Low-Frequency Stimulation of Trpv1-Lineage Peripheral Afferents Potentiates the Excitability of Spino-Periaqueductal Gray Projection Neurons.

High-threshold dorsal root ganglion (HT DRG) neurons fire at low frequencies during inflammatory injury, and low-frequency stimulation (LFS) of HT DRG neurons selectively potentiates excitatory synapses onto spinal neurons projecting to the periaqueductal gray (spino-PAG). Here, in male and female mice, we have identified an underlying peripheral sensory population driving this plasticity and its effects on the output of spino-PAG neurons. We provide the first evidence that Trpv1-lineage sensory neurons predominantly induce burst firing, a unique mode of neuronal activity, in lamina I spino-PAG projection neurons. We modeled inflammatory injury by optogenetically stimulating Trpv1+ primary afferents at 2 Hz for 2 min (LFS), as peripheral inflammation induces 1-2 Hz firing in high-threshold C fibers. LFS of Trpv1+ afferents enhanced the synaptically evoked and intrinsic excitability of spino-PAG projection neurons, eliciting a stable increase in the number of action potentials (APs) within a Trpv1+ fiber-induced burst, while decreasing the intrinsic AP threshold and increasing the membrane resistance. Further experiments revealed that this plasticity required Trpv1+ afferent input, postsynaptic G protein-coupled signaling, and NMDA receptor activation. Intriguingly, an inflammatory injury and heat exposure in vivo also increased APs per burst, in vitro These results suggest that inflammatory injury-mediated plasticity is driven though Trpv1+ DRG neurons and amplifies the spino-PAG pathway. Spinal inputs to the PAG could play an integral role in its modulation of heat sensation during peripheral inflammation, warranting further exploration of the organization and function of these neural pathways.

Sex differences in pain catastrophizing and its relation to the transition from acute pain to chronic pain.

BACKGROUND AND IMPORTANCE: Differences exist between sexes in pain and pain-related outcomes, such as development of chronic pain. Previous studies suggested a higher risk for pain chronification in female patients. Furthermore, pain catastrophizing is an important risk factor for chronification of pain. However, it is unclear whether sex differences in catastrophic thinking could explain the sex differences in pain chronification. OBJECTIVES: The aim of this study was to examine sex differences in pain catastrophizing. Additionally, we investigated pain catastrophizing as a potential mediator of sex differences in the transition of acute to chronic pain. DESIGN, SETTINGS AND PARTICIPANTS: Adults visiting one of the 15 participating emergency departments in the Netherlands with acute pain-related complaints. Subjects had to meet inclusion criteria and complete questionnaires about their health and pain. OUTCOMES MEASURE AND ANALYSIS: The outcomes in this prospective cohort study were pain catastrophizing (short form pain catastrophizing) and pain chronification at 90 days (Numeric Rating Scale ≥ 1). Data was analysed using univariate and multivariable logistic regression models. Finally, stratified regression analyses were conducted to assess whether differences in pain catastrophizing accounted for observed differences in pain chronification between sexes. MAIN RESULTS: In total 1,906 patients were included. Females catastrophized pain significantly more than males (p < 0.001). Multiple regression analyses suggested that pain catastrophizing is associated with pain chronification in both sexes. CONCLUSIONS: This study reported differences between sexes in catastrophic cognitions in the development of chronic pain. This is possibly of clinical importance to identify high-risk patients and ensure an early intervention to prevent the transition from acute to chronic pain.

Characterizing opioid use in a Dutch cohort with migraine.

BACKGROUND: There is lack of data on opioid (over)use for migraine in Europe. METHODS: We performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used. RESULTS: In total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003). CONCLUSION: Opioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine.

Changes in gamma-aminobutyric acid and glutamate/glutamine levels in the right thalamus of patients with episodic and chronic migraine: A proton magnetic resonance spectroscopy study.

OBJECTIVE: To explore gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the right thalamus of patients with episodic migraine (EM) and chronic migraine (CM) and their effects on the chronification of migraine. BACKGROUND: Migraine affects approximately 1 billion people worldwide, with 2.5%-3% of people with EM progressing to CM each year. Magnetic resonance spectroscopy studies have revealed altered GABA and Glx levels in the thalamus of patients with migraine without aura, but these neurometabolic concentrations are underexplored in the thalamus of patients with CM. METHODS: In this cross-sectional study, patients with EM and CM were recruited. Mescher-Garwood point resolved spectroscopy sequence was used to acquire neurotransmitter concentrations in the right thalamus of patients with EM and CM and matched healthy controls (HCs). RESULTS: A total of 26 patients (EM, n = 11; CM, n = 15) and 16 age- and sex-matched HCs were included in the analysis. There were significantly lower GABA+/Water levels in the right thalamus of the CM group (mean ± standard deviation: 2.27 ± 0.4 [institutional units]) than that of the HC group (2.74 ± 0.4) (p = 0.026; mean difference [MD] = -0.5 [i.u.]), and lower Glx/Cr levels in the EM group (mean ± SD: 0.11 ± < 0.1) than in the HCs (0.13 ± < 0.1) and CM group (0.13 ± < 0.1) (p = 0.023, MD < -0.1, and p = 0.034, MD < -0.1, respectively). The GABA+/Glx ratio was lower in the CM group (mean ± SD: 0.38 ± 0.1) compared to the EM group (0.47 ± 0.1) (p = 0.024; MD = -0.1). The area under the curve for GABA+/Water levels in differentiating patients with CM from HCs was 0.83 (95% confidence interval 0.68, 0.98; p = 0.004). Correlation analyses within the migraine group revealed no significant correlation between metabolite concentration levels and headache characteristics after Bonferroni correction. CONCLUSION: Reduced GABA+/Water levels and imbalance of excitation/inhibition in the right thalamus may contribute to migraine chronification.

The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies.

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine.

[Effects of preoperative neurobiological education on postoperative outcome : A systematic review]. / Effekte von präoperativer neurobiologischer Edukation auf das postoperative Outcome : Ein systematisches Review.

BACKGROUND: Pain may have a crucial impact on human quality of life. An increase in knowledge about neurobiological and neuroscientific processes alone can positively influence the subjective perception of pain as well as psychometric variables. There are different forms of preoperative patient education with the aim to explain postoperative pain. Based on current literature, preoperative biomedical education has a low level of evidence. It can increase the preoperative anxiety and stress level of patients, which has a negative impact on the postoperative outcome. In contrast, the neuroscientific understanding considers postoperative pain from the viewpoints of the plasticity of the nervous system and involves sensitizational processes in the central and peripheral nervous systems. PURPOSE: To systematically investigate short- and long-term effects of pain neuroscience education (PNE) in patients before spine surgery. MATERIALS AND METHODS: The literature search involved a search of medical databases according to the PI(C)O scheme, and 83 articles were shortlisted. Nine articles that met the inclusion and exclusion criteria were finally included. RESULTS: Preoperative pain neuroscience education can positively influence postoperative catastrophizing tendencies as well as postoperative kinesiophobia but has no influence on postoperative pain and function. CONCLUSION: Preoperative reduction of anxiety and pain-maintaining factors mainly on the psychological and social level may have a positive effect on postoperative subjective pain evaluation, which is reflected in a reduction of anxiety, catastrophizing tendencies, and a lower utilization of postoperative health care services.

Time-Dependent Changes in Protein Composition of Medial Prefrontal Cortex in Rats with Neuropathic Pain.

Chronic pain is associated with time-dependent structural and functional reorganization of the prefrontal cortex that may reflect adaptive pain compensatory and/or maladaptive pain-promoting mechanisms. However, the molecular underpinnings of these changes and whether there are time-dependent relationships to pain progression are not well characterized. In this study, we analyzed protein composition in the medial prefrontal cortex (mPFC) of rats at two timepoints after spinal nerve ligation (SNL) using two-dimensional gel electrophoresis (2D-ELFO) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). SNL, but not sham-operated, rats developed persistent tactile allodynia and thermal hyperalgesia, confirming the presence of experimental neuropathic pain. Two weeks after SNL (early timepoint), we identified 11 proteins involved in signal transduction, protein transport, cell homeostasis, metabolism, and apoptosis, as well as heat-shock proteins and chaperones that were upregulated by more than 1.5-fold compared to the sham-operated rats. Interestingly, there were only four significantly altered proteins identified at 8 weeks after SNL (late timepoint). These findings demonstrate extensive time-dependent modifications of protein expression in the rat mPFC under a chronic neuropathic pain state that might underlie the evolution of chronic pain characterized by early pain-compensatory and later aberrant mechanisms.

Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray with episodic and chronic migraine: a proton magnetic resonance spectroscopy study.

BACKGROUND: The pathogenesis of migraine chronification remains unclear. Functional and structural magnetic resonance imaging studies have shown impaired functional and structural alterations in the brains of patients with chronic migraine. The cerebellum and periaqueductal gray (PAG) play pivotal roles in the neural circuits of pain conduction and analgesia in migraine. However, few neurotransmitter metabolism studies of these migraine-associated regions have been performed. To explore the pathogenesis of migraine chronification, we measured gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the dentate nucleus (DN) and PAG of patients with episodic and chronic migraine and healthy subjects. METHODS: Using the MEGA-PRESS sequence and a 3-Tesla magnetic resonance scanner (Signa Premier; GE Healthcare, Chicago, IL, USA), we obtained DN and PAG metabolite concentrations from patients with episodic migraine (n = 25), those with chronic migraine (n = 24), and age-matched and sex-matched healthy subjects (n = 16). Patients with chronic migraine were further divided into those with (n = 12) and without (n = 12) medication overuse headache. All scans were performed at the Beijing Tiantan Hospital, Capital Medical University. RESULTS: We found that patients with chronic migraine had significantly lower levels of GABA/water (p = 0.011) and GABA/creatine (Cr) (p = 0.026) in the DN and higher levels of Glx/water (p = 0.049) in the PAG than healthy controls. In all patients with migraine, higher GABA levels in the PAG were significantly associated with poorer sleep quality (GABA/water: r = 0.515, p = 0.017, n = 21; GABA/Cr: r = 0.522, p = 0.015, n = 21). Additionally, a lower Glx/Cr ratio in the DN may be associated with more severe migraine disability (r = -0.425, p = 0.055, n = 20), and lower GABA/water (r = -0.424, p = 0.062, n = 20) and Glx/Water (r = -0.452, p = 0.045, n = 20) may be associated with poorer sleep quality. CONCLUSIONS: Neurochemical levels in the DN and PAG may provide evidence of the pathological mechanisms of migraine chronification. Correlations between migraine characteristics and neurochemical levels revealed the pathological mechanisms of the relevant characteristics.

Merging care and prevention: preventive properties of antiretroviral drugs and HIV chronification in the case of Switzerland.

Medication is closely involved in the subjective experience of chronic diseases, but also in the chronification process of illnesses which is described in this paper in the specific case of HIV. The development of antiretroviral drugs (ARVs) and the progressive recognition of their potential dual use as treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP) reshape the experience of HIV and its transmission. Acknowledging the importance of a socioanthropological approach to drugs, this paper highlights how therapeutic strategies of treatment and prevention currently shape the process of HIV chronification and its experience for people concerned with ARVs in Switzerland, whether they are seropositive patients on lifelong treatment or seronegative people affected by the preventive properties of drugs.

[Diagnostics and therapy in children and adolescents with chronic pain : Trends in interventions potentially dangerous to health]. / Diagnostik und Therapie bei Kindern und Jugendlichen mit chronischem Schmerz : Zeitliche Entwicklung potenziell gesundheitsgefährdender Maßnahmen.

BACKGROUND AND OBJECTIVES: Current research on the treatment of chronic pain in children suggests an increasing trend internationally in the quantity as well as invasiveness of diagnostic and therapeutic interventions. The objective of this research was to examine the interventions received by patients before starting specialized inpatient pain treatment. MATERIALS AND METHODS: A retrospective survey was conducted analyzing patient files from a tertiary children's pain center from 2004, 2008, 2012 and 2016 (N = 585). In addition to diagnostic and therapeutic interventions, pain and patients' characteristics were collected. The identified measures were subsequently evaluated by an interdisciplinary expert panel regarding their invasiveness, potential risk and degree of mental burden. RESULTS: An increase in diagnostic measures and medication was found up to 2012. Thereafter, a decreasing trend was identified (χ2(3) = 11.708; p = 0.008). Invasiveness (χ2(3) = 13.342; p = 0.004), risk (χ2(3) = 13.135; p = 0.004) and mental burden (χ2(3) = 14.403; p = 0.002) showed the same pattern of change. Patients with abdominal and limb pain are particularly at risk for highly invasive and high risk diagnostics. CONCLUSIONS: Evidence for an increase in diagnostic and therapeutic measures in chronic pain was found up to 2012. Patients presenting with certain complaints receive comparably more invasive, risky and burdensome measures.

[Prediction and prevention of chronic postoperative pain]. / Prädiktion und Prävention chronischer postoperativer Schmerzen.

Chronic postoperative pain has been identified as a major medical and socioeconomic problem. A prevention of the chronification processes is potentially possible and preventive treatment could start early (e.g. preoperatively). So far, however, evidence for the effectiveness of preventive strategies is basically low. Important reasons for this dilemma are the lack of appropriate risk assessment as well as effective and mechanism-based preventive (procedure-sepcific) strategies for the chronification process, a lack of stratification of treatment approaches and a so far barely investigated combination of various treatment approaches. In this review article recent findings on the appropriate identification of patients at risk for developing postoperative chronic pain are presented, predictive models for the valid estimation of the individual risk of patients are assessed and studies on pharmaceutical and regional analgesia techniques influencing the pain chronification process are discussed. As a chronification process is, however, extremely complex and dynamic and also necessitates adaptation of the prevention during the course of the process, only combinations of treatment, interdisciplinary and if necessary even longer term approaches might be successful. Future studies are needed to address with which preventive treatment strategies and in which patients chronic pain after surgery can effectively be prevented.

[Targeted treatment of posttraumatic disorders-what can confrontation therapy achieve?] / Zielgerichtete Behandlung von Traumafolgestörungen ­ was kann eine konfrontative Therapie leisten?

Confrontation with aversive trauma symptoms is a key element in the treatment of stress-associated disorders, especially posttraumatic stress disorder. It is aimed at working through and reattributing aversive memories and situations. Various techniques enable confrontation in sensu (i.e. imagined) and in vivo (in reality). Confrontation techniques are highly effective; however, since there is a risk of temporarily enhanced, possibly previously suppressed traumatic memories, confrontation must be carefully prepared and revised.

A Continuous Model of Three Scenarios of the Infection Process with Delayed Immune Response Factors.

The course of an infection was modeled as a controlled nonlinear process. Understanding the substantial differences observed in the trajectory of the disease caused by the new coronavirus SARS-CoV-2 is of critical importance at the moment. Numerous factors have been considered to explain the fact that symptoms vary highly among different people and the infection transmission rate varies among local populations. Virus replication within the host cell and the development of an immune response to virus antigens in the body are two interdependent processes, which have aftereffects and depend on the preexisting states of the cell and virus populations. Different scenarios with the same input parameters are necessary to consider for modeling the properties of the states. The efficiency of the immune response is the most important factor, including the time it takes to develop defense responses from three levels of the immune system, which is a complex system of the body. A computational description of infection scenarios was proposed on the basis of a delay differential equation with two values of the time lag. In the new model, transitions between phases of infectious disease depend on the initial virus dose and the delayed immune response to infection. A variation in the dose of the virus and response time can lead to a transition from an acute phase of the disease with overt symptoms to a chronic phase or fatal outcome. Asymptomatic transmission of viral infection was calculated and described in the model as a situation where the virus is rapidly and efficiently suppressed after a short replication phase, while still persisting in the body in minor amounts. An analysis of the model behavior is consistent with the theory that the initial number of virions can affect the quality of the immune response. The reasons that high individual differences are observed in the trajectory of COVID-19 disease and the formation of types of the immune response to coronavirus are still poorly understood. Known trajectories of hepatitis C virus (HCV) infection were used as a basis for model scenarios.

Compare and contrast: pediatric cancer versus adult malignancies.

Cancer is a leading cause of death in both adults and children, but in terms of absolute numbers, pediatric cancer is a relatively rare disease. The rarity of pediatric cancer is consistent with our current understanding of how adult malignancies form, emphasizing the view of cancer as a genetic disease caused by the accumulation and selection of unrepaired mutations over time. However, considering those children who develop cancer merely as stochastically "unlucky" does not fully explain the underlying aetiology, which is distinct from that observed in adults. Here, we discuss the differences in cancer genetics, distribution, and microenvironment between adult and pediatric cancers and argue that pediatric tumours need to be seen as a distinct subset with their own distinct therapeutic challenges. While in adults, the benefit of any treatment should outweigh mostly short-term complications, potential long-term effects have a much stronger impact in children. In addition, clinical trials must cope with low participant numbers when evaluating novel treatment strategies, which need to address the specific requirements of children.

The clinical and public health implications and risks of widening the definition of chronic migraine.

BACKGROUND: The definition of chronic migraine has long been debated. Recently, it was suggested to define subjects with at least 8/migraine days as chronic migraine; that is, incorporating so-called high frequency episodic migraine (eight or more migraine days but less than 15 headache days per month). METHODS: We addressed the possible problems that might arise based on this proposal accounting for clinical, pathophysiological, impact and public health aspects. RESULTS AND CONCLUSIONS: Defining chronic migraine on the basis of headache frequency alone does not account for clinical and pathophysiological aspects, as well as for the impact of chronic migraine in terms of disability and quality of life. Moreover, it is potentially harmful for patients in terms of allocation of resources. These issues are discussed in the present manuscript, and we support the idea of defining high frequency episodic migraine as an independent entity as a viable path to follow.

Cognitive Networks Disarrangement in Patients With Migraine Predicts Cutaneous Allodynia.

BACKGROUND: Two-thirds of patients with migraine without aura (MwoA) complain ictal cutaneous allodynia (CA), clinical sign of central nociceptive pathway sensitization, and independent predictor for migraine chronification. AIM: We aimed to investigate whether functional abnormalities, structural, or microstructural changes of the main cognitive networks (default mode network [DMN], salience network [SN], and central executive network [CEN]) could predict the development of CA in patients with MwoA. METHODS: Baseline 3-Tesla MRI images of 50 patients with MwoA were analyzed between 2009 and 2015. Over a three-year period, patients were then stratified into 2 groups based on CA development and compared with matched healthy controls (HC). Group-level independent components analysis was used to investigate intrinsic functional connectivity (FC) differences within the cognitive resting-state networks. Voxel-based morphometry (VBM) was used to assess whether group differences in cognitive network FC were related to structural differences. Tract-based spatial statistical analyses (TBSS) were conducted to assess the microstructural properties of white matter tracts. We also compared internetwork connectivity between patients. Finally, a logistic regression analysis was used to investigate baseline imaging predictors of CA development. RESULTS AND DISCUSSION: We observed a significantly reduced FC of both DMN and CEN in patients with MwoA developing CA (MwoA d CA) when compared with both patients with MwoA not developing CA (MwoA nd CA) and HC. Within the DMN, the PCC/precuneus is a key hub aimed to anti-nociception and multisensory integration. The reduced intrinsic PCC/precuneus FC observed in patients with MwoA d CA could subtend abnormal inputs integration, from different sensory modalities, allowing the development of CA. On the other hand, within the CEN, a central role in pain modulation as well as in executive functions is played by ACC and MFG. Our finding of reduced ACC and MFG FC in MwoA d CA may represent the neuronal substrate of both subclinical impairment of complex executive functions and dysfunctional anti-nociceptive pathway, making these patients more prone to migraine chronification. TBSS analyses showed a statistically significant reduced corpus callosum (CC) FA in patients with MwoA d CA as previously demonstrated in migraine patients with other chronification factors such as medication overuse or affective disorders. No VBM differences in both global and local volumes were revealed between groups. No significant correlations have been found between the observed functional and microstructural changes and clinical parameters of disease severity. Logistic regression analysis indicated that the full model containing all predictors was statistically significant while the decreased ACC-FC was significantly associated with CA development. CONCLUSION: We suggest that DMN and CEN FC abnormalities as well as CC microstructural changes could represent a prognostic imaging biomarker able to identify migraine patients more prone to experiencing CA and therefore, more inclined to chronic migraine. In the new pharmacological scenario, it would be useful to address therapeutic resources to specific migraine populations with a high risk of more severe clinical phenotype.

[Chronic pain syndromes and other persistent functional somatic symptoms]. / Chronische Schmerzsyndrome und andere persistierende funktionelle Körperbeschwerden.

Somatic symptoms including pain are everyday human experiences. They usually result from a complex interaction of stimuli, interpretation and reaction, and are not necessarily proportional to structural damage. Persistent functional somatic symptoms can be associated with a significant impairment of quality of life and functioning, even without mental or somatic comorbidity. Dysfunctional experiences, expectancies and behavior, not only by patients but also by physicians, can increase the risk of chronification. From the outset, management should be graded with respect to the severity and biopsychosocial aspects, with thorough but cautious diagnostics and with psychoeducative, active and coping-oriented treatment.

Excess abdominal fat is associated with cutaneous allodynia in individuals with migraine: a prospective cohort study.

OBJECTIVE: To investigate the specific relationship between cutaneous allodynia (CA) and the percentages of body fat (BF) and abdominal fat in migraineurs. Additionally, we compared serum levels of inflammatory biomarkers in patients with and without CA. BACKGROUND: Excess abdominal fat might facilitate progressive changes in nociceptive thresholds causing central sensitization, clinically reflected as CA, which could drive migraine progression. METHODS: This prospective cohort study included 80 patients with migraine (mean age 39 years, 81.2% female) and 39 non-migraine controls. We analysed each participant's height, body weight, and body mass index (BMI). The amount and distribution of BF was also assessed by air displacement plethysmography (ADP) and ViScan, respectively. We analysed serum levels of markers of inflammation, during interictal periods. RESULTS: We studied 52 patients with episodic migraine (EM) and 28 with chronic migraine (CM). Of the 80 patients, 53 (53.8%) had CA. Migraineurs with CA had a higher proportion of abdominal fat values than patients without CA (p = 0.04). The independent risk factors for CA were the use of migraine prophylaxis (OR 3.26, 95% CI [1.14 to 9.32]; p = 0.03), proportion of abdominal fat (OR 1.13, 95% CI [1.01 to 1.27]; p = 0.04), and presence of sleep disorders (OR 1.13, 95% CI [00.01 to 1.27]; p = 0.04). The concordance correlation coefficient between the ADP and BMI measurements was 0.51 (0.3681 to 0.6247). CA was not correlated with the mean plasma levels of inflammatory biomarkers. CONCLUSIONS: There is a relation between excess abdominal fat and CA. Abdominal obesity might contribute to the development of central sensitization in migraineurs, leading to migraine chronification.

Migraine Progression: A Systematic Review.

BACKGROUND: Migraine is a common and often debilitating neurological disease. It can be divided into episodic and chronic subforms based on the number of monthly headache days. Because only a subset of individuals with episodic migraine (EM) progress to chronic migraine (CM) over any given time period, understanding the factors that predict the new onset of CM or "migraine progression" may provide insights into the mechanisms, pathophysiology, prevention, and treatment of CM. In this review, we identify and summarize studies that report risk factors associated with the new onset of CM or related chronic headache diagnoses, group these risk factors and report the strength of evidence for the identified risk factors. OBJECTIVE: To conduct a systematic review of studies that identify risk factors for the new onset of CM or related chronic headache diagnoses such as transformed migraine (TM) and chronic daily headache (CDH). METHODS: Herein we summarize the findings of studies of risk factors associated with the new onset of CM/TM, CDH, or related diagnoses from the English language literature published before March 2018. The PubMed database was searched for relevant studies. Longitudinal studies with follow-up data and case-control studies were included in this qualitative synthesis. We report methodology, analytic criteria, and results for each manuscript and for the parent study. Next, we review the strength of evidence for each of the identified risk factors using a modified version of AB Hill's criteria for causation and rank evidence as fair, moderate, or strong. We categorized risk factors as nonmodifiable, modifiable and based on putative mechanisms. We further categorized risk factors into sociodemographics, lifestyle factors and habits, headache features, comorbid and concomitant diseases and conditions and pharmacologic treatment-related. Finally, we review theories of the pathophysiology underlying the development of new onset chronic migraine or increasing attack frequency. RESULTS: The PubMed search yielded 1870 records after duplicates were removed. Nine additional records were identified through expert consultation and other methods (eg, citations found as references in manuscripts identified in the literature review and through communication with the authors of manuscripts included in the review). The 1879 manuscripts were screened against the inclusion and exclusion criteria and 109 were found to be potentially eligible. Of 109 full-text articles, 17 studies were identified as meeting the prespecified criteria based on the consensus of all authors. Of the 17 full texts, 13 were longitudinal cohort studies and 4 were case-controlled studies. We found strength of evidence ranging from fair to strong for the identified risk factors. The strongest data were found for increased headache day frequency, depression, and medication overuse/high-frequency use. Risk factors for new onset CM and CDH in children and adolescents were similar to those identified in adults. CONCLUSIONS: A range of risk factors for the new onset of CM/TM, CDH, or related chronic headache diseases were identified with the strongest data supporting increased headache day frequency, acute medication overuse/high-frequency use and depression, which are potentially modifiable risk factors. Modifiable risk factors may provide targets for intervention. The lack of strong evidence or any evidence does not imply that there is not a relationship between a particular risk factor and new onset CM or related disease; but may indicate little or no research or that research did not have sufficient methodological rigor. In addition, it is likely that additional risk factors exist which have not yet been identified. Putative factors include pro-inflammatory states and pro-thrombotic states. Development of central sensitization and increased activation of the trigeminal nociceptive pathways may be drivers of the new onset of CM or CDH. Future research may include the systematic testing of interventions targeting modifiable risk factors to determine if progression can be prevented as well as continued exploration of the benefits of treating these risk factors among people with CM in an effort to increase rates of remission. Future work should also consider the natural fluctuations in headache day frequency and examine progression in terms of continuous definitions rather than or in addition to a dichotomous boundary.

Pain Pathways and Nervous System Plasticity: Learning and Memory in Pain.

Objective This article reviews the structural and functional changes in pain chronification and explores the association between memory and the development of chronic pain. Methods PubMed was searched using the terms "chronic pain," "central sensitization," "learning," "memory," "long-term potentiation," "long-term depression," and "pain memory." Relevant findings were synthesized into a narrative of the processes affecting pain chronification. Results Pain pathways represent a complex sensory system with cognitive, emotional, and behavioral influences. Anatomically, the hippocampus, amygdala, and anterior cortex-central to the encoding and consolidation of memory-are also implicated in experiential aspects of pain. Common neurotransmitters and similar mechanisms of neural plasticity (eg, central sensitization, long-term potentiation) suggest a mechanistic overlap between chronic pain and memory. These anatomic and mechanistic correlates indicate that chronic pain and memory intimately interact on several levels. Longitudinal imaging studies suggest that spatiotemporal reorganization of brain activity accompanies the transition to chronic pain, during which the representation of pain gradually shifts from sensory to emotional and limbic structures. Conclusions The chronification of pain can be conceptualized as activity-induced plasticity of the limbic-cortical circuitry resulting in reorganization of the neocortex. The state of the limbic-cortical network determines whether nociceptive signals are transient or chronic by extinguishing pathways or amplifying signals that intensify the emotional component of nociceptive inputs. Thus, chronic pain can be seen as the persistence of the memory of pain and/or the inability to extinguish painful memories. Ideally, pharmacologic, physical, and/or psychological approaches should reverse the reorganization accompanying chronic pain.