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OBJECTIVES: Previous studies have established the role of the cortico-mesolimbic and descending pain modulation systems in chronic pain prediction. Mild traumatic brain injury (mTBI) is an acute pain model where chronic pain is prevalent and complicated for prediction. In this study, we set out to study whether functional connectivity (FC) of the nucleus accumbens (NAc) and the periaqueductal gray matter (PAG) is predictive of pain chronification in early-acute mTBI. METHODS: To estimate FC, resting-state functional magnetic resonance imaging (fMRI) of 105 participants with mTBI following a motor vehicle collision was acquired within 72 hours post-accident. Participants were classified according to pain ratings provided at 12-months post-collision into chronic pain (head/neck pain ≥30/100, n = 44) and recovery (n = 61) groups, and their FC maps were compared. RESULTS: The chronic pain group exhibited reduced negative FC between NAc and a region within the primary motor cortex corresponding with the expected representation of the area of injury. A complementary pattern was also demonstrated between PAG and the primary somatosensory cortex. PAG and NAc also shared increased FC to the rostral anterior cingulate cortex (rACC) within the recovery group. Brain connectivity further shows high classification accuracy (area under the curve [AUC] = .86) for future chronic pain, when combined with an acute pain intensity report. INTERPRETATION: FC features obtained shortly after mTBI predict its transition to long-term chronic pain, and may reflect an underlying interaction of injury-related primary sensorimotor cortical areas with the mesolimbic and pain modulation systems. Our findings indicate a potential predictive biomarker and highlight targets for future early preventive interventions. ANN NEUROL 2022;92:819-833.
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Concussão Encefálica , Dor Crônica , Humanos , Concussão Encefálica/complicações , Concussão Encefálica/diagnóstico por imagem , Dor Crônica/diagnóstico por imagem , Dor Crônica/etiologia , Encéfalo/diagnóstico por imagem , Substância Cinzenta Periaquedutal , Mapeamento Encefálico/métodosRESUMO
BACKGROUND AND PURPOSE: Advanced analysis of electroencephalography (EEG) data has become an essential tool in brain research. Based solely on resting state EEG signals, a data-driven, predictive and explanatory approach is presented to discriminate painful from non-painful diabetic polyneuropathy (DPN) patients. METHODS: Three minutes long, 64 electrode resting-state recordings were obtained from 180 DPN patients. The analysis consisted of a mixture of traditional, explanatory and machine learning analyses. First, the 10 functional bivariate connections best differentiating between painful and non-painful patients in each EEG band were identified and the relevant receiver operating characteristic was calculated. Later, those connections were correlated with selected clinical parameters. RESULTS: Predictive analysis indicated that theta and beta bands contain most of the information required for discrimination between painful and non-painful polyneuropathy patients, with area under the receiver operating characteristic curve values of 0.93 for theta and 0.89 for beta bands. Assessing statistical differences between the average magnitude of functional connectivity values and clinical pain parameters revealed that painful DPN patients had significantly higher cortical functional connectivity than non-painful ones (p = 0.008 for theta and p = 0.001 for alpha bands). Moreover, intra-band analysis of individual significant functional connections revealed a positive correlation with average reported pain in the previous 3 months in all frequency bands. CONCLUSIONS: Resting state EEG functional connectivity can serve as a highly accurate biomarker for the presence or absence of pain in DPN patients. This highlights the importance of the brain, in addition to the peripheral lesions, in generating the clinical pain picture. This tool can probably be extended to other pain syndromes.
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Polineuropatias , Humanos , Biomarcadores , Encéfalo , Eletroencefalografia , Dor , Polineuropatias/diagnósticoRESUMO
BACKGROUND: To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors. METHODS: The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy. RESULTS: Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN. CONCLUSIONS: Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model's performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions.
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Diabetes Mellitus , Neuropatias Diabéticas , Humanos , Teorema de Bayes , Estudos Transversais , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/epidemiologia , Hemoglobinas Glicadas , Aprendizado de Máquina , Dor , Qualidade de VidaRESUMO
BACKGROUND: Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome. METHODS: ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059. FINDINGS: Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population. INTERPRETATION: Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome. FUNDING: BrainsGate Ltd.
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Isquemia Encefálica/terapia , Terapia por Estimulação Elétrica/métodos , Gânglios Parassimpáticos/fisiopatologia , Neuroestimuladores Implantáveis , Acidente Vascular Cerebral/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/fisiopatologia , Método Duplo-Cego , Terapia por Estimulação Elétrica/efeitos adversos , Feminino , Gânglios Parassimpáticos/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Acidente Vascular Cerebral/fisiopatologia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
INTRODUCTION: Small fiber polyneuropathy (SFPN) is associated with a variety of clinical conditions. Common to these conditions is the deviation from healthy physiological homeostatic balance, which hinders small fiber neurons viability, resulting in their damage. The most common cause for SFPN in the western world is diabetes, followed by a long list of other risk-factors, some are age-related. Accumulating evidence suggests that in young patients a leading cause (up-to 50% of cases) is autoimmune-related. A variety of symptoms can be seen in SFPN. Commonly, first to appear are sensory symptoms in the extremities. Autonomic symptoms can then join, or even be the presenting symptoms. This sensory-autonomic combination can have a dramatic mal-effect on the patient's quality of life. Diagnosis is based primarily on skin biopsy and/or Autonomic-Functional-Testing. Often, in cases where no etiology is identified, EMG is normal and the skin biopsy/autonomic testing is not performed, clinicians tend to incorrectly diagnose a non-organic situation. Correct and preferably early diagnosis is of essence since peripheral fibers can recover if the disease pathophysiological factor is removed, leading to less suffering and improved quality of life of patients.
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Polineuropatias/diagnóstico , Biópsia , Humanos , Polineuropatias/terapia , Qualidade de Vida , PeleRESUMO
OBJECTIVE: To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. BACKGROUND: There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. METHODS: This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints. RESULTS: Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). CONCLUSIONS: REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.
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Transtornos de Enxaqueca/terapia , Manejo da Dor/métodos , Estimulação Elétrica Nervosa Transcutânea/instrumentação , Estimulação Elétrica Nervosa Transcutânea/métodos , Tecnologia sem Fio/instrumentação , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVES: Assessment of pain inhibitory mechanisms using conditioned pain modulation (CPM) is relevant clinically in prediction of pain and analgesic efficacy. Our objective is to provide necessary estimates of intersession CPM reliability, to enable transformation of the CPM paradigm into a clinical tool. DESIGN: Two cohorts of young healthy subjects (N = 65) participated in two dual-session studies. In Study I, a Bath-Thermode CPM protocol was used, with hot water immersion and contact heat as conditioning- and test-stimuli, respectively, in a classical parallel CPM design introducing test-stimulus first, and then the conditioning- and repeated test-stimuli in parallel. Study II consisted of two CPM protocols: 1) Two-Thermodes, one for each of the stimuli, in the same parallel design as above, and 2) single test-stimulus (STS) protocol with a single administration of a contact heat test-stimulus, partially overlapped in time by a remote shorter contact heat as conditioning stimulus. Test-retest reliability was assessed within 3-7 days. RESULTS: The STS-CPM had superior reliability intraclass correlation (ICC2 ,: 1 = 0.59) over Bath-Thermode (ICC2 ,: 1 = 0.34) or Two-Thermodes (ICC2 ,: 1 = 0.21) protocols. The hand immersion conditioning pain had higher reliability than thermode pain (ICC2 ,: 1 = 0.76 vs ICC2 ,: 1 = 0.16). Conditioned test-stimulus pain scores were of good (ICC2 ,: 1 = 0.62) or fair (ICC2 ,: 1 = 0.43) reliability for the Bath-Thermode and the STS, respectively, but not for the Two-Thermodes protocol (ICC2 ,: 1 = 0.20). CONCLUSIONS: The newly developed STS-CPM paradigm was more reliable than other CPM protocols tested here, and should be further investigated for its clinical relevance. It appears that large contact size of the conditioning-stimulus and use of single rather than dual test-stimulus pain contribute to augmentation of CPM reliability.
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Condicionamento Psicológico , Manejo da Dor/normas , Medição da Dor/normas , Dor/psicologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Dor/diagnóstico , Manejo da Dor/métodos , Medição da Dor/métodos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
OBJECTIVE: The α2-agonist clonidine is an analgesic agent, whose yet uncertain action may involve either increase in pain modulation efficiency, change in autonomic function, and/or decrease in anxiety level. The present study aimed to examine the effect of oral clonidine on pain perception in healthy subjects in order to reveal its mode of action. DESIGN: Randomized, double-blind, placebo-controlled study. SUBJECTS: Forty healthy subjects. METHODS: Subjects received either 0.15 mg oral clonidine or placebo. We measured pain parameters of heat pain thresholds, tonic heat stimulus, mechanical temporal summation, offset analgesia (OA) and conditioned pain modulation (CPM); autonomic parameters of deep breathing ratio and heart rate variability indices obtained before, during, and after tonic heat stimulus; and psychological parameters of anxiety and pain catastrophizing. RESULTS: Clonidine decreased systolic blood pressure (P = 0.022) and heart rate (P = 0.004) and increased rMSSD (P = 0.020), though no effect was observed on pain perception, pain modulation, and psychological parameters. Autonomic changes were correlated with pain modulation capacity; for OA, the separate slope model was significant (P = 0.008); in the clonidine group, more efficient OA was associated with lower heart rate (r = 0.633, P = 0.005), unlike in the placebo group. CONCLUSIONS: The change in autonomic function that was related to the increase in pain modulation capacity, and the lack of change in anxiety, suggest a combined modulatory-autonomic mode of analgesic action for clonidine.
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BACKGROUND: Previous studies have identified relationships between autonomic function and pain perception. Anxiety was found to influence both autonomic and pain responses. We examined the effect of anxiety level on parasympathetic function and pain perception as well as on the relationships between these 2 systems. METHODS: Thirty healthy females were divided into high- and low-anxiety groups according to their trait anxiety levels. Parasympathetic function was obtained using heart rate variability, deep breathing, and Valsalva ratios. Pain perception parameters of heat pain thresholds, pain rating of supra-thresholds stimulus, mechanical temporal summation, and conditioned pain modulation response were examined. RESULTS: The low-anxiety and high-anxiety groups exhibited no significant differences in the parasympathetic function and pain perception parameters. Assessment of the associations revealed that in the high-anxiety group, higher mean ratings of the tonic heat pain stimulus were significantly correlated with higher rMSSD (r2 = 0.358, P = 0.019), but this was not found for the low-anxiety group (P = 0.282). In addition, in the high-anxiety group, efficient conditioned pain modulation response was correlated with higher deep breathing ratio (r2 = 0.363, P = 0.023); however, in the low-anxiety group, the correlation did not reach significance (P = 0.109). CONCLUSIONS: This study demonstrates the role of anxiety level on the relationships between parasympathetic function and pain perception. We suggest that a situation of high anxiety leads to higher norepinephrine levels that can influence both parasympathetic function and pain perception, thus explaining the significant relationships found between these 2 systems only in subjects with high anxiety.
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BACKGROUND: Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored. METHODS: Healthy middle-age subjects (n = 28) completed the TPQ, Spielberger's State Anxiety Inventory, and the Pain Catastrophizing Scale and were assessed for CPM paradigms using thermal phasic temporal summation as the "test stimulus" and hand immersion into hot water bath (CPM water) or contact heat (CPM contact) for "conditioning stimulus." RESULTS: Higher levels of HA were associated with less-efficient CPM responses obtained by both paradigms: CPM water (r = 0.418, P = 0.027) and CPM contact (r = 0.374, P = 0.050). However, NS and RD were not associated with the other measurements. No significant relationship was observed between state anxiety and pain catastrophizing levels and the CPM responses. CONCLUSIONS: The relationship between the capacity of endogenous analgesia and the tendency to avoid aversive experience can be explained by mutual mechanisms involving similar neurotransmitters or brain areas. These findings illuminate the key role of harm avoidance obtained by the TPQ in determining the characteristics of pain modulation profile.
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Analgesia/psicologia , Dor/psicologia , Personalidade , Ansiedade/psicologia , Catastrofização/psicologia , Condicionamento Psicológico , Feminino , Voluntários Saudáveis , Temperatura Alta , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Medição da Dor , Testes de Personalidade , Caracteres SexuaisRESUMO
ABSTRACT: It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.
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The endogenous analgesia (EA) system is psychophysically evaluated using various paradigms, including conditioned pain modulation (CPM) and offset analgesia (OA) testing, respectively, the spatial and temporal filtering processes of noxious information. Though both paradigms assess the function of the EA system, it is still unknown whether they reflect the same aspects of EA and consequently whether they provide additive or equivalent data. Twenty-nine healthy volunteers (15 males) underwent 5 trials of different stimulation conditions in random order including: (1) the classic OA three-temperature stimulus train ('OA'); (2) a three-temperature stimulus train as control for the OA ('OAcon'); (3) a constant temperature stimulus ('constant'); (4) the classic parallel CPM ('CPM'); and (5) a combination of OA and CPM ('OA + CPM'). We found that in males, the pain reduction during the OA + CPM condition was greater than during the OA (P = 0.003) and CPM (P = 0.07) conditions. Furthermore, a correlation was found between OA and CPM (r = 0.62, P = 0.01) at the time of maximum OA effect. The additive effect found suggests that the two paradigms represent at least partially different aspects of EA. The moderate association between the CPM and OA magnitudes indicates, on the other hand, some commonality of their underlying mechanisms.
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Analgesia/psicologia , Condicionamento Psicológico/fisiologia , Medição da Dor/psicologia , Dor/psicologia , Percepção Espacial/fisiologia , Percepção do Tempo/fisiologia , Adulto , Feminino , Temperatura Alta/efeitos adversos , Humanos , Masculino , Medição da Dor/métodos , Psicofísica , Adulto JovemRESUMO
BACKGROUND: Dysexcitability characterizes the interictal migraineous brain. The main central expressions of this dysexcitability are decreased habituation and enhanced anticipation and attention to pain and other external sensory stimuli. OBJECTIVE: This study evaluates the effects of anticipation on pain modulation and their neural correlates in migraine. METHODS: In 39 migraineurs (20 migraine with aura [MWA] and 19 migraine without aura [MOA]) and 22 healthy controls, cortical responses to 2 successive trains of noxious contact-heat stimuli, presented in either predicted or unpredicted manner, were analyzed using standardized low-resolution electromagnetic tomography key. RESULTS: A lack of habituation to repeated predicted pain was associated with significantly increased pain-evoked potential amplitudes in MWAs (increase of 3.9 µV) and unchanged ones in MOAs (1.1 µV) but not in controls (decrease of 5 µV). Repeated unpredicted pain resulted in enhanced pain-evoked potential amplitudes in both MWA and MOA groups (increase of 5.5 µV and 4.4 µV, respectively) compared with controls (decrease of 0.2 µV). Source localization revealed reduced activations in the anterior-medial prefrontal cortices and subsequent increased somatosensory activity in migraineurs (P < .05). The prefrontal-somatosensory dysfunction positively correlated with lifetime headache duration (P < .05) and concern of upcoming migraine attacks (P < .05) in MWAs, and with frequency of migraine attacks in MOAs (P < .05). CONCLUSIONS: Our findings of impaired modulation of anticipated pain in migraine suggest a heightened state of anticipatory readiness combined with ineffective recruitment of prefrontal inhibitory pathways during experience of pain; the latter might account for the former, at least partially. In line, less efficient inhibitory capability is a plausible mechanistic explanation for patients' high concern about their upcoming migraine attacks.
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Antecipação Psicológica/fisiologia , Eletroencefalografia/métodos , Habituação Psicofisiológica/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Dor/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/psicologia , Dor/diagnóstico , Dor/psicologia , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine. BACKGROUND: One of the most explored mechanisms underlying the pain modulation system is "diffuse noxious inhibitory controls," which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation. METHODS: Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) "test-stimulus" (Ts) alone that was given first followed by (2) parallel CPM application (CPM-parallel), and (3) sequential CPM application (CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition "0" consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application. RESULTS: Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs (P = .005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P = .028). CONCLUSIONS: Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine.
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Condicionamento Psicológico/fisiologia , Transtornos de Enxaqueca/diagnóstico , Medição da Dor/métodos , Limiar da Dor/fisiologia , Dor/diagnóstico , Adulto , Feminino , Temperatura Alta , Humanos , Pessoa de Meia-Idade , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/psicologia , Dor/fisiopatologia , Dor/psicologia , Adulto JovemRESUMO
Traumatic brain injuries following motor vehicle collisions (MVCs) are ubiquitous. Surprisingly, there are no correlates between concussion impact force and long-term pain outcomes. To study the molecular underpinnings of chronic pain after MVC, we assembled a prospective cohort of 36 subjects that experienced MVC and suffered documented mild traumatic brain injuries. For each participant, a first blood sample was drawn within 72 hours of the collision, then a second one at the 6-month mark. Pain was also assessed at the second blood draw to determine if pain became chronic or resolved. Blood samples enabled transcriptomics analyses for immune cells. At the transcriptome-wide level, we found that Sterile Alpha Motif Domain Containing 15 (SAMD15) mRNA was significantly upregulated with time in subjects who resolved their pain whereas unregulated in those with persistent pain. Using several large publicly available datasets, such as the UK Biobank and the GTeX portal, we then linked elevated SAMD15 gene expression, elevated neutrophils cell counts, and decreased risk for chronic pain to increased dosage of the T allele at SNP rs4903580, situated within SAMD15's gene locus. The causality between the components of our model was established and supported by Mendelian randomization. Overall, our results support the role of SAMD15 as a potential gene effector for neutrophil-dependent chronic pain development. PERSPECTIVE: This article highlights the potential protective role of the SAMD15 gene against chronic pain following a mild traumatic brain injury. The expression of the gene is associated with a SNP rs4903580, which is itself associated with neutrophils counts as well as chronic pain in large genetic studies.
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Concussão Encefálica , Dor Crônica , Humanos , Dor Crônica/genética , Estudos Prospectivos , Transcriptoma , Motivo Estéril alfa , Veículos AutomotoresRESUMO
ABSTRACT: The International Association for the Study of Pain (IASP) has a 50-year history of publishing educational and research materials, ranging from traditional print format books, journals, and other informational formats to online and electronic formats. Here we provide a historical overview of IASP publications and reflections from the perspective of 5 former or current Editors-in-Chief.
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Editoração , EscolaridadeRESUMO
ABSTRACT: Mild traumatic brain injury (mTBI), is a leading cause of disability worldwide, with acute pain manifesting as one of its most debilitating symptoms. Understanding acute postinjury pain is important because it is a strong predictor of long-term outcomes. In this study, we imaged the brains of 157 patients with mTBI, following a motorized vehicle collision. We extracted white matter structural connectivity networks and used a machine learning approach to predict acute pain. Stronger white matter tracts within the sensorimotor, thalamiccortical, and default-mode systems predicted 20% of the variance in pain severity within 72 hours of the injury. This result generalized in 2 independent groups: 39 mTBI patients and 13 mTBI patients without whiplash symptoms. White matter measures collected at 6 months after the collision still predicted mTBI pain at that timepoint (n = 36). These white matter connections were associated with 2 nociceptive psychophysical outcomes tested at a remote body site-namely, conditioned pain modulation and magnitude of suprathreshold pain-and with pain sensitivity questionnaire scores. Our findings demonstrate a stable white matter network, the properties of which determine an important amount of pain experienced after acute injury, pinpointing a circuitry engaged in the transformation and amplification of nociceptive inputs to pain perception.
Assuntos
Dor Aguda , Concussão Encefálica , Substância Branca , Humanos , Dor Aguda/diagnóstico por imagem , Dor Aguda/etiologia , Encéfalo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Percepção da DorRESUMO
BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid. OBJECTIVES: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel. METHODS: We evaluated eight patients clinically and genetically during the years 2006 to 2011. RESULTS: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotoraxonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation. CONCLUSIONS: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.
Assuntos
Neuropatias Amiloides Familiares/genética , DNA/genética , Mutação , Pré-Albumina/genética , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Análise Mutacional de DNA , Feminino , Seguimentos , Predisposição Genética para Doença , Testes Genéticos , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Pré-Albumina/metabolismo , Prevalência , Estudos RetrospectivosRESUMO
Pain variability can be partially attributed to psycho-cognitive features involved in its processing. However, accumulating research suggests that simple linear correlation between situational and dispositional factors may not be sufficiently explanatory, with some positing a role for mediating influences. In addition, acute pain processing studies generally focus on a post-operative model with less attention provided to post-traumatic injury. As such, this study aimed to investigate a more comprehensive pain processing model that included direct and indirect associations between acute pain intensity in the head and neck, pain catastrophizing (using pain catastrophizing scale (PCS)), and pain sensitivity (using the pain sensitivity questionnaire (PSQ)), among 239 patients with post-motor vehicle collision pain. The effect of personality traits (using Ten Items Personality Inventory (TIPI)) and emotional status (using Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS)) on that model was examined as well. To this end, three Structural Equation Modeling (SEM) analyses were conducted. Overall, the data had good fit to all the models, with only PSQ found to have a direct correlation with acute pain intensity. The SEM analyses conversely revealed several mediations. Specifically, that: first, PSQ fully mediated the relationship between PCS and pain intensity; second, PCS and PSQ together fully mediated the relationship between conscientiousness (personality trait) and pain intensity; and finally, emotional status had direct and indirect links with PSQ and pain intensity. In conclusion, these models suggest that during the acute post-collision phase, pain sensitivity intermediates between emotional states and personality traits, partially via elevated pain catastrophizing thoughts.