Fibromyalgia (FM) is a chronic, common pain disorder characterized by hyperalgesia. A key mechanism by which cognitive-behavioral therapy (CBT) fosters improvement in pain outcomes is via reductions ...in hyperalgesia and pain-related catastrophizing, a dysfunctional set of cognitive-emotional processes. However, the neural underpinnings of these CBT effects are unclear. Our aim was to assess CBT's effects on the brain circuitry underlying hyperalgesia in FM patients, and to explore the role of treatment-associated reduction in catastrophizing as a contributor to normalization of pain-relevant brain circuitry and clinical improvement.
In total, 16 high-catastrophizing FM patients were enrolled in the study and randomized to 4 weeks of individual treatment with either CBT or a Fibromyalgia Education (control) condition. Resting state functional magnetic resonance imaging scans evaluated functional connectivity between key pain-processing brain regions at baseline and posttreatment. Clinical outcomes were assessed at baseline, posttreatment, and 6-month follow-up.
Catastrophizing correlated with increased resting state functional connectivity between S1 and anterior insula. The CBT group showed larger reductions (compared with the education group) in catastrophizing at posttreatment (P<0.05), and CBT produced significant reductions in both pain and catastrophizing at the 6-month follow-up (P<0.05). Patients in the CBT group also showed reduced resting state connectivity between S1 and anterior/medial insula at posttreatment; these reductions in resting state connectivity were associated with concurrent treatment-related reductions in catastrophizing.
The results add to the growing support for the clinically important associations between S1-insula connectivity, clinical pain, and catastrophizing, and suggest that CBT may, in part via reductions in catastrophizing, help to normalize pain-related brain responses in FM.
Objective
While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain‐related brain activity often ...reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulation's painfulness. Therefore, this study was undertaken to test our hypothesis that FM patients would demonstrate elevated brain responses to both pain onset and offset—2 salient sensory events of opposing valences.
Methods
Thirty‐eight FM patients (mean ± SD age 46.1 ± 13.4 years; 33 women) and 15 healthy controls (mean ± SD age 45.5 ± 12.4; 10 women) received a moderately painful pressure stimulus to the leg during blood oxygen level–dependent (BOLD) functional magnetic resonance imaging. Stimulus onset and offset transients were analyzed using a general linear model as stick functions.
Results
During pain onset, higher BOLD signal response was observed in FM patients compared to healthy controls in dorsolateral and ventrolateral prefrontal cortices (DLPFC and VLPFC, respectively), orbitofrontal cortex (OFC), frontal pole, and precentral gyrus (PrCG). During pain offset, higher and more widespread BOLD signal response was demonstrated in FM patients compared to controls in frontal regions significantly hyperactivated in response to onset. In FM patients, some of these responses were positively correlated with pain unpleasantness ratings (VLPFC, onset; r = 0.35, P = 0.03), pain catastrophizing scores (DLPFC, offset; r = 0.33, P = 0.04), or negatively correlated with stimulus intensity (OFC, offset; r = −0.35, P = 0.03) (PrCG, offset; r = −0.39, P = 0.02).
Conclusion
Our results suggest that the increased sensitivity exhibited by FM patients in response to the onset and offset of painful stimuli may reflect a more generalized hypersensitivity to salient sensory events, and that brain hyperactivation may be a mechanism potentially involved in the generalized hypervigilance to salient stimuli in FM.
Objective
While patients with fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. This study was ...undertaken to investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain, such as anticipation of pain and anticipation of pain relief.
Methods
Thirty‐one FM patients and 14 controls underwent functional magnetic resonance imaging, while receiving cuff pressure pain stimuli on the leg calibrated to elicit a pain rating of ∼50 on a 100‐point scale. During the scan, subjects also received visual cues informing them of the impending onset of pain (pain anticipation) and the impending offset of pain (relief anticipation).
Results
Patients exhibited less robust activation during both anticipation of pain and anticipation of relief within regions of the brain commonly thought to be involved in sensory, affective, cognitive, and pain‐modulatory processes. In healthy controls, direct searches and region‐of‐interest analyses of the ventral tegmental area revealed a pattern of activity compatible with the encoding of punishment signals: activation during anticipation of pain and pain stimulation, but deactivation during anticipation of pain relief. In FM patients, however, activity in the ventral tegmental area during periods of pain and periods of anticipation (of both pain and relief) was dramatically reduced or abolished.
Conclusion
FM patients exhibit disrupted brain responses to reward/punishment. The ventral tegmental area is a source of reward‐linked dopaminergic/γ‐aminobutyric acid–releasing (GABAergic) neurotransmission in the brain, and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may be related to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.
Objective. Previous vagus nerve stimulation (VNS) studies have demonstrated antinociceptive effects, and recent noninvasive approaches, termed transcutaneous‐vagus nerve stimulation (t‐VNS), have ...utilized stimulation of the auricular branch of the vagus nerve in the ear. The dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration can optimize t‐VNS.
Design. Counterbalanced, crossover study.
Patients. Patients with chronic pelvic pain (CPP) due to endometriosis in a specialty pain clinic.
Interventions/Outcomes. We evaluated evoked pain analgesia for respiratory‐gated auricular vagal afferent nerve stimulation (RAVANS) compared with nonvagal auricular stimulation (NVAS). RAVANS and NVAS were evaluated in separate sessions spaced at least 1 week apart. Outcome measures included deep‐tissue pain intensity, temporal summation of pain, and anxiety ratings, which were assessed at baseline, during active stimulation, immediately following stimulation, and 15 minutes after stimulus cessation.
Results. RAVANS demonstrated a trend for reduced evoked pain intensity and temporal summation of mechanical pain, and significantly reduced anxiety in N = 15 CPP patients, compared with NVAS, with moderate to large effect sizes (η2 > 0.2).
Conclusion. Chronic pain disorders such as CPP are in great need of effective, nonpharmacological options for treatment. RAVANS produced promising antinociceptive effects for quantitative sensory testing (QST) outcomes reflective of the noted hyperalgesia and central sensitization in this patient population. Future studies should evaluate longer‐term application of RAVANS to examine its effects on both QST outcomes and clinical pain.
Objective
Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for ...evoked pain. While several studies have demonstrated altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system and its role in both somatic and nonsomatic FM symptoms. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity and to explore how sustained, evoked deep tissue pain modulates this connectivity.
Methods
We acquired functional magnetic resonance imaging and electrocardiography data on FM patients and healthy controls during rest (the rest phase) and during sustained mechanical pressure–induced pain over the lower leg (the pain phase). Functional connectivity associated with different S1 subregions was calculated, while S1leg connectivity (representation of the leg in the primary somatosensory cortex) was contrasted between the rest phase and the pain phase and was correlated with clinically relevant measures in FM.
Results
During the rest phase, FM patients showed decreased connectivity between multiple ipsilateral and cross‐hemispheric S1 subregions, which was correlated with clinical pain severity. Compared to the rest phase, the pain phase produced increased S1leg connectivity to the bilateral anterior insula in FM patients, but not in healthy controls. Moreover, in FM patients, sustained pain–altered S1leg connectivity to the anterior insula was correlated with clinical/behavioral pain measures and autonomic responses.
Conclusion
Our study demonstrates that both somatic and nonsomatic dysfunction in FM, including clinical pain, pain catastrophizing, autonomic dysfunction, and amplified temporal summation, are closely linked with the degree to which evoked deep tissue pain alters S1 connectivity to salience/affective pain‐processing regions. Additionally, diminished connectivity between S1 subregions during the rest phase in FM may result from ongoing widespread clinical pain.
Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain, hyperalgesia, and other disabling symptoms. Although the brain response to experimental pain in FM patients has been ...the object of intense investigation, the biological underpinnings of painful after-sensations (PAS), and their relation to negative affect have received little attention. In this cross-sectional cohort study, subjects with FM (n = 53) and healthy controls (n = 17) were assessed for PAS using exposure to a sustained, moderately painful cuff stimulus to the leg, individually calibrated to a target pain intensity of 40 of 100. Despite requiring lower cuff pressures to achieve the target pain level, FM patients reported more pronounced PAS 15 seconds after the end of cuff stimulation, which correlated positively with clinical pain scores. Functional magnetic resonance imaging revealed reduced deactivation of the medial temporal lobe (MTL; amygdala, hippocampus, parahippocampal gyrus) in FM patients, during pain stimulation, as well as in the ensuing poststimulation period, when PAS are experienced. Moreover, the functional magnetic resonance imaging signal measured during the poststimulation period in the MTL, as well as in the insular and anterior middle cingulate and medial prefrontal cortices, correlated with the severity of reported PAS by FM patients. These results suggest that the MTL plays a role in PAS in FM patients.
PAS are more common and severe in FM, and are associated with clinical pain and catastrophizing. PAS severity is also associated with less MTL deactivation, suggesting that the MTL, a core node of the default mode network, may be important in the prolongation of pain sensation in FM.
Scots pine (
Pinus sylvestris
L.) seeds have variable levels of primary dormancy which reflect within-species adaptation to local environments. The objective of this study was to use a thermal time ...approach to determine whether primary dormancy levels in seeds were correlated with mean ambient temperature during temperature-sensitive phases of the reproductive cycle. Seedlots were obtained from a single open-pollinated clonal seed orchard in five crop years and germinated over a wide temperature range (7–35 °C) to calculate base temperature for germination with and without pre-chills (4 and 8 weeks). Primary dormancy levels varied amongst seedlots collected in different crop years (CY). Unchilled seeds were the most dormant for CY2007 (T
b
= 10.9 °C) and least dormant for CY2012 (T
b
= 5.6 °C). Base temperatures for germination were correlated with mean ambient temperature during different phases of the reproductive cycle. There was a strong positive correlation between base temperature for germination of unchilled seeds and mean temperature during pollination and early pollen tube growth. This suggests that maternal environmental effects during this phase could potentially select for dormant or non-dormant seeds, which has implications for tree breeding and seedling production in forest nurseries.
Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of ...psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress.
This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain.
To examine the influence of anxiety and pain-related catastrophizing on the time course of acute interleukin-6 (IL-6) responses to standardized noxious stimulation among patients with chronic pain.
...Data were collected from 48 participants in the following demographically matched groups: patients with chronic pain (n=36) and healthy controls (n=12). Participants underwent a series of Quantitative Sensory Testing (QST) procedures assessing responses to mechanical and thermal stimuli during two separate visits, in a randomized order. One visit consisted of standard, moderately painful QST procedures, while the other visit involved nonpainful analogs to these testing procedures. Blood samples were taken at baseline, and then for up to 2 hours after QST in order to study the time course of IL-6 responses.
Results of multilevel analyses revealed that IL-6 responses increased across assessment time points in both visits (
<0.001). While patients with chronic pain and healthy controls did not differ in the magnitude of IL-6 responses, psychological factors influenced IL-6 trajectories only in the chronic pain group. Among patients, increases in catastrophizing over the course of the QST session were associated with elevated IL-6 responses only during the painful QST session (
<0.05). When controlling for anxiety, results indicated that the main multilevel model among patients remained significant (
<0.05).
Under specific conditions (eg, application of a painful stressor), catastrophizing may be associated with amplified proinflammatory responses in patients with persistent pain. These findings suggest that psychosocial interventions that reduce negative pain-related cognitions may benefit patients' inflammatory profiles.
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