Cognitive Performance, Physical Pain and Psychological Distress in Women with Fibromyalgia During The COVID-19 Pandemic in Chile: A Case-Control Study

Fibromyalgia (FMS) is a chronic condition that encompasses widespread pain associated with cognitive impairment and significant emotional distress related to functional disability that affects mainly women. However, the mechanisms underlying the origin of the cognitive impairments and how the current COVID-19 pandemic impacts remain elusive. This study aimed to determine whether there is an association between cognitive performance in executive functions, physical pain, and psychological distress caused by the pandemic in a group of Chilean women with FMS using a novel online protocol of neuropsychological evaluation. We found that women with FMS present cognitive impairment predominantly explained by pain and anxiety symptoms, which are associated with the difficulties experienced from the COVID-19 pandemic. These results point out the importance of considering a broader perspective for treatment, including anxiety symptoms and the psychological distress caused by the pandemic as a therapeutic target for cognitive impairments.


Introduction
Fibromyalgia (FMS) is a chronic syndrome characterized by complex symptomatology, the core of which is generalized and persistent musculoskeletal pain that also comprises fatigue, sleep disturbances, morning joint stiffness, depression, and anxiety 1,2 . This syndrome is one of the most common causes of widespread chronic pain and is a common condition in the general population 3,4 . The worldwide prevalence of FMS is between 2% and 5%, regardless of the territory, and it mainly affects women 5 .
Despite lacking studies in Chile, a similar prevalence is estimated, with predominance in women as well 6 . On the other hand, FMS has been associated with the suffering of physical and emotional trauma and a history of post-traumatic stress 7,8 . Its impact on quality-of-life compromises physical, psychological, and social domains 9, 10 , including performing adequately in the work context 11 .
Additionally, cognitive impairments in FMS patients have been reported, such as forgetfulness, concentration di culties and/or mental slowness. These impairments are known as brofog and are considered among the most severe symptoms of the disease 12,13 . Several affected cognitive functions have been identi ed in a variety of studies, such as attention and memory 14,15 , and cognitive processing speed 15 . Furthermore, executive function impairment has also been con rmed, including planning 16 , abstract thinking 17 , and cognitive exibility 18 . In this line, a recent meta-analysis that included 37 FMS case studies and controls concluded a decrease in the performance of memory, attention, processing speed, and mainly executive functions 19 .
The mechanisms underlying the origin of the aforementioned impairments are not well understood yet.
However, the Neurocognitive Model of Attention to Pain might provide a theoretical framework to understand and test whether the pain interferes with attention processes. According to this model, any cognitive dysfunction in the context of chronic pain is the result of the interference between attention focused on both the peripheral input (pain) and the goal-directed activity 20,21 . In other words, pain and high interoceptive monitoring might lead to reduced attention performance in cognitively demanding tasks or activities, in turn increasing the susceptibility to distraction and slowing down the information processing, interfering with cognitive function 21 .
Additionally, there is a susceptibility to suffering from anxiety and depressive disorders in patients with FMS 22,23 , which can increase the reported cognitive de cits 24 . In this line, there is a crucial link between cognitive decline, pain, and psychological distress.
Currently, the emergency due to COVID-19 has seriously impacted the population's mental health 25 . In this context, it has been reported that FMS patients who experience chronic pain present a higher risk of increased psychological distress 26 . However, how the pandemic and its potential effect on the mental health of FMS patients is related to their cognitive performance remains elusive. Besides, there is a lack of these types of studies on the Latin American population, which might be of particular interest considering both the socio-cultural aspects and that the response to the pandemic has been slower and with fewer resources than developed countries 27 .
Here we aimed to determine whether there is a relationship between cognitive performance, physical pain, and psychological distress in Chilean women with FMS during the COVID-19 pandemic using a novel online protocol of neuropsychological evaluation. In order to do this, a group of FMS patients and controls were contacted and evaluated using online platforms in an asynchronous way rst, where they answered a sociodemographic scale, pain level rating, psychological distress, and executive functions assessment using behavioral scales. Afterward, they were contacted to conduct a synchronic online evaluation with trained neuropsychologists using traditional virtually adapted cognitive tests (Fig. 1).
We hypothesize that FMS patients present higher levels of psychological distress due to the pandemic and conjointly with physical pain; in agreement with the Neurocognitive Model of Attention to Pain, it will negatively impact their cognitive functions. Our results will contribute to the scienti c body of knowledge and the clinical eld since they may impact the development of clinical guidelines and health personnel training. Likewise, it is possible to promote and develop public policies that bene t patients with FMS, considering that there is still an under-consideration of these cases 28 .

Results
We found no signi cant differences between groups in sociodemographic characteristics. However, there were higher scores in depressive symptoms, panic attacks, and pharmacological treatment in the clinical dimension of our sample. Table 1 shows a summary of the sociodemographic and clinical descriptive statistics. To analyze physical pain differences, di culties due to the pandemic, mood, and their impact in FMS, we performed statistical comparisons showing that FMS patients exhibited higher levels of generalized physical pain, greater di culties due to the pandemic in general and in several speci c dimensions: mood, pain, nancial, family, health, food supply. Table 2 summarizes the statistical comparisons in physical pain, di culties due to the pandemic, mood, and their impact on FMS. Cognitive performance was evaluated in different domains. Interestingly, we found no differences in memory performance and phonological uency. However, the executive functions exhibited impairment in the FMS group. Speci cally, the semantic uency and the attention measured using the Symbol-Digit test. Additionally, the executive functions evaluated using the self-rating Dysexecutive Questionnaire (DEX-Sp) also showed lower performance in all dimensions: impulsivity and disorganization (Fig. 3). Table 3 shows the statistical comparisons between groups in cognitive performance. To determine whether there is a relationship between time since diagnosis, anxiety score, depression score, the impact of FMS, pain rating, di culties due to COVID-19, DEX-sp, SDMT, and FVS, we performed Pearson's r correlations between these parameters. We found various correlations (Table 4). Afterward, in order to determine the effect of the di culties due to the pandemic, physical pain, and psychological distress over cognitive performance, we performed a stepwise linear regression.
Importantly, we found that the predictor variables have a signi cant effect on cognitive performance (Table 5). Table 5 Stepwise Linear Regression. Pain, Anxiety, and Fibromyalgia explaining cognitive performance a .

Discussion
In this study, the cognitive performance of FMS patients was evaluated to determine whether cognitive functions were affected by physical pain and/or psychological distress due to the pandemic. To address this question, we designed a novel online protocol that can be reproduced for clinical purposes. We found impairment in executive functions or high-order cognitive functions for the FMS group, where the physical pain explained part of this signi cant result. This nding was in line with our predictions since it has previously been reported that physical pain reduces attention capacity, affecting overall cognitive performance 20 , which agrees with the Neurocognitive Model of Attention to Pain 29 .
Furthermore, FMS patients exhibited semantic uency impairment suggesting semantic access di culties, which involves executive action to retrieve information from long-term memory 30 . This result is in line with studies showing de cits in this area 31 . Additionally, we have found for the rst time an association between dysexecutive symptoms, pain, time since diagnosis of FMS, di culties due to the pandemic, and anxiety symptoms.
This study has some limitations. Firstly, we evaluated only women from an urban context; thus, these ndings are not extrapolatable to other groups, such as men with FMS or people from rural zones. Secondly, Results involving the di culties due to pandemic evaluation have to be taken with precautions since these were conducted without previous psychometric properties data of this instrument, which might affect the level of reliability of this particular nding. Finally, we strongly recommend for future research including other social groups (for instance, men and rural groups) to strengthen the results and subsequent interpretations.

Conclusions
Our results show that Chilean women with Fibromyalgia exhibit subjective and objective cognitive impairments, predominantly in executive functions or high cognitive demanding tasks. These impairments are mainly explained by pain and anxiety symptoms that they suffer, which are positively associated with the di culties experienced from the COVID-19 pandemic. Additionally, these results express the relevance of considering the treatment of pain and anxiety symptoms as a therapeutic target for cognitive impairments and the effect of the pandemic on their daily functioning.

Methods
This study is case-control, cross-sectional, descriptive, and non-experimental. The sampling technique was non-probabilistic. All the procedures were carried out remotely in tele-neuropsychology format 32 due to the health emergency caused by COVID-19 pandemic. The ethics committee of the Universidad Santo Tomás approved procedures, and all methods were carried out in accordance with the relevant guidelines and regulations.

Subjects
Data was collected from seventy right-handed and Chilean adult women. From the total sample, there was a group of fty women diagnosed with FMS (mean age = 44.05, SD = 8.71) and nineteen healthy women as a paired-match (sex, age, nationality, demographic similarities) control group (mean age = 40.63, SD = 9.79). The sample size followed the gold standard reported in the meta-analysis by Bell et al. 19 . Patients with FMS were diagnosed by a specialist following the 1990 American College of Rheumatology criteria for FMS 28 and were recruited from Fibromyalgia Associations located in distributed regions of Chile, while participants belonging to the control group were recruited based on demographic similarities with patients. Exclusion criteria for the control group were neurological or psychiatric disorders and medical background of severe somatic diseases. All participants signed an informed consent form before the beginning of the study.

Instruments -Sociodemographic Questionnaire:
We designed an open-ended and multiple options questionnaire instrument that measures general demographic characteristics (age, medications, illnesses, schooling, history of mental disorders, medical background, among other aspects). Additionally, in this questionnaire a likert scale was included to evaluate di culties due to the pandemic (mood, physical pain, nancial problems, family, health, fear of being infected, food, and fear of dying).
-Hospital Anxiety and Depression Scale (HAD) 33 : The HAD is a self-assessment scale that detects states of depression and anxiety in patients with different chronic conditions, assessing the cognitive and behavioral symptoms of anxiety and depression. It is composed of two subscales (Depression and Anxiety), each of them has 7 items. Each score varies between 0 to 21. The response options range from: absence / minimum presence = 0 to maximum presence = 3. The higher the score obtained, the greater the intensity or severity of the symptoms. This scale has been validated in patients with FMS from a Spanish population and has good psychometric properties 33 .
-Disexecutive Questionnaire (DEX-Sp) 34 : The DEX-sp is a brief and easy to complete Likert-type selfreport test with twenty items, and ve response options between 'never' (0 points) and 'very often' (4 points) used to estimate executive dysfunction. This test assesses abstract thinking, planning, insight, temporal sequencing, impulse control, response inhibition, decision-making, as well as the presence of fables, impulsivity, euphoria, apathy, aggressiveness, restlessness motor, super cial affective responses, perseverance, distractibility, and disregard for social rules 35 . This scale presents good psychometric properties and has been validated in the Spanish-speaking population 34 .
Visual Analog Scale of Pain (VAS): The VAS is a subjective measure of acute and chronic pain intensity. Scores are recorded by making a handwritten mark on a 10-cm line representing a continuum between "no pain" and " the worst pain imaginable." The VAS is a reliable and valid scale for many patient populations 36 . A value lower than 4 on the VAS means mild or mild-moderate pain, while a value between 4 and 6 implies moderate-severe pain. A value higher than 6 implies the presence of very intense pain.
Cognitive variables -Hopkins Verbal Learning Test (HVLT) 37 : The HVLT is a verbal memory test consisting of a 12-item word list composed of 3 semantic categories, which subjects should recall after the list has been read to them. This procedure is repeated three times. 25 minutes later, subjects are asked to recall the list of words again. Then, for a yes/no recognition, a list of 24 words is read, which consists of the 12 original/target words, 6 distractors from the same semantic categories and 6 unrelated distractors. This test provides scores for a learning curve, long-term memory, and recognition/discrimination. The HVLT is a valid instrument in the Latin American Spanish-speaking adult population with good psychometric properties 37 .
-Symbol Digit Modalities Test (SDMT): The SDMT measures sustained attention and speed of information processing 38 consisting of nine digits paired with symbols underneath. Participants are asked to provide the corresponding number for each symbol for 90 s. The SDMT is a valid instrument in the Latin American Spanish-speaking adult population with good psychometric properties 39 .
F-A-S Test: These tests evaluate executive functions since they demand participants to be exible, organize information, provide effort, and control inhibition when it is needed 40 . In order to evaluate these complex cognitive functions, we used the phonological and semantic uency tasks, which both have been validated and normalized in the Latin American Spanish-speaking adult population with good psychometric properties 40 .
-Phonological Verbal Fluency: This test aims to ask participants to create as many words as possible, beginning with a speci c letter (F, A, S) for 60 seconds. If a participant does not respond within 10 seconds, the examiner gives prompts 40 .
-Semantic Verbal Fluency: This test demands participants to produce items that belong to a given category (e.g., animals) within 60 seconds. The participants are also provided with prompts for this test when they do not respond within 10 seconds 40 .
Digit Span tests: These are verbal tasks, with stimuli presented auditorily. These tests aim to assess attention (Digit Span Forward) and working memory capacity (Digit Span Reverse) 41 .
-Digit Span Forward: In this test, the experimenter says a sequence of digits (one digit per second); at the end, the participant is asked to repeat the digits back to the experimenter in the same order that was given. The task begins with a few digit sequences, and then the number of digits increases 41 .
-Digit Span Reverse: This version of the test has the same structure as the Digit Span Forward. The difference is that the participant is asked to repeat the digits in reverse order which requires manipulation of information, thus working memory function 41 .

Procedure
After the ethics committee of the Universidad Santo Tomás approved the research project, this was formally presented at the Fibromyalgia Association of Chile. Women diagnosed with FMS members of the association along the country were voluntarily recruited. Afterward, patients were contacted to con rm computer/tablet or smartphone availability with an internet connection. Subsequently, they received an online form that included a brief description of the research, informed consent, sociodemographic questionnaire, medical history, and the instruments: di culties due to the pandemic, the DEX-Sp, VAS, and HAD scales.
After the rst data collection, the second part of the process was to conduct the online neurocognitive protocol consisting of the HVLT, SDMT, F-A-S, and Digit Span tests. The evaluation protocol lasted approximately 30 minutes and was applied through the Whereby platform from March to May 2021.
Later, the control group with similar characteristics as the FMS patient group was recruited. The control group was evaluated following the same procedure aforementioned. Finally, once all data were collected, statistical analyses were performed (Figure 2).

Data Analysis
The student's t-test was used to compare variables between groups. Additionally, Cohen's d test was performed to estimate the size effect. Moreover, we conducted the Chi square test and the Cramer's V test for nominal variables, respectively. To determine the association level between variables, we used the Pearson r correlation test. Furthermore, in order to determine the effect of pandemic di culties, physical pain, and psychological distress on cognitive performance, a stepwise linear regression was used, including 5000 samples bootstrap. All statistical analyzes were performed using the SPSS 25 statistical software synchronized with JASP, considering a signi cance threshold of p <0.05.

Declarations Data availability
The data of the current study are available from the authors upon reasonable request. Figure 1 Representative neuropsychological online protocol. A trained neuropsychologist explained and guided the cognitive evaluation to FMS and control groups through the Whereby platform.