further details of
chiatric comorbidities were: anxiety disorders (panic disorder N = 4; the assessment of childhood maltreatment, including the CTQ cut-off
social phobia N = 3; generalized anxiety disorder N = 3; specific phobias scores, please see the Supplementary Materials.
N = 4); obsessive-compulsive disorder in the past 6 years, and never Demographic, IQ, clinical, and CTQ data of the sample are presented
treated when symptomatic before (N = 2); mild and non-chronic alcohol in Tables 1 and 2.
use disorder (N = 3); lifetime sedatives, hypnotics, and anxiolytics use
disorder (N = 3) in full remission for more than 2 years; cluster C per­
sonality disorders (dependent N = 3, avoidant N = 2). The mean age of 2.3. The facial emotion recognition paradigm
disease onset was 26.11 ± 9.41 years. The mean duration of illness was
6.86 ± 7.46 years (range 0.4–26 years). Thirty-nine (95%) patients with The facial emotion recognition task is a well-established task that has
MDD received antidepressant medication (selective serotonin reuptake been employed in numerous neuroimaging studies to characterize the
inhibitor: 25; serotonin and noradrenaline reuptake inhibitor: 3; activity of the amygdala and related cortico-limbic structures. Here, we
noradrenergic and specific serotonergic antidepressant: 9; bupropion: 1, used a modified version of the original facial emotion recognition task
agomelatine: 4, trazodone: 2; combined with mood stabilizer: 3; (Hariri et al., 2002) using fearful (F), angry (A), and sad (S) images from
augmented by low-dose atypical antipsychotics: 6). the FACES database (Ebner et al., 2010).
Based on the severity of childhood maltreatment, depressed patients Our block design facial emotion recognition fMRI paradigm included
were divided into two study groups, one with a low incidence of six blocks of facial emotion processing (face matching) tasks alternating
childhood maltreatment (MDD group, N = 19), another one with a with six blocks of sensorimotor (shape matching) control tasks (C)
history of severe maltreatment (MDD + CM group, N = 21). (For (Fig. 1). One-half of the trials required left-handed, while the other half
methods used for the assessment of childhood maltreatment please see required right-handed responses. One block lasted 30sec and contained
section 2.2. “Clinical status and childhood trauma assessment” and the 6 sequential matching trials. Each trial was presented for 5sec, with no
Supplementary Materials.) interstimulus interval. The entire paradigm included a total of 12 blocks
The healthy control group (N = 21) was matched in age, sex, and and 72 trials (6 trials per block; 6 face matching, and 6 shape matching
level of education to the entire MDD group. Control subjects were blocks) and lasted for 360sec (e.g., CFCACSCFCACS, see Fig. 1A). Before
screened by a qualified psychiatrist (MS) to ascertain the absence of scanning, subjects underwent detailed instructions about the facial
lifetime or family history of mental disorders; besides, Symptom- emotion recognition fMRI task, followed by a short training session in­
Checklist-90-R (Derogatis, 1994; Unoka et al., 2004) was applied to side the scanner including both the face matching and the shape
rule out subthreshold psychiatric symptoms. None of the healthy matching tasks.

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Table 1
Demographic, IQ, and clinical data of the sample.
Control MDD MDD + CM Between-group differences
N = 21 N = 19 N = 21

Age (yrs)a 33.24 ± 8.37 33.21 ± 7.55 32.52 ± 9.55 F(2,58) = 0.46, p = 0.955†
(21–48) (21–50) (18–54)
No. of females (%) 14 (66.67%) 12 (63.16%) 14 (66.67%) χ2(2) = 0.07; p = 1.000#
Years of educationb 15 (12–17) 12 (12–17) 12 (11–15) χ2(2) = 7.753, p = 0.021¥; post hoc Dunn-Bonferroni: MDD + CM vs HC p < 0.05 MDD
+ CM vs MDD p < 0.05 MDD vs HC p = 0.63
IQc 112.1 ± 6.58 114.74 ± 4.71 110.95 ± 5.79 F(2,58) = 0.213, p = 0.809†
Beck Depression Inventoryc 4.29 ± 2.92 21.53 ± 3.26 23.10 ± 5.66 F(2,58) = 130.655, p < 0.001†; Games-Howell post hoc: MDD + CM vs HC p < 0.001,
MDD vs HC p < 0.001, MDD vs MDD + CM p = 0.529
Beck Anxiety Inventoryb 3 (0.5–10.5) 18 (8–24) 21 (16–33) χ2(2) = 30.916; p < 0.001¥; post hoc Dunn-Bonferroni: MDD + CM vs HC p < 0.001,
MDD vs HC p < 0.001, MDD vs MDD + CM p = 0.453
Age at illness onset (yrs)b – 29 (18–34) 21 (16.5–32.5) U = 153.0, p = 0.207§
Length of illness (yrs)b – 4 (1–7) 7 (0.4–12.5) U = 179.0, p = 0.578§
Number of MDD episodesb – 2 (1–2) 2 (1–3) U = 166.0, p = 0.332§
Antidepressant medication – 1/18 0/21 χ2(1) = 1.134, p = 0.4758*
(No/Yes)
Psychiatric co-morbidities (Yes/No)
panic disorder – 1/18 3/18 χ2(1) = 0.902, p = 0.3422*
social anxiety disorder – 2/17 2/19 χ2(1) = 0.011, p = 0.9159*
specific phobia – 2/17 2/19 χ2(1) = 0.011, p = 0.9159*
generalized anxiety – 1/18 2/19 χ2(1) = 0.261, p = 0.6094*
OCD in remission – 1/18 1/20 χ2(1) = 0.005, p = 0.9421*
AUD in remission – 1/18 2/19 χ2(1) = 0.261, p = 0.6094*
SHAUD in remission – 2/17 1/20 χ2(1) = 0.478, p = 0.4894*
dependent PD – 2/17 1/20 χ2(1) = 0.478, p = 0.4894*
avoidant PD – 0/19 1/20 χ2(1) = 0.928, p = 0.3354*

† One-way ANOVA; # Chi-square test; ¥ Kruskal-Wallis H test; § Mann-Whitney U test; * Fisher’s exact test; a mean ± SD (range); b median (interquartile range); c mean
± SD.
Abbreviations: AUD: alcohol use disorder, HC: healthy control; IQ: intelligence quotient; MDD: major depressive disorder; MDD + CM: major depressive disorder with
childhood maltreatment. OCD: obsessive-compulsive disorder, PD: personality disorder, SHAUD: sedatives, hypnotics and anxiolytics use disorder.

2.3.1. Emotional face matching task emotional stimuli, i.e. geometric forms are presented to the subjects. We
In the emotional face matching task, we used images only with used geometric shapes instead of neutral faces because they may provide
negative facial expressions. Each face matching block (F, A, and S) was a more truly neutral baseline for comparison, particularly when patients
repeated twice with images of different people, balanced for gender in a are involved (Filkowski and Haas, 2017). During the shape matching
pseudorandomized order. A target face (on the top of the display) and task, participants completed trials involving abstract geometric forms
two test faces (bottom left and right) were presented in a triangular (circles, vertical and horizontal ellipses) in an analogous configuration
arrangement using Presentation software (Neurobehavioral System, Inc, as the face matching task. Subjects were asked to choose one of the two
Berkley, CA, USA). Prior to the examination, subjects were instructed to test forms on the bottom that has the same geometric form as the target
choose one of the two test faces on the bottom that displayed the same on the top of the screen. Similarly, a yellow square on the screen marked
facial emotion as the target face on the top of the screen. The other, the participant’s decision (see Fig. 1A). During all trials, response ac­
incongruent test face was always displaying a neutral facial expression. curacy and reaction times for the stimuli were recorded and analyzed as
The face photographs from the FACES database (Ebner et al., 2010) described in 2.3.1.
depicted young people (mean age = 24.2, standard deviation = 3.4, age
range = 19–31 years) wearing identical standard grey T-shirts without
2.4. Magnetic resonance imaging
jewelry, glasses, make-up, or other eye-catching items (Fig. 1B).
All stimuli were presented via MRI-compatible goggles (Visual­
All measurements were carried out using a 3T Magnetom TIM Trio
System NordicNeuroLab AS, Bergen, Norway) specifically designed for
whole-body MRI scanner (Siemens AG, Erlangen, Germany) with a 12-
fMRI studies. Subjects made responses by MR-compatible response
channel head coil. Functional imaging was acquired using a 2D single-
buttons (ResponseGrip, NordicNeuroLab AS, Bergen, Norway) pressing
shot echo-planar imaging sequence (TR/TE = 2500/30 ms; Flip angle
their left or right thumb fingers depending upon the choice. The decision
= 76◦ ; 36 axial slices with a thickness of 3 mm; FOV = 192 × 192 mm2;
was marked by a yellow square on the screen, and changes were not
matrix size = 64 × 64; receiver bandwidth = 2170 Hz/pixel; no gap;
possible (Fig. 1A). The presentation of visual stimuli and the recording
interleaved slice order to avoid crosstalk between contiguous slices). For
of subject’s responses were implemented in Presentation software
distortion correction purposes, field mapping sequence (TR/TE1/TE2 =
(Neurobehavioral Systems, Inc., Berkeley, CA, USA). Reaction time and
402/5.20/7.66 ms; Flip angle = 60◦ ; 36 axial slices; FOV = 228 × 228
matching accuracy were obtained offline for each subject from the log
mm2; matrix size = 76 × 76; receiver bandwidth = 259 Hz/pixel) with
files generated during the fMRI measurement. Mean reaction time (ms)
the same voxel size, orientation and adjustment parameters as the fMRI
and matching accuracy (% of accurate matches) were calculated sepa­
scan was acquired right after the fMRI measurement. Anatomical images
rately for the shape- and face matching tasks as well as for each subtype
were obtained using an isotropic T1-weighted 3D-MPRAGE sequence
of the face matching task (i.e. fearful, angry, and sad faces). Between-
(TR/TI/TE: 2530/1100/3.37 ms; Flip angle = 7◦ ; 176 sagittal slices with
group differences in reaction time and matching accuracy data were
a thickness of 1 mm; FOV = 256 × 256 mm2; matrix size = 256 × 256;
assessed by Kruskal-Wallis H test followed with Dunn-Bonferroni pair­
receiver bandwidth = 200 Hz/pixel).
wise post hoc comparisons.

2.3.2. Shape matching task 2.5. fMRI data analysis

The shape matching task was used here as a control task, where non-
For the detailed description of the preprocessing, noise classification

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Table 2
Childhood trauma questionnaire data.
Control MDD MDD + CM Between-group differences
N = 21 N = 19 N = 21

CTQ suma 28 (26.5–33) 34 (31–38) 59 (52.5–70) χ2(2) = 43.323; p < 0.001¥; post hoc Dunn-Bonferroni:
MDD + CM vs HC p < 0.001,
MDD vs HC p = 0.304,
MDD vs MDD + CM p < 0.001
CTQ physical abusea 5 (5–5) 5 (5–5) 9 (6.5–12) χ2(2) = 28.952; p < 0.001¥; post hoc Dunn-Bonferroni:
MDD + CM vs HC p < 0.001,
MDD vs HC p = 1.000,
MDD vs MDD + CM p < 0.001
CTQ physical neglecta 5 (5–5) 5 (5–5) 10 (3–13) χ2(2) = 38.636; p < 0.001¥; post hoc Dunn-Bonferroni:
MDD + CM vs HC p < 0.001,
MDD vs HC p = 0.550,
MDD vs MDD + CM p < 0.001
CTQ emotional abusea 6 (5–8) 7 (5–8) 18 (11.5–20) χ2(2) = 36.165; p < 0.001¥; post hoc Dunn-Bonferroni:
MDD + CM vs HC p < 0.001,
MDD vs HC p = 1.000,
MDD vs MDD + CM p < 0.001
CTQ emotional neglecta 8 (6–10.5) 11 (8–14) 17 (15–19.5) χ2(2) = 39.747; p < 0.001¥; post hoc Dunn-Bonferroni:
MDD + CM vs HC p < 0.001,
MDD vs HC p = 0.133,
MDD vs MDD + CM p < 0.001
CTQ sexual abusea 5 (5–5) 5 (5–5) 5 (5–9.5) U = 128.0, p = 0.014§

Percent of subjects reporting maltreatment Control MDD MDD þ CM

N ¼ 21 N ¼ 19 N ¼ 21

Physical abuse
none: 95.2% 100% 38.1%
low: 4.8% – 23.8%
moderate: – – 28.6%
severe: – – 4.8%
Physical neglect
none: 100% 90.5% 14.3%
low: – 9.5% 28.6%
moderate: – – 33.3%
severe: – – 23.8%
Emotional abuse
none: 85.7% 78.9% 4.8%
low: 14.3% 21.1% 28.6%
moderate: – – 9.5%
severe: – – 57.1%
Emotional neglect
none: 57.1% 42.1% –
low to moderate: 42.9% 57.9% 4.8%
moderate: – – 52.4%
severe: – – 42.8%
Sexual abuse:
none: 100% 94.7% 57.1%
low: – 5.3% 14.3%
moderate: – – 23.8%
severe: – – 4.8%

¥ Kruskal-Wallis H test; Abbreviations: CTQ: Childhood Trauma questionnaire. HC: healthy control; MDD: major depressive disorder; MDD + CM: major depressive
disorder with childhood maltreatment.
a
median (interquartile range)

and clean-up please see the Supplementary Materials. After these steps, iii. Between-group differences of activation patterns during the facial
whole-brain general linear model (GLM) time-series statistical analyses emotion matching task controlled for age and gender (pairwise
of the individual data sets were carried out using FILM (FMRIB’s group comparisons were performed, if the omnibus F-test was
Improved Linear Model) with local autocorrelation correction. significant);
To examine the association of severe to extreme childhood iv. Between-group differences of deactivation patterns during the
maltreatment a higher-level mixed-effects analyses were carried out facial emotion matching task controlled for age and gender
using FLAME (FMRIB’s Local Analysis of Mixed Effects, stage 1 and 2) (pairwise group comparisons were performed if the omnibus F-
with outlier de-weighting in the following order: test was significant);
v. Clinical data (and CTQ scores) × group interaction effect on the
i. Within-group activations: activation pattern during the facial BOLD response during the facial emotion matching task.
emotion matching task in the control, MDD, and MDD + CM
groups separately (face matching task > shape matching task For steps iii., iv., and v. (i.e. in between-group comparisons, as well
contrasts, or positive BOLD responses); as when estimating variable × group interaction effects) a voxel-wise F-
ii. Within group-deactivations: deactivation pattern during the test was applied to detect any significant general effect. If the F-test
facial emotion matching task in the control, MDD, and MDD + yielded a significant effect, then further pairwise t-tests (for steps iii. and
CM groups separately (shape matching task > face matching task iv.) and correlations (for step v.) were used to determine the direction of
contrasts, or negative BOLD responses); the difference. Voxels overlaid with the F-test were interpreted only for

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

Fig. 1. Experimental design of our facial emotion recognition task with examples of images with emotional stimuli. A: After a short training session (1 trial of face
and 1 trial of shape), the block design task included 6 blocks of a 30-s-long shape matching task (control) alternating with a 30-s-long face matching task (face). The
face matching task contained a total of 2 fearful, 2 angry, and 2 sad faces blocks interleaved with control (shape matching) tasks. One block contained 6 sequential
matching trials, each was presented for 5s with no interstimulus interval. The whole run contained a total of 12 blocks and 72 trials (6 face match and 6 shape match
blocks) and it lasted for 360 s without the training session. Subjects were instructed to match one of the two test shapes or faces on the bottom that were similar (in
shape) or expressed the same emotion as the target shape/face on the top of the screen. B: Representative images of faces with various emotional expressions. Each
match emotion trial included a trio of male or female faces expressing neutral, fearful, angry, and sad emotions.

each separate t-test. Family-wise error (FWE) correction was used to 2.6. Statistical analysis of demographic, clinical, and behavioral data
control for multiple comparisons. Statistical maps were considered to be
significant at Z > 2.3 and an FWE corrected cluster significance Data analysis was performed using an SPSS statistical software
threshold of p = 0.05 (Worsley, 2001). Brain regions with significant package (Version 23.0, IBM Corp.). Nonparametric data and datasets
BOLD responses were located using the Harvard Oxford cortical and with skewed distributions were compared with the Mann-Whitney U
subcortical structural atlas, part of FSL 5.0.7 ([Link] test, as well as with the Kruskal-Wallis H test followed with Dunn-
fsl/fslwiki/Atlases). Bonferroni pairwise post hoc comparison. The level of significance
was set at p < 0.05.

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3. Results Table 4
BOLD responses during the facial emotion matching task in the control group.
No significant differences were observed between the three groups Cluster No. of Areas Z- x y z
for age, sex, and IQ. MDD + CM patients had significantly fewer years of voxels score
education compared to MDD patients and control subjects (Table 1). Activation pattern (face matching > shape matching contrast)
Clinical variables of the two clinical groups with major depression did 1 38057 left occipital face area 5.69 − 46 − 79 − 12
not significantly differ (Table 1). Due to the group assignment criteria, right occipital face 6.47 46 − 76 − 6
MDD + CM patients’ CTQ scores differed significantly from those of both area
left amygdala 5.42 − 22 − 6 − 16
the control and MDD groups on each subscale (Table 1). There was no right amygdala 5.28 18 − 4 − 18
significant between-group difference in CTQ scores of MDD patients left middle frontal 4.83 − 48 28 28
(without a history of childhood maltreatment) and controls. gyrus
left inferior frontal 5.48 − 46 12 28
gyrus
3.1. Reaction time and matching accuracy during the facial emotion left hippocampus 4.52 − 24 − 28 − 10
matching task right hippocampus 4.72 24 − 30 − 6
2 5851 right middle frontal 5.39 50 30 24
3.1.1. Matching accuracy of facial emotions gyrus
right inferior frontal 6.02 46 16 24
Participants had a high overall response accuracy. There was no gyrus
significant between-group difference in the shape-matching accuracy. Deactivation pattern (shape matching > face matching contrast)
However, study groups significantly differed in matching facial emo­ 1 2386 left accumbens 3.93 − 12 10 − 10
tions (χ2(2) = 6.019; p = 0.049), the MDD + CM group performed right accumbens 3.23 6 10 − 6
subcallosal cortex 4.84 − 2 28 10
significantly worse compared to HC (posthoc Dunn-Bonferroni pairwise
−
anterior cingulate 3.19 − 6 38 − 2
comparison, p = 0.037, mean rank scores: MDD + CM = 24.81, HC = gyrus
36.31, p = 0.045). Moreover, we found a significant between-group 2 2051 posterior cingulate 4.38 2 − 24 38
difference in the matching accuracy of sad faces (χ2(2) = 6.286; p = gyrus
0.043, Table 3). MDD + CM patients were significantly less accurate in Statistical maps were considered to be significant at Z > 2.3 and an FWE cor­
matching sad faces than the healthy controls (posthoc Dunn-Bonferroni rected cluster significance threshold of p = 0.05.
pairwise comparison, p = 0.037, mean ranks sores: HC = 36.50, MDD = Z-score: Z-scores of local maxima; x-, y- and z values correspond to the MNI
31.18, MDD + CM = 25.33). There was no between-group difference in coordinates of local maxima in mm; several local maxima are reported if the
the accuracy of matching fearful and angry faces. cluster encompasses more than one anatomical location. BOLD: blood-oxygen-
level-dependent.
3.1.2. Reaction time
There was a significant between-group difference in the reaction face processing, as well as recognition, including the occipital face area,
times in response to sad faces (χ2(2) = 7.054; p = 0.029). MDD patients the amygdala, the hippocampus, the middle and the inferior frontal gyri
reacted significantly slower compared to controls (posthoc Dunn- in all three groups (Tables 4 and 5; Figs. 2A, 3A and 4A). Other regions
Bonferroni pairwise comparison, p = 0.024, mean rank scores: HC = like the occipital pole, the thalamus, the posterior paracingulate gyrus,
24.14, MDD = 39.05, and MDD + CM = 30.57). No other statistically the lingual gyrus, the intra- and the supracalcarine cortices, the pre­
significant between-group difference was found in the reaction times. central gyrus, the posterior division of the superior temporal gyrus, the
All matching accuracy and reaction time data are presented in posterior supramarginal gyrus, the medial frontal cortex, and the insular
Table 3. cortex were also activated (Figs. 2A, 3A and 4A).

3.2. Functional MRI [Link]. Groupwise deactivation patterns. Control subjects exhibited
significant deactivation in regions responsible for processing reward,
3.2.1. Within-group BOLD responses fearful stimuli, and emotional regulation: i.e. n. accumbens, subcallosal
cortex, anterior and posterior cingulate gyrus (Table 4, Fig. 2B), but no
[Link]. Groupwise activation patterns. We found significant activation significant deactivation pattern was found in the n. accumbens of MDD
in typical visual-limbic and prefrontal regions involved in emotion, and patients (Table 5, Fig. 3B) and the n. accumbens and subcallosal cortex

Table 3
Reaction time and response accuracy in the facial emotion matching task: between-group comparisons.
Groups* Between-group comparisons**

HC MDD MDD + CM Kruskal-Wallis H test HC vs. MDD HC vs. MDD + CM MDD + CM [Link]
Reaction time (ms)
Shape matching tasks 1011.87 ± 250.43 1103.38 ± 324.73 1104.71 ± 282.16 ns – – –
Face matching tasks 1567.87 ± 368.41 1841.40 ± 376.23 1749.38 ± 496.70 ns – – –
fearful faces 1522.17 ± 366.11 1738.75 ± 386.30 1641.37 ± 448.65 ns – – –
angry faces 1505.00 ± 379.38 1724.95 ± 390.43 1765.66 ± 588.86 ns – – –
sad faces 1676.44 ± 425.37 2060.49 ± 459.13 1841.13 ± 521.83 0.029 0.024 ns ns
Matching accuracy (% of correct responses)
Shape matching tasks 98.67 ± 1.67 98.68 ± 1.70 97.62 ± 3.86 ns – – –
Face matching tasks 99.34 ± 1.21 98.68 ± 1.94 96.83 ± 3.76 0.049 ns 0.045 ns
fearful faces 99.60 ± 1.82 99.12 ± 2.63 97.62 ± 4.67 ns – – –
angry faces 99.60 ± 1.82 100.00 ± 0.00 99.60 ± 1.82 ns – – –
sad faces 98.81 ± 2.99 96.93 ± 4.98 93.65 ± 8.70 0.043 ns 0.037 ns

*Data are presented as mean ± standard deviation.

HC: healthy control, MDD: major depressive disorder (without childhood maltreatment); MDD + CM: major depressive disorder with childhood maltreatment.
**Assessed by Kruskal-Wallis H and Dunn–Bonferroni posthoc pairwise comparison tests. In case of statistically significant results, p-values are presented. ns: not
significant.

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Table 5
BOLD responses during the facial emotion matching task in the MDD group.
Cluster No. of voxels Areas Z-score x y z

Activation pattern (face matching > shape matching contrast)

1 38471 left occipital face area 5.14 − 38 − 80 − 12
right occipital face area 5.98 40 − 82 − 10
left amygdala 4.98 − 24 − 2 − 18
right amygdala 4.71 20 − 4 − 14
left middle frontal gyrus 4.00 − 50 24 28
right middle frontal gyrus 5.66 48 30 24
left inferior frontal gyrus 4.40 − 54 18 23
right inferior frontal gyrus 5.75 48 14 22
left hippocampus 4.43 − 22 − 32 − 6
right hippocampus 4.05 22 − 32 − 6
Deactivation pattern (shape matching > face matching contrast)
1 2472 subcallosal cortex 3.93 2 28 − 8
anterior cingulate gyrus 4.24 2 36 − 2
2 2316 posterior cingulate gyrus 5.27 2 − 24 42

Statistical maps were considered to be significant at Z > 2.3 and an FWE corrected cluster significance threshold of p = 0.05.
Z-score: Z-scores of local maxima; x-, y- and z-values correspond to the MNI coordinates of local maxima in mm; several local maxima are reported if the cluster
encompasses more than one anatomical location. BOLD: blood-oxygen-level-dependent; MDD: major depressive disorder.

of the MDD + CM group (Table 6, Fig. 4B). In the MDD + CM group, 4. Discussion
additional significant deactivation was found in the pre-, and postcentral
gyri (Table 6, Fig. 4B). Other regions like the anterior paracingulate To our best of knowledge, our present fMRI study is the first in the
gyrus, the planum temporale, the parietal operculum cortex, the anterior literature to investigate brain activation patterns of control subjects and
supramarginal gyrus, the angular gyrus, and the precuneus cortex were MDD patients with and without a history of childhood maltreatment
also deactivated in all three groups (Figs. 2B, 3B and 4B). using a facial emotion recognition task. Participants of the three
experimental groups were matched for age, gender, and IQ. We report
3.2.2. Between-group differences in BOLD responses here that MDD patients with childhood maltreatment had impaired ac­
There was no statistically significant between-group difference in curacy in facial emotion recognition in general and that they were
activation patterns during the facial emotion matching tasks. However, significantly less accurate in recognizing sad facial expressions. Several
after controlling for age and gender, significant differences in negative brain areas were activated and deactivated during the facial emotion
BOLD response were found between the control, MDD, and MDD + CM recognition task, but we could not find any group differences in the
groups in the right accumbens, the subcallosal cortex, the anterior activation patterns. Instead, group differences emerged only when we
paracingulate gyrus, the right pre- and postcentral gyri (Fig. 5). compared the deactivation patterns of the three groups. MDD patients
Pairwise t-tests revealed that control subjects had significantly with childhood maltreatment had significantly reduced negative BOLD
increased negative BOLD response during the facial emotion matching response in their right accumbens, subcallosal cortex and anterior par­
tasks in the right accumbens, the subcallosal cortex, and the anterior acingulate gyrus compared to controls. Furthermore, MDD + CM pa­
paracingulate gyrus compared to the MDD + CM group. Also, the pair­ tients had reduced negative BOLD signals in the anterior paracingulate
wise between-group comparison confirmed significantly increased gyrus compared to the MDD group. Finally, depressed patients with
negative BOLD response in the anterior paracingulate gyrus of MDD childhood maltreatment had significantly increased negative BOLD
patients compared to MDD + CM patients. The right precentral and signals in their right precentral and postcentral gyri compared to con­
postcentral gyrus were characterized by a significantly increased nega­ trols. In harmony with our original hypothesis, MDD patients who suf­
tive BOLD response in patients with MDD + CM compared to the control fered childhood maltreatment displayed altered emotional processing in
group (Table 7). a facial emotion recognition task, but we found little difference between
the MDD and MDD + CM groups.
3.2.3. Interaction effect between clinical data and groups on the BOLD
response
There was a significant interaction effect between clinical data and 4.1. Experience of childhood maltreatment impairs facial emotion
MDD versus MDD + CM groups on the BOLD response (in face matching recognition
versus shape matching contrasts) in respect to the number of depressive
episodes and age at illness onset. Significant group × number of A large body of evidence indicates that the developing brain is
depressive episodes interaction was found in the anterior cingulate and particularly vulnerable to stressful childhood experiences. The repeated
posterior paracingulate gyri. Further analysis showed a positive corre­ or sustained hyperactivation of the stress response system during brain
lation of BOLD response and the number of depressive episodes in the development may alter the maturation of core aspects of socio-cognitive
anterior cingulate and posterior paracingulate gyri of MDD + CM pa­ functions and often results in disrupted emotion regulation, altered
tients (Table 8, Fig. 6A), while there was no significant correlation in the reward processing, and cognitive impairments (Shonkoff et al., 2009;
MDD group. Significant group × age at illness onset interaction was Pechtel and Pizzagalli, 2011; Rokita et al., 2018; Kraaijenvanger et al.,
found in the posterior division of the left superior and the middle tem­ 2020). An increasing amount of neuroimaging studies document
poral gyri with a significant positive correlation between BOLD signal long-lasting alterations in the activity of limbic circuits which in turn
and age at illness onset in the MDD group (see Table 8 and Fig. 6B), but modify the functioning of four key domains: emotion and memory
no significant correlation was found in MDD + CM patients. processing, inhibitory control, and reward processing (McCrory et al.,
There was no other significant group × clinical variable interaction 2017; Kraaijenvanger et al., 2020).
including depression (Beck Depression Inventory), and anxiety (Beck In our study, MDD patients who were exposed to childhood
Anxiety Inventory) scores, as well as CTQ scores. maltreatment were impaired in facial emotion recognition, their
emotion recognition accuracy was reduced, especially when matching
the sad face stimuli. There are a few reports in the literature that

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Fig. 2. Group level activations, i.e. face matching > shape matching contrast (A) and deactivations, i.e. shape matching > face matching contrast (B) during the
facial emotion recognition task in healthy controls (HC). Images were thresholded using clusters determined by Z > 2.3 and an FWE corrected cluster significance
threshold of p = 0.05. Axial slices are shown in radiological convention for MNI slice coordinates from Z = -72 mm to Z = 84 mm.

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

Fig. 3. Group level activations, i.e. face matching > shape matching contrast (A) and deactivations, i.e. shape matching > face matching contrast (B) during the
facial emotion recognition task in MDD patients. Images were thresholded using clusters determined by Z > 2.3 and an FWE corrected cluster significance threshold
of p = 0.05. Axial slices are shown in radiological convention for MNI slice coordinates from Z = -72 mm to Z = 84 mm.

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

Fig. 4. Group level activations, i.e. face matching > shape matching contrast (A) and deactivations, i.e. shape matching > face matching contrast (B) during the
facial emotion recognition task in MDD + CM patients. Images were thresholded using clusters determined by Z > 2.3 and an FWE corrected cluster significance
threshold of p = 0.05. Axial slices are shown in radiological convention for MNI slice coordinates from Z = -72 mm to Z = 84 mm.

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

Table 6
BOLD responses during the facial emotion matching task in the MDD + CM group.
Cluster No. of voxels Areas Z-score x y z

Activation pattern (face matching > shape matching contrast)

1 25586 left occipital face area 6.47 − 42 − 82 − 12
right occipital face area 5.93 40 − 86 − 6
2 14515 left amygdala 5.03 − 26 − 4 − 18
right amygdala 4.27 20 − 4 − 16
left middle frontal gyrus 3.87 − 48 28 26
right middle frontal gyrus 4.07 48 30 24
left inferior frontal gyrus 4.23 − 50 16 26
right inferior frontal gyrus 4.96 48 16 24
left hippocampus 3.39 − 26 − 30 − 8
right hippocampus 3.33 24 − 32 − 6
Deactivation pattern (shape matching > face matchin contrastg)
1 3212 right precentral gyrus 3.20 60 2 30
right postcentral gyrus 3.43 54 − 12 44
2 1790 left precentral gyrus 3.15 − 58 − 2 30
left postcentral gyrus 2.98 − 60 − 18 40
3 1043 posterior cingulate gyrus 5.14 6 − 32 44
4 500 anterior cingulate gyrus 3.20 0 36 − 4

Statistical maps were considered to be significant at Z > 2.3 and an FWE corrected cluster significance threshold of p = 0.05.
Z-score: Z-scores of local maxima; x-, y- and z-values correspond to the MNI coordinates of local maxima in mm; several local maxima are reported if the cluster
encompasses more than one anatomical location. BOLD: blood-oxygen-level-dependent; MDD + CM: major depressive disorder with childhood maltreatment.

demonstrated that childhood adversity can result in impairment of facial To our best of knowledge, there are hardly any studies which
emotion recognition. For example, a study that examined young street investigated the influence of childhood maltreatment on emotional
children in a forced-choice facial expressions recognition task reported recognition in depressed patients. A recent study which examined the
that the maltreated children had impaired recognition accuracy for fear effect of early life adversity in a heterogeneous (trans-diagnostic) group
and sad faces and increased accuracy for angry faces (Ardizzi et al., of patients with internalizing psychopathology included some patients
2015). Another study that investigated abused and non-abused children with MDD as well. They found that participants with a combined history
using the children’s version of the Reading the Mind in the Eyes Test of maltreatment and internalizing psychopathology had increased cor­
found that abused children were significantly impaired in emotion ticolimbic reactivity to fearful facial expressions and greater activation
recognition and that their recognition accuracy rates for positive of somatosensory areas during fear and anger processing (Peters et al.,
emotion stimuli were significantly lower, but not for negative emotion 2019). They stated that childhood adversity among patients with
stimuli (Koizumi and Takagishi, 2014). Using the Reading the Mind in internalizing psychopathology “augments the engagement of brain re­
the Eyes Test in adults, we also found that the experience of childhood gions involved in emotion processing, above and beyond what is
adversity was associated with an impaired response accuracy in accounted for by current symptoms” (Peters et al., 2019). Another study
depressed patients and that the number of childhood adversities was a investigated the influence of childhood maltreatment on attentional
significant predictor of the total Reading the Mind in the Eyes Test scores biases to sad and happy facial expressions in depressed individuals and
in MDD (Simon et al., 2019). Furthermore, the impaired recognition reported a positive association between childhood trauma and atten­
accuracy of anger was reported in patients with bipolar disorder who tional bias to sad faces (Günther et al., 2015). While more recently,
experienced childhood trauma (Russo et al., 2015). Altogether, accu­ another study examining attentional bias using an eye-tracking method
mulating evidence suggests that childhood adversity may result in a reported that depressed patients showed shorter gaze durations for
lasting deficit in facial emotion recognition. happy faces, and that childhood maltreatment was associated with

Fig. 5. The significant results of pairwise between-group comparisons of BOLD responses during the facial emotion matching task among the three groups, i.e.
Control versus MDD, Control versus MDD + CM and MDD versus MDD + CM. To account for the post-hoc character of these between-group statistical tests and to
reduce the chance of false-positive findings, only those voxels are shown as significant, where the omnibus F-test also revealed a significant group effect. Significant
differences were found in the negative BOLD response during the facial emotion matching task, i.e. Control > MDD + CM, MDD > MDD + CM and MDD + CM >
Control, where “>” means increased negative BOLD signal. Since there were only a few differences, these are presented here in a single figure. More details about
these group-differences are presented in Table 7. The images were thresholded using clusters determined by Z > 2.3 and an FWE corrected cluster significance
threshold of p = 0.05. The presented results are controlled for age and sex and masked with significant F-test results (Z > 2.3, cluster-wise p < 0.05) to avoid false-
positive findings. Axial slices are shown in radiological convention for MNI slice coordinates from Z = -20 to 40 mm.

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S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

Table 7
Between-group differences in negative BOLD response during the facial emotion matching task.
Contrast Cluster No. of voxels Areas Z-score x y z

HC > MDD + CM 1 636 right accumbens 3.74 10 18 − 6

subcallosal cortex 3.17 − 4 22 − 16
anterior paracingulate gyrus 3.92 − 10 50 0
MDD > MDD + CM 1 119 anterior paracingulate gyrus 3.50 − 10 52 6
MDD + CM > HC 1 148 right precentral gyrus 3.38 60 2 28
right postcentral gyrus 4.65 56 − 6 36

Statistical maps were considered to be significant at Z > 2.3 and an FWE corrected cluster significance threshold of p = 0.05 Between-group differences were controlled
for age and gender.
Z-score: Z-scores of local maxima; x-, y- and z-values correspond to the MNI coordinates of local maxima in mm; several local maxima are reported if the cluster
encompasses more than one anatomical location. BOLD = blood-oxygen-level-dependent; HC = healthy control; MDD: major depressive disorder; MDD + CM: major
depressive disorder with childhood maltreatment.

Table 8
Correlation of clinical data with BOLD response in the MDD + CM and the MDD groups.
Clinical parameter Group Cluster No. of voxels Areas Z-score x y z

Number of episodes MDD + CM 1 220 anterior cingulate gyrus 4.57 6 14 38

posterior paracingulate gyrus 3.98 6 18 44
Age of illness onset MDD 1 185 left superior temporal gyrus, posterior division 3.69 − 58 − 26 − 2
left middle temporal gyrus, posterior division 4.32 − 58 − 32 − 8

Statistical maps were considered to be significant at Z > 2.3 and an FWE corrected cluster significance threshold of p = 0.05.
Z-score: Z-scores of local maxima; x-, y- and z-values correspond to the MNI coordinates of local maxima in mm; several local maxima are reported if the cluster
encompasses more than one anatomical location. BOLD: blood-oxygen-level-dependent; MDD + CM: major depressive disorder with childhood maltreatment; MDD:
major depressive disorder.

Fig. 6. Group level positive associations between BOLD response and number of depressive episodes in the MDD + CM group (A) and between BOLD response and
age at illness onset in MDD subjects (B) during the facial emotion matching task. Images were thresholded using clusters determined by Z > 2.3 and an FWE corrected
cluster significance threshold of p = 0.05. Axial slices are shown in radiological convention for MNI slice coordinates from Z = 32–44 mm (A) and Z = -8 to 4 mm (B).
Significant interaction effects were masked with the results of the F-test to avoid false-positive results.

reduced attention for angry and sad facial expressions, suggesting that 4.2. Between-group differences in negative BOLD response
maltreated individuals avoid threatening or burdensome stimuli (Bod­
enschatz et al., 2019). In the present study, we found between-group differences only in the
negative BOLD response. MDD patients with childhood maltreatment
had significantly reduced negative BOLD responses in their right
accumbens, subcallosal cortex and anterior paracingulate gyrus and

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increased negative BOLD responses in their right precentral and post­ (Northoff et al., 2007). To our best of knowledge GABAergic neuro­
central gyri compared to controls. The nucleus accumbens and the transmission has not been investigated specifically in depressed patients
subcallosal cortex are subareas of the reward system (Breiter et al., with childhood maltreatment, but there are numerous reports for
1997; Breiter and Rosen, 1999). As a part of the mood regulation GABAergic disturbances in depressed patients (Luscher et al., 2011;
network, the subcallosal gyrus (BA 25/32) is of key importance in MDD Duman et al., 2019). Furthermore, animal experiments demonstrate
and has been a target for deep brain stimulation in treatment-resistant lasting alterations of GABAergic signaling in response to early life stress
depression (Hamani et al., 2011). It is well documented, that the (Martisova et al., 2012; Albrecht et al., 2017).
ventromedial medial prefrontal cortex plays a vital role in emotion Contrary to some previous research findings, we did not find a sig­
recognition and emotion experience (Heberlein et al., 2008). Moreover, nificant between-group difference in the BOLD response of the amygdala
the medial PFC is involved in mentalizing (or theory of mind) and other to negative facial emotions. However, amygdala hyperactivation has
higher-order social cognitive functions that require inferring other been found to be one of the core features of the pathophysiology of MDD
people’s minds (Walter et al., 2004; Gallagher et al., 2000; Amodio and (Price and Drevets, 2010) and the normalized amygdala has been
Frith, 2006). The ventral-rostral part of the medial PFC has also been considered as a key component of symptom remission (Sheline et al.,
implicated to have a regulatory function on limbic regions involved in 2001; Fu et al., 2004). Moreover, increased amygdala reactivity to sad
producing emotional responses and dampening fear responses (Etkin face stimuli has been documented repeatedly both in depressed patients
et al., 2011). Also, as part of the default mode network, cortical midline (Dannlowski et al., 2007; Peluso et al., 2009; Victor et al., 2010) and in
structures, such as the anterior region of the medial PFC are involved in individuals who experienced childhood adversity (Dannlowski et al.,
self-referential thinking (Buckner et al., 2008). Self-focus and 2012, 2013; Hein and Monk, 2017; Heany et al., 2018; Kraaijenvanger
self-ruminative patterns of thoughts are key issues in MDD, and func­ et al., 2020). Notably, negative findings also exist in the literature (e.g.
tional brain imaging studies have typically found abnormal activation Peters et al., 2019). A plausible explanation for our negative finding is
patterns in the ventromedial PFC (Hamani et al., 2011). Similarly, that all patients, except one, in this study were treated with antide­
significantly lower deactivation of the ventromedial PFC occurred in pressant drugs and antidepressant medication is known to dampen the
MDD + CM patients when they were compared with the MDD group, activity of the amygdala in response to socio-affective stimuli (Sheline
while there was no difference between the control and MDD groups. et al., 2001; Fu et al., 2004). Moreover, in our study, noises that can
Thus, depressed patients’ diminished neural response in regions cause false activations in the amygdala region were rigorously filtered
involved in reward processing, mood regulation, mentalizing, and con­ out, and F-test was applied when comparing study groups.
trolling self-referential thinking during the confrontation with faces
expressing negative emotions seems to be specific to depressed patients 4.3. Correlation of clinical data with the BOLD response
with a history of childhood maltreatment, but not to MDD without
maltreatment when compared with healthy controls. In MDD + CM patients, a higher number of episodes was associated
Patients with MDD + CM had significantly higher negative BOLD with increased BOLD response in the dorsal medial PFC (dorsal ACC and
signals in their right precentral and postcentral gyri. The precentral posterior paracingulate gyrus) that is involved in evaluative mecha­
gyrus is the site of the primary motor cortex which controls voluntary nisms and reappraisal of emotional stimuli (Etkin et al., 2011). Thus,
movements, whereas, the postcentral gyrus is the location of the primary MDD patients with childhood maltreatment presented a greater activa­
somatosensory cortex. The increased negative BOLD signal in the right tion in this brain region parallel with the increasing number of episodes,
primary motor and somatosensory cortices of the MDD + CM patients which can be interpreted as a reaction to the illness progression in the
might have also contributed to their impaired performance in the facial maltreated group, where significant dysfunctions in regions of reward
emotion recognition task, since they had to respond to the face stimuli system, mood regulatory, and mentalizing networks were found in our
with a voluntary finger movement, i.e. pressing with their left (or right) sample.
thumb fingers depending on the choice. Furthermore, it has been shown On the other hand, in the MDD (without maltreatment) group, later
that the right somatosensory cortex is required for the recognition of onset of the illness was associated with a higher positive BOLD response
facial emotion expressions, and damage to this brain area results in in posterior temporal areas: posterior part of the medial and superior
emotion recognition deficits (Adolphs et al., 2000). The theory temporal gyri (BA21/22) involving the posterior sulcus temporalis su­
explaining this mechanism is that we recognize another individual’s perior which plays a central role in the integration of the face network
emotional state by using our internal representation of a facial expres­ (Wang et al., 2016). Hence, later onset of the illness implicates a better
sion maintained in our somatosensory cortex. integration of the face network only in MDD patients without trauma.
In our study, we found between-group differences only in the nega­
tive BOLD responses during the facial emotion matching task. Most fMRI 4.4. Limitations
studies focus an rely on positive BOLD responses, but negative BOLD
responses have also been reported in emotion processing fMRI tasks. Our results should be interpreted in the context of limitations. This
Altered negative BOLD responses in the default-mode network have was a cross-sectional study with a relatively low number of subjects. The
been documented in depressed patients and this decreased negative main reason for that was that we aimed to create rather homogenous
BOLD response correlated with depression severity and feelings of and matched clinical groups. Since psychiatric comorbidities are higher
hopelessness (Grimm et al., 2009). Reduced deactivation in reward in depressed patients with childhood maltreatment, it was not possible
circuitry and midline structures have been reported in borderline per­ to exclude all MDD + CM patients with comorbid disorders, but
sonality disorder (Enzi et al., 2013), and bipolar patients respond with comorbidities with relevant brain functional changes in regions
decreased activation in their frontal cortex and left posterior cortical involving emotional regulation were consistently excluded. Moreover,
midline structures (Marchand et al., 2011). The exact cellular mecha­ there was no study group with healthy controls with moderate or severe
nisms underlying the negative BOLD responses are not yet clear. The childhood maltreatment. Control subjects were also meticulously
most likely explanation is neural inhibition (Sten et al., 2017), but screened for any clinical symptoms. During recruitment, we identified
increased neuronal activity has also been implicated in the generation of only 4 individuals with no psychopathology and having been exposed to
negative BOLD signals (Schridde et al., 2008). Notably, an fMRI study at least moderate level of the childhood maltreatment. As we could not
using an emotional processing paradigm and resting-state magnetic extend this group, these four individuals were not enrolled in the study.
resonance spectroscopy measurements reported that the negative BOLD We assessed childhood maltreatment retrospectively and it has been
responses in the anterior cingulate cortex correlated with shown that the congruence between retrospective and prospective
gamma-aminobutyric acid (GABA) concentration in the same region measures can be poor or modest (Reuben et al., 2016; Baldwin et al.,

14
S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

2019). Prospective, long-term studies, involving a larger number of in­ framework of the 5. thematic program of the Pécs University. SAN was
dividuals may yield different results. Furthermore, we did not assess the supported by the János Bolyai Research Scholarship of the Hungarian
timing of adversity whereas, most likely the age at the time of abuse has Academy of Sciences, ÚNKP-20-5-PTE-715 New National Excellence
significant importance. Program of the Ministry for Innovation and Technology and PTE ÁOK-
Our main findings were the significant differences in negative BOLD KA-2020-08. MS was supported by the ÁOK-KA Szolcsányi János
responses, but the exact neurobiological mechanisms underlying nega­ research fund.
tive BOLD responses are still uncertain. While earlier studies suggested
that negative BOLD responses carry limited stimulus-specific informa­ CRediT authorship contribution statement
tion, a more recent study demonstrated that visual stimulation can
evoke meaningful, stimulus-specific negative BOLD responses (Bressler Szilvia Anett Nagy: Conceptualization, Methodology, Investigation,
et al., 2007). Formal analysis, Visualization, Writing – original draft. Zsófia Kürtös:
Finally, the emotional face processing fMRI paradigms have been Methodology, Investigation, Formal analysis, Visualization. Nándor
criticized for being unreliable as putative fMRI biomarkers (Nord et al., Németh: Conceptualization, Methodology, Investigation, Formal anal­
2017). Patients with MDD were medicated with the most varied classes ysis. Gábor Perlaki: Methodology, Writing – review & editing. Eszter
of antidepressants, sometimes combined with mood-stabilizing medi­ Csernela: Investigation, Formal analysis. Flóra Elza Lakner: Investi­
cations or augmented with atypical antipsychotics. Therefore, it was not gation, Formal analysis. Tamás Dóczi: Supervision, Funding acquisi­
possible to create homogenously medicated groups to control the effect tion. Boldizsár Czéh: Conceptualization, Methodology, Resources,
of medication. Another problematic issue is whether one can unequiv­ Writing – original draft, Writing – review & editing, Project adminis­
ocally express his/her emotional state with facial movements, and how tration, Funding acquisition, Supervision. Maria Simon: Conceptuali­
easily another person recognizes that. zation, Methodology, Investigation, Formal analysis, Writing – original
draft, Writing – review & editing, Resources, Supervision.
4.5. Conclusions
Declaration of competing interest
MDD is a highly heterogeneous disorder and patients with a history
of childhood trauma may either form a distinct subgroup within the
The authors declare that the research was conducted in the absence
illness (Heim et al., 2008), or there might be a dose-response relation­
of any commercial or financial relationships that could be construed as a
ship between cumulative childhood maltreatment and illness severity
potential conflict of interest.
(Steine et al., 2017). In any case, the history of childhood maltreatment
has significant implications for the clinical presentation (earlier onset,
Acknowledgments
more severe MDD, more episodes, more suicidality, worse quality of life
and functionality, and more psychiatric comorbidities), as well as for the
We are grateful to the FACES Database (Max Planck Institute for
treatment response (Medeiros et al., 2020; Negele et al., 2015; Nemeroff
Human Development, Center for Lifespan Psychology, Berlin, Germany)
et al., 2003). Here, we found altered functioning of fronto-limbic reward
for providing us the images of the faces that were used in this study.
and mood regulatory systems, as well as altered responses of mentalizing
neural networks specifically in the MDD + CM subgroup. Our data
Appendix A. Supplementary data
support the concept that maladaptive processing of socio-emotional
information might represent a pathway by which childhood trauma
Supplementary data to this article can be found online at [Link]
initiates a risk for psychopathology.
org/10.1016/[Link].2021.100399.
CRediT authorship contribution statement
References
Szilvia Anett Nagy: Conceptualization, Methodology, Investigation,
Adolphs, R., Damasio, H., Tranel, D., Cooper, G., Damasio, A.R., 2000 Apr 1. A role for
Formal analysis, Visualization, Writing - Original Draft. Zsófia Kürtös: somatosensory cortices in the visual recognition of emotion as revealed by three-
Methodology, Investigation, Formal analysis, Visualization. Nándor dimensional lesion mapping. J. Neurosci. 20 (7), 2683–2690. [Link]
10.1523/JNEUROSCI.20-07-02683.2000.
Németh: Conceptualization, Methodology, Investigation, Formal anal­
Albrecht, A., Müller, I., Ardi, Z., Çalışkan, G., Gruber, D., Ivens, S., Segal, M., Behr, J.,
ysis. Gábor Perlaki: Methodology, Writing - Review & Editing. Eszter Heinemann, U., Stork, O., Richter-Levin, G., 2017 Mar. Neurobiological
Csernela: Investigation, Formal analysis. Flóra Elza Lakner: Investiga­ consequences of juvenile stress: a GABAergic perspective on risk and resilience.
tion, Formal analysis. Tamás Dóczi: Supervision, Funding acquisition. Neurosci. Biobehav. Rev. 74 (Pt A), 21–43. [Link]
neubiorev.2017.01.005.
Boldizsár Czéh: Conceptualization, Methodology, Resources, Writing - Allen, L., Dwivedi, Y., 2020 Feb. MicroRNA mediators of early life stress vulnerability to
Original Draft, Writing - Review & Editing, Project administration, depression and suicidal behavior. Mol. Psychiatr. 25 (2), 308–320. [Link]
Funding acquisition, Supervision. Maria Simon: Conceptualization, 10.1038/s41380-019-0597-8.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental
Methodology, Investigation, Formal analysis, Writing - Original Draft, Disorders, fifth ed. [Link]
Writing - Review & Editing, Resources, Supervision. Amodio, D.M., Frith, C.D., 2006 Apr. Meeting of minds: the medial frontal cortex and
social cognition. Nat. Rev. Neurosci. 7 (4), 268–277. [Link]
nrn1884.
Funding Anda, R.F., Felitti, V.J., Bremner, J.D., Walker, J.D., Whitfield, C., Perry, B.D., Dube, S.
R., Giles, W.H., 2006 Apr. The enduring effects of abuse and related adverse
This work was financially supported by the following grant agencies: experiences in childhood. A convergence of evidence from neurobiology and
epidemiology. Eur. Arch. Psychiatr. Clin. Neurosci. 256 (3), 174–186. [Link]
Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002) and org/10.1007/s00406-005-0624-4.
by the European Union, co-financed by the European Social Funds Anderson, K.M., Collins, M.A., Kong, R., Fang, K., Li, J., He, T., Chekroud, A.M., Yeo, B.T.
(EFOP-3.6.2-16-2017-00008, „The role of neuroinflammation in neu­ T., Holmes, A.J., 2020 Oct 6. Convergent molecular, cellular, and cortical
neuroimaging signatures of major depressive disorder. Proc. Natl. Acad. Sci. U. S. A.
rodegeneration: from molecules to clinics” and EFOP-3.6.1.-16-2016-
117 (40), 25138–25149. [Link]
00004, “Comprehensive Development for Implementing Smart Ardizzi, M., Martini, F., Umiltà, M.A., Evangelista, V., Ravera, R., Gallese, V., 2015 Oct
Specialization Strategies at the University of Pécs”). Further support was 28. Impact of childhood maltreatment on the recognition of facial expressions of
received from the Thematic Excellence Program 2020 - Institutional emotions. PloS One 10 (10), e0141732. [Link]
pone.0141732.
Excellence Sub-programme/National Excellence Sub-program of the Assed, M.M., Khafif, T.C., Belizario, G.O., Fatorelli, R., Rocca, CC. dA., de Pádua
Ministry for Innovation and Technology in Hungary, within the Serafim, A., 2020. Facial emotion recognition in maltreated children: a systematic

15
S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

review. J. Child Fam. Stud. 29 (5), 1493–1509. [Link] Ebner, N.C., Riediger, M., Lindenberger, U., 2010 Feb. FACES–a database of facial
019-01636-w. expressions in young, middle-aged, and older women and men: development and
Baldwin, J.R., Reuben, A., Newbury, J.B., Danese, A., 2019 Jun 1. Agreement between validation. Behav. Res. Methods 42 (1), 351–362. [Link]
prospective and retrospective measures of childhood maltreatment: a systematic BRM.42.1.351.
review and meta-analysis. JAMA Psychiatr. 76 (6), 584–593. [Link] Enzi, B., Doering, S., Faber, C., Hinrichs, J., Bahmer, J., Northoff, G., 2013 Feb. Reduced
10.1001/jamapsychiatry.2019.0097. deactivation in reward circuitry and midline structures during emotion processing in
Bellis, M.A., Hughes, K., Leckenby, N., Jones, L., Baban, A., Kachaeva, M., Povilaitis, R., borderline personality disorder. World J. Biol. Psychiatr. 14 (1), 45–56. [Link]
Pudule, I., Qirjako, G., Ulukol, B., Raleva, M., Terzic, N., 2014 Sep 1. Adverse org/10.3109/15622975.2011.579162.
childhood experiences and associations with health-harming behaviours in young Etkin, A., Egner, T., Kalisch, R., 2011 Feb. Emotional processing in anterior cingulate and
adults: surveys in eight eastern European countries. Bull. World Health Organ. 92 medial prefrontal cortex. Trends Cognit. Sci. 15 (2), 85–93. [Link]
(9), 641–655. [Link] 10.1016/[Link].2010.11.004.
Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbaugh, J., 1961. An inventory for Felitti, V.J., Anda, R.F., Nordenberg, D., Williamson, D.F., Spitz, A.M., Edwards, V.,
measuring depression. Arch. Gen. Psychiatr. 4, 53–63. [Link] Koss, M.P., Marks, J.S., 1998 May. Relationship of childhood abuse and household
archpsyc.1961.01710120031004. dysfunction to many of the leading causes of death in adults. The Adverse Childhood
Beck, A.T., Epstein, N., Brown, G., Steer, R.A., 1988. An inventory for measuring clinical Experiences (ACE) Study. Am. J. Prev. Med. 14 (4), 245–258. [Link]
anxiety: psychometric properties. J. Consult. Clin. Psychol. 56, 893–897 [Link]/ 10.1016/s0749-3797(98)00017-8.
10.1037/0022-006X.56.6.893. Filkowski, M.M., Haas, B.W., 2017 May. Rethinking the use of neutral faces as a baseline
Bernstein, D.P., Stein, J.A., Newcomb, M.D., Walker, E., Pogge, D., Ahluvalia, T., in fMRI neuroimaging studies of axis-I psychiatric disorders. J. Neuroimaging 27 (3),
Stokes, J., Handelsman, L., Medrano, M., Desmond, D., Zule, W., 2003. Development 281–291. [Link]
and validation of a brief screening version of the Childhood Trauma Questionnaire. First, M.B., Williams, J.B.W., Karg, R.S., Spitzer, R.L., 2015. Structured Clinical Interview
Child Abuse Negl. 27 (2), 169–190. [Link] for DSM-5 Disorders - Clinician Version. American Psychiatric Association
0. Publishing, Arlington, USA [In Hungarian: First MB, Williams JBW, Karg RS, Spitzer
Bérubé, A., Turgeon, J., Blais, C., Fiset, D., 2021 Jul 9. Emotion recognition in adults RL. Strukturált klinikai interjú a DSM-5® zavarok felmérésére. Oriold és Társai,
with a history of childhood maltreatment: a systematic review, Budapest (2016)].
15248380211029403 Trauma Violence Abuse. [Link] First MB, M.D., Williams JBW, PhD., Smith Benjamin, L., Spitzer, R.L., 2016. In:
15248380211029403 (Epub ahead of print). Structured Clinical Interview for DSM-5® Personality Disorders, first ed. American
Bodenschatz, C.M., Skopinceva, M., Ruß, T., Suslow, T., 2019 May. Attentional bias and Psychiatric Association Publishing, Arlington, VA [In Hungarian: First MB, M.D.,
childhood maltreatment in clinical depression - an eye-tracking study. J. Psychiatr. Williams JBW, Ph.D., Smith Benjamin L, Spitzer RL. Strukturált Klinikai Interjú a
Res. 112, 83–88. [Link] DSM-5® Személyiségzavarok Vizsgálatára. Oriold és Társai, Budapest, (2018)].
Breiter, H.C., Rosen, B.R., 1999 Jun 29. Functional magnetic resonance imaging of brain Fu, C.H., Williams, S.C., Cleare, A.J., Brammer, M.J., Walsh, N.D., Kim, J., Andrew, C.M.,
reward circuitry in the human. Ann. N. Y. Acad. Sci. 877, 523–547. [Link] Pich, E.M., Williams, P.M., Reed, L.J., Mitterschiffthaler, M.T., Suckling, J.,
10.1111/j.1749-6632.1999.tb09287.x. Bullmore, E.T., 2004 Sep. Attenuation of the neural response to sad faces in major
Breiter, H.C., Gollub, R.L., Weisskoff, R.M., Kennedy, D.N., Makris, N., Berke, J.D., depression by antidepressant treatment: a prospective, event-related functional
Goodman, J.M., Kantor, H.L., Gastfriend, D.R., Riorden, J.P., Mathew, R.T., magnetic resonance imaging study. Arch. Gen. Psychiatr. 61 (9), 877–889. https://
Rosen, B.R., Hyman, S.E., 1997 Sep. Acute effects of cocaine on human brain activity [Link]/10.1001/archpsyc.61.9.877.
and emotion. Neuron 19 (3), 591–611. [Link] Gallagher, H.L., Happé, F., Brunswick, N., Fletcher, P.C., Frith, U., Frith, C.D., 2000.
80374-8. Reading the mind in cartoons and stories: an fMRI study of ’theory of mind’ in verbal
Bressler, D., Spotswood, N., Whitney, D., 2007 May 2. Negative BOLD fMRI response in and nonverbal tasks. Neuropsychologia 38 (1), 11–21. [Link]
the visual cortex carries precise stimulus-specific information. PloS One 2 (5), e410. s0028-3932(99)00053-6.
[Link] Gilbert, R., Widom, C.S., Browne, K., Fergusson, D., Webb, E., Janson, S., 2009 Jan 3.
Brown, D.W., Anda, R.F., Tiemeier, H., Felitti, V.J., Edwards, V.J., Croft, J.B., Giles, W. Burden and consequences of child maltreatment in high-income countries. Lancet
H., 2009 Nov. Adverse childhood experiences and the risk of premature mortality. 373 (9657), 68–81. [Link]
Am. J. Prev. Med. 37 (5), 389–396. Grant, M.M., Cannistraci, C., Hollon, S.D., Gore, J., Shelton, R., 2011 Jul. Childhood
Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., 2008 Mar. The brain’s default trauma history differentiates amygdala response to sad faces within MDD.
network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, J. Psychiatr. Res. 45 (7), 886–895. [Link]
1–38. [Link] jpsychires.2010.12.004.
Carr, C.P., Martins, C.M., Stingel, A.M., Lemgruber, V.B., Juruena, M.F., 2013 Dec. The Grimm, S., Boesiger, P., Beck, J., Schuepbach, D., Bermpohl, F., Walter, M., Ernst, J.,
role of early life stress in adult psychiatric disorders: a systematic review according Hell, D., Boeker, H., Northoff, G., 2009 Mar. Altered negative BOLD responses in the
to childhood trauma subtypes. J. Nerv. Ment. Dis. 201 (12), 1007–1020. [Link] default-mode network during emotion processing in depressed subjects.
org/10.1097/NMD.0000000000000049. Neuropsychopharmacology 34 (4), 932–943. [Link]
Costafreda, S.G., Brammer, M.J., David, A.S., Fu, C.H., 2008 Jun. Predictors of amygdala Günther, V., Dannlowski, U., Kersting, A., Suslow, T., 2015 Jun 6. Associations between
activation during the processing of emotional stimuli: a meta-analysis of 385 PET childhood maltreatment and emotion processing biases in major depression: results
and fMRI studies. Brain Res. Rev. 58 (1), 57–70. [Link] from a dot-probe task. BMC Psychiatr. 15, 123. [Link]
brainresrev.2007.10.012. 015-0501-2.
Csernela, E., Németh, N., Csuta, C., Lakner, F.E., Tényi, T., Czéh, B., Simon, M., 2021. Hamani, C., Mayberg, H., Stone, S., Laxton, A., Haber, S., Lozano, A.M., 2011 Feb 15. The
[An evaluation of a Hungarian questionnaire to assess childhood adversities: a pilot subcallosal cingulate gyrus in the context of major depression. Biol. Psychiatr. 69
study]. Psychiatr. Hung. 36 (1), 26–39. (4), 301–308. [Link]
Danese, A., Lewis, J., S, 2017 Jan. Psychoneuroimmunology of early-life stress: the Hamilton, M., 1967. Development of a rating scale for primary depressive illness. Br. J.
hidden Wounds of childhood trauma? Neuropsychopharmacology 42 (1), 99–114. Clin. Psychol. 6, 278–296. [Link]
[Link] Hamilton, J.P., Etkin, A., Furman, D.J., Lemus, M.G., Johnson, R.F., Gotlib, I.H., 2012
Dannlowski, U., Ohrmann, P., Bauer, J., Kugel, H., Arolt, V., Heindel, W., Kersting, A., Jul. Functional neuroimaging of major depressive disorder: a meta-analysis and new
Baune, B.T., Suslow, T., 2007 Nov. Amygdala reactivity to masked negative faces is integration of base line activation and neural response data. Am. J. Psychiatr. 169
associated with automatic judgmental bias in major depression: a 3 T fMRI study. (7), 693–703. [Link]
J. Psychiatry Neurosci. 32 (6), 423–429. Hariri, A.R., Mattay, V.S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., Egan, M.F.,
Dannlowski, U., Stuhrmann, A., Beutelmann, V., Zwanzger, P., Lenzen, T., Grotegerd, D., Weinberger, D.R., 2002 Jul 19. Serotonin transporter genetic variation and the
Domschke, K., Hohoff, C., Ohrmann, P., Bauer, J., Lindner, C., Postert, C., response of the human amygdala. Science 297 (5580), 400–403. [Link]
Konrad, C., Arolt, V., Heindel, W., Suslow, T., Kugel, H., 2012 Feb 15. Limbic scars: 10.1126/science.1071829.
long-term consequences of childhood maltreatment revealed by functional and Hart, H., Rubia, K., 2012 Mar 19. Neuroimaging of child abuse: a critical review. Front.
structural magnetic resonance imaging. Biol. Psychiatr. 71 (4), 286–293. [Link] Hum. Neurosci. 6, 52. [Link]
org/10.1016/[Link].2011.10.021. Heany, S.J., Groenewold, N.A., Uhlmann, A., Dalvie, S., Stein, D.J., Brooks, S.J., 2018
Dannlowski, U., Kugel, H., Huber, F., Stuhrmann, A., Redlich, R., Grotegerd, D., Oct. The neural correlates of Childhood Trauma Questionnaire scores in adults: a
Dohm, K., Sehlmeyer, C., Konrad, C., Baune, B.T., Arolt, V., Heindel, W., meta-analysis and review of functional magnetic resonance imaging studies. Dev.
Zwitserlood, P., Suslow, T., 2013 Nov. Childhood maltreatment is associated with an Psychopathol. 30 (4), 1475–1485. [Link]
automatic negative emotion processing bias in the amygdala. Hum. Brain Mapp. 34 Heberlein, A.S., Padon, A.A., Gillihan, S.J., Farah, M.J., Fellows, L.K., 2008 Apr.
(11), 2899–2909. [Link] Ventromedial frontal lobe plays a critical role in facial emotion recognition.
Demers, L.A., McKenzie, K.J., Hunt, R.H., Cicchetti, D., Cowell, R.A., Rogosch, F.A., J. Cognit. Neurosci. 20 (4), 721–733. [Link]
Toth, S.L., Thomas, K.M., 2018 Feb. Separable effects of childhood maltreatment and Heim, C., Binder, E.B., 2012 Jan. Current research trends in early life stress and
adult adaptive functioning on amygdala connectivity during emotion processing. depression: review of human studies on sensitive periods, gene-environment
Biol. Psychiatr. Cogn. Neurosci. Neuroimag. 3 (2), 116–124. [Link] interactions, and epigenetics. Exp. Neurol. 233 (1), 102–111. [Link]
10.1016/[Link].2017.08.010. 10.1016/[Link].2011.10.032.
Derogatis, L., 1994. Symptom Checklist-90-R (SCL-90-R): Administration, Scoring, and Heim, C., Newport, D.J., Mletzko, T., Miller, A.H., Nemeroff, C.B., 2008 Jul. The link
Procedures Manual, third ed. MN NCS Pearson, Minneapolis. between childhood trauma and depression: insights from HPA axis studies in
Duman, R.S., Sanacora, G., Krystal, J.H., 2019 Apr 3. Altered connectivity in depression: humans. Psychoneuroendocrinology 33 (6), 693–710. [Link]
GABA and Glutamate neurotransmitter deficits and reversal by novel treatments. psyneuen.2008.03.008.
Neuron 102 (1), 75–90. [Link] Hein, T.C., Monk, C.S., 2017 Mar. Research Review: neural response to threat in children,
adolescents, and adults after child maltreatment - a quantitative meta-analysis. JCPP

16
S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

(J. Child Psychol. Psychiatry) 58 (3), 222–230. [Link] Nanni, V., Uher, R., Danese, A., 2012 Feb. Childhood maltreatment predicts unfavorable
jcpp.12651. course of illness and treatment outcome in depression: a meta-analysis. Am. J.
Helm, K., Viol, K., Weiger, T.M., Tass, P.A., Grefkes, C., Del Monte, D., Schiepek, G., 2018 Psychiatr. 169 (2), 141–151. [Link]
Oct 17. Neuronal connectivity in major depressive disorder: a systematic review. Erratum in: Am J Psychiatry. 2012 Apr;169(4):439.
Neuropsychiatric Dis. Treat. 14, 2715–2737. [Link] Negele, A., Kaufhold, J., Kallenbach, L., Leuzinger-Bohleber, M., 2015. Childhood
S170989. trauma and its relation to chronic depression in adulthood. Depress Res. Treat. 2015,
Hughes, K., Bellis, M.A., Hardcastle, K.A., Sethi, D., Butchart, A., Mikton, C., Jones, L., 650804. [Link]
Dunne, M.P., 2017 Aug. The effect of multiple adverse childhood experiences on Nemeroff, C.B., Heim, C.M., Thase, M.E., Klein, D.N., Rush, A.J., Schatzberg, A.F.,
health: a systematic review and meta-analysis. Lancet Publ. Health 2 (8), e356–e366. Ninan, P.T., McCullough Jr., J.P., Weiss, P.M., Dunner, D.L., Rothbaum, B.O.,
[Link] Kornstein, S., Keitner, G., Keller, M.B., 2003 Nov 25. Differential responses to
Humphreys, K.L., LeMoult, J., Wear, J.G., Piersiak, H.A., Lee, A., Gotlib, I.H., 2020 Apr. psychotherapy versus pharmacotherapy in patients with chronic forms of major
Child maltreatment and depression: a meta-analysis of studies using the Childhood depression and childhood trauma. Proc. Natl. Acad. Sci. U.S.A. 100 (24),
Trauma Questionnaire. Child Abuse Negl. 102, 104361. [Link] 14293–14296. [Link]
chiabu.2020.104361. New, A.S., Hazlett, E.A., Buchsbaum, M.S., Goodman, M., Mitelman, S.A., Newmark, R.,
Jedd, K., Hunt, R.H., Cicchetti, D., Hunt, E., Cowell, R.A., Rogosch, F.A., Toth, S.L., Trisdorfer, R., Haznedar, M.M., Koenigsberg, H.W., Flory, J., Siever, L.J., 2007 Jul.
Thomas, K.M., 2015 Nov. Long-term consequences of childhood maltreatment: Amygdala-prefrontal disconnection in borderline personality disorder.
altered amygdala functional connectivity. Dev. Psychopathol. 27 (4 Pt 2), Neuropsychopharmacology 32 (7), 1629–1640. [Link]
1577–1589. [Link] npp.1301283.
Kaufman, A.S., Ishikuma, T., Kaufman-Packer, J.L., 1991. Amazingly short forms of the Ng, T.H., Alloy, L.B., Smith, D.V., 2019 Nov 11. Meta-analysis of reward processing in
WAIS-R. J. Psychoeduc. Assess. 9, 4–15. [Link] major depressive disorder reveals distinct abnormalities within the reward circuit.
073428299100900101. Transl. Psychiatry 9 (1), 293. [Link]
Kessler, R.C., McLaughlin, K.A., Green, J.G., Gruber, M.J., Sampson, N.A., Zaslavsky, A. Nord, C.L., Gray, A., Charpentier, C.J., Robinson, O.J., Roiser, J.P., 2017 Aug 1.
M., Aguilar-Gaxiola, S., Alhamzawi, A.O., Alonso, J., Angermeyer, M., Benjet, C., Unreliability of putative fMRI biomarkers during emotional face processing.
Bromet, E., Chatterji, S., de Girolamo, G., Demyttenaere, K., Fayyad, J., Florescu, S., Neuroimage 156, 119–127. [Link]
Gal, G., Gureje, O., Haro, J.M., Hu, C.Y., Karam, E.G., Kawakami, N., Lee, S., Northoff, G., Walter, M., Schulte, R.F., Beck, J., Dydak, U., Henning, A., Boeker, H.,
Lépine, J.P., Ormel, J., Posada-Villa, J., Sagar, R., Tsang, A., Ustün, T.B., Vassilev, S., Grimm, S., Boesiger, P., 2007 Dec. GABA concentrations in the human anterior
Viana, M.C., Williams, D.R., 2010 Nov. Childhood adversities and adult cingulate cortex predict negative BOLD responses in fMRI. Nat. Neurosci. 10 (12),
psychopathology in the WHO World mental health surveys. Br. J. Psychiatry 197 (5), 1515–1517. [Link]
378–385. [Link] Otte, C., Gold, S.M., Penninx, B.W., Pariante, C.M., Etkin, A., Fava, M., Mohr, D.C.,
Kessler, R., Schmitt, S., Sauder, T., Stein, F., Yüksel, D., Grotegerd, D., Dannlowski, U., Schatzberg, A.F., 2016 Sep 15. Major depressive disorder. Nat. Rev. Dis. Primers 2,
Hahn, T., Dempfle, A., Sommer, J., Steinsträter, O., Nenadic, I., Kircher, T., 16065. [Link]
Jansen, A., 2020 Jun 3. Long-term neuroanatomical consequences of childhood Palmer, S.M., Crewther, S.G., Carey, L.M., START Project Team, 2015 Jan 14. A meta-
maltreatment: reduced amygdala inhibition by medial prefrontal cortex. Front. Syst. analysis of changes in brain activity in clinical depression. Front. Hum. Neurosci. 8,
Neurosci. 14, 28. [Link] 1045. [Link]
Koizumi, M., Takagishi, H., 2014 Jan 20. The relationship between child maltreatment Pechtel, P., Pizzagalli, D.A., 2011 Mar. Effects of early life stress on cognitive and
and emotion recognition. PloS One 9 (1), e86093. [Link] affective function: an integrated review of human literature. Psychopharmacology
pone.0086093. (Berlin) 214 (1), 55–70. [Link]
Kraaijenvanger, E.J., Pollok, T.M., Monninger, M., Kaiser, A., Brandeis, D., Peluso, M.A., Glahn, D.C., Matsuo, K., Monkul, E.S., Najt, P., Zamarripa, F., Li, J.,
Banaschewski, T., Holz, N.E., 2020 Jun. Impact of early life adversities on human Lancaster, J.L., Fox, P.T., Gao, J.H., Soares, J.C., 2009 Aug 30. Amygdala
brain functioning: a coordinate-based meta-analysis. Neurosci. Biobehav. Rev. 113, hyperactivation in untreated depressed individuals. Psychiatr. Res. 173 (2),
62–76. [Link] 158–161. [Link]
Li, M., D’Arcy, C., Meng, X., 2016 Mar. Maltreatment in childhood substantially Peters, A.T., Burkhouse, K.L., Kinney, K.L., Phan, K.L., 2019 Oct. The roles of early-life
increases the risk of adult depression and anxiety in prospective cohort studies: adversity and rumination in neural response to emotional faces amongst anxious and
systematic review, meta-analysis, and proportional attributable fractions. Psychol. depressed adults. Psychol. Med. 49 (13), 2267–2278. [Link]
Med. 46 (4), 717–730. [Link] S0033291718003203.
Li, X., Wang, J., 2021 Apr. Abnormal neural activities in adults and youths with major Plichta, M.M., Schwarz, A.J., Grimm, O., Morgen, K., Mier, D., Haddad, L., Gerdes, A.B.,
depressive disorder during emotional processing: a meta-analysis. Brain Imag. Sauer, C., Tost, H., Esslinger, C., Colman, P., Wilson, F., Kirsch, P., Meyer-
Behav. 15 (2), 1134–1154. [Link] Lindenberg, A., 2012 Apr 15. Test-retest reliability of evoked BOLD signals from a
Lim, L., Radua, J., Rubia, K., 2014 Aug. Gray matter abnormalities in childhood cognitive-emotive fMRI test battery. Neuroimage 60 (3), 1746–1758. [Link]
maltreatment: a voxel-wise meta-analysis. Am. J. Psychiatr. 171 (8), 854–863. org/10.1016/[Link].2012.01.129.
[Link] Price, J.L., Drevets, W.C., 2010 Jan. Neurocircuitry of mood disorders.
Luscher, B., Shen, Q., Sahir, N., 2011 Apr. The GABAergic deficit hypothesis of major Neuropsychopharmacology 35 (1), 192–216. [Link]
depressive disorder. Mol. Psychiatr. 16 (4), 383–406. [Link] npp.2009.104.
mp.2010.120. Reuben, A., Moffitt, T.E., Caspi, A., Belsky, D.W., Harrington, H., Schroeder, F.,
Mandelli, L., Petrelli, C., Serretti, A., 2015 Sep. The role of specific early trauma in adult Hogan, S., Ramrakha, S., Poulton, R., Danese, A., 2016 Oct. Lest we forget:
depression: a meta-analysis of published literature. Childhood trauma and adult comparing retrospective and prospective assessments of adverse childhood
depression. Eur. Psychiatr. 30 (6), 665–680. [Link] experiences in the prediction of adult health. JCPP (J. Child Psychol. Psychiatry) 57
eurpsy.2015.04.007. (10), 1103–1112. [Link]
Martisova, E., Solas, M., Horrillo, I., Ortega, J.E., Meana, J.J., Tordera, R.M., Ramírez, M. Rokita, K.I., Dauvermann, M.R., Donohoe, G., 2018 Sep. Early life experiences and social
J., 2012 Apr. Long lasting effects of early-life stress on glutamatergic/GABAergic cognition in major psychiatric disorders: a systematic review. Eur. Psychiatr. 53,
circuitry in the rat hippocampus. Neuropharmacology 62 (5–6), 1944–1953. https:// 123–133. [Link]
[Link]/10.1016/[Link].2011.12.019. Russo, M., Mahon, K., Shanahan, M., Solon, C., Ramjas, E., Turpin, J., E Burdick, K., 2015
McCrory, E.J., Gerin, M.I., Viding, E., 2017 Apr. Annual Research Review: childhood Oct 30. The association between childhood trauma and facial emotion recognition in
maltreatment, latent vulnerability and the shift to preventative psychiatry - the adults with bipolar disorder. Psychiatr. Res. 229 (3), 771–776. [Link]
contribution of functional brain imaging. JCPP (J. Child Psychol. Psychiatry) 58 (4), 10.1016/[Link].2015.08.004.
338–357. [Link] Saarinen, A., Keltikangas-Järvinen, L., Jääskeläinen, E., Huhtaniska, S., Pudas, J., Tovar-
McDermott, T.J., Kirlic, N., Aupperle, R.L., 2018 May 7. Roadmap for optimizing the Perdomo, S., Penttilä, M., Miettunen, J., Lieslehto, J., 2021 Jul. Early adversity and
clinical utility of emotional stress paradigms in human neuroimaging research. emotion processing from faces: a meta-analysis on behavioral and
Neurobiol. Stress 8, 134–146. [Link] neurophysiological responses. Biol. Psychiatr. Cogn. Neurosci. Neuroimag. 6 (7),
McLaughlin, K.A., Green, J.G., Gruber, M.J., Sampson, N.A., Zaslavsky, A.M., Kessler, R. 692–705. [Link]
C., 2010 Feb. Childhood adversities and adult psychiatric disorders in the national Schridde, U., Khubchandani, M., Motelow, J.E., Sanganahalli, B.G., Hyder, F.,
comorbidity survey replication II: associations with persistence of DSM-IV disorders. Blumenfeld, H., 2008 Aug. Negative BOLD with large increases in neuronal activity.
Arch. Gen. Psychiatr. 67 (2), 124–132. [Link] Cerebr. Cortex 18 (8), 1814–1827. [Link]
archgenpsychiatry.2009.187. Sergerie, K., Chochol, C., Armony, J.L., 2008. The role of the amygdala in emotional
Marchand, W.R., Lee, J.N., Garn, C., Thatcher, J., Gale, P., Kreitschitz, S., Johnson, S., processing: a quantitative meta-analysis of functional neuroimaging studies.
Wood, N., 2011 Aug 15. Aberrant emotional processing in posterior cortical midline Neurosci. Biobehav. Rev. 32 (4), 811–830. [Link]
structures in bipolar II depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry neubiorev.2007.12.002.
35 (7), 1729–1737. [Link] Sheline, Y.I., Barch, D.M., Donnelly, J.M., Ollinger, J.M., Snyder, A.Z., Mintun, M.A.,
Medeiros, G.C., Prueitt, W.L., Minhajuddin, A., Patel, S.S., Czysz, A.H., Furman, J.L., 2001 Nov 1. Increased amygdala response to masked emotional faces in depressed
Mason, B.L., Rush, A.J., Jha, M.K., Trivedi, M.H., 2020 Nov. Childhood subjects resolves with antidepressant treatment: an fMRI study. Biol. Psychiatr. 50
maltreatment and impact on clinical features of major depression in adults. (9), 651–658. [Link]
Psychiatr. Res. 293, 113412. [Link] Shin, L.M., Wright, C.I., Cannistraro, P.A., Wedig, M.M., McMullin, K., Martis, B.,
Nagybányai Nagy, O., Rózsa, S., 2006. A mentális képességek tesztelése. In: Rózsa, S., Macklin, M.L., Lasko, N.B., Cavanagh, S.R., Krangel, T.S., Orr, S.P., Pitman, R.K.,
Nagybányai Nagy, O., Oláh, A. (Eds.), A Pszichológiai Mérés Alapjai. Elmélet, Whalen, P.J., Rauch, S.L., 2005 Mar. A functional magnetic resonance imaging study
Módszer És Gyakorlati Alkalmazás. Bölcsész Konzorcium, pp. 181–198. of amygdala and medial prefrontal cortex responses to overtly presented fearful faces

17
S.A. Nagy et al. Neurobiology of Stress 15 (2021) 100399

in posttraumatic stress disorder. Arch. Gen. Psychiatr. 62 (3), 273–281. [Link] Henauw, S., 2012 May. Prevalence of psychosomatic and emotional symptoms in
org/10.1001/archpsyc.62.3.273. European school-aged children and its relationship with childhood adversities:
Shonkoff, J.P., Boyce, W.T., McEwen, B.S., 2009 Jun 3. Neuroscience, molecular biology, results from the IDEFICS study. Eur. Child Adolesc. Psychiatr. 21 (5), 253–265.
and the childhood roots of health disparities: building a new framework for health [Link]
promotion and disease prevention. J. Am. Med. Assoc. 301 (21), 2252–2259. van Bodegom, M., Homberg, J.R., Henckens, M.J.A.G., 2017 Apr 19. Modulation of the
[Link] hypothalamic-pituitary-adrenal Axis by early life stress exposure. Front. Cell.
Simon, M., Németh, N., Gálber, M., Lakner, E., Csernela, E., Tényi, T., Czéh, B., 2019 Dec Neurosci. 11, 87. [Link]
17. Childhood adversity impairs theory of mind abilities in adult patients with major van Harmelen, A.L., van Tol, M.J., Demenescu, L.R., van der Wee, N.J., Veltman, D.J.,
depressive disorder. Front. Psychiatr. 10, 867. [Link] Aleman, A., van Buchem, M.A., Spinhoven, P., Penninx, B.W., Elzinga, B.M., 2013
fpsyt.2019.00867. Apr. Enhanced amygdala reactivity to emotional faces in adults reporting childhood
Sten, S., Lundengård, K., Witt, S.T., Cedersund, G., Elinder, F., Engström, M., 2017 Sep. emotional maltreatment. Soc. Cognit. Affect Neurosci. 8 (4), 362–369. [Link]
Neural inhibition can explain negative BOLD responses: a mechanistic modelling and org/10.1093/scan/nss007.
fMRI study. Neuroimage 158, 219–231. [Link] Victor, T.A., Furey, M.L., Fromm, S.J., Ohman, A., Drevets, W.C., 2010 Nov. Relationship
neuroimage.2017.07.002. between amygdala responses to masked faces and mood state and treatment in major
Steine, I.M., Winje, D., Krystal, J.H., Bjorvatn, B., Milde, A.M., Grønli, J., Nordhus, I.H., depressive disorder. Arch. Gen. Psychiatr. 67 (11), 1128–1138. [Link]
Pallesen, S., 2017 Mar. Cumulative childhood maltreatment and its dose-response 10.1001/archgenpsychiatry.2010.144.
relation with adult symptomatology: findings in a sample of adult survivors of sexual Walter, H., Adenzato, M., Ciaramidaro, A., Enrici, I., Pia, L., Bara, B.G., 2004 Dec.
abuse. Child Abuse Negl. 65, 99–111. [Link] Understanding intentions in social interaction: the role of the anterior paracingulate
chiabu.2017.01.008. cortex. J. Cognit. Neurosci. 16 (10), 1854–1863. [Link]
Teicher, M.H., Samson, J.A., 2016 Mar. Annual Research Review: enduring 0898929042947838.
neurobiological effects of childhood abuse and neglect. JCPP (J. Child Psychol. Wang, X., Song, Y., Zhen, Z., Liu, J., 2016 May. Functional integration of the posterior
Psychiatry) 57 (3), 241–266. [Link] superior temporal sulcus correlates with facial expression recognition. Hum. Brain
Teicher, M.H., Samson, J.A., Anderson, C.M., Ohashi, K., 2016 Sep 19. The effects of Mapp. 37 (5), 1930–1940. [Link]
childhood maltreatment on brain structure, function and connectivity. Nat. Rev. Wechsler, D., 1997. Wechsler Adult Intelligence Scale, third ed. WAIS-3®). Harcourt
Neurosci. 17 (10), 652–666. [Link] Assessment. San Antonio, TX, USA.
Torres-Berrío, A., Issler, O., Parise, E.M., Nestler, E.J., 2019 Dec. Unraveling the Worsley, K.J., 2001. Testing for signals with unknown location and scale in a χ2 random
epigenetic landscape of depression: focus on early life stress߭. Dialogues Clin. field, with an application to fMRI. Adv. Appl. Probab. 33, 773–793. [Link]
Neurosci. 21 (4), 341–357. [Link] 10.1239/aap/1011994029.
Unoka, Z., Rózsa, S., Kő, N., Kállai, J., Fábián, Á., Simon, L., 2004. Validity and reliability Zhang, W.N., Chang, S.H., Guo, L.Y., Zhang, K.L., Wang, J., 2013 Nov. The neural
of the SCL-90 in a Hungarian population sample. Psychiatr. Hung. 19, 235–243. correlates of reward-related processing in major depressive disorder: a meta-analysis
Vanaelst, B., De Vriendt, T., Ahrens, W., Bammann, K., Hadjigeorgiou, C., Konstabel, K., of functional magnetic resonance imaging studies. J. Affect. Disord. 151 (2),
Lissner, L., Michels, N., Molnar, D., Moreno, L.A., Reisch, L., Siani, A., Sioen, I., De 531–539. [Link]

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