Diana Kadetoff

Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients with fibromyalgeia

Summary Treatment with Cognitive Behavioral Therapy leads to clinical improvements in fibromyalgia patients, paired with increased activity and connectivity in the brain’s pain modulatory regions. ABSTRACT Interventions based on Cognitive Behavioral Therapy (CBT) are widely used to treat chronic pain, but the brain mechanisms responsible for these treatment effects are poorly understood. The aim of this study was to validate the relevance of the cortical control theory in response to an exposure‐based form of CBT, Acceptance and Commitment Therapy, in patients with chronic pain. Forty‐three female patients diagnosed with fibromyalgia syndrome were enrolled in a randomized, 12‐week, waiting‐list controlled clinical trial (CBT n = 25; controls n = 18). CBT was administered in groups of six patients during 12 weekly sessions. Functional magnetic resonance imaging (fMRI) during pressure‐evoked pain was assessed before and after treatment or the 12‐week period. Self‐report questionnaires of depression and anxiety were administered pre‐ and posttreatment as well as 3 months following end of treatment. Patients treated with CBT reported larger improvement of fibromyalgia on the Patient Global Impression of Change measure, and improved depression and anxiety symptoms, compared to the waiting‐list controls. However, there were no effects on clinical pain or pain sensitivity measures. An analysis of fMRI scans revealed that CBT led to increased activations in the ventrolateral prefrontal/lateral orbitofrontal cortex; regions associated with executive cognitive control. We suggest that CBT changes the brain’s processing of pain through an altered cerebral loop between pain signals, emotions, and cognitions; leading to increased access to executive regions for reappraisal of pain. Our data thereby support our hypothesis about the activation of a cortical control mechanism in response to CBT treatment in chronic pain.

Acceptance and commitment therapy for fibromyalgia: A randomized controlled trial

Fibromyalgia (FM) is characterized by widespread pain and co‐morbid symptoms such as fatigue and depression. For FM, medical treatments alone appear insufficient. Recent meta‐analyses point to the utility of cognitive behaviour therapy (CBT), but effects are moderate. Within the continuous development of CBT, the empirical support for acceptance and commitment therapy (ACT) has increased rapidly. ACT focuses on improving functioning by increasing the patients ability to act in accordance with personal values also in the presence of pain and distress (i.e., psychological flexibility). However, no study has yet explored the utility of ACT in FM.

The effects of static muscular contraction on blood pressure, heart rate, pain ratings and pressure pain thresholds in healthy individuals and patients with fibromyalgia

Aberrations of cardiovascular regulation and dysfunction of endogenous pain modulation have been reported in fibromyalgia (FM) patients. This study aimed at investigating the interactions between cardiovascular regulation and pain perception during static muscle contractions. Seventeen FM patients and 17 healthy controls performed a standardised static contraction (m. quadriceps femoris dx) until exhaustion. Blood pressure (BP), heart rate (HR), ratings of exertion/fatigue and pain intensity as well as pressure pain thresholds (PPTs) (at m. quadriceps dx and m. deltoideus dx) were assessed before, during and 15 min following contraction. Systolic and diastolic BP increased during contraction (p < 0.001) and decreased following contraction (p < 0.001) in both groups alike. A significant increase in HR was seen during contraction in FM patients (p < 0.001), but not in healthy controls (difference between groups p < 0.02). The rated exertion/fatigue and pain intensity increased more during contraction and remained elevated longer following contraction in the patient group. PPTs were lower in patients compared to controls at both sites at all times (p < 0.001). No group differences in PPT changes over time were found. In conclusion, no indication of an attenuated cardiovascular response to exercise was found in our FM patients. The more pronounced HR increase in patients during contraction was most likely due to deconditioning. No exercise related change in PPTs was seen in either group, most likely due to insufficient exercise intensity, but the contraction induced pain was more pronounced in the FM patients.

Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels

Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. To our knowledge, this is the first study assessing intrathecal concentrations of pro-inflammatory substances in fibromyalgia. We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms.

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain--interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis.

The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).

EVIDENCE OF REDUCED SYMPATHO-ADRENAL AND HYPOTHALAMIC- PITUITARY ACTIVITY DURING STATIC MUSCULAR WORK IN PATIENTS WITH FIBROMYALGIA

OBJECTIVE To assess activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis during static exercise in patients with fibromyalgia. PATIENTS AND METHODS Sixteen patients with fibromyalgia and 16 healthy controls performed a static knee extension until exhaustion. Plasma catecholamines, adrenocorticotropic hormone and cortisol, as well as blood pressure and heart rate, were assessed before, during and following contraction. Plasma C reactive protein was analysed at baseline. RESULTS Blood pressure and heart rate increased during contraction (p < 0.001) and decreased following contraction (p < 0.001) in both groups alike. Compared with baseline, plasma catecholamines increased during contraction in both groups (p < 0.001), but patients with fibromyalgia had lower levels of plasma adrenaline (p < 0.04) and noradrenaline (p < 0.08) at all times. Adrenocorticotropic hormone increased at exhaustion in controls (p < 0.001), but not in patients with fibromyalgia, who also had lower adrenocorticotropic hormone at exhaustion (p < 0.02) compared with controls. There were no group differences, or changes over time in plasma cortisol. High sensitivity C reactive protein was higher in patients with fibromyalgia compared with controls (p < 0.02). CONCLUSION Patients with fibromyalgia exhibited a hypoactive sympatho-adrenal system as well as a hypo-reactive hypothalamic-pituitary axis during static exercise.

A proposed mechanism for autonomic dysfunction in rheumatoid arthritis – reduced vagal activity related to high intrathecal IL-1β levels

Objective Rheumatoid arthritis (RA) is known to be associated with autonomic dysfunction, with a decreased vagus tone. However, the mechanisms have not been completely elucidated. Nervus vagus function is regulated by action of muscarinic receptors in the CNS (Pavlov, PNAS, 2006), and earlier investigations have shown that the pro-inflammatory cytokine interleukin (IL)-1beta may cause dysfunction in cholinergic neurotransmission (Schliebs, Brain Res 2006). Here the authors investigated autonomic activity in RA and controls in relation to serum and cerebrospinal fluid (CSF, only RA) levels of IL-1β and IL-6. Methods Fourteen female patients with RA and 15 female age matched healthy controls (HC) were enrolled in this study. Median DAS28 score for RA patients was 3.6 (range 1.5 to 6.6). No patient/control had any neurological or heart disorder. Heart rate variability (HRV) was measured with Holter ECG over 24 h using spectral analysis of Low frequency (LF) power (0.04 to 0.15 Hz), High frequency power (HF) (0.15 to 0.40 Hz) and the ratio of LF and HF (LF/HF). The measures were calculated from an entire 24 h ambulatory ECG recording. Lumbar puncture was performed in RA patients only and CSF was analysed with high sensitivity ELISA for IL-1β and IL-6. Serum samples were analysed with ELISA for IL-1β and IL-6. Results There were significant differences between RA and HC in heart rate (74±6 vs 66±5 bpm; p<0.001), LF (522±213 ms2 vs 885±523 ms2; p<0.02), HF (252±280 ms2 vs 560±657 ms2; p<0.005) and a tendency of difference in LF/HF (2.5±0.7 vs 1.9±1; ns). These data are consistent with reduced vagal function in RA patients. In RA, IL-1β levels in CSF were markedly higher than serum levels (8.35±12.59 vs 0.00±0.06 pg/ml; p<0.005) indicating intrathecal production. In contrast, CSF IL-6 levels were lower in CSF than serum (2.59±1.43 pg/ml vs 6.25±4.21 pg/ml, p=0.01). CSF IL-1β, but not IL-6, correlated positively with HRV, as measured with LF/HF (r=0.64; p<0.05). Serum IL-1β was not correlated to HRV, but serum IL-6 correlated inversely to LF both in RA (r=−0,55 p<0.05) and controls (r=-0.46; p<0.05).. Conclusions The decreased autonomic function in RA, reflected in low vagus activity and thereby reduced control of systemic inflammation, may further impair the disease. Our data indicate that intrathecal IL-1beta and possibly also other inflammatory mechanisms in the CNS may have importance for the reduced vagal function of RA. These mechanisms may constitute future targets for improvement of cholinergic immune-suppression of the disease.

507 CNS INFLAMMATION IN FIBROMYALGIA — CEREBROSPINAL PRODUCTION OF TNF‐ALPHA IS RELATED TO FATIGUE AND IL‐8 TO FIBROMYALGIA IMPACT

active MTrPs were found in healthy controls. The local and referred pain pattern induced from active MTrPs bilaterally in the trapezius muscle were similar to the ongoing pain pattern in the neck and shoulder region in patients with FMS. Conclusion: Active MTrPs bilaterally in the upper trapezius muscle contributes to the neck and shoulder pain pattern in FMS. Active MTrPs constitute one of the peripheral sources of pain in FMS. The study was supported by The American Fibromyalgia Syndrome Association, Inc.

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (ps ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (ps < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.