In N-AL group, a significant regression model was obtained for VAS as the dependent variable and DIF, EOT, HADS-A, HADS-D and QUID-A as predictors, with a good level of fit with the data (R 2 = 0.53) (**Table 8**). HADS-A positively predict VAS (β = 0.381, p = 0.009). In AL group, VAS was predicted by QUID-S (β = 12.636, p < 0.0001) and the regression model explained the 50% of the variance of the data.

### DISCUSSION

The main purpose of the research was to investigate the prevalence of psychological distress and alexithymia in fibromyalgia patients, compared to those suffering from arthritis and healthy controls. Moreover, we aimed to describe the role of these variables in pain perception (affective and sensory dimensions) and pain intensity.

The results showed higher levels of alexithymia in patients with fibromyalgia, arthritis and other painful rheumatic conditions compared with healthy controls, according to previous research (Steinweg et al., 2011; Baeza-Velasco et al., 2012; Montoro et al., 2016; Di Tella et al., 2017). Alexithymia scores were higher in all three TAS-20 dimensions. These results may highlight the presence of a greater difficulty in identifying and expressing emotions and an external oriented cognitive style in patients with chronic pain conditions compared to general population. No significant differences were found between the FMS and RD groups, suggesting that both chronic pain conditions may have similar impairment in awareness and emotional regulation.

In regard to psychological distress, we found comorbidities between painful chronic conditions and anxious or depressive clinical symptoms, matching previous studies (Dell'Osso et al., 2011; Clauw, 2014; Løge-Hagen et al., 2018; Conversano et al., 2019). Our clinical groups exhibited a greater psychological impairment compared to healthy controls, with higher levels

HADS-A; Hamilton Anxiety and Depression Scale-Anxiety, HADS-D; Hamilton Anxiety and Depression Scale-Depression.

of anxiety and depression, similarly to the ones reported in Castelli et al. (2012); 60% prevalence of depression (HADS-D) and a 52.7% of anxiety (HADS-A) in FMS group). Despite other studies reporting higher levels of depressive symptoms and psychological distress in the FMS group compared to other chronic rheumatologic disorders (Ozcetin et al., 2007; Piccinni et al., 2011; Scheidt et al., 2014), our findings showed that patients with FMS and RD displayed similar anxiety and depression levels. These discrepancies in results may be due to differences in samples characteristics, for example fibromyalgia patients treated with antidepressant therapies that have relieved clinical symptoms or to the use of different scales to measure psychological variables.

In agreement with Scheidt et al. (2014) results, fibromyalgia patients showed higher levels of pain intensity than RD patients. Moreover, FMS patients had higher scores than RD patients in the affective component of pain, in agreement with Di Tella et al. (2017). Both results are in consistent with the phenomenon of allodynia and pain sensitivity of the FMS syndrome: while FMS patients experienced an increased pain response to non-painful stimuli due to central sensitization, their pain perception seems to be more related to fear, tension and autonomic reaction to stimuli than RD patients.

TABLE 5 | Questionnaire scales and subscales scores in alexithymia vs. no alexithymia groups.

Same abbreviations as Table 2. P values from t-test for independent samples.

Concerning associations between alexithymia and pain or psychological distress in FMS group, we found that alexithymia was not related to pain experience or intensity. This result suggest that lower emotional awareness does not play a primary role in pain perception, and it might be a transitional state related to severity of psychological distress, as other authors already highlighted (Steinweg et al., 2011; Marchesi et al., 2014; Montoro et al., 2016). In line with that, a significant relationship was found between DIF and anxiety, confirming the strong association between alexithymia and psychological distress in FMS. Moreover, pain experience and psychological distress had a significant relationship in the FMS group and this result is in line with previous research (Van Houdenhove and Luyten, 2006; Homann et al., 2012). In the light of these findings, we could hypothesize that in patients with FMS anxiety and depression affect both pain experience and emotional awareness and therefore they should be identified and taken into account in the treatment.

Strong correlations between alexithymia, pain and psychological distress were found in RD group. The positive correlation between difficulty in identifying feelings and the different components of pain was maintained, even after anxiety and depression was controlled. This finding suggests that in RD patients, alexithymia plays a more important role in influencing pain, regardless of the presence and severity of comorbid anxiety or depression.

With the aim of exploring the potential impact of alexithymia on the intensity and perception of pain, the clinical group (FMS + RD) was divided into patients with or without alexithymia, according to TAS-20 cut-off scores. Alexithymic patients (AL) had higher scores on anxiety, depression, pain intensity and perception than non-alexithymic ones (N-AL), according to previous studies (Makino et al., 2013; Saariaho et al., 2013; Di Tella et al., 2017). Two different regression models were obtained for AL vs. N-AL groups. In AL group, pain intensity was positively predicted by the sensory dimension of pain. In contrast with previous researches (Di Tella et al., 2017) our sample of patients experienced higher pain intensity that appeared not to be related with psychological distress and alexithymia, but only

TABLE 6 | Significant Pearson correlation coefficients r: associations between alexithymia, psychological distress and pain in patients with alexithymia (n = 40).

Same abbreviations as Table 2. Bold data indicate correlations that are significant. ∗p < 0.05; ∗∗p < 0.001.

TABLE 7 | Significant Pearson correlation coefficients r: associations between alexithymia, psychological distress and pain in non-alexithymic patients (n = 34).

Same abbreviations as Table 2. Bold data indicate correlations that are significant. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.

with the sensory dimension of pain (periodic, pulsing, pounding, penetrating, burning, smarting, tender). Meanwhile, in this group, the relationship between psychological distress and alexithymia was confirmed, suggesting that alexithymia in chronic pain patients might be a state that arise from other psychological conditions (i.e., high levels of depression or anxiety). In the N-AL group instead, anxiety positively predicted pain intensity, confirming the association between

TABLE 8 | Results of multiple regression analysis predicting pain intensity (VAS) from DIF, EOT, HADS-A, HADS-D in alexithymic (n = 40) and non-alexithymic patients (n = 34).

DIF, Difficulty Identifying Feelings; EOT, Externally-Oriented Thinking; HADS-A, Hamilton Anxiety and Depression Scale-Anxiety; HADS-D, Hamilton Anxiety and Depression Scale-Depression; β, unstandardized beta; S.E., standard error. Bold data indicate significant variables in regression model. ∗p < 0.01; ∗∗p < 0.001.

psychological distress, alexithymia and pain whereas variables scores are subthreshold. These results were also confirmed in healthy subjects, where strong correlations between al clinical variables were found.

Our results suggest that while clinical symptoms (pain intensity and experience, alexithymia, anxiety and depression) are increased in patients with fibromyalgia or RD, the relationship between pain and other variables disappeared. Two separated blocks of significant correlations appeared: on the one side, pain perception and pain experience are associated, on the other side alexithymia is related to negative affects states. This result also suggest that alexithymia may be a state phenomenon that arise from psychological distress and might be investigated with different scales or within longitudinal studies. Meanwhile, when symptoms of psychological distress and alexithymia were subthreshold, correlations with pain experience and intensity became stronger.

### Limitations

The present study has some limitations that should be considered. The cross-sectional nature of the study does not allow inferences about the causal relations among the variables. Prospective studies could clarify the relation between alexithymia, pain and emotional distress and its trend over time. Moreover, the use of a self-report measure (TAS-20) to assess alexithymia may not have investigated this construct properly, since it requires subjects to identify and describing affects, which is compromised in alexithymic subjects. The future research could use clinical interviews to assess alexithymia. Moreover, the use of a small sample did not permit the generalizability of the results to the fibromyalgia and arthritis patients population.

### DATA AVAILABILITY

fpsyg-10-01735 July 30, 2019 Time: 15:29 # 9

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

### ETHICS STATEMENT

The studies involving human participants were reviewed and approved by Department of Surgical, Medical and Molecular

### REFERENCES

Pathology, Critical and Care Medicine, University of Pisa. The patients/participants provided their written informed consent to participate in this study.

### AUTHOR CONTRIBUTIONS

CC conceived the assessment. LM, FM, LB, and CC planned the assessment. LM, FM, and SL contributed to the healthy subjects' data acquisition. LM, FM, and SL contributed to the patients' data acquisition. MM and GO contributed to the data analysis. MM, GO, CC, and AG contributed to the data interpretation. LM, FM, GO, RC, PKH, and CC drafted the manuscript. All authors critically revised the manuscript and approved the final version to be published.

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Perceptions about the sexuality of women with fibromyalgia syndrome: a phenomenological study. J. Adv. Nursing 73, 1646–1656. doi: 10.1111/jan. 13262

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Marchi, Marzetti, Orrù, Lemmetti, Miccoli, Ciacchini, Hitchcott, Bazzicchi, Gemignani and Conversano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Examining the Influence of Early Life Stress on Serum Lipid Profiles and Cognitive Functioning in Depressed Patients

Ágnes Péterfalvi1,2† , Nándor Németh1† , Róbert Herczeg3 , Tamás Tényi4 , Attila Miseta2 , Boldizsár Czéh1,2 and Maria Simon1,4 \*

1 Neurobiology of Stress Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary, 2 Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary, 3 Bioinformatics Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary, 4 Department of Psychiatry and Psychotherapy, Medical School, University of Pécs, Pécs, Hungary

#### Edited by:

Carmelo Mario Vicario, University of Messina, Italy

#### Reviewed by:

Andrea Caputo, Sapienza University of Rome, Italy Valentina Nannini, Sapienza University of Rome, Italy

#### \*Correspondence:

Maria Simon<EMAIL_ADDRESS>†These authors have contributed equally to this work

#### Specialty section:

This article was submitted to Psychology for Clinical Settings, a section of the journal Frontiers in Psychology

> Received: 07 May 2019 Accepted: 19 July 2019 Published: 06 August 2019

#### Citation:

Péterfalvi Á, Németh N, Herczeg R, Tényi T, Miseta A, Czéh B and Simon M (2019) Examining the Influence of Early Life Stress on Serum Lipid Profiles and Cognitive Functioning in Depressed Patients. Front. Psychol. 10:1798. doi: 10.3389/fpsyg.2019.01798 Background: Early childhood adversity is a strong predictor of the development of major depressive disorder (MDD), but not all depressed patients experience early life stress (ELS). Cardio-metabolic diseases and cognitive deficits often coincide in MDD and worsen its course and outcome. Adverse childhood experiences have been associated with elevated risk for cardiovascular disease (CVD), but little is known on the impact of ELS on cardiovascular risk factors in MDD. Here, we examined MDD patients with and without ELS to explore the effects of ELS on serum lipid and lipoprotein levels and on cognitive performances of the patients.

Methods: Participants with a mean age of 35 years (18–55 years) were recruited from the university mental health clinic and general community. Three groups, matched in age, gender and lifestyle were examined: MDD patients with ELS (n = 21), MDD patients without ELS (n = 21), and healthy controls (n = 20). The following CVD risk factors were assessed: serum lipids (total cholesterol, triglycerides, high- and lowdensity lipoproteins), body mass index and exercise in a typical week. MDD severity was measured by the Beck Depression Inventory. Childhood Trauma Questionnaire was used to assess early life adversities. Executive functions and attentional processes were assessed by the Wisconsin Card Sorting and Conners' Continuous Performance tests.

Results: Major depressive disorder patients with ELS had higher serum triglyceride and lower HDL-cholesterol concentrations compared to MDD patients without ELS. Linear regression analysis revealed that the severity of ELS had a significant negative association with HDL-cholesterol levels and significant positive associations with the serum levels of TG and TC/HDL-cholesterol index. We also found significant associations between some specific trauma types and lipid profiles. Finally, we could detect significant associations between depression severity and specific domains of the cognitive tests as well as between lipid profiles and certain domains of the Wisconsin Card Sorting Test. However, we could not detect any association between the severity of ELS and cognitive performance.

Conclusion: After controlling for depressive symptom severity and lifestyle variables, ELS was found to be a strong predictor of serum lipid alterations. Several, intercorrelated pathways may mediate the undesirable effects of ELS on the course and outcome of MDD.

Keywords: adverse childhood experience, childhood adversity, cardiovascular risk, cholesterol, depression, HDL, major depressive disorder, triglyceride

### INTRODUCTION

Major depressive disorder is a key public health concern today (Kessler, 2012), as it is a commonly occurring and an often recurring condition associated with considerable functional impairments, diminished quality of life, increased medical morbidity, and mortality (Kessler and Bromet, 2013). MDD often coincides with somatic illnesses such as metabolic syndrome (Pan et al., 2012) and CVD (Hare et al., 2014); nevertheless, the direction of the causal relationship between depression and cardio-metabolic diseases, as well as the specific underlying mechanisms, have not yet been fully understood. Moreover, patients suffering from MDD often present neurocognitive deficits (Austin et al., 2001; McDermott and Ebmeier, 2009; Lee et al., 2012; McIntyre et al., 2013; Rock et al., 2014).

Major depressive disorder is a clinically heterogeneous disorder, which is a result of manifold etiological factors, as well as developmental pathways. ELS, such as adverse childhood experiences (ACEs) (e.g., physical, emotional, and sexual abuse, neglect, parental loss, and poverty), have long been known to be strong predictors of MDD in adulthood (e.g., Widom et al., 2007; Norman et al., 2012; Lindert et al., 2014). A recent metaanalysis of 26 studies revealed that childhood emotional abuse and neglect showed the strongest association with depression risk in adults, while sexual/physical abuse or family violence have been proved to be non-specific risk factors for various mental disorders (Mandelli et al., 2015). Adult MDD with prior ELS is associated with earlier onset, more severe symptomatology, a greater number and longer duration of depressive episodes, a tendency to be chronic or therapy-resistant, higher rates of psychiatric comorbidities, as well as suicidal behavior or impulsivity compared to MDD without ELS (Brodsky et al., 2001; Zlotnick et al., 2001; Klein et al., 2009; Wiersma et al., 2009; Hovens et al., 2010; Miniati et al., 2010; Nanni et al., 2012). Moreover, ELS is also a risk factor for severe metabolic alterations and central obesity (Pervanidou and Chrousos, 2012; Davis et al., 2014) and CVD (Rich-Edwards et al., 2012; Loria et al., 2014). Furthermore, a recent study which analyzed data on cardio-metabolic markers of 9000 cohort members found that physical and sexual abuse was associated with high LDL-C and low serum levels of HDL-C, and that childhood neglect, as well as emotional abuse, was associated with raised TG and lower HDL-C (Li et al., 2019). In sum, ELS appears to be related to adult cardio-metabolic complications and comorbidities by two etiologic mechanisms: (1) the direct effect of early and late life stress; (2) general factors that are compensatory behaviors, as well as attempts at self-help by food and agents (Kesebir, 2014).

Serum lipid concentrations have been widely investigated in MDD, however, studies yielded inconsistent results. Both higher (Ledochowski et al., 2003; Nakao and Yano, 2004; Moreira et al., 2017) and lower serum TC levels (Olusi and Fido, 1996; Maes et al., 1997; Ong et al., 2016) were registered in patients with MDD compared to controls, and null findings have also been reported (Lehto et al., 2008; van Reedt Dortland et al., 2010; Enko et al., 2018). Alterations of serum concentrations of LDL-C were most widely studied in MDD. Recently, a comprehensive meta-analysis found significantly lower crosssectional LDL-C serum concentrations in MDD compared to HCs, when LDL-C was modeled as a continuous measure (Persons and Fiedorowicz, 2016). The authors suggested a U-shaped relationship between depression severity and LDL-C. Nevertheless, this meta-analysis did not consider the effect of ELS on LDL-C concentration in depression. Studies that investigated the relationship between HDL-C and MDD had produced contradictory findings. Some studies found no association at all (Aijänseppä et al., 2002; Rice et al., 2010), while others revealed a correlation between lower HDL-C and depression (Kim et al., 2004; Ancelin et al., 2010) and one study reported higher HDL-C than matched controls (Olusi and Fido, 1996). Similarly, contradictory findings have been published in serum triglyceride levels in depressed patients. Kinder and co-workers reported on a positive correlation between triglyceride blood levels and depression in women aged between 17 and 39 years (Kinder et al., 2004), and a positive correlation between triglyceride blood levels and the BDI score was also found in women who had received coronary angiography (Vaccarino et al., 2008). But there are also negative findings demonstrating no difference in serum TG levels between control and depressed subjects (Pjrek et al., 2007). A number of theories have been put forward to explain the contradictory findings on serum lipid disturbances in depression. Most of them emphasize the influence of the methodology used for the clinical evaluation of depression (e.g., dimensional or categorical assessment), or the impact of demographic, lifestyle and clinical variables (van Reedt Dortland et al., 2010). Furthermore, some results imply that the inconsistent findings might be due to the heterogeneity of the illness and that the

**Abbreviations:** ACEs, adverse childhood experiences; BDI, Beck Depression Inventory; BMI, body mass index; CPT-II, Conner's Continuous Performance Test-II; CTQ EA, Childhood Trauma Questionnaire Emotional Abuse; CTQ EN, Childhood Trauma Questionnaire Emotional Neglect; CTQ PA, Childhood Trauma Questionnaire Physical Abuse; CTQ PN, Childhood Trauma Questionnaire Physical Neglect; CTQ SA, Childhood Trauma Questionnaire Sexual Abuse; CTQ, Childhood Trauma Questionnaire; CVD, cardiovascular disease; ELS, early life stress; HC, healthy control; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDD, major depressive disorder; TC, total cholesterol; TG, triglycerides; WCST, Wisconsin Card Sorting Test.

lipid disturbances may be characteristic for only certain specific subgroups within the MDD.

So far, only a few studies considered the role of ELS in the association between depression and metabolic disturbances. McIntyre et al. (2012) found a significantly lower level of HDL-C in depressed patients who experienced childhood adversity, but there was no statistically significant difference in the overall rate of dyslipidemia and metabolic syndrome between subjects with and without childhood adversity. Ding et al. (2014) did a metabonomic analysis and reported that MDD patients had lower TC levels compared to controls, but patients with ELS had higher TC levels compared to the MDD only group. Wingenfeld et al. (2017) conducted a women-only study in a physically healthy clinical sample and found no difference in TG, cholesterol, HDL-C, LDL-C and other metabolic risk markers between MDD patients with and without sexual or physical abuse. However, one should carefully interpret these null findings, as the exclusion of obese individuals (with body mass index > 30 kg/m2 ) might have led to an underrepresentation of subjects with existing obesity linked to ELS. More recently Deschênes et al. (2018) reported that ACEs are indirectly associated with diabetes via depressive symptoms and cardio-metabolic dysregulations. While Kraav et al. (2019) found decreased serum TC in depressed outpatients with a childhood history of physical violence. Importantly, most of these earlier studies – when they carried out the statistical analysis of their data – did not control for the effects of ELS, while it is well-known that the prevalence of ACEs is much higher in depressed patients compared to the general population, thus, the presence of ELS might be a confounding variable influencing the outcome of these investigations.

Psychodynamic factors, such as the loss of "good self " or "damaged self " might also have a significant impact. Individuals with ELS experience a defective or "wounded" self, and distressing feelings of shame originating from the internalization of bad or unworthy parents. According to the object relation theory, stressful life events can distort the mental representations of the self and others. This can significantly influence the individual's behavior, i.e., his or her affective states and selfcare. Moreover, the damaged self can negatively impact health behavior and the adaptation to emerging somatic illnesses as well (Kohut, 1977; Ulman and Brothers, 1988; Marchini et al., 2018). Recent psychodynamic theories focus on the role of the attachment and attachment-based mentalizing capacities in the etiology and treatment of depressive disorders, and in the development of somatic disorders in individuals with ELS. Adopting a developmental approach, Luyten and Fonagy (2018) emphasized that ELS can lead to insecure attachment that impairs adaptation to stressful social situations and disrupts the regulation of the stress response. If social stress emerges, hypermentalizing and hypomentalizing can occur on the basis of the insecure attachment. These can lead to deficits of stress regulation, and to dysfunctional compensatory strategies (e.g., drug abuse, self-harm, sexual promiscuity, risk-taking, eating disorders). Due to the unhealthy behavior and the neurobiological changes as a result of ELS, MDD patients with ELS may suffer from stress-related cardiovascular and metabolic diseases more often.

In the present study, we hypothesized that serum lipid levels might be determined by ACEs in depressed patients, based on the following observations: (i) ELS can result in serum lipid alterations both in psychiatric (McIntyre et al., 2012; Misiak et al., 2015) and non-psychiatric samples (van Reedt Dortland et al., 2012; Spann et al., 2014); (ii) lipid disturbances were detected mostly in depressed patients with atypical or melancholic symptoms, or suicidal tendencies, which are more characteristic to depression with ELS (Harkness and Monroe, 2002; Matza et al., 2003; Klein et al., 2009). To investigate this hypothesis, we measured serum lipid and lipoprotein profiles in MDD patients with high and low ELS scores, and in ageand gender-matched HCs. Atherogenic indices (TC/HDL-C, LDL-C/HDL-C) and BMI was also calculated and we collected sociodemographic and clinical data on the participants' lifestyle as well. Finally, we used two well-established neuropsychological tests to measure the participant's executive functions (Wisconsin Card Sorting Test) and their attentional processes (Conners' Continuous Performance Test-II).

### MATERIALS AND METHODS

### Participants

Forty-two patients with MDD and 20 healthy controls (HCs) participated in this study. Patients with MDD were recruited from the Affective Disorder Unite of the Department of Psychiatry and Psychotherapy, University of Pécs, Hungary. The local Research Ethics Committee of the University of Pécs approved the study design and protocol (Ethical Approval Nr.: 2015/5626) and all participants provided written informed consent. To exclude the effects of aging, only subjects aged between 18 and 55 were involved in the study, because several studies reported an increased prevalence of dyslipidemia in the elderly population (Bechtold et al., 2006; Shanmugasundaram et al., 2010; Liu and Li, 2015).

All patients fulfilled the DSM-5 diagnostic criteria of MDD (American Psychiatric Association, 2013). Inclusion criteria of the MDD group included: (1) age 18–55 years; (2) a diagnosis of MDD in a current major depressive episode as assessed by a trained psychiatrist using the Structured Clinical Interview for DSM-5, Clinical Version, (SCID-5-CV) (First et al., 2015, 2016b) and the Structured Clinical Interview for DSM-5, Personality Disorders (SCID-5-PD) (First et al., 2016a, 2018). Exclusion criteria for the patient group were: current substance abuse or dependence (if the patient met diagnostic criteria, he or she had to be abstinent for at least 2 years), bipolar disorder, posttraumatic stress disorder, a history of any psychotic disorder, and current eating disorders. HC participants were recruited by online advertisements and via personal contacts of the researchers. The control sample was screened by a qualified psychiatrist to ascertain the absence of lifetime or family history of mental disorders. In addition, SCL-90 (Derogatis, 1977) was applied to rule out relevant subthreshold psychiatric symptoms in potentially healthy individuals. Exclusion criteria for both the patients and the controls were: liver or kidney disease, severe CVD, uncontrolled thyroid disorders, uncontrolled

diabetes mellitus, and current inflammatory illness. Subjects with known familial hyperlipidemia were not included. Subjects with neurological disorders, in addition, those with a history of head injury and with severe hearing or visual impairment, and an IQ < 85 were also excluded.

In the MDD group, treatment with antidepressant medication or psychotherapy were not exclusion criteria once the diagnosis had been established. Current psychotropic medication data were collected: 41 (97.6%) MDD subjects were taking antidepressants (20 patients were taking SSRIs, 12 mirtazapine, 2 mianserine, 2 venlafaxine, 1 duloxetine, 1 trazodone, 1 vortioxetine, 1 agomelatine), 21 (50%) low dose antipsychotics (17 quetiapine, 1 ziprasidone, 1 aripiprazole, 1 thiothixene), 5 (11.9%) mood stabilizing medications. None of the control subjects took psychotropic medication.

One MDD patient was on lipid-lowering drug (atorvastatin) treatment at the time of the study. Two patients and two control subjects kept a vegetarian diet.

### Laboratory Analyses

Cubital venous blood was drawn from the participants between 7 and 8 AM in order to avoid any possible effect of circadian variations. The samples were collected following 8–12 h of fasting. Serum concentrations of TC, LDL-C, HDL-C, and TG were all measured with a Roche Modular (module P800) clinical chemistry analyzer, using enzymatic colorimetric test methods according to the manufacturer's instructions (Roche Diagnostics, Hungary).

### Questionnaires

### Beck Depression Inventory

The severity of actual depressive symptoms was assessed using the BDI (Beck et al., 1961; Hungarian adaptation: Petö et al., 1987; Rózsa et al., 1998). This is a 21-item self-report questionnaire rating the presence and extent of sadness, pessimism, past failure, loss of pleasure, self-dislike, self-criticism, and suicidal thoughts and wishes in the past week. The scores range from 0 to 63 points and higher scores indicate more severe depression. In this study, Cronbach's alfa values were excellent for the total BDI scores (0.95) and for the cognitive subscale scores (0.91), and good for the somatic-affective subscale (0.86).

### Childhood Trauma Questionnaire-Short Form

Early life stress was surveyed with the 28-item retrospective selfreport questionnaire of the Childhood Trauma Questionnaire-Short Form (CTQ) (Bernstein et al., 2003), that assesses the severity of five types of maltreatment before the age of 18 years: physical abuse (CTQ PA), emotional abuse (CTQ EA), physical neglect (CTQ PN), emotional neglect (CTQ EN), and sexual abuse (CTQ SA). Each subscale is measured with five 5 point scale items. The short form of the questionnaire is the most widely used version, which includes clinical cut-offs for significant abuse and neglect. Childhood maltreatment exposure was entered in the statistical analyses as a continuous variable with row scores, or it was coded into a two-level variable for dividing the MDD sample into low-ELS and high-ELS subgroups. Patients with MDD were assigned to the MDD Only subgroup if they had not experienced any types of moderate to severe childhood trauma. MDD patients were put into the MDD + ELS subgroup if they had at least one type of moderate to severe childhood trauma. In the present sample, the internal consistencies were excellent for the CTQ total score, and for the subscales of physical abuse, emotional abuse, sexual abuse, as well as for emotional neglect (Cronbach's alphas > 0.9). The internal consistency was acceptable for the subscale of physical neglect (Cronbach's alpha = 0.77). The Hungarian translation of the original (English) CTQ was done using the back-translation procedure (Sperber, 2004). Two senior authors (MS and BC) translated the English version to Hungarian. To ensure that the translated version is equivalent with the source version a bilingual linguist translated the early Hungarian version back to English. Errors of meaning and concept inconsistencies between the translated versions were discussed and corrected.

### Sociodemographic Data on BMI and Lifestyle

A self-report questionnaire determined the various sociodemographic data, including education, lifestyle habits of regular exercise. Measurements for height and body mass were obtained using a wall-mounted stadiometer and electronic scale, respectively. BMI was calculated as body mass in kilograms divided by height in meters squared.

### Neurocognitive Tests Wisconsin Card Sorting Test

Executive functions were assessed by the computerized version of the WCST (Heaton, 1981). In the test, cards with geometric shapes (different in their number, color, and form) have to be matched according to varying sorting principles. The actual method of sorting has to be found out by the subject based on the provided feedback (correct or incorrect). Besides the number of total correct responses and non-perseverative errors, we detected the number of perseverative errors and conceptual level responses as a measure of shifting ability and conceptual ability, respectively. The WCST is a commonly used cognitive measure in clinical investigations including the studies examining cognitive changes related to depression (see e.g., Li et al., 2010; Giel et al., 2012; McGirr et al., 2012, etc.). Moreover, the WCST has been found to be a highly reliable test already decades ago (e.g., Tate et al., 1998).

### Conner's Continuous Performance Test-II

Attentional processes were assessed by the CPT-II (Conners, 2000). In this task, respondents are required to press the space bar when any letter except X appears. The inter-stimulus intervals are variable (1, 2, or 4 s) with display time of 250 ms. There are six blocks, with three sub-blocks each containing 20 trials. The procedure takes 14 min to complete. Omission errors and commission errors, as well as hit reaction time and detectability (a measure of the difference between the signal [non-X] and noise [X] distributions), were assessed.

Conner's Continuous Performance Test-II is one of the most widely used, computer-administered cognitive test of attention and impulsivity. Since it is not a verbal test, and no language

adaptation is necessary thus, the reliability testing of this test was out of the scope of our study. A recent publication reported that CPT-II has a strong internal consistency, adequate testretest reliability for commission errors and response time, and a relatively poor test-retest reliability for omission errors, and practice effects for omission and commission errors (Shaked et al., 2019). Moreover, CPT-II performances were unrelated to those in other cognitive tests, such as Stoop Color-Word test (Shaked et al., 2019). CPT-II is often used in clinical research on depression (see e.g., Godard et al., 2011; Parlar et al., 2016).

Since none of the clinical studies listed above (using either the CPT-II or the WCST) investigated the reliability of these cognitive tests, we followed the examples of the literature and assumed that both CPT-II and WCST were sufficiently reliable tests.

### The Sequence of Data Collection

Research participants underwent the following study procedures. First, the clinical interviews and questionnaires were completed to assess the severity of depression and ELS. Then, a senior clinician blinded to the results of the CTQ data conducted a semi-structured interview about the stressful early life-events during childhood and adolescence. CTQ sores and the interview responses were compared, discrepancies were discussed with the participants. In the case of unresolvable discrepancies, participants were excluded from the study (n = 3). Cognitive functions were assessed separately the next day or the day after the next day. Blood samples were taken in the morning within 24 h after the initial clinical assessments.

### Statistical Analysis

Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS), version 21.0. Normality was checked by normal probability plots and by the Shapiro-Wilk and the Kolmogorov-Smirnov tests. Lipid and cognitive variables that showed skewed distributions were log-transformed, and all subsequent analyses were done with these transformed data. Between-group differences in demographic, lifestyle and clinical variables were analyzed by chi-square test and by ANOVA or non-parametric tests (Mann–Whitney U and Kruskal–Wallis). Differences between the study groups in the serum lipid and lipoprotein values, as well as cognitive performances, were tested first by one-way ANOVA. If the homogeneity assumption (tested by Levene's statistic) was violated, Welch-probe was used for the group comparisons. Fisher's LSD and Games-Howell tests were applied for post hoc pairwise comparisons. In the next step, between-group differences in the main variables were analyzed using ANCOVA with demographic and lifestyle variables as covariates and post hoc comparisons were done with Bonferroni correction.

After the group comparisons, hierarchical multiple linear regression analyses were run in the entire MDD group in order to explore whether the heterogeneity of lipid and lipoprotein levels were explained rather by the severity of depression or by the severity of ELS and whether there were associations between the revealed lipid alterations and the patients' cognitive performances. Due to the relatively large number of background variables and the relatively small sample size, in the regression analyses, we selected the most relevant confounders using the forward procedure, and predictor variables of main interest were added to the models with the enter method. In the forward procedure, the predictor variables were sequentially included in the regression models depending on the strength of their correlation with the criterion variable (P to enter < 0.05). The entering procedure enters the predictor variables in the models irrespective of their significance with the criterion. In all analyses, P-values (two-tailed) below 0.05 were considered statistically significant. Effect sizes were measured by calculating Cohen's d, η 2 (for ANOVAs) as well as Cohen's f 2 (for multiple regression analyses).

### RESULTS

### Demographic, Lifestyle, and Clinical Data Two-Group Comparisons: Healthy Controls Versus the Entire MDD Group

There were no significant between-group differences in age (F(1,60) = 0.024, P = 0.877), gender ratio (X 2 (1) = 1.303, P = 0.254), BMI (U = 398.000, Z = −0.331, P = 0.740), and regular physical activity (U = 345.500, Z = −1.167, P = 0.243).

### Three-Group Comparisons: Healthy Controls Versus MDD Only Versus MDD + ELS

The three groups did not differ in age (F(2,59) = 0.125, P = 0.883), gender ratio (X 2 (2) = 1.428, P = 0.490), BMI (X 2 (2) = 0.142, P = 0.931), and physical activity (X 2 (2) = 3.083, P = 0.214), however, a significant difference could be observed between groups in years of education (X 2 (2) = 14.079, P = 0.001). Pairwise comparisons showed that the level of education was significantly lower in the MDD Only and in the MDD + ELS groups compared to HC (P = 0.025, P = 0.001, respectively).  The severity of ELS was significantly higher for physical and emotional neglect in the MDD Only group compared to HC (CTQ PN: P = 0.039; CTQ EN: P = 0.012),

TABLE 1 | Demographic, lifestyle and clinical characteristics of patients with MDD and HCs.

aMeans and standard deviations are presented. bMedians and inter-quartile ranges are presented. Two-group comparisons: overall MDD group compared to HC: ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Three-group comparisons: MDD Only compared to MDD + ELS: +P < 0.05, ++P < 0.01, +++P < 0.001. MDD Only or MDD + ELS compared to HC: § P < 0.05, §§ P < 0.01, §§§ P < 0.001. BDI, Beck Depression Inventory; CTQ, Childhood Trauma Questionnaire-Short Form; ELS, early life stress; HC, healthy controls; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDD, major depressive disorder; TC, total cholesterol.

but there was no significant difference in CTQ total score, as well as in physical, emotional, and sexual abuse between these two groups (CTQ Total: P = 0.051; CTQ PA: P = 0.596; CTQ EA: P = 0.149; CTQ SA: P = 0.515). There was significant difference between the groups in BDI score (Welch's F(2.29,0) = 80.404, P < 0.001) and the pairwise comparisons demonstrated that both MDD subgroups had significantly higher BDI score than the HC group (P < 0.001), whereas depression severity was similar in the two MDD subgroups (P = 0.113) (**Table 1**).

### Lipid Profile

### Two-Group Comparisons: Healthy Controls Versus the Entire MDD Group

No difference was found between the two groups by oneway ANOVA when we compared serum TC (F(1,60) = 0.782, P = 0.380), TG (F(1,60) = 0.426, P = 0.516), HDL-C (F(1,60) = 0.609, P = 0.438), LDL-C (F(1,60) = 1.062, P = 0.307), and the two atherogenic indices (LDL-C/HDL-C: F(1,60) = 2.052, P = 0.157, TC/HDL-C: F(1,60) = 2.036, P = 0.159) (**Table 1**). In order to control for the effects of demographic and lifestyle variables on lipid and lipoprotein levels, ANCOVAs were conducted with age, gender, level of education, physical exercise, and BMI as covariates, but again no significances were found (**Figure 1** and **Supplementary Table 1**).

### Three-Group Comparisons: Healthy Controls Versus MDD Only Versus MDD + ELS

Results of the ANOVA omnibus tests indicated significant between-group differences in TG (Welch's F(2,35.4) = 4.367, P = 0.020), HDL-C (F(2,59) = 3.293, P = 0.044), and TC/HDL-C (F(2,59) = 3.434, P = 0.039). Post hoc comparisons (Fisher's LSD and Games-Howell tests) showed that the level of HDL-C was significantly lower (P = 0.018), while the level of TG (P = 0.015) and also the ratio TC/HDL-C (p = 0.034) were significantly higher in the MDD + ELS than in the MDD Only group. The ratio of TC/HDL-C of the MDD + ELS group was also significantly higher when compared to the HC group (P = 0.022) There were no significant differences between groups in TC (Welch's F(2,38.7) = 4.367, P = 0.645), LDL-C (F(2,59) = 0.733, P = 0.485), and LDL-C/HDL-C (F(2,59) = 2.562, P = 0.086) (**Table 1**). Cohen's d-values for all significant group differences ranged from 0.68 to 0.78 indicating medium-to-large effect sizes.

After controlling for the effects of age, gender, level of education, physical exercise and BMI by ANCOVA, betweengroup differences remained significant in TG (F(2,54) = 6.320, P = 0.003), HDL-C (F(2,54) = 3.409, P = 0.040), and TC/HDL-C (F(2,54) = 4.854, P = 0.012), and a new significant difference emerged in LDL-C/HDL-C (F(2,54) = 3.794, P = 0.029). As it is shown in **Figure 1**, post hoc Bonferroni comparisons demonstrated that HDL-C was significantly lower in MDD patients with ELS than in MDD Only patients, as well as the TG and the TC/HDL-C index, were significantly higher in the MDD + ELS group compared both to the MDD Only and to the HC groups. Moreover, higher LDL-C/HDL-C ratio was revealed in MDD + ELS patients relative to the HC. There were no significant differences between groups by ANCOVA in TC

(F(2,54) = 0.742, P = 0.481) and LDL-C (F(2,54) = 1.454, P = 0.243) (**Figure 1**). For the significant group comparisons, Cohen's d-values ranged from 0.63 to 0.94 (medium-to-large effect sizes).

### Multiple Linear Regression Analyses: The Effects of Depression Severity and ELS on Serum Lipid/Lipoprotein Levels

Next, we performed a series of hierarchical linear regression analyses in the entire MDD group to determine whether the heterogeneity of each lipid/lipoprotein level is explained by the severity of depression or by the amount of ELS after controlling for each other and for potentially confounding factors. Relevant confounders were selected from the demographic variables (age, gender, years of education) in Block 1, and from the lifestyle variables (BMI, physical exercise per week) in Block 2 using the forward variable selection procedure. Because we were interested in how the statistical effect of current depression severity on lipid/lipoprotein levels changes after including ELS in the models, next, in Block 3, depression severity (BDI score), and finally, in Block 4, the amount of ELS (CTQ total score) were added to the regression models using the enter method.

After running hierarchical regression analyses for each lipid and lipoprotein parameters as dependent variables, we found that in Block 3, BDI score predicted only HDL-C (P = 0.010) significantly. However, when the CTQ total score was also added in Block 4, the relationship between BDI and HDL-C lost its significance (P = 0.068) and no other significantly predictive relationship emerged between depression severity and any of the lipid profile elements (**Table 2**). However, in Block 4, the severity of ELS had a significant negative association with HDL-C level (P = 0.040) and a significant positive association with the serum level of TG (P = 0.014) and TC/HDL-C index (P = 0.043) (for details see **Supplementary Table 2**). Cohen's f 2 -values for these significant associations ranged from 0.11 to 0.18 indicating moderate effect sizes.

### The Relationship Between the Different Subtypes of ELS and Serum Lipid/Lipoprotein Levels

Within the entire MDD group, additional series of hierarchical linear regressions were calculated to determine which subtypes of childhood adversities can significantly predict the parameters of the lipid profile as dependent variables after controlling for demographic variables (Block 1), lifestyle variables (Block 2), and depression severity (BDI score; Block 3) with the forward variable selection method. In Block 4, the CTQ subscores of the different trauma types, as predictor variables of main interest, were added to the models using the 'enter' procedure.

As it is shown in **Table 3**, we found significant negative associations between physical neglect and abuse and between HDL-C. We also found significant positive associations between physical and emotional neglect and abuse, and the levels of TG. Moreover, significant positive associations were found between physical and emotional neglect and the indices of LDL-C/HDL-C and TC/HDL-C. Sexual abuse had no statistically significant relationship between any of the lipid parameters (**Table 3**; for details see **Supplementary Table 3**).

### Neurocognitive Tests

### Two-Group Comparisons: Healthy Controls Versus the Entire MDD Group

One-way ANOVA revealed significant group differences when we compared omission errors of the Conner's Continuous Performance Test (Welch's F(1,58.5) = 7.464, P = 0.008, Cohen's d = 0.75). Similarly, one-way ANOVA revealed significant group differences when we compared perseverative errors of the WCST (Welch's F(1,50.8) = 5.463, P = 0.023, Cohen's d = 0.63) (for details see **Supplementary Table 4**). After controlling by ANCOVA for age, gender, and level of education, however, these differences lost their significance (**Supplementary Table 5**).

### Three-Group Comparisons: Healthy Controls Versus MDD Only Versus MDD + ELS

The ANOVA omnibus tests revealed that omission errors of the Conner's Continuous Performance Test were significantly different in the three groups (Welch's F(2,36.6) = 3.780, P = 0.032, Cohen's d = 0.64). Further comparison with the Games-Howell post hoc test revealed that the CPT omission errors were significantly higher in the MDD + ELS group than in the HC (P = 0.045, Cohen's d = 0.65) (for details see **Supplementary Table 4**). However, after controlling for the effects of demographic variables, no significant betweengroup differences were found in the neurocognitive variables (**Supplementary Table 5**).

### The Effect of Serum Lipid/Lipoprotein Levels on Neurocognitive Performances in MDD

Finally, hierarchical multiple linear regressions were calculated to predict parameters of neurocognitive tests based on lipid parameters after controlling for demographic variables (Block 1), lifestyle variables (Block 2), severity of depression (i.e., BDI score; Block 3), and severity of ELS (i.e., CTQ total score; Block 4) that were included in the regression models with the forward procedure. The lipid profile elements, as predictor variables of main interest, were added to the models using the enter method in Block 5.

Depression severity predicted commission errors in the Conner's Continuous Performance Test (β = 0.289, P = 0.024) and detectability (β = −0.304, P = 0.020), as well as conceptual level responses in the WCST (β = −0,416, P = 0.006) in Block 3 (for details see **Supplementary Tables 6**, **7**). For these significant associations between depression severity and cognitive performances, Cohen's f 2 -values ranged from 0.15 to 0.20 suggesting moderate effect sizes. However, we could not find any association between the amount of ELS and any of the neurocognitive test results in Block 4. No relationship was found between lipid parameters and any of the Conner's Continuous Performance Test results (**Supplementary Table 6**). However, we could detect significant negative associations between the lipid profiles and between specific domains of the WCST. There were significant negative associations between HDL-C and WCST perseverative errors, between LDL-C/HDL-C ratio and WCST total correct responses, and also between the indices LDL-C/HDL-C and TC/HDL-C, and WCST conceptual level responses (**Table 4**, for details, see **Supplementary Table 7**).

Cohen's f 2 -values for these results ranged from 0.10 to 0.16 suggesting moderate effect sizes.

### DISCUSSION

The principal aim of the present study was to examine the impact of childhood adversities on serum lipid profiles in depressed patients. In our statistical analysis, we asked the question of whether depression severity or the severity of ACEs have a stronger influence determining serum lipid levels. Overall, ELS was a stronger predictor of serum lipid profiles than depression severity. Furthermore, we found that depressed patients with ELS had significantly higher serum triglyceride and lower HDLcholesterol concentrations compared to MDD patients without ELS. The atherogenic indices, LDL-C/HDL-C, and TC/HDL-C were also higher in patients with ELS. We also found significant associations between the different trauma types and lipid profiles.

3: depression severity (BDI score); Block 4: early life stress (CTQ total score). †P < 0.1,∗P < 0.05, ∗∗P < 0.01. β, standardized beta coefficient at the current step; β', the standardized beta coefficient in the final model; BDI, Beck Depression Inventory; CTQ, Childhood Trauma Questionnaire-Short Form; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDD; major depressive disorder; TC, total cholesterol. Bold values indicate the significant differences related to depression severity and ELS.

TABLE 3 | Linear regression analyses with serum lipid and lipoprotein levels as dependent variables, and with trauma types (CTQ sub-scores) as predictors in the entire MDD group.

aAdjusted for age and body mass index. bAdjusted for physical exercise per week. cAdjusted for depression severity. dAdjusted for age and physical exercise per week. CTQ, Childhood Trauma Questionnaire Short Form; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDD, major depressive disorder; TC, total cholesterol. Bold values indicate the significant differences.

TABLE 4 | Linear regression analyses of serum lipid and lipoprotein levels as predictors of executive functioning (WCST scores) in the entire MDD group.

aAdjusted for age and education. bAdjusted for education. cAdjusted for depression severity. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MDD; major depressive disorder; TC, total cholesterol; WCST, Wisconsin Card Sorting Test. Bold values indicate the significant differences.

Both physical and emotional neglect and abuse had a significant positive association with serum triglyceride levels, while physical neglect and abuse had a significant negative association with HDL-cholesterol. Finally, we could detect significant associations between depression severity and specific domains of the cognitive tests as well as between lipid profiles and certain results of the WCST. But in our study, ELS had no influence on the cognitive performance of the subjects.

A vast number of studies report that early life adversity may increase cardiovascular risk factors and the occurrence of CVD (Batten et al., 2004; Dong et al., 2004; Goodwin and Stein, 2004; Danese et al., 2009; Fuller-Thomson et al., 2010, 2012; Korkeila et al., 2010; Stein et al., 2010; Scott et al., 2011; Rich-Edwards et al., 2012; Basu et al., 2017; Murphy et al., 2017; Reid et al., 2018; Doom et al., 2019; Obi et al., 2019). These studies document that childhood adversities are associated with hypertension (Danese et al., 2009; Stein et al., 2010; Reid et al., 2018; Doom et al., 2019), higher BMI (Doom et al., 2019), ischemic heart disease (Dong et al., 2004) and myocardial infarction (Fuller-Thomson et al., 2012). Adverse childhood experience may alter serum lipid/lipoprotein profiles as adults with ELS may have elevated serum TG, LDL-cholesterol and TC as well as low HDLcholesterol (Danese et al., 2009; Spann et al., 2014; Reid et al., 2018; Doom et al., 2019). Furthermore, a recent study reported that the different trauma types can be associated with specific changes in serum levels, i.e., physical and sexual abuse were associated with high LDL-C and low HDL-C, and childhood neglect with raised TG and low HDL-C (Li et al., 2019). The exact physiological pathways connecting ELS with CVD risk factors and CVD are yet unknown. Recently, a hypothesis has been put forward that experiencing social threat and adversity upregulates pro-inflammatory cytokines which in turn may elicit depressive symptoms as well as metabolic syndrome and CVD (Slavich and Irwin, 2014).

Large body of evidence indicate that there is a strong association between MDD and CVD (Musselman et al., 1998; Penninx et al., 2001; Carney et al., 2002; Barth et al., 2004; Whooley, 2006; Van der Kooy et al., 2007; Goldstein et al., 2015). While the exact relationship between these two disorders remains obscure there is evidence that the presence of depressive symptoms can increase the risk of CVD (Joynt et al., 2003; Almeida et al., 2007; Vancampfort et al., 2014; Pérez-Piñar et al., 2016). Among the various CVD risk factors dyslipidemia has also been associated with depressed mood (Huang et al., 2003; Papakostas et al., 2004; van Reedt Dortland et al., 2010, 2013; Chien et al., 2013). However, the studies investigating serum lipid concentrations in MDD yielded inconsistent results. There are reports on higher (Ledochowski et al., 2003; Nakao and Yano, 2004; Moreira et al., 2017) as well as lower serum TC levels (Olusi and Fido, 1996; Maes et al., 1997; Ong et al., 2016) compared to controls, while others found no difference (Lehto et al., 2008; van Reedt Dortland et al., 2010; Enko et al., 2018). Other studies found that TG levels are increased in patients with MDD and that TG levels show a positive relationship with depression severity (Sevincok et al., 2001; Huang and Chen, 2004; Liu et al., 2016).

So far only a handful of studies examined the influence of childhood adversity on lipid profiles in depressed patients. McIntyre et al. (2012) examined a clinical population with unipolar depression and found a significantly lower level of HDL-C in patients who experienced traumatic life events during their childhood compared to those without childhood adversities. However, there was no statistically significant difference in the overall rate of dyslipidemia and/or metabolic syndrome between subjects with and without childhood adversity. Wingenfeld et al. (2017) conducted a women-only study in a physically healthy clinical sample and detected no difference in TG, cholesterol, HDL-C, LDL-C and other metabolic risk markers between MDD patients with and without sexual or physical abuse. More recently Deschênes et al. (2018) reported that ACEs are indirectly associated with diabetes via depressive symptoms and cardiometabolic dysregulations. The most recent study found decreased TC levels in adult outpatients with MDD with a childhood history of physical violence (Kraav et al., 2019). The same study found no differences in serum levels of HDL-C and LDL-C between the groups (Kraav et al., 2019). In our present study, we could detect higher serum triglyceride and lower HDL-cholesterol levels in MDD patients who experienced childhood adversity compared to MDD patients without ELS. Furthermore, we also found that the severity of ELS had a negative association with HDL-cholesterol levels and positive associations with the serum level of TG and TC/HDL-C index. Thus, our present data support the notion that childhood adversity may influence serum lipid levels also in depressed individuals and that MDD patients with a history of childhood adversity may represent a specific sub-group within MDD. We could also detect significant associations between the different trauma types and lipid profiles. Physical neglect and

abuse had a significant negative association with HDL-cholesterol while physical and emotional neglect and abuse had a significant positive association with serum triglyceride levels. Our findings are in harmony with the recent report of Li et al. (2019), which reported that physical abuse was associated with low HDL-C, while neglect was associated with raised TG and lower HDL-C. In our present study, we could not detect any association between sexual abuse and serum lipid/lipoprotein levels. Others found that sexual abuse was associated with high LDL-C and low HDL-C (Li et al., 2019). There is, in fact, ample evidence in the literature that childhood sexual abuse can increase the incidence of CVD: a US study involving 5 900 subjects reported that childhood sexual abuse was associated with increased risk of cardiac disease (Goodwin and Stein, 2004). Another US survey involving 12 900 individuals found that specifically in men childhood sexual abuse was associated with heart attack (Fuller-Thomson et al., 2012). One should add that there are negative findings as well, e.g., a recent retrospective study involving 3 600 individuals could not reveal any consistent association between the specific type of early psychosocial adversity and CVD risk factors (Anderson et al., 2018). This study examined associations of specific types of psychosocial adversities, such as lack of maternal care, maternal overprotection, parental mental illness, household dysfunction, sexual abuse, physical and emotional abuse, and neglect in childhood with CVD risk factors including BMI, TG, low and high density lipoprotein cholesterol (Anderson et al., 2018).

A vast body of work has linked early life adversity to various types of cognitive deficits later in life (see e.g., Evans and Schamberg, 2009; Mueller et al., 2010; Pechtel and Pizzagalli, 2011; Gould et al., 2012; Chen and Baram, 2016). Cognitive impairments are also frequently present in depressed individuals (Porter et al., 2003; Marazziti et al., 2010; Ahern and Semkovska, 2017). A meta-analysis found significant cognitive deficits in executive function, memory and attention in depressed patients relative to controls (Rock et al., 2014), yet another one revealed significant correlations between depression severity and specific domains of episodic memory, executive function, and processing speed (McDermott and Ebmeier, 2009). In our present study, we could also detect significant associations between depression severity and specific domains of attention (examined with the CPT-II) and executive functions (investigated with the WCST). However, we could not find any association between ELS and cognitive performance using these two tests.

Numerous clinical and preclinical data suggest that dyslipidemia can be linked to cognitive deficits and decline (Yaffe et al., 2002; Farr et al., 2008; Gendle et al., 2008; Morley and Banks, 2010; Reynolds et al., 2010) though this issue is not without controversies (see e.g., Panza et al., 2006; Anstey et al., 2008). For example, there are reports that high TG are associated with poor memory and general cognitive decline (de Frias et al., 2007; Morley and Banks, 2010), and that high triglyceride levels inversely correlate with executive function in non-demented elderly adults (Parthasarathy et al., 2017). Furthermore, a recent study documented elevated triglyceride levels in patients with MDD, which was associated with cognitive impairments (Shao et al., 2017). In our study, we found negative associations between lipid profiles (HDL-C and LDL-C/HDL-C, TC/HDL-C ratios) and specific domains of the WCST measuring executive functions. Low levels of HDL cholesterol have been associated with poor memory (Singh-Manoux et al., 2008; Feinkohl et al., 2019), impaired executive functions (Sun et al., 2019) and cognitive decline (van Exel et al., 2002), as well as with lower gray matter volumes (Ward et al., 2010). It should be added here that higher levels of HDL-C have been associated with a decreased risk of Alzheimer's disease (Reitz et al., 2010) and that low HDL-C levels can result in cerebral amyloidosis (Reed et al., 2014).

The low sample size is a major limitation of this study. A further important limitation is that we used a retrospective selfreport to asses ELS. Ideally, the long-term effects of childhood adversities should be studied in prospective longitudinal studies and using qualitative or mixed methods can also add further valuable information when studying the impact of experienced traumas (see e.g., Boeije et al., 2013; Esposito et al., 2019), especially because self-reports can be biased. For example, social desirability can be an important potential bias when reporting past traumatic events especially in health-related research (see e.g., Adams et al., 2005; van de Mortel, 2008; Caputo, 2017 on this topic). Another limitation of our study design is that it does not allow to derive causal relations, but only associations. To compensate these limitations we did our best to carefully select the participants and match them in age, gender, lifestyle habits, and clinical data. Notably, only a few studies (Ding et al., 2014; Wingenfeld et al., 2017) included a control group in their studies, besides the MDD patients with or without ELS. We also carefully analyzed the influence of the various ACE subtypes. Finally, we also assessed the cognitive performance of our subjects and none of the earlier studies did such measurements.

Our present findings, together with the results available in the literature, have important clinical implications regarding the psychological interventions in case of depressed patients with ELS. Several studies demonstrated that depressed adults who experienced ELS react less well to conventional treatments than those who were not exposed to stressful life events during childhood (reviewed by Targum and Nemeroff, 2019). There is some evidence that MDD with ELS reacts much better to cognitive behavioral therapy (Nemeroff et al., 2003; Niciu et al., 2015) or interpersonal therapy (Zobel et al., 2011) than to pharmacotherapy. Psychodynamic therapies, as well as mentalizing-based therapy, can also be beneficial for MDD patients with ELS (Alessi and Kahn, 2017; Luyten and Fonagy, 2018). Our data emphasize the importance of the screening for ELS in the clinical MDD population. In case of early emotional abuse and emotional and physical neglect, we should consider psychotherapeutic interventions. Relying on relational cooperation, psychodynamic psychotherapy interventions can be especially helpful for patients with ELS, as they can establish an atmosphere of acceptance and safety, factors that are extremely relevant in early traumatized individuals. The holding environment and containment, created in this way, can provide a basis for the therapy of mood symptoms, and it may also reduce the risks for somatic complications. In addition, mentalizing based therapy can support early traumatized patients with an insecure attachment to regulate their negative affective states, and

reduce stress, instead of using unhealthy methods to cope with stressful situations.

In summary, our present data provide further evidence that childhood adversity may increase the risk of CVD. We found that depressed patients with ELS had higher serum triglyceride and lower HDL-cholesterol concentrations compared to patients without ELS. The severity of childhood adversity and the different trauma types showed specific associations with the lipid profiles, but we could not find any association between the severity of ELS and cognitive performance. Further research is needed to clarify the exact intermediary factors in order to gain a better understanding on the physiological mechanisms linking childhood adversities to cardio-metabolic disease, including the exploration of the difference as well as common pathways for specific maltreatment. Importantly, these issues should preferably be investigated in longitudinal studies as the retrospective selfreported measures might be biased. Finally, our present findings highlight the importance of controlling ELS, especially when a psychiatric sample is studied and treated.

### DATA AVAILABILITY

All datasets generated for this study are included in the manuscript and/or the **Supplementary Files**.

### ETHICS STATEMENT

The local Research Ethics Committee of the University of Pécs approved the study design and protocol (Ethical Approval Nr.: 2015/5626) and all participants provided written informed consent.

### AUTHOR CONTRIBUTIONS

ÁP, BC, and MS conceived the study, designed the experiments, and wrote the manuscript. NN carried out the psychological

### REFERENCES

and neurocognitive tests with the subjects, analyzed the data, prepared the tables and the figure, and wrote the manuscript. RH helped with the statistical analysis. MS selected the patients and made the diagnosis. TT and AM provided supervision and had helpful comments on the interpretation of the data. All authors contributed to the writing of the manuscript and/or revising it critically for important intellectual content, approved the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

### FUNDING

This work was financially supported by the following grant agencies: EU Social Funds (EFOP-3.6.3-VEKOP-16-2017- 00009 and EFOP-3.6.2-16-2017-00008, "The role of neuroinflammation in neurodegeneration: from molecules to clinics" and GINOP-2.3.2.-15-2016-00050, "PEPSYS"), the Hungarian Brain Research Program (KTIA\_NAP\_13-2-2014-0019 and 20017-1.2.1-NKP-2017-00002), and The Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the 20765- 3/2018/FEKUTSTRAT 5th thematic program of the University of Pécs. Further financial support was received from the Medical School of the University of Pécs. These grant agencies had no influence on study design; on the collection, analysis, and interpretation of data; on the writing of the report; and on the decision to submit the article for publication.

### SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyg. 2019.01798/full#supplementary-material

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**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Péterfalvi, Németh, Herczeg, Tényi, Miseta, Czéh and Simon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Effects of Metabolic Syndrome on Cognitive Performance of Adults During Exercise

Marco Guicciardi1 \*, Antonio Crisafulli2 , Azzurra Doneddu2 , Daniela Fadda1 and Romina Lecis1

1 Department of Pedagogy, Psychology and Philosophy, Faculty of Humanities, University of Cagliari, Cagliari, Italy, 2 Sports Physiology Laboratory, University of Cagliari, Cagliari, Italy

The metabolic syndrome (MS) has been associated with poor performances in multiple cognitive domains, as processing speed, visuo-spatial abilities, and executive functioning. Exercise is a critical factor for MS people's vulnerability to cognitive dysfunction, because this may be beneficial to reduce cognitive impairment, but limited physical activity and impaired cerebral blood flow in response to exercise have been reported by individuals suffering from MS. Using an attentional interference test, the Bivalent Shape Task (BST), and metaboreflex, we analyzed cognitive performance and cerebral oxygenation (COX) in 13 MS people (five women), and 14 normal age-matched control (CTL, six women). Five different sessions were administered to all participants, each lasting 12 min: control exercise recovery (CER), post-exercise muscle ischemia (PEMI) to activate the metaboreflex, CER + BST, PEMI + BST, and BST alone. During each session, cognitive performance was assessed by means of response times and response accuracy with which participants make the decision and COX was evaluated by near infrared spectroscopy with sensors applied in the forehead. Compared to CTL, MS group performed significantly worse in all sessions (F = 4.18; p = 0.05; ES = 0.13): their poorest performance was observed in the BST alone session. Moreover, when BST was added to PEMI, individuals of the CTL group significantly increased their COX compared to baseline (103.46 ± 3.14%), whereas this capacity was impaired in MS people (102.37 ± 2.46%). It was concluded that: (1) MS affects cognitive performance; (2) people with MS were able to enhance COX during exercise, but they impair their COX when an attentional interference task was added.

Keywords: metabolic syndrome, exercise, cognitive processes, NIRS, attentional task

## INTRODUCTION

The metabolic syndrome (MS) is a cluster of interrelated conditions, increasing the risk of heart disease, heart disease, Type 2 diabetes mellitus, and stroke, among other health problems. The International Diabetes Federation estimated that 20–25% of the global adult population suffers from MS (International Diabetes Federation, 2015), which increases in older adults, but rates of MS ranging between 0 and 19.2% were also reported among children and adolescents (Friend et al., 2013). According to clinical guidelines, an individual suffers from MS if three or more risk factors

#### Edited by:

Gabriella Martino, University of Messina, Italy

#### Reviewed by:

Santo Di Nuovo, University of Catania, Italy Ciro Conversano, University of Pisa, Italy

\*Correspondence: Marco Guicciardi<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychopathology, a section of the journal Frontiers in Psychology

Received: 14 June 2019 Accepted: 26 July 2019 Published: 08 August 2019

#### Citation:

Guicciardi M, Crisafulli A, Doneddu A, Fadda D and Lecis R (2019) Effects of Metabolic Syndrome on Cognitive Performance of Adults During Exercise. Front. Psychol. 10:1845. doi: 10.3389/fpsyg.2019.01845

as high blood glucose, high blood pressure, high plasma triglycerides, high waist circumference, and low HDL cholesterol are present (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001; Alberti et al., 2009).

The MS has been correlated to cognitive dysfunction and poor performances in multiple domains as processing speed, memory, semantic fluency, visuo-spatial abilities, sustained attention, and executive function (Yaffe et al., 2004; Segura et al., 2009; van den Berg et al., 2009; Solfrizzi et al., 2011; Yates et al., 2012; Wooten et al., 2019). In order to explain the effects of MS on cognitive impairments different risk factors such as neuroinflammation, oxidative stress, impaired vascular reactivity, and abnormal brain lipid metabolism have been taken into account (Yates et al., 2012).

Although every single risk factor plays some role in the decline of cognitive function, the question was raised as to whether these risk factors taken together have a higher predictive value for cognitive deterioration. Cohort studies with cross-sectional research designs (Yaffe et al., 2004; Segura et al., 2009; Vieira et al., 2011) or longitudinal (Yaffe et al., 2009; Akbaraly et al., 2010) build a strong case for MS being associated with poor cognitive performance than its individual components. MS is mostly associated with impaired executive functioning, among all reported deficits (Wooten et al., 2019), although findings are mixed, with some cross-sectional studies reporting no effects (Tournoy et al., 2010; Kim et al., 2011) or even better cognitive performance among older women suffering from MS (Laudisio et al., 2008). Clearly, some of the ambiguity in the results obtained could be the effect of methodological issues as cognitive domains selected, demographic characteristics (i.e., differences in age, race, gender, educational level, and socioeconomic position), MS status vs. persistent MS, health status of experimental and control group, and complexity in splitting the impact of individual factors from that of the MS itself (Akbaraly et al., 2010); further studies incorporating some protective factors have been also claimed (Yates et al., 2012).

The vascular risk factors as, for example, high blood sugar and low level of HDL cholesterol, are all potentially reversible and current recommendations for the treatment of MS encourage intensive therapeutic lifestyle changes such as increasing regular physical activity and reducing the dietary intake of saturated fat and cholesterol. Regular physical activity of moderate intensity can reduce singular metabolic risk factors while benefits of exercise on multiple risk factors were also reported (Laaksonen et al., 2002; Katzmarzyk et al., 2003; Holme et al., 2007). Previous researches show evidence that a lower prevalence of MS is associated with at least 150 min weekly of moderate-intensity PA (Strasser, 2013). However, to appreciate the benefits of movement it is relevant to distinguish among physical activity and exercise: while physical activity refers to any movement produced by skeletal muscles that require energy, exercise enhances the capacity and efficiency of the cardiorespiratory system and muscular strength associated with health and functional capacity (Caspersen et al., 1985). Improvements in fitness are noticeable in enhancement in executive-control processes such as, inhibition, planning, scheduling, coordination, and working memory. Due to brain activation and to the increase of cerebral blood flow (CBF) exercise may be therefore beneficial to reduce cognitive impairment (Secher et al., 2008; Kim et al., 2011). Interventions, such as exercise training programs, increase the cognitive performance of one-half standard deviation on average, regardless of the type of training method, cognitive task, or participants' characteristics (Colcombe and Kramer, 2003). Other potential mechanisms that account for the cognition-enhancing effects of exercise encompassed vascularization, neuroendocrine response to stress, neuroinflammation, brain amyloid burden, or other favorable effects on neuronal survivability and function (Baker et al., 2010).

Moreover, muscle metaboreflex activated by metabolites accumulating in the muscle during contraction can enhance the sympathetic tone and consequently the sympathetic nervous system (SNS) activity (Boushel, 2010). However, in people with metabolic disorders impaired CBF was reported whether caused by exercise (Kim et al., 2015; Vianna et al., 2015) or by stimulation of metaboreflex (Delaney et al., 2010; Milia et al., 2015; Crisafulli, 2017). Consequently, we have assumed that exercise is a critical factor for MS people's vulnerability to cognitive dysfunction, because may support cognitive functions, but limited physical activity and impaired CBF after exercise has been reported by individuals suffering from MS. When cerebral oxygenation (COX) is reduced after exercise (or stimulation of metaboreflex) cognitive functions can deteriorate and people experience early fatigue (González-Alonso et al., 2004; Rasmussen et al., 2010). Subclinical alterations in cerebrovascular reactivity and cerebral metabolism may denote early brain compromise associated with peripheral metabolic disturbances (Yates et al., 2012). Individuals with MS may not be able to retain an optimal neuronal environment, mostly when a high demanding cognitive task is superimposed to exercise. We hypothesized therefore that the association between metaboreflex and a contemporary mental task could result in an impairment of cognitive performance and in a reduced COX, in people suffering from MS.

### MATERIALS AND METHODS

### Participants

Two groups of participants were enrolled:

by any metabolic disease as resulted from anamnesis and physical examination.

In addition to age ≤18 and ≥65 years, exclusion criteria encompassed significant medical disease that could interfere with the autonomic function. Smokers and individuals taking sympatho-mimetics, β-blockers, and/or tricyclic antidepressants were also excluded.

### Procedure

After enrolment, participants attended the laboratory on two occasions: one preliminary baseline visit and one experimental phase.

Baseline visit: All participants received a medical examination with anamnesis, anthropometric measures (weight, height, body mass index, waist circumference, and body composition), ECG, and blood pressure. To assess physical capacity all participants performed a cardiopulmonary exercise test (CPT) on a cycle ergometer (CUSTO Med, Ottobrunn, Germany): maximum heart rate (HRmax), maximal oxygen uptake (VO2max), and maximum workload (Wmax) were recorded. During the baseline visit, the participants familiarized with the laboratory equipment and staff.

Experimental phase: this phase started after at least 3 days (range 3–7 days) from baseline visit and included in random order five sessions (**Figure 1**). All participants were randomly assigned to the following five sessions. All sessions were composed of four blocks each lasting 3 min, for a total of 12 min. Sessions were spaced by at least 15 min of recovery. Recovery was considered complete when the heart rate was not higher than 5 bpm compared with the pre-exercise level. Participants were requested to abstain from alcohol, caffeinated beverages, and heavy exercise for 12 h prior to coming to the laboratory.

This study was carried out in accordance with the recommendations of the Code of Ethics for Research in Psychology, Italian Association of Psychology. The protocol was approved by the ethics committee of the University of Cagliari. All participants gave written informed consent in accordance with the Declaration of Helsinki.

The experimental phase started after at least 3 days (range 3–7 days) from baseline visit and included in random order the following five sessions (**Figure 1**):

Specifically, sessions were as follows:

level. Values are mean ± SD. A horizontal bracket indicates the overall main effect of groups; a vertical bracket indicates the overall main effect of

condition. ∗p < 0.05 vs. CER test of the same group.

shape is presented either in blue, red, or an unfilled black outline. Visual response cues are provided below the stimulus, indicating the side of the response and are shaded in either red or blue. Three trial types were presented: neutral trials in which the stimulus is black and white; congruent trials, in which the (irrelevant) color of the stimulus matches the response cue; and incongruent, in which the (irrelevant) color mismatches the response cue. Compared to the condition in which the dominant response and the activated response are the same (e.g., congruent trials), a response interference is stimulated whenever the dominant response has to be suppressed in order to give the instructed response, as in the incongruent trials: this results in a deterioration of the performances. Dependent measures are the speed and accuracy with which participants take the decision: the speed was assessed in ms, the accuracy as percent of correct responses. The MT started after 6 min of rest and lasted for 3 min. Three further minutes of recovery was allowed after the termination of MT.

• CER + MT: the same rest-exercise protocol used for CER was performed. The exercise phase was followed by a MT session of 3 min, i.e., the same duration of the MT session described previously. Three further minutes of recovery was allowed after the termination of MT.

• PEMI + MT: the same rest-exercise protocol used for PEMI was performed. The exercise phase was followed by 3 min of contemporary PEMI and MT. Three further minutes of recovery was allowed after the termination of the PEMI + MT period.

Throughout sessions, COX was assessed by means of near infrared spectroscopy (NIRS; Nonin, SenSmart X-100, Plymouth, MN, United States), which provided a measure of oxygenated Hb in the brain tissue. It is recognized that changes in COX are representative of cortical activation (Strangman et al., 2002) and COX assessments by means of NIRS during mental tasks such as calculation, interference, or Stroop tasks were already reported (Plichta et al., 2006; Verner et al., 2013; Ferreri et al., 2014). Two NIRS sensors were placed on the right and left subject's forehead above the eyebrow, in the regions between Fp1 and F3 (international EEG 10–20 system) and adjusted according to the strong signal. Oxygenated Hb measured by NIRS can be considered an index of regional tissue blood flow as previously reported (Suzuki et al., 2004). Since the absolute concentration of oxygenated Hb could not be acquired, because the path length of NIRS light within the brain tissue was unknown, relative changes of NIRS signals against the baseline values were taken into account.

This study was carried out in accordance with the recommendations of the Code of Ethics for Research in Psychology, Italian Association of Psychology. The protocol was approved by the ethics committee of the University of Cagliari. All participants gave written informed consent in accordance with the Declaration of Helsinki.

### Data Analysis

Preliminary analysis showed that all the BST protocols were valid with an accuracy of responses equal or above the predetermined threshold. A preliminary check of data, executed by means of the Kolmogorov–Smirnov test with Lilliefors correction that renders this test less conservative, has confirmed a normal distribution for all parameters examined. The t-test for independent groups was used to assess differences in anthropometric characteristics, levels of triglycerides, HDL cholesterol, fasting glucose, and results of the CPT. Two-way ANOVA (factors: group and condition) was executed to assess (a) response times (ms) on BST; (b) change in COX reported as % changes from rest. Statistics were carried out utilizing commercially available software (GraphPad Prism and SPSS ver. 17.0). Statistical significance was established as a p-value of <0.05 in all cases.

### RESULTS

The protocol was completed by all participants none reported discomfort or unbearable pain during PEMI. Anthropometric characteristics of both groups together with results of the baseline visit are shown in **Table 1**.

Participants of the MS group had a higher weight, BMI, waist circumference, FM, SBP, DBP, and fasting glucose with respect to the CTL group. **Table 1** also shows that FFM, TBW, VO2max, Wmax, and HRmax were lower in the MS than in the CTL group.

TABLE 1 | Anthropometric characteristics of both groups together with results of the screening medical examination and of cardiopulmonary test.

Values are mean ± SD. CTL = controls (n = 14), MS = Metabolic Syndrome patients (n = 13).

**Table 2** shows that the significant differences between groups were found only in BST scores, while COX was significantly affected by the condition. In particular, MS group, compared to CTL group, performed significantly worse in all sessions were MT was included (F = 4.18; p = 0.05; ES = 0.13). In both groups, COX increased during the CER, the PEMI, the CER + MT, and the PEMI + MT tests compared to the MT test.

Moreover, when MT was added to PEMI, individuals of the CTL group significantly increased their COX compared to baseline (103.46 ± 3.14%), whereas this capacity was impaired in MS people (102.37 ± 2.46%, see **Figure 2**).

### DISCUSSION

The management of chronic diseases requires to assume and maintain an active role centered on: (a) acquisition of selfregulated behavior; (b) suppression of interferent habitual response (such as sitting after meals); and (c) replacement of habit with other healthier behavior (such as going for a walk) (Settineri et al., 2019). Exercise appears to be a useful strategy to treat MS, because it could reduce cognitive impairment and risk to develop Type 2 diabetes mellitus, stroke, and heart diseases. However, adults with MS may be at increased risk of non-adherence exercise due to a concurring rise in behavioral requests (e.g., nutrition planning, glucose tracking, medication timing) and decrease in cognitive function (Olson et al., 2017). Compared to modifications of nutrition or taking medications, exercise requires more time to be practice and deliberate continuous effort of planning and monitoring: people suffering from chronic diseases often perceive its adoption as a significant and difficult change in their lifestyle (Guicciardi et al., 2014).

The principal aim of the present investigation was to characterize the mental performance and the COX in people suffering from MS during exercise, associating a mental task (BST) to metaboreflex activated by means of the PEMI method.

About the mental performance, significant differences in response times were found between groups: the participants suffering from the MS took longer to discriminate the shapes of BST. Compared to CTL group, their performances were always worse, supporting the hypothesis that MS can impair executive functions, such as interference suppression. The difference in cognitive performance due to MS was small (ES = 0.13); however, considering the high prevalence of MS, the burden of impaired cognition due to the MS may be substantial in the overall population (Vieira et al., 2011). The individuals suffering from MS may not be able to maintain an optimal performance during high demanding tasks as BST, which requires participants to control the interference due to the stimulus characteristic (e.g., color) and focus on the relevant information (e.g., shape) to give the correct response. Both groups have reported their poorest cognitive performance in the MT alone trial, but when PEMI or CER was superimposed their response times improved even if not significantly. As know, exercise has more effect on executive functions, than on any other type of cognitive process (Colcombe and Kramer, 2003); however, to evaluate concurrent improvements in other cognitive processes, such as working memory, sustained attention, or visuospatial abilities further researches should be conducted using more suitable tasks.

About the COX, participants suffering from MS, compared with healthy controls, were unable to increase COX when BST was superimposed to the PEMI-induced metaboreflex activation. This occurrence suggests that people suffering from MS were not able to increase COX to the same extent of CTL groups when a mental task was superimposed to the PEMI-induced metaboreflex activation. In both groups during the mental task, COX tended to slightly increase with respect

TABLE 2 | Bivalent shape test (BST) scores and cerebral oxygenation (COX) during the mental task (MT), control exercise recovery + mental task (CER + MT), and post-exercise muscle ischemia + mental task (PEMI + MT) tests for control (CTL, n = 14) and metabolic syndrome (MS, n = 13) groups.

Values are mean ± SD. ∗p < 0.05 vs. MT test of the same group.

to the baseline. This MT-induced raise in COX was probably the consequence of the increased brain activity due to the mental task, which enhanced brain metabolism and led to COX elevation (Willie et al., 2014). All COX levels were similar among conditions with an exception: during the PEMI + MT test of the CTL group, COX was significantly more elevated than the baseline. This could demonstrate that adding a mental task to the PEMI-induced metaboreflex activation increased COX in normal individuals, but not in individuals suffering from MS, who were not able to increase COX to the same extent of CTL participants.

We examined the effects of experimental sessions on response times and we used these data to infer information about the brain mechanisms involved while performing a mental task during an exercise. We cannot provide any ultimate explanation for the lacking increase of COX in MS group when a mental task was superimposed to PEMI: individuals could have an elevated SNS drive which impaired the capacity to enhance COX or an impaired cerebral vascular reactivity or a reduced capacity to maintain COX at a proper level. Whatever the cause results suggest that individuals suffering from MS have impaired executive control and are unable to properly increase COX when a mental task activity was superimposed the metaboreflex obtained by means of PEMI maneuver. This phenomenon could explain why individuals suffering from MS do not meet physical activity recommendation, since executive functions are necessary for behavior change and can affect an individual's capability to successfully adopt and maintain physical activity behavior change (Olson et al., 2017).

### Limitations of the Study

One possible limitation of this study is the response times of BST assumed as proxies to assess executive functions. Attention and processing speed are typically categorized as a general cognitive function; however, they are more related to executive function domain and to a successful behavioral change (Olson et al., 2017). The BST is an attentional test, where color and shape are varied within trials. The task is similar to other traditional interference tasks (e.g., the Simon interference task, the color-word Stroop test, and Eriksen's flanker task), but not prompts verbal reactions. The task was already used to assess the ability to suppress irrelevant information in non-linguistic settings, but more studies are required to validate this task with adults suffering from MS. Another possible limitation of the present investigation is that SNS activity was not directly assessed. This kind of measure are somewhat invasive and not applicable in experimental settings such as the present one, with ongoing psychological stress. A further potential limit of this study is related to the use of NIRS, compared to other brain imaging techniques, such as transcranial Doppler (TCD) or functional magnetic resonance imaging (FMRI). Several studies have confirmed the sensitivity of NIRS to measure subtle changes in COX during arithmetic or neuropsychological tasks involving the frontal lobe such as Stroop test (Ferreri et al., 2014). However, NIRS suffers of low spatial resolution which makes difficult to detect

changes in areas located distant from the monitored site. On the other hand, NIRS offers some advantages as portability, good motion tolerance, non-invasiveness, and low maintenance costs. A further limitation of this study is the small size of the sample of individuals suffering from MS, that asks for studies replications. Finally, we cannot exclude that asking participants to refrain from caffeinated beverages, alcohol, and heavy exercise for 12 h before the experimental phase, may have affected their routine, and therefore every participant's average performance.

### CONCLUSION

In conclusion, the results of the present investigation provide evidence that individuals suffering from MS had worse cognitive performance, compared to control group, in an attentional interference task, which involves executive functions. Individuals with MS were able to enhance COX during handgrip and during the metaboreflex activation; however, they could not further enhance COX when a mental task was superimposed to the metaboreflex. This conclusion could be intriguing as it may provide a potential psycho–physio– pathological basis of the scarce predisposition to exercise often reported in people with MS, since metaboreflex and cognitive performance are both operating during exercise (Wasmund et al., 2002) and executive functions are necessary to initiate and maintain physical activity behavior change (Olson et al., 2017).

### DATA AVAILABILITY

The datasets generated for this study are available on request to the corresponding author.

### AUTHOR CONTRIBUTIONS

The final version of this manuscript was written by MG and AC who contributed equally to the theoretical and empirical aspects of the study. AD collected and analyzed the medical data and wrote a preliminary version of this manuscript. RL and DF, respectively, collected and analyzed the psychological data.

### FUNDING

This study was supported by the Fondazione di Sardegna (agreement between Fondazione di Sardegna and University of Cagliari, year 2016) and by the University of Cagliari.

### ACKNOWLEDGMENTS

This manuscript updates and extends a preliminary research report presented at ECHW2019.

### REFERENCES

fpsyg-10-01845 August 7, 2019 Time: 18:7 # 7

isometric exercise in type 2 diabetes patients. Am. J. Physiol. Heart Circ. Physiol. 308, H681–H687. doi: 10.1152/ajpheart.00343.2014

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Guicciardi, Crisafulli, Doneddu, Fadda and Lecis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Emotional Suppression and Oneiric Expression in Psychosomatic Disorders: Early Manifestations in Emerging Adulthood and Young Patients

#### Salvatore Settineri1 , Fabio Frisone2,3, Angela Alibrandi4 and Emanuele Maria Merlo2,3 \*

1 Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy, 2 Department of Cognitive Sciences, Psychology, Educational and Cultural Studies (COSPECS), University of Messina, Messina, Italy, 3 CRISCAT (International Research Center for Theoretical and Applied Cognitive Sciences) University of Messina and Universitary Consortium of Eastern Mediterranean, Noto (CUMO), University of Messina, Messina, Italy, 4 Department of Economics, Unit of Statistical and Mathematical Sciences, University of Messina, Messina, Italy

#### Edited by:

Viviana Langher, Sapienza University of Rome, Italy

#### Reviewed by:

Cristiano Scandurra, University of Naples Federico II, Italy Ion G. Motofei, Carol Davila University of Medicine and Pharmacy, Romania

> \*Correspondence: Emanuele Maria Merlo<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Psychopathology, a section of the journal Frontiers in Psychology

Received: 15 June 2019 Accepted: 01 August 2019 Published: 20 August 2019

#### Citation:

Settineri S, Frisone F, Alibrandi A and Merlo EM (2019) Emotional Suppression and Oneiric Expression in Psychosomatic Disorders: Early Manifestations in Emerging Adulthood and Young Patients. Front. Psychol. 10:1897. doi: 10.3389/fpsyg.2019.01897 Background: The function of emotions, beginning from the proto-emotions, is the adaptation to the environment. This is based on the Homeorhesis, the equilibrium due to the adaptive operation of excitement and the dissipation of emotions. The object relations of the participants foresee the practice of defense mechanisms in a continuum that goes from the consciousness to the oneiric activities. The predominant and maladaptive use of defense mechanisms in the psychosomatic phenomenology, can be identified with deficits in emotional awareness, with the impossibility to manage excitement and dissipation of emotions foreseen by the oneiric phenomena.

Methods: The observation group is composed by 140 participants, 56 males (43%) and 84 females (57%),with pathological-functional disorders of psychosomatic domain. The study had been conducted with the use of measures related to the conscious defense of suppression (Suppression Mental Questionnaire), to the emotional awareness linked to the psychosomatic phenomena (Diagnostic Criteria for Psychosomatic Research Structured Interview-DCPR-SI) and to the states of perturbation and conservation of oneiric activities (The Manheim Dream Questionnaire-MADRE).

Results: Significant inverse correlations emerged among rationalization, repressive function and illness Denial, as for the suppression mental questionnaire factors and irritable mood, but for Regression in the service of the Ego; inverse and significant correlations emerged among suppression, repressive function, rationalization and gastrointestinal psychosomatic outcomes and among suppression, repression and cardiological psychosomatic outcomes. Regarding alexithymia, a positive correlation emerged with rationalization and inverse with Regression in the service of the Ego. Positive correlations emerged between illness denial and overall emotional tone, for disease phobia and meaningfulness and for cardiological psychosomatic outcomes and nightmare distress and recurring nightmares.

Conclusion: The study of such outcomes due to a prevalent defensive style based on suppression, suggest the identification of a key phenomenon, which translates into maladjustment that goes from functional disorders to parasomnia. The bridge established by the obfuscation of conscious contents until the manifestations of disturbance of ancient activities such as oneiric ones, expresses the need to transform an emotional maladaptive style, in line with classic literature and the current state of art.

Keywords: psychosomatics, suppression, dreams, psychological factors, emotional

### INTRODUCTION

As suggested by Berney et al. (2014), the clinical study of defense mechanisms allows us to comprehend and to explain affective dynamics, particularly relevant in clinical and therapeutic fields. In line with other defense mechanisms, the suppression has an adaptive meaning when its use is well integrated and directed to the managing of environmental and inner necessities (Metzger, 2014) and it is considered as a mature defense (Perry, 1990; Vaillant, 2000; Perry and Henry, 2004). The use and the polarization on suppression is considered by classical psychosomatic research as the main psychological figure for the occurrence of relevant organic outcomes (Marty and Fain, 1952).

We assist to affective dynamics whose un-expression and difficulties in the mentalization processes, are then translated in body manifestations on target organs and tissues. Differently from other defense mechanisms, the particular constitution of suppressive functioning is based on the need to face conflicts consciously recognized, so that its use is common, conscious and familiar to everyone's daily life (De Burge, 2001; Settineri et al., 2016).

In this sense, the outcome of the dysfunctional defense use, finding an indirect expression for us known in the products as symbolization, functional disturbance and organic lesions. This particular body-mind dynamic, is close to the current topics of the body-mind problem (Motofei and Rowland, 2018) and the necessity to confront classical approaches to current research practices.

In this sense, some of the classical considerations treated relevant dynamics such as dream contents (Kupper, 1947; French and Shapiro, 1949; Levitan, 1978; Warnes, 1982), dreams preceding psychosomatic illness (Warnes and Finkelstein, 1971) and the failure of defense dynamics in dreams of psychosomatic patients (Levitan, 1981). Recent approaches allow us to maintain the strong basis of previous research (Settineri et al., 2018) with the help of technology and modern practices (Schredl et al., 2014; Settineri et al., 2016, 2019c).

With particular attention to early psychosomatic manifestations and periods preceding somatic crisis, it is known in past literature, how psychosomatic illness is a substitute and following concomitant during emotional states of anxiety, depression, anger, guilt, and fear (Warnes and Finkelstein, 1971; Merlo et al., 2018; Vicario et al., 2019). Dreams are triggered by this emotional state, which in turn facilitates somatic reactivity in predisposed individuals. As for the conscious nature of suppression, the study of dream through consciousness is possible with the empirical research on recall phenomena (Cory et al., 1975; Cernovsky, 1984; Schredl and Engelhardt, 2001; Beaulieu-Prévost and Zadra, 2005; Schredl, 2007; Schredl and Göritz, 2015; Mangiaruga et al., 2018) and with reference to their characteristics and contents (Schredl, 2010). As for the relevance of dream recall, the presence of maladjustment in psychopathological conditions is also expressed through oneiric manifestations (Schredl and Engelhardt, 2001; Llewellyn and Desseilles, 2017; Aviram and Soffer-Dudek, 2018), such as nightmares (Schredl and Göritz, 2018) since childhood to adulthood (Kajeepeta et al., 2015) and above mentioned relevant characteristics of dreaming.

Currently, the need of providing new research instruments close to the purpose of clinical psychology in psychosomatics, was foreseen by the integration of those phenomena that go beyond the nosographic framework (Porcelli and Rafanelli, 2010; Fava et al., 2017). As suggested by Porcelli and Rafanelli (2010), the use of certain psychodiagnostic instruments allow us to diagnose from 2 to 3 syndromes that are not diagnosable with DSM. A particular interest is due to alexithymia, whose relevance has a long history in literature and strong evidence in clinical and neuroscientific contexts (Tesio et al., 2019). The same authors suggest a prevalence psychosomatic syndromes in different clinical settings, such as Dermatology (Picardi et al., 2006), Cardiovascular (Grandi et al., 2001; Rafanelli et al., 2003, 2006), Gastrointestinal (Porcelli et al., 2000; Carrozzino and Porcelli, 2018; Kano et al., 2018), and others.

### The Current Study

The scope of this study was to highlight the characteristics related to the role of different factors of suppression and their outcomes through the revelation of oneiric perturbation and pathological psychosomatic phenomena.

Hypothesis:

HP-1 we hypothesize that different Suppression factors are significantly and inversely (−) associated with the Psychosomatic Syndromes and the pathological diagnosed groups;

HP-2 we hypothesize that the different Psychosomatic Syndromes are significantly and positively associated with Oneiric phenomena, plus the pathological diagnosed groups;

### MATERIALS AND METHODS

fpsyg-10-01897 August 17, 2019 Time: 15:43 # 3

### Procedure and Participants

The observation group consists of 140 participants, 56 males (43%), and 84 females (57%). The age of the participants included in the study is between 19 and 30 years old, with an average of 23.58 years (SD = 2.06).

The research was carried out within the UOC of Psychiatry of the University Hospital G. Martino of Messina.

The participants of the research were considered on the basis of the diagnosed psychosomatic clinical reality, of the related evident psychological components and subsequently subjected to psychodiagnostic practice.

The participants were invited to continue the diagnostic process in order to produce clinical evidence, useful to highlight the psychological characteristics underlying the recognized medical condition and to use the data for research.

The study with the participants and the subsequent diagnostic phases lasted about 2 h for each patient. The compilation of the questionnaires was of a paper and pencil type and each participant before the signing of the informed consent was informed about the anonymous nature of the methods of data processing, as required by the procedures of the ethical committee evidenced by the approval.

### Statistical Analysis

The numerical data were expressed as mean and standard deviation and the categorical variables as number and percentage.

The Spearman test was applied in order to evaluate the correlation among Suppression, Dream and Psychosomatic variables of the following instruments.

Statistical analyses were performed using SPSS 20.0 for Window package.

A P-value smaller than 0.050 was considered to be statistically significant.

### Instruments

#### Suppression Mental Questionnaire

The suppression metal questionnaire was developer in 2016 by Settineri et al., it provide for a total score about Suppression and three factors, respectively, Repressive function, Regression in the Service of the Ego and Rationalization. An app version was also developed in 2019 (Settineri et al., 2019c).

The Mannheim Dream Questionnaire was developed by Schredl et al. (2014). An Italian adaptation of the questionnaire was provided by Settineri et al. (2019a). The instrument involves 20 factors about dreams and related phenomena. In this study the selected items were: Overall Emotional Tone, Nightmare Frequency, Nightmare Distress, Recurring Nightmares, Percentage of recurring Nightmares, Meaningfulness.

The reliability indexes of the considered Madre items (Dyck et al., 2017; Settineri et al., 2019a) are reported below.

Overall Emotional Tone:0.764 (0.708 to 0.797) Nightmare Frequency:0.876 (0.843 to 0.918) Nightmare Distress:0.823 (0.754 to 0.901)

Recurring Nightmares:0.899 (0.825 to 0.958) Percentage of recurring Nightmares:0.971 (0.962 to 0.984) Meaningfulness:0.775 (0.687 to 0.869)

Diagnostic Criteria for Psychosomatic Research (DCPR), is a clinical interview based on diagnostic criteria provided by Fava et al. (1995) whose structured interview is contained in the monograph by Porcelli and Sonino (2007); a set of 12 syndromes was provided: disease phobia, thanatophobia, health anxiety, illness denial, persistent somatization, functional somatic symptoms secondary to a psychiatric disorder, conversion symptoms, anniversary reaction, irritable mood, type A behavior, demoralization, and alexithymia. According to Galeazzi et al. (2004) the items of the DCPR showed a high showed interrater reliability with kappa values:

Disease phobia, kappa 0.97; Thanatophobia, kappa 0.92; Type A behavior, kappa 0.92, Illness denial, kappa 0.90; Demoralization, kappa 0.90; Anniversary reaction, kappa 0.90; Health anxiety, kappa 0.89; Alexithymia, kappa 0.89; Conversion symptoms, kappa 0.82, Persistent somatization, kappa 0.70; Irritable mood, kappa 0.69.

### RESULTS

### Descriptive Statistics

Descriptive statistics (mean and standard deviation) were reported in **Tables 1**–**3**, in order to highlight the presence of considered phenomena.

Hypothesis 1:

As regards the hypothesis 1 and as shown in **Table 4**, we found significant inverse correlations among Rationalization, Repressive function and Illness Denial, suggesting that decreasing level rationality and suppression corresponds to increasing denial level about diseases consideration and fear.

TABLE 1 | Suppression Mental Questionnaire factors and total score mean and standard deviation.

TABLE 2 | Mannheim Dream Questionnaire-Italian Adaptation considered variables mean and standard deviation.

TABLE 3 | Diagnostic Criteria for Psychosomatic Research (DCPR) frequency and percentage (N = 140).

Higher scores on Suppression mental questionnaire were associated with lower scores on irritable mood, but for Regression in the service of the Ego. In particular, the increase of Suppression, Repressive function and Rationalization suggest that rational practices related to thought correspond to decreasing irritable mood, anger, and other related phenomena.

Contrary to what emerged about conscious attempts to reduce irritability, the practice of fantasy and inner images as a way to have a deeper understanding of unconscious figures, has an increasing direction as for irritable mood. In this sense, the knowledge about the role of conscious defense such as suppression, confirm the phenomenology of decreasing affective dynamics and mood regulation.

TABLE 4 | Correlation coefficients among SMQ and DCPR variables.

In line with what emerged, Rationalization and Regression in the service of the Ego represent two opposite dynamics. Referring to their relation with Alexithymia, a positive correlation with Rationalization and an inverse relation with Regression in the service of the Ego has emerged. In particular these relations suggest that the non-rationality of the unconscious contents related to emotions are associated with the decreasing of Alexithymia and that a more rational approach to emotions and affectivity is closer to emotive crystallization.

In reference to the use of rationality treating emotions, negative significant correlations emerged among Suppression, Repressive function, Rationalization and Gastrointestinal psychosomatic outcomes. In the same way, negative significant correlations emerged among Suppression, Repression and Cardiological psychosomatic outcomes. In this sense, the directions assumed by the phenomena would inform us about the defensive value of the suppression and the associated phenomena. Specifically, the conscious dynamics linked to pathological outcomes, images and emotions were associated with attempts at adaptation that were still functional for the participants. This is to be considered with respect to the peculiarities of the participants, in their early psychosomatic manifestation. This would represent a good psychotherapic index, designed to avoid a crystallization on certain defense mechanisms (which then turns out to be dysfunctional) and the enrichment of adaptive modalities and management of disease representations.

#### Hypothesis 2:

As regards the hypothesis 2 and as shown in **Table 5**, we found that the results involving psychosomatic syndromes and dream outcomes demonstrate positive and significant correlations among Health anxiety with Recurring nightmares, the Percentage of Recurring Nigtmares and Disease Phobia with Meaningfulness.

∗p < 0.05 (two-tailed); ∗∗p < 0.01 (two-tailed).

∗p < 0.05 (two-tailed); ∗∗p < 0.01 (two-tailed).

In particular, considering the participants involved in this study with their early psychosomatic manifestations, these results show that at the beginning of the somatic manifestations we assist to an association linked to health and corporeal anxiety and the oneiric disturbance.

Beyond the highlighted associations, it is known as the managing of excitement and the dissipation of emotions ceases to be adaptive in pathological experience.

In the same direction, Illness Denial and Overall emotional tone were in a positive relation, suggesting the direction of emotions involved in this interruption of the adaptive managing of emotions. As for other relevant phenomena, the meaning related to dreams and to experience have a strong role in the adaptation processes. In particular, a positive correlation emerged between Disease Phobia and Meaningfulness, where the increase of phobias related to health and diseases corresponds to the increase of search for meaning.

In line with oneiric disturbance, Cardiological psychosomatic outcomes had positive associations with Nigtmare Distress and Recurring Nightmares, in order to confirm the relevance of dreaming related to the perception of somatic anguish and agitation.

### DISCUSSION

The current study was aimed at highlighting the relationships between emotional suppression and typical oneiric expressions in psychosomatic individuals in their first pathological manifestations.

For this reason, the choice to use specific instruments for the phenomena expressed, was been extended to participants who experimented pathological experiences of dermatological, cardiological and gastroenterological domain. The results showed that it was possible to observe phenomena related to emotional suppression in association with psychosomatic dynamics and between dream expressions and disorders mentioned above. In support of the first hypothesis of this study, we found an inverse general trend was found regarding the practice of emotional suppression, in relation to specific psychosomatic realities and large diagnostic groups. Considering the different nature between the first two factors of repression and the regression in the service of the Ego (less conscious fantasies), an important datum emerged in relation to the continuous and positive trend of the aforementioned dynamic and psychosomatic factors. In our research experience and in line with what was expressed in the results, conscious attempts to stem the psychosomatic experience appear in a reverse and therefore functional direction. In support of the second hypothesis, regarding oneiric manifestations we found dysfunctional experiences emerged in positive association with psychosomatic pathological experiences. Nightmares and dysfunctional emotionality emerged positively associated with specific psychosomatic dynamics and in particular (recurrence of nightmares) with cardiac disorders.

It is known how hard the impossibility to distance ourselves from pathological phenomena can be, such as psychosomatic ones, since childhood (Szwec, 2018). Our experience was referred to participants in their early pathological manifestations and to the reasons for symptom formation, all conflicts, defenses and previous traumatic experiences (Wolf et al., 2018). The main scope of this research was to highlight directly and undirectly related phenomena, in order to prevent the typical loss of an adaptive Self (Marchini et al., 2018) and psychological manifestations whose mechanisms can predict the serious incoming pathological realities, their complex denial (Livneh, 2009) and subsequent decreasing quality of life and body satisfaction (Guicciardi et al., 2014; Catalano et al., 2018; Martino et al., 2018) for both patients and caregivers (Ferrario et al., 2017; Settineri et al., 2019b).

In our experience, rationality and conscious suppressive functions emerged as opposite to denial phenomena, so that the defense function appears as an adaptive way to manage emotions related to the pathological reality. This result was in line with recent perspectives about denial, where the managing of negative emotions due to the onset of pathological manifestations, together with resistance to change, represent a relevant step in the conscious elaboration of disease (Nowak et al., 2015; Ferrario et al., 2017).

As suggested by Ferrario et al. (2017) the unconscious nature of defense mechanisms, different to coping strategies, is unintentionally (Cramer, 2000). Our case involved a conscious phenomenon, so the inverse relation between suppression and denial confirm the distance and the effect that each factor had on the other.

As for the unconscious nature of denial, the reasons on the basis of mood misadjustment can be unknown. The role of suppression on negative emotions, such those related to irritability and anger, was found as relevant in our experience. As suggested by Wolf et al. (2018), the onset of somatic symptoms involves different defense mechanisms, useful to manage emotional distress.

In particular neurotic manifestations such as irritability, tension, anxiety, impulse have the role to avoid intolerable feelings. The role of the studied factors in our contributions, distinguishes between defenses closer to consciousness and others, related to unconscious necessities. In line with the emerged results in the case of denial, even for irritable mood, the role of rational functions has an effective decreasing role, contrary to regression dynamics. In our experience, the role of fantasy and rationality changes in front of alexithymia and his relation with physical illness (Porcelli and Taylor, 2018).

According to Porcelli and Taylor (2018), the role of alexithymia in the production of somatic symptoms is relevant. As for the inverse effect of suppression on alexithymia (and the positive effect of fantasy and regression in the service of the Ego), the results highlighted the same dynamic also extended to gastrointestinal and cardiovascular disorders, according to Porcelli and Taylor and the above-mentioned literature about somatic symptoms and research methodology.

With particular reference to those pathological psychosomatic outcomes, other relationships emerged in term of oneiric manifestations. Health anxiety and illness denial were directly related to nightmares, in terms of recurring phenomena and emotional tone. The link between nightmares distress and frequency with psychosomatic manifestations is known in literature (Nguyen et al., 2002; Fantoni et al., 2007; Molina et al., 2016).

In our experience the central emotive core of fear about diseases, involved the search of sense and meaning, as expressed by dreams (Levitan, 1976), as highlighted by the relation between the conscious consideration of anniversaries and the decreasing manifestation of nightmares. In line with the above-mentioned considerations about the innovative use of instruments related to psychosomatics, we suggest our research experience, as linked to the integration and promotion of psychodynamic phenomena, before less considered clinically and psychometrically. Our direct experience with the construction of a psychometric instrument linked to suppression is close to this purpose. The use of this instrument represented a clinical consideration specifically dedicated to the primary phenomena associated with suppression and consequently to psychosomatics.

### Limitations and Conclusion

This study has a diversity of limitations that should be overcome in future studies. Besides the small sample size (140 participants), we assist just to the early psychosomatic manifestations in our young patients. This fact can be read through two opposing points of view. The first concerns this precise study, in which the first pathological manifestations are still not chronic and structured, although there are significant physical outcomes. This state is justified by the difficulty to express disturbing contents, which justifies the use of projective methods. Through the use of pareidolia and apperception (respectively, for Rorschach and Thematic Apperception Test) we reach equivalents whose revelation is due to the indirect request. The use of scales and psychometric measures is always useful, more with large samples and advanced pathological realities. The second point of view concerns the occasion given by this kind of studies, in terms of psychotherapy interventions. More advanced pathological states give light to a large number of relations among different variables, even if it could be harder to intervene on the phenomena in progress. Our purpose is referred to young patients, and in particular to the possibility to notice those phenomena on which it is possible to intervene instantly.

Further studies should focus in particular on investigating the relationships emerged, and should explore the causal links for which the outcomes we are witnessing are structured.

## DATA AVAILABILITY

The datasets generated for this study are available on request to the corresponding author.

### ETHICS STATEMENT

This study was approved by the local Institutional Ethical Committee. All the participants gave their consent to participate in this study and were evaluated by the clinical psychologists and physicians. This research was conducted with respect for the rights of the participants, according to the World Medical Association Declaration of Helsinki and its amendments. All administered instruments, including questionnaires, rating scales, and clinical structured interviews, were performed as a part of normal clinical practice assessment of patients. The data was analyzed anonymously. Each participant was properly informed about the research aim and study, and after comprehension signed the informed written consent.

### AUTHOR CONTRIBUTIONS

fpsyg-10-01897 August 17, 2019 Time: 15:43 # 7

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. SS made significant contribution to design the research study, and draft the manuscript and revise it critically. FF provided

### REFERENCES

substantial contribution in drafting the part of the manuscript. AA performed the statistical analysis and provided significant contribution to draft the part of the manuscript. EM made significant contribution to design the research study, provided the interpretation of data, a substantial contribution to draft the manuscript, and gave the final approval.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Settineri, Frisone, Alibrandi and Merlo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Depression According to ICD-10 Clinical Interview vs. Depression According to the Epidemiologic Studies Depression Scale to Predict Pain Therapy Outcomes

#### Sabine Fiegl1 \*, Claas Lahmann2 , Teresa O'Rourke1 , Thomas Probst1† and Christoph Pieh1†

1 Department for Psychotherapy and Biopsychosocial Health, Danube University Krems, Krems an der Donau, Austria, 2 Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Freiburg, Freiburg im Breisgau, Germany

#### Edited by:

Gabriella Martino, University of Messina, Italy

#### Reviewed by:

Oriana Mosca, Roma Tre University, Italy M. A. Salehienjad, Ruhr University Bochum, Germany

\*Correspondence: Sabine Fiegl<EMAIL_ADDRESS>†These authors have contributed equally to this work as senior authors

#### Specialty section:

This article was submitted to Psychopathology, a section of the journal Frontiers in Psychology

Received: 16 May 2019 Accepted: 29 July 2019 Published: 20 August 2019

#### Citation:

Fiegl S, Lahmann C, O'Rourke T, Probst T and Pieh C (2019) Depression According to ICD-10 Clinical Interview vs. Depression According to the Epidemiologic Studies Depression Scale to Predict Pain Therapy Outcomes. Front. Psychol. 10:1862. doi: 10.3389/fpsyg.2019.01862 Purpose: Pain and depression have been shown to have a bidirectional interaction. Although several outcome studies have been conducted, it is still unclear if and how depression influences pain outcome. The current study aims to further clarify this relationship by comparing the predicting value of an interview- and a questionnairebased assessment of depression.

Patients and Methods: This retrospective study analyzed data of N = 496 chronic pain patients who received a multimodal pain management program. Multilevel models were performed with depression as predictor, pain measures as dependent variables, and the respective pain score at baseline as covariate. Depression was measured at baseline with (1) a semi-structured psychiatric interview corresponding to the ICD-10 and (2) the Center for Epidemiologic Studies Depression Scale (CES-D).

Results: At post-treatment, pain intensity (NRS) was higher in patients with depression. This result emerged for interview- (ICD-10) and questionnaire- (CES-D) based depression. These results were significant after correction for multiple testing as well. Moreover, affective pain perception (PSS-A) at post-treatment was higher in patients with depression. Again, this result emerged for interview- (ICD-10) and questionnaire- (CES-D) based depression but it was not significant anymore after correction for multiple testing. Furthermore, pain disability (PDI) was higher at post-treatment in patients with depression according to the CES-D than in those without CES-D depression and this difference in the PDI did not emerge for interview-based depression. Yet, this difference on the PDI between the CES-D depression group and the CES-D no depression group was not significant anymore after correction for multiple testing.

Conclusion: The hypothesis that how depression is assessed – interview-based corresponding to the ICD-10 or with the CES-D – contributes to the association between depression and pain treatment outcome could not be confirmed. Future research should use more than one interview and questionnaire to assess depression, since our results are limited to the clinical ICD-10 interview and the CES-D.

Keywords: mood disorder, self-assessment, evaluation, disability, interdisciplinary treatment

### INTRODUCTION

fpsyg-10-01862 August 20, 2019 Time: 17:20 # 2