Interhemispheric and Corticothalamic White-Matter Dysfunction Underlies Affective Morbidity and Impaired Pain Modulation in Chronic Pain.

BACKGROUND: Although patients with chronic pain show behavioral signs of impaired endogenous pain modulation, responsible cerebral networks have yet to be anatomically delineated. We used diffusion tensor imaging (DTI) to examine the white-matter alterations in patients with chronic pain compared with healthy subjects. We further measured thermal pain modulatory responses using the offset analgesia (OA) paradigm. We tested whether the white-matter indices be associated with psychophysical parameters reflecting morbidity and modulatory responses of pain in patients, and whether they could serve as diagnostic biomarkers of chronic pain. METHODS: Twenty-six patients with chronic pain and 18 age- and gender-matched healthy controls were enrolled. After completing psychophysical questionnaires, they underwent OA measurement and whole-brain DTI in a 3 Tesla magnetic resonance imaging scanner. Fractional anisotropy (FA) and radial diffusivity (RD) of the white-matter were computed and compared between the groups with tract-based spatial statistics using the FMRIB Software Library (FSL) software. Correlations were sought among white-matter indices, thermal pain responses, and psychophysical parameters. The white-matter indices and OA-related parameters were tested whether they distinguish patients from controls by receiver operating characteristic analysis. RESULTS: During OA, patients showed a shorter latency to the maximum (maximum visual analog scale [VAS] latency, 16.0 ± 3.7 vs 18.9 ± 3.1 second [mean ± standard deviation, SD]; P = .032) but a longer latency to the minimum pain (OA latency, 15.6 ± 3.5 vs 11.1 ± 4.2 seconds; P = .004) than controls. They showed a smaller mean FA (0.44 ± 0.12 vs 0.45 ± 0.11; P = .012) and a larger mean RD of the global white-matter (0.00057 ± 0.00002 vs 0.00056 ± 0.00002; P = .038) than controls, at specific areas including the corpus callosum, anterior thalamic radiation, and forceps major. FA of the splenium of the corpus callosum was associated with maximum VAS latency (r = 0.493) and OA latency (r = -0.552). The Pain Catastrophizing Scale scores showed strong negative correlations with FA across those specific areas (r = -0.405). Those latencies during OA and white-matter metrics distinguished patients from controls (P < .05). CONCLUSIONS: Patients with chronic pain showed dysfunction of the white matter concerned with interhemispheric communication of sensorimotor information as well as descending corticothalamic modulation of pain in association with affective morbidity and altered temporal dynamics of pain perception. We suggest that an impaired interhemispheric modulation of pain, through the corpus callosum, might be a novel cerebral mechanism in chronification of pain.

Neural Mechanisms of Offset Analgesia.

One feels a disproportionately large decrease of pain sensation on a slight decrease of thermal pain stimulus. Such phenomenon is termed offset analgesia and considered mediated by endogenous analgesic mechanisms. Offset analgesia was found attenuated in patients with neuropathic pain. We further found that such attenuation occurred in a more heterogeneous population of patients with chronic pain. By functional magnetic resonance imaging, we also found negative blood oxygenation level-dependent signals at those areas concerned with descending pain modulatory and reward systems during offset analgesia in the same cohort of patients. We propose that dysfunction of those systems, as revealed by attenuation of offset analgesia, might well be part of neural mechanisms of pain chronification.

Suppressed descending pain modulatory and enhanced sensorimotor networks in patients with chronic low back pain.

PURPOSE: Although cerebral structural and functional changes were uncovered by neuroimaging in patients with chronic low back pain (CLBP), their associations remain to be clarified. We co-analyzed anatomical and functional magnetic resonance imaging data in those patients and tested whether cortical gray matter volume changes are associated with altered pain modulatory networks underlying chronification of pain. METHODS: In 16 patients with CLBP and 16 heathy controls, we performed functional magnetic resonance imaging during mechanical pain stimulation on the lower back followed by anatomical imaging. We performed voxel-based morphometry and functional connectivity analysis from the seeds with altered gray matter volume, and examined correlations between imaging and psychophysical parameters. RESULTS: Patients showed decreases in gray matter volume at the right dorsolateral prefrontal cortex, middle occipital gyrus, and cerebellum, and showed increases at the bilateral primary sensorimotor cortices, left fusiform gyrus, and right cerebellum compared with controls (P < 0.001). Dorsolateral prefrontal and fusiform volumes showed negative associations with affective comorbidity, whereas motor cortex volume with impaired daily activity (P < 0.05). Connectivity was decreased between the cerebellar and limbic, and increased between the bilateral sensorimotor regions (PFDR < 0.05). Higher pain intensity and unpleasantness correlated with enhanced bilateral sensorimotor and dorsolateral-medial prefrontal networks, respectively (P < 0.05). CONCLUSION: Patients showed a decreased volume of cortical center for descending pain modulation and an increased volume of sensorimotor network, in association with suppressed descending pain modulatory and cerebellum-limbic networks and enhanced sensorimotor network during pain. Such structural and functional alterations might be part of cerebral pathophysiology of CLBP.

Attenuation of offset analgesia is associated with suppression of descending pain modulatory and reward systems in patients with chronic pain.

Background Offset analgesia is a disproportionate decrease of pain perception following a slight decrease of noxious thermal stimulus and attenuated in patients with neuropathic pain. We examined offset analgesia in patients with heterogeneous chronic pain disorders and used functional magnetic resonance imaging to explore modification of cerebral analgesic responses in comparison with healthy controls. Results We recruited seventeen patients with chronic pain and seventeen age-, sex-matched healthy controls. We gave a noxious thermal stimulation paradigm including offset analgesia and control stimuli on the left volar forearm, while we obtained a real-time continuous pain rating and a whole-brain functional magnetic resonance imaging. Baseline, first plateau (5 s), increment (5 s), and second plateau (20 s) temperatures of offset analgesia stimulus were set at 32°C, 46°C, 47°C, and 46°C, respectively. Control stimulus included 30-s 46°C stimulus or only the first 10 s of offset analgesia stimulus. We evaluated magnitude of offset analgesia, analyzed cerebral activation by thermal stimulation, and further compared offset analgesia-related activation between the groups. Magnitude of offset analgesia was larger in controls than in patients (median: 28.9% (interquartile range: 11.0-56.0%) vs. 19.0% (4.2-48.7%), p = 0.047). During the second plateau, controls showed a larger blood oxygenation level-dependent activation than patients at the putamen, anterior cingulate, dorsolateral prefrontal cortices, nucleus accumbens, brainstem, and medial prefrontal cortex ( p < 0.05), which are known to mediate either of descending pain modulation or reward responses. Offset analgesia-related activity at the anterior cingulate cortex was negatively correlated with neuropathic component of pain in patients with chronic pain ( p = 0.004). Conclusions Attenuation of offset analgesia was associated with suppressed activation of the descending pain modulatory and reward systems in patients with chronic pain, at least in the studied cohort. The present findings might implicate both behavioral and cerebral plastic alterations contributing to chronification of pain. Clinical trial registry: The Japanese clinical trials registry (UMIN-CTR, No. UMIN000011253; http://www.umin.ac.jp/ctr /).

Correction to: Attenuation of cortical activity triggering descending pain inhibition in chronic low back pain patients: a functional magnetic resonance imaging study.

Inadvertently, the Fig. 7 was published incorrectly in the original publication of the article. The correct figure should be as below.

Disrupted offset analgesia distinguishes patients with chronic pain from healthy controls.

Offset analgesia (OA) represents a disproportionately large decrease of pain perception after a brief, temporary increment of thermal pain stimulus and was reported attenuated in patients with neuropathic pain. We examined whether OA depends on the increment duration before offset, and whether individual features of OA distinguish patients with chronic pain and healthy controls. We used a Peltier-type thermal stimulator and OA paradigms including 5-, 10-, or 15-s duration of 1°C-increment (T2) over 45°C. We first examined OA response, on the left volar forearm, at 3 different T2's in 40 healthy volunteers, and OA and constant stimulus responses in 12 patients with chronic pain and 12 matched healthy controls. We measured magnitude of OA ([INCREMENT]OA) and maximum visual analogue scale (VAS) latency (time to peak VAS) during constant stimulus for each individual. Pain perception kinetics were compared with analysis of variance and sought for correlations with psychophysical parameters with a significance threshold at P < 0.05. In healthy controls, longer T2 at 10 or 15 seconds resulted in larger [INCREMENT]OA compared with T2 at 5 seconds (P = 0.04). In patients, [INCREMENT]OA was significantly smaller than controls at T2 = 5 or 10 seconds (P < 0.05) but grew comparable at T2 = 15 seconds with controls. Maximum VAS latency was longer in patients than in controls and negatively correlated with [INCREMENT]OA in patients. An OA index ([INCREMENT]OA/[maximum VAS latency]) proved diagnostic of chronic pain with an area under the receiver operating characteristic curve at 0.897. Patients with chronic pain showed impairment of OA and reduced temporal sharpening of pain perception, which might imply possible disturbance of the endogenous pain modulatory system.

Attenuation of cortical activity triggering descending pain inhibition in chronic low back pain patients: a functional magnetic resonance imaging study.

PURPOSE: A considerable portion of chronic low back pain (cLBP) patients lack anatomical abnormality, resist conventional therapeutic interventions, and their symptoms are often complicated with psychological and social factors. Such patients have been reported to show cerebral abnormalities both in anatomy and function by neuroimaging studies. Here we examined differences in cerebral reactivity to a simulated low back pain stimulus between cLBP patients and healthy controls by functional magnetic resonance imaging (fMRI), and their behavioral correlates from a psychophysical questionnaire. METHODS: Eleven cLBP patients and 13 healthy subjects (HS) were enrolled in this study. After psychophysical evaluation on-going pain with McGill Pain Questionnaire Short Form (MPQ), they underwent whole-brain fMRI in a 3-Tesla MRI scanner while receiving three blocks of 30-s mechanical pain stimuli at the left low back with a 30-s rest in between, followed by a three-dimensional anatomical imaging. Functional images were analyzed with a multi-subject general linear model for blood oxygenation level-dependent (BOLD) signal changes associated with pain. Individual BOLD signal amplitudes at activated clusters were examined for correlation with psychophysical variables. Two in the cLBP and five data sets in the HS groups were excluded from analysis because of deficient or artifactual data or mismatch in age. RESULTS: The HS group showed LBP-related activation at the right insular cortex, right dorsolateral prefrontal cortex (DLPFC), left anterior cingulate cortex (ACC), and left precuneus; and deactivation in a large area over the parietal and occipital cortices, including the bilateral superior parietal cortex. On the other hand, the cLBP group did not show any significant activation at those cortical areas, but showed similar deactivation at the bilateral superior parietal cortex and part of the premotor area. An HS > cLBP contrast revealed significantly less activity at the ACC and DLPFC in the cLBP group, which was negatively correlated with higher MPQ scores. CONCLUSIONS: The cLBP patients showed attenuated reactivity to pain at the ACC and DLPFC, known cortical areas mediating affective component, and top-down modulation, of pain. The present results might be associated with possible dysfunction of the descending pain inhibitory system in patients with chronic low back pain, which might possibly play a role in chronification of pain.

Dysfunction of Nucleus Accumbens Is Associated With Psychiatric Problems in Patients With Chronic Low Back Pain: A Functional Magnetic Resonance Imaging Study.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: The aim of this study was to evaluate activity of the nucleus accumbens (NAc) in response to lumbar mechanical stimulation in patients with chronic low back pain (cLBP) using functional magnetic resonance imaging (fMRI). SUMMARY OF BACKGROUND DATA: Although a modified activity of the NAc was characterized in cLBP patients, its pathological significance has yet to be determined. We hypothesized that NAc activation in response to pain might differ depending on the extent of psychiatric problems, which might be associated with the affective/motivational background of chronic pain. METHODS: Twenty-one patients with cLBP (four men, 17 women) were recruited. Subjects were divided into two groups on the basis of scores on the patient version of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) scores: ≥17 (High Score, HiS group) and <17 (non-High Score, non-HiS group). Each subject was placed in the prone position on a 3-Tesla magnetic resonance imaging (MRI) scanner and stimulated by mechanical stimulation on the left lower back. Three blocks of 30-second pain stimulus calibrated at either 3 or 5 on an 11-grade numerical rating scale (NRS) were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. Functional images were analyzed using a multisubject general linear model with Bonferroni multiple comparisons. RESULTS: Subjects in the HiS group had more intense daily pain and lower quality of life than those in the non-HiS group (P < 0.05). Catastrophic thinking in relation to pain experience did not differ between the groups. Activation at the NAc was smaller in the HiS group than in the non-HiS group (P < 0.001). CONCLUSION: The presence of psychiatric problems was associated with attenuated activity of the NAc in cLBP patients. Dysfunction of the NAc might potentially be involved in the affective/motivational factors in the chronification of LBP. LEVEL OF EVIDENCE: N/A.

A case of malignant catatonia with idiopathic pulmonary arterial hypertension treated by electroconvulsive therapy.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal cardiovascular disease if left untreated. In patients with IPAH with psychiatric illness or other complications, careful attention is required when administering medical therapies that may affect their hemodynamics. Patients suffering from IPAH who undergo anesthesia and surgery have a high mortality and morbidity rate. We describe the treatment of intractable psychiatric symptoms with electroconvulsive therapy (ECT) in a patient with IPAH. CASE PRESENTATION: A 23-year-old woman with IPAH and type I diabetes mellitus (DM) presented with malignant catatonia. Her heart function was classified as New York Heart Association (NYHA) class III. She required a rapid cure and ECT due to various psychiatric symptoms resistant to conventional medications. Pulmonary hypertensive (PH) crisis is the most concerning complication that can be induced by the sympathetic stimulation of ECT. To avoid PH crisis, we administered oxygen using a laryngeal mask and administered remifentanil for anesthesia. We also prepared standby nitric oxide for possible PH crisis, although it was ultimately not needed. With 14 ECT sessions, her malignant catatonia was ameliorated without physical complications. CONCLUSION: ECT is an acceptable option for the treatment of medication-refractory psychiatric disturbances in patients with IPAH, provided careful management is assured to prevent or address complications.

[Clinical application of multimodal magnetic resonance imaging to explore cerebral biomarkers of chronic pain].

Much evidence has been accumulated on the cerebral mechanisms of pain perception owing to rapid and diverse development in magnetic resonance imaging and its analysis techniques over the last decades. In addition to pain-evoked cerebral activities, our knowledge now extends into chronic pain-associated alterations in cerebral connectivity over networks and in gray matter density, which characterize cerebral steady-state pathological properties underlying chronic pain conditions. A dynamic cerebral model for chronification of pain is presented, in which a bottom-up nociception via the lateral system leads to a reactive, top-down hyperactivity of the medial system, and eventually to both functional and anatomical degeneration of pain modulatory mechanisms and reward systems. All such biomarkers of "chronic pain brain" revealed by neuroimaging will hopefully help us in diagnosis of chronic pain and evaluation of therapeutics for each patient on an outpatient basis.

[Anesthetic mechanisms revealed by functional brain imaging].

Recent advancement in functional brain imaging techniques has revealed much of the global effects of general anesthetics on the human brain. General anesthetics preferentially suppress specific brain areas including the parietal association cortex and the thalamus, part of which appears to mirror the default mode network. Low-level sensory areas are relatively preserved and remain activated even under deep sedation by anesthetics. Functional connectivity analysis by resting-state functional magnetic resonance imaging has shown that general anesthetics moderately suppress functional connectivity of the default mode network. Midazolam-induced loss of consciousness is associated with remarkable suppression of cortico-cortical propagation of evoked currents. Overall, those results prompt us to hypothesize that general anesthetics induce loss of consciousness by disrupting the integrative properties of the cerebral cortex.

Augmented damage of islets by impaired exocrine acinar cells undergoing apoptosis that is possibly converted to necrosis during isolation.

Islet damage attributed to impaired exocrine cells during pancreas preservation and isolation procedure remains elusive, although released exocrine enzymes could directly damage islets. The aim of this study is to investigate the cellular mechanisms associated with exocrine cells and their possible impact on the islet cell survival and function after isolation. Mouse pancreata were stored in cold University of Wisconsin preservation solution for 0, 24 and 48 h and incubated with or without collagenase at 37°C for 15 min. During preservation, the percentage of exocrine cells with necrosis, which means impaired cellular membrane that allows intracellular enzymes to be released, remains low (< 10%) regardless of preservation time; whereas the percentage of exocrine cells with apoptosis, which means impaired nucleus and possible intact cellular membrane, increases over time of preservation. After collagenase-free incubation, however, the percentage of exocrine cells with necrosis became higher in longer preservation time, and more than 60% of the necrotic exocrine cells contained apoptosis as well. Islet cells located in pancreata with intact structure are almost kept away either from necrotic or apoptotic changes even after 48 h preservation followed by collagenase-free incubation. However, when islets are isolated after collagenase-containing incubation, the percentage of islet cells with necrosis increases over time of preservation up to approximately 40%. This study suggests that exocrine cells with necrosis could cause damage of isolated islets when the pancreas is dissociated and that the necrosis in exocrine cells might be induced mainly as the conversion from apoptosis that has already existed during preservation.

[A potential role of functional magnetic resonance imaging in the diagnosis of pain].

Functional neuroimaging techniques have revealed the cerebral substrates of pain perception (pain matrix) in humans, which include the thalamus, as well as primary, secondary somatosensory, insular, anterior cingulate, and prefrontal cortices. Functional magnetic resonance imaging (fMRI) could be the most suitable candidate for routine clinical use in the evaluation of pain because of its relatively low cost and the absence of irradiation. Here the author summarizes the practical aspects of fMRI studies on pain, and proposes the "bottom-up/top-down theory" of cerebral pain processing that explains possible interaction among discrete parts of pain matrix. Long-term, plastic changes induced by such interaction could play a pivotal role in the exaggerated brain activity of chronic pain patients. The top-down component of pain matrix also explains basic neuroimaging findings on the anticipation, empathy, and placebo effects of pain, and on the cortical trigger of the descending pain inhibitory system. Finally, the author summarizes his recent research on the cerebral substrates of chronic low back pain, and shows a case study on neuropathic pain using fMRI, which hopefully should help in planning clinical fMRI studies for a longitudinal follow-up of chronic pain patients.

Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: an FMRI study.

STUDY DESIGN: Cerebral activation by lumbar mechanical stimulus was investigated by functional magnetic resonance imaging in healthy subjects and patients with chronic low back pain (LBP). OBJECTIVES: To characterize the cerebral substrates of LBP, and to explore a possible pathologic pattern of cerebral activation in chronic LBP patients. SUMMARY OF BACKGROUND DATA: The cerebral substrates of LBP have been poorly defined in contrast to those of cutaneous somatic pain. METHODS: Eight healthy volunteers and 6 patients with idiopathic, chronic LBP were recruited. Each subject was placed in the prone position on a 3 Tesla MRI scanner, and stimulated by manual pressure with the tail of an air-filled, 20-mL syringe at 5 cm left of the fourth-fifth lumbar spinal interspace. Three blocks of 30-second painful stimulus, calibrated at either 3 or 5 on the 10-cm visual analog scale (VAS), were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. VAS of pain intensity and unpleasantness were evaluated after each session. Functional imaging was analyzed using a multisubject general linear model with Bonferroni multiple comparisons at P < 0.05. RESULTS: Pain thresholds were smaller (P < 0.05) and VAS of unpleasantness was larger in LBP patients than in healthy subjects. Activation was observed at the prefrontal, insular, posterior cingulate cortices (PCC), supplementary motor, and premotor areas predominantly in the right hemisphere, but not at the somatosensory cortices. LBP patients showed augmented activation compared with healthy volunteers specifically at the right insula, supplementary motor, and PCC. CONCLUSION: Chronic LBP patients showed increased tenderness at the lower back, higher aversive reaction to pain, and augmented LBP-related cerebral activation. The LBP-related activation is characterized by the absence of sensory-discriminative component and the involvement of PCC.

[Case of coronary spasm during thoracic surgery under combined epidural-general anesthesia].

A 70-year-old woman, who had neither complication nor risk factors of ischemic heart disease, was scheduled for a partial resection of the left lung. After an epidural catheter was placed at the T7-8 interspace, general anesthesia was induced and maintained with propofol and fentanyl. Once stable vital signs had been confirmed, 3 ml of 0.5% ropivacaine was given through the epidural catheter. Bradycardia with hypotension progressively developed and continued despite the intravenous administration of phenylephrine, ephedrine, and atropine. Fourteen minutes after the injection of ropivacaine, the electrocardiogram showed an elevation of the ST segment. One minute later, the heart rhythm changed to a 2:1-type second degree block. Although a bolus of 1 mg epinephrine was injected intravenously, severe hypotension and bradycardia persisted, leading to the complete block and paroxysmal ventricular tachycardia. Continuous infusion of nitroglycerin as well as cardiopulmonary resuscitation was started. The sinus rhythm with normal ST segment was eventually restored with subsequent hemodynamic stability. Intraoperative transesophageal echocardiography indicated a satisfactory cardiac wall motion. Coronary spasm was suspected because of the transient ST segment elevation and the absence of wall motion abnormality after the recovery. The clinical course of the A-V block appearing shortly after ST segment elevation suggested that the right coronary artery, perfusing the A-V node areas, was involved.