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Increased limbic and brainstem activity during migraine attacks following olfactory stimulation
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.
... The OFC, a component of the secondary olfactory cortex is recognized as the central hub for cognitive processing and memorization of odors. [36][37][38][39] The left OFC is more involved in the pleasantness and unpleasantness processing of one odor. 40 Prior research has indicated that the medial OFC is activated in response to pleasant odors. ...
... It is significantly associated with the processes of learning and memory retention of these odors. 36,46 Furthermore, the amygdala is specifically activated during the intensity coding of both pleasant and unpleasant odors. 36 Our findings indicate an upsurge in activity within the left OFC, right ACC, and right IFG in the MOT group. ...
... 36,46 Furthermore, the amygdala is specifically activated during the intensity coding of both pleasant and unpleasant odors. 36 Our findings indicate an upsurge in activity within the left OFC, right ACC, and right IFG in the MOT group. It appears that when an odor could be readily identified, its retention in working memory was manifested as sustained activity, predominantly in the IFG region. ...
Purpose
and background: Neuroimaging studies have increasingly found functional connectivity (FC) changes and structural cortical abnormalities in patients with post-traumatic anosmia (PTA). Training and repeated exposure to odorants lead to enhanced olfactory capability. This study is conducted to investigate the correlations between FC and cortical thickness on the olfaction-related regions of the brain in PTA after olfactory training (OT).
Methods
Twenty-five PTA patients were randomly divided in three groups: (1) 9 control patients who did not receive any training, (2) 9 patients underwent classical OT by 4 fixed odors, and (3) 7 patients underwent modified OT coming across 4 sets of 4 different odors sequentially. Before and after the training period, all patients performed olfactory function tests, and magnetic resonance imaging (MRI). Sniffin’ Sticks test was used to assess olfactory function. MRI data were analyzed using functional connectivity analysis and brain morphometry.
Results
Modified OT resulted in heightened activation in the medial orbitofrontal cortex and anterior cingulate cortex and increased FC between the piriform cortex (PIRC) and the caudate cortex. Conversely, classical OT induced increased activation in the insula cortex and greater FC between the PIRC and the pre-central gyrus. Furthermore, after OT, both training groups achieved significantly improved scores in the changes in brain connectivity associated with OT, which were attributable to anatomical measures.
Conclusions
This study demonstrates that intensive olfactory training can enhance functional connectivity, and this improvement correlates with structural changes in the brain’s olfactory processing areas.
... Moreover, odors, especially perfumes and cleaning products, can trigger headaches in around 45% of these patients [5,6,9], and this seems to be specific to migraine headaches [10][11][12][13]. Although the olfactory system has central role in migraine, there are to date only few imaging studies evaluating how the brain of people with migraine process olfactory [14][15][16][17] or intranasal trigeminal stimulation [15,[18][19][20]. Migraine patients are subjected to specific cerebral states, as shown by an enhanced deep cerebral activity for these patients in the amygdala, the insula, the rostral pons, the piriform cortex, the temporal pole and the antero-superior temporal gyrus in the interictal state [14], during spontaneous migraine attacks [17], in resting-state [14] or in response to odors [14,17]. ...
... Although the olfactory system has central role in migraine, there are to date only few imaging studies evaluating how the brain of people with migraine process olfactory [14][15][16][17] or intranasal trigeminal stimulation [15,[18][19][20]. Migraine patients are subjected to specific cerebral states, as shown by an enhanced deep cerebral activity for these patients in the amygdala, the insula, the rostral pons, the piriform cortex, the temporal pole and the antero-superior temporal gyrus in the interictal state [14], during spontaneous migraine attacks [17], in resting-state [14] or in response to odors [14,17]. Decreased cortical activity during odor processing [14][15][16], together with increased cortical activity during trigeminal processing was also reported [15]. ...
... Although the olfactory system has central role in migraine, there are to date only few imaging studies evaluating how the brain of people with migraine process olfactory [14][15][16][17] or intranasal trigeminal stimulation [15,[18][19][20]. Migraine patients are subjected to specific cerebral states, as shown by an enhanced deep cerebral activity for these patients in the amygdala, the insula, the rostral pons, the piriform cortex, the temporal pole and the antero-superior temporal gyrus in the interictal state [14], during spontaneous migraine attacks [17], in resting-state [14] or in response to odors [14,17]. Decreased cortical activity during odor processing [14][15][16], together with increased cortical activity during trigeminal processing was also reported [15]. ...
Background
Accumulating data emphasizes the importance of olfaction in migraine pathophysiology. However, there are only a few studies evaluating how the migraine brain processes olfactory stimulation, and virtually no studies comparing patients with and without aura in this context.
Methods
This cross-sectional study recorded event-related potentials from 64 electrodes during a pure olfactory or pure trigeminal stimulus in females with episodic migraine with aura (n = 13) and without aura (n = 15), to characterize the central nervous processing of these intranasal stimuli. Patients were tested in interictal state only. Data were analyzed in the time domain and in the time–frequency domain. Source reconstruction analysis was also performed.
Results
Patients with aura had higher event-related potentials amplitudes for left-sided trigeminal and left-sided olfactory stimulations, and higher neural activity for right-sided trigeminal stimulation in brain areas related to trigeminal and visual processing. Following olfactory stimulations patients with aura displayed decreased neural activity in secondary olfactory structures compared to patients without aura. Oscillations in the low frequency bands (< 8 Hz) differed between patient groups.
Conclusions
Altogether this may reflect hypersensitivity to nociceptive stimuli in patients with aura relative to patients without aura. Patients with aura have a bigger deficit in engaging secondary olfactory-related structures, possibly leading to distorted attention and judgements towards odors. The cerebral overlap between trigeminal nociception and olfaction might explain these deficits.
... 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). ...
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.
... 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]. ...
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.
... 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. ...
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.
... In this study, significant activation was observed in the MOB. Previous reports have indicated a relationship between odor and the trigeminal-nociceptive pathway in the pathophysiology of migraine [43]. Sleep disorders, anxiety, depression-like behaviors, and cognitive impairment are common comorbidities in patients with migraine. ...
Background
Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets.
Methods
By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST.
Results
In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05).
Conclusions
fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.
Graphical Abstract
... These results suggest that sensitivity increases with increasing migraine burden [6,7]. Although the relationship between migraine and osmophobia is not clear, connections between the olfactory system and the trigeminal nociceptive system have been emphasized [8,9]. ...
Introduction
Osmophobia is hypersensitivity to certain odors. Although osmophobia is a symptom related to migraine, it is also reported in tension-type headache (TTH). Osmophobia is recommended for inclusion in the migraine diagnostic criteria because it increases sensitivity and shows absolute specificity. However, there is no evidence of the association between TTH and osmophobia. This study aimed to evaluate the prevalence and clinical characteristics of osmophobia in a cohort of migraine and TTH patients.
Methods
For the current analysis, patients who met the inclusion criteria among patients diagnosed with migraine and TTH according to the International Classification of Headache Disorders III criteria in the neurology outpatient clinics of Ankara City Hospital and Akyazı State Hospital were selected retrospectively. A total of 214 patients (129 with migraine and 85 with TTH) were included in the study. Patients’ characteristics, visual analog scale (VAS) pain scores, and Migraine Disability Assessment Scale (MIDAS) scores were recorded. Osmophobia characteristics in migraine and TTH patients were compared along with clinical parameters between the groups and within the groups.
Results
Osmophobia was found in 68% of migraine patients. The most common type of smell that migraine patients experienced was the scent of perfume. A total of 31.3% of the patients with TTH had osmophobia. While the most irritating odorant in migraine patients was perfume (32%), in TTH patients, it was the smell of food (10.5%). There were no significant differences between osmophobia, and age, education level, disease duration, pain frequency, attack duration, or VAS score in both migraine patients and TTH patients. There was also no significant difference between migraine patients with (2.42) and without (2.33) osmophobia in terms of the MIDAS score.
Discussion
Our study indicates that osmophobia observed in migraine is valuable in differential diagnosis. However, it can be significantly identified in TTH patients. It should be used together with other supporting criteria in differential diagnosis. It would also be useful to question the characteristics of osmophobia in more detail in the anamnesis.
... These results suggest that sensitivity increases with increasing migraine burden (5,6). Although the relationship between migraine and osmophobia is not clear, connections between the olfactory system and trigeminal nociceptive system have been emphasized (7,8). ...
Introduction:
Osmophobia is an isolated phobia that is especially common in patients with primary headaches. Osmophobia is recommended for inclusion in the migraine diagnostic criteria because it increases sensitivity and shows absolute specificity. Although there are publications supporting the frequency of osmophobia in patients with tension-type headache (TTH), the association between TTH and osmophobia has not been definitively demonstrated, and various studies have been conducted on this subject. This study aimed to evaluate the prevalence and clinical characteristics of osmophobia in a cohort of migraine and TTH patients selected from two different centers.
Methods:
For the current analysis, patients who presented to the neurology outpatient clinic and were diagnosed with migraine or TTH according to the International Classification of Headache Disorders III were selected. A total of 214 patients (129 with migraine and 85 with TTH) were included in the study. Patients’ characteristics, medical visual analog scale (VAS) pain scores and migraine disability assessment (MIDAS) scores wererecorded. Osmophobia characteristics in Migraine and TTH patients were compared along with clinical parameters between the groups and within the groups.
Results:
Sixty-eight percentof the migraine patientshad osmophobia. The most common type of smell that migraine patients experienced was the scent of perfume. A total of31.3% of the patients with TTH had osmophobia. While the most irritating odorant in migraine patients was perfume, in TTH patients, it was the smell of food. There wereno significant differences between osmophobia and age, education level, disease duration, pain frequency, attack duration, or VAS score in both migraine patients and TTH patients. There was no significant difference between migraine patients with and without osmophobia in termsof the MIDAS score.
Discussion:
Our study indicates that osmophobia mostly supports migraine as a differential diagnosis in clinical practice. However, osmophobia can be described to a considerable extent in patients with TTH, and it would be useful to use supporting criteria for differential diagnosis and to question the characteristics of osmophobia more deeply.
... Specific brain regions such as the amygdala and prefrontal cortex also play major roles. The amygdala, which is involved in emotion processing, also functions in the emotionalization of pain [8]. The enhanced connectivity between the amygdala and visual processing areas in patients with CM, which has been implicated in pain and emotional response, may account for their increased pain sensitivity and emotional distress. ...
Purpose of Review
In this narrative review, we aim to summarize recent insights into the complex interplay between environmental and genetic factors affecting the etiology, development, and progression of chronic migraine (CM).
Recent Findings
Environmental factors such as stress, sleep dysfunction, fasting, hormonal changes, weather patterns, dietary compounds, and sensory stimuli are critical triggers that can contribute to the evolution of episodic migraine into CM. These triggers are particularly influential in genetically predisposed individuals. Concurrently, genome-wide association studies (GWAS) have revealed over 100 genetic loci linked to migraine, emphasizing a significant genetic basis for migraine susceptibility.
Summary
In CM, environmental and genetic factors are of equal importance and contribute to the pathophysiology of the condition. Understanding the bidirectional interactions between these elements is crucial for advancing therapeutic approaches and preventive strategies. This balanced perspective encourages continued research into the complex gene-environment nexus to improve our understanding and management of CM.
... Considering that the odor threshold may related to the peripheral portion of the olfactory and trigeminal nerves, and central olfactory structures. Although, it is known that the interaction between trigeminal and olfactory pathways in migraine patients with osmophobia, its effect on olfactory sensitivity has not been elucidated yet [26,27]. Olfactory cognition including identification and discrimination is a complex process involving many different cortical structures and pathways. ...
... Due to the difficulties in examining spontaneous attacks, some studies have used other methods to image the pre-ictal or pre-headache phase of migraine. Some of these have included the assessment of brain responses of patients with migraine compared to healthy controls to nociceptive or olfactory stimulation of the trigeminal system at intervals using fMRI [27,28]. Others have used the imaging of triggered PS [29][30][31][32][33][34][35]. ...
Background
The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that has been learned about this phase in recent times has come from the outcomes of functional imaging studies. This review will summarise these studies to date and use their results to provide some feasible insights into migraine neurobiology.
Main body
The ability to scan repeatedly a patient without radiation and with non-invasive imaging modalities, as well as the recognition that human experimental migraine provocation compounds, such as nitroglycerin (NTG) and pituitary adenylate cyclase activating polypeptide (PACAP), can trigger typical premonitory symptoms (PS) and migraine-like headache in patients with migraine, have allowed feasible and reproducible imaging of the premonitory phase using NTG. Some studies have used serial scanning of patients with migraine to image the migraine cycle, including the ‘pre-ictal’ phase, defined by timing to headache onset rather than symptom phenotype. Direct observation and functional neuroimaging of triggered PS have also revealed compatible neural substrates for PS in the absence of headache. Various imaging methods including resting state functional MRI (rsfMRI), arterial spin labelling (ASL), positron emission tomography (PET) and diffusion tensor imaging (DTI) have been used. The results of imaging the spontaneous and triggered premonitory phase have been largely consistent and support a theory of central migraine attack initiation involving brain areas such as the hypothalamus, midbrain and limbic system. Early dysfunctional pain, sensory, limbic and homeostatic processing via monoaminergic and peptidergic neurotransmission likely manifests in the heterogeneous PS phenotype.
Conclusion
Advances in human migraine research, including the use of functional imaging techniques lacking radiation or radio-isotope exposure, have led to an exciting opportunity to study the premonitory phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry and therapeutic targets. Emerging migraine-specific therapies, such as those targeting calcitonin gene-related peptide (CGRP), are showing promise acutely when taken during premonitory phase to reduce symptoms and prevent subsequent headache. Therapeutic research in this area using PS for headache onset prediction and early treatment is likely to grow in the future.
... 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. ...
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.
... 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. ...
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.
... 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]. ...
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]. ...
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.
... 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. ...
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]. ...
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 ...
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.
... 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]. ...
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.
... 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]. ...
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.
... 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) . ...
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.
... 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. ...
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.
... We know that there is a functional connection between smelling and trigeminal nociceptive system. The central sensitization induced by recurrent stimulation of pain may cause disruption in the sense of smell (osmophobia) or alternatively, recurrent stimulation of olfactory may induce the central sensitization process and cause recurrent pain stimulation in the patients with hypersensitivity against olfactory stimulation [13,17]. Sense of smell is closely associated with many areas such as eating, drinking, personal care, social life, and sexual life. ...
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.
... 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. ...
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]. ...
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.
... 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]. ...
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]. ...
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. ...
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.
Objective
To investigate the location of white matter lesions (WMLs) in migraineurs with right-to-left shunt (RLS); the relationships among the severity of WMLs, changes in brain structural volume and RLS shunts; and the relationships among the severity of WMLs, changes in brain structural volume and degree of headache in RLS migraine patients.
Methods
A total of 102 migraineurs with RLS admitted to the affiliated Central Hospital of Dalian University of Technology from December 2018 to December 2022 were enrolled in this study. RLS flow and the 6-item Headache Impact Test (HIT-6) scores were recorded to reflect the degree of headache. The brain structural volumes of 102 migraineurs with RLS were calculated from T1-weighted images using artificial intelligence, and the brain structural volumes of healthy controls matched according to age and sex were also calculated. The correlations among WML location, RLS, headache degree, WML severity and brain structural volume changes in migraineurs were analysed.
Results
1. The WMLs of migraineurs with RLS were concentrated mainly in the white matter of the lateral ventricular margin and deep white matter. Subcortical WMLs were concentrated mainly in the parietal lobe, occipital lobe and frontal lobe. 2. There were no significant differences in the WML variables of cerebral white matter high signal volume, ratio of high-signal white matter volume to whole-brain white matter volume (%) or Fazekas score among migraineurs with different RLS flows, but there were significant differences in WML variables among migraineurs with RLS with different HIT-6 grades and MIDAS grades. RLS flow, HIT-6 score and MIDAS grade were not correlated with the WML variables measured in this study. 3. There was a significant difference in the volume of the precentral gyrus between migraineurs with RLS and normal controls (P < 0.001), and there was a significant difference between migraineurs with different RLS flows and different HIT-6 scores and peripheral cerebrospinal fluid volumes. There was also a positive correlation between frontal pole structural volume and RLS flow. The volume of the precentral gyrus was negatively correlated with RLS flow, whereas the volume of the pons gyrus was positively correlated with the HIT-6 score. The volume of the temporal pole was negatively correlated with the HIT-6 score.
Conclusion
1. The WMLs of migraineurs with RLS were concentrated mainly in the white matter of the lateral ventricular margin and deep white matter. Subcortical WMLs were concentrated mainly in the parietal lobe, occipital lobe and frontal lobe. 2. There was no correlation between WML severity and RLS flow in migraineurs with RLS. 3. There was no correlation between WML severity and migraine severity in migraineurs with RLS. 4. Volume changes occur in some brain structures of migraineurs with RLS. 5. Shunt flow and the degree of headache in migraineurs with RLS were correlated with structural volume changes in specific brain regions.
IntroductionOsmophobia is associated with a greater intensity of the headache, a more significant presence of affective symptoms, and the appearance of cutaneous allodynia.Objectives
To determine the sociodemographic and clinical characteristics of patients with episodic and chronic migraine associated with osmophobia.MethodsA cross-sectional analytical observational study, 100 patients were included.Results65% of the patients presented osmophobia, 64.6% of patients with osmophobia had chronic migraine, and 35.4% had episodic migraine without statistically significant differences p=0.120. Regarding the clinical characteristics, pulsatile pain was the most frequent in 49%, and severe intensity was present in 81%. Statistically significantrelationships were found between osmophobia and photophobia [(95.4 vs 77.1]; p=0.005), phonophobia ([96.9 vs 74.3); p=0.001) and allodynia ([75.4 vs 45.7); p=0.002). The that become chronic factors were more frequent in the group with osmophobia, in which an association with the excessive use of analgesics ([43.8%vs. 22.9%]; p=0.029) and a history of anxiety and depression ([32.8% vs. 14.3%]; p=0.045). In the multivariate model, the variables associated with osmophobia with statistically significant differences were photophobia, allodynia, and botulinum toxin application.Conclusions
In this first study of osmophobia in migraine in Colombia, osmophobia is a frequent symptom in patients with chronic migraine; it has related to markers of central sensitization; it is also related to that become chronic factors and the use of botulinum toxin. Therefore, it is likely that osmophobia can predict the risk of that factor, causing the disease to become chronic.
Migraine can be considered through the lens of a computational model of interoception and body regulation. Interoception is the physiologic system providing an internal state that enables individuals to survive in the environment using homeostasis and allostasis. From this point, internal and external sensory channels connected with relevant information are essential for internal state and subject survival. The central part of the interoceptive system is represented by a model of the internal state, which is supposed to be located in the central nervous system and operating under the influence of our past experiences and knowledge. This enables us to infer incoming sensory information and to create appropriate responses, including our behavior. An essential feature of the internal state model is neuroplasticity’s acceptability of changes. Migraine is supposed to result from an inappropriate internal interoceptive model, which forms precise interoceptive predictions leading to interoceptive error. The result is sensitization of the nervous system, which could be considered an allostatic load. Calcitonin gene-related peptide (CGRP) is an important molecule in nervous system sensitization. Therefore, effective clinical measures are directed toward CGRP using CGRP-monoclonal antibodies and gepants. Long-term management should be focused on improving the model of the internal state to be more stable, which enables migraineurs to respond effectively and adapt to complex environmental changes.KeywordsInteroceptionMigraineHomeostasisAllostasisPredictive codingInteroceptive errorSensitizationCGRPMetacognitionMindfulness
Migraine is one of the most common neurological diseases and it has a huge social and personal impact. Although head pain is the core symptom, individuals with migraine can have a plethora of non-headache symptoms that precede, accompany, or follow the pain. Neuroimaging studies have shown that the involvement of specific brain areas can explain many of the symptoms reported during the different phases of migraine. Recruitment of the hypothalamus, pons, spinal trigeminal nucleus, thalamus, and visual and pain-processing cortical areas starts during the premonitory phase and persists through the headache phase, contributing to the onset of pain and associated symptoms. Once the pain stops, the involvement of most brain areas ends, although the pons, hypothalamus, and visual cortex remain active after acute treatment intake and resolution of migraine symptoms. A better understanding of the correlations between imaging findings and migraine symptomatology can provide new insight into migraine pathophysiology and the mechanisms of novel migraine-specific treatments.
MS is the most common inflammatory demyelinating disease of the central nervous system (CNS) and primarily involves the brain, optic nerves, and spinal cord. This disease frequently occurs in young and middle-aged adults, affecting more than 2.5 million patients worldwide, and is one of the major causes of disability among younger patients. The incidence of MS varies by population, as evidenced by a meta-analysis that included 59 countries which revealed that the incidence of MS increased significantly with increasing geographic latitude. The exact etiology and pathological mechanisms of MS are not fully understood. It is currently believed that the onset of this disease is jointly determined by genetic and environmental factors, with autoimmunity and neurodegeneration playing a dominant role in its pathological processes. The pathological features of MS are primarily characterized by inflammation, demyelination, axonal injury, and gliosis, and when axonal injury exceeds a specific threshold, MS clinically manifests as a progressive phase. MS can be classified based on its disease course into relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (PMS), while the latter can be further subdivided into primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS).
Background:
Real-world data on the effectiveness of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) in migraine patients are needed.
Methods:
We performed a single-center, real-world study with an observation period of up to 12 months (mean 7.5 ± 3.4 months) after CGRP mAb administration. A total of 228 Japanese patients with episodic or chronic migraine (age, 45.9 ± 13.2 years; 184F; 45 erenumab; 60 galcanezumab; 123 fremanezumab) who were treated with CGRP mAbs for at least three months were ultimately included in this study.
Results:
In the total cohort, after CGRP mAb treatment, mean monthly migraine days decreased by 7.2 ± 4.8, 8.3 ± 4.7, and 9.5 ± 5.0 at three, six and 12 months, respectively. The ≥50% monthly migraine day reduction rates at three, six and 12 months were 48.2%, 61.0% and 73.7%, respectively. In the logistic regression analysis, the presence of osmophobia and fewer baseline monthly migraine days contributed to ≥50% responders at three, six and 12 months. The ≥50% responders at three or six months were useful in predicting ≥50% responders at 12 months. In subgroups of patients with difficult-to-treat migraine (those with medication overuse headache or psychiatric comorbidities) and previous CGRP mAb users, monthly migraine days were substantially reduced over 12 months. There was no difference in monthly migraine day reduction over 12 months among three different CGRP mAbs. Adverse reactions were observed in 28 (12.3%) patients, with injection site reactions being the most common (n = 22) though generally mild in severity.
Conclusion:
This real-world study confirmed the efficacy and safety of three different CGRP mAbs for prophylactic treatment of patients with migraine.
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.
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.
In migraine, the trigeminal nerve is intimately involved in the pathophysiology of the disease. We hypothesized that alterations in the sensory trigeminal activation in migraine would be reflected by EEG-derived event-related potentials (ERP). We aimed to investigate differences in the temporal and spatial processing of trigeminal stimuli between interictal migraine patients and healthy subjects.
ERP to trigeminal stimuli were recorded at 128-channels to allow localization of their cortical sources with high temporal resolution. Seventeen patients with episodic migraine without aura, with episodic migraine with aura, and 17 healthy subjects participated in the study. The first branch of the trigeminal nerve was stimulated using intranasal chemical (CO2), cutaneous electrical, and cutaneous mechanical (air puff) stimuli. Analyses were performed with regard to micro-state segmentation, ERP source localization, and correlation with the patients’ clinical characteristics.
Topographical assessments of EEG configurations were associated with the pathological condition. The source analysis revealed altered trigeminal-sensory response patterns in the precuneus, temporal pole, and cerebellum for both migraine groups during the interictal phase. The estimated current source density was positively correlated with migraine disease duration, indicating brain functional and structural changes as a consequence of the disease. Hyperactivity of the cerebellar posterior lobe was observed as a specific trigeminal response of migraine patients with aura.
In conclusion, our results suggest the presence of brain changes accompanying the advancement of migraine as an expression of dysfunctional central pain processing. Hence, we identified EEG patterns in response to mechano-/chemosensory stimuli that can serve as biomarkers of migraine.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Received November 6, 2000. Revised June 8, 2001. Second revision August 10, 2001. Accepted August 29, 2001.
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
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.
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.
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.
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.
One of the most exciting developments in modern neuroscience has been the application of imaging techniques to provide new insights into the organization of the human brain in vivo. Functional imaging methods, such as PET and functional MRI, have become the preferred techniques for detection of the structure-function relationships within the brain that are characteristic of headache. This Review focuses on neuroimaging as a diagnostic tool for headache and highlights the advances made with functional and structural neuroimaging techniques in the study of primary headache syndromes such as migraine and trigeminal autonomic headaches. Several independent functional studies have reinforced the crucial role of the brainstem in acute and chronic migraine and of the hypothalamic area in trigeminal autonomic headaches. Structural abnormalities that have been identified in the visual network of motion-processing areas could account for, or result from, the cortical hyperexcitability observed in patients with migraine. Several morphometric studies suggest that gray matter volume and/or concentration is decreased in pain-transmitting areas in patients with migraine or tension-type headache. Given the rapid advances in functional neuroimaging, this technique will continue to be of paramount importance in patients with headache and might ultimately serve as the bridge between molecular and clinical domains in headache research.
Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.
Electrophysiologic and lesion studies of animals increasingly implicate the amygdala in aspects of emotional processing. Yet, the functions of the human amygdala remain poorly understood. To examine the contributions of the amygdala and other limbic and paralimbic regions to emotional processing, we exposed healthy subjects to aversive olfactory stimuli while measuring regional cerebral blood flow (rCBF) with positron emission tomography. Exposure to a highly aversive odorant produced strong rCBF increases in both amygdalae and in the left orbitofrontal cortex. Exposure to less aversive odorants produced rCBF increases in the orbitofrontal cortex but not in the amygdala. Change of rCBF within the left amygdala and the left OFC was highly intercorrelated, indicating a strong functional interaction between these brain regions. Furthermore, the activity within the left amygdala was associated significantly with subjective ratings of perceived aversiveness. These findings provide evidence that the human amygdala participates in the hedonic or emotional processing of olfactory stimuli.
Affective experience has been described in terms of two primary dimensions: intensity and valence. In the human brain, it is intrinsically difficult to dissociate the neural coding of these affective dimensions for visual and auditory stimuli, but such dissociation is more readily achieved in olfaction, where intensity and valence can be manipulated independently. Using event-related functional magnetic resonance imaging (fMRI), we found amygdala activation to be associated with intensity, and not valence, of odors. Activity in regions of orbitofrontal cortex, in contrast, were associated with valence independent of intensity. These findings show that distinct olfactory regions subserve the analysis of the degree and quality of olfactory stimulation, suggesting that the affective representations of intensity and valence draw upon dissociable neural substrates.
Neuroimaging studies with positron emission tomography and functional magnetic resonance imaging have begun to describe the functional neuroanatomy of human emotion. Taken separately, specific studies vary in task dimensions and in type(s) of emotion studied, and are limited by statistical power and sensitivity. By examining findings across studies in a meta-analysis, we sought to determine if common or segregated patterns of activations exist in different emotions and across various emotional tasks. We surveyed over 55 positron emission tomography and functional magnetic resonance imaging activation studies, which investigated emotion in healthy subjects. This paper will review observations in several regions of interest in limbic (eg, amygdala, anterior cingulate cortex) and paralimbic (eg, medial prefrontal cortex, insula) brain regions in emotional responding.
Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.
In logic a conjunction is defined as an AND between truth statements. In neuroimaging, investigators may look for brain areas activated by task A AND by task B, or a conjunction of tasks (Price, C.J., Friston, K.J., 1997. Cognitive conjunction: a new approach to brain activation experiments. NeuroImage 5, 261-270). Friston et al. (Friston, K., Holmes, A., Price, C., Buchel, C., Worsley, K., 1999. Multisubject fMRI studies and conjunction analyses. NeuroImage 10, 85-396) introduced a minimum statistic test for conjunction. We refer to this method as the minimum statistic compared to the global null (MS/GN). The MS/GN is implemented in SPM2 and SPM99 software, and has been widely used as a test of conjunction. However, we assert that it does not have the correct null hypothesis for a test of logical AND, and further, this has led to confusion in the neuroimaging community. In this paper, we define a conjunction and explain the problem with the MS/GN test as a conjunction method. We present a survey of recent practice in neuroimaging which reveals that the MS/GN test is very often misinterpreted as evidence of a logical AND. We show that a correct test for a logical AND requires that all the comparisons in the conjunction are individually significant. This result holds even if the comparisons are not independent. We suggest that the revised test proposed here is the appropriate means for conjunction inference in neuroimaging.
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 in obligatory thalamic relay. While such findings are almost exclusively derived from animal data, recent cytoarchitectonic studies indicate a close anatomical correspondence between non-huan 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. (c) 2005 Elsevier B.V. All rights reserved.
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.
Previous positron emission tomography studies of right-handed individuals show that the left orbitofrontal cortex is dominant during emotional processing of odors. We collected functional magnetic resonance imaging data from 28 subjects to study this network as a function of odor hedonic valence (pleasant vs. unpleasant), active hedonic judgments versus passive sensation of hedonically charged odors, handedness, and gender. Two functional runs were performed, with pleasant and unpleasant odors presented in different epochs. In the first run, subjects passively smelled odorants, whereas in the second run they rated degree of odor pleasantness or unpleasantness by using a "finger-span" technique that simulated a visual rating scale. Electrodermal and plethysmography responses were simultaneously recorded to control for covert, physiological manifestations of the emotional response. The piriform-amygdala area and ventral insula were activated more for unpleasant than pleasant odors. More extreme ratings were also associated with higher electrodermal amplitude, suggesting that activation stemmed more from emotional or hedonic intensity than valence, and that unpleasant odors induced more arousal than pleasant odors. Unpleasant odors activated the left ventral insula in right-handers and the right ventral insula in left-handers, suggesting lateralized processing of emotional odors as a function of handedness. Active decisions about odor pleasantness induced specific left orbitofrontal cortex activation, implicating the role of this area in the conscious assessment of the emotional quality of odors. Finally, left orbitofrontal cortex was more active in women than men, potentially in relation to women's well-documented advantage in odor identification.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Migraine is related to numerous factors such as hormones, stress or nutrition, but information about their actual importance is limited. Therefore, we analysed prospectively a wide spectrum of factors related to headache in migraineurs. We examined 327 migraineurs recruited via newspapers who kept a comprehensive diary for 3 months. Statistical analysis comprising 28 325 patient days and 116 dichotomous variables was based on the interval between two successive headache attacks. We calculated univariate Cox regression analyses and included covariables with a P-value of <0.05 in two stepwise multivariate Cox regression analyses, the first accounting for a correlation of the event times within a subject, the second stratified by the number of headache-free intervals. We performed similar analyses for the occurrence of migraine attacks and for the persistence of headache and migraine. Menstruation had the most prominent effect, increasing the hazard of occurrence or persistence of headache and migraine by up to 96%. All other factors changed the hazard by <35%. The two days before menstruation and muscle tension in the neck, psychic tension, tiredness, noise and odours on days before headache onset increased the hazard of headache or migraine, whereas days off, a divorced marriage, relaxation after stress, and consumption of beer decreased the hazard. In addition, three meteorological factors increased and two others decreased the hazard. In conclusion, menstruation is most important in increasing the risk of occurrence and persistence of headache and migraine. Other factors increase the risk less markedly or decrease the risk.
Intolerance to smell is often reported by migraine patients. This study evaluates osmophobia in connection with the diagnosis of migraine and episodic tension-type headache (ETTH). The characteristics of this symptom are also investigated. We recruited from our Headache Centre 1005 patients (772 female, 233 male; age 37 +/- 11 years), of whom 677 were migraine without aura (MoA), 130 migraine with aura (MA) and 198 TTH. Patients with two or more forms of primary headache were excluded. Among migraine patients, 43.9% with MoA and 38.5% with MA reported osmophobia during the attacks; none of the 198 TTH patients suffered this symptom. Most frequently offending odours were scents (63.9%), food (55.2%) and cigarette smoke (54.8%). Osmophobia appears structurally integrated into the migraine history of the patient. It seems to be a peculiar symptom favouring the diagnosis of migraine (MoA and MA) in the differential diagnosis with ETTH.
Migraine is a very common disorder occurring in 20% of women and 6% of men. Central neuronal hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Since there are no consistent structural disturbances in migraine, physiological and psychophysical studies have provided insight into the underlying mechanisms. This is a review of the neurophysiological studies which have provided an insight to migraine pathogenesis supporting the theory of hyperexcitability.
Although migraineurs appear in general to be hypersensitive to external stimuli, they maybe also have increased daytime sleepiness and complain of fatigue. Neurophysiological studies between attacks have shown that for a number of different sensory modalities the migrainous brain is characterised by a lack of habituation of evoked responses. Whether this is due to increased cortical hyperexcitability, possibly due to decreased inhibition, or to an abnormal responsivity of the cortex due a decreased preactivation level remains disputed. Studies using transcranial magnetic stimulation in particular have yielded contradictory results. We will review here the available data on cortical excitability obtained with different methodological approaches in patients over the migraine cycle. We will show that these data congruently indicate that the sensory cortices of migraineurs react excessively to repetitive, but not to single, stimuli and that the controversy above hyper- versus hypo-excitability is merely a semantic misunderstanding. Describing the migrainous brain as 'hyperresponsive' would fit most of the available data. Deciphering the precise cellular and molecular underpinnings of this hyperresponsivity remains a challenge for future research. We propose, as a working hypothesis, that a thalamo-cortical dysrhythmia might be the culprit.