Brainstem changes in 5-HT1A receptor availability during migraine attack.

BACKGROUND: Among serotonin receptors, 5-HT(1A) receptors are implicated in the regulation of central serotoninergic tone and could be involved in the abnormal brain 5-HT turnover suspected in migraineurs. The aim of this study was to investigate 5-HT(1A) receptors' availability during migraine attacks. METHODS: Ten patients suffering from odor-triggered migraine attacks and 10 control subjects were investigated using positron emission tomography (PET) and [(18)F]MPPF PET tracer, a selective 5-HT(1A) antagonist. All subjects underwent calibrated olfactory stimulations prior to the PET study. RESULTS: Four patients developed a migraine attack during the PET study. In these patients, statistical parametrical mapping and region of interest analyses showed an increased [(18)F]MPPF binding potential (BP(ND)) in the pontine raphe when compared to headache-free migraineurs and control subjects. This ictal change was confirmed at the individual level in each of the four affected patients. In comparison with the headache-free migraineurs, patients with a migraine attack also showed significantly increased [(18)F]MPPF BP(ND) in the left orbitofrontal cortex, precentral gyrus and temporal pole. No significant change in [(18)F]MPPF BP(ND) was observed between headache-free migraineurs and controls. CONCLUSIONS: Our results emphasize the role of 5HT(1A) receptors in the pontine raphe nuclei during the early stage of migraine attacks.

Subliminal fear priming potentiates negative facial reactions to food pictures in women with anorexia nervosa.

BACKGROUND: To investigate hedonic reactivity and the influence of unconscious emotional processes on the low sensitivity to positive reinforcement of food in anorexia nervosa (AN). METHOD: AN and healthy women were exposed to palatable food pictures just after a subliminal exposure to facial expressions (happy, disgust, fear and neutral faces), either while fasting or after a standardized meal (hunger versus satiety). Both implicit [facial electromyographic (EMG) activity from zygomatic and corrugator muscles, skin conductance, heart rate, and videotaped facial behavior] and explicit (self-reported pleasure and desire) measures of affective processes were recorded. RESULTS: In contrast to healthy women, the AN patients did not display objective and subjective indices of pleasure to food pictures when they were in the hunger states. Pleasure to food cues (liking) was more affected than the desire to eat (wanting) in AN patients. Subliminal 'fear faces' increased corrugator muscle reactivity to food stimuli in fasting AN patients, as compared to controls. CONCLUSIONS: The results suggest that unconscious fear cues increase the negative appraisal of alimentary stimuli in AN patients and thus contribute to decreased energy intake.

Cerebral imaging and olfactory disorders: a review.

Cerebral imaging and olfactory disorders: a review. Olfactory disorders are often misjudged and rarely given due clinical consideration. Nevertheless, they occur in a wide range of neurological disorders, and their evaluation can help in diagnosis. Whereas psychophysical tests have been used to evaluate olfactory dysfunction in numerous diseases, functional brain imaging using olfactory stimuli is an emergent technique and few studies have been published to date. After a reminder of cerebral imaging and analysis techniques and a rapid description of our actual knowledge of olfactory processes in healthy subjects, the current review focuses on cerebral imaging studies performed on patients with neurological disorders and presenting olfactory dysfunction. Neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, migraine, multiple chemical sensitivity and schizophrenia are examined.

Olfactory hypersensitivity in migraineurs: a H(2)(15)O-PET study.

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.

[Olfaction and neurological diseases: a review of the literature]. / Olfaction et pathologies neurologiques: revue de la littérature.

Olfactory disorders are often misjudged and rarely rated in the clinical setting. They are nevertheless described in a wide range of neurological disorders, and their evaluation can be useful for diagnosis. Usually irreversible olfactory dysfunction is a well-known complication after head trauma. Severe changes in olfactory tests are observed in Parkinson's disease. Dysfunction is present at disease onset and evidenced with all behavioral tests. Regarding other parkinsonian syndromes, olfactory performances are severely impaired in Lewy body disease, less pronounced in multiple system atrophy and usually preserved in corticobasal degeneration. Olfactory deficits are an early feature in Alzheimer's disease and worsen with disease progression. Rarely reported by patients, they must be searched for with olfactory tests. Though epilepsy is mainly known for its olfactory hallucinatory disorders, alterations of olfactory abilities are also described, especially in mesial temporal epilepsy. Disorders of olfactory perception are finally reported in patients with multiple sclerosis and migraine. After a reminder of anatomical data on the olfactory system, and the different methods of testing used to rate olfactory performances, the current review focuses on the type of olfactory dysfunction and damaged brain areas of the olfactory system encountered in the main neurological diseases.

Rating of olfactory judgements in migraine patients.

The aim of this study was to evaluate olfactory hypersensitivity (OHS) between attacks in migraine patients. Seventy-four migraine patients and 30 controls were enrolled. The presence of OHS was evaluated using an oral questionnaire and a chemical odour intolerance index. Subjects had to rate the intensity and hedonicity of 12 odourants using a linear rating scale. Twenty-six patients (35.2%) but no control subjects reported an interictal OHS (P<0.001). Logistic regression analysis showed that patients with OHS presented a greater attack frequency, a higher number of odour-induced migraines and visual hypersensitivity when compared with other patients. Disease duration, age, gender and auditory hypersensitivity were not associated with OHS. OHS patients judged odours less pleasant than did other patients and controls, whereas the intensity scores were identical in both groups. OHS between attacks was significantly associated with odour-triggered migraine and an alteration of hedonic judgement.

5-Hydroxytryptamine action in the rat olfactory bulb: in vitro electrophysiological patch-clamp recordings of juxtaglomerular and mitral cells.

The olfactory bulb, first relay of olfactory pathways, is densely innervated by serotoninergic centrifugal fibers originating from the raphe nuclei. Although serotonin innervation was reported to be involved in olfactory learning in mammals, the action of this neurotransmitter on its putative cellular targets has been never described through unitary recordings. This lack of data initiated the present study where the effects of 5HT on juxtaglomerular and mitral cells are analyzed using whole-cell recordings on olfactory bulb slices. Serotonin depolarizes 34% of 525 JG cells. A multivariate statistical analysis of juxtaglomerular cells characteristics shows that the serotonin responsive cell group can be individualized regarding their tonic discharge-mode in response to a direct current injection, their lower expression of hyperpolarization-activated cation current and their low membrane capacities. The use of ion channel blockers and ramp voltage protocol indicate that serotoninergic depolarization of juxtaglomerular cells may be due to a nonselective cation current with a reversal potential of -44 mV. Pharmacological tests with serotonin receptor antagonists and agonists reveal that 5HT action on juxtaglomerular cells would be mainly mediated by 5HT2C receptors. In mitral cells, serotonin acts on 49.1% of the 242 tested cells, inducing two types of responses. A first subset of mitral cells (26.8%, n=65) were hyperpolarized by serotonin. This response would be indirect and mediated by action of GABA on GABAA receptors since it was antagonized by bicuculline. The involved GABAergic neurons are hypothesized to be juxtaglomerular and granular cells, on which serotonin would act mainly via 5HT2C and via 5HT2A receptors respectively. The second subset of mitral cells (22.3%, n=54) were directly depolarized by serotonin acting through 5HT2A receptors. Our data on serotonin action on juxtaglomerular cells and mitral cells reveal a part of functional mechanisms whereby serotonin can act on olfactory bulb network. This is expected to enrich the understanding of its determining role in olfactory learning.

A stimulation method using odors suitable for PET and fMRI studies with recording of physiological and behavioral signals.

A design for a semi-automatic olfactometric system is described for PET and fMRI experiments. The olfactometer presents several advantages because it enables the use of an 'infinite' number of odorants and the synchronization of stimuli with breathing. These advantages mean that the subject is recorded while breathing normally during olfactory judgment tasks. In addition, the design includes a system for recording the behavioral (rating scale) and physiological (breathing, electrodermal reaction (ED), plethysmography (PL)) signals given by the subject. Both systems present the advantage of being compatible with fMRI magnetic fields since no ferrous material is used in the Faraday cage and signals are transmitted via an optical transmission interface to an acquisition system.

Drosophila melanogaster innate immunity: an emerging role for peptidoglycan recognition proteins in bacteria detection.

Over the past years, parallel studies conducted in mammals and flies have emphasized the existence of common mechanisms regulating the vertebrate and invertebrate innate immune systems. This culminated in the discovery of the central role of the Toll pathway in Drosophila immunity and in the implication of Toll-like receptors (TLRs)/interleukin-1(IL-1) in the mammalian innate immune response. In spite of clear similarities, such as shared intracellular pathway components, important divergences are expected between the two groups, whose last common ancestor lived more than half a billion years ago. The most obvious discrepancies lie in the mode of activation of the signalling receptors by microorganisms. In mammals, TLRs are part of protein complexes which directly recognize microbe-associated patterns, whereas Drosophila Toll functions like a classical cytokine receptor rather than a pattern recognition receptor. Recent studies demonstrate that members of the evolutionarily conserved peptidoglycan recognition protein family play an essential role in microbial sensing during immune response of Drosophila.

Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein.

Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections. Genetic screens have identified a range of genes involved in these intracellular signalling cascades, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent contrast with the mammalian Toll-like receptors and raises the question of which host molecules actually recognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.

Odorants elicit evoked potentials in the human amygdala.

Electroencephalographical (EEG) recording studies have shown that odorants produce olfactory evoked potentials (OEPs) on the scalp surface. However, EEGs can only provide limited information about the intracerebral sources from where the OEPs are generated. By contrast, intracerebral EEG recordings enable direct examination of the electrophysiological activity from a given cerebral area. In the present study, neural activity was recorded from the amygdala of seven epileptic patients undergoing intracerebral EEG recordings prior to surgical treatment for relief of intractable seizures. Two olfactory tests were used: a passive-stimulation test consisting of the successive presentation of 12 common odorants and a suprathreshold detection test including both odorant and non-odorant stimulations. Recordings from the amygdala revealed that all odorant stimulations induced large and reproducible OEPs, whereas the non-odorant stimulations did not. It was also found that repetition of the same odorant stimulation led to a decrease in the latency of the first OEP component. This modulation, which corresponds to a faster olfactory processing, strongly suggests that the amygdala is involved in early olfactory attentional processes. In conclusion, it appears that the human amygdala discriminates the incoming information from the nasal airflow as being odorant or not and, additionally, that its speed of processing is sensitive to recent experience with an odor.

Rating of different olfactory judgements in Alzheimer's disease.

Using simple successive tasks we assessed the influence of Alzheimer's disease on the processing of different odours. Fifteen patients with Alzheimer's disease, 15 old control subjects and 15 young control subjects were tested. The experiment included two sessions. Initially 12 odorants were presented, one odorant every minute. For each odour the subjects were asked to rate intensity, pleasantness, familiarity and edibility using linear rating scales. The odorants were then presented a second time and the subjects were asked to identify them. The results show that the intensity scores were lower in old control subjects and Alzheimer patients than in the young control subjects and that familiarity and identification scores were lower in Alzheimer patients than in old control and young control subjects. When we compared the five olfactory tasks the impairment of performance in Alzheimer patients was relatively higher for identification than familiarity, itself higher than the intensity judgement. No difference was observed between the three groups of subjects for pleasantness and edibility judgements.

Functional neuroanatomy of different olfactory judgments.

Humans routinely make judgments about olfactory stimuli. However, few studies have examined the functional neuroanatomy underlying the cognitive operations involved in such judgments. In order to delineate this functional anatomy, we asked 12 normal subjects to perform different judgments about olfactory stimuli while regional cerebral blood flow (rCBF) was measured with PET. In separate conditions, subjects made judgments about the presence (odor detection), intensity, hedonicity, familiarity, or edibility of different odorants. An auditory task served as a control condition. All five olfactory tasks induced rCBF increases in the right orbitofrontal cortex (OFC), but right OFC activity was highest during familiarity judgments and lowest during the detection task. Left OFC activity increased significantly during hedonic and familiarity judgments, but not during other odor judgments. Left OFC activity was significantly higher during hedonicity judgments than during familiarity or other olfactory judgments. These data demonstrate that aspects of odor processing in the OFC are lateralized depending on the type of olfactory task. They support a model of parallel processing in the left and right OFC in which the relative level of activation depends on whether the judgment involves odor recognition or emotion. Primary visual areas also demonstrated a differential involvement in olfactory processing depending on the type of olfactory task: significant rCBF increases were observed in hedonic and edibility judgments, whereas no significant rCBF increases were found in the other three judgments. These data indicate that judgments of hedonicity and edibility engage circuits involved in visual processing, but detection, intensity, and familiarity judgments do not.

Evidence for separate perceptive and semantic memories for odours: a priming experiment.

Sixty-four subjects participated in an olfactory priming experiment comprising separate study and test phases. Priming was measured within the olfactory modality (intramodal condition) and from the visual modality to the olfactory modality (intermodal condition). In the study phase of the intramodal condition, subjects were exposed twice to a series of odours: once performing a semantic orientation task (deciding which of seven categories odour stimuli belonged to) and once performing a perceptual orientation task (judging the intensity, the hedonicity and the familiarity of odour stimuli). Half of the odour stimuli corresponded to edible products, the other half did not. The study phase of the intermodal condition was similar, with the exception that the names of the odours (instead of the odours themselves) were presented. In the test phase, subjects were presented with primed and non-primed odour targets and had to decide as fast as possible whether the target corresponded to an edible product or not. Response times and types were recorded by a computer. The analysis of response times revealed a priming effect in the intramodal condition only. Results are discussed in terms of separate perceptual and semantic subsystems that store odour representations.

Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study.

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 gyrus, in the left hemisphere. Emotionally valenced olfactory and visual but not auditory stimuli produced additional rCBF increases in the hypothalamus and the subcallosal gyrus. Only emotionally valenced olfactory stimuli induced bilateral rCBF increases in the amygdala. These findings suggest that pleasant and unpleasant emotional judgments recruit the same core network in the left hemisphere, regardless of the sensory modality. This core network is activated in addition to a number of circuits that are specific to individual sensory modalities. Finally, the data suggest a superior potency of emotionally valenced olfactory over visual and auditory stimuli in activating the amygdala.

Functional anatomy of perceptual and semantic processing for odors.

The functional anatomy of perceptual and semantic processings for odors was studied using positron emission tomography (PET). The first experiment was a pretest in which 71 normal subjects were asked to rate 185 odorants in terms of intensity, familiarity, hedonicity, and comestibility and to name the odorants. This pretest was necessary to select the most appropriate stimuli for the different cognitive tasks of the second experiment. The second one was a PET experiment in which 15 normal subjects were scanned using the water bolus method to measure regional cerebral blood flow (rCBF) during the performance in three conditions. In the first (perceptual) condition, subjects were asked to judge whether an odor was familiar or not. In the second (semantic) condition, subjects had to decide whether an odor corresponded to a comestible item or not. In the third (detection) condition, subjects had to judge whether the perceived stimulus was made of an odor or was just air. It was hypothetized that the three tasks were hierarchically organized from a superficial detection level to a deep semantic level. Odorants were presented with an air-flow olfactometer, which allowed the stimulations to be synchronized with breathing. Subtraction of activation images obtained between familiarity and control judgments revealed that familiarity judgments were mainly associated with the activity of the right orbito-frontal area, the subcallosal gyrus, the left inferior frontal gyrus, the left superior frontal gyrus, and the anterior cingulate (Brodmann's areas 11, 25, 47, 9, and 32, respectively). The comestibility minus familiarity comparison showed that comestibility judgments selectively activated the primary visual areas. In contrast, a decrease in rCBF was observed in these same visual areas for familiarity judgments and in the orbito-frontal area for comestibility judgments. These results suggest that orbito-frontal and visual regions interact in odor processing in a complementary way, depending on the task requirements.

Notchless encodes a novel WD40-repeat-containing protein that modulates Notch signaling activity.

Signaling by Notch family receptors is involved in many cell-fate decisions during development. Several modifiers of Notch activity have been identified, suggesting that regulation of Notch signaling is complex. In a genetic screen for modifiers of Notch activity, we identified a gene encoding a novel WD40-repeat protein. The gene is called Notchless, because loss-of-function mutant alleles dominantly suppress the wing notching caused by certain Notch alleles. Reducing Notchless activity increases Notch activity. Overexpression of Notchless in Xenopus or Drosophila appears to have a dominant-negative effect in that it also increases Notch activity. Biochemical studies show that Notchless binds to the cytoplasmic domain of Notch, suggesting that it serves as a direct regulator of Notch signaling activity.

A re-estimation of the number of glomeruli and mitral cells in the olfactory bulb of rabbit.

Although morphological characteristics of mammalian olfactory bulb (OB) are well documented in rodents (rat, mice), only one study has been performed in rabbit, which is also commonly used in olfactory research. The study carried out by Allison and Warwick in 1949 led to surprising results still quoted in recent literature. The present study re-examined this question in young rabbit OB, while it was also conducted with rat as control. In five animals of each species, areas and coordinates of glomeruli and mitral profiles were measured in 10 coronal sections uniformly distributed along the rostrocaudal axis of the OB, and a distribution-free stereological method was used to compute values along this axis. For glomeruli, the estimated number was 4200 in rat and 6300 in rabbit. While this estimation matched with those found in literature in rat, it strikingly differed from the Allison and Warwick's value of 1900 only. For mitral cell number, we found 59,600 while the preceding study found 45,000 only. In contrast to the number of glomeruli, the mitral cell number in rat and rabbit were very close. Indeed, results showed 56, 200 in rat. The results suggest that the numbers of olfactory glomeruli and mitral cells has been previously underestimated in rabbit, and that the number of glomeruli changes as a function of species. In addition, both the results of the present study and reports in the literature suggest the number of mitral cells to be rather similar in mouse, rat and rabbit. As a consequence, the glomerular/mitral cell ratio is likely to varied in a wide range across species.

Role of verbal encoding in short- and long-term odor recognition.

The role of verbal encoding in odor recognition memory was investigated using odors of low familiarity to subjects before the experiment began. The experimental procedure included two phases--odor learning (first phase) and odor memory testing (second phase)--separated by a delay of 7 days. Five experimental conditions were established: three conditions of odor learning with names (labeling conditions), one condition of odor learning without names (sensory familiarization), and one condition of no learning prior to testing (control conditions). The labeling conditions differed from each other regarding label characteristics. The names were those of odor sources (veridical names), those personally generated by subjects (generated names), or those derived from the chemical names of the odorants (chemical names). Subjects were required to learn 20 fixed associations between odors (targets or distractors) and 20 names during two daily sessions. The learning sessions included two identification tests and ended by a verbal memory test in which subjects recalled odor names. The odor memory test was split into two parts separated by a retention interval of either 20 min (short-term memory) or 24 h (long-term memory). Data showed that olfactory recognition memory was enhanced in subjects who associated veridical or generated names to odors during the learning session. Chemical names were not appropriate to facilitate odor recognition. Similarly, the level of odor identification was higher for veridical and generated names than for chemical names, though the level of verbal memory for chemical names was substantial. Recognition response latencies were systematically longer for a target odor implying a positive response than for a distractor odor implying a negative response. Together, these data suggest that odor recognition and identification are sensitive to the semantic content of labels associated with odors. Odor memory was adversively influenced by time, but this influence was less pronounced when the names were endowed with a rich semantic content.

Establishing primordia in the Drosophila eye-antennal imaginal disc: the roles of decapentaplegic, wingless and hedgehog.

The eye-antennal imaginal discs of Drosophila melanogaster form the head capsule of the adult fly. Unlike the limb primordia, each eye-antennal disc gives rise to morphologically and functionally distinct structures. As a result, these discs provide an excellent model system for determining how the fates of primordia are specified during development. In this study, we investigated how the adjacent primordia of the compound eye and dorsal head vertex are specified. We show that the genes wingless (wg) and orthodenticle (otd) are expressed throughout the entire second instar eye-antennal disc, conferring a default fate of dorsal vertex cuticle. Activation of decapentaplegic (dpp) expression in the posterior eye disc eliminates wg and otd expression, thereby permitting eye differentiation. We also demonstrate that otd is activated by wg in the vertex primordium. Finally, we show that early activation of dpp depends on hedgehog (hh) expression in the eye anlage prior to morphogenetic furrow formation.