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Often, persistent post-traumatic headache and migraine are phenotypically similar. However, the similarities and differences in the neuropathological underpinnings of persistent post-traumatic headache and migraine require further understanding. We used diffusion tensor imaging (DTI) and a novel method for detecting subtle changes in fibertract integrity by measuring node-by-node parameters along each tract to compare fibertract profiles between those with migraine and those with persistent post-traumatic headache, and compared both cohorts to a group of controls.
Learn More >Fibromyalgia (FM) is a highly prevalent and disabling syndrome characterized by chronic widespread musculoskeletal pain and a broad range of cognitive and affective symptoms. Up to now, the pathogenesis of FM is unknown although a peripheral and central sensitization involving an imbalance on immune biomarkers appears to have a relevant role in its aetiology. The aim of this study was to extend previous clinical findings of Mindfulness-Based Stress Reduction (MBSR) to both its impact on clinical symptomatology and immune biomarkers (IL-6, CXCL8, IL-10 and hs-CRP), and also to explore the role of biomarkers as predictors of efficacy.
Learn More >Excitatory interneurons account for the majority of dorsal horn neurons, and are required for perception of normal and pathological pain. We have identified largely non-overlapping populations in laminae I-III, based on expression of substance P, gastrin-releasing peptide, neurokinin B and neurotensin. Cholecystokinin (CCK) is expressed by many dorsal horn neurons, particularly in the deeper laminae. Here we have used immunocytochemistry and in situ hybridisation to characterise the CCK cells. We show that they account for ~7% of excitatory neurons in laminae I-II, but between a third and a quarter of those in lamina III. They are largely separate from the neurokinin B, neurotensin and gastrin-releasing peptide populations, but show limited overlap with the substance P cells. Laminae II-III neurons with protein kinase Cγ (PKCγ) have been implicated in mechanical allodynia following nerve injury, and we found that around 50% of CCK cells were PKCγ-immunoreactive. Neurotensin is also expressed by PKCγ cells, and among neurons with moderate to high levels of PKCγ, ~85% expressed CCK or neurotensin. A recent transcriptomic study (Häring et al, Nat. Neurosci., 2018) identified mRNA for thyrotropin-releasing hormone (TRH) in a specific subpopulation of CCK neurons, and we show that these account for half of the CCK/PKCγ cells. These findings indicate that CCK cells are distinct from other excitatory interneuron populations that we have defined. They also show that PKCγ cells can be assigned to different classes based on neuropeptide expression, and it will be important to determine the differential contribution of these classes to neuropathic allodynia. This article is protected by copyright. All rights reserved.
Learn More >: While migraine with aura is a complex neurological syndrome with a well-characterized clinical phenotype, its pathophysiology still has grey areas which could be partially clarified by microstructural and functional neuroimaging investigations. : This article, summarizing the most significant findings from advanced neuroimaging studies, aims to achieve a unifying pathophysiological model of the migraine aura. A comprehensive review has been conducted of PubMed citations by entering the key word 'neuroimaging' combined with 'migraine with aura' AND/OR 'MRI.' Other keywords included 'grey matter' OR 'white matter', 'structural' OR 'functional'. : Converging evidence from advanced neuroimaging investigations underlined the critical role of the extrastriate visual cortex, and in particular the lingual gyrus, in the genesis of the aura phenomenon. However, the relationship between the aura and the headache phase of migraine attacks has not been completely clarified, to date, and underlying pathophysiological mechanisms need to be further elucidated.
Learn More >Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood.
Learn More >The American College of Rheumatology (ACR) 2016 criteria for fibromyalgia (FM) is recommended for use in primary and referral setting. However, neither the ACR 2016 nor its predecessor ACR 2010 criteria have been validated in a referral setting. We hypothesized that the presence of higher comorbidities in the referral care setting may affect the performance of the ACR 2016. All patients referred to a tertiary care hospital with widespread pain for more than 3 months were screened using (1) the ACR 2016 criteria and (2) by a blinded expert physician (using ACR 1990 criteria). Using the ACR 1990 as reference standard, the sensitivity and specificity were calculated. Also, concomitant depression (BPHQ: Brief Patient Health Questionnaire), anxiety disorder (GAD7: Generalized Anxiety Disorder-7) and alexithymia (TAS-20: Toronto Alexithymia Scale-20) were screened for using standardized instruments. Other central sensitization syndromes were also screened clinically. Of 147 patients (132 females; median age 36 [30-45] years, median symptom duration 4 [1-6] years), 112 met the ACR 1990 criteria while 93 met the ACR 2016 criteria. There was disagreement between the two criteria in 47 patients. The sensitivity and specificity of ACR 2016 were 71% and 60%, respectively. Patients diagnosed by ACR 2016 criteria alone, had higher GAD7 scores than those diagnosed by the ACR 1990 alone. However, BPHQ and TAS-20 did not differ between the groups. Patients diagnosed by the ACR 2016 criteria had a greater odds (OR 5.2 CI 1.3-21.7, p = 0.022) of having concomitant restless leg syndrome or post-traumatic stress disorder or chronic fatigue syndrome. The sensitivity/specificity of the ACR 2016 in tertiary settings matched those found in previous primary care-based studies. Thus, the ACR 2016 criteria are valid for use in the tertiary setting. However, patients diagnosed by only the ACR 2016 criteria (and not by the ACR 1990) have high probability of having another concomitant comorbidity.
Learn More >Low back pain (LBP) is a global public health challenge, which causes high health-care costs and the highest burden on society in terms of years lived with disability. While patient expectations for improvement may have effects on LBP treatment outcomes, it remains unclear if psychological profiles modify this relationship. Therefore, the objectives of this study were to investigate if (1) patient expectations predicted short-term outcome, and (2) psychological profile, pain intensity, and self-rated health modified the relationship between expectations and outcome.
Learn More >Spinal cord injury (SCI) results in not only motor dysfunction but also chronic neuropathic pain. Allodynia, an abnormal sensation that evokes pain against non-noxious stimuli, is a major symptom of post-SCI neuropathic pain. Astrocytic activation is a cause of post-SCI neuropathic pain and is considered a key treatment target. However, no effective treatment for these problems is available to date. ONO-2506 is a novel agent that suppresses astrocytic activation by inhibition of S100B production from astrocytes. Recently, it has been demonstrated that ONO-2506 inhibits secondary injury and improves motor function after SCI.
Learn More >Placebo effects can be induced by learning and conditioning processes, which in turn are influenced and modulated by glucocorticoids. Accordingly, previous research has shown that intervention-related associative learning can be modulated through exogenous as well as endogenous glucocorticoids. Thus, the aim of this study was to elucidate whether placebo effects induced by conditioning is modulated by daily fluctuations of endogenous cortisol levels in healthy male and female subjects. Overall 77 participants underwent a two-phased placebo conditioning paradigm for pain analgesia. Subjects were randomized in two groups, which underwent placebo preconditioning either in the morning (08:00-10:00, i.e. with high endogenous cortisol levels) or in the afternoon (16:00-18:00, i.e. with low endogenous cortisol levels). Placebo effects were assessed two days later at noontime (12:00-13:00), with possible differences between groups as an indicator of glucocorticoid modulation on the placebo learning. Results indicated a significant conditioned placebo-induced analgesia, resulting in a placebo effect of small to medium size. Cortisol levels on conditioning day significantly differed between groups and cortisol levels were similar during assessment of placebo effects. Groups did not differ in their mean reduction in pain sensation, thus the placebo effect was not affected by differences in cortisol levels during the conditioning of placebo effects. The present study does not indicate a moderation of placebo conditioning by endogenous glucocorticoid levels.
Learn More >Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons, that is, masked by tonic inhibitory controls. We explored mechanisms of latent sensitization with an established four-step approach: (1) induction of inflammation; (2) allow pain hypersensitivity to resolve; (3) interrogate latent sensitization with a channel blocker, mutant mouse, or receptor antagonist; and (4) disrupt compensatory inhibition with a receptor antagonist so as to reinstate pain hypersensitivity. We found that the neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice and was prevented with intrathecal co-administration of a pharmacological blocker to the N-methyl-D-aspartate receptor (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), transient receptor potential cation channel A1 (TRPA1), channel V1 (TRPV1), or exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both pain reinstatement and touch-evoked pERK expression in dorsal horn; the former was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An Epac activator also evoked pain reinstatement and pERK expression. We conclude that PKA and Epac are sufficient to maintain long-lasting latent sensitization of dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. Furthermore, we have identified and characterized 2 novel molecular signaling pathways in the dorsal horn that drive latent sensitization in the setting of chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. New treatments for chronic inflammatory pain might either increase endogenous NPY analgesia or inhibit AC1, PKA, or Epac.
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