TYPE Original Research PUBLISHED 10 May 2023 DOI 10.3389/fmed.2023.1039223 Validation of the neuroconnective OPEN ACCESS endophenotype questionnaire (NEQ): a new clinical tool for EDITED BY Victoria Bunik, Belosersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Russia medicine and psychiatry resulting from the contribution of REVIEWED BY Sandhya Maheshwari, Aligarh Muslim University, India Isabelle Brock, Independent Researcher, New York, United States Ehlers–Danlos syndrome Alan Hakim, University College London Hospitals NHS Foundation Trust, United Kingdom Antonio Bulbena1,2*, Silvia Rosado2 , Marina Cabaleiro1,2 , *CORRESPONDENCE María Martinez1,2 , Carolina Baeza-Velasco3,4,5 , Antonio Bulbena abulbena@gmail.com Luis-Miguel Martin2 , Santiago Batlle2 and Andrea Bulbena-Cabré6 1 SPECIALTY SECTION Department Psychiatry and Forensic Medicine, Universitat Autonoma Barcelona, Barcelona, Spain, 2 This article was submitted to Anxiety Unit, Hospital del Mar, Institute Neuropsychiatry and Addictions (INAD) CIBERSAM, Barcelona, Translational Medicine, Spain, 3 Laboratoire de Psychopathologie et Processus de Santé, Université Paris Cité, Paris, France, 4 a section of the journal Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France, 5 Institute Frontiers in Medicine of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France, 6 Icahn School of Medicine, Mount Sinai, New York, NY, United States RECEIVED 07 September 2022 ACCEPTED 22 March 2023 PUBLISHED 10 May 2023 Introduction: The link between anxiety disorders and joint hypermobility CITATION Bulbena A, Rosado S, Cabaleiro M, Martinez M, syndrome (now under hypermobility spectrum disorders, which include Baeza-Velasco C, Martin L-M, Batlle S and hypermobile Ehlers–Danlos syndrome) has been widely replicated over the Bulbena-Cabré A (2023) Validation of the past 30 years and has grown beyond the initial nosological limits. To integrate neuroconnective endophenotype questionnaire (NEQ): a new clinical tool for clinical and research progress in this field, a new neuroconnective endophenotype medicine and psychiatry resulting from the (NE) and its corresponding instrument, the Neuroconnective Endophenotype contribution of Ehlers–Danlos syndrome. Questionnaire (NEQ), have been developed. This new clinical construct, created Front. Med. 10:1039223. doi: 10.3389/fmed.2023.1039223 with the active participation of patients, includes both somatic and psychological dimensions and symptoms and resilience items. COPYRIGHT © 2023 Bulbena, Rosado, Cabaleiro, Martinez, Methods: The NE includes five dimensions: (1) sensorial sensitivity, (2) body Baeza-Velasco, Martin, Batlle and signs and symptoms, (3) somatic conditions, (4) polar behavioral strategies, and Bulbena-Cabré. This is an open-access article distributed under the terms of the Creative (5) psychological and psychopathological dimensions. The NEQ information Commons Attribution License (CC BY). The use, is collected through four self-administered questionnaires (sensorial sensitivity, distribution or reproduction in other forums is body signs and symptoms, polar behavioral strategies, and psychological permitted, provided the original author(s) and the copyright owner(s) are credited and that characteristics) and a structured diagnostic part that should be completed by the original publication in this journal is cited, in a trained observer. This hetero-administered part incorporates (a) psychiatric accordance with accepted academic practice. diagnoses (using structured criteria, e.g., MINI), (b) somatic disorders diagnosis, No use, distribution or reproduction is permitted which does not comply with these using structured criteria, and (c) assessment of joint hypermobility criteria. terms. Results: In a sample of 36 anxiety cases with 36 matched controls, the NEQ obtained high scores for test–retest, inter-rater reliability, and internal consistency. As for predictive validity, cases and controls significantly differed in all five dimensions and hypermobility measurements. Discussion: We can conclude that the NEQ has achieved acceptable reliability and validity values and, therefore, is ready to be used and tested in different samples. This original and consistent construct including somatic and mental items may improve clinical specificity, the search for more comprehensive therapies, and their genetic and neuroimaging bases. KEYWORDS Ehlers-Danlos syndrome, anxiety, psychosomatic medicine, reliability, validity, joint hypermobility, neuroconnective endophenotype Frontiers in Medicine 01 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 Introduction psychiatric diagnosis? In a retrospective study, half of the HSD/hEDS patients from a hospital sample presented psychiatric After the counterintuitive finding of the strong association conditions, mainly mood and anxiety disorders (14). A recent between joint hypermobility syndrome and anxiety disorders by review showed the growing group of disorders associated with our group in 1988, subsequent clinical research has confirmed this HSD/hEDS (12). Of note, in one of the few incidence studies, solid association between these two conditions (1). a 15-year prospective follow-up, HSD/hEDS showed a relative Ehlers–Danlos syndrome was named after the observation risk of 22.3 for developing anxiety disorders, which is one of of two dermatologists (Edvard Ehlers and Henri-Alexandre the highest risk factors described so far (15). However, it is very Danlos) at the beginning of the 20th century. Nowadays, it important not to attribute HSD/hEDS to a psychiatric origin; is considered a multi-systemic condition that includes a wide in fact, many HSD/hEDS symptoms are subjective and, given range of musculoskeletal features, and over the years, extra- the lack of biological findings, these patients have often been articular symptoms, such as gastrointestinal or allergies, have wrongly considered “somatisers” or “functional,” which delayed gained recognition. Moreover, individuals frequently present with the proper diagnostic process and, worse still, led to a mistaken stress-sensitive illnesses, such as fibromyalgia or chronic fatigue psychiatrization (16). syndrome (2). The association between HSD/hEDS and anxiety disorders There are several diagnostic methods established for identifying has also been replicated across different populations including joint hypermobility (JHM) (3–5), the Beighton score being the most children and elderly samples and, most recently, this association extensively used (5). was replicated in a different species. Bowen et al. (17) found Prior to the 2017 introduction of the international criteria significantly higher excitability in dogs with JHM, which is a on the Ehlers–Danlos syndromes and hypermobility spectrum unique finding suggesting that this association may be a favorable disorders, the term joint hypermobility syndrome (JHS) covered a evolutionary trait. wide group of patients some of whom had signs and symptoms that Anxious patients and hypermobile subjects also share other were primarily musculoskeletal (so-called hypermobility syndrome biological features, such as enhanced somatosensory perception (HMS) in past terminology) and some that could equally be (18, 19), and an association with functional gastrointestinal described as having the hypermobile type of Ehlers–Danlos disorders (20, 21). syndrome (hEDS). The interchangeable use of the terms JHS and Despite the solid association between these clinical variables, hEDS in some practices (but not all) was confusing because not all the neurobiological substrate behind this remains unclear. Given people with JHS had hEDS and many had HMS. the hereditary nature of Ehlers–Danlos syndrome, a pedigree The 2017 international criteria introduced a much stricter study looking for genetic links with anxiety and phobias found a definition for hEDS (6). In introducing the 2017 criteria, the term common duplication in chromosome 15; however, like multiple JHS was dropped. For those individuals with hypermobility-related single-gene association studies, this finding could not be replicated problems that were more akin to HMS and who did not have hEDS (22, 23). Interestingly, both share several psychophysiological by the 2017 criteria (or any other heritable disorders of connective features including dysautonomia, reduced proprioception, and tissue or other syndromic or primary cause for their condition), enhanced interoception (24). Neuroimaging studies showed the term hypermobility spectrum disorder (HSD) was developed some commonalities in the amygdala, insular structures, and (7). Without such an inclusion, a very large, indeed the largest, and hippocampus (25–27). In addition, different review studies also most encountered patient population with a hypermobility-related confirmed the transdiagnostic relevance of connective tissue condition would not have been represented in the revised criteria. variants with neuropsychiatric symptom expression (28, 29). Certainly, from a clinical perspective, many of the comorbid The neuroconnective endophenotype (NE) model was concerns, including anxiety disorders, that arise across the developed by our team to collect and assess all the somatic and spectrum of HSD and hEDS can be considered the same both psychological characteristics observed at a higher frequency in terms of assessment and treatment (8). Currently, aiming to in patients suffering from anxiety and other disorders and be pragmatic when describing past research and the relation to HSD/hEDS (30). The term for the new concept includes “neuro” contemporary concepts, the term JHM is used for observations and “connective” components, appealing both to the body-mind related to joint hypermobility per se, and the term HSD/hEDS connectivity and connective tissue, whereas the prefix “endo” is (but not HSD/EDS) is encouraged for observations previously used as the phenotype has a genetic component (HSD/hEDS). termed JHS. The NE includes the following five dimensions: The association of hEDS and anxiety disorders has also been 1) Sensorial sensitivity, entailing, among others, high olfactory, found in other groups of psychiatric disorders, such as depression, visual and auditive sensitivity, high interoception and personality disorders, eating disorders, and neurodevelopment exteroception, low proprioception, sighing, feelings of dyspnea, disorders (9–12). and fatigue, unsteadiness, palpitations, dysphagia, urogenital The overlap between HSD/hEDS, anxiety, and other psychiatric or oral dynias, pain (articular or visceral) and intolerances conditions can be seen from both sides: (a) How many psychiatric or enhanced sensitivities to heat or cold, weather, and drugs patients (e.g., panic and agoraphobia) meet HSD/hEDS criteria? (particularly psychotropic). In case–control studies, 70% of panic patients but only 15% 2) Body signs and symptoms include sprains and dislocations, of psychiatric controls fulfilled HSD/hEDS criteria (13). (b) easy bruising, especially among women, dark or blue sclerae, How many HSD/hEDS patients meet anxiety criteria or another hypertrophic scars or keloids, dysautonomia, abdominal Frontiers in Medicine 02 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 bloating, globus pharyngeus, ectomorphic somatotype, avoidance–intrusion, and isolation–dependence. Four answers are prolapses, and allergies. offered: neither end, both ends, one end, and the other end. 3) Somatic conditions include irritable bowel syndrome, The psychological and psychopathological dimension fibromyalgia, chronic fatigue, postural tachycardia syndrome (characteristics and sensations) includes 29 self-administered (POTS), temporomandibular–jaw syndrome, mast cell questions with multiple Likert-type responses with five answers activation, benign positional vertigo, hypothyroidism, asthma, (no = 0, extremely = 4). migraine, tensional headache, cervical instability, dysfunctional The hetero-administered component applied by a trained esophagus, gluten intolerance, and bruxism. interviewer includes the following: 4) Polar behavioral strategies. This block gathers some adaptative Psychiatric diagnosis in a yes/no form (categorical form), and defense strategies, generally identifiable by their tendency always following the MINI interview system using homogeneous toward the two extremes of the same axis. The five axes of criteria. Collecting lifetime prevalence is encouraged. the model are self-others, supercontrol-uncontrol, fight-flight, Somatic conditions diagnosis in a yes/no form with a total of avoidance-intrusion, and isolation-dependence. 15 somatic diagnoses collected (plus an open field) using defined 5) Psychological and psychopathological dimensions diagnostic criteria. This block also includes the clinical examination (characteristics and sensations), which is a block that includes of JHM using the validated nine-item scale, which includes all a variety of anxiety and depression symptoms and psychiatric Beighton criteria (34). This nine-scale substantially overlaps but the diagnoses but also some resilience characteristics, like “In a difference is that the nine-item scale requires only one side of the real emergency situation, do you quickly find solutions, that body to be positive, whereas the Beighton scale allows one point is, are you one of those who react effectively to solve it?”; “in for each side in several items. We always use it as complementary moments of discussion and fighting, are you especially capable to the Beighton scale. It is important to remember that these scales and a good warrior?” can only be assessed by clinicians who have been previously trained and validated by an expert on this condition (35). The relevance of the NE stems from its potential to evaluate Therefore, the main aim of this study was to calibrate the psychiatric and psychosomatic patients in a global manner, reliability and validity data of the Neuroconnective Endophenotype focusing on both “mental” and “somatic” signs and symptoms. Questionnaire (NEQ). This new clinical construct has been developed with the active participation of patients and includes not only symptoms and signs but also resilience features. With the new approach afforded by NE, Methods patients can improve their knowledge regarding their symptoms and perceptions and, subsequently, they may reach an enhanced Reliability. For test–retest and inter-rater reliability measures, understanding and better management of their condition. Often intraclass correlation coefficients (ICCs) were calculated for neglected areas, like body perception (31) and proprioception (32, continuous variables and kappa values for categorical variables. 33) are particularly important in the NE, which introduces the Since different NEQ dimensions have different scoring, we systematic assessment of these important subjective perceptions, calculated the sample size for each one, selecting the main objective whose presence in both EDS subjects and anxiety patients is as standard, as recommended by Bujang and Baharum (36) and common and holds great potential value. Bujang et al. (37). Hence, accepting an alpha risk of 0.05 and a beta The Neuroconnective Endophenotype Questionnaire (NEQ) risk of 0.2 in a two-sided test, sample sizes for each estimate varied (Figure 1) was developed to assess the five dimensions of the model. from 12 to 42 subjects to detect an estimated ICC of 0.7. To this end, NEQ information is collected through four self-administered between 30 and 40 participants were considered to assess reliability questionnaires (sensorial sensitivity, body signs and symptoms, throughout the dimensions of the questionnaire. polar behavioral strategies, and psychological characteristics) and Validity. Content validity (very relevant when beginning to another structured diagnostic part that should be completed by develop an instrument) refers to the degree to which an assessment a trained observer. This hetero-administered part incorporates instrument is relevant to, and representative of, the targeted (a) psychiatric diagnoses (using structured criteria, e.g., MINI), construct it is designed to measure. It includes face validity and (b) somatic disorders diagnosis, using structured criteria, and (c) construct validity. In the case of NEQ, the five neuroconnective assessment of joint hypermobility criteria. dimensions are new concepts obtained via clinical observations The sensory sensitivity scale includes 19 self-administered and literature searches. Regarding face validity, this instrument questions with multiple Likert-type responses with five answers (no took some time to develop because, after the first draft, we wanted = 0, extremely = 4). to obtain the most specific information possible from patients The body signs and symptoms scale comprises 20 questions and professionals. To optimize the questionnaire’s content, we with yes/no answers that include the presence of bodily organized several formal and informal sessions with professionals manifestations often associated with HSD/hEDS. Pain calibration and patients to discuss and modify each item, both at the Anxiety is added in the form of intensity (0 = no pain to 5 = unbearable) Unit at the Hospital del Mar and with the Asociación Nacional de and a figure to locate the site. Síndromes de Ehlers-Danlos e Hiperlaxitud Articular (ANSEDH). The polar behavioral strategies scale captures some adaptation In these process meetings, both clinicians and patients contributed and defensive patterns, generally identifiable by their tendency toward minimizing potential errors, such as underrepresentation, toward the two extremes of the same axis. The five axes of this block overrepresentation, and misrepresentation, while it is of some value are as follows: me–others, supercontrol–uncontrol, fight–flight, to having the test appear to be valid; face validity alone is just Frontiers in Medicine 03 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 FIGURE 1 The neuroconnective questionnaire. the first step toward establishing that the test is measuring what once the technical and ethical conditions were properly accepted. it claims to measure. The present version (19th) includes all the Two patients dropped out, one for minor surgical procedures and items and the expressions that obtained maximum consensus. another because they moved away during the study, therefore, the For construct validity at this early stage, Cronbach’s alpha will be final sample was 36 participants. calculated for each scale. Controls were healthy volunteers who agreed to participate in ANOVAs were applied to compare case and control means, and the study after being contacted by email and summoned afterward median comparisons with Wilcoxon Z-scores were also calculated in person. Inclusion criteria included those aged between 18 and to obtain non-parametric methods. 75 years and residing in the province of Barcelona. All participants Chi-squared tests were applied to compare rates and gave their informed consent before starting the study. Exclusion proportions among categorical variables between cases and criteria for controls included the presence of active anxiety disorder, control. Considering the exploratory nature of this preliminary or in remission, assessed via the MINI, any form of cognitive study, correction for multiple comparisons was not applied. impairment, and musculoskeletal conditions or muscle spasticity For predictive validity scorings, each NEQ dimension will be secondary to neuromuscular diseases that hindered the correct compared between cases and controls. Again, the sample size evaluation of joint laxity. was obtained via GRANMO (38); accepting an alpha risk of 0.05 The case group consisted of 24 women and 12 men, whereas 21 and a beta risk of 0.2 in a two-sided test, a minimum of 26 women and 15 men were in the control group. Cases and controls participants per group were necessary to recognize a difference did not differ by gender (χ2 = 0.534; p-value = 0.46) or age (cases: greater than or equal to 8 units as statistically significant. The mean (±SD) 42.13 years (± 11.9); controls: mean (±SD) 45.69 common standard deviation was assumed to be 10 and a drop-out years (±18.9)) (ANOVA F = 0.9; p = 0.34). rate of 5% was anticipated. Internal consistency, measured by Cronbach’s alpha, was 0.866 Informed consent was obtained from each participant and the for the sensorial sensitivity 19-item scale, 0.763 for the Body protocol was approved by the local Ethical Committee. signs and symptoms 20-item scale, 0.876 for the psychological characteristics-sensations 30-item scale, 0.724 for polar behavior strategies 5-item scale, and 0.792 for the hypermobility 9-item Results scale (Table 1). Reliability (test–retest) was calculated for each item of the five Sample, a total of 38 patients from the Anxiety Unit at the scales and the total scale. ICC was established for self-administered Hospital del Mar (Parc de Salut Mar, Barcelona) and 38 matched controls were invited to participate in the study; informed consent continuous scales in the form of test–retest with an interval of (16 ± was obtained from each participant before entering the study 2) days, whereas Cohen’s kappa was calculated for categorical items Frontiers in Medicine 04 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 TABLE 1 Reliability neuroconnective questionnaire NEQ. Alpha Cronbach Intraclass corr. coefficient Kappa coefficient∗ Sensorial sensitivity (19 item) 0.861 0.986 - Body signs and symptoms (20 item) 0.763 - 0.6–1 Somatic conditions (19 item) - - 0.45–1 Polar strategies (5 item) 0.724 0.8–1 - Psychological dimensions (30 item) 0.876 0.996 Psychiatric diagnosis (20 item) - 0.65–1 Hypermobility score (9 item) 0.792 0.967 - ∗ Kappa values are obtained for item yes/no. (i.e., yes/no). Sensorial sensitivity and psychological scales obtained In polar behavioral axes, the anxiety cases showed significantly ICC coefficients higher than 0.9. For body signs and symptoms, higher polar tendencies than controls on four of the five kappa values ranged between 0.6 and 1, whereas for polar behavior axes: supercontrol/lack of control (χ2 = 11.364; p = 0.0099), strategies, the range was between 0.8 and 1. dependency/isolation (χ2 = 25.768; p = <.0001), fight /flight Inter-examiner reliability was also calculated for (χ2 = 17.068; p = 0.0007), and me/others (χ2 = 9.085; p = hypermobility items obtaining a range of ICC values between 0.002), whereas avoidance/ intrusion (χ2 = 6.299; p = 0.0979) 0.7 and 1. did not reach statistical significance. Total scoring for the polar Psychiatric diagnoses, evaluated via MINI, also obtained behavior scale was significantly higher for the anxiety cases [mean a high degree of concordance between examiners, with (±SD) 6.63 (±2.77)] than for controls [mean (±SD) 3.50 (±2.71)] kappa values between 0.65 and 1. Medical diagnosis applying (ANOVA F 23.63 p < 0.0001) (Table 2). the criteria list ad hoc to each diagnostic label obtained Eight of the 13 medical diagnoses (irritable bowel kappa values of 0.45 to 1. The lowest value was found for syndrome, functional dyspepsia, somatoform vertigo, the cyclic vomit item, which prompted authors to review chronic fatigue syndrome, fibromyalgia, hypothyroidism, this criterion. asthma, and temporomandibular-mandibular syndrome) were significantly more prevalent in the anxiety case group. However, dysfunctional esophagus, postural orthostatic tachycardia syndrome, tensional headache, migraines, multiple chemical Cases and controls sensitivity (not just intolerances or allergic reactions), gluten intolerance, and intolerance to some medications did not reach Anxiety cases and controls were compared in every dimension statistical significance. of the neuroconnective model. Most sensorial items scored Psychiatric diagnoses were only found in the anxiety case significantly higher in the anxiety cases but none scored higher in group, as expected, although one control appeared to have an the control group; those items not reaching significance were the unclear history of a bipolar episode in their youth. least prevalent in both samples. The total sensory scale showed The anxiety cases [mean (±SD) 4.50 (±2.72)] scored significantly higher scoring for the anxiety cases [mean (±SD) = significantly higher in the hypermobility scale than the controls 33.19 (±11.5)] than the controls, [mean (±SD) = 14.77 (±5.98)] [mean (±SD) 2.50 (±2.15)] (ANOVA F = 11.94, p = 0.0009), as (ANOVA F:72.58 p < 0.0001). they did for most of the individual items of the scale. In the absence In the body signs and symptoms scale, 12 of the 20 items of a gold standard for Ehlers–Danlos, it is mandatory to calculate were significantly higher among the anxiety cases, but none scored different cut-off points to obtain different degrees of prevalence. higher in the control group. Again, those not reaching significance Hence, after applying different cut-off points to this scale, results were the least prevalent in both samples. The total body signs and show significant differences in every grouping. In the 3/4 cut-off, symptoms scale scored significantly higher for the anxiety cases there were 24 cases (66.67%) and 8 controls (22.22%) classified as (mean (±SD) 7.86 (±2.88)) than for the controls [(mean (±SD) hypermobile, χ2 = 14.955, p = 0.0001. In the 4/5 cut-off, there were 4.22 (±3.39)] (ANOVA F 12.033 p = 0.0011). 19 cases (52.78%) and 7 controls (19.44%) classified as hypermobile, In the psychological characteristics scale, 23 of 31 items χ2 = 8.921, p = 0.0028. In the 5/6 cut-off, there were 15 cases were significantly higher among the anxiety cases. As expected, (41.67%) and 4 controls (11.11%) classified as hypermobile, χ2 = most items reflecting psychopathological traits showed significant 9.082, p = 0.0026. In every cut-off, the obtained “case” groups meet differences between groups. On the other hand, this scale also modern criteria for HSD/hEDS. contains items reflecting some advantageous or positive traits and most of them scored higher among the anxiety cases; however, they did not reach statistical significance. The entire psychological scale Discussion scored significantly higher in the anxiety cases, with a mean (±SD) of 48.61 (±17.90) than in controls, with a mean (±SD) of 27.61 The instrument proposed for this new clinical endophenotype (±10.55) (ANOVA 36.757, p < 0.0001). has shown good psychometric standards of reliability and validity. Frontiers in Medicine 05 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 TABLE 2 NEQ comparison cases and controls. CASE Median CONTROL Median F p Z p Mean (±SD) Mean (±SD) ANOVA (Wilcoxon) Sensory sensitivity 33.19 (±11.5) 32 14.77 (±5.98) 14 72.58 0.0001 6,351 <0.0001 Body signs and 7.86 (±2.88) 7 4.22 (±3.39) 3.5 12.33 0.0011 3,474 0.0005 symptoms Psychological 48.61 (±17.90) 46 27.61 (±10.55) 24 36.76 <0.0001 51,001 <0.0001 characteristics Polar behavior CASE (n) % CONTROL (n) % x² p strategies Both supercontrol and 14 38.9 4 11.11 11,364 0.0099 lack of control None supercontrol nor 8 22.22 20 56.56 lack of control Only one of them 14 38.9 12 33.33 Both dependent and 29 80.56 11 30.56 25,768 <0.0001 isolated None dependent nor 6 16.67 18 50 isolated Only one of them 1 2.78 7 19.4 Both avoidance and 12 33.33 5 13.89 6,299 0.0979 intrusion None avoidance nor 20 55.56 25 69.44 intrusion Only one of them 4 11.11 6 16.67 Both fight and fly 24 66.67 10 27.78 17,068 0.0007 None fight nor fly 6 16.67 20 55.56 Only one of them 6 16.67 6 16.67 Both me and others 25 69.44 13 36.11 9,085 0.0282 None me nor others 5 13.89 14 38.89 Only one of them 6 16.67 9 25.01 Internal consistency has achieved acceptable figures for each scale. precipitants may be present, however, acknowledging these often- Test–retest reliability was quite satisfactory since most coefficients neglected HSD/hEDS symptoms will provide new clues to better were above 0.8, and the inter-examiner kappa values obtained were understand patients. within a similar range. The psychological (characteristics and sensations) scale In the comparison between the anxiety cases and controls, includes a variety of the old “neurotic ambit” items, such as each NEQ scale obtained significantly higher scoring. The sensory anticipatory anxiety, worry, social anxiety, fears, phobias, health scale score was higher among the anxiety cases, which confirms anxiety, and functional neurologic or gastrointestinal symptom, previous findings by different groups (39–41), and in a non- together with other resilience features also suggested by the clinical population using the 10-item Barsky’s Somatosensory patient groups. This is a new line for clinical assessment, often only Amplification Scale (SSAS) (42). We decided to develop a new centered on negative items, whereas items related to clinical anxiety list of items following proposals from patients that allowed us to scored significantly higher in patients, some related to resilience, capture more specific perceptions. albeit always higher in patients, did not reach significance. This The body signs and symptoms scale was significantly higher may be due to sampling reasons as the cases seen in a country- among the anxiety cases, reflecting the value of considering these reference anxiety unit might include more severe cases, which may somatic characteristics and clues among anxiety patients. Most hamper obtaining more positive answers. of these are closely related to Ehlers–Danlos features and it is The polarized behavior scale is based on several basic very important not only to assess them in patients with anxiety adaptive strategies that can be represented between two poles: but to especially avoid premature misattribution to psychogenic overcontrol/lack of control, dependency/isolation, fight/flight, causation or even to the blurry somatization group now renamed me/others, and avoidance/ intrusion. These are tendencies as somatic symptom disorder in DSM 5. Psychological factors and that have been related to personality patterns as well as Frontiers in Medicine 06 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 clinical conditions, particularly anxiety. The hypothesis was cases and controls. This procedure will be performed in the next that patients would show more polarized tendencies either validation study, where each scale will be analyzed in terms of uni-directionally (43–46) or bi-directionally, along the lines concurrent validity with selected scales. Seventh, to apply NEQ, of coexisting dichotomies like altruism/ egoism (47) and some training will be necessary and, therefore, one should not use overcontrol/uncontrol (48, 49). it without proper (although brief) training to be able to assess The results obtained confirmed that patients with anxiety joint hypermobility. showed a greater tendency than the controls toward these polarized Four points prompted us to develop this Neuroconnective behaviors. These preliminary findings provide grounds to include Endophenotype Questionnaire. First, the extensive research on this scale in the phenotype. One of the potential advantages the association between HSD/hEDS and anxiety has been of this axis is that it provides psychological clues that can overwhelmingly replicated. These patients suffer the clinical guide psychotherapeutic approaches, as has been the case for manifestations of both disorders, but they often receive only overcontrol/uncontrol with radically open dialectical behavior one of the two assessments and treatments. Furthermore, it therapy (50). is well known that HSD/hEDS is a systemic condition well One important contribution of the neuroconnective beyond the musculoskeletal system, also affecting gastrointestinal, endophenotype is the systematic assessment of somatic conditions, neurological, immuno-allergology, gynecological, and urological which were found to be prevalent, either among anxiety disorders systems, among others. Since the association with HSD/hEDS is so or in HSD/hEDS. The patients proposed quite a few clinical extensive, it is likely that those patients suffering from anxiety may conditions; however, the final list included 15, which were properly also suffer from the clinical conditions of these systems. Second, defined by written diagnostic criteria. present nosological approaches do not allow the concurrent In the comparison between the anxiety cases and the controls, inclusion of both mental and somatic conditions together. Instead, only half of these somatic ailments (irritable bowel, functional the approaches both of DSM and ICD take the direction of dyspepsia, somatoform vertigo, chronic fatigue, fibromyalgia, causality, and emphasis is placed on the secondary appearance, asthma, and temporomandibular–jaw syndrome) were significantly but not on coexistence. Examples of these views are DSM 5: 316 more common among the anxiety cases; however, general Psychological Factors Affecting Other Medical Conditions 316 (F54) frequencies were low. Most of them had been related to anxiety but or, in the inverse direction, Anxiety Disorder Due to Another not the joint hypermobility spectrum. Medical Condition DSM-5 293.84. Some isolated but interesting As expected, the prevalence of hypermobility was again found proposals like ALPIM (anxiety, laxity, pain, immune, and mood) to be significantly higher among the patients with anxiety, which have been described along the lines of comorbidity (51). confirms previous research. Even applying different cut-off points, Third, since most patients show mixed subjective and objective these differences remained significant. Albeit prevalence was not manifestations, in most instances their own words could better an objective of this study, the figures obtained (66% in the 3/4 capture this clinical information. The NEQ has tackled the cut-off point and 53% in the 5/6 cut-off point) agreed with previous challenge of the patient’s participation and this questionnaire was publications (13, 19). constructed with the active cooperation of patients, who suggested This study has several limitations. First, from the early joint and corrected most items, which is a significant step toward hypermobility syndrome in the 80s, this syndrome has been clinical validity. redefined, particularly after the historical EDS meeting in New Fourth, a new endophenotype requires proper psychometric York in 2016 where new nosological approaches were introduced, assessment, and the first step is to develop an instrument with such as the hypermobility spectrum disorder (HSD). This produces good reliability and proper validity measures. The development some difficulties to reconcile past and present papers, although period took some time because the authors wanted to maximize there is intense overlap among most criteria. In this case, face validity, given the original and transversal nature of the we have taken the advice to collect them under the heading proposal. After many sessions with patients, professionals, and HSD/hEDS which provides strict specificity. Second, sample sizes, patient associations, the present version was considered ready for although appropriate for reliability studies, were relatively small calibration. This study deals with the Spanish version of the NEQ, (but properly calculated) to compare the anxiety cases and the but English, French, and Catalan versions are on the way. Also, controls. More cases and controls would be necessary to figure cultural validation will be made with the Spanish and Colombian out the value of each item and each scale and to carry out the Spanish versions. necessary multivariate analysis to ascertain the predictive validities After almost 30 years of successful research on the association of NEQ. Third, an assessment of somatic conditions is made via between joint hypermobility and anxiety disorders and other an interview with the participant, which may be affected by recall psychiatric conditions, the subsequent step was to identify a bias. To palliate this bias, medical records of cases and controls core endophenotype that can gather these clinical features. This were screened with the permission of each study participant. endophenotype might afford more strength to clinical practice Fourth, anxiety cases included only patients diagnosed in our panic, and research. For patients, the acknowledgment of this broad agoraphobia, social phobia, specific phobia, and generalized anxiety spectrum makes them able to realize the mixed nature of their disorder units. In this sample, there were no cases of obsessive- condition; in our experience, this results in great relief and compulsive disorder or stress-related disorders. Fifth, cases were understanding for patients. For psychiatrists and mental health taken from an anxiety unit, which may represent a more severe workers, assessment and treatment of both somatic and mental sample. However, in different studies to date, most results concur. symptoms can be a relevant step toward a better understanding of Sixth, no specific anxiety or depression scales were applied to the these patients’ suffering. Considering that both anxiety disorders Frontiers in Medicine 07 frontiersin.org Bulbena et al. 10.3389/fmed.2023.1039223 and Ehlers–Danlos hypermobility types have strong heritability Author contributions without any specific genetic testing as yet, engaging in new research with this more comprehensive endophenotype might provide AB, SR, and AB-C contributed to the conception and design new grounds to obtain improved specificity of the genetic basis. of the study. SR, CB-V, MM, MC, L-MM, and SB carried The originality of NEQ is that it includes both objective and out assessments, fieldwork, and contributed to the first draft subjective features, both patient and professional contributions, and first version of the manuscript. AB and AB-C performed both somatic and psychological features, and both negative and the revision of the manuscript. All authors contributed to positive (resilience) features. the manuscript revision, and have read and approved the This study is the necessary first step toward the full validation submitted version. process of a new clinical construct. We envisage larger and varied samples to determine cut-off points and extensive predictive validity studies will lead to biological studies (i.e., genetic and Acknowledgments neuroimaging) to obtain external validity. Also, NEQ will need to be validated in bigger HSD/hEDS samples and common comorbid We are thankful to all patients, professionals, and relatives for conditions, such as fibromyalgia, chronic fatigue syndrome, mast participating in person and through online meetings. We are also cell activation disorders, and postural orthostatic tachycardia grateful to the Asociación Nacional de Sindromes de Ehlers-Danlos, syndrome, as well in those psychiatric conditions that have shown Hiperlaxitud y Colagenopatías (ANSEDH) for its support during high HSD/hEDS prevalence. the project, as well as Prof. Rafael Torrubia for his critical review Most importantly, therapeutic trials, beyond of the manuscript, and Helena Kruyer for her thorough English psychopharmacological approaches, need to be carried out. Perhaps language revision. the most promising path is the design of preventive programs for children with this phenotype, which we anticipate should contain educational, psychological, and physical components. Conflict of interest NEQ has obtained acceptable figures regarding reliability, internal consistency, and both face and predictive validity in the The authors declare that the research was conducted in the comparisons with matched controls; it is ready to be used and absence of any commercial or financial relationships that could be tested. To carry out this study in children, we envisage developing construed as a potential conflict of interest. a specific children’s version of the NEQ, which, as yet, is in the early stages. Publisher’s note All claims expressed in this article are solely those of the Data availability statement authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the The raw data supporting the conclusions of this article will be reviewers. Any product that may be evaluated in this article, or made available by the authors, without undue reservation. claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Ethics statement Supplementary material The studies involving human participants were reviewed and approved by Comité de Ética de la Investigación con medicamentos The Supplementary Material for this article can be found del Parc de Salut MAR. The patients/participants provided their online at: https://www.frontiersin.org/articles/10.3389/fmed.2023. written informed consent to participate in this study. 1039223/full#supplementary-material References 1. Bulbena A, Duro JC, Mateo A, Porta M, Vallejo J. Joint hypermobility syndrome 5. Juul-Kristensen B, Schmedling K, Rombaut L, Lund H, Engelbert and anxiety disorders. Lancet. (1988) 2:694. doi: 10.1016/S0140-6736(88)90514-4 RH. 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