Pathophysiology and mechanisms of hearing impairment related to neonatal infection diseases.

The inner ear, the organ of equilibrium and hearing, has an extraordinarily complex and intricate arrangement. It contains highly specialized structures meticulously tailored to permit auditory processing. However, hearing also relies on both peripheral and central pathways responsible for the neuronal transmission of auditory information from the cochlea to the corresponding cortical regions. Understanding the anatomy and physiology of all components forming the auditory system is key to better comprehending the pathophysiology of each disease that causes hearing impairment. In this narrative review, the authors focus on the pathophysiology as well as on cellular and molecular mechanisms that lead to hearing loss in different neonatal infectious diseases. To accomplish this objective, the morphology and function of the main structures responsible for auditory processing and the immune response leading to hearing loss were explored. Altogether, this information permits the proper understanding of each infectious disease discussed.

Comparison between two viscosupplementation protocols for temporomandibular joint osteoarthritis.

OBJECTIVE: This clinical trial aimed to compare the efficacy of two protocols using high molecular weight hyaluronic acid (HA) intra-articular injection in patients with temporomandibular joint (TMJ) osteoarthritis and evaluate involvement of subchondral bone changes and psychosocial factors as predictors of HA treatment. METHODS: Twenty-one individuals were divided into two groups: (A) received three intra-articular HA injections, and (B) received one injection. Outcomes observed were pain intensity, functional limitation, maximum voluntary mouth opening, maximum assisted mouth opening, and treatment tolerability. Follow-ups were performed weekly for 21 days, and two months after the treatment started. RESULTS: No statistically significant intergroup differences were observed in any of the evaluated outcomes. However, Group A showed significant improvement in all outcomes, whereas Group B showed significant improvement only in pain intensity and functional limitation. CONCLUSION: This study demonstrated the effectiveness of both protocols in terms of pain intensity and functional limitation caused by osteoarthritis.

The role of aquaporins in hearing function and dysfunction.

The inner ear is composed by tiny and complex structures that, together with peripheral and central auditory pathways, are responsible for hearing processing. However, not only the anatomy of the cochlea, its compartments and related structures are complex. The mechanisms involved in the regulation of homeostasis in the inner ear fluid, which determines the ionic gradient necessary for hearing and balancing sensory excitability, is an intricate phenomenon that involves several molecules. Among them, Aquaporins (AQP) play a significant role in this process. AQP are part of a family of small, integral membrane proteins that regulate different processes, including bidirectional water and ionic flow in the inner ear. Changes in the expression of these proteins are essential to auditory physiology and several pathophysiological processes in the inner ear. This review focuses on the role of AQP in health and disease of the auditory system.

Study Protocol of tDCS Based Pain Modulation in Head and Neck Cancer Patients Under Chemoradiation Therapy Condition: An fNIRS-EEG Study.

Background: Multiple therapeutic strategies have been adopted to reduce pain, odynophagia, and oral mucositis in head and neck cancer patients. Among them, transcranial direct current stimulation (tDCS) represents a unique analgesic modality. However, the details of tDCS mechanisms in pain treatment are still unclear. Aims: (1) to study the analgesic effects of a protocol that encompassed supervised-remote and in-clinic tDCS sessions applied in head and neck patients undergoing chemoradiation therapy; (2) to explore the underlining brain mechanisms of such modulation process, using a novel protocol that combined functional near-infrared spectroscopy (fNIRS), and electroencephalograph (EEG), two distinct neuroimaging methods that bring information regarding changes in the hemodynamic as well as in the electrical activity of the brain, respectively. Methods: This proof-of-concept study was performed on two subjects. The study protocol included a 7-week-long tDCS stimulation procedure, a pre-tDCS baseline session, and two post-tDCS follow-up sessions. Two types of tDCS devices were used. One was used in the clinical setting and the other remotely. Brain imaging was obtained in weeks 1, 2, 5, 7, 8, and after 1 month. Results: The protocol implemented was safe and reliable. Preliminary results of the fNIRS analysis in weeks 2 and 7 showed a decrease in functional connections between the bilateral prefrontal cortex (PFC) and the primary sensory cortex (S1) (p < 0.05, FDR corrected). Changes in EEG power spectra were found in the PFC when comparing the seventh with the first week of tDCS. Conclusion: The protocol combining remote and in-clinic administered tDCS and integrated fNIRS and EEG to evaluate the brain activity is feasible. The preliminary results suggest that the mechanisms of tDCS in reducing the pain of head and neck cancer patients may be related to its effects on the connections between the S1 and the PFC.

Short-Term Functional and Morphological Changes in the Primary Cultures of Trigeminal Ganglion Cells.

Several studies have proved that glial cells, as well as neurons, play a role in pain pathophysiology. Most of these studies have focused on the contribution of central glial cells (e.g., microglia and astrocytes) to neuropathic pain. Likewise, some works have suggested that peripheral glial cells, particularly satellite glial cells (SGCs), and the crosstalk between these cells and the sensory neurons located in the peripheral ganglia, play a role in the phenomenon that leads to pain. Nonetheless, the study of SGCs may be challenging, as the validity of studying those cells in vitro is still controversial. In this study, a research protocol was developed to examine the potential use of primary mixed neuronal-glia cell cultures obtained from the trigeminal ganglion cells (TGCs) of neonate mice (P10-P12). Primary cultures were established and analyzed at 4 h, 24 h, and 48 h. To this purpose, phase contrast microscopy, immunocytochemistry with antibodies against anti-ßIII-tubulin and Sk3, scanning electron microscopy, and time-lapse photography were used. The results indicated the presence of morphological changes in the cultured SGCs obtained from the TGCs. The SGCs exhibited a close relationship with neurons. They presented a round shape in the first 4 h, and a more fusiform shape at 24 h and 48 h of culture. On the other hand, neurons changed from a round shape to a more ramified shape from 4 h to 48 h. Intriguingly, the expression of SK3, a marker of the SGCs, was high in all samples at 4 h, with some cells double-staining for SK3 and ßIII-tubulin. The expression of SK3 decreased at 24 h and increased again at 48 h in vitro. These results confirm the high plasticity that the SGCs may acquire in vitro. In this scenario, the authors hypothesize that, at 4 h, a group of the analyzed cells remained undifferentiated and, therefore, were double-stained for SK3 and ßIII-tubulin. After 24 h, these cells started to differentiate into SCGs, which was clearer at 48 h in the culture. Mixed neuronal-glial TGC cultures might be implemented as a platform to study the plasticity and crosstalk between primary sensory neurons and SGCs, as well as its implications in the development of chronic orofacial pain.

Neuromechanisms of SARS-CoV-2: A Review.

Recent studies have suggested the neuroinvasive potential of severe acute respiratory coronavirus 2 (SARS-CoV-2). Notably, neuroinvasiveness might be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). Some studies have demonstrated that synapse-connected routes may enable coronaviruses to access the central nervous system (CNS). However, evidence related to the presence of SARS-CoV-2 in the CNS, its direct impact on the CNS, and the contribution to symptoms suffered, remain sparse. Here, we review the current literature that indicates that SARS-CoV-2 can invade the nervous system. We also describe the neural circuits that are potentially affected by the virus and their possible role in the progress of COVID-19. In addition, we propose several strategies to understand, diagnose, and treat the neurological symptoms of COVID-19.

Positron emission tomography imaging of endogenous mu-opioid mechanisms during pain and migraine.

The enormous advancements in the medical imaging methods witnessed in the past decades have allowed clinical researchers to study the function of the human brain in vivo, both in health and disease. In addition, a better understanding of brain responses to different modalities of stimuli such as pain, reward, or the administration of active or placebo interventions has been achieved through neuroimaging methods. Although magnetic resonance imaging has provided important information regarding structural, hemodynamic, and metabolic changes in the central nervous system related to pain, magnetic resonance imaging does not address modulatory pain systems at the molecular level (eg, endogenous opioid). Such important information has been obtained through positron emission tomography, bringing insights into the neuroplastic changes that occur in the context of the pain experience. Positron emission tomography studies have not only confirmed the brain structures involved in pain processing and modulation but also have helped elucidate the neural mechanisms that underlie healthy and pathological pain regulation. These data have shown some of the biological basis of the interindividual variability in pain perception and regulation. In addition, they provide crucial information to the mechanisms that drive placebo and nocebo effects, as well as represent an important source of variability in clinical trials. Positron emission tomography studies have also permitted exploration of the dynamic interaction between behavior and genetic factors and between different pain modulatory systems. This narrative review will present a summary of the main findings of the positron emission tomography studies that evaluated the functioning of the opioidergic system in the context of pain.

The efficacy of transcranial direct current stimulation and transcranial magnetic stimulation for chronic orofacial pain: A systematic review.

BACKGROUND: Transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS) have been described as promising alternatives to treat different pain syndromes. This study evaluated the effects of TMS and tDCS in the treatment of chronic orofacial pain, through a systematic review. METHODS: An electronic search was performed in major databases: MEDLINE, Scopus, Web of Science, Cochrane, Embase, LILACS, BBO, Open Gray and CINAHL. The eligibility criteria comprised randomized clinical trials (RCTs) that applied TMS or tDCS to treat chronic orofacial pain. The variables analyzed were pain, functional limitation, quality of life, tolerance to treatment, somatosensory changes, and adverse effects. The risk of bias was assessed through the Cochrane Collaboration tool, and the certainty of evidence was evaluated through GRADE. The protocol was registered in the PROSPERO database (CRD42018090774). RESULTS: The electronic search resulted in 636 studies. Thereafter, the eligibility criteria were applied and the duplicates removed, resulting in eight RCTs (four TMS and four tDCS). The findings of these studies suggest that rTMS applied to the Motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC) and the secondary somatosensory cortex (S2) provide adequate orofacial pain relief. Two studies reported significant pain improvement with tDCS applied over M1 while the other two failed to demonstrate significant effects compared to placebo. CONCLUSIONS: rTMS, applied to M1, DLPFC or S2, is a promising approach for the treatment of chronic orofacial pain. Moreover, tDCS targeting M1 seems to be also effective in chronic orofacial pain treatment. The included studies used a wide variety of therapeutic protocols. In addition, most of them used small sample sizes, with a high risk of biases in their methodologies, thus producing a low quality of evidence. The results indicate that further research should be carried out with caution and with better-standardized therapeutic protocols.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

The Contribution of Endogenous Modulatory Systems to TMS- and tDCS-Induced Analgesia: Evidence from PET Studies.

Chronic pain is an important public health issue. Moreover, its adequate management is still considered a major clinical problem, mainly due to its incredible complexity and still poorly understood pathophysiology. Recent scientific evidence coming from neuroimaging research, particularly functional magnetic resonance (fMRI) and positron emission tomography (PET) studies, indicates that chronic pain is associated with structural and functional changes in several brain structures that integrate antinociceptive pathways and endogenous modulatory systems. Furthermore, the last two decades have witnessed a huge increase in the number of studies evaluating the clinical effects of noninvasive neuromodulatory methods, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), which have been proved to effectively modulate the cortical excitability, resulting in satisfactory analgesic effects with minimal adverse events. Nevertheless, the precise neuromechanisms whereby such methods provide pain control are still largely unexplored. Recent studies have brought valuable information regarding the recruitment of different modulatory systems and related neurotransmitters, including glutamate, dopamine, and endogenous opioids. However, the specific neurocircuits involved in the analgesia produced by those therapies have not been fully elucidated. This review focuses on the current literature correlating the clinical effects of noninvasive methods of brain stimulation to the changes in the activity of endogenous modulatory systems.

Efficacy of viscosupplementation with hyaluronic acid in temporomandibular disorders: A systematic review.

OBJECTIVE: To perform a systematic review of the viscosupplementation effectiveness with hyaluronic acid (HA) in the articular Temporomandibular Dysfunctions (TMDs) clinical management. METHOD: Electronic searches were performed in the following databases: MEDLINE (via PubMed), Scopus, Web of Science, Cochrane Library, EMBASE, LILACS, BBO, SIGLE (System for Information on Grey Literature in Europe), ClinicalTrials.gov, and the Brazilian Clinical Trials Registry (ReBec). Only randomized clinical trials that evaluated the intra-articular administration of HA or its derivatives in osteoarthritis and/or anterior displacement of the temporomandibular joint (TMJ) disc were included. The primary outcomes evaluated were patients' self-report of pain and/or discomfort in the TMJ. Each study was assessed for the risk of bias, using the Cochrane collaboration's risk of bias tool. RESULTS: A total of 640 studies were obtained in the electronic search. After the application of the eligibility criteria, manual search, and duplicate removal, 21 articles were included. Five articles classified their volunteers with internal derangements of the TMJ, in 4 articles the treatment was directed to participants with disc displacement with reduction and the other articles evaluated HA therapy in osteoarthritis. The protocols presented heterogeneity, varying in the form of application, associated or not with arthrocentesis, number of applications, molecular weight, dose and concentration. Nine studies presented high risk of bias. CONCLUSION: Due to the heterogeneity and methodological inconsistencies of the studies evaluated, it was not possible to establish the efficacy of HA in articular TMDs.

Changes in the vibration sensitivity and pressure pain thresholds in patients with burning mouth syndrome.

OBJECTIVE: To investigate the presence of changes in vibration detection and pressure pain threshold in patients with burning-mouth syndrome (BMS). DESIGN OF THE STUDY: Case-control study. The sample was composed of 30 volunteers, 15 with BMS and 15 in the control group. The pressure-pain threshold (PPT) and vibration-detection threshold (VDT) were examined. The clinical evaluation was complemented with the McGill Pain Questionnaire (MPQ), Douleur Neuropathique 4 (DN4) and Beck Depression and Anxiety Inventories (BDI and BAI, respectively). RESULTS: BMS subjects showed a statistically significant higher PPT in the tongue (p = 0.002), right (p = 0.001) and left (p = 0.004) face, and a significant reduction of the VDT in the tongue (p = 0.013) and right face (p = 0.030). Significant differences were also found when comparing the PPT and the VDT of distinct anatomical areas. However, a significant interaction (group × location) was only for the PPT. BMS subjects also showed significantly higher levels of depression (p = 0.01), as measured by the BDI, compared to controls; and a significant inverse correlation between the VDT in the left face and anxiety levels was detected. CONCLUSIONS: The study of somatosensory changes in BMS and its correlations with the clinical features as well as the levels of anxiety and depression expands current understanding of the neuropathic origin and the possible contribution of psychogenic factors related to this disease.

miRNAs: Important Targets for Oral Cancer Pain Research.

Pain is a symptom shared by an incredible number of diseases. It is also one of the primary conditions that prompt individuals to seek medical treatment. Head and neck squamous cell carcinoma (HNSCC) corresponds to a heterogeneous disease that may arise from many distinct structures of a large, highly complex, and intricate region. HNSCC affects a great number of patients worldwide and is directly associated with chronic pain, which is especially prominent during the advanced stages of oral squamous cell carcinoma (OSCC), an anatomical and clinical subtype that corresponds to the great majority oral cancers. Although the cellular and molecular bases of oral cancer pain have not been fully established yet, the results of recent studies suggest that different epigenetic mechanisms may contribute to this process. For instance, there is strong scientific evidence that microRNAs (miRNAs), small RNA molecules that do not encode proteins, might act by regulating the mechanisms underlying cancer-related pain. Among the miRNAs that could possibly interfere in pain-signaling pathways, miR-125b, miR-181, and miR-339 emerge as some of the most promising candidates. In fact, such molecules apparently contribute to inflammatory pain. Moreover, these molecules possibly influence the activity of endogenous pain control systems (e.g., opioidergic and serotonergic systems), which could ultimately result in peripheral and central sensitization, central nervous system (CNS) phenomena innately associated with chronic pain. This review paper focuses on the current scientific knowledge regarding the involvement of miRNAs in cancer pain, with special attention dedicated to OSCC-related pain.

Reward Circuitry Plasticity in Pain Perception and Modulation.

Although pain is a widely known phenomenon and an important clinical symptom that occurs in numerous diseases, its mechanisms are still barely understood. Owing to the scarce information concerning its pathophysiology, particularly what is involved in the transition from an acute state to a chronic condition, pain treatment is frequently unsatisfactory, therefore contributing to the amplification of the chronic pain burden. In fact, pain is an extremely complex experience that demands the recruitment of an intricate set of central nervous system components. This includes cortical and subcortical areas involved in interpretation of the general characteristics of noxious stimuli. It also comprises neural circuits that process the motivational-affective dimension of pain. Hence, the reward circuitry represents a vital element for pain experience and modulation. This review article focuses on the interpretation of the extensive data available connecting the major components of the reward circuitry to pain suffering, including the nucleus accumbens, ventral tegmental area, and the medial prefrontal cortex; with especial attention dedicated to the evaluation of neuroplastic changes affecting these structures found in chronic pain syndromes, such as migraine, trigeminal neuropathic pain, chronic back pain, and fibromyalgia.

Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo.

OBJECTIVE: To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia. METHODS: We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase. RESULTS: Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge. CONCLUSIONS: Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release.

Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively.

State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control.

Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes' placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10-20 or 10-10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder.

µ-Opioid activation in the midbrain during migraine allodynia - brief report II.

We investigated in vivo the allodynic response of the central µ-opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Females were scanned during the mid-late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with µOR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high µOR activation in the migraineurs' brains in response to their allodynic experience.