Review of Cognitive Dysfunction in Fibromyalgia: A Convergence on Working Memory and Attentional Control Impairments

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Neuroimaging research has begun to implicate alterations of brain reward systems in chronic pain. Previously, using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in fibromyalgia. In the present study, we aimed to test the replicability of these altered neural responses to reward in a separate fibromyalgia cohort. In addition, the present study was conducted at a distinct U.S. location but involved a similar study design. For the present study, 20 patients with fibromyalgia and 20 healthy controls participated in MID task fMRI scan procedures and completed clinical/psychological questionnaires. fMRI analyses comparing patient and control groups revealed a consistent trend of main results which were largely similar to the prior reported results. Specifically, in the replication fibromyalgia cohort, medial prefrontal cortex (MPFC) response was reduced during gain anticipation and was increased during no-loss (non-punishment) outcome compared to controls. Also consistent with previous findings, the nucleus accumbens response to gain anticipation did not differ in patients vs. controls. Further, results from similarly-designed behavioral, correlational, and exploratory analyses were complementary to previous findings. Finally, a novel network-based functional connectivity analysis of the MID task fMRI data across patients vs. controls implied enhanced connectivity within the default mode network in participants with fibromyalgia. Together, based on replicating prior univariate results and new network-based functional connectivity analyses of MID task fMRI data, we provide further evidence of altered brain reward responses, particularly in the MPFC response to reward outcomes, in patients with fibromyalgia.

The bidirectional relationship between pain and working memory (WM) deficits is well-documented but poorly understood. Pain catastrophizing—exaggerated, negative cognitive and emotional responses toward pain—may contribute to WM deficits by occupying finite, shared cognitive resources. The present study assessed the role of pain catastrophizing as both a state-level process and trait-level disposition in the link between acute pain and WM. Healthy, young adults were randomized to an experimentally-induced ischemic pain or control task, during which they completed verbal and non-verbal WM tests. Participants also completed measures of state- and trait-level pain catastrophizing. Simple mediation analyses indicated that participants in the pain group (vs. control) engaged in more state-level catastrophizing about pain, which led to worse verbal and non-verbal WM. Moderated mediation analyses indicated that the indirect (mediation) effect of state-level pain catastrophizing was moderated by trait-level pain catastrophizing for both verbal and non-verbal WM. Participants in the pain group who reported a greater trait-level tendency to catastrophize about pain experienced greater state-level catastrophizing about pain during the ischemic task, which led to worse verbal and non-verbal WM performance. These results provide evidence for pain catastrophizing as an important mechanism and moderating factor of WM deficits in acute pain. Future research should replicate these results in chronic pain samples, investigate other potential mechanisms (e.g., sleep disturbances), and determine if interventions that target pain catastrophizing directly can ameliorate cognitive deficits in people with pain.

This article presents a laboratory study examining the relationships among pain, pain catastrophizing, and working memory in healthy participants. The results shed new light on these relationships and raise the possibility that interventions that reduce catastrophizing may lead to improved cognitive function among people with pain.

Mirogabalin is a novel potent and selective ligand for the α₂δ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain accompanied by symptoms like fatigue, insomnia, depression, anxiety and cognitive impairments. In addition to central nervous pain sensitization, emotional dysregulation may be involved in FMS pathogenesis. This study investigated central nervous correlates of affective and attentional processing in FMS using an implicit task.

Event-related potentials (ERPs) of the EEG were recorded in 25 FMS patients and 37 healthy controls while they had to name the frame color of pictures displaying emotional expressions (angry, painful, happy, neutral). The actual picture had to be ingored. Symptoms of pain, depression and anxiety were also assessed.

Patients exhibited smaller P2 and late positive potential (LPP) amplitudes, and a greater N250 amplitude, than controls. The N250 amplitude varied according to the emotional expressions displayed in patients, but not in controls. No group differences arose for the P1 or N170 amplitudes. Patients had longer reaction times and made more errors on the task; task performance was more closely related to pain severity than to other symptoms.

The reduced P2 and LPP amplitudes indicate deficient short-term mobilization of attentional resources and sustained attention in FMS; the greater N250 amplitude may reflect greater engagement in the decoding of complex facial features, which is necessary to compensate for attentional impairments. Affective modulation of the N250 suggests that the neural mechanisms underlying complex visual processes are particularly susceptible to emotional influences in FMS. The behavioral data confirm attentional deficits in the disorder and implicate clinical pain therein.

The relationship between pain and cognition has primarily been investigated in patients with chronic pain and healthy participants undergoing experimental pain. Recently, there has been interest in understanding the disruptive effects of non-experimental pain in otherwise healthy individuals. Recent studies suggest that healthy individuals reporting pain also demonstrate decrements in working memory (WM) performance, however factors contributing to this relationship remain poorly understood. The present study examined the association between pain and WM in a large community-based sample of healthy individuals and investigated whether self-reported affective distress and medial frontal cortex activity might help to explain this relationship. To address these research questions, a large publicly available dataset from the Human Connectome Project (N = 416) was sourced and structural equation modeling was utilized to examine relationships between pain intensity experienced over the past 7 days, self-reported affective distress, performance on a WM (n-back) task, and task-related activation in the medial frontal cortex. Examining participants who reported non-zero pain intensity in the past 7 days (n = 228), we found a direct negative association between pain intensity and performance on the WM n-back task, consistent with prior findings. Self-reported affective distress was not associated with WM performance. Additionally, pain intensity was indirectly associated with WM performance via WM task-related activity in the ventromedial prefrontal cortex (vmPFC). Our findings suggest that pain experienced in everyday life by otherwise healthy individuals may directly impact WM performance. Furthermore, WM task-related increases in vmPFC activity may be a factor contributing to this relationship.