Retinal changes in generalized anxiety disorder patients

Abstract

Objective

Optical coherence tomography (OCT) is a method that allows high-resolution cross-sectional imaging of biological tissues. It was suggested that changes in the cranial structure or functions would be reflected in the retina. OCT has been an important method in the diagnosis and follow-up of diseases via morphometric or quantitative retinal measurements. Free radicals, inflammatory processes, and neurotransmission disorders play a role in the etiology of generalized anxiety disorder (GAD). The study aimed to demonstrate the retinal changes in GAD patients due to neurodegeneration based on the comparison of the OCT data of the GAD patients and controls, and the differences between OCT findings of GAD patients and those of controls.

Methods

The study group included 21 GAD patients. The control group included 21 individuals without any known psychiatric or organic disease, including eye diseases.

Results

There was a statistically significant difference between the macular volumes (MV) of the GAD and control groups, the macular volume was lower in the GAD group. There were positive correlations between BDI scores and MV, GCLT, RNFLT-i, RNFLT-n, between BAE scores and (RNFLT-n), and between the CGI severity scale scores and MV, RNFLT-n, and RNFLT-t.

Conclusion

OCT analysis of the GAD patients demonstrated that MV values were lower when compared to the control group. Patients with GAD should be screened for these retinal changes. OCT, a simple, non-invasive, and relatively inexpensive method could be employed as a supplementary method in the follow-up of GAD patients.

Keywords

anxiety disorders tomography optical coherence retina nerve fibers

Introduction

Generalized anxiety disorder (GAD) was described as excessive anxiety about certain events or activities and accompanying somatic symptoms on most days of at least 6 months. Anxiety or somatic symptoms could lead to clinically significant distress or impairment in social, occupational, or other significant functions.¹ The lifetime GAD prevalence was reported as 5.1% and the twelve-month prevalence as 3.1%.² The incidence among females is twice that of males (lifetime prevalence is 6.6% and 3.6%, respectively).² Psychogenic, genetic, and neurobiological factors play a role in the etiology of GAD. The amygdala plays a role in the induction of the anxiety response. The amygdala controls potential threats, activates the sympathetic nervous system and HPA axis through its connections with the hypothalamus, and mediates behavioral defense responses such as fight-or-flight and freeze.³ Certain studies reported that inflammation, free radicals, and neurotransmitter dysregulation play a role in the etiology.^4-6 It is known that all the above-mentioned processes lead to neuropsychiatric conditions via neurodegeneration.^4-6 The literature review did not reveal any study where the etiology was investigated with the OCT method in GAD patients.

Optical coherence tomography (OCT) is a non-invasive method that allows in vivo retinal imaging. Via morphometric or quantitative measurements of the retina and anatomical regions such as the optic disc and macula, the method allows the examination of intraretinal structures such as the retinal nerve fiber, photoreceptors, and retinal pigment epithelium.⁷ It provides cross-sectional tissue and pathology images similar to ultrasound but with much higher resolution [1-15 microns (μm)] by measuring the reflection delay and intensity of the ∼800 nm wavelength infrared light sent to the tissues and reflected by various tissue layers.⁸ The retina is an extension of the central nervous system that includes high-density laminar neuronal cells. Pathologies such as inflammatory responses in the retina and age-related cellular loss are similar to those observed in the brain.⁹ Since the anatomical structure of the retina is quite similar to the brain, the examination of the retina could give an idea about the signaling mechanisms, degenerative processes, and the effects of cerebral neuroprotective agents.⁹ In the literature, studies were conducted on retinal and neural network alterations with the OCT method in neurodegenerative diseases such as Alzheimer’s and Parkinson's diseases, multiple sclerosis, and retinal degeneration consistent with the clinic of the disease was identified. The findings demonstrated that the retina was a significant anatomical structure where clinicians could monitor degeneration.^10-13 Examination of retinal alterations with OCT has also been popular in studies on the etiopathogenesis of psychiatric disorders. It was determined that there were visual deficits in the early stages of schizophrenia, and recent studies demonstrated that dopamine was a major modulatory neurotransmitter in the retina.¹⁴ The first employment of OCT in psychiatry was on schizophrenia patients since the mechanism responsible for the pathophysiology was explained by reduced retinal dopamine in these patients.^15,16 Then, OCT studies were conducted to investigate the etiology of bipolar disorder (BD), major depression (MD), obsessive-compulsive disorder (OCD), and even substance use disorders.^14,17-19 Findings such as the presence of structural brain abnormalities that could be observed in both acute and remission stages of bipolar disorder (BD), structural cranial abnormalities during the first attack, and a progressive decrease in the total brain gray matter volume could be a sign of progressive neurodegeneration.²⁰ These findings led to a focus on retinal neural networks in recent years. The etiology of MD was investigated based on the monoamine hypothesis that includes serotonin, dopamine, and norepinephrine.²¹ Furthermore, studies on the activation of the inflammatory process in MD, which includes pro-inflammatory cytokines such as Interleukin-1 beta, IL-6, interferon-gamma, tumor necrosis factor-alpha, and their neurotoxic effects, which lead to cranial neurodegeneration, could be found in the literature and researchers focused on OCT findings.^17,21 A literature review on OCT suggested that there was a prolonged eye movement latency in OCD patients and certain dysfunctional and motor control regions in OCD. Thus, OCT has been employed in studies that investigated the etiology of OCD.^18,22 The findings of the rapidly increasing studies demonstrated that retinal examination with OCT could be a valid, easily accessible, and non-invasive method to investigate brain pathology in neuropsychiatric disorders.^8,17-22 Additionally, since it does not technically involve a closed area like CT or MR imaging, it may play a role in facilitating patient compliance in GAD, which is often accompanied by panic attacks and claustrophobia.

Thus, the present study aimed to compare the OCT data of GAD patients and controls to demonstrate the differences between the OCT findings of patients with GAD and those of controls, and the presence of neurodegeneration in GAD.

Methods

The study was carried out in the Psychiatry and Ophthalmology outpatient clinics of Firat University between June 2018 and January 2020 after the decision of the university ethics committee (31.05.2018-10/19). The study was conducted in accordance with the Declaration of Helsinki.²³

Participants

Patients

The psychiatric evaluations were made by a senior psychiatry assistant (AK). Twenty-five patients who consecutively applied to the psychiatry outpatient clinic and were diagnosed with GAD based on the DSM-5 were invited to participate in the study.¹

Three patients refused to participate and one patient was excluded from the study due to glaucoma diagnosis. The study group included 21 GAD patients who were between the ages of 18 and 65, literate, without a neurological disease or any significant physical pathology or physiological disease that would affect psychiatric symptoms. Those with a psychiatric or physiological disease excluding GAD, any eye disease that would affect OCT findings [ocular trauma, age-related macular degeneration, amblyopia, intraocular pressure (IOP) higher than 21 mmHg, glaucoma, optic neuropathy, uveitis, ocular surgery, hypertension, diabetes mellitus, refractive errors greater than ±2.0 diopters of spherical equivalence, opacity that may prevent OCT examination] were excluded. The patient group included individuals who were diagnosed with GAD but were not on medication for the previous month.

Controls

The control group included 21 healthy individuals without any known psychiatric or organic disease, including eye diseases, who met the study criteria and matched the patient group. After the anamnesis, the control group underwent detailed psychiatric and eye examinations, and it was determined that they did not have any psychiatric, eye, or other organic diseases. The psychiatric evaluations were conducted by a senior psychiatry assistant (AK) based on DSM-5.¹ The findings were confirmed by scanning the data recorded in the hospital system.

Detailed psychiatric assessment of all participants was conducted by a senior psychiatry assistant (AK) and detailed ophthalmological examinations were conducted on both eyes for visual acuity, refraction, anterior segment bio-microscopy, and intraocular pressure by an ophthalmologist (HY).

All the participants signed the informed consent form. A semi-structured sociodemographic data form containing information such as age, disease duration, smoking history, Clinical Global Impression Scale (CGI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI) was administered to the participants.

Questionnaires

Sociodemographic and clinical data form

The Sociodemographic and Clinical Data Form used was prepared taking into consideration the aims of the study. This form was a semi-structured form including sociodemographic information such as age, gender, level of education, occupation, and smoking and clinical data such as duration of the disease, number of hospitalizations, and presence of psychosocial support.

Beck anxiety inventory

Beck Anxiety Inventory has been used to determine the frequency of anxiety symptoms in individuals. The inventory is a 3-point Likert-type scale with 21 items. A score between 0-7 indicates minimal, 8-15 mild, 16-25 moderate, 26 and above severe anxiety.²⁴

Beck depression inventory

The BDI measures the severity of cognitive, emotional, and motivational symptoms of depression. The inventory includes 21 items evaluated on a 4-point Likert-type scale.²⁵ The cut-off score is 17.

Clinical global impressions scale

Clinical global impressions scale is a three-dimensional Likert-type ordinal scale that identifies the severity of the disease, or the degree of improvement based on the clinician's judgment. The severity of the disease is determined in the first dimension, recovery in the second dimension, and the severity of the adverse drug effects in the third dimension of the scale. In the present study, a seven-point form of the disease severity scale was employed.²⁶

Optical coherence tomography Measurements

Optical coherence tomography measurements were performed using Cirrus HD-OCT 5000 Software version 6.5 (Carl Zeiss Meditec, Dublin, CA) by the same experienced author (HY). Right and left eye, macular volume, central macular thickness, retinal nerve fiber layer, choroidal and ganglion cell layer thickness measurements were performed with the OCT device. Five measurements were performed for the RNFL measurement in each eye: nasal (n), inferior (i), superior (s), temporal (t), and global. The signal strength of all participants above 6 was included in the study. The choroidal thickness was compared using OCT. This measurement was made by using the OCT device measurement tool. Manually, a vertical line was drawn from the outer layer of the retinal pigment epithelium to the choroid-sclera border, and its length was recorded. Three different measurements were performed from the fovea to the nasal and temporal poles at 500-μm intervals. We calculated the mean choroidal thickness from separate measurements of three regions.

Statistical analysis

Data were expressed as mean ± standard deviation. The statistical analyses were made with IBM SPSS for Windows, version 25.0 (IBM statistics for Windows version 25, IBM Corporation, Armonk, NY, USA). The normality of the distribution of values was assessed using the Kolmogorov–Smirnov test. According to this test, the Independent-Samples T-test and Mann-Whitney U test were used to compare the groups. Spearman test was used for correlation analysis. The value of P < .05 was considered statistically significant.

Results

In the study, it was determined that the mean age was 46.71 ± 12.60 in the GAD group, and it was 28.71 ± 4.71 in the control group. There was a significant difference between the group mean ages, and the mean age was higher in the GAD group (P < .05). There were 16 female (76.2%) and 5 male (23.8%) patients in the GAD group. The control group included 13 female (61.9%) and 8 male (38.1%) participants. There was no difference between the groups based on gender (P > .05).

The mean disease duration was 57.1%, 5 years or higher in the GAD group.

Six patients (28.6%) in the GAD group and 2 participants (9.5%) in the control group were smokers. There was a statistically significant difference between the groups based on the number of smokers, there was a higher number of smokers in the GAD group (P = .026). The regression analysis revealed no effect of smoking on macular volume. The sociodemographic participant data are presented in Table 1.

Table 1.

The sociodemographic data of the groups.

		Generalized anxiety disorder		Control		P ^a
		N	%	N	%	P ^a
Gender	Female	16	76.20	13	61.90	.157
Gender	Male	5	23.80	8	38.10	.157
Marital status	Married	16	76.20	8	38.10	<.001
	Single	2	9.50	13	61.90
	Divorced	2	9.50
	Widow	1	4.80
Education	Literate	1	4.80			<.001
	Primary	10	47.60
	Secondary	3	14.30
	High	3	14.30	5	23.80
	University	2	9.50	16	76.20
	Illiterate	2	9.50
Smoking	Yes	6	28.60	2	9.50	.026
Smoking	No	15	71.40	19	90.50	.026
Illness duration	No			21	100.00	<.001
	0-6 months	3	14.30
	6-12 months
	1-2 years
	2-5 years	6	28.60
	Above 5 years	12	57.10
Clinical global impression – Severity scale (CGI-S)	No			21	100.00	<.001
	Mildly ill	3	14.30
	Moderately ill	9	42.90
	Markedly ill	9	42.90

^aChi-Square test.

There was a statistically significant difference in terms of Macular Volume between the GAD group and the control group in GAD, which was lower in the GAD group (respectively 10.01 ± .36; 10.2 ± .48, P = .016). No significant difference was found between the patients and the control group in terms of other OCT parameters in GAD (P > .05). The OCT, BDI, and BAI scores of the groups are presented in Table 2.

Table 2.

The OCT values and BDI, BAI scores of the groups.

	n	Generalized anxiety disorder		Control		P
	n	Mean	Std. Deviation	Mean	Std. Deviation	P
Age	21	46.71	12.60	28.71	4.71	<.001 ^b
Height	21	163.10	9.11	167.38	8.93	.046 ^b
Weight	21	70.81	11.31	64.95	12.05	.005 ^b
Body Mass index	21	26.71	4.18	23.17	3.99	<.001 ^a
Age at onset	21	36.24	12.54	.00	.00	<.001 ^b
Beck depression inventory	21	17.76	9.48	1.24	1.95	<.001 ^b
Beck anxiety inventory	21	23.52	9.70	.00	.00	<.001 ^b
Central macular thickness	42	249.00	23.62	251.79	21.07	.388^b
Macular volume	42	10.01	.36	10.20	.48	.016 ^b
Ganglion cell layer thickness	42	80.00	8.85	82.45	6.17	.255^b
Retinal nerve fiber layer thickness-superior	42	120.18	17.15	122.07	13.56	.582^a
Retinal nerve fiber layer thickness-inferior	42	122.44	21.17	128.71	18.03	.194^b
Retinal nerve fiber layer thickness-nasal	42	72.92	14.15	70.29	10.94	.349^a
Retinal nerve fiber layer thickness-temporal	42	64.51	11.10	67.36	9.89	.226^a
Central choroidal thickness	42	373.30	66.42	380.10	67.52	.653^b

OCT: Optical Coherence Tomography; BDI: Beck Depression Inventory; BAI: Beck Anxiety Inventory.

^aIndependent Sample T test.

^bMann-Whitney U test.

In the Spearman correlation analysis, in GAD; there was a negative correlation between age and Central Choroidal Thickness (CCT) (rho = −.339; P = .032). There was a negative correlation between Body Mass Index (BMI) and Ganglion Cell Layer Thickness (GNCLT) (rho = −.315; P = .048). There was a negative correlation between age at onset and CCT (rho = −.339; P = .032. There was a negative correlation between illness durations and Retinal Nerve Fiber Layer Thickness-temporal (RNFLT-t) (rho = −.555; P < .001). There was a positive correlation between number of hospitalizations and MV, RNFLT-n (respectively; rho = .328 P = .034; rho = .324 P = .044). There was a positive correlation between the BDI score and Macular Volume (MV) (rho = .402; P = .008.) There was a positive correlation between the BDI score and Ganglion Cell Layer Thickness (GCLT) (rho = .358; P = .023). There was a positive correlation between the BDI score and Retinal Nerve Fiber Layer Thickness-inferior (RNFLT-i) (rho = .442; P = .005). There was a positive correlation between the BDI score and Retinal Nerve Fiber Layer Thickness-nasal (RNFLT-n) (rho = .360; P = .025). There was a positive correlation between CGIS severity score and MV (rho = .339; P = .028). There was a positive correlation between CGIS severity score and RNFLT-n (rho = .567; P < .001). There was a negative correlation between CGIS severity score and RNFLT-t (rho = −.328; P = .041).

Correlations between the clinical characteristics of the GAD group and OCT values are shown in Table 3.

Table 3.

Bivariate correlations between the clinical characteristics of GAD group and OCT values.

Spearman		Macular volume	Ganglion cell layer thickness	Retinal nerve fiber layer thickness-inferior	Retinal nerve fiber layer thickness-nasal	Retinal nerve fiber layer thickness-temporal	Central choroidal thickness
Age	rho						−.339
Age	P						.032
Gender	rho	.519	.464
Gender	P	<.001	.003
Height	rho	.708	.575
Height	P	<.001	<.001
Weight	rho	.523			.382
Weight	P	<.001			.016
Body Mass index	rho		−.315
Body Mass index	P		.048
Age at onset	rho						−.339
Age at onset	P						.032
Number of hospitalizations	rho	.328			.324
Number of hospitalizations	P	.034			.044
History of psychiatric treatment	rho				−.440	.352
History of psychiatric treatment	P				.005	.028
History of psychiatric treatment in family	rho	−.370
History of psychiatric treatment in family	P	.016
Illness durations	rho					−.555
Illness durations	P					<.001
Beck depression inventory	rho	.402	.358	.442
Beck depression inventory	P	.008	.023	.005
Beck anxiety inventory	rho				.360
Beck anxiety inventory	P				.025
Clinical global impression – Severity scale (CGI-S)	rho	.339			.567	−.328
Clinical global impression – Severity scale (CGI-S)	P	.028			<.001	.041

GAD: Generalized Anxiety Disorder; OCT: Optical Coherence Tomography.

Discussion

In the present study, it was determined that the MV of the GAD patients was lower when compared to the controls. Studies on the etiopathogenesis of GAD reported accumulating data on oxidative stress, inflammatory processes, and neurotransmitter dysfunction.^4-6,27,28 It was demonstrated that activated nitrous-oxide pathways lead to anxiety and anxiety disorders, and the oxidant status and oxidative stress index of the patients with GAD were different when compared to healthy controls.^27,29 Various studies reported low levels of certain antioxidants or antioxidant enzymes in GAD.^29,30 The oxygen metabolism leads to the release of oxygen ions and various free radicals.³¹ Free radicals could damage cellular structure and functions.³¹ Since the brain consumes about 20% of basal oxygen, it is susceptible and very sensitive to oxidative stress.³¹ Retina and brain have common neurodevelopmental biological origins; both originated from the ectoderm.³² Thus, the retina is considered a part of the central nervous system that opens to the outside world. It was suggested that cranial structure or function changes would be reflected in the retina.³² In the present study, the MV values were lower in GAD patients when compared to the controls, which was attributed to the involvement of oxidative stress in the pathogenesis of GAD, and degenerative cranial processes induced by oxidative stress, leading to retinal changes. It is known that anxiety symptoms are associated with high cytokine levels, especially the C reactive protein (CRP).³³ The increasing number of clinical trials indicated that inflammatory markers such as IL-6, IL-1β, and IL-5 were high in anxiety disorders, emphasizing the role of inflammatory processes in the pathogenesis of anxiety disorders.^34,35 Anxiety is highly associated with cardiovascular risk factors such as atherosclerosis, metabolic syndrome, and coronary artery disease. Low-level inflammation is known to be involved in the etiology of these somatic conditions.³⁶ It was hypothesized that inflammation plays a role in anxiety disorders and may be the link between anxiety disorders and cardiovascular burden.³⁶ Anxiety disorders also exhibit high comorbidity with depression, which is strongly associated with immune dysregulation.³⁷ In recent studies, differences were reported between OCT findings of healthy controls and those with psychiatric disorders such as schizophrenia, bipolar disorder, depressive disorder, and obsessive-compulsive disorder.^8,15,17,22 The common denominator in the above-mentioned psychiatric conditions is the involvement of inflammation in the pathogenesis.^8,15,17,22 The involvement of inflammatory processes in the pathogenesis of GAD suggests differences between the OCT findings of healthy controls and GAD patients.

Another factor in the etiology of anxiety disorders is the dysregulation of dopamine and especially serotonin transmission. It was demonstrated that deviations in dopamine and serotonin transmission affect electroretinogram (ERG) measurements, and it was suggested that irregularities in ERG may be associated with central monoaminergic dysfunction.³⁸ Serotonin, which plays a key role in the development of GAD, was also demonstrated to play a role in retinal processes.³⁹ All the above-mentioned data suggest neurotransmitter dysfunction, which plays a role in the etiology of GAD, as well as retinal abnormalities, and suggest differences between the retinal evaluation findings of GAD patients and healthy controls.

The number of smokers was significantly higher in the GAD group when compared to the study group. Since nicotine is a sedative with stress-reducing properties, this could have led to smoking by GAD patients as self-medication.⁴⁰ It is known that smoking leads to a decrease in OCT measurements.⁴¹ Smoking could have been behind the lower CMT values in the patient group. However, regression analysis revealed no effect of smoking on macular volume in the current study.

In the study, negative correlations were determined between age, the onset of disease, disease duration, BMI, and OCT findings (CCT; GNCLT; CCT; RNFLT-t, respectively). With age and the length of the disease, the incidence and number of diagnosed or not yet diagnosed diseases in other systems increased. Accompanying pathophysiological mechanisms may also affect OCT findings. It is known that metabolic syndrome components such as hypertension, hyperlipidemia, hypertriglyceridemia, and diabetes are associated with high BMI.⁴² The involvement of oxidative stress and inflammation in the etiopathogenesis of these processes could explain their effects on OCT findings. A similar mechanism could be involved in the positive correlation between the number of hospitalizations and OCT findings (MV, RNFLT-n). The higher the number of hospitalizations in history, the more acute and exacerbation periods of the disease. Furthermore, with each acute stage, degenerative processes increase and accelerate in the nervous and other systems, especially in the CNS. Hospitalizations and acute periods also lead to multiple and high-dose drug use. A correlation was determined between psychiatric treatment history and RNFLT-n and RNFLT-t in the study. Certain studies reported that antidepressant therapy was effective in OCT findings in anxiety disorders.^43,44 The review of the above-mentioned findings would suggest that hospitalization history is associated with OCT parameters. In the current study, there was a positive correlation between BDI score and MV, GCLT, RNFLT-i, RNFLT-n, and there was a positive correlation between CGI severity scale score and MV, RNFLT-n and RNFLT-t. In a previous study, the increase in OCT findings was associated with state-related neuroinflammation.⁴⁵ The findings of previous studies that investigated the correlation between the scales employed in depression and OCT findings were inconsistent.^21,38 Certain study findings demonstrated that there was a correlation between the scale scores and the OCT findings, while others reported no correlation.^21,38 It was suggested that this could be due to state-related neuroinflammation.^21,38 A similar mechanism (neuroinflammation) plays a role in the etiology of GAD. The correlation between OCT findings and the scale scores could be interpreted in this context.

In a recent study, Özısık and Kıraz determined that there was a thinning of the macula and macular layers with OCT in medication-naïve GAD patients when compared to the control group. Our study findings were consistent with that study.⁴⁶ The above-mentioned study demonstrated that psychological stress is a risk factor for central serous chorioretinopathy (SSCR) and the etiology of SSCR could be explained by high endogenous cortisol, epinephrine, catecholamines, and increased sympathetic activity with exogenous cortisol. In retinal diseases such as SSCR, which were associated with anxiety, increased sympathetic activity and changes in catecholamine could affect the retina. The increase in sympathetic activity and catecholamine changes involved in the etiology of retinal diseases such as SSCR, which were associated with anxiety, could provide insight into the etiology of anxiety disorder and treatment methods.⁴⁶ Recent studies reported thinning of the retinal structures in patients with psychiatric disorders. These studies demonstrated that these changes were associated with the severity and duration of the disease.^8,9 Thus, OCT could be beneficial for the follow-up of psychiatric diseases.

Study limitations

The present study has several limitations. The sample size was relatively small. It is cross-sectional study, preventing causality. Future prospective studies are required to further elucidate progressive retinal neurodegeneration which is an indicator or a consequence of GAD. Confounding conditions such as medications, smoking, nutrition, and exercise were not excluded as possible explanations of the study findings. Nevertheless, the present study is one of the few research in the literature where GAD patients were evaluated with OCT.⁴⁶

Conclusions

The present study determined lower MV in GAD patients with OCT when compared to controls. GAD patients should be screened for retinal changes. OCT is a simple, non-invasive and relatively inexpensive method that could be employed to follow-up of the GAD patients. Future prospective studies would contribute to the determination of the causality of the present study findings. The subjects should be controlled for medications, smoking, alcohol use, and nutritional habits in these studies to minimize the confounding factors. Such research could explain other changes in the CNS of the patients due to GAD by investigating the etiology of retinal changes.

Footnotes

Acknowledgements

We would like to thank the Firat University Project Unit (FUBAP).

Authors’ contribution

SB, AK; substantial contributions to the conception or design of the work. SB, HY; acquisition and interpretation of data for the work; HOK, HY, AK; drafting the work and revising it critically for important intellectual content, SB, HOK, DDK; give their final approval of the version to be published, SB, HY, AK, MFT, DDK, HOK; agree 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.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Sema Baykara

Aslı Kazğan

Muhammed Fatih Tabara

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