Objectively investigating memory and attention in individuals living with endometriosis

Background and Rationale Endometriosis is a chronic inflammatory disease experienced by approximately 10% of people assigned female at birth, which translates to around 200 million women and adolescents globally (As-Sanie et al., 2019). The condition is characterised by the migration of endometrial cells from the uterus to areas outside, most frequently in the pelvic cavity, where these cells form lesions (Ferrero et al., 2018). These lesions are commonly associated with severe pain and common symptoms of endometriosis include dyspareunia (genital pain during sexual intercourse), dysmenorrhea (menstrual cramps), dyschezia (constipation), pelvic pain, infertility, gastrointestinal problems and lower abdominal pain (De Graaff et al., 2013). In addition, 95% of patients report the occurrence of at least one other comorbid disease, including irritable bowel syndrome (IBS), migraines, chronic fatigue syndrome (CFS), uterine fibroids, ovarian cysts and fibromyalgia (Maddern et al., 2020). Affected individuals are also at a greater risk of developing ovarian, breast and cutaneous melanoma cancers, as well as rheumatoid arthritis and cardiovascular disease (As-Sanie et al., 2021). Endometriosis has significant impacts on many domains of life and is associated with poorer quality of life (Facchin et al., 2015; Vitale et al., 2017) and psychological distress, including anxiety disorders and depression (Sullivan-Myers et al., 2021; Vannuccini et al., 2018; Wang et al., 2021). This condition impacts on sexual relations, sleep, social activities (As-Sanie et al., 2021) as well as workplace activity, with research indicating that 6.3 hours per week of workplace productivity are lost, commonly due to presenteeism (lowered productivity) (Armour et al., 2019; As-Sanie et al., 2019). Thus, endometriosis carries a great symptom burden and affects a large number of women worldwide; yet despite this, research to date has tended to focus on the aetiology and treatment of the condition, as opposed to the psychosocial and cognitive impacts of this condition (Aerts et al., 2018; As-Sanie et al., 2019). Cognitive Functioning and Endometriosis In particular, scant research has focused on potential deficits in cognitive functioning including difficulties with information processing, attention, problem solving and executive functioning (Sherwin, 2003). The current research indicates that individuals living with endometriosis may experience cognitive dysfunction, specifically through two qualitative studies, in which a participant reported “mental fatigue” and another participant reported “no mental clarity” (DiBenedetti et al., 2020). In addition, neuroimaging studies have identified reduced gray matter volume in areas of the brain important for cognition, suggesting potential cognitive difficulties (Maulitz et al., 2022). In order to explore this potential relationship in detail, a mixed-methods study completed as part of the student researchers’ Honours thesis was conducted. An online survey collecting both qualitative and quantitative measures was distributed in 2021 (n=1239), finding that the sample reported significantly lower cognitive functioning than a sample of cancer survivors (Kiang et al., 2016) and 80% of the sample were classified as cognitive impaired (Van Dyk et al., 2017). Participants also reported qualitatively the negative impacts of their endometriosis on their cognition, particularly reporting the negative influences of endometriosis-related pain, fatigue and treatments and depression on cognition, and the negative impacts of these cognitive impairments on their ability to function, particularly in their occupation. A wide range of impairments were qualitatively reported by participants including issues with concentration, memory and communication skills. This study demonstrated for the first time that individuals living with endometriosis experience significant cognitive deficits, yet this relationship needs to be explored in further detail. Factors Associated with Cognitive Functioning A major symptom of endometriosis which may help explain these cognitive deficits in endometriosis is pain (Maddern et al., 2020; Schliep et al., 2015). The experience of pain is central to endometriosis, with almost half of patients reporting cyclic pelvic pain and chronic pain (Schliep et al., 2015) and results from the student researcher’s Honour’s thesis found that participants reported significantly high levels of pain, even greater than a chronic pain population (Lovejoy et al., 2012). Clinical studies across various chronic pain conditions, such as fibromyalgia and chronic musculoskeletal pain, indicate a high incidence of cognitive functioning difficulties (Higgins et al., 2018; Innes & Sambamoorthi, 2020; Moriarty et al., 2011; Zhang et al., 2021). Specifically, attentional (Higgins et al., 2018; Moriarty et al., 2011) and memory deficits (Higgins et al., 2018; Moriarty et al., 2011; Oosterman et al., 2011) are consistently reported in chronic pain populations. A further symptom that is central to endometriosis is fatigue, with 50.7% of participants in one study reporting frequent fatigue (Ramin-Wright et al., 2018) as well as qualitative accounts detailing the negative impact of fatigue on quality of life and functioning (DiBenedetti et al., 2020). Fatigue has been strongly associated with cognitive functioning difficulties across several chronic conditions, including in chronic fatigue syndrome (CFS) and breast cancer (Boneva et al., 2019; Ocon, 2013; Teodoro et al., 2018; Von Ah & Tallman, 2015). Additionally, endometriosis symptoms have been linked to depressive symptoms consistently (Facchin et al., 2017; Facchin et al., 2015; Sullivan-Myers et al., 2021; Vannuccini et al., 2018). These depressive symptoms are associated with cognitive functioning difficulties across multiple domains (e.g., executive function, memory and attention) in both healthy (Douglas et al., 2018; Knight & Baune, 2018; Rock et al., 2014) and chronic illness (i.e., pain) populations (Rock et al., 2014). In results from the student researcher’s Honour’s thesis, higher levels of pain, fatigue and depression were all significantly associated with greater levels of self-reported cognitive functioning. Rationale for Current Study Therefore, there is current cross-sectional evidence of widespread subjective cognitive deficits in individuals with endometriosis. However, these cognitive complaints were subjectively measured and as such, there is a need to use neurocognitive tests to objectively measure cognitive functioning in individuals with endometriosis. These objective measures have been utilised in many other chronic health populations to measure potential cognitive deficits, including in Fibromyalgia (Tesio et al., 2015; Wu et al., 2018), chronic fatigue syndrome (Cockshell & Mathias, 2010), chronic pain (Higgins et al., 2018; Oosterman et al., 2011) and multiple sclerosis (Chiaravalloti & DeLuca, 2008; Patti, 2009). Thus, this study will explore for the first time whether individuals with endometriosis experience cognitive difficulties, measured using objective neurocognitive tests. In particular, the domains most commonly measured in these populations are: memory, attention, processing speed, learning and verbal fluency (Cockshell & Mathias, 2010; Higgins et al., 2018; Wu et al., 2018). Thus, these domains of cognition will be measured in the current study. In order to determine whether participants show cognitive deficits, a case control study design will be utilised, with participants with endometriosis compared to healthy matched controls. Thus, performance on neurocognitive tests, and a subjective measure of cognition will be compared with matched healthy controls, which is commonly utilised in other chronic health populations; in fibromyalgia (Gelonch et al., 2018; Tesio et al., 2015; Wu et al., 2018); chronic fatigue syndrome (Cockshell & Mathias, 2010); multiple sclerosis (Chiaravalloti & DeLuca, 2008; Patti, 2009) and chronic pain (Berryman et al., 2013; Oosterman et al., 2011). Participants are typically matched on age, sex and education level, which allows for controlling of these variables in the study, which are commonly associated with cognitive functioning (Boscher et al., 2020; Chiaravalloti & DeLuca, 2008; Lenehan et al., 2015). In addition, there is a need to investigate associations of pain, fatigue and depression with objective measures of cognitive functioning, which builds upon previous research demonstrating their links with subjective measures of cognition. This case-control study aims to: Aims: 1. Characterise cognitive functioning using objective neurocognitive tests in individuals with endometriosis in several cognitive domains, including memory and attention, and compare these cognitive functioning domains with healthy matched controls 2. Investigate the association of cognitive functioning (measured objectively) with subjective cognitive functioning, pain, depression and fatigue, in individuals with endometriosis.