3.2.2. Regression Analysis

Table 3 shows the results of the multiple regression analysis performed to determine the ability of BMI and the clinical variables to predict cognitive performance. Regarding selective and sustained attention, BMI negatively predicted performance in the d2\_TR, d2\_CON and d2\_TOT conditions. Regarding information processing speed, BMI (in the first model) and sensorial pain (in the second model) were positively associated with the time taken to perform TMT Condition 2; moreover, the time taken to perform Conditions 3 and 4 of the 5DT was positively predicted by BMI. With respect to visuospatial memory, memory execution (ROCF) was negatively predicted by sensorial pain (MPQ). Regarding verbal memory, the RI\_AT TAVEC condition was positively predicted by state anxiety (STAI), and the RI\_CP TAVEC condition was negatively predicted by BMI. Finally, state anxiety was positively associated (in the first model) with sensorial pain and negatively related (in the second model) to the RI\_LP TAVEC condition.


**Table 3.** Results of multiple regression analysis performed to determine the ability of clinical factors and BMI to predict cognitive performance in FM patients.

Note: d2 = d2 Attention test; D-KEFS = Delis–Kaplan Executive Function Test Battery Trail Making Test; ROCF = Rey–Osterrieth Complex Figure Test; 5DT = Five Digit Test; TAVEC = Test de.

#### **4. Discussion**

This study explored the cognitive domains of attention, memory, and information processing speed in FM patients using a neuropsychological test battery that comprehensively assesses selective, sustained, and divided attention, visuospatial and verbal memory, and cognitive processing speed. In addition, we explored the influence of BMI and clinical variables such as pain, anxiety, depression, fatigue, insomnia, and medication use on the cognitive performance of these patients.

Compared to healthy participants, FM patients showed lower performance in the domains of selective and sustained attention, divided attention, processing speed, and visuospatial memory. These results support the notion of markedly impaired attention, visuospatial memory, and information processing speed in FM and are in accordance with previous studies [5,18,23,28,29,74,75]. However, in opposition to our preceding findings [58] no group differences were observed in verbal memory (as measured by the TAVEC). Although at first glance the lack of differences in verbal memory between FM and healthy participants may seem striking, the literature on this matter is in fact inconsistent. Indeed, and in accordance with the present findings, Castel et al. [30,76] did not find differences in verbal memory (as measured by the TAVEC) between FM patients and controls. These discrepant results may be explained in part by differences in the dependent variables (i.e., TAVEC conditions) selected to index verbal memory performance. In the present study, we selected three measures of immediate free recall, as well as measures of short- and long-term recall, while in our previous study [58], two measures of immediate free recall, errors of omission, false-positive responses, and an index of discrimination were used. It is also important to mention that, in the present study, the effect of BMI was controlled for in the group comparisons, and that BMI significantly affected verbal memory performance (see below a further discussion of this issue). In conclusion, not all studies have demonstrated differences in verbal memory between FM and healthy participants (e.g., [27,30,32,76] for negative results). More research is needed to shed light on the verbal memory performance of FM patients.

Significant effects of BMI on selective and sustained attention, information processing speed, and verbal memory were also found in this study; higher BMI was associated with lower performance in these cognitive domains. By contrast, BMI did not significantly affect divided attention or visuospatial memory. Correlation and regression analysis confirmed that higher BMI was associated with lower performance in FM. Specifically, higher BMI predicted slower processing speed, less sustained and selective attention, and poorer verbal memory. However, BMI was not associated with variables indexing divided attention and visuospatial memory.

The findings regarding BMI are of special importance, as obesity and overweight are often seen in FM [55]. A higher BMI has been related to more severe FM and to the occurrence of musculoskeletal pain in the general population [55,77]. The complex relationships between obesity and pain may be mediated by mechanical overload and multiple proinflammatory and neurohormonal mechanisms [78]. In agreement with a recent review by D'Onghia et al. [55] revealing a high prevalence of obesity in European FM patients, the mean BMI in our FM sample was 28.29 kg/m<sup>2</sup> (class 1 obesity; [51]). Moreover, higher rates of pain complaints and chronic pain have been reported among individuals with obesity [79].

Obesity has been cited a risk factor for poor cognitive performance in the general population [80], especially in the domains of attention/vigilance, visual and verbal memory, information processing speed, and executive function [53,54,81–84]. Our results confirm the role of BMI in cognitive deficits in FM, including not only complex cognitive functions (i.e., executive function) as reported in a previous study (see Muñoz Ladrón de Guevara et al. [16]), but also more basic cognitive processes such as sustained and selective attention, verbal memory, and processing speed. The precise mechanisms linking cognitive performance and obesity have not yet been identified, although altered brain structure, blood–brain barrier and leptin regulation, poorer cerebrovascular function and blood flow

cerebral perfusion, arterial hypertension, oxidative stress, and inflammation have also been implicated [80,85–92].

Against this background, the mechanisms underlying the relationship between obesity and pain might explain the detrimental effect of BMI on cognitive performance in FM. Several pronociceptive and antinociceptive pathways have suggested to have an important role in the relation between obesity and pain sensitivity, particularly the presence of inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) [93]. Interestingly, Okifuji et al. [56] found that, in women with FM, CRP was positively associated with BMI. Additionally, higher CRP levels have been associated with poor memory, attention, and processing speed in clinical samples [94].

Similarly, elevated levels of leptin (a hormone synthesized in adipose tissue and produced in excess in obese subjects) have been associated with body pain in healthy postmenopausal women with a BMI > 25 kg/m2 and in FM patients whose average weight was 81.17 kg/m2 [95]. Peripheral leptin penetrates the cerebrospinal fluid and central nervous system and interacts with the hypothalamus and hippocampus [96,97], which are thought to be altered in FM [98,99]. The involvement of the hippocampus in memory processes is well known, and leptin has been implicated in memory impairment in obese populations [85]. From a behavioral perspective, physical inactivity and a sedentary lifestyle may be contributing factors. Physical inactivity is frequent in FM, which promotes obesity and impaired cognitive performance [100,101]. Increased physical activity, specifically an increase in aerobic capacity, is one of the most effective methods for treating FM [102]. Several studies have shown an association between aerobic exercise and improvements in attention, processing speed, executive function, and memory in the general population [103,104].

Regarding the effect of clinical factors on the cognitive performance of FM patients, our results showed a negative association between the different pain components (sensorial, affective, and miscellaneous) and visuospatial memory. Regression analysis confirmed the association for sensorial pain. These findings corroborate the well-known interfering effect of pain on cognitive function in FM [16,19,28,29,36,39,47].

Although our FM patients with and without a diagnosis of depression or anxiety did not differ in cognitive performance, the regression analysis showed that state anxiety was a positive predictor of some TAVEC verbal memory variables. This association of cognitive improvement with state anxiety is striking, as other studies either suggested a negative influence of anxiety on working memory, attention, and general cognitive function [42,43,105], or no effect of anxiety [16,19,28,29,39]. This result is difficult to explain, but it is possible that higher state anxiety promotes greater arousal, where increased activation can lead to improved performance [106,107]. Finally, our non-significant results for fatigue, insomnia, and medication use (for all four types of drugs) are in line with previous studies suggesting a minor role of these factors in the cognitive impairment seen in FM patients [40,47,108].

A limitation of the present study was the relatively small size of the patient sample, as well as the smaller number of participants in the healthy group relative to the FM patient group. This might have limited the statistical power of the group comparisons. Nevertheless, our sample size was comparable to or larger than those in most other studies in this field [25–27,40,108]. Additionally, another limitation of this study pertains to the lack of information about the possible influence of medication on the assessed variables; this could have been explored by comparing patients grouped according to the use of particular medications or combinations thereof. The sample size was insufficient to form such patient subgroups, although previous studies did not suggest substantial effects of medication on cognitive performance in FM [40]. Nonetheless, it is important to highlight that previous literature has reported some side effects on cognition and weight associated to the medication use. For instance, an increase of greater cognitive deterioration [109] and significant weight gain [110,111] have been associated to anticonvulsants use in adults. Furthermore, factors such as fatigue, mental effort, and distraction during performance of the tests were not controlled for, similar to most other studies. These factors can impact

the cognitive performance of FM patients [23,112]. Likewise, given the inverse association revealed in this study between the experience of clinical pain and cognitive performance in FM, and the lack of research evaluating differences between FM severity subgroups on these factors, it should be considered as a future line of research. Finally, although the relevance of BMI to the cognitive performance of our FM patients is clear, possible mediating mechanisms, such as physical exercise and general level of fitness, were not measured and should be considered in future research.

## **5. Conclusions**

In conclusion, our findings confirm the presence of deficits in cognitive basic processes, such as selective, sustained, and divided attention; visuospatial memory; and information processing speed (but not verbal memory), in FM patients. Moreover, BMI negatively affected the cognitive performance of our patients. In light of the high prevalence of overweight and obesity in FM [55], our findings suggest the need for interventions to reduce the body weight of these patients. In particular, tailored physical exercise is strongly recommended for FM. Interventions improving physical capacity, disability, and fatigue could increase cognitive performance directly, as well as indirectly via the associated reduction in body weight. Finally, given the empirical support for the presence of cognitive deficits in FM, neuropsychological rehabilitation programs for these patients are recommended.

**Author Contributions:** Conceptualization, G.A.R.d.P., M.J.F.S. and C.I.M.; methodology, G.A.R.d.P., C.M.L.d.G., M.J.F.S. and C.I.M.; validation, G.A.R.d.P., C.M.L.d.G., M.J.F.S. and C.I.M.; formal analysis, G.A.R.d.P., C.M.L.d.G. and C.I.M.; investigation, G.A.R.d.P., C.M.L.d.G. and C.I.M.; resources, G.A.R.d.P.; data curation, C.M.L.d.G. and M.J.F.S.; writing—original draft preparation, C.M.L.d.G.; writing—review and editing, G.A.R.d.P. and C.I.M.; visualization, G.A.R.d.P., C.M.L.d.G., M.J.F.S. and C.I.M.; supervision, G.A.R.d.P. and C.I.M.A; project administration, G.A.R.d.P.; funding acquisition, G.A.R.d.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported by a grant from the Spanish Ministry of Science and Innovation co-financed by FEDER funds (RTI2018-095830-B-I00/ AEI/10.13039/501100011033).

**Institutional Review Board Statement:** All subjects gave their informed consent for inclusion before they participated in the study. They were free to leave the experiment at any time. The study was conducted in accordance with the Declaration of Helsinki and in accordance with the recommendations of national and international ethics guidelines, Psychologist Code of Ethics, American Psychological Association, Code of Good Research Practices of author´s institution and the Spanish Law 5/2018 of 5 December and was approved by the Ethics Committee of University of Jaén. The study did not involve any invasive procedure, and it did not carry any risk to the participants' mental or physical health, thus not requiring ethics approval according to the Spanish law BOE 14/2007.

**Informed Consent Statement:** All the data have been collected from adults who have voluntarily participated in the research and have given informed consent as subjects for this study.

**Data Availability Statement:** The authors claim that this manuscript describes an original research work which has not been preregistered. The data presented in this study are available on request from authors. The data are not publicly available due to compliance with privacy laws.

**Conflicts of Interest:** The authors declare no conflict of interest.
