Central sensitivity syndromes are characterized by distressing symptoms, such as pain and fatigue, in the absence of clinically obvious pathology. The scientific underpinnings of these disorders are not currently known. Modern neuroimaging techniques promise new insights into mechanisms mediating these postulated syndromes. We review the results of neuroimaging applied to five central sensitivity syndromes: fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, temporomandibular joint disorder, and vulvodynia syndrome. Neuroimaging studies of basal metabolism, anatomic constitution, molecular constituents, evoked neural activity, and treatment effect are compared across all of these syndromes. Evoked sensory paradigms reveal sensory augmentation to both painful and non-painful stimulation. This is a transformative observation for these syndromes, which were historically considered to be completely of hysterical or feigned in origin. However, whether sensory augmentation represents the cause of these syndromes, a predisposing factor, an endophenotype, or an epiphenomenon cannot be discerned from the current literature. Further, the result from cross-sectional neuroimaging studies of basal activity, anatomy, and molecular constituency are extremely heterogeneous within and between the syndromes. A defining neuroimaging “signature” cannot be discerned for any of the particular syndromes or for an over-arching central sensitization mechanism common to all of the syndromes. Several issues confound initial attempts to meaningfully measure treatment effects in these syndromes. At this time, the existence of “central sensitivity syndromes” is based more soundly on clinical and epidemiological evidence. A coherent picture of a “central sensitization” mechanism that bridges across all of these syndromes does not emerge from the existing scientific evidence.

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n ϭ 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n ϭ 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient.

Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum, but has varied co-morbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that life-style choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by non-pharmacological interventions.

The subjective experience of cognitive dysfunction (“fibrofog”) is common in fibromyalgia. This study investigated the relation between subjective appraisal of cognitive function, objective cognitive task performance, and brain activity during a cognitive task using functional magnetic resonance imaging (fMRI). Sixteen fibromyalgia patients and 13 healthy pain-free controls completed a battery of questionnaires, including the Multiple Ability Self-Report Questionnaire (MASQ), a measure of self-perceived cognitive difficulties. Participants were evaluated for working memory performance using a modified N-back working memory task while undergoing Blood Oxygen Level Dependent (BOLD) fMRI measurements. Fibromyalgia patients and controls did not differ in working memory performance. Subjective appraisal of cognitive function was associated with better performance (accuracy) on the working memory task in healthy controls but not in fibromyalgia patients. In fibromyalgia patients, increased perceived cognitive difficulty was positively correlated with the severity of their symptoms. BOLD response during the working memory task did not differ between the groups. BOLD response correlated with task accuracy in control subjects but not in fibromyalgia patients. Increased subjective cognitive impairment correlated with decreased BOLD response in both groups but in different anatomic regions. In conclusion, “fibrofog” appears to be better characterized by subjective rather than objective impairment. Neurologic correlates of this subjective experience of impairment might be separate from those involved in the performance of cognitive tasks.