Neurometabolic correlates of depression and disability in episodic cluster headache

A close association between pain, depression and disability has been shown. However, the neurometabolic correlates of this association have been barely investigated in disease states. Episodic cluster headache is a severe headache syndrome and represents a suitable disease model for the investigation of episodic pain. The aim of this study was to explore the relationship between depression and disability as well as pain scores and brain metabolism in patients with cluster headache during the disease period with repetitive pain attacks, but outside an acute attack. Thirteen patients with cluster headache underwent 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission (FDG-PET) and completed questionnaires on depression and disability as well as a pain visual analogue rating scale (VAS). A positive correlation between the depression scores and glucose metabolism was observed in the insular cortex. A positive correlation between the pain disability scores and brain metabolism was detected in the amygdala. The same applied to the pain visual analogue rating scores. Our data underline the association between severe episodic pain, depression and disability. In addition to this clinical observation, our results stress the importance of the insula and amygdala in pain processing and suffering

Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping

Central post-stroke pain of thalamic origin is an extremely distressing and often refractory disorder. There are no well-established predictors for pain development after thalamic stroke, and the role of different thalamic nuclei is unclear. Here, we used structural magnetic resonance imaging to identify the thalamic nuclei, specifically implicated in the generation of central post-stroke pain of thalamic origin. Lesions of 10 patients with central post-stroke pain of thalamic origin and 10 control patients with thalamic strokes without pain were identified as volumes of interest on magnetic resonance imaging data. Non-linear deformations were estimated to match each image with a high-resolution template and were applied to each volume of interest. By using a digital atlas of the thalamus, we elucidated the involvement of different nuclei with respect to each lesion. Patient and control volumes of interest were summed separately to identify unique areas of involvement. Voxelwise odds ratio maps were calculated to localize the anatomical site where lesions put patients at risk of developing central post-stroke pain of thalamic origin. In the patients with pain, mainly lateral and posterior thalamic nuclei were affected, whereas a more anterior-medial lesion pattern was evident in the controls. The lesions of 9 of 10 pain patients overlapped at the border of the ventral posterior nucleus and the pulvinar, coinciding with the ventrocaudalis portae nucleus. The lesions of this area showed an odds ratio of 81 in favour of developing thalamic pain. The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of thalamic origin early after thalamic insults. This provides a basis for pre-emptive treatment studie

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60–90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8–13 Hz) and beta (14–29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time–frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain

Sensory Symptom Profiles and Co-Morbidities in Painful Radiculopathy

Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD

Fibromyalgia and neuropathic pain - differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia

<p>Abstract</p> <p>Background</p> <p>Patients with diabetic neuropathy (DPN) and fibromyalgia differ substantially in pathogenetic factors and the spatial distribution of the perceived pain. We questioned whether, despite these obvious differences, similar abnormal sensory complaints and pain qualities exist in both entities. We hypothesized that similar sensory symptoms might be associated with similar mechanisms of pain generation. The aims were (1) to compare epidemiological features and co-morbidities and (2) to identify similarities and differences of sensory symptoms in both entities.</p> <p>Methods</p> <p>The present multi-center study compares epidemiological data and sensory symptoms of a large cohort of 1434 fibromyalgia patients and 1623 patients with painful diabetic neuropathy. Data acquisition included standard demographic questions and self-report questionnaires (MOS sleep scale, PHQ-9, Pain<it>DETECT</it>). To identify subgroups of patients with characteristic combinations of symptoms (sensory profiles) a cluster analysis was performed using all patients in both cohorts.</p> <p>Results</p> <p>Significant differences in co-morbidities (depression, sleep disturbance) were found between both disorders. Patients of both aetiologies chose very similar descriptors to characterize their sensory perceptions. Burning pain, prickling and touch-evoked allodynia were present in the same frequency. Five subgroups with distinct symptom profiles could be detected. Two of the subgroups were characteristic for fibromyalgia whereas one profile occurred predominantly in DPN patients. Two profiles were found frequently in patients of both entities (20-35%).</p> <p>Conclusions</p> <p>DPN and fibromyalgia patients experience very similar sensory phenomena. The combination of sensory symptoms - the sensory profile - is in most cases distinct and almost unique for each one of the two entities indicating aetiology-specific mechanisms of symptom generation. Beside the unique aetiology-specific sensory profiles an overlap of sensory profiles can be found in 20-35% of patients of both aetiologies.</p

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (&gt;60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches

Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features

Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features

Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients

Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia

Background Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN. Methods Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8). Results IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar. Conclusion While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered