A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review

Background Functional cognitive disorder (FCD) describes cognitive dysfunction in the absence of an organic cause. It is increasingly prevalent in healthcare settings yet its key neuropsychological features have not been reported in large patient cohorts. We hypothesised that cognitive profiles in fibromyalgia (FM), chronic fatigue syndrome (CFS) and functional neurological disorders (FNDs) would provide a template for characterising FCD. Methods We conducted a systematic review of studies with cognition-related outcomes in FM, CFS and FND. Results We selected 52 studies on FM, 95 on CFS and 39 on FND. We found a general discordance between high rates of subjective cognitive symptoms, including forgetfulness, distractibility and word-finding difficulties, and inconsistent objective neuropsychological deficits. Objective deficits were reported, including poor selective and divided attention, slow information processing and vulnerability to distraction. In some studies, cognitive performance was inversely correlated with pain, exertion and fatigue. Performance validity testing demonstrated poor effort in only a minority of subjects, and patients with CFS showed a heightened perception of effort. Discussion The cognitive profiles of FM, CFS and non-cognitive FND are similar to the proposed features of FCD, suggesting common mechanistic underpinnings. Similar findings have been reported in patients with mild traumatic brain injury and whiplash. We hypothesise that pain, fatigue and excessive interoceptive monitoring produce a decrease in externally directed attention. This increases susceptibility to distraction and slows information processing, interfering with cognitive function, in particular multitasking. Routine cognitive processes are experienced as unduly effortful. This may reflect a switch from an automatic to a less efficient controlled or explicit cognitive mode, a mechanism that has also been proposed for impaired motor control in FND. These experiences might then be overinterpreted due to memory perfectionism and heightened self-monitoring of cognitive performance.

To assess the impact of FM in patient´s lives (focus groups) The focus groups conducted with fibromyalgia patients identified symptom domains that had the greatest impact on their quality of life including pain, sleep disturbance, fatigue depression, anxiety, and cognitive impairment. Participants reported that FM affected their cognition, particularly memory and thought processes. Difficilties included not being able to operate at the same levels of mental acuity than they had prior to onset, forgeting important tasks, inability to focus and express themselves clearly, feeling more disorganized, difficulty with planning, inability to respond quickly to a question or when asked to perform a task and driving difficulties. Participants found it difficult to become motivated to begin tasks because the constant presence of pain disrupted patients' concentration and depleted them of energy. Of these patients, 21% failed a stand-alone SVT, whereas an additional 15% failed both a standalone and embedded SVT. Individuals who failed both stand-alone and embedded cognitive SVTs had higher scores on a number of MCMI-III personality subscales and had elevated scores on MCMI-III modifying indices compared to individuals who passed cognitive SVTs. Moreover, SVT performance was significantly correlated with multiple MCMI-III scores, including modifying indices, as well as the somatoform, depression, and anxiety subscales. In sum, cognitive and psychological symptom validity scores were significantly related Patients with FM displayed spatial memory impairments as evidenced by significantly more errors in performing both the Bpxes Rooms and the virtual Morris Water Maze. The fact that there was no difference between the groups in navigating to a visible platform suggests that these spatial memory deficits are not due to differences in understanding the tasks, motivational factors, using the joystick or computer programs. These spatial memory deficits corroborate some of the studies indicating hippocampal or temporal lobe abnormalities in people with FM. In contrast, there were no significant differences between the groups in the neuropsychological tests.

Cherry 2011
Physical Better physical performance was significantly associated with better cognitive performance for the TMT-A (complex attention, executive function) and the composite cognitive score, which included all 3 measures of cognitive function (TMT-A, TMT-B, and DSST) after controlling for age and symptom burden, but only when objective physical performance measures were used to assess physical function.
performance measures were a better predictor of these cognitive domains than perceived or self-reported physical function.

Cherry 2012
Positive Women with FM had a higher present-self / idealself discrepancy (lower correlation is associated with a lower self esteem) and a lower perceived adequacy of others (A negative correlation may indicate that the subject is dissatisfied with the people that surround her, and a high positive correlation might suggest a positive (or even an idealized, if extreme) image of others) and it was more likely to find implicative dilemmas among them compared to controls (implicative dilemmas represent a cognitive structure in which the symptom, represented by the nondesirable pole of one construct, is associated with positive characteristics of the self-identity system in which change is not desire). These dilemmas are a type of cognitive conflict in which the symptom is construed as "enmeshed" with positive characteristics of the self. An improvement in these patients' physical health status could be construed by a substantial proportion of women with fibromyalgia as an undesirable change in their current morally appropriate self-image. Similarly, they would tend to view people in their lives who do not have pain as being selfish or with any other undesired moral trait. Thus, not having pain involves, in their system of meanings, becoming another type of person characterized by undesirable moral attributes. Conversely, those who suffer from pain are viewed as good people (e.g., altruistic, responsible, or hardworking.

Coppieters 2015
Cognitive Performance of standardized everyday attentional tasks was impaired in the FMS group compared to controls. Working memory was also found to be impaired in this group. Stimulus interference was found to be significantly worse in the FMS group as the demands of the tasks increased. These effects were found to exist independent of the measures of mood and sleep disruption. However, when pain levels were accounted for statistically, no differences existed between groups on cognitive measures. These findings point to disrupted working memory as a specific mechanism that is disrupted in this population. The results of this study suggest that pain in FMS may play an important role in cognitive disruption.

Duschek 2013
Implicit memory function in fibromyalgia syndrome FM (18) HC (25) Word-steam task C To assess implicit memory in FMD patients with a word-stem completion task (WST) paradigm.

Word-stem completion
As a main result, the study revealed markedly lower performance on a word-stem completion task for patients with fibromyalgia than for healthy individuals. This suggests impaired implicit memory function in terms of reduced influence of unconscious priming on the patients' behavior. In other words, the lower performance cannot be ascribed to incomplete effort that has been suspected to produce invalid results in cognitive testing with FMS patients. Instead, the functional aberrances may relate to the patients' primary pain complaints, presumably constituting an effect of inference between central nervous nociceptive activity and cognitive processing

MMSE
The hippocampus was dysfunctional in patients with FM, as shown by lower NAA levels compared to controls, representing neuronal or axonal metabolic dysfunction. As the hippocampus plays crucial roles in maintenance of cognitive functions, sleep regulation, and pain perception, we suggest that metabolic dysfunction of hippocampus may be implicated in the appearance of these symptoms associated with this puzzling syndrom. In our study all patients showed variable degrees of cognitive impairment. Subjective cognitive impairment is a common complaint among patients with FM, the so-called "fibro fog". It was

Spectroscop y
found that patients perform more poorly on tests of immediate and delayed recall, and their ratings of both their memory abilities and sleep quality were lower than those of controls.
Fayed 2012 Brain dysfunction in fibromyalgia and somatizatio n disorder using proton magnetic resonance spectroscop y: a controlled study FM (10) STD (10); agematched healthy control subjects (10) U To evaluate the brain metabolite patterns in patients with fibromyalgia (FM) and somatization disorder (STD) through spectroscopy techniques and correlate these patterns with psychological variables.

MMSE
The results from this study demonstrate a significant increase in the levels of Glx, a combined measure of glutamate (Glu) and glutamine (Gln), within the PCC in FM and, to a lesser extent in Somatization disorder, as compared with controls. This factor also correlates with the PCS and the MMSE, suggesting that elevated levels of Glx in the posterior cingulate are associated with increased pain catastrophizing and cognitive impairment. *** The MMSE scores suggested symptoms of cognitive dysfunction in FM and STD, but at levels less severe than those found in patients with dementia.
The groups showed no differences in RTs and/or accuracy in executive functioning assessment. The authors commented that this was not surprising, given that a simple Go/No-Go paradigm was used, and deficits in performance in individuals with FM are typically only seen on very demanding tasks. fMRI analyses, on the other hand, revealed significant differences between the FM and HC groups with a hypo-activation in FM in the premotor cortex, SMA, MCC, putamen, and, after controlling for anxiety, in the right IC. Hyperactivation was seen in the right inferior temporal gurys/fusiform gyrus. The cognitive costs of distraction appear to be considerable and may be a defining feature of memory vulnerability in patients with fibromyalgia. It was a key parameter along which patients with FM differ. With no distraction on the ACT, immediate memory was largely intact. They fully remembered a small file of information. However, following a distraction of 9 seconds, the loss of information was disproportionately large. This distraction erased almost 58% of the same information, suggesting that even limited distraction harms recall of new information. Indeed, people with FM lost simple information at a rate that was 44% greater than an age matched group presenting with memory problems and almost 3 times greater than the normative sample *** Some insight into why FM patients largely perform psychometrically normally on routine tests of memory, yet are troubled by memory gaps for everyday events, may be gained by highlighting skills that are assessed by memory measures in routine use. Most measures encode information into storage in highly structured, distraction-free situations. These conditions are not representative of difficulties encountered in real life, which is full of stimulus competition that actively interrupts the encoding of new information before it can be rehearsed and stored. In study one, it was found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, the authors found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, there was normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients. Patients with FM, on the other hand, had defi cits in the tests assessing operational memory (LM-I, VFT-SeAn, SIM, and DB), as well as perseverance errors in 5PT, which also refer to executive function disorders. Low educational level and advanced age were associated with various degrees of impairment in the different cognitive functions in the three pathological groups. FM and SLE groups showed significantly higher means of the neuropsychiatric symptoms of anxiety, irritability and hallucinations than the RA group in the neuropsychiatric inventory.

Mercado 2013
Brain correlates of cognitive inhibition in fibromyalgia : Emotional intrusion of symptomrelated words FM (25) HC (25) C To characterize cognitive inhibition mechanisms, as part of the attentional control functions, in patients with fibromyalgia.
Emotional Stroop task Symptom-related words elicited greater frontal P450 amplitudes and enhanced activation within right inferior frontal gyrus as compared to the rest of stimuli. This effect was only true for the fibromyalgia group. Behavioral contrasts, however, did not produce significant differences. Scalp and source estimation findings suggest the presence of a specific difficulty in cognitive inhibition in fibromyalgia patients (under conditions intimately linked with the core concerns of their disease). Data point to the involvement of right inferior frontal cortices in this inefficient mechanism, which might cause an enhanced and dysfunctional effort of processing to achieve only a comparable performance to healthy people. Implications of these results are discussed. ANT-I (alertness, orienting and executive control functions of attention)

Miro 2011
Results showed that FM patients have impaired executive control (greater interference), reduced vigilance (slower overall reaction time) and greater alertness (higher reduction in errors after a warning cue). With regards to the other attentional networks, no effect was observed in orienting.

Miro 2015
Men Significant group differences were found for Stroop Color-Word Test (SCWT) and Multi-Source Interference Test (MSIT) performance in both the neutral (N) and interference (I) conditions with slower reaction times in patients versus controls. However, no significant group differences were found for the difference (I-N) or proportion (I/N) scores, or on the number of errors made. Experimental pressure pain thresholds correlated significantly to several indices of cognition. Psychosocial variables were not related to cognitive test performance. Fibromyalgia patients performed worse on both cognitive inhibition test but to a similar extent for the neutral condition and the interference condition, indicating that there is no specific problem in cognitive inhibition. Evidence of decreased mental processing and/or psychomotor speed was found in patients with fibromyalgia.

Verdejo-Garcia 2009
Executive function and decisionmaking in women with fibromyalgia women FM (36) healthy women (36)matched in age education and socioeconomic status C The aim was to examine possible impairment of executive function and decision making in FM.
Performance of in F and HC were compared for two measures of executive functioning: the Wisconsin Card Sorting Test (WCST), which assesses cognitive flexibility skills, and the Iowa Gambling Tasks (IGT; original and variant versions), which assess emotion-based decision-making. They also examinated the relationship between executive function performance and pain experience, and between executive function and personality traits of noveltyseeking, harm avoidance, reward dependence, and persistence (measured by the Temperament and Character Inventory-Revised).
Results showed that on the WCST, FM women showed poorer performance than healthy comparison women on the number of categories and non-perseverative errors, but not on perseverative errors. FM patients also showed altered learning curve in the original IGT (where reward is immediate and punishment is delayed), suggesting compromised emotion-based decision-making; but not in the variant IGT (where punishment is immediate but reward is delayed), suggesting hypersensitivity to reward. Personality variables were very mildly associated with cognitive performance in FM women.