Functional neurological symptom disorder (FNSD) is a somatic symptom disorder, in which clinical symptoms cannot be explained by another neurological or medical condition or mental illness and progress with loss of voluntary motor or sensory functions [1]. Symptoms include weakness, paralysis, difficulty swallowing, unusual speech and sensory symptoms, and drowsiness or mixed symptoms [2]. Its prevalence has been reported to be 1%-3% in the developed countries and approximately 10% in the developing countries. In Turkey, the prevalence of it has been reported in a wide range ranging from 4.5%-32%, in adults. It is most frequently seen between the ages of 15-35, while the female/male sex ratio has been reported to be 2-10: 1 [3].

Exaggerated or prolonged stress may predispose to mental illnesses by causing pathophysiological changes in the brain and immune system [4]. In the studies conducted in Turkey, it has been shown that stress factors were present in 17%-45% of the cases before the development of FNSD [5]. Stressful life events and mental conflicts can trigger the symptoms. Distressing stimuli, personality patterns that facilitate expression through psychosomatic means, personality disorders, traumatic experiences, communication problems, psychiatric or neurobiological disorders are predisposing factors for FNSD [6]. However, the mechanism of the neuroendocrine regulation associated with the stress response has not been clearly explained yet. Vasopressin and oxytocin hormones, which are synthesized in the paraventricular (PVN) and supraoptic (SCN) cores of the hypothalamus and released into the brain and peripheral circulation through the posterior pituitary, take part in the stress response cycle by mutual interaction [7]. Both oxytocin and vasopressin receptors are found abundant in the nervous system regions that regulate social, emotional, and adaptive behaviors, including the amygdala, the HPA axis, and the autonomic nervous system [8]. Oxytocin has been shown to be related with behavioral aspects that include attachment, affiliation, prosocial behavior, stress regulation, memory and learning under very stressful conditions, especially social learning [9]. The increase in plasma oxytocin has been found to be associated with the weakening of the hormonal response that occurs after stress and a decrease in anxiety [10]. Stress-protective and anxiolytic properties of oxytocin have been shown in studies conducted on animal models [11]. Conversely, decreased oxytocin levels have been found to be associated with psychiatric diseases such as depression, schizophrenia, and autism spectrum disorder [12]. In animal experiments, it has been shown that the stress- protective effects of oxytocin are resulted from its regulating action in the hypopituitary-pituitary-adrenal (HPA) axis [13]. In addition, usually, oxytocin does not act alone, interactions between vasopressin and oxytocin help to explain the importance of social behavior in the regulation of anxiety and responses to threats, which in some cases are promoted by vasopressin [14].

Vasopressin plays a role in emotional behavior including fear, anxiety and aggression as well as its effects on fluid hemostasis and regulation of blood pressure. Increases in autonomic responses to social threats and anxiety have been associated with vasopressin [15]. In males, vasopressin was shown to cause aggressive behavioral response to social stimulus [16,17]. On the other hand, oxytocin is a component of social and passive coping skills and allows active and mobilized coping strategies through interaction with vasopressin [18]. To the best of our knowledge, in the literature, there is no study investigating the roles of oxytocin and vasopressin in the pathogenesis of FNSD.

In our study, we hypothesized that oxytocin levels might be lower in FNSD and the balance between oxytocin and vasopressin may have altered, considering the stress-balancing effects of oxytocin and also interaction between these hormones. We believe that understanding the roles of oxytocin and vasopressin in the stress response will contribute to the understanding of FNSD pathophysiology. The aim of this study is to determine how oxytocin and vasopressin levels are affected in persistent FNSD patients compared to controls.

This study included 27 female patients between the ages of 20 and 57 years, who admitted to the Turgut Ozal Medical Center Psychiatry Outpatient Clinic with conversion seizures and were diagnosed with FNSD with debility or stroke (paralysis) according to DSM-5, and 27 healthy controls, who were matched by age and gender. Males were also invited to the study; however the number of patients was not sufficient to be evaluated statistically. Patients with chronic medical diseases, neurological diseases, alcohol and other substance dependence (excluding smoking), and a history of drug use during the last six months were excluded from the study. The control group included healthy subjects without a medical disease, without an axis I diagnosis according to DSM-5, and with no first-degree relatives with any psychiatric disease. The patient and control groups were evaluated according to DSM-5 by a face to face interview conducted by a psychiatrist and laboratory tests were performed. Childhood trauma variable, “Have you ever experienced an event in your childhood (<18 years) that affected you mentally such as neglect, accident, loss of parents, sexual trauma, etc.?” questioned by the question. This study was conducted in accordance with the Declaration of Helsinki and approval was obtained from the Ethics Committee of Inonu University Faculty of Medicine, dated 03.05.2011, number 2011/40. Informed written consent was obtained from all participants.

The sample of this study consisted of 27 female patients diagnosed with FNSD and 27 healthy controls. Mean age was 30.22±9.18 years in the patient group and 29.62±9.16 years in the control group; mean duration of education was 8.00±4.67 years in the patient group and 14.92±3.57 years in the control group. There was no significant difference between the groups in terms of age, while the duration of education was significantly longer in the control group compared to the patient group (p=0.84, p=0.001, respectively). The ratio of those working in a regular job (yes/no), education status (literate/illiterate) was lower (p=0.001, p=0.001, respectively), and raising up in rural areas and still living there was higher in the patient group compared to the healthy controls (p=0.001, p=0.001, respectively) (Table 1). Table 2 shows the frequency of the variables related with FNSD including frequency of disease symptoms (once a month or less, more than once a month), presence of pre-symptom stress factors, and a history of medical treatment and FNSD subtypes (motor, sensory, seizure or mixed symptoms).

In our study, serum vasopressin levels were statistically significantly lower in the patient group compared to the control group (p=0.019). Oxytocin levels were also relatively higher in the patient group, however the difference was not statistically significant (p=0.26) (Table 3).

Childhood traumas, including separation from the mother, disintegrated family and known history of sexual trauma were more common in the patient group compared to the control group (p=0.01). The mean level of oxytocin was lower in patients with a history of a childhood trauma compared to the control group (p=0.09), whereas there was no significant difference between the groups in terms of vasopressin levels (p=0.53) (Table 4).

The mean duration of disease was found to be 30.25±28.24 months and the mean age at onset of the disease was 25.27± 10.40 years in the patient group. Since the mean duration of disease was >6 months in our sample, the patients in our study were classified as “persistent type FNSD” according to DSM-5 criteria. The duration of disease was not found to be associated with oxytocin and vasopressin levels (p>0.05). We found that, there was a negative correlation between the oxytocin levels and the age of patients and the age of onset (p=0.008, r= 0.497 and p=0.01, r=470, respectively), whereas no relationship was found between the vasopressin levels and the age of the patients or age of onset.

Oxytocin and vasopressin are neuromodulators that play a role in the regulation of lifelong social behaviors and provide mechanisms to be prepared for and to adapt to life’s difficulties. In this study, serum oxytocin and vasopressin levels of 27 female patients with FNSD 27 age and sex matched healthy controls were compared in terms of clinical and individual variables. Our sample consisted of FNSD patients with a duration of disease longer than 6 months and no history of treatment for the last 6 months. To the best of our knowledge, in the literature, there is no study investigating oxytocin and vasopressin levels in FNSD patients. In the clinic picture of FNSD, initiating stressors may play a role and anxiety and depression symptoms may accompany. Vasopressin is a peptide that plays a role in the regulation of various social behaviors such as intimacy, mate attachment, and aggression, and may have a role in the increasing tendency to anxiety and depression. In addition, vasopressin receptors found to be associated with social recognition memory and social aggression pattern [19]. In our study, serum vasopressin levels of FNSD patients were found to be lower compared to the healthy controls (p=0.019). In participants with an average duration of illnesses of longer than 24 months, the mean level of vasopressin, which is known to be an activator of the HPA axis, may have been found low due to prolonged and intense stress perception. In an animal study that supports our results, a significant decrease in salivary vasopressin levels was found after intense exposure to stress, however vasopressin levels were not affected at low exposure to stress [20]. In FNSD patients, especially in the chronic period, stress tolerance decreases and stress management is impaired. Vasopressin, which is associated with anxiety and mobilization, is known to allow more active coping skills [21].

In addition, vasopressin improves threat perception abilities [22]. According to our results, FNSD patients may have difficulty perceiving or detecting threats from the external environment associated with lower vasopressin levels [22]. Low levels of vasopressin may lead to inability to activate coping skills, and may also be associated with vulnerability to mental illness. This may be an important reason for the inadequacy of psychotherapeutic interventions in persistent FNSD.

In contrast to vasopressin, oxytocin, which is defined as a social hormone, is involved in anxiety regulation, coping with stress and social communication, in mammals, primates, and humans [23]. Contrary to our hypothesis, we could not find a significant difference between the patient group and the control group in terms of oxytocin levels. Primarily, conducted on female patients, oxytocin levels may be affected by individual factors other than the disease [24]. Gender differences, individual factors, positive or negative life experiences and social interactions can lead to changes in oxytocin level [25]. Studies have found that oxytocin expression is generally higher in females [26]. It is known that co-activation of the HPA axis and oxytocin occurs immediately after the onset of stress, in the early phase and leads to a rapid recovery [27]. It is also known that oxytocin can regulate vasopressin activity [19]. In addition, acute and chronic stress produces physiologically distinct adaptive responses [28]. In most cases, oxytocin release continues against a chronic stress that may follow acute stress [29]. However, we found no difference in terms of oxytocin levels. In our study, it is possible that oxytocin, which may have increased in the early stage, returned to stable levels in the chronic period.

An important finding of our study, the mean oxytocin level was lower in patients with both persistent FNSD and childhood trauma compared to controls (p=0.09), however, no significant difference was found between the whole FNSD group and healthy controls. Childhood trauma is associated with impaired recognition and expression of feelings, impaired emotion regulation, problems in attachment and interpersonal relationships [30]. Traumatic and stressful experiences may lead to hormonal changes, primarily hypo- or hyper activity in the HPA axis. Dysfunction in HPA axis contributes to weakening of the immune system, to increased vulnerability to psychopathologies, and to the inability to cope with stressful/traumatic events [31]. Evidence suggests that oxytocin release plays role in regulating cortisol levels that allow the body to rapid return to its pre-stressed state [27,32]. Also, stressful experiences might affect the function of the suprachiasmatic nucleus and lead to reduce endogenous oxytocin release and synthesis [33,34]. Women with childhood abuse and higher anxiety levels found to have lower oxytocin release in the cerebrospinal fluid with increased anxiety [35]. Another study found lower oxytocin levels associated with more severe prepubertal stressors in adult males. Also, oxytocin pathway alters in response to early life trauma in adults and children [36]. Furthermore, intranasal administration of oxytocin may decrease stress reactivity [27], as well as salivary cortisol levels [37]. In addition to its physiological roles, oxytocin could facilitate passive coping skills, which are important during exposure to chronic stress, and protect against inactivity in the face of fear [38]. In our study, the low levels in serum oxytocin, may reduce the pro-social functions of FNSD patients, thereby reducing coping and resilience mechanisms. Ineffective regulation for stress could lead to common interpersonal difficulties and impaired stress regulation in FNSD patients. Low oxytocin may be associated with problems in attachment and difficulty in interpersonal relations [39]. In this context, traumatic experiences are known to play role in vulnerability to mental illness [36]. FNSD patients without trauma exposure may benefit better from the anti-stress effects of oxytocin. FNSD patients who exposed to childhood trauma appear physiologically more vulnerable to stress. Lower serum oxytocin levels may be an indicator of early age trauma in persistent FNSD.

In contrast to oxytocin, no significant difference was found in terms of vasopressin levels, between groups with childhood trauma. When exposed to early life stress, vasopressin improves threat perception abilities, while oxytocin protects social bonds [22]. Oxytocin and vasopressin increase alertness to threats and support survival for those who experience intense stress in early life [27]. It was reported that vasopressin expression increased after neglect or other negative social experiences at an early age [40]. Adversities in early life sensitize the vasopressin system and regulate the AVPR1A receptor [41]. Conversely, in the presence of low early life stress, vasopressin creates a less alert response to threat and consequently maintains metabolic energy [28]. The lower serum vasopressin levels, we found in FNSD patients, was not different in those exposed to trauma. Our result may point to an adaptation mechanism associated with the increase serum vasopressin in those with childhood trauma. We thought that there might be an enhanced threat expectation associated with the increase in vasopressin after exposed to traumatic events. This adaptation may associated with either a more active or mobilized defensive behavior or aggressive behavior later in life [22]. Vasopressin may have a modulator role in threat perception, security behavior and coping with stress. In addition, our results suggest that vasopressin has regulatory effects on chronic (> 6 months) stress response.

In our study, similar to the literature, we found that the frequency of FNSD was higher in the population with a low education level, in those living in rural areas, unmarried, and those without a regular job [42]. In the literature, it was reported that living in rural areas, living under low socioeconomic conditions, having a low education level, and having an insufficient insight and low intelligence level are risk factors for FNSD [7]. It is also possible that individual factors may be perceived by patients as cumulative stress. Cumulative stress has different effects than acute stress. A recent study found that cumulative stress associated with PTSD and anxiety caused impairment in the neural pathways, associated with endurance in adulthood through the oxytocin and AVP pathway [43].

The limitations of our study include the limited number of cases, the absence of male patients and the lack of evaluation in the acute period. Our results are difficult to generalize due to the fact that our sample was consisted of female patients. However, an important point is that oxytocin and vasopressin are hormones with different expressions according to gender [25]. It was reported that females were found to be twice as likely to be exposed to trauma or other adversities generally. They are significantly more vulnerable to disorders such as depression and post-traumatic stress disorder [44]. In this context, it is thought that defects in oxytocin and vasopressin or their receptors are more likely to affect women. It is important to study a single sex, as in our research, to exclude a confounding factor such as gender.

In conclusion, the results of our study comparing oxytocin and vasopressin levels in FNSD patients and healthy controls suggest that oxytocin and vasopressin may have a role in the pathogenesis of FNSD. As an important finding low oxytocin levels may be and indicator of childhood trauma in FNSD, and may play a role in vulnerability to FNSD patients who exposed to early life trauma. The mutual interaction of these two peptide hormones may have an important role in neuroendocrine balance for emotional behavior. Therefore, in order to understand the role of neuromodulators in FNSD, prospective studies with large samples and including both genders and investigating both acute and persistent cases are needed.