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Increased limbic and brainstem activity during migraine attacks following olfactory stimulation

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Abstract

Migraine patients have dysfunctional cortical olfactory processing and very often report hypersensitivity and phobic symptoms to odors during acute headache attacks. However, imaging data of how the brain processes associate migraine symptoms, such as photophobia, phonophobia, or osmophobia, are rare. The present study aimed to explore neuronal processing in response to olfactory stimulation (rose odor) in migraine patients in and outside acute headache attacks. Using event-related fMRI we studied 20 migraine patients and compared behavioral and imaging data with sex- and age-matched healthy controls. Additionally, 13 of the 20 patients were scanned within 6 hours after the onset of a spontaneous migraine attack. Imaging data showed that interictal migraineurs did not differ from control subjects. However, during spontaneous and untreated attacks, migraine patients showed significantly higher blood oxygen level-dependent signal intensities in brain areas including limbic structures (amygdala and insular cortices) and, more specifically, in the rostral pons in response to olfactory stimulation. Increased activity in the rostral part of the pons has previously been specifically linked to the pain of the migraine attack. The present finding suggests that the activity level of this structure can be triggered by olfactory input and thus points to the strong physiologic relationship between the olfactory and the trigemino-nociceptive pathway in the pathophysiology of migraine disease.

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... Imaging studies of cerebellar activity and functional connectivity were conducted in migraine patients in response to different stimuli, e.g., visual (Kreczmanski et al., 2019), thermal (Moulton et al., 2011;Maleki et al., 2012Maleki et al., , 2021Russo et al., 2012;Schwedt et al., 2014a), olfactory (Stankewitz and May, 2011), and trigeminal nociceptive (Mehnert and May, 2019) stimuli. ...
... May and colleagues observed cerebellar changes during olfactory stimulation in healthy controls and migraine patients. They found that the cerebellum was activated in both healthy controls (Stankewitz et al., 2010) and migraine patients (Stankewitz and May, 2011) who showed higher cerebellar activation in the ictal phase compared to the interictal phase in response to odors (Stankewitz and May, 2011). ...
... May and colleagues observed cerebellar changes during olfactory stimulation in healthy controls and migraine patients. They found that the cerebellum was activated in both healthy controls (Stankewitz et al., 2010) and migraine patients (Stankewitz and May, 2011) who showed higher cerebellar activation in the ictal phase compared to the interictal phase in response to odors (Stankewitz and May, 2011). ...
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Migraine is a disabling neurological disease characterized by moderate or severe headaches and accompanied by sensory abnormalities, e.g., photophobia, allodynia, and vertigo. It affects approximately 15% of people worldwide. Despite advancements in current migraine therapeutics, mechanisms underlying migraine remain elusive. Within the central nervous system, studies have hinted that the cerebellum may play an important sensory integrative role in migraine. More specifically, the cerebellum has been proposed to modulate pain processing, and imaging studies have revealed cerebellar alterations in migraine patients. This review aims to summarize the clinical and preclinical studies that link the cerebellum to migraine. We will first discuss cerebellar roles in pain modulation, including cerebellar neuronal connections with pain-related brain regions. Next, we will review cerebellar symptoms and cerebellar imaging data in migraine patients. Lastly, we will highlight the possible roles of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine symptoms, including preclinical cerebellar studies in animal models of migraine.
... The first observations of an increased cerebral blood flow bilaterally in the hypothalamus during spontaneous headache attacks have been made with positron emission tomography (PET) (14) . However, due to the unpredictable onset of migraine attacks, the investigation of the cyclic behaviour of hypothalamic activity is challenging and the group size of studies is therefore often limited (15)(16)(17) . To cut short the natural but uncertain course of the migraine cycle, some studies applied nitroglycerin to patients in order to trigger headache attacks (18,19) . ...
... By contrast, the hypothalamus was not active during the migraine attack (17) . Using the same trigemino-nociceptive and olfactory stimulation design, previous studies did not find any hypothalamic alterations neither during (15,16) nor within the last 72h prior to spontaneous headache attacks (16) . ...
... Due to its important role in integrating incoming stimuli, an impaired limbic system is most likely responsible for the altered sensory processing in migraine patients (34, 35) . Functional MRI studies revealed enhanced limbic activity during migraine attacks in response to painful (36) and olfactory stimulation (15) . In contrast, hypometabolism of limbic areas, particularly the insula, cingulate and prefrontal cortices, was observed during the pain-free interval, compared to healthy controls (37) . ...
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To assess the natural trajectory of brain activity over the migraine cycle, we assessed (1) the cerebral perfusion and (2) the hypothalamic connectivity during spontaneous headache attacks with follow-up recordings towards the next migraine attack. Using pseudo-continuous arterial spin labelling and resting-state functional magnetic resonance imaging, 12 migraine patients were examined in 82 sessions. We detected cyclic changes of brain perfusion in the limbic circuit (insula, hippocampus, and nucleus accumbens), with the highest perfusion during headache attacks. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval, then collapsing during the headache. Our data provide strong evidence for the predominant role of the hypothalamus as a zeitgeber for generating migraine attacks. Our findings suggest that migraine attacks are the result of the hypothalamus losing control over the limbic system.
... [23][24][25] These studies have enhanced our understanding of hypersensitivity in migraine, including the identification of brain regions contributing to the atypical processing of sensory stimuli. 26 This abnormal processing is a key feature of the migraine brain, leading to increased sensitivity to pain as well as to Considering the predominance of perfumes and pleasant odors in migraine olfactory phenomena, it could be subject of further studies to investigate the pathways involved in the hedonic assessment and migraine pain. 8,37 Notably, it was shown that the specific migraine subset with O-P seems to present the lowest odor discriminatory score compared with the whole migraine group. ...
... [54][55][56] The complex relationship between the olfactory and limbic networks in migraine has been further supported by advanced neuroimaging studies using olfactory stimulation in patients experiencing migraine without aura and migraine with aura, both during ictal and interictal period. 26 Interestingly, migraine patients and healthy controls did not show any differences in both odor perception and neuroimaging findings during interictal phases, whilst a significantly increased activity in limbic areas (known to play a key role in both migraine pathophysiology and advanced olfactory processing) and in the rostral pons (a structure previously defined as "migraine generator") in response to olfactory stimuli was observed during spontaneous migraine attacks. 26 ...
... 26 Interestingly, migraine patients and healthy controls did not show any differences in both odor perception and neuroimaging findings during interictal phases, whilst a significantly increased activity in limbic areas (known to play a key role in both migraine pathophysiology and advanced olfactory processing) and in the rostral pons (a structure previously defined as "migraine generator") in response to olfactory stimuli was observed during spontaneous migraine attacks. 26 ...
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Objective Migraine is a primary headache with a constellation of neurovegetative and sensory-related symptoms, comprehending auditory, visual, somatosensorial and olfactory dysfunctions, in both ictal and interictal phases. Olfactory phenomena in migraine patients consist in ictal osmophobia, interictal olfactory hypersensitivity and an increased sensitivity to olfactory trigger factors. However, osmophobia is not listed as an associated symptom for migraine diagnosis in ICHD-3. Design We reviewed the literature about the anatomical circuits and the clinical characteristics of olfactory phenomena in migraine patients, and highlighted also the common comorbidities with psychiatric disorders. Discussion The evidence suggests a potential role of the olfactory dysfunctions as diagnostic, prognostic and risk biomarker of migraine in clinical practice. Olfactory assessment could be useful in reducing the overlap between migraine and other primary headaches-especially the tension type one-or secondary headaches (ictal osmophobia, olfactory trigger factors), and in predicting migraine onset and its chronic transformation (ictal osmophobia). Furthermore, ictal osmophobia and olfactory hypersensitivity showed to be related with an increased risk of psychiatric comorbidities and suicidality, probably beacause of the sharing of anatomical circuits (in particular the limbic system). Conclusion In conclusion, the assessment during clinical interviews of olfactory phenomena, with the validation of scales or scores to measure olfactory dysfunctions, surpassing the binary presence/absence paradigm, could improve the diagnostic and prognostic possibilities, especially in tertiary headache centers. the induced perception) and hedonic tone (defining the pleasantness of odors). 8 Quantitative olfactory dysfunctional changes have been described in various neurological diseases. 9, 10 In particular, among headache syndromes, olfactory impairment has been identified as a clinical feature of idiopathic intracranial hypertension and the lowering of increased intracranial pressure is able to improve hyposmia. Nonetheless, in migraine, also quality characterization, as the ability to identify specific odors, has shown to be affected. 3, 12, 13 Olfactory modifications in migraine have been studied with both subjective and objective (e.g. electrophysiolo-gical) tests. 14-17 However, due to the high prevalence of hyposmic and anosmic patients in the general population (almost 20%) 18 specific migraine-related olfactory changes are difficult to identify. In this review, we elaborated on the anatomical and functional substrates of olfaction and the olfactory phenomena characterizing migraine, with particular focus on ictal O-P, interictal O-HS and olfactory stimuli as O-TFs. Moreover, we investigated changes observed in migraine psychiatric comorbi-dities. To review the role of olfactory phenomena in migraine, we performed a Pubmed-based literature search until April 2020 using the keywords "Olfactory", "Osmophobia", "Sensory hypersensitivity", "Headache" and "Migraine". A total number of 135 articles written in English were found. To remove outdated content we selected 118 articles excluding papers written before the 1995. Among them we also excluded clinical case reports, studies where the keywords referred to different and unrelated subjects (e.g. drug delivery, other diseases, biochemical receptors studies, etc)
... In another fMRI study of olfactory-induced migraine attacks in 20 migraine patients, there was increased blood oxygen level-dependent (BOLD) signal intensity in the insula, amygdala, and the rostral pons (locus ceruleus and raphe nucleus), highlighting the link between the olfactory system, the salience network (the insula as a node), and the trigeminovascular system (dorsal pons) [14]. ...
... Activation of TRPA-1 induces the release of SP and CGRP by trigeminovascular activation, explaining the generation of a migraine headache [15][16][17]. Olfactory stimulation also leads to increased activity of the limbic system and the dorsal pons, which induces inflammatory mediator (CGRP, SP) release and activation of nociceptors and vasodilation of meningeal vessels [14]. ...
Article
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We define a migraine trigger to be an endogenous agent or agency such as the menses or an exogenous agent or agency such as red wine or a drop in barometric pressure, and their ability to reduce the threshold of a migraine attack in those predisposed to migraine. This definition excludes agents with idiosyncratic mechanisms that may trigger a migrainous (migraine-like) headache in non-migraineurs such as benign cough headaches or headaches due to altitude-sickness. We also assume as axiomatic that migraine has as its basis the activation of the trigeminovascular pathway (TVP) and the key role of serotonin and the calcitonin gene-related peptide (CGRP). The network activation of the visual/auditory association cortices and the rostrodorsal pons (locus ceruleus and raphe nucleus) are also accepted as key features of activation of the TVP. In addition, we outline the role of the superior salivatory nucleus-sphenopalatine ganglion-greater superficial petrosal nerve (SSN-SPG-GSPN) arc in migraine activation. We also explore how olfactory afferents intermingle with trigeminal nerve collaterals in the glomeruli of the olfactory bulb thus allowing volatile molecules to activate the TVP and induce a migraine. The classification of migraine triggers is complex, as there is a wide panorama of inciting agents, including atmospheric conditions, a wide-ranging variety of foods and beverages, endogenous hormonal influences, synthetic alkaloids and dyes, and volatile molecules (odorants). We will explore the high-frequency migraine- provoking agents in each category. There are exciting and intriguing hypotheses regarding the role of atmospheric chemistry when the barometric pressure drops; the role of hot, dry desert winds and lightning discharges in the generation of cations and the turnover of serotonin in the nervous system. We will explore the effects of a drop in barometric pressure on the vestibular nuclei and the modulation of sympathetically mediated pain. The role of volatile odorants and their activation of the transient receptor potential ankyrin- 1 (TRPA-1) receptor will be outlined. We will streamline the highly complex role of estrogen fluctuation in the precipitation of migraine headaches, its pharmacodynamic effects, and the role of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the hypothalamus. We will also adumbrate the protean effects of alcohol and its congeners and the role of stress and sleep disturbances in the allostatic load model of salience network-pain perception.
... More recent studies went further and consistently identified a network of brain structures that is activated after painful stimulation of trigeminal dermatome. This network includes the thalamus, insular, anterior cingulate cortex (ACC), and primary and secondary somatosensory cortices (S1 and S2) (Schulte et al., 2016;Stankewitz and May, 2011). The topic of neuroimaging in headache disorders have been reviewed in details elsewhere (May, 2009;Schulte and May, 2016b;Sprenger and Goadsby, 2010). ...
... The headache does not fit into the category of nociceptive or neuropathic pain; (iii) several headache disorders, such as migraine and cluster headache, showed prominent fluctuation in symptoms during the different phases of the disease, such as the interictal phase, preictal phase, and ictal phase (Peng and May, 2019;Schulte and May, 2016a). The activation pattern and pain sensitivity in the absence of drug is already heavily dependent with regards of a conditional difference, e.g., migraine vs. health control, and also a phasic difference, e.g., ictal vs. interictal phase (Peng and May, 2019;Schulte and May, 2016a;Stankewitz and May, 2011). ...
Chapter
Purpose: The current review provides a recapitulation of recent advances in pharmacological neuroimaging in headache, a promising tool to understanding of how a drug works in the brain and how it may lead to new insights of disease mechanisms of headache. Results: Pharmacological positron emission tomography with radioligand-labeled medication may provide evidence whether and where a medication binds in the brain but is still mostly restricted to animal work. Pharmacological functional MRI using task-specific approaches identified central modulation patterns as a consequence of attack and preventative headache medication, which may be distinct to a specific drug mechanism. Pharmacological neuroimaging and specifically in combination with functional imaging is a promising tool to better understand not only certain medications but also certain disease mechanisms. Summary: Pharmacological imaging techniques have advanced over the last few years and showed great potential of providing new insights into drug pharmacodynamics and disease mechanism. There are still limitations and challenges to be overcome.
... This indicates a predominant role of these brain regions within the preictal phase of migraine. Furthermore, in the seed to voxel analysis, the nucleus accumbens showed enhanced functional coupling with the dorsal rostral pons, a region which has been shown to increase activity shortly before and during migraine attacks (8,10,11,15,26,27). In the ictal phase, on the other hand, we found significantly higher functional coupling of the dorsal pons, as defined by previously published coordinates of this brain region (10) with the hypothalamus as compared to the scan 3 days before headache onset. ...
... In the ictal phase, on the other hand, we found significantly higher functional coupling of the dorsal pons, as defined by previously published coordinates of this brain region (10) with the hypothalamus as compared to the scan 3 days before headache onset. While we were not able to replicate earlier findings of altered thalamic connectivity during induced migraine attacks in our spontaneous migraine attacks (27), these findings are in line with our previous data: In one migraine patient, the hypothalamus showed enhanced pain-dependent functional coupling to the dorsal rostral pons within the ictal state as compared to the interictal state (15). Whereas, however, our previous data used a taskdependent design and were thus only able to depict pain-dependent functional connectivity changes, the current data represent task free resting state changes within the migraine brain and are thus even more likely to represent a mechanism underlying cycling changes in migraine pathophysiology. ...
Article
Objective The aim of the current study was to identify typical alterations in resting state connectivity within different stages of the migraine cycle and to thus explore task-free mechanisms of headache attack generation in migraineurs. Background Recent evidence in migraine pathophysiology suggests that hours and even days before headache certain changes in brain activity take place, ultimately leading to an attack. Here, we investigate changes before headache onset using resting state functional magnetic resonance imaging (fMRI). Methods Nine episodic migraineurs underwent daily resting state functional magnetic resonance imaging for a minimum period of 30 consecutive days, leading to a cumulative number of 282 total days scanned. Thus, data from 15 spontaneous headache attacks were acquired. This allows analysing not only the ictal and the interictal phase of migraine but also the preictal phase. ROI-to-ROI (region of interest) and ROI-to-voxel connectivity was calculated over the migraine cycle. Results Within the ROI-to-ROI analysis, the right nucleus accumbens showed enhanced functional connectivity to the left amygdala, hippocampus and gyrus parahippocampalis in the preictal phase compared to the interictal phase. ROI-to-voxel connectivity of the right accumbens with the dorsal rostral pons was enhanced during the preictal phase compared to interictally. Regarding custom defined ROIs, the dorsal pons was ictally functionally more strongly coupled to the hypothalamic area than interictally. Conclusions This unique data set suggests that particularly connectivity changes in dopaminergic centres and between the dorsal pons and the hypothalamus are important within migraine attack generation and sustainment.
... 66 The activity of temporal pole was enhanced during the migraine attacks compared to the interictal phase, as well as in patients with more frequent attacks than those with fewer attacks. 21,70 When enhancing excitability of temporal pole by anodal transcranial direct current stimulation, the migraine patients presented with normal habituation responses to visual stimulation compared with untreatment state. 71 Another PET study showed that the temporal pole of interictal migraineurs had significant increased glucose metabolism in left temporal pole compared to healthy individuals during olfactory stimuli, which reflected the unique role of temporal pole in odor hypersensitivity and odor-triggered migraine. ...
... 130 Furthermore, the activation of the cerebellum in response to nociceptive input was higher during the migraine attack than in interictal periods. 70 These functional studies add proof to the cerebellar dysfunction and cerebellum involvement in migraine. Here, we would like to add some results other than fMRI studies. ...
Article
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Migraine is the second most prevalent disorder in the world; yet, its underlying mechanisms are still poorly understood. Cumulative studies have revealed pivotal roles of cerebral cortex in the initiation, propagation, and termination of migraine attacks as well as the interictal phase. Investigation of basic mechanisms of the cortex in migraine not only brings insight into the underlying pathophysiology but also provides the basis for designing novel treatments. We aim to summarize the current research literatures and give a brief overview of the cortex and its role in migraine, including the basic structure and function; structural, functional, and biochemical neuroimaging; migraine-related genes; and theories related to cortex in migraine pathophysiology. We propose that long-term plasticity of synaptic transmission in the cortex encodes migraine.
... Using positron emission tomography in these patients, a specific role of the piriform cortex and the antero-superior temporal gyrus in odor triggered migraine has been suggested [8]. Further, odor stimulation during an fMRI experiment in acute migraine attacks induced an increased activity of the rostral pons, a structure involved in the trigemino-nociceptive pathway in migraine pathophysiology pointing towards a close link between olfaction and pain [9]. The prevalence of osmophobia in migraine has been reported to be very high whereas published data differ widely between 24.7% and 95.5% [10][11][12]. ...
... In addition, activation of olfactory neurons has impact on the default mode network of the brain [27]. Furthermore, rostral pons has been found to be activated by olfactory stimuli and is involved in migraine progression [9]. In a rat model of migraine, increased connectivity of the insular cortex and the pons, the midbrain, the thalamus, the visual and sensory cortices has been demonstrated, suggesting that chronification of migraine may be related to higher brain centers and limbic cortices [28]. ...
Article
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Background Sensitization to sensory stimuli is an essential feature of migraine attacks. The relationship between the clinical course of migraine and increased sensitivity to olfactory stimuli has been little studied so far. Methods We analyzed the frequency and quality of osmophobia depending on the phase of migraine in patients with episodic and chronic migraine treated in an tertiary headache center with regard to gender, age, medical history and migraine disability assessment score (MIDAS). Standardized diagnostic questions were used for the assessment of osmophobia. Results In our cross-sectional investigation ( n = 113), 38.1% of the patients showed an increased preictal hypersensitivity to odors, whereas 61.9% described ictal and 31.9% interictal hypersensitivity to odors, odor-triggered migraine was described in 30.1%. Median migraine disease duration has been statistically significantly longer in patients who suffered from interictal hypersensitivity to odors (28.5 years vs. 20 years; p = 0.012). There was a significant correlation between interictal hypersensitivity and higher age (54.50 vs. 45; p = 0.015). Patients with higher migraine disability in MIDAS experienced more frequently preictal and interictal olfactory sensitization and odor triggered migraine attacks. Conclusions In patients with longer migraine disease duration and higher migraine-related impairment, osmophobia was more frequently observed. These results might support the hypothesis of increasing sensitization with increasing burden of migraine.
... It is worth noting that the salience network, which in this study showed increased FD during the attack, was previously found to be involved during the headache phase of migraine either in response to noxious stimulation [21] or at rest [22]. These results together with ours provide further evidence in favor of a reorganization of cortical functional networking during a migraine attack, likely an expression of the complex interaction between the different components that form the multidimensional nature of pain. ...
Article
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The role of the hypothalamus and the limbic system at the onset of a migraine attack has recently received significant interest. We analyzed diffusion tensor imaging (DTI) parameters of the entire hypothalamus and its subregions in 15 patients during a spontaneous migraine attack and in 20 control subjects. We also estimated the non-linear measure resting-state functional MRI BOLD signal’s complexity using Higuchi fractal dimension (FD) and correlated DTI/fMRI findings with patients’ clinical characteristics. In comparison with healthy controls, patients had significantly altered diffusivity metrics within the hypothalamus, mainly in posterior ROIs, and higher FD values in the salience network (SN). We observed a positive correlation of the hypothalamic axial diffusivity with migraine severity and FD of SN. DTI metrics of bilateral anterior hypothalamus positively correlated with the mean attack duration. Our results show plastic structural changes in the hypothalamus related to the attacks severity and the functional connectivity of the SN involved in the multidimensional neurocognitive processing of pain. Plastic changes to the hypothalamus may play a role in modulating the duration of the attack.
... Positron emission tomography studies unveiled neuronal activation in the brainstem, especially the dorsolateral pons, during spontaneous migraine attack [35,36] and induced migraine [37]. Similarly, eventrelated fMRI studies disclosed BOLD signal increases in the brainstem encompassing the trigeminal nucleus or dorsal pons during migraine attack in response to nociceptive stimulation, highlighting the importance of TCC abnormality in the predisposition and generation of migraine headache [38][39][40]. Both macrostructural (e.g., volume reduction, shape deformation) and microstructural (e.g., increased mean diffusivity) abnormalities of the brainstem including trigeminal nucleus, dorsolateral pons, and periaqueductal grey were demonstrated in migraineurs in morphometric MRI and diffusion tensor imaging studies, respectively [41,42]. ...
Article
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Background Recent resting-state fMRI studies demonstrated functional dysconnectivity within the central pain matrix in migraineurs. This study aimed to investigate the spatial distribution and amplitude of low-frequency oscillations (LFOs) using fractional amplitude of low-frequency fluctuation (fALFF) analysis in migraine patients without aura, and to examine relationships between regional LFOs and clinical variables. Methods Resting-state fMRI data were obtained and preprocessed in 44 migraine patients without aura and 31 matched controls. fALFF was computed according to the original method, z -transformed for standardization, and compared between migraineurs and controls. Correlation analysis between regional fALFF and clinical variables was performed in migraineurs as well. Results Compared with controls, migraineurs had significant fALFF increases in bilateral ventral posteromedial (VPM) thalamus and brainstem encompassing rostral ventromedial medulla (RVM) and trigeminocervical complex (TCC). Regional fALFF values of bilateral VPM thalamus and brainstem positively correlated with disease duration, but not with migraine attack frequency or Migraine Disability Assessment Scale score. Conclusions We have provided evidence for abnormal LFOs in the brainstem including RVM/TCC and thalamic VPM nucleus in migraine without aura, implicating trigeminothalamic network oscillations in migraine pathophysiology. Our results suggest that enhanced LFO activity may underpin the interictal trigeminothalamic dysrhythmia that could contribute to the impairments of pain transmission and modulation in migraine. Given our finding of increasing fALFF in relation to increasing disease duration, the observed trigeminothalamic dysrhythmia may indicate either an inherent pathology leading to migraine headaches or a consequence of repeated attacks on the brain.
... Functional brain imaging studies show that patients with migraine have atypical brain activation in response to nociceptive, olfactory, and visual stimuli as well as atypical functional connectivity involved in sensory-discriminative pain processing, affective emotional processing, cognitive processing, and pain modulation [13]. Additionally, in migraine patients, exposure to odors activates the limbic and rostral pons [14], and increased activation of the visual cortex following visual stimulation has been reported [15]. Neuroimaging and electrophysiological studies have supported sensory hypersensitivity in migraine by observing that migraine patients being exposed to sensory stimuli show increased brain activation, a lack of habituation to repeated stimuli, and increased attention to incoming stimuli [16]. ...
Article
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Objective Sensory hypersensitivities such as photophobia, phonophobia, and osmophobia are common in patients with migraine. We investigated the burden of these multiple sensory hypersensitivities in migraine. Methods In this cross-sectional study, 187 consecutive patients with migraine (26 men/161 women; age, 45.9 ± 13.2 years) were included. Sensory hypersensitivity symptoms such as photo−/phono−/osmophobia and accompanying symptoms were determined by neurologists in interviews. The Migraine Disability Assessment (MIDAS) was used to assess headache-related disability. The Kessler Psychological Distress Scale (K6) was also administered. Results Photophobia, phonophobia and osmophobia were observed in 75.4%, 76.5% and 55.1% of the patients with migraine, respectively. A significant overlap in sensory hypersensitivities (photo−/phono−/osmophobia) was found; the proportions of patients with 2 and 3 coexisting sensory hypersensitivities were 33.2% and 41.7%, respectively. The MIDAS score was higher in those with 3 sensory hypersensitivity symptoms than in those with 0 to 2 sensory hypersensitivity symptoms. A generalized linear model with ordinal logistic regression analysis revealed that multiple sensory hypersensitivities, younger age, more migraine days per month, and a higher K6 score were significantly related to the higher MIDAS score. Conclusion Our study showed that sensory hypersensitivities commonly occur and overlap in patients with migraine and that multiple sensory hypersensitivity symptoms have a significant impact on headache-related disability.
... Despite the cyclic nature of the migraine disease, longitudinal studies are sparse 5 . The majority of neuroimaging studies have used cross-sectional designs and found deviant cortical activity 6,7 , seed-based connectivity 8 , and resting-state network connectivity in migraineurs. Here, we conducted an intra-individual rs-fMRI study to follow the trajectory of intrinsic cortical networks over the entire migraine cycle. ...
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Background Episodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI). Methods Intrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack. Results We found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and “dropped” to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms. Conclusion Our results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.
... This increased understanding of dynamic and oscillating brain changes throughout a migraine attack, as well as more fixed functional and structural changes related to disease activity and chronicity, suggest that we now have a plausible anatomical, biological, and neurochemical link between migraine and disorders of mood and fatigue. Emerging evidence suggests that the strong implication of limbic connectivity in migraine is a feature throughout the attack (O'Carroll, 2007;Burstein and Jakubowski, 2009;Stankewitz and May, 2011;Hadjikhani et al., 2013;Wilcox et al., 2016;Chen et al., 2017;Chong et al., 2017;Karsan et al., 2020a). ...
Article
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Migraine is a symptomatically heterogeneous condition, of which headache is just one manifestation. Migraine is a disorder of altered sensory thresholding, with hypersensitivity among sufferers to sensory input. Advances in functional neuroimaging have highlighted that several brain areas are involved even prior to pain onset. Clinically, patients can experience symptoms hours to days prior to migraine pain, which can warn of impending headache. These symptoms can include mood and cognitive change, fatigue, and neck discomfort. Some epidemiological studies have suggested that migraine is associated in a bidirectional fashion with other disorders, such as mood disorders and chronic fatigue, as well as with other pain conditions such as fibromyalgia. This review will focus on the literature surrounding alterations in fatigue, mood, and cognition in particular, in association with migraine, and the suggested links to disorders such as chronic fatigue syndrome and depression. We hypothesize that migraine should be considered a neural disorder of brain function, in which alterations in aminergic networks integrating the limbic system with the sensory and homeostatic systems occur early and persist after headache resolution and perhaps interictally. The associations with some of these other disorders may allude to the inherent sensory sensitivity of the migraine brain and shared neurobiology and neurotransmitter systems rather than true co-morbidity.
... Compared to healthy subjects, the vast majority of studies carried out in migraineurs between attacks revealed an increase in BOLD activity of cortico-subcortical brain areas involved in noxious information processing and anti-nociception [53][54][55][56][57][58]. Most of these areas are anchored to the so-called pain neuromatrix, which nowadays is known as salience network, devoted to select the most relevant internal and external events [59], as for instance the unpleasant feeling of pain and the threatening sensation of receiving pain. ...
Article
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A neuronal dysfunction based on the imbalance between excitatory and inhibitory cortical-subcortical neurotransmission seems at the basis of migraine. Intercritical neuronal abnormal excitability can culminate in the bioelectrical phenomenon of Cortical Spreading Depression (CSD) with secondary involvement of the vascular system and release of inflammatory mediators, modulating in turn neuronal activity. Neuronal dysfunction encompasses the altered connectivity between the brain areas implicated in the genesis, maintenance and chronic evolution of migraine. Advanced neuroimaging techniques allow to identify changes in functional connectivity (FC) between brain areas involved in pain processes. Through a narrative review, we re-searched case-control studies on FC in migraine, between 2015 and 2020, by inserting the words migraine, fMRI, EEG, MEG, connectivity, pain in Pubmed. Studies on FC have shown that cortical processes, in the neurolimbic pain network, are likely to be prevalent for triggering attacks, in response to predisposing factors, and that these lead to a demodulation of the subcortical areas, at the basis of migraine maintenance. The link between brain dysfunction and peripheral interactions through the inhibition of CGRP, the main mediator of sterile migraine inflammation needs to be further investigated. Preliminary evidence could suggest that peripheral nerves inference at somatic and trigeminal levels, appears to change brain FC.
... Their study demonstrated that (1) topical application of N-methyl-D-aspartate to the central amygdala led to a high expression of c-fos in the amygdaloid neurons and CSD; and (2) sumatriptan attenuated c-fos expression that was thought to result from the induction of CSD. An in vitro electrophysiological recording on the amygdala-hippocampus-cortex slices further indicated that CSD modulates synaptic transmission of the lateral amygdala producing synaptic plasticity [53] . Human imaging data showed that migraine patients during spontaneous and untreated attacks had significantly higher blood oxygen level-dependent signal intensities in the limbic structures (amygdala and insular cortices) [54] . ...
Article
Clinical studies have suggested that internal and/or external aversive cues may produce a negative affective-motivational component whereby maladaptive responses (plasticity) of dural afferent neurons are initiated contributing to migraine chronification. However, pathophysiological processes and neural circuitry involved in aversion (unpleasantness)-producing migraine chronification are still evolving. An interdisciplinary team conducted this narrative review aimed at reviewing neuronal plasticity for developing migraine chronicity and its relevant neurocircuits and providing the most cutting-edge information on neuronal mechanisms involved in the processing of affective aspects of pain and the role of unpleasantness evoked by internal and/or external cues in facilitating the chronification process of migraine headache. Thus, information presented in this review promotes the understanding of the pathophysiology of chronic migraine and contribution of unpleasantness (aversion) to migraine chronification. We hope that it will bring clinicians' attention to how the maladaptive neuroplasticity of the emotion brain in the aversive environment produces a significant impact on the chronification of migraine headache, which will in turn lead to new therapeutic strategies for this type of pain.
... In one case report, migraine attacks triggered by the smell of onions and garlic were relieved by inhalation of peppermint oil [103]. Odors are known to trigger migraine attacks; studies have found atrophy of the olfactory bulb in migraine patients [104] and increased activity in response to olfactory stimulation in the brain areas (piriform, insular and orbitofrontal cortices, amygdala, hippocampus) [105] that process pain and chemical sensation, showing, once again, a link at the neural level. ...
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Every day our sensory systems perceive and integrate a variety of stimuli containing information vital for our survival. Pain acts as a protective warning system, eliciting a response to remove harmful stimuli; it may also be a symptom of an illness or present as a disease itself. There is a growing need for additional pain-relieving therapies involving the multisensory integration of smell and taste in pain modulation, an approach that may provide new strategies for the treatment and management of pain. While pain, smell, and taste share common features and are strongly linked to emotion and cognition, their interaction has been poorly explored. In this review, we provide an overview of the literature on pain modulation by olfactory and gustatory substances. It includes adult human studies investigating measures of pain threshold, tolerance, intensity, and/or unpleasantness. Due to the limited number of studies currently available, we have structured this review as a narrative in which we comment on experimentally induced and clinical pain separately on pain–smell and pain–taste interaction. Inconsistent study findings notwithstanding, pain, smell, and taste seem to interact at both the behavioral and the neural levels. Pain intensity and unpleasantness seem to be affected more by olfactory substances, whereas pain threshold and tolerance are influenced by gustatory substances. Few pilot studies to date have investigated these effects in clinical populations. While the current results are promising for the future, more evidence is needed to elucidate the link between the chemical senses and pain. Doing so has the potential to improve and develop novel options for pain treatment.
... In this study, the left STG region showed a significantly increased connectivity. Previous neuroimaging studies, using different methodological approaches, have consistently provided evidence of disrupted activities in the STG in migraine patients (Maleki et al. 2012, Stankewitz andMay 2011). However, Schwedt et al. found the opposite pattern of neural activity in the STG in episodic migraineurs compared to HCs. ...
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The present study aimed to explore associations between brain activity in the auditory cortex and clinical and psychiatric characteristics in patients with migraine without aura (MwoA) during interictal periods. Resting-state data were acquired from patients with episodic MwoA (n = 34) and healthy controls (n = 30). Independent component analysis was used to extract and calculate the resting-state auditory network. Subsequently, we analyzed the correlations between spontaneous activity in the auditory cortex and clinical and psychiatric features in interictal MwoA. Compared with healthy controls, patients with MwoA showed increased activity in the left superior temporal gyrus (STG), postcentral gyrus (PoCG) and insula. Brain activity in the left STG was positively correlated with anxiety scores, and activity in the left PoCG was negatively correlated with anxiety and depression scores. No significant differences were found in intracranial volume between the two groups. This study indicated that functional impairment and altered integration linked to the auditory cortex existed in patients with MwoA in the interictal period, suggesting that auditory-associated cortex disruption as a biomarker may be implemented for the early diagnosis and prediction of neuropsychiatric impairment in interictal MwoA patients.
... Comparing with hippocampus, relatively more has been known about the role of amygdala in migraine. In migraineurs, increased amygdalar activity can be induced by olfactory stimulation during migraine attack (Stankewitz and May, 2011), relating to the negative emotion of migraine. There is also increased functional connectivity between cortex and amygdala after repetitive episodes of CSD (Hadjikhani et al., 2013). ...
Article
Despite robust evidence on the role of calcitonin gene-related peptide (CGRP) in migraine via both central and peripheral actions, relatively less is known about how CGRP in the limbic system is involved in migraine progression. This study investigated whether CGRP production machinery exists in the two key limbic regions including hippocampus and amygdala using cortical spreading depression (CSD) as a model of migraine and whether such alteration by CSD is sensitive to N-methyl-D-aspartate (NMDA) receptor regulation in rats. A single or repetitive CSD was induced by topical application of KCl and monitored using electrophysiological methods. The NR2A-containing NMDA receptor antagonist, NVP-AAM077, or its vehicle, was perfused into the con-tralateral cerebroventricular ventricle of rat. Quantitative PCR was used to measure CGRP mRNA levels in the ipsilateral and contralateral hippocampus and amygdala after CSD events and compared to respective sham treatments. The results showed that neither a single CSD nor repetitive CSD affected CGRP mRNA levels in both the contralateral and ipsilateral hippocampus at 24 h post CSD induction. Differently, significant elevation of CGRP gene expression was observed in the ipsilateral amygdala at 24 h post multiple CSD, but not contralateral side, and not post-single CSD. Further results showed that the CSD-induced CGRP gene expression in the amygdala was markedly reduced by NVP-AAM077 and this reduction corresponded to a reduced cortical susceptibility to CSD in rats. We conclude that repetitive CSD events induce CGRP gene expression in amygdala, which is sensitive to NR2A regulation.
... These 2 potent and inflammatory vasodilatory substances trigger the painful phenomenon [1]. In addition, there is evidence that migraine patient on olfactory stimulation have increased the activity of the limbic system and brain stem, unlike normal individuals [20]. ...
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Introduction: Headache attacks may be triggered by several factors, among them odors, especially in migraine patients. Objectives: The aim of this study wasto determine the association between gasoline odor and headache attacks in patients with migraine or tension-type headache (TTH). Subjects and methods: The study was prospective, cross-sectional, with comparison of groups, using nonrandom sample and convenience. Fifty-two gas station workers diagnosed with migraine or TTH according to ICHD-3 criteria were interviewed on the relationship between gasoline odor and headache. Results: Of the 52 gas station workers with headaches, there were 39 (75%) with migraine without aura and 13 (25%) with TTH. The age ranged from 19 to 50 years, with a mean of 29.5 ± 7.2 years. Osmophobia during headache attacks predominated in workers with migraine (29/39; 74.4%). The onset of headache due to odor exposure occurred in 23/39 (60%) of the workers with migraine and in 2/13 (15.4%) in TTH. These differences were statistically significant (χ2 = 7.4; p = 0.016). Osmophobia in the absence of pain (period between attacks) predominated in workers with migraine (17/39, 43.6%), but with no statistical value. Conclusions: Gas station workers diagnosed with migraine or TTH may experience osmophobia and headache triggered by the odor of gasoline.
... The left STG region showed signi cantly increased connectivity in our study. Previous neuroimaging studies have repeatedly provided evidence of disrupted activation in the STG in migraine patients by using different methodological approaches [28,29]. However, Schwedt et al [30] illustrated the opposite pattern of neural activation in the STG in episodic migraineurs compared with HC. ...
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Background: Resting-state functional magnetic resonance imaging has confirmed auditory network dysfunction in migraine without aura (MwoA). Epidemiological investigations have disclosed that migraine is comorbid with many psychiatric symptoms. However, the underlying mechanisms of auditory cortex dysfunction linked to psychiatric disorders in MwoA remain unclear. The present study aimed to explore associations between brain activation in the auditory cortex and clinical and psychiatric characteristics in patients with MwoA during interictal periods. Methods: Resting-state data were acquired from patients with episodic MwoA (n=34) and healthy controls (n=30). Independent component analysis was used to extract and calculate the resting-state auditory network. Subsequently, we analyzed the correlations between spontaneous activation in the auditory cortex and clinical and psychiatric features in MwoA. Results: Compared with healthy controls, patients with MwoA showed increased activation in the left auditory cortex (i.e., superior temporal gyrus (STG), postcentral gyrus (PoCG) and insula). Brain activation in the left STG was positively correlated with anxiety scores, and activation in the left PoCG was negatively correlated with anxiety and depression scores. No significant differences were found in intracranial volume between the two groups. Conclusions: This study indicated that functional impairment and altered integration within the auditory cortex existed in patients with MwoA in the interictal period, suggesting that auditory cortex disruption as a biomarker may be implemented for the early diagnosis and prediction of neuropsychiatric impairment in MwoA.
... Neuroimaging studies with PET or fMRI during migraine attack have shown an area of activation in the dorsal rostral brainstem. [1][2][3][4] Moreover, a study using voxel-based morphometry in patients with migraine with aura (MA) showed increased gray matter density in the dorso-lateral pons suggesting permanent structural changes. 5 However, the dorsolateral pons encompasses several gray matter nuclei, and the limited resolution of neuroimaging approaches precludes any precise identification of activated/modified structures. ...
Article
Introduction: The locus coeruleus (LC) is one of the brainstem nuclei that may be activated during migraine attack. As LC contains neuromelanin, a by-product of norepinephrine synthesis, it can be delineated in vivo using neuromelanin sensitive magnetic resonance imaging (MRI). The neuromelanin content in LC has been suggested to reflect previous LC activation. We investigated LC MRI contrast in patients with migraine with aura (MWA) and its correlation with migraine features. Methods: This matched cohort study compared 23 MWA patients aged 30-55 and without comorbidity, to 23 sex- and age-matched healthy controls. The study was conducted in a University Hospital. LC contrast was measured with T1 neuromelanin-sensitive-weighted 3T MRI. Voxels were manually selected by 2 independent researchers and comparison was made twice using intersection and union of the voxels selected by the 2 observers. Results: No difference was found in neuromelanin LC contrast between MWA patients and controls with both the INTER method (0.224 ± 0.042 vs 0.228 ± 0.048; difference: 0.0001 (95%CI: -0.032 to 0.026), P = .799) and UNION method (0.218 ± 0.043 vs 0.222 ± 0.047; difference: -0.0012 (95%CI: -0.031 to 0.026), P = .775). Global LC volume was also similar between the 2 groups with INTER method (15.087 ± 3.965 vs 13.739 ± 3.583; difference: 2 (95%CI: -1 to 4), P = .233) and UNION method (17.522 ± 4.440 vs 16.087 ± 4.274; difference: 1 (95%CI: -2 to 4), P = .270). Moreover, no correlations were found between neuromelanin LC contrast and migraine features (duration of migraine and frequency of attacks). Conclusion: These negative findings do not support the use of neuromelanin LC contrast as a biomarker of MA.
... In addition, the perception of taste is processed in the anterior insular cortex, an area that also responds to olfactory stimulation [38], and there are reports that in migraine patients, the insula may be involved in the aversive response or disgust to food to protect from symptoms of nausea and vomiting [39]. Whilst osmophobia is less common than photophobia and phonophobia, there is evidence that migraineurs in the interictal phase experience olfactory hypersensitivity [40]. Though abnormal excitability and integration between visual, auditory, olfactory/gustatory and somatosensory cortices are relatively wellaccepted, there are con icting reports regarding abnormal excitability of motor cortices. ...
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Background Migraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine. Methods To explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks (n= 32) and in healthy controls (n=71). Significant differences between groups were determined using two-sample random effects procedures (p<0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables). ResultsIn the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices. Conclusions These data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.
... Osmophobic patients seem to have a more florid clinical picture and more affective symptoms. These findings suggest that Osmophobia is related to a broader sensorial hypersensivity which include photophobia, phonophobia, and allodynia during migraine attacks [36][37][38] evolving in the course of the disease [5,39]. ...
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Background: Osmophobia, is common among primary headaches, with prevalence of migraine. The study aimed to evaluate prevalence and clinical characteristics of patients with osmophobia in a cohort of primary headache patients selected at a tertiary headache center. The second aim was to verify the possible predicting role of osmophobia in preventive treatment response in a sub cohort of migraine patients. Methods: This was an observational retrospective cohort study based on data collected in a tertiary headache center. We selected patients aged 18-65 years, diagnosed as migraine without aura (MO), migraine with aura (MA) or Chronic Migraine (CM), Tension-Type Headache (TTH); and Cluster Headache (CH). We also selected a sub-cohort of migraine patients who were prescribed preventive treatment, according to Italian Guidelines, visited after 3 months follow up. Patients were considered osmophobic, if reported this symptom in at least the 20% of headache episodes. Other considered variables were: headache frequeny, the migraine disability assessment (MIDAS), Allodynia Symptom Checklist, Self-rating Depression scale, Self-rating Anxiety scale, Pain intensity evaluated by Numerical Rating Scale-NRS- form 0 to 10. Results: The 37,9% of patients reported osmophobia (444 patients with osmophobia, 726 without osmophobia). Osmophobia prevailed in patients with the different migraine subtypes, and was absent in patients with episodic tension type headache and cluster headache (chi square 68.7 DF 7 p < 0.0001). Headache patients with osmophobia, presented with longer hedache duration (F 4.91 p 0.027; more severe anxiety (F 7.56 0.007), depression (F 5.3 p 0.019), allodynia (F 6 p 0.014), headache intensity (F 8.67 p 0.003). Tension type headache patients with osmophobia (n° 21), presented with more frequent headache and anxiety. A total of 711 migraine patients was visited after 3 months treatment. The change of main migraine features was similar between patients with and without osmophobia. Conclusions: While the present study confirmed prevalence of osmophobia in migraine patients, it also indicated its presence among chronic tension type headache cases, marking those with chronic headache and anxiety. Osmophobia was associated to symptoms of central sensitization, as allodynia. It was not relevant to predict migraine evolution after first line preventive approach.
... The cerebellum has canonically been implicated in various forms of motor control and coordination [27,28]; however, recent evidence has suggested that it may have a role in regulating migraine [18]. Some MRI studies of migraine showed significantly increased cerebellar activity during the ictal phase compared to that during the interictal phase [29][30][31]. Increased cerebellar activity has been demonstrated in response to trigeminal noxious stimuli in patients with migraine and healthy subjects [32][33][34][35]. Several structural imaging studies have found ischemic cavities, subclinical infarcts, and lesions in the cerebellar cortex and white matter in patients with migraine, suggesting that the cerebellum is particularly vulnerable to atrophy and injury [36][37][38][39][40][41]. ...
Article
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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.
... In addition, the perception of taste is processed in the anterior insular cortex, an area that also responds to olfactory stimulation [43], and there are reports that in migraine patients, the insula may be involved in the aversive response or disgust to food to protect from symptoms of nausea and vomiting [44]. Whilst osmophobia is less common than photophobia and phonophobia, there is evidence that migraineurs in the interictal phase experience olfactory hypersensitivity [45]. Though abnormal excitability and integration between visual, auditory, olfactory/gustatory and somatosensory cortices are relatively well-accepted, there are conflicting reports regarding abnormal excitability of motor cortices. ...
Article
Full-text available
Background Migraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine. Methods To explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks ( n = 32) and in healthy controls ( n = 71). Significant differences between groups were determined using two-sample random effects procedures ( p < 0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables). Results In the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices. Conclusions These data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.
... 48 In fact, patients with migraine exhibit atypical brain activation in response to painful, olfactory, and visual stimuli and atypical functional connectivity in the sensory-discriminative processing of pain, affective emotional processing, cognitive processing, and pain modulation. 49 In migraine patients, activation of the limbic and rostral pons has been reported following exposure to odors, 50 and activation of the visual cortex has been reported following visual stimulation. 51 Clinical Studies on Migraine and Central Sensitization Table 2 shows clinical studies on CS in patients with migraine. ...
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Keisuke Suzuki, Shiho Suzuki, Tomohiko Shiina, Saro Kobayashi, Koichi Hirata Department of Neurology, Dokkyo Medical University, Mibu, JapanCorrespondence: Keisuke Suzuki, Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga, Mibu, Tochigi, 321-0293, Japan, Tel +81-282-86-1111, Fax +81-282-86-5884, Email keisuke@dokkyomed.ac.jpAbstract: Central sensitization (CS) is an increase in the responsiveness of nociceptive neurons in the central nervous system to their normal afferent input. As a result, even minor irritation can induce severe pain, leading to the chronicity and severity of various diseases, such as neurological disorders. CS is associated with migraine, which is a major neurological disorder that inflicts a high disability in daily life. Specifically, CS is thought to be involved in the pathogenesis of cutaneous allodynia as well as chronification of migraine. In this article, we reviewed the association between CS and migraine, including pathophysiological aspects and evidence from clinical studies. We suggest that appropriate screening and management of CS in migraine could further improve the quality of life of migraine patients.Keywords: migraine, central sensitization, cutaneous allodynia, restless legs syndrome
... Estructuras como las cortezas periamigdaloides y piriformes involucradas en procesos olfatorios, así como regiones en el núcleo anterior cortical amigdaloide, locus ceruleus y núcleo del rafé, comprometidos en procesos de dolor, inflamación e hipersensibilidad olfatoria, presentarían cambios funcionales y anatómicos, los cuales conducirían a la presencia de aversión, disgusto y fobia a los olores (28) . Asimismo, la asociación entre migraña y la estimulación olfativa se ha descrito en sujetos durante ataques migrañosos, donde con la ayuda de resonancia magnética funcional, se encontraron mayores niveles de oxígeno en sangre e hiperactividad en la amígdala y protuberancia rostral del tallo cerebral en respuesta a estímulos olfatorios (29) . En el caso de la amígdala, su activación se da tanto por olores placenteros como desagradables, y tiene la capacidad de diferenciar la intensidad de estos (30) . ...
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Objetivo: La migraña vestibular, es uno de los tipos de alteraciones vestibulares periféricas más comunes, asociada a la presentación de síntomas como cefalea, fotofobia, fonofobia y auras visuales. Otros como la osmofobia, si bien son reconocidos en la práctica clínica, son usualmente subregistrados y potencialmente pueden relacionarse con la presencia de episodios de migraña vestibular. Se realizó una revisión de la literatura acerca de la frecuencia e implicaciones clínicas entre migraña vestibular y osmofobia. Fuentes de datos: La búsqueda bibliográfica en las bases de datos PubMed, EBSCO, Scielo, Google Scholar y Bvsalud de artículos publicados entre los años 2011 y 2021 con los términos ‘vertigo and olfaction disorders’, ‘dizziness and olfaction disorders’, ‘migraine disorders and olfaction disorders’. Selección de estudios: Se encontraron 12 artículos donde se consignó la presencia de criterios diagnósticos de la Sociedad de Bárány, documentación de síntomas clínicos y porcentajes de presentación. De estos, únicamente 2 estudios en idioma inglés presentaron información relevante acerca de osmofobia y migraña vestibular. Extracción y síntesis de datos: De los 277 participantes diagnosticados con migraña vestibular participantes en dos estudios observacionales, sólo el 5% al 12% reportaron la presencia de osmofobia. Hasta el momento, sólo se conoce un reporte de caso que detalla en extensión la relación entre migraña vestibular y osmofobia. Conclusiones: La presencia de osmofobia podría estar sub-diagnosticada y sub registrada en pacientes con migraña vestibular. Se requieren más estudios a nivel clínico para determinar dicha asociación. Palabras clave: vértigo; trastornos migrañosos; trastornos del olfato.
... Another study using fMRI to compare responses to the smell of roses found higher blood oxygen level-dependent activity in the amygdala and insular cortices of the amygdala and also in the midbrain, particularly the rostral pons. However, the smell of roses did not show significant interictal differences compared to the controls [142]. Activation of the amygdala and orbitofrontal cortex might be related, respectively, with the intensity and valence of the smell emotional experience [143]. ...
Article
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Migraine is a complex and debilitating disorder that is broadly recognised by its characteristic headache. However, given the wide array of clinical presentations in migraineurs, the headache might not represent the main troublesome symptom and it can even go unnoticed. Understanding migraines exclusively as a pain process is simplistic and certainly hinders management. We describe the mechanisms behind some of the most disabling associated symptoms of migraine, including the relationship between the central and peripheral processes that take part in nausea, osmophobia, phonophobia, vertigo and allodynia. The rationale for the efficacy of the current therapeutic arsenal is also depicted in this article. The associated symptoms to migraine, apart from the painful component, are frequent, under-recognised and can be more deleterious than the headache itself. The clinical anamnesis of a headache patient should enquire about the associated symptoms, and treatment should be considered and individualised. Acknowledging the associated symptoms as a fundamental part of migraine has permitted a deeper and more coherent comprehension of the pathophysiology of migraine.
... During the ictal phase of spontaneous migraine attacks, Positron Emission Tomography (PET) studies revealed activation of bilateral insula cortex as well as other cortical areas, brainstem and diencephalic nuclei [8,9]. In addition, functional MRI studies during the ictal phase showed a stronger activation of the anterior insula in response to olfactory stimulations, but a decreased functional connectivity (FC) of the anterior insula with the medial prefrontal cortex within the Default Mode Network (DMN) inversely proportional to the pain intensity [10,11]. Another study showed a higher FC between the right thalamus and the left insular cortex during spontaneous migraine attacks [12]. ...
Article
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Introduction Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. Methods Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. Results Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. Discussion The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. Conclusion The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. Trial registration NCT02708797.
... The cerebellum has canonically been implicated in various forms of motor control and coordination [24,25]; however, recent evidence has suggested that it may have a role in regulating migraine [18]. Some MRI studies of migraine showed signi cantly increased cerebellar activity during the ictal phase compared to that during the interictal phase [26][27][28]. Increased cerebellar activity has been demonstrated in response to trigeminal noxious stimuli in patients with migraine and healthy subjects [29][30][31][32]. Several structural imaging studies have found ischemic cavities, subclinical infarcts, and lesions in the cerebellar cortex and white matter in patients with migraine, suggesting that the cerebellum is particularly vulnerable to atrophy and injury [33][34][35][36][37][38]. ...
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Full-text available
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.
... Some researchers found that patients with both MwoA and MwA had more triggers for MwoA attacks than WMA attacks [37]. According to previous findings, sleep-wake cycle disturbance [38], changes in mood [39], stress [40], and fears to specific odor [41] are closely related to hypothalamic function, limbic structures and descending modulation of the brainstem. The difference of triggers suggested different activity levels of these structures between the two subtypes. ...
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Background The aim of the study was to investigate whether MwoA and MwA are different manifestations of a single disease, distinct clinical entities, or located at two poles of a spectrum. Methods In this cross-sectional study, 5438 patients from 10 hospitals in China were included: 4651 were diagnosed with migraine without aura (MwoA) and 787 with migraine with aura (MwA). We used a validated standardized electronic survey to collect multidimensional data on headache characteristics and evaluated the similarities and differences between migraine subtypes. To distinguish migraine subtypes, we employed correlational analysis, factor analysis of mixed data (FAMD), and decision tree analysis. Results Compared to MwA, MwoA had more severe headaches, predominantly affected females, were more easily produced by external factors, and were more likely to have accompanying symptoms and premonitory neck stiffness. Patients with MwA are heterogeneous, according to correlation analysis; FAMD divided the subjects into three clear clusters. The majority of the differences between MwoA and MwA were likewise seen when typical aura with migraine headache (AWM) and typical aura with non-migraine headache (AWNM) were compared. Furthermore, decision trees analysis revealed that the chaotic MwA data reduced the decision tree’s accuracy in distinguishing MwoA from MwA, which was significantly increased by splitting MwA into AWM and AWNM. Conclusions The clinical phenomics of headache phenotype varies gradually from MwoA to AWM and AWNM, and AWM is a mid-state between MwoA and AWNM. We tend to regard migraine as a spectrum disorder, and speculate that different migraine subtypes have different “predominant regions” that generate attacks.
... During the ictal phase of spontaneous migraine attacks, Positron Emission Tomography (PET) studies revealed activation of bilateral insula cortex as well as other cortical areas, brainstem and diencephalic nuclei [8,9]. In addition, functional MRI studies during the ictal phase showed a stronger activation of the anterior insula in response to olfactory stimulations, but a decreased functional connectivity (FC) of the anterior insula with the medial prefrontal cortex within the Default Mode Network (DMN) inversely proportional to the pain intensity [10,11]. Another study showed a higher FC between the right thalamus and the left insular cortex during spontaneous migraine attacks [12]. ...
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Introduction : Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. Methods : Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. Results : Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. Discussion : The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. Conclusion : The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. Trial registration : NCT02708797
... These responses were absent in melanopsin-knockout mice. 74 In humans, the amygdala and insular areas have a higher activity during spontaneous migraine attacks, 123 ...
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A preference for darkness is one of the main associated features in people with migraine, the cause remaining a mystery until some decades ago. In this article, we describe the epidemiology of photophobia in migraine and explain the pathophysiological mechanisms following an anatomical structure. In addition, we review the current management of migraine and photophobia. Ongoing characterization of patients with photophobia and its different manifestations continues to increase our understanding of the intricate pathophysiology of migraine and vice versa . Detailed phenotyping of the patient with photophobia is encouraged.
Article
Objectives: In this study, we aimed to evaluate the clinical significance of osmophobia and its effect on quality of life in people with migraine. Methods: A total of 145 people with migraine were included in this cross-sectional study. Patients were evaluated with the migraine data form, the Migraine 24-Hour Quality of Life Questionnaire (24-HrMQoLQ), the Migraine Disability Assessment Scale (MIDAS), the Patient Health Questionnaire-9 (PHQ-9), the Insomnia Severity Index (ISI), the Generalized Anxiety Disorder-7 (GAD-7), the Allodynia Symptom Checklist (ASC), and the Fatigue Severity Scale (FSS). To evaluate the presence of osmophobia retrospectively, a semi-structured interview was conducted with the patients by the neurologist. Results: The mean 24-Hr-MQoLQ of patients with osmophobia was significantly lower than those without osmophobia. The decrease in the 24-Hr-MQoLQ was statistically significant in the areas of feeling and concerns and social functionality. The mean of the MIDAS scale was higher significantly in patients with osmophobia than those without osmophobia. In addition, the mean ISI, PHQ-9, FSS and ASC scores of patients with osmophobia were statistically significantly higher than those without osmophobia. Conclusions: Both 24-h and 3-month quality of life of people with migraine with osmophobia were more affected than those without osmophobia. At the same manner, insomnia, depression, fatigue and allodynia were observed at higher rates in people with migraine with osmophobia than in migraine without osmophobia. Osmophobia, which is one of the specific symptoms that distinguishes migraine from other headache disorders, deserves further and multifaceted investigation.
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Introduction Vestibular migraine as an entity was described in 1999 and its pathophysiology is still not established. Simultaneously with research to better understand vestibular migraine, there has been an improvement in vestibular function assessment. The video-head impulse test is one of the latest tools to evaluate vestibular function, measuring its vestibular-ocular reflex gain. Objective To evaluate vestibular function of vestibular migraine patients using video-head impulse test. Methods Cross-sectional case-control study homogeneous by age and gender with vestibular migraine patients according to the 2012–2013 Barany Society/International Headache Society diagnostic criteria submitted to video-head impulse test during intercrisis period. Results 31 vestibular migraine patients were evaluated with a predominantly female group (90.3%) and mean age of 41 years old. Vestibular function was normal in both patient and control groups. Gain values for horizontal canals were similar between the two groups, but gain values for vertical canals were higher in the group with vestibular migraine (p < 0.05). Patients with vestibular migraine felt more dizziness while performing the video-head impulse test than control subjects (p < 0.001). Conclusions Patients with vestibular migraine present normal vestibular function during intercrisis period when evaluated by video-head impulse test. Vertical canals, however, have higher gains in patients with vestibular migraine than in control subjects. Vestibular migraine patients feel dizziness more often while conducting video-head impulse test.
Article
Objective: The objectives of this study are to study osmophobia and odor-triggered headaches among headache pediatric patients. Background: Achieving the correct diagnosis for headaches in younger children can be challenging. The presence of osmophobia could constitute a helpful piece of information for making the correct diagnosis of headaches among adults. Methods: This was a cross-sectional study. Children and adolescents with headaches who were seen consecutively at a pediatric outpatient service and had at least 1 headache attack over the previous 12 months were included. We used a semi-structured questionnaire, Pediatric Migraine Disability Assessment, State-Trait Anxiety Inventory, and Children's Depression Inventory. Results: About 300 patients were included; 253 had migraine, 47 had a tension-type headache; 137 had osmophobia during headaches (135 were migraineurs). "Osmophobia during headaches" for diagnosing migraine: Sensitivity: 54.4% (95% CI: 48.2%-60.5%); specificity: 95.8% (95% CI: 85.8%-98.8%); positive predictive value (PPV): 98.5% (95% CI: 94.8%-99.6%); negative predictive value (NPV): 28.5% (95% CI: 22.0%-36.0%). Osmophobia was associated with higher intensity (OR: 2.90; 95% CI: 1.63, 5.15; P < .001) and duration of the headache (OR: 5.73; 95% CI: 2.29, 14.3; P < .001) and with vomiting (OR: 3.56; 95% CI: 1.83, 6.96; P < .001) (logistic regression). There were 62 patients (all of them migraineurs) with odor-triggered headaches: sensitivity for diagnosing migraine: 24.9% (95% CI: 19.9%-30.6%); specificity: 100% (95% CI: 92.4%-100%), PPV: 100% (95% CI: 94.8%-100%), NPV: 20% (95% CI: 16%-26.0%). Odor-triggered headaches were associated with higher intensity (OR: 3.47; 95% CI: 1.64, 7.35; P = .001) and duration of the headache (OR: 3.28; 95% CI: 1.37, 7.86; P = .001), vomiting (OR: 2.37; 95% CI: 1.19, 4.74; P = .014), and phonophobia (OR: 2.40; 95% CI: 1.08, 5.32; P = .031) (logistic regression). Osmophobia was associated with higher-impact migraine (OR: 4.65; 95% CI: 1.30, 16.6; P = .018) and emergency care (OR: 4.65; 95% CI: 1.81, 12.0; P = .001) (logistic regression). Conclusions: Osmophobia and odors as triggers for headaches are useful in diagnosing migraine and are markers for the severity of migraine in the pediatric population.
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Background Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. Objective To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. Methods Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. Results Overall, Tg mice showed significantly faster propagation velocity ( p < 0.01) and longer full-width-at-half-maximum ( p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals ( p < 0.01). Conclusion The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.
Article
This review summarizes major findings and recent advances in magnetic resonance spectroscopy (MRS) of migraine. A multi database search of PubMed, EMBASE, and Web of Science was performed with variations of magnetic resonance spectroscopy and headache until 20th September 2021. The search generated 2897 studies, 676 which were duplicates and 1836 were not related to headache. Of the remaining 385 studies examined, further exclusions for not migraine (n=114), and not MRS of human brain (n=128), and non-original contributions (n=51) or conferences (n=24) or case studies (n=11) or non-English (n=3), were applied. The manuscripts of all resulting reports were reviewed for their possible inclusion in this manuscript (n=54). The reference lists of all included reports were carefully reviewed and articles relevant to this review were added (n=2). Included are 56 studies of migraine with and without aura that involve magnetic resonance spectroscopy of the human brain. The topics are presented in the form of a narrative review. This review aims to provide a summary of the metabolic changes measured by MRS in patients with migraine. Despite the variability reported between studies, common findings focused on regions functionally relevant to migraine such as occipital cortices, thalamic nuclei, cerebellum and cingulate. The most reproducible results were decreased N-acetyl-aspartate (NAA) in cerebellum in patients with hemiplegic migraine and in the thalamus of chronic migraine patients. Increased lactate (Lac) in the occipital cortex was found for migraine with aura but not in subjects without aura. MRS studies support the hypothesis of impaired energetics and mitochondrial dysfunction in migraine. Although results regarding GABA and Glu were less consistent, studies suggest there might be an imbalance of these important inhibitory and excitatory neurotransmitters in the migraine brain. Multinuclear imaging studies in migraine with and without aura, predominantly investigating phosphorous, report alterations of PCr in occipital, parietal, and posterior brain regions. There have been too few studies to assess the diagnostic relevance of sodium imaging in migraine.
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Background It is important to implement disease-specific precautions to develop quality of life in migraine. The effect of osmophobia, which is one of the specific symptoms of migraine that might help to differentiate migraine from other headache disorders, on quality of life is unknown. The aim of the present study was to develop a practicable and reliable scale that assesses the effect of osmophobia on quality of life in migraine. Methods This cross-sectional study was carried out with 163 patients with migraine and 110 healthy individuals for control group. The scale items were constructed based on after literature review, expert opinions, and preliminary trial stage. A semi-structured interview was conducted with the patients by the Neurologist to evaluate the presence of osmophobia retrospectively. Migraine osmophobia-related quality of life assessment (MORA) consisted of 6 items including personal care, eating or cooking, house cleaning, close relationship, social life and traveling. Results The Cronbach's α coefficient was 0.86; and the Guttman split-half coefficient was 0.83. Receiver operating characteristic analysis showed an area under the curve of 0.943 (95%) confidence interval [CI] = 0.902–0.984), a cut off score of > 9.5, a sensitivity of 91.6%, a specificity of 85.7%. Mean scores of the MORA differed between people with migraine (with and without osmophobia) and healthy controls (<0.001). Conclusion MORA is a valid and reliable self-report questionnaire that assesses the effect of osmophobia on quality of life in migraine. This questionnaire appears to be practicable diagnostic instrument in clinical practice and research.
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Migraine is a common neurological disease with a still-unclear etiology and pathogenesis. Patent foramen ovale (PFO) is a kind of congenital heart disease that leads to a right-to-left shunt (RLS). Although previous studies have shown that PFO has an effect on migraine, a clear conclusion about the link between PFO and migraine is lacking. We first summarized the PFO potential mechanisms associated with migraine, including microembolus-triggered cortical spreading depression (CSD), the vasoactive substance hypothesis, impaired cerebral autoregulation (CA), and a common genetic basis. Further, we analyzed the changes in brain structure and function in migraine patients and migraine patients with PFO. We found that in migraine patients with PFO, the presence of PFO may affect the structure of the cerebral cortex and the integrity of white matter, which is mainly locked in subcortical, deep white matter, and posterior circulation, and may lead to changes in brain function, such as cerebellum and colliculus, which are involved in the processing and transmission of pain. In summary, this paper provides neuroimaging evidence and new insights into the correlation between PFO and migraine, which will help to clarify the etiology and pathogenesis of migraine , and aid in the diagnosis and treatment of migraine in the future.
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Migraine is a common neurological disease with a high prevalence and unsatisfactory treatment options. The specific pathophysiological mechanisms of migraine remain unclear, which restricts the development of effective treatments for this prevalent disorder. The aims of this study were to 1) compare the spontaneous brain activity differences between Migraine without Aura (MwoA) patients and healthy controls (HCs), using amplitude of low-frequency fluctuations (ALFF) calculation method, and 2) explore how an effective treatment (verum acupuncture) could modulate the ALFF of MwoA patients. One hundred MwoA patients and forty-six matched HCs were recruited. Patients were randomized to four weeks' verum acupuncture, sham acupuncture, and waiting list groups. Patients had resting state BOLD-fMRI scan before and after treatment, while HCs only had resting state BOLD-fMRI scan at baseline. Headache intensity, headache frequency, self-rating anxiety and self-rating depression were used for clinical efficacy evaluation. Compared with HCs, MwoA patients showed increased ALFF in posterior insula and putamen/caudate, and reduced ALFF in rostral ventromedial medulla (RVM)/trigeminocervical complex (TCC). After longitudinal verum acupuncture treatment, the decreased ALFF of the RVM/TCC was normalized in migraine patients. Verum acupuncture and sham acupuncture have different modulation effects on ALFF of RVM/TCC in migraine patients. Our results suggest that impairment of the homeostasis of the trigeminovascular nociceptive pathway is involved in the neural pathophysiology of migraines. Effective treatments, such as verum acupuncture, could help to restore this imbalance.
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Introduction : La migraine avec aura (MA) augmente le risque d'accident vasculaire cérébral (AVC). Parmi les hypothèses pouvant expliquer cette association, un défaut d'autorégulation cérébrale (AC) et un risque accru de fibrillation atriale sont évoqués. L'AC est en partie contrôlée par des noyaux du tronc cérébral tel que le locus coeruleus qui peut être exploré par une IRM de neuromélanine. La fibrillation atriale peut être déclenchée par des lésions de l'insula, qui est activée au cours des crises de migraine. Nous avons recherché des biomarqueurs du risque d'AVC dans la MA en étudiant d'une part le signal du locus coeruleus et l'AC et d'autre part la connectivité de l'insula et la régulation du rythme cardiaque. Méthodes : Dans une étude cas-contrôle, nous avons comparé 23 migraineux avec aura, âgés de 30 à 55 ans, à 23 contrôles. L'évaluation de l'AC a reposé sur le calcul d'indices de corrélations temporel et fréquentiel entre la vitesse circulatoire cérébrale mesurée par doppler transcrânien et la pression artérielle mesurée par photo-pléthysmographie. La variabilité de la fréquence cardiaque a été évaluée dans le domaine fréquentiel par une analyse spectrale. Le signal et le volume du locus coeruleus ont été mesurés grâce à une IRM de neuromélanine et la connectivité de l'insula grâce à une IRM fonctionnelle de repos. Résultats : Aucune différence d'AC ni de la variabilité de la fréquence cardiaque n'a été trouvée. Toutefois il existait une corrélation négative entre les performances d'AC et l'ancienneté de la migraine (rho = - 0.62 ; p = 0,002). Le LC ne différait pas en signal ni en volume entre migraineux avec aura et contrôles. Une faible corrélation entre les performances d'AC et le signal de LC a été identifiée (rho = 0,33 ; p = 0,030). L'insula antérieure dorsale et bilatérale était plus fortement corrélée avec le cervelet (vermis VI) dans la migraine avec aura (à droite : T = 6,24 ; p < 0,0001, à gauche : T = 5,02 ; p < 0,0001). Cependant, cette connectivité accrue n'était pas corrélée à la variabilité de la fréquence cardiaque. Discussion : La corrélation négative entre l'AC et l'ancienneté de la migraine avec aura suggérait une altération de l'AC au début de la maladie, ce qui est cohérent avec un risque d'AVC accru à un âge jeune dans la MA. L'AC n'était que faiblement corrélée à l'intensité de neuromélanine du locus coeruleus et aucune différence du locus coeruleus n'était trouvée dans la MA, ce qui ne fait pas du locus coeruleus un bon biomarqueur. L'insula antérieure dorsale droite et gauche étaient plus fortement connectée au vermis VI dans la MA. Les données de la littérature suggèrent un rôle du vermis supérieur dans le contrôle du système nerveux autonome cardiovasculaire. Des travaux ultérieurs pourraient chercher à explorer le lien entre cette connectivité accrue, la dysautonomie et le risque de fibrillation atriale dans la MA. Conclusion : Le signal de neuromélanine du LC ne semblait pas être un biomarqueur du défaut d'AC dans la MA. En revanche, la connectivité accrue de l'insula antérieure dorsale bilatérale avec le vermis VI justifierait des recherches complémentaires pour comprendre son lien avec le contrôle du système nerveux autonome.
Article
Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.
Thesis
Attention is the cognitive ability which allows us to select and preferentially process relevant information in our environment. It relies on a balance between top-down and bottom-up processes and is heavily influenced by the ongoing arousal levels. Thereby, salient sounds in our environment can both hinder our performance during a task by capturing our attention or on the contrary boost our performance by triggering a transient increase in arousal. Attentional mechanisms are disturbed in numerous neurological and psychiatric disorder. Migraine is a neurological disorder which is not limited to recurrent and severe headaches: it is also characterized by sensory hypersensitivity which climaxes during migraine attack but also persists at a lower level in the pain-free period. Recent studies suggest that the attentional process of sensory inputs is dysfunctional in migraine: a deficient attentional filter may participate to sensory symptoms associated with the disorder. The aim of this work was made possible in part thanks to MEG and EEG recordings during a competitive attention task designed to evaluate conjointly voluntary attention, involuntary attention and phasic arousal. First, we attempted to isolate an electrophysiological marker of phasic increases in arousal triggered by the onset of salient sounds among healthy participants. The early-P3, an event-related response classically associated to attention capture, turned out to be a good candidate as a marker of phasic arousal. Then, we demonstrated that migraineurs presented a disrupted attentional processing of sounds, namely at the level of bottom-up attention and top-down inhibitory processes. These results were corroborated by a questionnaire study which revealed that migraineurs complain about attention difficulties in the everyday life and that these difficulties correlate with the sensory disturbances they experience. Finally, we aimed to detect anomalies of brain structure in migraine by analyzing newly acquired anatomical MRI and diffusion tensor imaging data, which we confronted to previous results of the literature. Neither the analysis of our anatomical data, nor the meta-analysis of the literature provided convincing evidence of an abnormal brain structure in migraine. This work provides new insights in the understanding of sensory symptoms in migraine and in parallel, offers a new tool to investigate phasic arousal.
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This is perhaps the largest repository of clinically invaluable data and critically-principled well-organized biologically-plausible and logically-robust opinion regarding cortical spreading depression and associated phenomenology of migraine. It is the extenuated saga of how successfully and skillfully CSD has been kept politically centre-stage and how it has dwarfed or thwarted science in migraine over the last 100 years. All headache researchers and therapists of this era and of all times to come have to have a sound grasp of the posits and limits of the concept of CSD. CSD is a classic example of irrational scepticism -- "keeping the mind open till the brain falls out" (Skrabanek P. Lancet 1986;i:960-961) and demarcates much that is absurd in migraine research and science, including failure of peer review as well as the uncritical accumulation of data. This version of my critique on CSD was rejected 10 years ago by the same journal that started the journey of CSD. One of the greatest values of pre-prints is that such "heretical" articles can find the light of publication, at least when the motive for search for scientific truth overcomes tenures, research grants, and patent searches, and brings back biological significance to the centrestage. Like Popperian logic, CSD-like big data remind us that it is only humans that err. While CSD is evolution of pure serendipity, acknowledgment of error renders the brain free of bias. The unending saga of CSD in migraine teaches all neurologists, headache- specialists, and other researchers in physiology / medicine, that fundamental logic and biological bias/insight far outweighs the increasing complexities of mathematical/statistical bias in research importance.
Chapter
Migraine is a chronic, neurobiological disorder characterized by attacks of head pain and various associated features. Attacks are often separated by periods of normal brain function. Even at times of symptom freedom, patients possess an underlying predisposition for migraine episodes. This predisposition is felt to arise from a biologically based inherent hypersensitivity of the central nervous system. Exposure to certain internal and external factors may trigger a migraine attack in those possessing this migraine-prone nervous system while leaving those without such a predisposition unaffected. There are several methodological challenges in studying migraine triggers, and most of the work has come from retrospective recall or checklist surveys. Differentiating migraine triggers from early premonitory features of the prodromal phase of migraine can sometimes be challenging. Stress, changes in female hormones, sleep or meal pattern disruptions, weather factors, and strong sensory light, sound, or odor stimuli are among the most frequently reported. Identification of patient-specific migraine triggers may provide therapeutic advantages. Patients may be educated to predict or avoid certain attacks, while acute intervention measures may be deployed more readily in others. The knowledge gained from clinical research on migraine triggers may help inform specific lifestyle management recommendations for this patient population.
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Background Episodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI). Methods Intrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack. Results We found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and “dropped” to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms. Conclusion Our results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.
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Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs’ brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.
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Acupuncture is commonly used as a treatment for migraines. Animal studies have suggested that acupuncture can decrease neuropeptides, immune cells, and proinflammatory and excitatory neurotransmitters, which are associated with the pathogenesis of neuroinflammation. In addition, acupuncture participates in the development of peripheral and central sensitization through modulation of the release of neuronal-sensitization-related mediators (brain-derived neurotrophic factor, glutamate), endocannabinoid system, and serotonin system activation. Clinical studies have demonstrated that acupuncture may be a beneficial migraine treatment, particularly in decreasing pain intensity, duration, emotional comorbidity, and days of acute medication intake. However, specific clinical effectiveness has not been substantiated, and the mechanisms underlying its efficacy remain obscure. With the development of biomedical and neuroimaging techniques, the neural mechanism of acupuncture in migraine has gained increasing attention. Neuroimaging studies have indicated that acupuncture may alter the abnormal functional activity and connectivity of the descending pain modulatory system, default mode network, thalamus, frontal-parietal network, occipital-temporal network, and cerebellum. Acupuncture may reduce neuroinflammation, regulate peripheral and central sensitization, and normalize abnormal brain activity, thereby preventing pain signal transmission. To summarize the effects and neural mechanisms of acupuncture in migraine, we performed a systematic review of literature about migraine and acupuncture. We summarized the characteristics of current clinical studies, including the types of participants, study designs, and clinical outcomes. The published findings from basic neuroimaging studies support the hypothesis that acupuncture alters abnormal neuroplasticity and brain activity. The benefits of acupuncture require further investigation through basic and clinical studies.
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Migraine encompasses a broader spectrum of sensory symptoms than just headache. These “other” symptoms, eg, sensory phobias, cognitive and mood changes, allodynia, and many others indicate an altered sensitivity to sensory input which can be measured, in principle, by quantifying sensory threshold changes longitudinally over time. Photophobia, for example, can be quantified by investigating the discomfort thresholds towards the luminance of light. The aim of this review is to look into how thresholds change in patients with migraine. We performed a PubMed search up to June 2018 targeting all peer-reviewed articles evaluating the changes in threshold, sensory phobia, or sensitivity in patients with migraine. Migraineurs, in general, exhibit lower sensory thresholds compared with healthy controls. These threshold changes seem to follow the different phases during a migraine cycle. In general, thresholds reach a nadir when the headache starts (the ictal phase), rise after the headache ends, and then gradually descend towards the next attack. The sensory modality of measurement – mechanical, thermal, or nociceptive – and the location of measurement –trigeminal vs somatic dermatome – also influence the sensory threshold. Functional imaging studies provide evidence that the hypothalamo-thalamobrainstem network may be the driving force behind the periodic threshold changes. In summary, there is evidence in the literature that migraine could be understood as a periodic sensory dysregulation originating from the brain. Nevertheless, the interstudy discrepancy is still high due to different study designs and a lack of focus on distinct migraine phases. Further well-designed and harmonized studies with an emphasis on the cyclic changes still need to be conducted.
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Neural correlates of responses to emotionally valenced olfactory, visual, and auditory stimuli were examined using positron emission tomography. Twelve volunteers were scanned using the water bolus method. For each sensory modality, regional cerebral blood flow (rCBF) during presentation of both pleasant and unpleasant stimuli was compared with that measured during presentation of neutral stimuli. During the emotionally valenced conditions, subjects performed forced-choice pleasant and unpleasant judgments. During the neutral conditions, subjects were asked to select at random one of a two key-press buttons. All stimulations were synchronized with inspiration, using an airflow olfactometer, to present the same number of stimuli for each sensory modality. A no-stimulation control condition was also performed in which no stimulus was presented. For all three sensory modalities, emotionally valenced stimuli led to increased rCBF in the orbitofrontal cortex, the temporal pole, and the superior frontal gyru
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The sensation and perception of smell (olfaction) are largely dependent on sniffing, which is an active stage of stimulus transport and therefore an integral component of mammalian olfaction. Electrophysiological data obtained from study of the hedgehog, rat, rabbit, dog and monkey indicate that sniffing (whether or not an odorant is present) induces an oscillation of activity in the olfactory bulb, driving the piriform cortex in the temporal lobe, in other words, the piriform is driven by the olfactory bulb at the frequency of sniffing. Here we use functional magnetic resonance imaging (fMRI) that is dependent on the level of oxygen in the blood to determine whether sniffing can induce activation in the piriform of humans, and whether this activation can be differentiated from activation induced by an odorant. We find that sniffing, whether odorant is present or absent, induces activation primarily in the piriform cortex of the temporal lobe and in the medial and posterior orbito-frontal gyri of the frontal lobe. The source of the sniff-induced activation is the somatosensory stimulation that is induced by air flow through the nostrils. In contrast, a smell, regardless of sniffing, induces activation mainly in the lateral and anterior orbito-frontal gyri of the frontal lobe. The dissociation between regions activated by olfactory exploration (sniffing) and regions activated by olfactory content (smell) shows a distinction in brain organization in terms of human olfaction.
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Efficient recognition of odorous objects universally shapes animal behavior and is crucial for survival. To distinguish kin from nonkin, mate from nonmate and food from nonfood, organisms must be able to create meaningful perceptual representations of odor qualities and categories. It is currently unknown where and in what form the brain encodes information about odor quality. By combining functional magnetic resonance imaging (fMRI) with multivariate (pattern-based) techniques, we found that spatially distributed ensemble activity in human posterior piriform cortex (PPC) coincides with perceptual ratings of odor quality, such that odorants with more (or less) similar fMRI patterns were perceived as more (or less) alike. We did not observe these effects in anterior piriform cortex, amygdala or orbitofrontal cortex, indicating that ensemble coding of odor categorical perception is regionally specific for PPC. These findings substantiate theoretical models emphasizing the importance of distributed piriform templates for the perceptual reconstruction of odor object quality.
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Functional imaging of human trigemino-nociceptive processing provides meaningful insights into altered pain processing in head and face pain diseases. Although functional magnetic resonance imaging (fMRI) offers high temporal and spatial resolution, most studies available were done with radioligand-positron emission tomography, as fMRI requires non-magnetic stimulus equipment and fast on–off conditions. We developed a new approach for painful stimulation of the trigeminal nerve that can be implemented within an event-related design using fMRI and aimed to detect increased blood-oxygen-level-dependent (BOLD) signals as surrogate markers of trigeminal pain processing. Using an olfactometer, 20 healthy volunteers received intranasally standardized trigeminal nociceptive stimuli (ammonia gas) as well as olfactory (rose odour) and odourless control stimuli (air puffs). Imaging revealed robust BOLD responses to the trigeminal nociceptive stimulation in cortical and subcortical brain areas known to be involved in pain processing. Focusing on the trigeminal pain pathway, significant activations were observed bilaterally in brainstem areas at the trigeminal nerve entry zone, which are agreeable with the principal trigeminal nuclei. Furthermore, increased signal changes could be detected ipsilaterally at anatomical localization of the trigeminal ganglion and bilaterally in the rostral medulla, which probably represents the spinal trigeminal nuclei. However, brainstem areas involved in the endogenous pain control system that are close to this anatomical localization, such as raphe nuclei, have to be discussed. Our findings suggest that mapping trigeminal pain processing using fMRI with this non-invasive experimental design is feasible and capable of evoking specific activations in the trigeminal nociceptive system. This method will provide an ideal opportunity to study the trigeminal pain system in both health and pathological conditions such as idiopathic headache disorders.
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Currently available techniques used in neurosciences and particularly cerebral imaging are contributing to a better understanding of human perception and the treatment of sensorial information. In this field, the chemical senses (taste and smell) have received little attention when compared with the auditory, visual and tactile senses. Nevertheless, recent research has been trying to overcome this. Brain regions involved in the processing of olfactory information have been investigated in several studies including a large number dealing with the question of lateralization. However, functional asymmetry in olfaction has still not been resolved and the resulting data have not been homogeneous. In this field, the contribution of cerebral imaging studies is very important insofar as it shows that the processes of functional lateralization in olfaction depend on many factors (nature of stimulus, nature of task, characteristics of subjects …) that future research will have to consider.
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Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.
Article
Functional imaging of human trigemino-nociceptive processing provides meaningful insights into altered pain processing in head and face pain diseases. Although functional magnetic resonance imaging (fMRI) offers high temporal and spatial resolution, most studies available were done with radioligand-positron emission tomography, as fMRI requires non-magnetic stimulus equipment and fast on-off conditions. We developed a new approach for painful stimulation of the trigeminal nerve that can be implemented within an event-related design using fMRI and aimed to detect increased blood-oxygen-level-dependent (BOLD) signals as surrogate markers of trigeminal pain processing. Using an olfactometer, 20 healthy volunteers received intranasally standardized trigeminal nociceptive stimuli (ammonia gas) as well as olfactory (rose odour) and odorless control stimuli (air puffs). Imaging revealed robust BOLD responses to the trigeminal nociceptive stimulation in cortical and subcortical brain areas known to be involved in pain processing. Focusing on the trigeminal pain pathway, significant activations were observed bilaterally in brainstem areas at the trigeminal nerve entry zone, which are agreeable with the principal trigeminal nuclei. Furthermore, increased signal changes could be detected ipsilaterally at anatomical localization of the trigeminal ganglion and bilaterally in the rostral medulla, which probably represents the spinal trigeminal nuclei. However, brainstem areas involved in the endogenous pain control system that are close to this anatomical localization, such as raphe nuclei, have to be discussed. Our findings suggest that mapping trigeminal pain processing using fMRI with this non-invasive experimental design is feasible and capable of evoking specific activations in the trigeminal nociceptive system. This method will provide an ideal opportunity to study the trigeminal pain system in both health and pathological conditions such as idiopathic headache disorders.
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Whereas there are many H(2)(15)O-positron emission tomography (PET) studies demonstrating neuronal activation during acute migraine attacks, little information is available on the interictal (headache-free period) glucose metabolic changes in migraine. We therefore conducted voxel-based statistical parametric mapping analysis of (18)F-fluorodeoxyglucose-PET to evaluate interictal metabolic differences between 20 episodic migraine patients (four with aura; three men; mean age 34.0 +/- 6.4 years) and 20 control subjects. Separate correlation analyses were performed to delineate a possible relationship between regional glucose metabolism and disease duration or lifetime headache frequency in migraine patients. Group comparison showed that migraine patients had significant hypometabolism in several regions known to be involved in central pain processing, such as bilateral insula, bilateral anterior and posterior cingulate cortex, left premotor and prefrontal cortex, and left primary somatosensory cortex (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Correlation analyses showed that regional metabolism of the insula and anterior cingulate cortex had significant negative correlations with disease duration and lifetime headache frequency (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Our findings of progressive glucose hypometabolism in relation to increasing disease duration and increasing headache frequency suggest that repeated migraine attacks over time lead to metabolic abnormalities of selective brain regions belonging to the central pain matrix.
Article
Olfactory hypersensitivity (OHS) may occur during migraine attacks and seems to be very specific to this form of headache. OHS is also observed during migraine-free periods and is associated with the presence of odour-triggered attacks. Yet the pathophysiology of OHS remains unknown. The aim of our study was to evaluate olfactory processing in migraineurs with OHS and to investigate whether regional cerebral blood flow (rCBF) associated with olfactory stimulation is modified in these patients compared with controls. Eleven migraineurs with OHS and 12 controls participated in a H(2)(15)O-positron emission tomography study, including three scans in which odours were delivered and three scans where only odourless air was delivered. rCBF during olfactory condition was compared with that for the odourless baseline condition. Between-group analyses were performed using voxel-based and region-of-interest analyses. During both olfactory and non-olfactory conditions, we observed higher rCBF in the left piriform cortex and antero-superior temporal gyrus in migraineurs compared with controls. During odour stimulation, migraineurs also showed significantly higher activation than controls in the left temporal pole and significantly lower activation in the frontal (left inferior as well as left and right middle frontal gyri) and temporo-parietal (left and right angular, and right posterior superior temporal gyri) regions, posterior cingulate gyrus and right locus coeruleus. These results could reflect a particular role of both the piriform cortex and antero-superior temporal gyrus in OHS and odour-triggered migraine. Whether these rCBF changes are the cause or a consequence of odour-triggered migraines and interictal OHS remains unknown. Further comparisons between migraineurs with and without OHS are warranted to address this issue. The abnormal cerebral activation patterns during olfactory stimulation might reflect altered cerebrovascular response to olfactory stimulation due to the migraine disease, or an abnormal top-down regulation process related to OHS.
Article
According to recent evoked potential studies, a fundamental, probably protective, feature of cortical information processing, ie, response habituation during stimulus repetition, is abnormal in migraine between attacks. The deficient habituation is found for different sensory modalities and experimental paradigms: pattern-reversal visual evoked potentials (same stimulus at a constant intensity), cortical auditory evoked potentials (same stimulus at increasing intensities) and auditory event-related potentials obtained in a passive "oddball" paradigm (novel stimulus). The abnormal information processing is an interictal cortical dysfunction most likely due to inadequate control by the so-called "state-setting, chemically-addressed pathways" originating in the brain stem, in particular by the serotonergic pathway, leading to a low preactivation level of sensory cortices. We suggest that it may play a pivotal role in migraine pathogenesis in conjunction with the reported decrease of brain mitochondrial energy reserve, by favouring a rupture of metabolic homeostasis and biochemical shifts capable of activating the trigeminovascular system and thus capable of producing a migraine attack. We postulate that both the deficient habituation in information processing and the deranged oxygen metabolism may have behavioral correlates. Which of these abnormalities are inherited, acquired or both remains to be determined.
Article
Olfactory thresholds for acetone and vanillin and the unpleasantness rating of concentrated acetone were measured in 20 migraine sufferers and 21 controls. The olfactory threshold for vanillin was lower in migraine sufferers than in controls. In addition, patients who reported that odours frequently seemed stronger during attacks of migraine were able to detect acetone at a lower concentration than most other patients. No differences were found between migraine sufferers and controls for ratings of the unpleasantness of concentrated acetone. These findings suggest that hyperacuity to odours persists between episodes of migraine. Sensitivity to odours could contribute to the migraine predisposition.
Article
This study investigated human BOLD responses in primary and higher order olfactory cortices following presentation of short- and long-duration odorant stimuli using a 3-T MR scanner. The goal was to identify temporal differences in the course of the response that might underlie habituation. A short-duration stimulus (9 s) consistently activated the primary olfactory cortex (POC). After a long stimulus (60 s), the temporal form of the response differed in different parts of the olfactory network: (1) The POC (piriform, entorhinal cortex, amygdala) and, interestingly, the hippocampus and, to a certain degree, the anterior insula show a short, phasic increase in the signal, followed by a prolonged decrease below baseline. (2) In the orbitofrontal cortex a sustained increase in activation was seen. This increase lasted approximately as long as the duration of odorant presentation ( approximately 60 s). (3) The mediodorsal nucleus of the thalamus and the caudate nucleus responded with an increase in signal which returned to baseline after approximately 15 to 30 s. The correlated biphasic hemodynamic response in the POC, hippocampus, and anterior insula during prolonged olfactory stimulation suggests that these three areas may interact closely with each other in the control of habituation. These results extend recent data which showed habituation of the rat piriform cortex and dissociation between the POC and the orbitofrontal cortex.
Article
The role of temporal lobe structures in olfactory memory was investigated by (i) the examination of odour learning and memory in patients who had undergone resection from a temporal lobe (including primary olfactory regions) for the treatment of intractable epilepsy; and (ii) the examination of brain function during odour memory tasks as assessed via PET imaging of healthy individuals. In order to study different stages of odour memory, recognition of a 'list' of odours was tested after a first exposure, again after four exposures and once more after a 24 h delay interval. Patients with resection from a temporal lobe performed significantly less well than control subjects on all trials, and no significant differences were noted as a function of side of resection, indicating that there is not a strong hemispheric superiority for this task. The PET data yielded different levels of activity in piriform cortex (primary olfactory cortex), in relation to the 'no-odour' baseline scan, depending on the type of processing: no increase in activity noted during odour encoding, a small increase bilaterally during short-term recognition and a larger increase bilaterally during long-term recognition. These findings, together with findings in animal studies, suggest that piriform cortex may have an active role in odour memory processing, not simply in odour perception. Taken together, the findings from the lesion study and functional brain imaging of healthy subjects suggest that olfactory memory requires input from left and right temporal lobe regions for optimal odour recognition, and that, unlike with verbal or non-verbal visual material, there is not a strong functional lateralization for olfactory memory.
Article
This study assesses osmophobia and taste abnormality for the first time in a large sample of migraine patients. Seven hundred and twenty seven migraineurs were evaluated. Osmophobia, taste abnormality, and perfume or odor trigger were graded from 0 to 3. In patients with data, 24.7% of 673 patients complained of osmophobia (12.5% occasional, 7% frequent, and 5.2% very frequent) and 24.6% of 505 of taste abnormality (13.5% occasional, 6.1% frequent, and 5.0% very frequent). Perfume or odor trigger of acute migraine occurred in 45.5% of 724 patients (22.7% occasional, 10.2% frequent, and 12.6% very frequent). Perfume or odor trigger was associated with osmophobia in 61.5% and taste abnormality 62.1%. Osmophobia without taste abnormality occurred in 28.3% and taste abnormality without osmophobia in 40.3%. A greater percentage of females than males had osmophobia (25.7 vs. 17.5), taste abnormality (25.4 vs. 17.9), and perfume or odor trigger (49.3 vs. 22.1), all P<.0001. Osmophobia and taste abnormality occur in about one quarter of migraineurs during an acute migraine attack while perfume or odor trigger migraine in almost 50% of patients. Osmophobia and taste abnormality in the acute migraine attack, as well as perfumes or odor as a migraine trigger, are more common in females than in males.
Article
The pathophysiological relationship between episodic migraine and chronic migraine is not fully understood. We aimed to examine transcranial magnetic stimulation (TMS) indices of cortical excitability in patients with episodic migraine (EM) and probable chronic migraine (PCM), and matched controls. Cortical excitability was assessed at baseline with two well-established methods: phosphene thresholds (PT) and magnetic suppression of perceptual accuracy (MSPA) profiles. Five EM patients, five PCM patients, and five normal controls participated in the main study. In addition, two patients were reassessed after 30 days of treatment with topiramate. Both PT and MPSA measures were consistent in indicating a continuum of excitability across the three groups: PCM patients had the highest excitability, followed by EM, then controls. In the two treated patients MPSA profiles appeared to normalize at a 100 mg dosage. Patients with PCM appear to be characterized by very high cortical excitability. This may contribute to their greatly increased attack frequency. TMS-based methods will be important for future research examining the evolution of chronic migraine from episodic migraine over time.
Article
It is widely accepted that the orbitofrontal cortex (OFC) represents the main neocortical target of primary olfactory cortex. In non-human primates, the olfactory neocortex is situated along the basal surface of the caudal frontal lobes, encompassing agranular and dysgranular OFC medially and agranular insula laterally, where this latter structure wraps onto the posterior orbital surface. Direct afferent inputs arrive from most primary olfactory areas, including piriform cortex, amygdala, and entorhinal cortex, in the absence of an obligatory thalamic relay. While such findings are almost exclusively derived from animal data, recent cytoarchitectonic studies indicate a close anatomical correspondence between non-human primate and human OFC. Given this cross-species conservation of structure, it has generally been presumed that the olfactory projection area in human OFC occupies the same posterior portions of OFC as seen in non-human primates. This review questions this assumption by providing a critical survey of the localization of primate and human olfactory neocortex. Based on a meta-analysis of human functional neuroimaging studies, the region of human OFC showing the greatest olfactory responsivity appears substantially rostral and in a different cytoarchitectural area than the orbital olfactory regions as defined in the monkey. While this anatomical discrepancy may principally arise from methodological differences across species, these results have implications for the interpretation of prior human lesion and neuroimaging studies and suggest constraints upon functional extrapolations from animal data.
Article
The relationship between odorant structure and odor quality has been a focus of olfactory research for 100 years, although no systematic correlations are yet apparent. Animal studies suggest that topographical representations of odorant structure in olfactory bulb form the perceptual basis of odor quality. Whether central olfactory regions are similarly organized is unclear. Using an olfactory version of fMRI cross-adaptation, we measured neural responses in primary olfactory (piriform) cortex as subjects smelled pairs of odorants systematically differing in quality and molecular functional group (as one critical attribute of odorant structure). Our results indicate a double dissociation in piriform cortex, whereby posterior regions encode quality (but not structure) and anterior regions encode structure (but not quality). The presence of structure-based codes suggests fidelity of sensory information arising from olfactory bulb. In turn, quality-based codes are independent of any simple structural configuration, implying that synthetic mechanisms may underlie our experience of smell.
Article
It is widely presumed that odor quality is a direct outcome of odorant structure, but human studies indicate that molecular knowledge of an odorant is not always sufficient to predict odor quality. Indeed, the same olfactory input may generate different odor percepts depending on prior learning and experience. Combining functional magnetic resonance imaging with an olfactory paradigm of perceptual learning, we examined how sensory experience modifies odor perception and odor quality coding in the human brain. Prolonged exposure to a target odorant enhanced perceptual differentiation for odorants related in odor quality or functional group, an effect that was paralleled by learning-induced response increases in piriform cortex and orbitofrontal cortex (OFC). Critically, the magnitude of OFC activation predicted subsequent improvement in behavioral differentiation. Our findings suggest that neural representations of odor quality can be rapidly updated through mere perceptual experience, a mechanism that may underlie the development of odor perception.