Hanke Marcus

Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network

BackgroundThere is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus.ResultsFM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0–100 visual analogue scale (p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients.ConclusionPatients with FM displayed less connectivity within the brain’s pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation.

Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain

OBJECTIVE There is vast evidence to support the presence of brain aberrations in patients with fibromyalgia (FM), and it is possible that central plasticity is critical for the transition from acute to chronic pain. The aim of the present study was to investigate the relationship between brain structure and function in patients with FM. METHODS Functional connectivity of the brain during application of intermittent pressure-pain stimuli and measures of brain structure were compared between 26 patients with FM and 13 age- and sex-matched healthy controls. Magnetic resonance imaging (MRI) was performed to obtain high-resolution anatomic images and functional MRI scans of the brain, which were used for measurements of pain-evoked brain activity. RESULTS FM patients displayed a distinct overlap between decreased cortical thickness, decreased brain volumes, and decreased functional regional coherence in the rostral anterior cingulate cortex. The morphometric changes were more pronounced with longer exposure to FM pain. In addition, there was evidence of an association between structural and functional changes in the mesolimbic areas of the brain and the severity of comorbid depression symptoms in FM patients. CONCLUSION The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain. These data may lead to the identification of early structural and functional brain alterations in response to pain, which could be used to develop markers for predicting the development of FM and other pain disorders.

Anxiety and Depressive Symptoms in Fibromyalgia Are Related to Poor Perception of Health but Not to Pain Sensitivity or Cerebral Processing of Pain

OBJECTIVE Mood disturbance is common among patients with fibromyalgia (FM), but the influence of psychological symptoms on pain processing in this disorder is unknown. We undertook the present study to investigate the differential effect of depressive symptoms, anxiety, and catastrophizing on 1) pain symptoms and subjective ratings of general health status and 2) sensitivity to pain and cerebral processing of pressure pain. METHODS Eighty-three women (mean ± SD age 43.8 ± 8.1 years) who fulfilled the American College of Rheumatology 1990 criteria for the classification of FM participated in the study. Patients rated pain intensity (100-mm visual analog scale [VAS]), severity of FM (Fibromyalgia Impact Questionnaire), general health status (Short Form 36), depressive symptoms (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and catastrophizing (Coping Strategies Questionnaire). Experimental pain in the thumb was induced using a computer-controlled pressure stimulator. Event-related functional magnetic resonance imaging was performed during administration of painful stimuli representing 50 mm on a pain VAS, as well as nonpainful pressures. RESULTS A correlation analysis including all self-ratings showed that depressive symptoms, anxiety, and catastrophizing scores were correlated with one another (P < 0.001), but did not correlate with ratings of clinical pain or with sensitivity to pressure pain. However, the subjective rating of general health was correlated with depressive symptoms and anxiety (P < 0.001). Analyses of imaging results using self-rated psychological measures as covariates showed that brain activity during experimental pain was not modulated by depressive symptoms, anxiety, or catastrophizing. CONCLUSION Negative mood in FM patients can lead to a poor perception of ones physical health (and vice versa) but does not influence performance on assessments of clinical and experimental pain. Our data provide evidence that 2 partially segregated mechanisms are involved in the neural processing of experimental pain and negative affect.

The Impact of Trendelenburg Position and Positive End-Expiratory Pressure on the Internal Jugular Cross-Sectional Area

BACKGROUND: Increasing the cross-sectional area (CSA) of the right internal jugular vein facilitates cannulation and decreases complications. Maneuvers such as the Trendelenburg tilt position and ventilation with a positive end-expiratory pressure (PEEP) may increase the CSA of the right internal jugular vein. We determined the changes in the CSA in response to different maneuvers. METHODS: The CSA (cm2) of the right internal jugular vein was assessed in 50 anesthetized adult cardiothoracic surgery patients using 2-dimensional ultrasound. First, the CSA was measured in response to supine position with no PEEP (control condition, S0) and compared with 5 different randomly ordered maneuvers: (1) PEEP ventilation with 5 cm H2O (S5), (2) PEEP with 10 cm H2O (S10), (3) a 20° Trendelenburg tilt position with a PEEP of 0 cm H2O (T0), (4) a 20° Trendelenburg tilt position combined with a PEEP of 5 cm H2O (T5), and (5) a 20° Trendelenburg tilt position combined with a PEEP of 10 cm H2O (T10). RESULTS: All maneuvers increased the CSA of the right internal jugular vein with respect to the control condition S0 (all P < 0.05). S5 increased the CSA on average by 15.9%, S10 by 22.3%, T0 by 39.4%, T5 by 38.7%, and T10 by 49.7%. CONCLUSION: In a comparison of the effectiveness of applying different PEEP levels and/or the Trendelenburg tilt position on the CSA of the right internal jugular vein, the Trendelenburg tilt position was most effective.

Preoperative Microvascular Dysfunction: A Prospective, Observational Study Expanding Risk Assessment Strategies in Major Thoracic Surgery

BACKGROUND Brachial artery reactivity testing (BART)--a surrogate test of microvascular function--predicts cardiac risk in the nonsurgical population and associates it with adverse outcome after vascular surgery. This pilot study investigated BART-derived variables, including flow-mediated dilation (FMD), in preoperative risk stratification for major thoracic surgery. METHODS After institutional review board approval, BART was performed in 63 patients before major thoracic surgery. Ultrasonography recorded two-dimensional images and Doppler flow signals of the brachial artery preoperatively at baseline and after induced reactive hyperemia. Variables derived using BART were correlated with preoperative risk factors, established risk scores, and postoperative complications. RESULTS The median preoperative FMD value in patients without postoperative complications was 11.5%. This value was used to delineate all patients into two groups: low (FMD < 11.5%) and high (FMD ≥ 11.5%) FMD cohorts. Patients in the low FMD group experienced more postoperative complications: 54% versus 30% had one or more adverse postoperative event, and 11% versus 0% had three or more adverse postoperative events (p < 0.001), respectively. The low FMD group required longer intensive care unit (3.9 ± 2.0 days versus 0.9 ± 0.3 days; p = 0.015) and hospital (14.0 ± 3.3 days versus 6.8 ± 0.6 days; p = 0.007) stays. This cutoff point for FMD accurately predicted 71% of the patients with adverse postoperative events, achieving 71.4% (95% confidence interval, 54.7 to 88.2) sensitivity and 48.6% (95% confidence interval, 32.0 to 65.1) specificity. CONCLUSIONS Using BART, preoperative microvascular dysfunction can be identified in patients at increased risk for postoperative complications. These data suggest that larger observational studies and studies exploring preoperative optimization strategies aimed at improving microvascular function are warranted.

Segregating the Cerebral Mechanisms of Antidepressants and Placebo in Fibromyalgia

UNLABELLED Antidepressant drugs are commonly used to treat fibromyalgia, but there is little knowledge about their mechanisms of action. The aim of this study was to compare the cerebral and behavioral response to positive treatment effects of antidepressants or placebo. Ninety-two fibromyalgia patients participated in a 12-week, double-blind, placebo-controlled clinical trial with milnacipran, a serotonin-norepinephrine reuptake inhibitor. Before and after treatment, measures of cerebral pain processing were obtained using functional magnetic resonance imaging. Also, there were stimulus response assessments of pressure pain, measures of weekly pain, and fibromyalgia impact. Following treatment, milnacipran responders exhibited significantly higher activity in the posterior cingulum compared with placebo responders. The mere exposure to milnacipran did not explain our findings because milnacipran responders exhibited increased activity also in comparison to milnacipran nonresponders. Stimulus response assessments revealed specific antihyperalgesic effects in milnacipran responders, which was also correlated with reduced clinical pain and with increased activation of the posterior cingulum. A short history of pain predicted positive treatment response to milnacipran. We report segregated neural mechanisms for positive responses to treatment with milnacipran and placebo, reflected in the posterior cingulum. The increase of pain-evoked activation in the posterior cingulum may reflect a normalization of altered default mode network processing, an alteration implicated in fibromyalgia pathophysiology. PERSPECTIVE This study presents neural and psychophysical correlates to positive treatment responses in patients with fibromyalgia, treated with either milnacipran or placebo. The comparison between placebo responders and milnacipran responders may shed light on the specific mechanisms involved in antidepressant treatment of chronic pain.

Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia

Abstract Background In recent years, the prescription of serotonin-noradrenalin reuptake inhibitors (SNRIs) for treatment of fibromyalgia (FM) has increased with reports of their efficacy. The SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of milnacipran on central pain processing has not been investigated. The primary objective of this study was to assess the effect of milnacipran on sensitivity to pressure-evoked pain in FM. Secondary objectives were to assess the effect of milnacipran on cerebral processing of pressure-evoked pain using fMRI and the tolerability and safety of milnacipran 200 mg/day in FM. Methods 92 patients were randomized to either 13-weeks milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and after treatment using a computer-controlled pressure-pain stimulator. Here, we present the results of several a priori defined statistical analyses. Results Milnacipran-treated patients displayed a trend toward lower pressure-pain sensitivity after treatment, compared to placebo, and the difference was greater at higher pain intensities. A single group fMRI analysis of milnacipran-treated patients indicated increased pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala after treatment, compared to before treatment; regions implicated in pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing milnacipran and placebo, before and after treatment, showed that milnacipran-treated patients had greater pain-evoked activity in the precuneus/posterior cingulate cortex after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of milnacipran-treated patients. Patients on milnacipran were more likely to discontinue treatment because of side effects. Conclusions Our results provide preliminary indications of increased pain inhibitory responses in milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-pain tolerance after treatment with milnacipran, compared to placebo, especially for higher pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential biomarker for abnormal central pain processing. Implications The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for chronic pain. Furthermore, our results point toward a potential mechanism for pain normalization in response to milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.

Assessing Cognitive and Psychomotor Performance in Patients with Fibromyalgia Syndrome

IntroductionPatients with fibromyalgia syndrome (FMS) generally present with chronic widespread pain, accompanied by a range of additional and non-specific symptoms, such as fatigue, disturbed sleep, and cognitive dysfunction, which tend to increase with overall severity. Previous studies have shown moderate cognitive impairment in patients with FMS, but there are few valid data explicitly assessing the relevance of these findings to everyday functions, such as driving ability. Therefore, we studied patients with FMS to assess the impact of FMS on tests that predict driving ability.MethodsFemale patients with FMS were prospectively compared to a historical control group of healthy volunteers. The test battery comprised assessments of visual orientation, concentration, attention, vigilance, motor coordination, performance under stress, and reaction time.ResultsA total of 43 patients were matched to 129 controls. The results indicated that the patients’ psychomotor and cognitive performances were significantly non-inferior when compared to healthy controls (with 0.05% alcohol), with the exception of motor coordination. Patients and healthy controls showed an age-related decline in test performance. Correlations were smaller in patients and reversed for vigilance which was linked to a greater FMS symptom load in younger patients.ConclusionThe results of the present study demonstrate that, in general, the driving ability of patients with FMS was not inferior to that of healthy volunteers based on a standardized computer-based test battery. However, variables, such as younger age, depression, anxiety, fatigue, pain, and poor motor coordination, likely contribute to the subjective perception of cognitive dysfunction in FMS.

Messung der Druckschmerzempfindlichkeit

ZusammenfassungHintergrundDie Messung der Druckschmerzschwelle und der überschwelligen Druckschmerzempfindlichkeit mit einem neu entwickelten computergesteuertem Algometer wurde in einer Pilotuntersuchung mit etablierten Methoden verglichen.Material und MethodenAn 37 Gesunden und 64 Probanden mit chronischen Schmerzen wurden die Druckschmerzschwellen mit einem elektronischen Algometer (Somedic) und dem computergesteuerten Algoforce PA3® bestimmt, anschließend Stimulus-Antwort-Kurven für schmerzhafte Reize mit dem Algoforce PA3® und einem hydraulischen Algometer.ErgebnisseDie Mittelwerte und Varianzen der Druckschmerzschwellen waren nicht signifikant verschieden. Für niedrige Schmerzschwellen ergab der Algoforce PA3® aber niedrigere Werte und für hohe Schmerzschwellen höhere Werte. Bei der Ermittlung der überschwelligen Schmerzempfindlichkeit fanden sich keine signifikanten Unterschiede. Geschlecht und chronische Schmerzen hatten keinen relevanten Einfluss auf die Messmethoden.SchlussfolgerungFür den klinischen Alltag liefern die verwendeten Algometer vergleichbare Ergebnisse. Für Studien, die eine hohe Präzision insbesondere bei niedriger Stimulation erfordern, könnte der Einsatz des Algoforce PA3® in Betracht gezogen werden.AbstractBackgroundMeasurement of the pressure pain threshold and suprathreshold pressure pain sensitivity using a newly developed computer controlled algometer was compared to established methods in this pilot study.MethodsThe pressure pain threshold was measured in 64 chronic pain patients and 37 healthy volunteers with a manual electronic algometer (Somedic) and the computer controlled Algoforce PA3. Stimulus-response curves with painful stimuli were applied using the Algoforce PA3 and a hydraulic algometer.ResultsOverall means and variance of the pressure pain thresholds for both methods were similar. For low pain thresholds the Algoforce PA3 generally resulted in lower values and for high pain thresholds in higher values. No differences were seen for suprathreshold pain sensitivity. Gender and the presence of chronic pain had no relevant effect on the different methods in both comparisons.ConclusionFor clinical use, the algometers investigated deliver comparable results. For studies requiring high precision with low levels of stimulation the use of the Algoforce PA3 could be considered.

Measuring pressure pain thresholds. Comparison of an electromechanically controlled algometer with established methods

ZusammenfassungHintergrundDie Messung der Druckschmerzschwelle und der überschwelligen Druckschmerzempfindlichkeit mit einem neu entwickelten computergesteuertem Algometer wurde in einer Pilotuntersuchung mit etablierten Methoden verglichen.Material und MethodenAn 37 Gesunden und 64 Probanden mit chronischen Schmerzen wurden die Druckschmerzschwellen mit einem elektronischen Algometer (Somedic) und dem computergesteuerten Algoforce PA3® bestimmt, anschließend Stimulus-Antwort-Kurven für schmerzhafte Reize mit dem Algoforce PA3® und einem hydraulischen Algometer.ErgebnisseDie Mittelwerte und Varianzen der Druckschmerzschwellen waren nicht signifikant verschieden. Für niedrige Schmerzschwellen ergab der Algoforce PA3® aber niedrigere Werte und für hohe Schmerzschwellen höhere Werte. Bei der Ermittlung der überschwelligen Schmerzempfindlichkeit fanden sich keine signifikanten Unterschiede. Geschlecht und chronische Schmerzen hatten keinen relevanten Einfluss auf die Messmethoden.SchlussfolgerungFür den klinischen Alltag liefern die verwendeten Algometer vergleichbare Ergebnisse. Für Studien, die eine hohe Präzision insbesondere bei niedriger Stimulation erfordern, könnte der Einsatz des Algoforce PA3® in Betracht gezogen werden.AbstractBackgroundMeasurement of the pressure pain threshold and suprathreshold pressure pain sensitivity using a newly developed computer controlled algometer was compared to established methods in this pilot study.MethodsThe pressure pain threshold was measured in 64 chronic pain patients and 37 healthy volunteers with a manual electronic algometer (Somedic) and the computer controlled Algoforce PA3. Stimulus-response curves with painful stimuli were applied using the Algoforce PA3 and a hydraulic algometer.ResultsOverall means and variance of the pressure pain thresholds for both methods were similar. For low pain thresholds the Algoforce PA3 generally resulted in lower values and for high pain thresholds in higher values. No differences were seen for suprathreshold pain sensitivity. Gender and the presence of chronic pain had no relevant effect on the different methods in both comparisons.ConclusionFor clinical use, the algometers investigated deliver comparable results. For studies requiring high precision with low levels of stimulation the use of the Algoforce PA3 could be considered.