Interoceptive attention regulation in Ehlers–Danlos syndromes: associations between pain and psychiatric symptom severity

Abstract

High rates of comorbid chronic pain, anxiety, and mood disorders among individuals with the Ehlers–Danlos syndromes (EDS+) are becoming increasingly recognized, though this complex symptomology remains poorly understood and undertreated. The current project examined whether interoceptive attention regulation is protective against depressive and anxiety symptoms in individuals with suspected EDS+. Data were collected from individuals participating in a transdisciplinary diagnostic visit within an EDS+ specialty consultation clinic. Participants were included in the current analyses (n = 49) if they had complete data on the following measures: the PHQ-8, the GAD-7, the Pain Severity subscale from the West Haven-Yale Multidimensional Pain Inventory, and the Attention Regulation subscale from the Multidimensional Assessment of Interoceptive Awareness. Consistent with expectations, the sample showed high levels of clinically significant anxiety and depressive symptoms. Pain severity ratings were significantly correlated with depressive but not anxiety severity. Moreover, higher levels of perceived interoceptive attention regulation abilities were significantly associated with less severe anxiety and depressive symptoms; however, attention regulation did not moderate the associations of pain with anxiety and depressive symptom severity.

Conclusions

The current project replicated recent findings that pain, anxiety, and depression are common in individuals with EDS+. The ability to focus and control somatic attention appears to be protective and a potential target for interventions in EDS+.

The ability to mindfully direct attention to or away from bodily states was associated with less anxiety and depressive symptoms in persons with suspected EDS+.

Implications.

Practice: Clinically significant anxiety and depressive symptoms are common among individuals with symptoms of Ehlers–Danlos syndromes (EDS+).

Policy: Policymakers who want to promote community engagement, inclusion, and reduction of disability should support transdisciplinary approaches for EDS+ populations, including psychology specialties.

Research: Future research should be aimed at identifying the most efficacious treatments for psychiatric comorbidities among individuals living with EDS+.

Introduction

The Ehlers–Danlos syndromes (EDS+) are a diverse group of hereditary connective tissue disorders characterized by a range of conditions, including—but not limited to – joint hypermobility, skin hyperextensibility, and tissue fragility [1]. Currently, there are 14 recognized subtypes of EDS+, but diagnostic criteria continue to be refined due to the inherent variability and overlap in genetic and phenotypic presentation. Although the ongoing revisions to the nosology of EDS+ are improving care, general medical knowledge of the syndromes has been historically limited and led to misdiagnosis and undertreatment [2]. Unfortunately, a lack of understanding regarding the relationship between an individual’s physical symptoms and their affective (e.g., anxiety, depression) and pain responses has contributed to a significant gap in care for those with EDS+. There remains a need to better understand how protective features are associated with pain and emotion.

EHLERS–DANLOS SYNDROMES (EDS+)

Estimated prevalence rates across subtypes of EDS+ are between 1:5,000 and 1:20,000 [3, 4]. As understanding of these syndromes improves, a clear need emerges for appropriate care to not only address symptomology but also improve quality of life [5]. To address this need, there is a call for team-based EDS+ clinics comprised of individuals possessing expertise across a range of disciplines [5, 6]. Transdisciplinary approaches to EDS+ care offer a more holistic approach to care, in which team members offer distinct expertise with shared responsibility and equivalent distribution of care [7]. Considering the diverse and numerous symptoms (e.g., pain, fatigue, neurologic, gastrointestinal, cardiovascular), complex conditions, like EDS+, directly benefit from a transdisciplinary approach.

One such cluster of care needs for individuals with EDS+ includes specialized psychological assessment and treatment [8]. Unfortunately, many individuals with EDS+ have experienced historic and harmful psychiatrization, in which limited clinical knowledge has led to misdiagnosis and inappropriate treatment [9, 10]. Despite this history, high rates of mental health concerns have been identified in these groups [8, 11]. For example, a review of studies looking at joint hypermobility syndrome and the hypermobile type of EDS+ indicated the presence of anxiety disorders among individuals with these conditions is double to triple that of healthy controls [8]. Depression has also emerged as a condition that is overrepresented among individuals with EDS+. A recent study demonstrated that depression was the most common psychiatric condition in a sample of EDS+ patients—with a twofold increase relative to the general population [11]. Accordingly, there is a need for specialty services like rehabilitation psychology to assess and treat these comorbid conditions. Specifically, the involvement of psychology specialties that address injury and chronic health conditions add value by pointing to novel intervention targets, which enhance the team-based approach to care and improve a range of psychosocial outcomes for the patient [6].

Better characterization of the risk factors for, and underlying mechanisms of, anxiety and mood disorders among individuals with EDS+ and related conditions is critical to identify and facilitate effective interventions. The numerous stressors of living with a chronic illness likely contribute to anxiety and mood disorders, which are common in the context of a number of chronic health conditions [12]. However, it is likely that there are factors that are unique to EDS+ that influence the high prevalence rates of anxiety and depression in this population. For example, the overlap between dysautonomia (i.e., autonomic nervous system dysfunction) and anxiety symptoms, as well as somatosensory amplification, are thought to be contributory pathways to the complex constellation of symptoms [8]. The experience of pain is also common among individuals with EDS+ syndromes [11]. Chronic pain is a well-documented risk factor for anxiety and mood disorders among a wide variety of populations [13, 14], including individuals with EDS+ [11].

Depression and anxiety as well as pain are all factors that have been known to cause individuals to limit/avoid activity and community engagement, which creates a cycle that can potentially lead to more pain through physical deconditioning. Cognitive behavioral therapy for chronic pain is a well-validated approach that helps individuals break this pain, avoidance, mood disorder cycle [15]. However, our understanding of other psychotherapeutic targets for anxiety and depression in EDS+ at this time is limited.

INTEROCEPTIVE AWARENESS AND EMOTION REGULATION

In addition to identifying potential risk factors and mechanisms within the EDS+ population, characterizing protective factors is also important to determine which strategies may best treat mental health comorbidities. The ability to mindfully regulate attention toward and away from bodily sensations is one such potentially protective (and malleable) factor that has been identified as an intervention for a range of psychopathologies [16]. Among other facets, this is a key aspect of interoceptive awareness or interoceptive sensibility [16, 17]. It is important to distinguish mindful attentional regulation to bodily states from more ruminative and somatic forms of interoceptive attention. Recently, the Multidimensional Assessment of Interoceptive Awareness (MAIA) [16, 18] was developed as a self-report assessment of individual differences in various interoceptive attentional styles. The MAIA [18] , and its revised version (MAIA-2) [19] measure eight distinct adaptive and maladaptive aspects of interoceptive bodily awareness (i.e., noticing, not ignoring, not worrying, attention regulation, emotional awareness, self-regulation, listening, trusting). Given the overwhelming amount of physical sensations (e.g., pain, dysautonomia) that EDS+ and other conditions with similar symptoms produce, the ability to mindfully regulate attention to bodily states may be particularly protective.

There is some evidence that mindful interoceptive attention regulation can be protective against depression and anxiety. For instance, this has been documented in non-EDS+ populations such as individuals with post-traumatic stress disorder (PTSD) or women with substance use disorders [16]. In addition, there is some preliminary evidence that mindful interoceptive attention may be protective against anxiety among individuals with some of the core symptoms of common EDS+ presentations. Specifically, Mallorquí-Bagué et al. [20] investigated connections between state anxiety and interoception among healthy volunteers with and without joint hypermobility. Results indicated that a better self-reported ability to mindfully regulate somatic attention was associated with lower state anxiety. Interestingly, objective interoceptive abilities on the heartbeat detection task were more accurate in individuals with joint hypermobility and improved accuracy was associated with an increase in state anxiety [20]. Taken together, these findings suggest that individuals with EDS+ symptoms may have increased somatic sensations/awareness of symptoms that contribute to increased rates of anxiety and depression. In turn, the ability to mindfully regulate attention to or away from these sensations could be protective against psychological distress in this population, thereby leading to decreased physical activity avoidance and increased community participation. However, this hypothesis awaits further empirical validation.

THE CURRENT STUDY

Individual differences in interoceptive awareness, as well as the degree to which this ability is associated with affective symptom severity, has not been studied among individuals with EDS+ and related disorders despite evidence suggesting that mindful body awareness may be highly relevant to these conditions. The current study addresses this gap in the literature by providing an improved description of the psychophysiological and affective symptomology in individuals undergoing an EDS+ specialty clinic visit and aims to inform more effective and holistic treatment strategies.

In this vein, we adopted two specific aims. First, we examined rates of anxiety, depression as well as associations between these variables with pain and interoceptive attention regulation, in a sample of individuals participating in a transdisciplinary (e.g., rehabilitation psychology, physiatry, physical therapy, medical genetics, neurogastroenterology) diagnostic visit to an EDS+ specialty consultation clinic. It was hypothesized that the current study would replicate past work demonstrating rates of clinically significant anxiety and depressive symptoms within an EDS+ clinical sample to be considerably increased (two or threefold) relative to the general population. We also hypothesized that we would replicate past work showing that self-reported mindful interoceptive attention regulation is associated with reduced anxiety and depression symptoms [16] and that pain increases the risk for anxiety and depression [11, 13]. For our second aim, we examined whether interoceptive attention regulation would moderate the association between pain and mood disorder symptoms, such that improved attention regulation would attenuate the strength of the association between pain severity and depressive and anxiety symptoms.

METHOD

Participants

Data were collected from individuals participating in a transdisciplinary (e.g., rehabilitation psychology, physiatry, physical therapy, medical genetics, neurogastroenterology) diagnostic visit within an EDS+ specialty consultation clinic. Participants were included in the statistical analyses (n = 49) if they had complete data on the following measures: the Patient Health Questionnaire Depression Scale (PHQ-8) [21]; the Generalized Anxiety Disorder 7-item (GAD-7) [22]; the Pain Severity subscale from the West Haven-Yale Multidimensional Pain Inventory (MPI) [23]; and the Attention Regulation subscale from the Multidimensional Assessment of Interoceptive Awareness (MAIA) [18]. Demographic information for the sample can be seen in Table 1, including PHQ-8 and GAD-7 scores.

Table 1.

| Sample characteristics

Variable	Total sample: mean (SD); range
Age (years)	28.43 (10.35); 14–52
Depression (PHQ-8)	11.27 (6.28); 0–23
Anxiety (GAD-7)	9.29 (5.86); 1–21
Pain severity (MPI)	3.80 (1.13); 1.67–6
Interoceptive attention regulation (MAIA)	2.96 (1.16); 0.14–5
Gender	Sample percentage (n)
Men	22.4% (11)
Women	77.6 % (38)
Race/ethnicity	Sample percentage (n)
White/Caucasian	89.8% (44)
Two or more races	8.2% (4)
Hispanic	2.0% (1)
Highest education received (ages 14–17, n = 8)	Subsample percentage (n)
Less than 9th grade	12.5% (1)
9–12th grade, no degree	87.5% (7)
Highest education received (ages 18+, n = 41)	Subsample percentage (n)
GED or alternative credential	4.9% (2)
High school diploma	7.3% (3)
Some college no degree	41.5% (17)
Associate’s degree	14.6% (6)
Bachelor’s degree	22% (9)
Master’s degree	9.8% (4)

Note. Total sample N = 49; PHQ-8 scores = eight-item Patient Health Questionnaire depression scale scores; GAD-7 scores = seven-item Generalized Anxiety Disorder scale scores; pain severity = pain severity subscale scores from the West Haven-Yale Multidimensional Pain Inventory; interoceptive attention regulation = attention.

Regulation subscale scores from the Multidimensional Assessment of Interoceptive Awareness; higher scores indicate more severe depressive and anxiety symptoms, greater pain severity, and better self-reported ability to regulate ones’ attention to bodily sensations.

Procedures

Data were derived from a group of patients seeking transdisciplinary specialty consultation services. This specialty clinic assessment included one-hour visits with medical genetics, neurogastronenterology, physiatry and physical therapy, and rehabilitation psychology, respectively. Each visit included assessment, diagnosis, and recommendations for future care needs. In addition to the measures of anxiety, depression, pain, and interoceptive awareness relevant to the current study, the psychological battery also included measures of posttraumatic stress, alcohol use, sleep, fatigue, social support, resilience, satisfaction with life, and health-related quality of life. This battery was accompanied by a clinical interview.

Measures

Depression and anxiety

The PHQ-8 [21] and the GAD-7 [22] are widely accepted measures of depression and anxiety symptom severity. Individuals rated items from each scale based on how often during the past two weeks they were bothered by symptomology associated with depression (i.e., “feeling down, depressed, or hopeless,” “Poor appetite or overeating”) or anxiety (“Feeling nervous, anxious, or on edge,” “Trouble relaxing”) on a scale of 0 (not at all) to 3 (nearly every day). Items for each questionnaire are summed, with scores of 10 or greater considered moderate/major anxiety or depression and scores of 15/20 or more considered severe anxiety or severe major depression. Both the PHQ-8 [Cronbach’s alpha = .863] and the GAD-7 (Cronbach’s alpha = .896) were shown to be reliable (i.e., internally consistent) instruments in the current sample.

Pain severity

The Pain Severity subscale from the West Haven-Yale MPI [23] is a three-item measure of pain severity, with each item assessing and individual’s “level,” “severity,” and “suffering” associated with their pain on a scale of 0 (“Not at all”) to 6 (“Extremely”). The pain severity subscale also demonstrated good reliability in the current sample (Cronbach’s alpha = .838).

Interoceptive attentional regulation

The Attention Regulation subscale from the MAIA [18] consists of seven items that assess an individuals’ ability to mindfully attend to (or away from) internal bodily states. Specific items are included in Table 2. Participants were asked to select a rating between 0 (“Never”) to 5 (“Always”) for each item while thinking about how they applied to them generally in daily life. In the current sample, the reliability of the attention regulation MAIA subscale was excellent (Cronbach’s alpha = .911).

Table 2.

| Attention regulation subscale from the Multidimensional Assessment of Interoceptive Awareness (MAIA)

Item
1. I can pay attention to my breath without being distracted by things happening around me.
2. I can maintain awareness of my inner bodily sensations even when there is a lot going on around me.
3. When I am in conversation with someone, I can pay attention to my posture.
4. I can return awareness to my body if I am distracted.
5. I can refocus my attention from thinking to sensing my body.
6. I can maintain awareness of my whole body even when a part of me is in pain or discomfort.
7. I am able to consciously focus on my body as a whole.

Statistical analyses

To estimate the prevalence of anxiety and depressive syndromes among this sample of individuals with suspected EDS+, the number of participants who fell above the recommended clinical significance cut-off of 10 for both the PHQ-8 [24] and the GAD-7 [22] were calculated. We predicted that pain and mood disorder symptoms would show a positive association and that better-perceived attention regulation ability would attenuate the strength of this relation. In order to test this hypothesis, two multiple linear regressions were conducted with PHQ-8 and GAD-7 scores each used as the dependent variables. For each regression, pain severity and interoceptive attention regulation scores were entered as lower-order independent variables followed by the interaction term. All lower-order terms were mean centered before creating the interaction to reduce multicollinearity [25]. Demographic variables were not entered as covariates in the analyses to limit the total number of predictor variables given the modest sample size. The statistical significance threshold for all tests was set at α < .05. All statistical analyses were conducted in IBM SPSS Statistics version 26.0 [26].

RESULTS

Descriptive and correlational analysis

A total of 61.2% of the sample showed clinically significant levels of depression as measured through PHQ-8 scores, whereas 49% of the sample showed clinically significant levels of anxiety as indexed by GAD-7 scores. Zero-order correlations among the primary independent and dependent variables are reported in Table 3. As illustrated Table 3, pain severity ratings were significantly correlated with depressive symptoms in the expected direction; however, pain severity was not significantly associated with anxiety symptoms. In addition, better self-reported ability to regulate attention to (or away from) internal sensations was significantly associated with less severe anxiety and depressive symptoms. Figure 1 illustrates the significant associations of interoceptive attention regulation with anxiety and depressive symptoms. (Results remained virtually unchanged if age and gender were included as covariates in the models.)

Table 3.

| Zero-order correlations between variables

	2	3	4
1. Depression (PHQ-8)	.651***	.440**	-.366**
2. Anxiety (GAD-7)	---	.153	-.438**
3. Pain severity (MPI)		---	-.089
4. Interoceptive Attention Regulation (MAIA)			---

Note. n = 49; PHQ-8 scores = eight-item Patient Health Questionnaire depression scale scores; GAD-7 scores = seven-item Generalized Anxiety Disorder scale scores; pain severity = pain severity subscale scores from the West Haven-Yale Multidimensional Pain Inventory; Interoceptive Attention Regulation = Attention Regulation subscale scores from the Multidimensional Assessment of Interoceptive Awareness; higher scores indicate more severe depressive and anxiety symptoms, greater pain severity, and better self-reported ability to regulate ones’ attention to bodily sensations.

* p < .05.

** p < .01.

*** = p < .001.

Fig 1 |.

Significant associations between the Attention Regulation subscale scores from the Multidimensional Assessment of Interoceptive Awareness and depressive and anxiety symptom severity. Better self-reported ability to direct attention to (or away from) bodily states is associated with less anxiety and depressive symptoms.

Multiple regression analyses

In the multiple regression analyses, all predictors entered accounted for 32.2% of variance in depressive symptoms [F(3,45) = 7.14, p = .001] and 22.4% of anxiety symptoms [F(3,45) = 4.32, p = .009], respectively. Full results of these two regressions can be seen in Table 4. As can be seen, interoceptive attention regulation and pain severity each accounted for a significant amount of unique variance in depressive symptoms severity. For anxiety, interoceptive attention regulation accounted for a significant amount of unique variance in symptom severity, but pain severity did not contribute to the model. Results also showed that interoceptive attention regulation did not significantly moderate the association of pain with either anxiety or depressive symptom severity. (Results remained virtually unchanged if age and gender were included as covariates in the models.)

Table 4.

| Multiple linear regressions predicting depressive and anxiety symptom severity by interoceptive attention regulation, pain severity, and the interaction term between interoceptive attention regulation and pain severity

Dependent variable	Predictor	B	Std. error	t	p
Depressive symptoms	Constant	11.18	0.76	14.61	<.001
	Interoceptive attention regulation	−1.89	0.67	−2.81	.007
	Pain severity	2.27	0.68	3.32	.002
	Interoceptive × pain	−0.71	0.60	−1.17	.247
Anxiety symptoms	Constant	9.21	0.77	12.04	<.001
	Interoceptive attention regulation	−2.25	0.67	−3.35	.002
	Pain severity	0.59	0.68	0.861	.394
	Interoceptive × pain	−0.63	0.60	−1.05	.300

Note. N = 49; PHQ-8 scores = eight-item Patient Health Questionnaire depression scale scores; GAD-7 scores = seven-item Generalized Anxiety Disorder scale scores; Pain Severity = pain severity subscale scores from the West Haven-Yale Multidimensional Pain Inventory; Interoceptive Attention Regulation = Attention Regulation subscale scores from the Multidimensional Assessment of Interoceptive Awareness; Interoceptive X Pain = interaction term of Attention Regulation subscale scores from the Multidimensional Assessment of Interoceptive Awareness by pain severity subscale scores from the West Haven-Yale Multidimensional Pain Inventory; Higher scores higher scores indicate more severe depressive and anxiety symptoms, greater pain severity, and better self-reported ability to regulate ones’ attention to bodily sensations.

Discussion

Individuals with EDS+ present with high rates of mental health conditions (e.g., anxiety, depression); however, to date, limited literature exists on the psychological symptomology in these populations [8, 11]. In the present study, we confirmed the presence of negative mental health symptoms in a sample of individuals with suspected EDS+ and established initial evidence for an unexplored protective factor relevant for future treatment strategies. In the current sample of individuals completing an EDS+ specialty clinic visit, a total of 61.2% of participants reported clinically significant depressive symptoms (as measured through the PHQ-8) and nearly half (49%) of participants reported clinically significant anxiety symptoms (through the GAD-7). These elevated rates of mental health concerns are consistent with some of the highest estimates for other chronic illnesses, such as cancer at the time of diagnosis or in the context of disease progression [12] and double to triple that of primary care samples [27, 28]. While this sample represents individuals undergoing a specialty clinic visit for EDS+ not individuals with confirmed EDS+ diagnosis, these findings nonetheless align with previous literature showing that clinically significant psychological symptoms are common among individuals with EDS+ [8, 11].

As expected, a significant and strong positive association was identified between pain severity and severity of depressive symptoms. The link between subjective severity of pain and depression is well-established in the literature. For example, Sharpe and colleagues [29] reported that pain severity independently predicted depressed mood amongst individuals with multiple existing conditions, even after controlling for the number and type of underlying illnesses. However, the association between pain severity and anxiety did not reach statistical significance. It is possible that in this population there was more “measurement noise” related to anxiety compared to depressive symptoms due to the overlap between the dysautonomia symptoms common among individuals with EDS+ and associated syndromes [8]. Therefore, it is critical that care providers consider that the physiological symptoms typically associated with anxiety (e.g., increased heart rate, pupil dilation, perspiration) could also be presenting from autonomic dysfunction as part of an underlying EDS+ diagnosis. This is especially relevant given the historical misdiagnosis and inappropriate treatment of EDS+ conditions, including dismissing all of an individual’s symptoms as psychiatric in nature [9, 10]. It is important to highlight that the presence of a true anxiety disorder and autonomic dysfunction that presents as physiological symptoms of anxiety are not mutually exclusive possibilities [30, 31]. Transdisciplinary strategies that include rehabilitation psychology services can help improve the characterization of psychiatric conditions in this population. Such a nuanced approach is likely to both decrease the invalidation felt by patients as well as ensure that potentially beneficial mental health treatment is pursued when needed.

Better self-reported interoceptive attention regulation abilities, as measured through the MAIA, were associated with lower anxiety and depressive symptoms in the current sample. This finding parallels past work that showed state anxiety is associated with higher interoceptive attention regulation abilities among both individuals with joint hypermobility [20] as well as a number of other non-EDS+ populations [16]. However, the expected moderation effect was not supported in that attention regulation scores did not attenuate the strength of the relations between pain severity and anxiety nor between pain severity and depressive symptoms. Despite the null interaction, the ability to mindfully direct attention to or away from bodily states was associated with lower anxiety and depressive symptoms severity in this sample. Accordingly, further investigation is warranted.

There is some emerging evidence that mindful interoceptive awareness can be improved through the use of specific psychotherapeutic techniques, and that this skill may be beneficial for a variety of clinical outcomes of interest. For example, improvement in interoceptive awareness (as measured by the MAIA) has been associated with reduced psychopathology symptoms among individuals with substance use disorders [32] and PTSD [19, 33]. Future research should continue exploring mindful interoceptive awareness as a treatment target more directly for individuals with EDS+ symptoms. Specifically, randomized intervention studies are needed to help understand whether mindfulness-based approaches have utility in reducing anxiety and depressive symptoms among individuals with EDS+. It is likely that these approaches would be effective given the promising evidence for mindfulness approaches to treat anxiety and depression in a variety of other clinical populations (for a review, see [34]). The studies reviewed above suggest that moving the needle on interoceptive awareness could moderate some of the beneficial effects derived from targeted interventions. However, this should be tested directly in future treatment studies.

It is possible that training in a mindful interoceptive awareness style would be most helpful to individuals prone to ruminative somatic attention and preoccupation. In that vein, future research should also explore whether the presence and severity of symptoms, such as dysautonomia, somatosensory amplification, and/or pain (all of which are likely to cause confusing or overwhelming physical sensations) could determine treatment selection. Regardless of the experimental approach utilized, objective measures of interoceptive attention regulation are also needed in future research. To date, studies have shown weak to null associations between objective measures of interoceptive awareness, such as the heartbeat detection task, and the MAIA [16] however, some evidence suggests that better performance on objective interoception tasks is both more common among individuals with joint hypermobility as well as associated with increased anxiety [20]. Although further work is needed, these objective tasks might be helpful in future research for identifying individuals with EDS+ symptoms who are the most prone to ruminative somatic attention and therefore may theoretically benefit the most from mindfulness and interoceptive attention training.

The present study has a number of limitations. First, self-report measures, such as the MAIA, are vulnerable to reporting biases. Therefore, it is possible that the associations documented, such as those between the attention regulation subscale and anxiety and depressive symptoms, could have been due to a social-desirability bias in which some individuals were more prone to present themselves in a positive light. Related, the interpretation of the current findings is limited by the use of correlational methods. Correlation of course does not equal causation, so it is possible that an unknown third variable or set of variables explains the relations identified. While the theoretical consistency seen in this study with past findings guards against that possibility, objective, experimental, and longitudinal methodologies are needed in future work. Finally, the modest sample size used in the current study limited statistical power and therefore the number and types of statistical analyses that could be conducted. The sample was also limited in terms of self-identified race/ethnicity and other forms of diversity. There remains a need for larger scale studies with diverse samples to test more complex models of the associations between somatic sensations, interoceptive abilities, and psychiatric symptoms severity. Other psychosocial factors that may contribute to depression and anxiety in this population should also be examined, such as time between symptoms onset and diagnosis and treatment.

In conclusion, this study offers additional evidence that clinically significant rates of anxiety and depression are common in individuals with symptoms of EDS+. While these psychiatric symptoms remain under-appreciated, the current findings add to our understanding of individual difference factors that are associated with variability in the severity of anxiety and depression. Namely, pain as a risk factor and mindful interoceptive attention as a protective factor represent fruitful candidates for potentially useful treatment target in future work. Broadly speaking, these findings align with calls for the involvement of specialty services in the care of EDS+ such as rehabilitation psychology [5], and could be used as a foundation for future research aimed at identifying the most efficacious treatments for psychiatric comorbidities among individuals living with EDS+. Continued empirical effort by researchers and clinicians who work with EDS+ populations and other related medical conditions will help fulfill the ultimate goal of promoting community engagement, inclusion, and reduction of disability.

Funding: This study was funded by LAP, Office of Research on Women’s Health of the NIH K12HD085852

Compliance with Ethical Standards

Authors’ Statement of Conflict of Interest and Adherence to Ethical Standards: All authors declare that they have no conflicts of interest.

Human Rights: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and IRB approval was secured for all data gathered.

Informed Consent: Informed consent was obtained from all individual participants included in the study.

Transparency statement: This study was not formally registered. The analysis plan was not formally pre-registered. De-identified data from this study are not available in a public archive. De-identified data from this study will be made available (as allowable according to institutional IRB standards) by emailing the corresponding author. Analytic code used to conduct the analyses presented in this study are not available in a public archive. They may be available by emailing the corresponding author. Materials used to conduct the study are not publicly available.